Next Article in Journal
Protein Disulfide Isomerase A3 Regulates Influenza Neuraminidase Activity and Influenza Burden in the Lung
Next Article in Special Issue
The Optimized Delivery of Triterpenes by Liposomal Nanoformulations: Overcoming the Challenges
Previous Article in Journal
The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain
Previous Article in Special Issue
The Role of Cyclodextrins in the Design and Development of Triterpene-Based Therapeutic Agents
Review

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues †

1
Ufa Institute of Chemistry, UFA Federal Research Centre of the Russian Academy of Sciences, Pr. Oktyabrya, 450054 Ufa, Russia
2
Laboratory of Metabotropic Drugs, Scientific Center for Innovative Drugs, Volgograd State Medical University, Novorossiyskaya St. 39, 400087 Volgograd, Russia
3
Department of Chemistry of Natural Compounds, University of Chemistry and Technology in Prague, Technicka’ 5, Prague 6, 16628 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Dedicated to the memory of Professor Genrikh Tolstikov, the worldwide known organic and natural product scientist.
Academic Editor: Se-Kwon Kim
Int. J. Mol. Sci. 2022, 23(3), 1075; https://doi.org/10.3390/ijms23031075
Received: 10 December 2021 / Revised: 12 January 2022 / Accepted: 14 January 2022 / Published: 19 January 2022

Abstract

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.
Keywords: squalamine; trodusquemine; ceragenine; claramine; triterpenoids; antibiotic; angiogenesis; obesity; diabetes squalamine; trodusquemine; ceragenine; claramine; triterpenoids; antibiotic; angiogenesis; obesity; diabetes

1. Introduction

Biogenic polymethylene polyamines are found in all living cells in significant quantities and are involved in many important biological processes [1,2]. The biosynthetic pathways to these polyamines in animals, plants, and microorganisms are well known and originate from amino acids. In addition to the simplest form as free aliphatic bases, they are often found as structural units of numerous alkaloids of plant and animal origin, which are usually referred to as secondary metabolites [3,4].
The study of metabolites of marine organisms in the second half of the last century became a separate major area of bioorganic and medicinal chemistry, influencing the development of synthetic organic chemistry. In a long line of marine metabolites, striking in the diversity and complexity of their structures, polyamine compounds occupy the main place. In contrast to the plant metabolites, which are mainly derived from putrescine, spermidine, and spermine, the metabolites of marine organisms are much more diverse structurally [5].
The history of steroid polyamines began in the early 1990s with the isolation by Moore et al. of the first representative compound squalamine 1 from the stomach of the shark S. acanthias (Figure 1) [6]. The name “squalamine” originated from the Latin “Squalus”, the genus name for the shark. The team leader, Prof. Zasloff, has long been intrigued in shark endurance and immunity to infections: when a shark is operated on, you do not have to worry about aseptic conditions, despite the fact that the immune system of sharks, especially a sea dog, is poorly developed. Squalamine was also isolated from other organs of the shark (spleen, intestines, ovaries) [7,8,9], its maximum content was noted in the liver and gallbladder. In addition, it was identified in the blood cells of the sea lamprey P. marinus [10]. Squalamine was later found to directly protect sharks from infections via broad-spectrum antibiotic activity [4,5,6,7,11,12,13]. In 1998, Sills et al. showed that squalamine effectively inhibits angiogenesis and tumor growth in several animal models [14]. Recently, squalamine proved effective as neuroprotective agent in animal model of Parkinson’s disease [15].
The chemical structure of squalamine 1 as 3β-N-1-(N-[3-(4-aminobutyl)]- 1,3-diaminopropane)-7α,24ζ-dihydroxy-5α-cholestan-24-sulfate was determined by methods of mass and NMR spectroscopy [6].
Later, seven other amino sterols 2–8 (Figure 1) with antibacterial activity, structurally similar to squalamine, were isolated from the liver of the shark S. acanthias [3]. They contain a cholestan skeleton conjugated to spermidine or spermine at the C3 position, while the side chain can be sulfated. One of them, trodusquemine (MSI-1436) 2, also has a broad spectrum of antimicrobial activity, even slightly surpassing squalamine [6,7]. Petromysonamine disulfate 9 was isolated from sea lamprey pheromone P. marines [16,17]. The authors of [16] suggest that squalamine 1 can be a biosynthetic precursor of PADS [18]. Subsequently, the 24S-epimer was synthesized from aldehyde-derived 24-methanal-7α-(methoxymethyl)cholestan-3-one [16].
As a result of these studies, squalamine became the first representative of a previously unknown class of natural antibiotics of animal origin, and its discovery stimulated extensive research on the complete synthesis, creation of various libraries of steroid polyamines, and the study of their properties. The interest shown in the chemistry and pharmacology of squalamine, trodusquemine, and their analogs is supported by thousands of patent applications that have been filed to date. Aminosterols have proven to be promising chemotherapeutic agents for the treatment of infectious and neoplastic diseases. Subsequently, the known biological activity of this class of compounds was significantly expanded and continues to be supplemented annually. Besides a promising antimicrobial activity [4] squalamine 1, trodusquemine 2, and their analogues 3–9 have been proposed for ameliorating blood pressure [19], treatment of Alzheimer’s disease [20], Parkinson’s disease [21], constipation [22], erectile dysfunction [23], cardiac conduction defects [24], cognitive impairment [25], autism spectrum disorder [26], multiple system atrophy [27], depression [28], schizophrenia [29] and viral infections [30].
Despite the fact that many works have been devoted to the chemistry and pharmacology of steroid polyamines, including reviews [11,12,31,32,33,34,35,36,37,38,39,40,41,42], until now the scientific literature has not summarized information on complete syntheses, various modifications and biological activity of steroid polyamines. The goal of this review is to systematize the information available in the literature (up to 2021 with impact up to the most recent years) on the chemistry and biological activity of steroid polyamines, including their influence on the synthesis, properties, and perspectives of terpenoids with polyamine fragments.

2. Syntheses of Squalamine from Cholic Acids

Due to the need for significant amounts of squalamine for biological tests, schemes for its synthesis from available steroids (3β-acetoxy-5-cholic acid, 3-keto-23,24-bisnorchol-4-en-22-ol, methyl-3-keto-5α-chenodeoxycholonate) were implemented [8,9,43]. The maximum overall yield (69%) was achieved in a 7-step synthesis by the reaction of reductive amination of 24R-sulfate of 3-ketocholesterol with azide and further catalytic hydrogenolysis [44]. The syntheses of squalamine are discussed below.

2.1. Synthesis Based on 3β-Acetoxy-5-Cholic Acid

The first synthesis of squalamine 1 was carried out by Moriarty et al. in 1994 based on 3β-acetoxy-5-cholic acid 10 (Scheme 1) [8,45]. Starting with the protection of the carboxyl group (compound 11), and then as a result of successive reactions (reduction, deprotection, and oxidation), the keto derivative 12 was obtained, which was converted to 3β-amino-7α-hydroxy-cholestan 13 [46,47,48]. The reaction of compound 13 with tosyl-N-(3-cyanopropyl)-N-propyl iodide 14 led to 3β-N-diaminopropyl-butyronitrile-7α-hydroxy-cholestan 15. After reduction of the cyano group, deprotection, and sulfation of the 24β-hydroxyl group, squalamine 1 was obtained [49,50]. The synthesis included 17 steps with a total yield of 0.3%.

2.2. Synthesis of 24R- and 24S-Squalamine’s from Stigmasterol

A year later, the same group presented a 19-step synthesis of 24R- and 24S-squalamine’s from stigmasterol 16 with a total yield of 19% (Scheme 2) [37]. Stigmasterol 16 in several stages (selective Boc-protection, ozonolysis) was converted into aldehyde 17, while its reduction, chlorination of the hydroxy derivative, treatment with sodium phenylsulfone led to phenylsulfone 18. Its interactions with enantiomeric epoxides 19a and 19b afforded 24R- and 24S-hydroxycholesterols 20a and 20b in quantitative yields. Further acetylation, oxidation of the corresponding diacetates, reduction of the obtained enones with Li/NH3, potassium tri-tert-butylborohydride and repeated acylation produced tris-acetates 21a and 21b, while their selective deacylation at position C3 and oxidation with Jones’s reagent led to 3-ketocholonates. At the last step, reductive amination with Boc-spermidine/NaBH3CN and sulfation resulted in 24R-1 and 24S-22 squalamines.

2.3. Synthesis from 7α-(Benzyloxy)-3-Dioxolan-Cholestan-24R-Ol

Zhang et al. in 1998 has carried out a five-step synthesis of squalamine 1 with a total yield of 60% from the readily obtained 7α-(benzyloxy)-3-dioxolan-cholestan-24R-ol 23. 24R-Sulfate 24 was synthesized, then the protective groups were removed, as a result of reductive amination of ketone 25 with diaminopropylbutyronitrile 26 in the presence of NaBH4/CH(OCH3)3, followed by catalytic hydrogenolysis, squalamine 1 was synthesized (Scheme 3) [51].

2.4. Synthesis from Cholic Acid Sulfate

A year later, Weis et al. put attention to the preparation of the spermidine fragment. The product of the alkylation of 1,3-diaminopropane 27 with chlorobutanol through the protection of amino- to 28 and alcohol groups to 29 was converted into azide 30, which, as a result of the reductive amination of 24R-sulfate of 3-ketocholesterol 31 and catalytic hydrogenolysis, was converted into squalamine 1 with a yield of 69% (Scheme 4) [44].

2.5. Synthesis from 3-Keto-23,24-Bisnorchol-4-En-22-Ol

In 2000, the same group published a 10-step synthesis of squalamine from 3-keto-23,24-bisnorchol-4-en-22-ol 32 with a total yield of 9% and a purity of 91% (Scheme 5) [9]. Biotransformation of compound 32 in the presence of bacteria D. gossipina formed 7α-hydroxy derivative 33. The following steps of preparation of the steroid skeleton included the reduction of the C5(C6) double bond (compound 34), protection of the C3 ketone (compound 35), oxidation to aldehyde 36, alkylation of C22 aldehyde with the Wadsworth–Emmons reagent to derivative 37, followed by oxidation with a mixture (R)-methyl ester of oxoazaborolidene (MeCBS) with a borane-tetrahydrofuran complex and reduction of 24-ketone to the hydroxy derivative 38. The ethylene ketal protection was removed by the action of p-toluenesulfonic acid, and the intermediate 39 was obtained by sulfation of the 24β-hydroxyl group with complex SO3-Py in dry pyridine. Reductive amination of 24R-sulfate 39 with spermidine and reduction of the resulting Schiff base with sodium cyanoborohydride led to the target squalamine 1 [52].

2.6. Synthesis from Methyl 3-Keto-5α-Chenodeoxycholonate

In 2001 Zhou et al. described the selective synthesis of squalamine 1 from methyl 3-keto-7α-chenodeoxycholonate 40 in 11 steps (Scheme 6) [53,54,55]. As in the cases described above, the key steps were aimed at preparing the steroid backbone. The stepwise protection of the 3-keto and 7α-hydroxy groups, chain lengthening of the aldehyde at position C23 by the Wittig reaction led to the desmosterol derivative 41. Its hydroxylation to compound 42, then dehydration of 24β-acetate 43 and catalytic hydrogenolysis of the isopropenyl group to form compound 44 with following removal of protective groups made 3-keto-24R-hydroxy derivative 45, which was introduced into a reductive amination reaction with protected spermidine in the presence of sodium borohydride to give mixtures of 3α- (10%) and 3β-anomers (66%) of squalamine, separated by flash chromatography [50,54,56,57,58,59,60]. The squalamine yield was 19% after removal of the di-tert-butyl protecting group in the compound 46 [61].

2.7. Synthesis from Desmosterol

In 2003, Okumura et al. synthesized squalamine 1 from desmosterol (Scheme 7) [62]. Pure desmosterol 47 is not a sufficiently available starting compound due to its high cost and low synthesis yields [59]. However, it was found that about 10–25% of desmosterol is contained in the cholesterol precipitate, which is isolated from lanolin alcohol obtained by saponification of animal fat. As in the case of compound 42 (Scheme 6), regioselective protection of diol 48 was carried out in the side chain, its dehydration to compound 49, and catalytic hydrogenolysis to 24R-benzoate 50. Ketone 51 obtained by allyl oxidation was hydrogenated over Adams’ catalyst to give a mixture of 7β-hydroxy and 7-oxo derivatives 52 and 53 [51,63,64]. Stereoselective reduction of ketone 54 with potassium tri-tert-butylborohydride led to the dihydroxy derivative 55, its regioselective oxidation with Ag2CO3 on zeolite was converted into the 3-keto derivative 56 with subsequent replacement of the 24R-benzoyl group by the sulfate group through the formation of 24-hydroxy derivative 57. The potassium salt of 3-oxo-7α-hydroxy-24R-sulfate-cholanic acid 58 was subjected to reductive amination with spermidine in the presence of NaBH3CN to form squalamine 1 in a total yield of 7.4% [62].

2.8. Synthesis from Methylhyodeoxycholonate

In 2006, Shen et al. proposed a selective 15-step synthesis of squalamine 1 based on methylhyodeoxycholonate 59 with a total yield of 5.6% (Scheme 8) [65]. The main stages in the preparation of the steroid skeleton included protection of the hydroxy group in the C6 position with tosyl chloride to compound 60, selective hydrolysis, acylation to acetate 61, and oxidation to ketone 62. Subsequent hydrogenation and reduction led to methyl 3β-acetoxy-5αH-7α-chenodeoxycholonate 63, which was converted to 24-aldehyde 66 through the steps of protecting compound 64 and extending the C24 side chain to form dihydroxy derivative 66. Further reductive amination with spermidine in the presence of sodium cyanoborohydride, sulfation, and deprotection led to squalamine 1.
Thus, the presented syntheses of squalamine included mainly the preparation the steroid backbone by the modifying of cholic acid scaffolds, obtaining a spermidine fragment, unblocking various protective groups, and sulfating the C24 position. In the following sections, we will consider the syntheses of squalamine analogs.

3. Syntheses of Squalamine Analogs

3.1. Synthesis of 3α-Episqualamine

The 3-episqualamine 74, being an 3α-analog of squalamine, was not found in nature, but was synthesized by the reductive amination reaction of Boc-protected spermidine 68, which was obtained from nitrile 67 and 7α-benzyloxy-24ζ-t-butyldimethylsilyloxycholestan-3-one 69 (Scheme 9) [66]. As a result of the reaction, a mixture of isomers 70 was obtained; after removal of the protective group a mixture of 3α- 71 and 3β- 72 isomers in equal proportions was formed and separated chromatographically. Sulfation to compound 73, and subsequent deprotection resulted in 3α-episqualamine 74 in 67% overall yield.

3.2. Synthesis of Squalamine Analogs from Cholic Acids

Methyl 3α,6α-dihydroxycholate 75 was prepared in several steps (oxidation to 3,6-diketone 76, selective dioxolane protection of the C3 position of compound 77, reduction of the C6 ketone, and deprotection to methyl 3-oxo-6β-hydroxy-5α-cholan-24-oat 78) [67]. Reductive amination of ketone 78 with ethylenediamine or spermidine made it possible to obtain conjugates 79a, 80a and 79b, 80b in 78–82% yields (Scheme 10). In the case of reductive amination with N,N′-dipropylaminopiperazine, a single 3β-isomer 81 was formed [66].
The reaction of methyl 3-oxo-cholate 82 with sulfur ylide (trimethylsulfoxonium iodide/NaH) led to 3β-oxirane 83, the nucleophilic opening of which with N-(Boc)-1,2-diaminoethane followed by a deprotection led to the compound 84 (Scheme 11) [68].

3.3. Synthesis of Steroid Methylenepolyamines from Cholic, Deoxycholic, Chenodeoxycholic, Ursodeoxycholic and Lithocholic Acids

On the basis of cholic, deoxycholic, lithocholic, chenodeoxycholic, and ursodeoxycholic acids by the reaction with methylamine, isopropylamine, diethylamine, diisopropylamine or cyclohexylamine in the presence of HOBT or DCC or BOP or methylchloroformate and subsequent oxidation with aluminum tri-tert-butoxide or aluminum triisopropoxide or Ag2CO3 in benzene or toluene or cyclohexane or trifluorotoluene, compounds of type 85 were received, then their reductive amination with amines in the presence of titanium isopropylate produced a series of steroids 86 (Scheme 12) [69]. The biological activity data are presented in Section 6.

3.4. Synthesis from 22-Hydroxy-23,24-Dinorchol-4-En-3-One and Its Analogs

The synthesis of a squalamine analog with a shorter side chain was described in [70]. Starting from 22-hydroxy-23,24-dinorchol-4-en-22-ol 32 by successive transformations, including isomerization of the double bond at position C5 (compound 87), allylic oxidation to C7 ketone 88, and its stereoselective reduction to 7α-hydroxy-derivative 89, removal of the protective group to form ketone 90, the action of lithium aluminum hydride on 3-benzyloxime 91 3β-amine 92 was obtained (Scheme 13). The reductive amination of 3β-aminosterol 92 with tert-butyl N-(4-aminobutyl)-N-3-(oxopropyl) dicarbonate 93 followed by deprotection and regioselective sulfation formed a conjugate with spermidine in the form of trichlorohydrate 94 [71].
Steroid ketones 95 and 96 reacted with Boc-substituted spermidine and spermine to form 3α- and 3β-aminobisnorsteroids 97–100 and 101–104, respectively. When they were treated with thionyl chloride, the protecting groups were removed and the hydrochlorides of steroid conjugates 105–112 were synthesized (Scheme 14) [72]. The data concerning their biological activity are presented in Section 6.

3.5. Synthesis of Steroid Methylenepolyamines from Cholestan, 4-Cholestene, 5-Cholesten-3-One, 6-Ketocholestanol and 3,7-Diketocholestene

The synthesis of more than 30 steroid polyamines with antibacterial activity was described in [73,74,75,76]. Reductive amination of 3-ketones of cholestane 113, 5-cholestene 114, 4-cholestene 115, 6-ketocholestanol 116 and 3,7-diketocholestene 117 with various amines (aliphatic, cyclic, and piperazines) in the presence of Ti(OiPr)4 and NaBH4 in 41–98% yield led to derivatives of type 118–120 and 121 (Scheme 15). The data concerning their biological activity are presented in Section 6 [73,76].

3.6. Synthesis from 3-Keto-7-Hydroxycholestane

The reaction of reductive amination of 3-keto-7-hydroxycholestane 123 with amines in the presence of titanium isopropylate produced compounds of type 124 (Scheme 16) [69]. The data concerning their biological activity are presented in Section 6 [69].

3.7. Synthesis of Squalamine Analogs from Cholesterol and Progesterone

The following approaches were used to obtain squalamine analogs containing a polyamine chain at the C7 position. By means of known methods, 3β-hydroxy-7-ketone 126 was obtained from cholesterol 125, the reductive amination of which with diaminopropane, due to steric factors, led to a single 7α-epimer 127 (Scheme 17). Its alkylation with 4-bromobutyronitrile and reduction produced 7α-spermidine-cholesterol 128 [37]. 7α-(1,4-Diaminobutane)-cholest-5-en-3β-ol 130 and 7β-derivatives 131 were synthesized by the reductive amination of ketones 129 or 126 with various amines [73,77]. The data concerning their biological activity are presented in Section 6 [78,79,80].
Extension of the polyamine chain at the 7-amino group of compound 133 obtained from 3-acetylcholesterol using cyanoethylation and alkylation with bromobutyronitrile followed by reduction afforded 7α- and 7β-spermidine conjugates 134a and 134b (Scheme 18). The gradual chain extension was performed from 6α-amino derivative of cholesterol 135, obtained in several stages from 3-acetyl-cholesterol 132 (Scheme 18) [37]. As a result of the reactions of its cyanoethylation, a reduction of LiAlH4, 6α-spermidinecholesterol 136, was obtained.
3,20-Diamino- and polyaminosteroid analogs of squalamine type 138 were synthesized by the reaction of reductive amination of progesterone 137 with various amines in 18–82% yields (Scheme 19). The data concerning their biological activity are presented in Section 6 [77,81,82].

3.8. Synthesis of Spermidino-7-Fluoro-3-Aminosteroids

Starting from commercially available 23,24-bisnorchol-4-ene 139, the synthesis of 7β-OH 140b (95%) and 7α-OH 140a (5%) derivatives was carried out in several stages, which included allylic oxidation to ketone, adding dioxolan and tert-butylsilyl protection and the action of lithium in liquid ammonia (Scheme 20). Fluorination and subsequent removal of the protective groups led to 7α-141a and 7β-fluoro-23,24-bisnorcholanates 141b in ratio 4:3 with 83% yield [83]. Subsequent reductive amination with Boc-spermidine, sulfation, and removal of Boc-protection led to the target 7-fluoro derivatives 142a, b.

3.9. Synthesis of Cholanic Acid Carboxamides with Alkane Polyamines

The interaction of 3β-acetoxy-23,24-dinor-5-cholenic acid 143 with Boc-spermidine or spermine by the DCC method led to amides, characterized as 3β-sulfates 144 (Scheme 21) [84].
Interaction of 3α,12α-dihydroxycholanic 145, 3α,7α,12α-trihydroxycholanic 146, 3α-hydroxycholanic 147, ursocholanic 148, 3α,6α-dihydroxycholanic 149, 3α,7α-dihydroxycholanic 150, and 23,24-bisnor-5-cholenic 151 acids with spermidine, triethylenetetramine or putrescine in the presence of DCC, followed by a deprotection afforded amides 151–167 (Scheme 22) [9,85,86]. The data concerning their biological activity are presented in Section 6 [50,56].
Stigmasterol succinate 168 was activated by the formation of pentafluorophenyl succinate 169, after removal of the protective group and interaction with Boc-polyamines, followed by removal of the Boc-protection, carbamates of type 170 have been synthesized (Scheme 23). The data concerning their biological activity are presented in Section 6 [87].
Compounds 156, 171–177 were synthesized by conjugation of spermine with cholic acids 146, 171–173 (Scheme 24). The data concerning their biological activity are presented in Section 6 [88].

3.10. Synthesis of Steroid Carbamates

A representative example of natural polyamine steroidal carbamates is bufotoxin 178, isolated from the venom of the toad Bufo Vulgaris, which disrupts the work of the heart muscle (Figure 2) [86]. Synthetic steroidal lipopolyamines 179–181 are more efficient than natural polyamines spermine and spermidine. Similar compounds can be used in fluorescence correlation spectroscopy as a means of studying supramolecular formations in gene delivery systems, and in non-viral gene therapy [89].
Synthetic approaches to the preparation of steroidal polyamine carbamates included the introduction of polyamine moieties at the C3 position or to the side chain. For example, the interaction of 3-cholesteryl chloroformate 182 with polyamines (spermine, 1,11-diamino-4,8-diazaundecane, 1,10-diamino-4,7-diazadecane, 1,9-diamino-3,7-diazanonane, tetraethylenepentamine, pentaethylenehexamine) led to 3-cholesterylpolyamine carbamates of type 183, which can be considered as a model for the formation of lipoplex (complexes of cationic, neutral lipids and DNA molecules, used as a system for cell transfection), which are key steps in gene therapy (Scheme 25) [90].
Carbamates 184 were useful in inhibiting the growth of bacteria in food due to the manifestation of weak basic properties in the gastrointestinal tract [35]. Carbamates 185, derivatives of cholic acid with Boc-spermidine or Boc-spermine (Figure 3) were tested against Gram-positive and Gram-negative bacteria [35,91,92].

3.11. Synthesis of Aminopropoxysteroids

3,7,12-tris-Aminopropoxysteroids with various side-chain substituents, named as ceragenins, were synthesized to mimic cationic peptide antibiotics such as polymyxin B [33,93]. Ceragenins have a broad spectrum of antibacterial activity. Ceragenin 186a (Figure 4) is active against H. pylori and against cariogenic and periodontopathic bacteria with MICs 0.275–8.9 and 1–16 μg/mL, respectively [93,94,95], was recommended for the treatment of chronic infections and inflammation in patients with cystic fibrosis [95,96,97], including for local application [98]. A technology was proposed that combines the antibacterial effect and medical imaging of ceragenin 186a with magnetic nanoparticles [41,99,100]. More details on its activity are presented in Section 6 [38,101,102,103]. The introduction of an aminopropoxy group into the cholic acid scaffold included alkylation with allylbromide followed by a reduction of the azido group [50]. Ceragenins 186b with various substituents in the side chain possessing antibacterial activity have been also synthesized [50,104].

3.12. Synthesis of Squalamine Phosphate

Zasloff et al. has synthesized aminosterol phosphate compositions and discovered their biological activity as anti-inflammatory, anti-viral, antimicrobial, and antifungal agents. The aminosterol phosphate compositions permit administration without associated tissue damage and achieve a sustained-release effect. Squalamine phosphate 187 (Figure 5) can be prepared simply by adding a soluble phosphate salt (i.e., sodium, potassium, ammonium) to a solution of squalamine [105].

3.13. Synthesis of Squalamine Analogues with Multiple Steroid Backbones

Derivatives 189–191 were synthesized on the basis of cholylglycine, containing one, two, or three steroid scaffolds linked through N-(3-aminopropyl)-1,3-propanediamine as a spacer in 8.5%, 6%, and 2% yields, respectively (Scheme 26) [106]. The data concerning their biological activity are presented in Section 6 [106].
The synthesis of dimeric conjugates 192–195 of cholic and deoxycholic acids (Scheme 27), which consist of two amphiphilic sterol-spermine units linked to each other by a carbamate moiety in the form of a head-tail, using DSC has been reported [107]. The data of biological activity are presented in Section 6 [108]. Conjugate 195 exhibited the same activity as squalamine, suggesting its use as a potential antibacterial agent [109].
The synthesis of phosphoramide conjugates of bile acids with 3′-azido-3′-deoxythymidine was described in [110,111,112]. The reaction of the polyamine derivative of phosphoroamide 196 with the acylchlorides of deoxycholic, cholic, and dihydrocholic acids led to polyaminoazidothymidine conjugates 197 (Scheme 28) [113]. The data of biological activity are presented in Section 6 [113].
Shawakfeh et al. has synthesized dimeric derivatives based on diosgenin 198. The dimers were formed through the amination reaction with 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, and spermidine and the aldehyde group of steroid 199 obtained as a result of the F-ring opening of diosgenin acetate in high yields (Scheme 29) [114].
Compounds with two steroid scaffolds 202 and 203 (Figure 6) possess antifungal activity against five types of fungi and against cancer cells HEp-2 and MCF-7 [36].
Umbrella dimers 204a,b, 205a–c, and tetramers 206a–c (Figure 7) are more active than monomeric analogs of squalamine, the presence of hydroxyl groups at C7 and C12 leads to high activity compared to analogs with a hydroxyl group only at C12. The results indicate that such conjugates act as antibiotics at the membrane level through the pore and channel formation. Compound 204a is responsible for the activation of pH bischarging across liposomal membranes at the level of antibiotic activity, which is comparable to the monomeric analogs of squalamine. Monomeric and dimeric analogs of squalamine are present in the bacterial membrane in an inactive form, and only small fractions are in the form of clusters that activate ion transport. Head-to-tail dimers are more active than head-to-head dimers [108].
Dimeric and tetrameric analogs in which two or four subunits were linked by a side chain to putrescine or spermine “head-to-head” or “tail-to-tail” demonstrated high antibacterial activity [108], Chen et al. became interested in conducting a detailed study structures-activity using linked sterol-polyamine conjugates, i.e., covalently linked dimers and tetramers. They synthesized a number of dimeric and tetrameric analogs, in which two or four subunits were linked a head-to-head or tail-to-tail to putrescine or spermine backbone [108].
Studies of antibacterial activity have shown that dimeric conjugates exhibit strong antibacterial activity against a wide range of gram-positive bacteria, while tetrameric conjugates exhibit very weak properties. The latter is believed to be a likely consequence of either an unfavorable steric interaction with peripheral proteins, or the result of a relatively high water solubility, which may prevent their efficient separation in the plasma membrane, or both of these factors. Dimeric and tetrameric conjugates of lithocholic acid did not show antibacterial activity. The lack of activity may be due to the lack of amphiphilicity.
Cholest-5-en-3β-oxyethane-tosylate 207 was synthesized using known approaches such as tosylation, saponification with ethylene glycol, and repeated tosylation. Further to a solution of cholest-5-en-3β-oxyethane-tosylate 207 in dry toluene desired amounts of PEI in dry MeOH was added, the reaction mixture was refluxed to produce lipopolymers type 208 (Scheme 30) [115]. These compounds have high transfection properties, low cytotoxicity, and high serum compatibilities. The transfection efficacies and cytotoxicity of the lipopolymers were found to be dependent on the percentage of cholesterol grafting and the molecular weight of PEI used for the synthesis of lipopolymers [116].

4. Synthesis of Trodusquemine and Its Analogs

The synthesis of trodusquemine 2, which is a spermine analog of squalamine 1, is also based on a reductive amination reaction [34]. Conjugates of 24-amino- and 24-hydroxy 3α- and 3β-cholestane derivatives with spermine 210a–b, 211a–b were obtained by reductive amination from 3,3-(ethylenedioxy)-cholestan-24-one 209 (Scheme 31) [34].
According to a similar approach, conjugates of 24-amino-, 24-hydroxy- and 24-sulfate-3α- and 3β,7β-hydroxy-5α-cholestane derivatives 2, 213–216 with spermine were synthesized from 3,3-(ethylenedioxy)-7β-hydroxy-5α-cholest-22-ene 212 (Scheme 32) [34]. The data of the biological activity of this series of compounds is presented in Section 6 [117].

5. Synthesis of Claramine and Its Analogues

Chen et al. and Govers et al. obtained an analog of trodusquemine-claramine 218, which is a conjugate of 3β-hydroxy-6β-cholestan with spermine. Claramines 219 and 220 were also synthesized by reductive amination reaction (Scheme 33) [118]. The data of biological testing is presented in Section 6 [119].
Starting from deoxycholic acid derivative 221 Blanchet et al. has obtained claramine A1 222 in three stages by reductive amination with spermine with a total yield of 33% (Scheme 34). The data of activity could be seen in Section 6 [120].
Summarizing the above results, we can conclude that the approach to the synthesis of analogs of squalamine, trodusquemine, and claramine was based on the introduction of a polyamine fragment at positions C3, C6, C7, C12, and C24 of the steroid scaffold by the reactions of reductive amination, cyanoethylation of amines, and acylation (synthesis of derivatives with two and three steroid fragments, steroid analogs of polymyxin B).

6. Biological Properties of Squalamine, Trodusquemine and Their Analogues

The diverse biological activity of aminosterols has been subjected to numerous reviews. Previous works covered the activity, mechanism of action, and prospects of squalamine and similar aminosterols as a new class of antibiotics capable of overcoming the problem of resistance [11,33,38,42,80,121], as well as their antifungal and antiviral properties [47,48]. Special attention was paid to their anti-angiogenic activity for the treatment of tumor diseases [122]. Antibacterial, fungicidal, and immunomodulatory properties of ceragenins and ceragenin-derived nanoparticles were recently reviewed in [123,124].

6.1. Biological Activity of Squalamine and Trodusquemine

6.1.1. Antibacterial and Antiviral Activity

Squalamine initially became known as a broad-spectrum bactericidal antibiotic effective against both Gram-positive and Gram-negative bacteria, including E. coli, P. aeruginosa, S. aureus, S. faecalis, P. vulgaris [38]. Later, squalamine was found in the membrane of sea lamprey (P. marinus) leukocytes [10], which confirmed its role as an important factor of humoral immunity [125]. The different electric charge of prokaryotic and eukaryotic cells allows squalamine to selectively bind to bacterial membranes [126], exhibiting low minimum inhibitory concentrations (MIC 1–8 μg/mL). At the same time, the minimum concentration causing hemolysis of erythrocytes exceeds 200 μg/mL, and it is not genotoxic [127]. Furthermore, unlike beta-lactam antibiotics, which have a similar spectrum of antibacterial activity, squalamine is a fungicide (C. albicans, A. fumigatus, A. niger, Fusarium spp.) and causes osmotic lysis of protozoa (P. caudatum).
It is especially important that squalamine retains activity even against clinically important multi-resistant strains of E. coli and P. aeruginosa, overexpressing various factors of resistance, including active excretion of drugs, changes in membrane permeability caused by the absence of porins, an enzymatic barrier that induces resistance to quinolones, β-lactam, phenicols, etc. [128]. In particular, it effectively eradicates fungi and multi-resistant Gram-negative and Gram-positive bacteria isolated from patients with cystic fibrosis [78,79] and fungemia [129]. Squalamine and its analog 138 are active against mupirocin-susceptible and resistant clinical isolates of S. aureus with MIC values of 3.125 µg/mL. Additionally, repeated exposure of a S. aureus strain to squalamine and 138 did not lead to the emergence of resistant bacteria, contrarily to mupirocin [82]. Trodusquemine 2 has a broad spectrum of antimicrobial activity (MIC 1–4 μg/mL for S. aureus, P. aeruginosa, and C. albicans), slightly outperforming squalamine [7].
In addition, squalamine at a concentration of 0.5–1 μg/mL causes the death of archaea species, e.g., M. smithii, M. oralis, M. arboriphilicus, M. concilii, and M. beijingense [130,131], and can be used to disinfect medical instruments instead of aggressive peracetic acid. At a concentration of 100 µg/mL, squalamine effectively destroys dormant cells of the causative agent of nosocomial infections A. baumannii, which are resistant to ciprofloxacin therapy [132]. Squalamine showed significant in vitro activity against Trichophyton and Microsporum dermatophytes with MICs ranging from 4–16 μg/mL (1–4 μg/mL for griseofulvin) [133].
Squalamine is a membrane-active compound. The bactericidal activity of squalamine is attributed to the combination of anionic bile acid with cationic spermidine, which individually exhibits significantly lower antibiotic activity [134,135]. The mechanism of action of squalamine is similar to cationic peptide antibiotics and consists of a selective violation of the integrity of the bacterial membrane or the formation of semi-stable pores in it due to electrostatic binding with phospholipids, followed by depolarization [126,136]. The selectivity of squalamine is explained by its affinity for bacterial lipopolysaccharides and the ability to penetrate into the lipid bilayer [137]. Disruption of the barrier function of the bacterial membrane leads to depletion of the intracellular ATP pool (loss of 80% ATP at a concentration of 20 μg/mL) and cell death [128]. Squalamine has the highest affinity for phosphatidylglycerol (the main component of bacterial membranes), and somewhat less for phosphatidylserine and cardiolipin [31]. Using fluorescently labeled dextrans, it was found that squalamine increases membrane permeability for substances with molecular weights up to 4 kDa, but less than 10 kDa. Moreover, its activity is completely suppressed by the presence of 5 mM Ca2+ or Mg2+ ions [128], which indicates a direct interaction of squalamine with membrane phospholipids. It is not a protonophore [138]. The surface antigen of E. coli O4 reduces the effectiveness of squalamine, while K54 has a sensitizing effect. The mechanism remains unclear [139]. Additionally, a recent study demonstrated that squalamine competitively inhibits the glycosyltransferase activity of penicillin-binding proteins of E. coli, which mediates the cell wall synthesis, although only in high concentrations (IC50 291 µM) [76].
The specificity of the interaction of squalamine with negatively charged phospholipids is confirmed by its inability to induce the death of mycobacteria, whose cell wall consists of arabinogalactan esterified with residues of fatty mycolic acids. Ghodbane et al. designed squalamine analogs where spermidine was replaced with other alkylamines to increase lipophilicity of compounds 223, 224 (Figure 8), which rendered them active against several mycobacteria species (MIC 5–25 μg/mL), but they did not affect the viability of the tuberculosis causative agent M. tuberculosis [140]. Squalamine itself, due to its selectivity towards bacteria, and especially S. aureus (MIC 3.12 μg/mL) and P. aeruginosa (MIC 8 μg/mL) can be used for decontamination and isolation of mycobacteria from sputum samples [141].
Further studies have shown that the membrane-permeabilizing effect of squalamine potentiates the activity of chloramphenicol, tetracycline, ciprofloxacin, etc. The combined use of squalamine in a subinhibitory concentration with antibiotics makes it possible to reduce their dose and overcome the resistance of antibiotic-resistant strains of E. aerogenes ATCC 13048 and CM-64, P. aeruginosa PA01 and PA124, K. pneumoniae KP63 and KP55, E. coli AG100 and AG100a [103].
Squalamine displayed great efficacy against A. baumannii dormant cells (i.e., persisters, which are responsible for recurrent infections) at the 100 μg/mL dose (below the minimum hemolytic concentration) [132].
In a mouse model, topical application of squalamine more effectively removes S. aureus from the skin than treatment with antiseptic mupirocin used in surgical practice [142]. Squalamine tablets have been developed to disinfect home nebulizers for patients with cystic fibrosis [143]. A squalamine concentration of 0.5 g/L 20 min is enough for disinfection. Aerosol of 3 mg squalamine showed efficacy exceeding 160 mg of colistin in rats with chronic pneumonia caused by P. aeruginosa [144]. Treatment with 1% squalamine ointment resulted in clinical improvement in patients with shingles after 3 weeks [145]. On the downside, squalamine is inactivated by calcium and magnesium cations (1 mM of Ca2+ blocks the activity of 2.5 μg/mL squalamine, whereas a normal range of Ca2+ in human serum is 2.0–2.5 mM [129]), which likely renders it ineffective against systemic infections.
A broad-spectrum antiviral activity has been described for squalamine (Dengue virus, hepatitis B, yellow fever, herpesviruses), indicating that squalamine interaction with cellular membranes prevents the adhesion and fusion of RNA and DNA viruses into cells [146,147]. Due to the positively charged spermidine moiety and affinity for anionic phospholipids, squalamine neutralizes the negative charge of the inner membrane of eukaryotic cells, displacing proteins electrostatically bound to the membrane, in particular Rac1 GTPase used by viruses to enter the cell. At the same time, no disruption or permeabilization of the cell membrane was observed. Zasloff et al. demonstrated a protective effect of parenteral squalamine administration against yellow fever and eastern equine encephalitis in Syrian hamsters and cytomegalovirus infection in BALB/c mice [30].

6.1.2. Neuroprotective Activity

Squalamine prevents aggregation of alpha-synuclein (αS) and competes with it for binding to phospholipid membranes (KD of squalamine 67 nM versus 380 nM for synuclein), which can be used to treat Parkinson’s disease [148]. Recent experiments confirmed that squalamine attenuates the toxicity of αS and amyloid-beta (Aβ) by altering their aggregation and displacing them from cell membranes [149]. Similar properties were later shown for trodusquemine and αS, amyloid-beta (Aβ), and HypF-N oligomers [118,150,151,152]. Squalamine effectively restores disordered colonic motility by restoring excitability of the enteric nervous system in a mouse model [15] and reduced toxicity of αS in a C. elegans model of Parkinson’s disease [153]. In experiments modeling Alzheimer’s disease in C. elegans, trodusquemine reduced the toxicity of Aβ aggregates by preventing their binding to cell membranes [154]. FRET and NMR studies revealed that polyamine tails of trodusquemine modulate physicochemical properties of the cell membranes themselves, making them more resistant to neurotoxic aggregates of misfolded proteins [118,155]. In a mouse model of Alzheimer’s disease, trodusquemine rescued NMDA-mediated neuronal plasticity [156] and prevented cognitive decline [157]. This highlights the potential of squalamine and trodusquemine for the treatment of Alzheimer’s and Parkinson’s diseases [158].

6.1.3. Antiangiogenic and Antitumor Activity

In 1998 Sills et al. showed that squalamine effectively inhibits angiogenesis and tumor growth in several animal models [14]. The authors linked the suppression of tumor neovascularization with the blocking of mitogen-induced proliferation and migration of endothelial cells. Squalamine has no significant effect on unstimulated endothelial cells and does not have a direct cytotoxic effect on tumor cells, nor does it alter the production of mitogens by tumor cells [159]. One of the components of antiangiogenic action is inhibition of sodium hydrogen exchanger NHE3 of endothelial cells through the C-terminal 76-amino acid fragment [160]. Moreover, it has been shown that squalamine prevents only mitogen-stimulated proliferation and migration of endothelial cells [14]. Besides, squalamine is the first calmodulin chaperone described, causing the translocation of the latter from the cell periphery to perinuclear endosomes [123], which can prevent signal transduction from mitogen receptors. Williams et al. showed that squalamine disrupts actin polymerization and intercellular cadherin-mediated adhesion of endothelial cells [161]. As a result, squalamine prevents mitogen-stimulated activation, migration, coordination, and proliferation of endothelial cells, and thus prevents neovascularization of tumors.
Squalamine itself has only a moderate effect on tumor growth [162]. However, its combination with cyclophosphamide, cisplatin, 5-fluorouracil, and paclitaxel sensitizes the tumor, delaying its growth 1.9–3.8 times compared with monotherapy with cytostatic drugs, which was first shown in rats with breast carcinoma and Lewis lung carcinoma [162]. The effectiveness of combined antitumor therapy with squalamine and platinum drugs has been confirmed by several preclinical studies using lung carcinoma [161]. The combination of squalamine with cisplatin is effective in ovarian cancer, including those with HER-2 overexpression, which is resistant to cisplatin monotherapy [150]. Furthermore, squalamine inhibits the growth of HER-2-negative breast cancer MCF-7 and HER-2-positive MCF-7 in combination with trastuzumab by blocking the action of the endogenous activator of angiogenesis VEGF [163].
It was suggested that squalamine is promising for other diseases characterized by neovascularization. It was shown that squalamine at a dose of 25 mg/kg/day subcutaneously is effective in a model of oxygen-induced retinopathy in mice [164] and suppresses neovascularization after laser injury in rats [165] and macaques even upon systemic administration [166].

6.2. Trodusquemine as a Unique PTP1B Inhibitor

6.2.1. Antiobesity and Weight Loss Activity

Further research expanded the known spectrum of biological activity of trodusquemine. It has been shown to inhibit HIV replication in human monocytes [167]. Additional studies carried out on various cell cultures found that the compound also affects the ionic currents of calcium, chloride, and protons [160,168]. In particular, in frog oocytes, trodusquemine caused the calcium-dependent opening of chlorine channels [169]. Surprisingly, it has been found that the administration of trodusquemine induces weight loss in rodents, dogs, and monkeys, which has prompted an in-depth study of the pharmacological properties and mechanism of action of the compound.
Trodusquemine has been shown to induce a reversible decrease in food and fluid intake in mammals, resulting in significant weight loss not associated with side effects, and exhibiting antidiabetic properties in genetically obese mice. Trodusquemine is active when injected into the third ventricle of the rat brain, suggesting a central mechanism of action. When trodusquemine was injected into db/db dyslipidemic mice, a decrease in adipose tissue and a correction of hyperglycemia were noted. Correction of obesity and glucose tolerance was shown in both genetically obese (ob/ob) and diabetic (db/db) mice [170]. The post-receptor mechanism of action of the compound was hypothesized [171].
The study by Ahima et al. confirmed these observations [172]. It was found that the main changes induced by trodusquemine are concentrated in the paraventricular nucleus of the hypothalamus. This area of the brain integrates nerve signals from the nuclei of the hypothalamus and the nucleus of the brain, regulating feeding behavior and several neuroendocrine functions. The introduction of trodusquemine into this region reduced the mRNA levels of the agouti-related peptide and neuropeptide Y in the hypothalamus, suppressing orexigenic pathways.
Many of the drugs that reduce food intake and body weight work in part by blocking the dopamine transporter, a protein responsible for the uptake of extracellular dopamine. Evaluation of the effect of trodusquemine on DAT function did not reveal significant changes in dopamine secretion and degradation while maintaining suppression of food intake [173].
Protein tyrosine phosphatase 1B negatively regulates signaling pathways of leptin and insulin, dephosphorylating their receptors and downstream components of the cascades. The important role of PTP1B in the pathogenesis of obesity and diabetes mellitus was confirmed by the deletion of the PTP1B gene in mice. Mice completely knocked out for the PTP1B gene were protected from the development of obesity and diabetes. Moreover, selective deletion of the PTP1B gene in the brain had the same effect on the weight and carbohydrate metabolism of animals. Deletions in muscle, liver, and adipocytes have no beneficial effect [174,175]. Although these results indicate the importance of PTP1B neuronal activity in maintaining energy homeostasis, peripheral PTP1B is also being investigated as a potential regulator of energy balance. In particular, the important role of hepatic PTP1B expression in glucose homeostasis and endoplasmic stress has been shown [176,177]. PTP1B activity is increased in obesity and type 2 diabetes and is a major cause of insulin resistance. The validation of PTP1B as a therapeutic target for obesity and diabetes has given rise to the development of selective inhibitors of PTP1B [178,179]. These efforts have led to the discovery of several classes of inhibitors, but their therapeutic potential has long been limited by low oral bioavailability [180].
As noted above, trodusquemine induces rapid and reversible weight loss in genetic models of obesity. To better understand the potential effects in the clinic, it was necessary to conduct studies on a model of diet-induced obesity. Lantz et al. administered trodusquemine to mice with alimentary obesity and demonstrated suppressed appetite, reduced body weight in a fat-specific manner, and decreased plasma levels of insulin and leptin [181]. Subsequent enzymatic screening by the authors confirmed that trodusquemine selectively inhibits PTP1B. At the same time, insulin-stimulated phosphorylation of the insulin receptor and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and in hypothalamic tissue in vivo was significantly increased. Thus, for the first time, it was shown that trodusquemine is an effective central and peripheral inhibitor of PTP1B.
This discovery was confirmed by studies of the role of the LMO4 protein, an endogenous inhibitor of PTP1B, in the hypothalamic nuclei [182]. It was found that the introduction of trodusquemine into the hypothalamus of LMO4-deficient mice restores central insulin signaling and improves the response of peripheral tissues to insulin [120]. Determination of the molecular mechanism of action of MSI-1436 prompted further research on its biological activity.
Despite the creation of effective, specific, and reversible low molecular weight inhibitors of PTP1B, the properties of the active site of the enzyme dictate that their molecules should be negatively charged (competitive inhibitors of PTP1B are phosphotyrosine mimetics [180]), which imposes restrictions on their bioavailability and limits their potential as drugs. Krishnan et al. revealed a new mechanism of allosteric inhibition of PTP1B, which is unique for trodusquemine [183]. The binding site located on the disordered C-terminal, the non-catalytic segment of PTP1B, as well as a second site close to the catalytic domain, were identified. The cooperative effect arising from the binding of the trodusquemine molecule to these centers blocks PTP1B in a catalytically inactive conformation [184].

6.2.2. Anticancer Activity

Being an important regulator of cell signaling pathways, PTP1B also regulates the activity of kinase cascades associated with carcinogenesis, and, in particular, is a therapeutic target for HER2-positive cancers of the breast [177], lung [185], prostate [186], stomach [187], and colon [188]. PTP1B stimulates ErbB2-induced oncogenesis at the level of Ras/mitogen-activated protein kinase and PI3/protein kinase B signaling pathways. Additionally, its substrates are oncogenic proteins: receptor tyrosine kinases EGFR, insulin-like growth factor 1 receptor, platelet derived growth factor receptor, colony stimulating factor 1 receptor; protein tyrosine kinase c-Src, Jak2, Tyk2, FAK; transcription factors STAT5a and STAT5b; and adapter proteins p130Cas, Crk, p62Dok, β-catenin [185,189,190,191].
Fan et al. used trodusquemine to elucidate the important role of PTP1B as a negative regulator of BRK and IGF-1Rβ signaling in ovarian cancer cells [192]. In the already-mentioned study [183], trodusquemine showed the ability to suppress the HER2 signaling pathway by inhibiting tumor formation in xenografts and metastasis in the mouse model of NDL2 breast cancer. Thus, not only the effectiveness of PTP1B inhibition as a therapeutic strategy in breast cancer was confirmed, but also the potential of disordered protein segments as specific binding sites for therapeutic small molecules was shown.

6.2.3. Antiatherogenic Properties

Cardiovascular disease is the most common cause of death in patients with type 1 or types 2 diabetes due to the development of endothelial dysfunction, accelerated atherosclerosis, and macrovascular complications [193,194,195]. Recent evidence suggests a strong relationship between atherosclerosis and insulin resistance due to impaired signaling through the insulin receptor [196,197,198]. In a mouse model of LDLR−/− atherosclerosis, single and chronic administration of trodusquemine not only reduced body weight and obesity and improved glucose homeostasis but also attenuated the formation of atherosclerotic plaques [199]. This was accompanied by both a decrease in the level of total circulating cholesterol and triglycerides, as well as a decrease in the level of expression of the macrophage-1 chemoattractant protein and hyperphosphorylation of Akt/protein kinase B and AMPKα in the aorta. Thus, the possibility of using PTP1B inhibitors for the prevention and reversal of the development of atherosclerosis and the reduction of the risk of cardiovascular diseases was demonstrated for the first time.

6.2.4. Regenerative Properties

The search for low molecular weight compounds with regenerative activity is a new and highly promising area of research [200]. Trodusquemine is the first-in-class regenerative drug prototype. Intraperitoneal administration of trodusquemine to adult zebrafish increased the rate of regeneration of the amputated caudal fin, which consists of bone, connective, cutaneous, vascular, and nervous tissue, and also increased the rate of myocardial regeneration. Intraperitoneal administration of trodusquemine to adult mice within 4 weeks after induction of myocardial infarction increased survival, improved heart function, decreased infarction size, decreased ventricular wall thickening, and increased cardiomyocyte proliferation. Doses effective in stimulating regeneration are 5–50 times lower than the maximum dose tolerated by humans. The shown safety and well-established pharmacological properties of trodusquemine underline the potential of this compound as a new treatment for myocardial infarction and other degenerative diseases [201,202].

6.2.5. Anxiolytic Properties

Chronic stress can lead to the development of anxiety and affective disorders. The prevalence of these disorders and the lack of effectiveness of existing drugs necessitate the search for new methods of treatment [203]. Recently, the pathogenetic role of PTP1B in the development of anxiety disorders has been identified [204]. This opens up exciting opportunities for the use of PTP1B inhibitors as anxiolytics [205].
Stress disrupts LMO4-dependent inhibition of PTP1B, which in turn inhibits mGluR5, disrupting its mediated endocannabinoid production. Qin et al. used trodusquemine to confirm the central role of PTP1B in the development of chronic stress-induced anxiety [204]. They showed that treatment of F11 neuroblastoma cells with trodusquemine leads to increased tyrosine phosphorylation of mGluR5. Moreover, administration of the inhibitor to the amygdala, as well as systemic administration by intraperitoneal injection, attenuated the phenotypic manifestations of anxiety and schizophrenia-like behaviors in LMO4 knockout mice [206]. Similar results were obtained after the introduction of lentiviral vectors expressing specific shRNA against PTP1B. In addition, they demonstrated that trodusquemine treatment inhibits the reduction of endogenous cannabinoid levels in the amygdala of stressed mice and reduces stress-induced anxiety.

6.3. Clinical Data

Phase 1 clinical trials have shown that squalamine is well tolerated in patients with advanced solid tumors [207,208]. When administered intravenously, a dose of 192–384 mg/m2/day did not cause toxic effects. Dose-limiting toxicity was observed at doses above 500 mg/m2/day as transient liver dysfunction (increased activity of hepatic transaminases and hyperbilirubinemia). Phase 1/2a clinical trials investigated the antitumor activity of a combination of 100–400 mg/m2/day squalamine with carboplatin and mg/m2/day paclitaxel in patients with stage IIIB–IV non-small cell lung cancer [209]. Thus, squalamine could be a valuable adjunct to the treatment of refractory cancers.
Squalamine lactate in the form of continuous intravenous infusion and eye drops has been clinically tested as a treatment for senile macular degeneration (abnormal growth of blood vessels in the choroid) [210]. Despite encouraging results and a good safety profile, trials of both drugs were suspended in 2007 and 2018 due to the introduction of monoclonal antibodies to VEGF into clinical practice. Later, in phase 2 clinical study in patients with macular edema caused by retinal vein occlusion, topical application of 0.2% squalamine in combination with intraocular administration of 0.5 mg ranibizumab (fragment of monoclonal antibodies to VEGF-A) restored vision more effective than ranibizumab monotherapy. The combination therapy was safe and well-tolerated [211]. A significant advantage of squalamine over anti-VEGF antibodies is the possibility of atraumatic topical application instead of intravitreal injections [212]. Despite these promising results, the phase 3 trial failed, presumably due to poor study design based on retrospective subgroup analysis [213,214].
Squalamine phosphate was orally administered in a pilot clinical study to patients with Parkinson’s disease (40 enrolled, 29 completed the dosing). The authors reported improved colon motility and significant amelioration of constipation along with some neurological and cognitive improvement. The effective dose ranged from 75 mg to 250 mg and was well tolerated, presumably due to low systemic bioavailability [22].
Currently, trodusquemine is the most-studied small molecule PTP1B inhibitor. The drug was originally developed by the compound’s discoverers, Magainin Pharmaceuticals, later renamed Genaera. It has successfully completed phase 1 clinical trials as a treatment for type 2 diabetes mellitus, showing good tolerability and pharmacokinetic profile in healthy individuals (NCT00509132, 2008), as well as in obese and type 2 diabetes patients (NCT00606112 and NCT00806338, 2009), and was planned to move to phase 2 trials. The financial difficulties of the developer prevented the implementation of these plans.
Trodusquemine is currently licensed to Depymed, which has launched phase 1 clinical trials for the treatment of HER-2 positive metastatic breast cancer (NCT02524951, 2017). The study was terminated in 2018 due to a lack of interest by the sponsor (Northwell Health, USA). Finally, the study of obstructive sleep apnea was announced by Angers University Hospital to evaluate the contribution of atherosclerosis and inflammation that can be ameliorated with trodusquemine (NCT04235023, 2020).

6.4. Synthetic Analogs of Squalamine and Trodusquemine and Structure-Activity Studies

The wide spectrum of pharmacological activity manifested by squalamine and trodusquemine prompted researchers to direct their efforts to structural analogs that are more accessible and can be scaled to industrial production.
In a study by Shu et al., a series of squalamine analogs were synthesized based on stigmasterol [34]. The 7α-hydroxyl substituent was either absent or replaced by 7β-hydroxyl. Analogs with 24-sulfate, 24-amino, and 24-hydroxy substituents were also synthesized to assess the importance of a functional design of the side chains for the manifestation of antimicrobial activity. All the derivatives obtained have significant antimicrobial activity, which indicates that the substitution of C7 and C24 for aminosterols does not play a decisive role in antibiotic properties. The most active compound, 210b, demonstrated MICs 1–2, 8, 8, 2 µg/mL against S. aureus, E. coli, P. aeruginosa, and C. albicans, respectively.
Similar patterns were revealed for a series of 3-amino- and polyaminosterol synthetic analogs of squalamine and trodusquemine lacking a sulfate group. The activity was shown to be highly dependent on the structure of the substituents at position C3, and one of the most active compounds comprised 3-(4-aminobutylamine)-moiety 117. For it, the minimum inhibitory concentrations against S. aureus, E. faecalis, E. hirae and E. coli were 6.25–25 μM [76].
Given the low availability of squalamine, numerous synthetically available analogs have been synthesized that exhibit broad-spectrum antibacterial activity with minimal inhibitory concentrations in the range of 2.5–40 μg/mL [33,34,76,81,110,215]. It was noted that analogs with a tetra ammonium polyamine fragment are more active than analogs with a shorter tris ammonium; while analogs with an axial (α)-hydroxyl substituent at C7 are more active than analogs with a corresponding equatorial (β)-hydroxyl group [70,216]. Derivatives with high activity against intracellular parasite T. brucei, the causative agent of African trypanosomiasis, and L. donovani, the causative agent of visceral leishmaniasis, have been described [85].
Recently, a series of cholestane squalamine analogs was described by Brunel et al. They lack sulfate moiety in the steroid side chain and, nevertheless, demonstrate similar squalamine activity against most common pathogens 124 [69]. Interestingly, an antibacterial and fungicidal activity comparable to squalamine was also observed for C7-spermidine analogs 134a and 134b [37], and 131 [78], suggesting that antibiotic properties of aminosterols depend on their amphiphilic nature and are not receptor-mediated.
Hydroxyl at C7 also seems to be dispensable for activity with compound 120 being more active than parent squalamine against S. cerevisiae, C. albicans and E. feacalis (MIC 6.25–12.5 µg/mL, but less active against S. aureus and E. coli) [74]. There is also a series of active derivatives against multi-resistant cocci, especially methicillin-resistant S. aureus at average concentrations of 2.5–5.0 μg/mL [75].
Another study focused on stereochemistry showed that 3β,5β-isomers have improved activity over α-counterparts with β-sperminyl-23,24-bisnor-5β-cholane 112 S. aureus having MIC value as low as 1 μg/mL against S. aureus ATCC6538P [73].
A series of compounds reported by Brunel et al. illustrated that the steroid backbone can tolerate amide functionality without compromising antibiotic activity [217]. Compounds exemplified by 225 (Figure 9) show high antibacterial and antifungal activty (MICs 2–8 μg/mL against and P. aeruginosa strains, MIC50 0.5 μg/mL against C. albicans) and ability to potentiate activity of other antibiotics along with low cytotoxicity against CHO cells (CC50 42 μg/mL). Conversion of squalamine zwitterion to amide-functionalized cations creates a valuable opportunity to overcome low intestinal absorption and inactivation by calcium ions.
Polyamine conjugates of stigmasterol showed diminished antibacterial activity (compound 170, MIC 50 µg/mL against S. aureus) [88].
Bile acid-polyamine conjugates as synthetic ionophores and squalamine mimics demonstrated potent synergism with rifampin against many Gram-negative bacteria with spermine conjugate 195 being the most active (MIC 0.78–6.25 µg/mL against E. coli, P. aeruginosa, and S. aureus, although with a relatively low MHC of 12.5 µg/mL) [215]. A structurally relevant series of 3α-hydroxy-23,24-bisnorcholane spermidine and spermine carbamates was also reported [92]. In this case, steroidal backbone was replaced with carbamate bioisostere. Authors concluded that A,B-cis is superior to A,B-trans configuration. Carbamate 185 was the most potent against S. aureus and P. aeruginosa (MIC 0.78 µg/mL and 3.13 µg/mL, respectively; MHC 25 µg/mL). Conjugates of glycocholic acid with polyamine linker were also developed as modifiers of cholic acids intestinal and hepatic uptake to potentially mitigate first pass effect and improve the safety of hepatotoxic drugs [107].
Conjugate 84 as a synthetic ionophore showed comparable antibacterial activity to gentamicin against S. aureus with IC50 values of 4.12 µg/mL and was less effective against fungi with Trichophyton mentagrophytes being the most susceptible [69].
A polyaminosterol derivative of claramine [218], containing a spermine residue in the C6 position, similarly to trodusquemine, retains the property of selectively inhibiting PTP1B, practically without affecting the activity of the closest homolog, TC-PTP phosphatase. In neuronal cell culture, F11 both claramine and trodusquemine activated the insulin signaling pathway, increasing the phosphorylation of insulin receptor-β (IRβ), Akt, and glycogen synthase kinase 3 beta (GSK3β). Intraperitoneal administration of claramine or trodusquemine effectively restored glycemic control in diabetic mice in glucose and insulin tolerance tests. A single intraperitoneal injection of claramine or an equivalent dose of trodusquemine reduced food intake and led to weight loss in animals without increasing energy expenditure. Moreover, claramine proved to have pronounced antitumor activity in animal models of IL13Rα2 overexpressing cancers, including glioblastoma and colorectal carcinoma [219]. Claramine A1 also exhibits bactericidal activity against a wide range of Gram-positive and Gram-negative bacteria, including multiply resistant bacteria, and, as an adjuvant, restores the antibacterial activity of doxycycline against P. aeruginosa PAO1 and E. aerogenes EA28 [121].
The compound 226 (Figure 9), an orally bioavailable effective inhibitor of PTP1B (IC50 100 nM versus 600 nM for MSI-1436) has also been described [220]. The MSI-1436-resistant mutant PTP1B L192A/S372P is inhibited by 226 with an IC50 of 1 μM. In addition, through several convincing experiments, the authors showed that 226 chelates the copper cation, which enhances its PTP1B-inhibitory activity. Compound 226 antidiabetic properties confirmed in an animal model of nutritional obesity [220].
Lou et al. has found that PDMS surfaces based on claramine derivative can be potentially useful for the elaboration of biomaterials preventing biofilm formation and addressing the issue of antibacterial resistance [221].

6.5. Ceragenins as Antibiotics

The discovery of ceragenins can be considered as a development of studies on the antibacterial activity of squalamine. As it was mentioned above (Section 3.11), ceragenins are positively charged polyamine derivatives of cholic acids that electrostatically interact with negatively charged phospholipids of bacteria, viruses, fungi, and protozoa and lead to an increase in fluidity, depolarization, and permeabilization of their membranes, which inhibits infectivity or results in bacteria death. Multi-resistant strains of bacteria that are susceptible to ceragenins include S. aureus, S. pneumoniae, S. pyogenes, H. influenza, P. aeruginosa, N. meningitides, L. pneumophila etc., Candida, C. neoformans, and A. fumigatus fungi, trypanosomes, as well as the vaccinia virus in 5 µM concentration [222,223,224].
These compounds exhibited antibacterial activity comparable or superior to polymyxin B against Gram-negative bacteria, and some also effectively permeabilize the outer membranes of Gram-negative bacteria [12,225,226].
The selectivity of the antibiotic action of the new compounds was assessed similarly to squalamine for its ability to induce lysis of eukaryotic cells. For example, 186a has a MIC for P. aeruginosa of 2 μg/mL and a minimum hemolytic concentration (MHC) of 29 μg/mL. In the presence of pluronic F-127, antibacterial activity of ceragenin 186a was only slightly decreased, but hemolytic activity was significantly inhibited. Ceragenin 186a exhibits bacterial killing activity against clinical isolates of S. aureus, including methicillin-resistant strains, P. aeruginosa present in cystic fibrosis sputa, and biofilms formed by different gram-positive and gram-negative bacteria [99,227]. These properties render ceragenins particularly useful in orthopedic medicine as antibiotics and implant coatings [228,229]. Silicone coating incorporating 186a developed by Williams et al. [230] proved to be biocompatible, safe, and effective against MRSA biofilms in vivo [231,232]. Another example is contact lenses made with covalently bound 186b or 186c releasing polymers that resist bacterial colonization with S. aureus or P. aeruginosa for 15–30 days (Figure 10) [233].
The selectivity of action is explained by the ability to bind to lipid A, specific for prokaryotic membranes, which was confirmed using amphiphilic steroids labeled with a fluorophore [105]. Ceragenin 186a builds into a phospholipid bilayer which results in increased fluidity and destabilization [234]. Similar to other aminosterols, ceragenins elicit bacterial membrane permeabilization and act synergetically with other antibiotics and antimicrobials, which was confirmed for colistin, tobramycin, ciprofloxacin, LL-37, lysozyme, and lactoferrin [99,235]. Importantly, ceragenins elicit different gene responses in E. coli as compared to cationic antimicrobial peptides, which is associated with a lower level of resistance [236]. Another important benefit of ceragenins is their improved activity in cystic fibrosis sputum. It was shown that ceragenin 186a is significantly less sensitive to extracellular polyanions that compromise the antibacterial activity of cationic antibacterial peptides [97]. CSA-13 186a has potent antibacterial and antibiofilm activity against Achromobacter spp. [237] and P. aeruginosa strains isolated from cystic fibrosis patients (MIC90 2 µg/mL) and acts synergetically with colistin, a polymyxin antibiotic [235]. Moreover, colistin-resistant and chlorhexidine-resistant Gram-negative bacteria strains remain susceptible to ceragenins 186b and 186c (Figure 10) [238,239]. On top of this, ceragenin 186c exceeds the activity of antimicrobial peptides against preformed bacterial and fungal-bacterial biofilms [240,241], and 186a also stimulates cell migration which facilitates wound healing [242]. These results were confirmed in the porcine model of burn wounds with ceragenin 186b [243]. Another hard-to-fight pathogen, B. subtilis spores, is also sensitive to CSA-13 186a treatment [244,245].
Moreover, CSA-17 effectively eradicates drug-resistant clinical isolates of H. pylori (MBC 0.275–8.9 μg/mL) and even retains activity in simulated gastric juice containing pepsin and mucins that inactivates peptide-based antibiotics [144]. Recently it was shown that ceragenins may be used to overcome bacterial resistance to carbapenems. NDM-1 carbapenemase-producing strains of E. coli, E. cloacae, and K. pneumoniae are susceptible to 186a–186c with MICs as low as 1–2 µg/mL [246]. Ceragenins 186a and 186c are also promising drugs against carbapenem-resistant A. baumannii strains [247], improving antibacterial activity of LL-37 peptide against drug-resistant E. coli strains isolated from patients with urinary tract infections [248], they retain activity against multi-drug resistant strains of K. pneumoniae [249].
Ceragenins possess high fungicidal activity against a broad spectrum of pathogenic fungi, e.g., 186a showed MIC in 0.5–4 µg/mL against C. albicans and Candida spp. [250,251], including fluconazole-resistant strains [252]. The mechanism of action of ceragenins against fungi is not precisely defined but as derivatives of cholic acid that mimic the morphology of natural antimicrobial peptides, they are expected to act similarly, causing damage and dysfunction of the plasma membrane. Ceragenins 186a and 186c have stronger candidacidal activity than natural peptide and omiganan against all tested fluconazole-resistant yeast cells as well as against young and mature biofilms [250].
In an attempt to further improve bactericidal activity and biocompatibility of 186a several nanoparticle formulations were developed. The MNP-CSA-13 nanoparticles demonstrate dual benefits: a decrease of ceragenin hemolytic activity and an increase of antimicrobial properties in body fluids [101]. MNP approach improved the antibacterial effect of CSA-13 against methicillin-resistant S. aureus and P. aeruginosa [253]. Ceragenins 186 and 186c attached to MNPs exceed the antibacterial activity of LL-37 or metronidazole against B. fragilis, P. acnes, and C. difficile and prevented formation of their biofilms [254]. Furthermore, MNP-CSA-13 prevents Candida spp. Biofilm formation which is relevant for the treatment of fungal infections in immunocompromised patients [255]. Silver nanoparticles conjugated with ceragenin, or cationic antimicrobials (CSA-SNPs) hold potential as Gram-positive selective antimicrobial [99]. Formulation of 186c in poloxamer micelles prevents damage to ciliated tissues while retaining bactericidal activity against established biofilms [256].
Later several studies revealed that the membrane-permeabilizing capability of 186a is linked not only to antimicrobial, but also anticancer properties [257]. Ceragenin 186a induces cell cycle arrest and apoptosis in wild-type and p53 null mutant HCT116 colon cancer cells at 5 µg/mL concentration [258]. MCF-7 and MDA-MB-231 breast cancer cells are also susceptible both to free CSA-17 and CSA-17-loaded magnetic nanoparticles unlikely to antimicrobial LL-37 peptide, which is protumorigenic [259]. Similar to antibacterial studies, ceragenins immobilized on metal nanoparticles demonstrate synergistically improved therapeutic potential against cancer cells. MNP-186a nanoparticles are also active against DLD-1 colon cancer cells [260]. In these cases, 186a was a carrier to internalize MNP and induce intracellular oxidative stress followed by apoptosis. Anticancer activity of MNP-186c at a 10 µg/mL dose was further confirmed against several colon and lung cancer cell lines [261].
To sum up the data of this section, we should conclude that aminosterols have several principal benefits over commonly used antibacterial drugs. Ceragenins hold promise to fight important human pathogens that are either multi-drug resistant or might become resistant to currently used antibiotics in a near future. The development of second-generation ceragenins and their nanoformulation in liposomes or nanoparticles demonstrated that a combination of efficacy against various bacteria and fungi, even in established biofilms, with biocompatibility and stability in vivo, is indeed possible. The mechanism of antibiotic action relies on physicochemical interaction with phospholipids of cellular membranes. Accordingly, there is no evidence that resistance to aminosterols may emerge since they do not engage protein targets and are not subjected to enzymatic inactivation or active efflux. In comparison with antimicrobial peptides, which share a similar mechanism of action, aminosterols are less expensive to produce, resistant to proteolytic degradation, which permits oral administration and retain their activity in biological fluids. Unlike peptides, they are thermally stable enough to permit autoclave sterilization and use in implant coatings or contact lenses, and even facilitate wound healing and reparation of bone fractures.
The second promising application is linked to antiangiogenic activity for the treatment of neoplastic diseases. Widely used cytostatic agents have intrinsic toxicity towards normal cells, which results in immunodepression, gastrointestinal disorders, and alopecia. Furthermore, high proliferation rates permit the expansion of mutant cancer cells that evade cytostatic therapy. Targeting vascularization of tumors instead is prone to the development of resistance and proved to be tolerable in clinical trials. Choroidal neovascularization is also effectively managed by topical squalamine administration that provides an alternative to traumatic injections of anti-VEGF antibodies in age-related macular edema and similar conditions.
Last but not least, trodusquemine and its synthetic analogs represent unique orally available and brain penetrant allosteric inhibitors of PTP1B. There are no clinically approved drugs targeting this important enzyme, thus aminosterols hold promise to be first-in-class drugs that may relieve the burden of such important diseases such as type 2 diabetes mellitus, obesity, cancer, neurodegenerative, cardiovascular, and psychiatric disorders, including depression and schizophrenia. Further clinical trials are warranted to confirm their safety and efficacy and to ultimately provide benefit to wide cohorts of patients (Table 1).

7. Terpene- and Triterpene-Based Polyamine Derivatives

As was mentioned above, the chemistry and biological activity of steroid polyamines had a strong impact on the synthesis of terpenoid-based polyamine derivatives that started in the first decade of the 21st century. Literature analysis shows that the main group of terpenoid polyamines is obtained on the basis of triterpenic acids. For example, two syntheses of C3 conjugates with spermidine have been realized. The interaction of methyl 3β-amino-3-deoxybetulinoate 227 with tert-butyl-N-(4-cyanobutyl)-N-3-(iodopropyl)-carbonate 228 led to betulin conjugate 229 in a 24% yield. In a yield of 21%, compound 229 was synthesized by reductive amination of derivative 227 with tert-butyl-N-(4-aminobutyl)-N-3-(oxopropyl) carbonate 230 in the presence of NaBH3CN. Conjugate 233 was obtained in a total yield of 34% by the reaction of methyl betulonoate 231 with N-(3-aminopropyl)-1,4-diaminobutane in the presence of Ti(OiPr)4 to form imine 232 and its subsequent reduction with NaBH3CN (Scheme 35) [262].
Another approach included the reaction of cyanoethylation of triterpene alcohols. Interaction of diols 234–237 with acrylonitrile in dioxane resulted in mixtures of 28-mono- and 3,28-biscyanoethyl ethers with the prevalence of the latter (Scheme 36). As a result of catalytic hydrogenolysis of cyano-derivatives, aminopropoxy-modificants of betulin, erythrodiol, uvol, and oleantriol of type 238 and 239 have been synthesized [263]. Aminopropoxytriterpenoids have proven to be highly active anticancer agents, inhibiting the growth of colon cancer, leukemia, breast cancer, and melanoma. 3,28-bis-Aminopropoxy-erythrodiol showed high antitumor activity against five transplanted mouse tumors [263,264]. 3,28-bis-Aminopropoxy-betulin was found to be a potent micromolar inhibitor of yeast α-glucosidase and simultaneously inhibit endosomal reticulum α-glucosidase, rendering it potentially capable to suppress tumor invasiveness and neovascularization in addition to the direct cytotoxicity [265]. Using the described approach, 3β,20R,28-tri-(3-aminopropoxy)-betulin 240 [266,267] and 2-cyanoethoxy- 241 and 3-aminopropoxy-betulinic N-methylpiperazinylamide 242 were synthesized and showed highly cytotoxic activities towards non-small cell lung, colon, breast, ovarian, leukemia, renal, melanoma, prostate and CNS cancer cells [264,268].
Triterpenoids with alkane polyamine fragments in the C28 side chain were synthesized on the basis of betulonic and oleanonic acids 243, 244. The reaction of cyanoethylation of the terminal amino group of triterpene carboxamides 245–247 led to the formation of mono- or bis-N-propionitriles, the reduction of which afforded 3-aminopropylamine derivatives 250 and 251 (Scheme 37). Compound 250 was converted to partially soluble sulfate 252 [266,269]. In a similar route, aminopropyl group was introduced into the structure of A-seco-3-aminobetulin 253 with the formation of 3-aminopropylamino-derivative 254 [270].
Cyanoethylation of methyl betulonoate oxime 255 led to 3-cyanopropoxy-amino derivative, the following reduction with diborane afforded methyl 3-deoxy-3β-(3-aminopropoxyamino)-20(29)dihydrobetulinoate, the terminal NH2-group of this compound was cyanoethylated again and reduced to form a polyamine 256. Stepwise interaction of 255 with acrylonitrile and hydroxylamine led to compound 257, and repeated cyanoethylation, and catalytic hydrogenolysis afforded derivative 258 (Scheme 38) [270].
A next series of derivatives was synthesized on the basis of monoterpenoids. Thus, the synthesis of isoprene polyamines 260–263 was reported by the interaction of citral 259 with polyamines (Scheme 39) [271,272]. The study of the activity of derivatives 260–263 together with the antibiotic doxycycline against the resistant strain of P. aeruginosa showed that compound 262 destabilizes the outer membrane and inhibits the outgoing cell pumps, which facilitates easy penetration of the antibiotic into the bacterium. Thus, they created an opportunity for the rejuvenation of forgotten antibiotic molecules with the help of “escort molecules” to improve their action [271]. They were assayed against clinical isolates and multi-drug-resistant strains. One of these compounds was able to decrease the MIC of doxycycline on the reference strain, efflux pump overproducers, and clinical isolates of P. aeruginosa, to the susceptibility level. Similar results were obtained using chloramphenicol as the antibiotic. Membrane permeation assays and real-time efflux experiments were used to characterize the mechanism of doxycycline potentiation. The results showed that the selected compound strongly decreases the efficiency of glucose-triggered efflux associated with a slight destabilization of the outer membrane. According to these data, targeting natural resistance may become an interesting way to combat MDR pathogens and could represent an alternative to already devised strategies.
Monoterpene derivatives 265 and 266 (Scheme 40), were successfully evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria of four antibiotics belonging to four different families. The mechanism of action against E. aerogenes of one of the most efficient of these chemosensitizing agents was precisely evaluated by using fluorescent dyes to measure outer-membrane permeability and to determine membrane depolarization. The weak cytotoxicity encountered led to performing an in vivo experiment dealing with the treatment of mice infected with S. typhimurium and affording preliminary promising results in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 266h-doxycycline combination [273].
Among triterpene-based polyamines, the most representative group is presented by triterpenic conjugates with linear and cyclic diamines 267–299 (Figure 11) [263,264,265,267,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299]. The reactions involved both native acids and their semi-synthetic derivatives. For almost all compounds, data on biological properties were obtained, mainly on cytotoxicity against cancer cells, antiviral, antibacterial, antidiabetic, and antifungal activity. It is interesting to note that conjugates of betulinic, oleanolic, ursolic, and platanic acids with spermine at the C28 or C3 positions through a succinate spacer exhibited not only antimicrobial and antitumor activity [298,300], but also self-assembled into J-type fibrous systems in aqueous media, and also form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids [298,301]. Triterpene aldimines with spermidine were found to be promising antibacterial agents against both Gram-positive and Gram-negative bacteria [302]. Amide BMS-955176, derived from betulin in seven steps, is an effective antiretroviral drug in phase 2b clinical trials [294,303]. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine and branched methyl 3-cyanoethylated polyamine betulonoate showed high cytotoxic activity against most of the tested cancer cell lines with the lowest GI50 1.09 µM. Betulonic acid diethylentriamine conjugate showed partial activity against methicillin-resistant S. aureus and the fungi C. neoformans [265].
Conjugates of oleanolic acid with spermine 300 and 301 were studied for the characteristics of their oleanolic acid backbone that is a conformationally rigid and convenient chiral building block for preparing functional soft materials. However, besides their supramolecular characteristics, conjugates displayed high cytotoxicity with a range IC50 0.8–3.7 µM (Figure 12) [305].
Oleanolic acid conjugate with diethylenetriamine 302 (Figure 13) demonstrated high inhibitory activity against C. trachomatis with chemotherapeutic index 8 and >8. Compounds 302 and 303 exhibited remarkable activities against the NCI-60 subpanel (GI50 ranges from 0.18 to 2.21 μM) exceeding the activity of sorafenib with compound 302 as a lead (GI50 0.17 μM for melanoma LOX IMVI) [306]. A series of oleanolic acid derivatives holding oxo- or 3-N-polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C28 with different long chain polyamines have been synthesized and showed good antimicrobial activities against Gram-positive S. aureus, S. faecalis and B. cereus (MIC values from 3.125 to 200 µg/mL) and Gram-negative E. coli, P. aeruginosa, and S. enterica (MIC ranging from 6.25 to 200 µg/mL) [307]. The testing of ability to restore antibiotic activity of doxycycline and erythromycin at a 2 µg/mL concentration in a synergistic assay showed that oleanonic acid conjugate with spermine spacered through propargylamide 304 led to a moderate improvement in terms of antimicrobial activities of the different selected combinations against both P. aeruginosa and E. coli. The study of mechanism of action of the lead conjugate 305 presenting a N-methyl norspermidine moiety showed the effect of disruption of the outer bacterial membrane of P. aeruginosa PA01 cells.

8. Conclusions

Squalamine and trodusquemine isolated from the dogfish shark Squalus acanthias at the turn of 1990–2000 were involved in the systematic chemical and clinical investigations. Due to the need for significant amounts for biological tests, different synthetic approaches were suggested for their preparation from available steroids and cholic acids. In vitro and in vivo studies of squalamine showed a broad-spectrum bactericidal antibiotic activity against both Gram-positive and Gram-negative bacteria, and antiviral activity against RNA- and DNA viruses, and an inhibition of pathological angiogenesis associated with cancer and retinopathy. Trodusquemine and its synthetic analogs represent unique orally available and brain penetrant allosteric inhibitors of PTP1B, and these aminosterols hold promise to be first-in-class drugs that may relieve the burden of such important diseases including type 2 diabetes mellitus, obesity, cancer, neurodegenerative, cardiovascular, and psychiatric disorders (Figure 14).
From the beginning of the first decade of the 21st century, the chemistry and biological activity of steroid polyamines had a strong impact on the synthesis of terpenoid-based polyamine derivatives. The study of isoprene polyamines together with the doxycycline against the resistant strain of P. aeruginosa revealed the derivative that destabilizes the outer membrane and inhibits the outgoing cell pumps, which facilitates easy penetration of the antibiotic into the bacterium, thus creating an opportunity for the rejuvenation of forgotten antibiotic molecules with the help of “escort molecules” to improve their action. Triterpenic conjugates with spermine, spermidine, triethylenetetramine, other linear and cyclic di- and polyamines as well as branched aminopropoxy-derivatives have been synthesized. For almost all compounds, data on cytotoxicity against cancer cells, antiviral, antibacterial, antidiabetic, and antifungal activities were obtained. Among them, conjugates of several triterpenic acids with spermine exhibited not only antimicrobial and antitumor activity, but also formed self-assembled systems and supramolecular networks in aqueous media, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Author Contributions

O.K.: conceptualization, writing, discussion, and editing; G.G.: screening of the literature, selection of the presented information, writing—original draft preparation and editing; D.B.: writing of Part 6, editing; Z.W.: preparation of Part 7, discussion and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study.

Acknowledgments

This work was supported by Federal programs No. 1021062311392-9-1.4.1 and No. 1021062311390-1-1.4.1.

Conflicts of Interest

The authors declare that they have no conflict of interest. All co-authors have seen and agreed with the contents of the manuscript and there is no financial interest to report.

Abbreviations

AktRAC-alpha serine/threonine-protein kinase
AMPK5′adenosine monophosphate-activated protein kinase
BOPN-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)-tyrosine sodium salt
BRKBRICK1 subunit of SCAR/WAVE actin nucleating complex
DATdopamine active transporter
DAST(diethylamino)sulfur trifluoride
(DHQD)2PHALhydroquinidine 1,4-phthalazinediyl diether
EEDQ2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
FAKfocal adhesion kinase
FRETförster or fluorescence resonance energy transfer
GTPaseguanosine triphosphate hydrolase
HOBt1-hydroxybenzotriazole
HypF-NN-terminal domain of the E. coli HypF carbamoyltransferase
IL13Rα2interleukin-13 receptor α2
Jak2Janus kinase 2
LDLRlow density lipoprotein receptor
LMO4LIM domain only 4
MBCminimum bactericidal concentration
MCP-1macrophage-1 chemoattractant protein
MDRmultidrug-resistant
mGluR5metabotropic glutamate receptor 5
MHCminimum hemolytic concentration
MNPmagnetic nanoparticles
mRNAmessenger RNA
MRSAmethicillin-resistant S. aureus
MECBS2-methyl-CBS-oxazaborolidine
NDM-1new Delhi metallo-beta-lactamase
NHEsodium-hydrogen exchanger
PADSpetromyzonamine disulfate
PDMSPolydimethylsiloxane
PI3Kphosphoinositide 3-kinase
PEIPolyethyleneimines
PTP1Bprotein tyrosine phosphatase 1B
PTSA4-toluenesulfonamide
shRNAsmall hairpin RNA
SNPsilver nanoparticle
STATsignal transducer and activator of transcription
TBHPtert-butyl hydroperoxide solution
TEMPO2,2,6,6-tetramethylpiperidine 1-oxyl
Tyk2non-receptor tyrosine-protein kinase 2
TMCStrimethylsilyl chloride
VEGFvascular endothelial growth factor

References

  1. Casero, R.A.; Woster, P.M. Terminally alkylated polyamine analogues as chemotherapeutic agents. J. Med. Chem. 2001, 44, 1–26. [Google Scholar] [CrossRef]
  2. Karigiannis, G.; Papaioannou, D. Structure, biological activity and synthesis of polyamine analogues and conjugates. Eur. J. Org. Chem. 2000, 2000, 1841–1863. [Google Scholar] [CrossRef]
  3. Rogoza, L.N.; Salakhutdinov, N.F.; Tolstikov, G.A. Polymethyleneamine alkaloids of animal origin: I. Metabolites of marine and microbial organisms. Russ. J. Bioorg. Chem. 2005, 31, 507–520. [Google Scholar] [CrossRef]
  4. Rogoza, L.N.; Salakhutdinov, N.F.; Tolstikov, G.A. Polymethyleneamine alkaloids of animal origin: II. Polyamine neurotoxins. Russ. J. Bioorg. Chem. 2006, 32, 23–36. [Google Scholar] [CrossRef]
  5. Stone, R. Deja vu guides the way to new antimicrobial steroid. Science 1993, 259, 1125. [Google Scholar] [CrossRef]
  6. Moore, K.S.; Wehrli, S.; Roder, H.; Rogers, M.; Forrest, J.N., Jr.; McCrimmon, D.; Zasloff, M. Squalamine: An aminosterol antibiotic from the shark. Proc. Natl. Acad. Sci. USA 1993, 90, 1354–1358. [Google Scholar] [CrossRef]
  7. Rao, M.N.; Shinnar, A.E.; Noecker, L.A.; Chao, T.L.; Feibush, B.; Snyder, B.; Sharkansky, I.; Sarkahian, A.; Zhang, X.; Jones, S.R.; et al. Aminosterols from the Dogfish Shark Squalus acanthias. J. Nat. Prod. 2000, 63, 631–635. [Google Scholar] [CrossRef]
  8. Moriarty, R.M.; Tuladhar, S.M.; Guo, L.; Wehrli, S. Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett. 1994, 35, 8103–8106. [Google Scholar] [CrossRef]
  9. Moriarty, R.M.; Enache, L.A.; Kinney, W.A.; Allen, C.S.; Canary, J.W.; Tuladhar, S.M.; Guo, L. Stereoselective synthesis of squalamine dessulfate. Tetrahedron Lett. 1995, 36, 5139–5142. [Google Scholar] [CrossRef]
  10. Yun, S.-S.; Li, W. Identification of squalamine in the plasma membrane of white blood cells in the sea lamprey, Petromyzon marinus. J. Lipid Res. 2007, 48, 2579–2586. [Google Scholar] [CrossRef]
  11. Brunel, J.M.; Letourneux, Y. Recent Advances in the Synthesis of Spermine and Spermidine Analogs of the Shark Aminosterol Squalamine. Eur. J. Org. Chem. 2003, 2003, 3897–3907. [Google Scholar] [CrossRef]
  12. Schmidt, E.J.; Boswell, J.S.; Walsh, J.P.; Schellenberg, M.M.; Winter, T.W.; Li, C.; Allman, G.W.; Savage, P.B. Activities of cholic acid-derived antimicrobial agents against multidrug-resistant bacteria. J. Antimicrob. Chemother. 2001, 47, 671–674. [Google Scholar] [CrossRef] [PubMed]
  13. Cushnie, T.P.T.; Cushnie, B.; Lamb, A.J. Alkaloids: An overview of their antibacterial, antibiotic-enhancingand antivirulence activities. Int. J. Antimicrob. Agents 2014, 44, 377–386. [Google Scholar] [CrossRef] [PubMed]
  14. Sills, A.K., Jr.; Williams, J.I.; Tyler, B.M.; Epstein, D.S.; Sipos, E.P.; Davis, J.D.; McLane, M.P.; Pitchford, S.; Cheshire, K.; Gannon, F.H.; et al. Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbsembryonic vasculature. Cancer Res. 1998, 58, 2784–2792. [Google Scholar]
  15. Westa, C.L.; Mao, Y.-K.; Delungahawatta, T.; Amin, J.Y.; Farhin, S.; McQuade, R.M.; Diwakarla, S.; Pustovit, R.; Stanisz, A.M.; Bienenstock, J.; et al. Squalamine restores the function of the enteric nervous system in mouse models of Parkinson’s disease. J. Parkinson’s Dis. 2020, 10, 1477–1491. [Google Scholar] [CrossRef]
  16. Hoye, T.R.; Dvornikovs, V.; Fine, J.M.; Anderson, K.R.; Jeffrey, C.S.; Muddiman, D.C.; Shao, F.; Sorensen, P.W.; Wang, J. Details of the structure determination of the sulfated steroids PSDS and PADS: New components of the Sea Lamprey (Petromyzon marinus) migratory pheromone. J. Org. Chem. 2007, 72, 7544–7550. [Google Scholar] [CrossRef]
  17. Fine, J.M.; Sorensen, P.W. Isolation and biological activity of the multi-component sea lamprey migratory pheromone. J. Chem. Ecol. 2008, 34, 1259–1267. [Google Scholar] [CrossRef]
  18. Seiler, N.; Knodgen, B.; Haegele, K. N-(3-Aminopropyl)pyrrolidin-2-one, a product of spermidine catabolism in vivo. Biochem. J. 1982, 208, 189–197. [Google Scholar] [CrossRef]
  19. Barbut, D.; Zasloff, M. Methods for Treating Blood Pressure Conditions Using Aminosterol Compositions. U.S. Patent 20200129528A1, 30 April 2020. [Google Scholar]
  20. Barbut, D.; Zasloff, M. Methods of Treating Alzheimer’s Disease Using Aminosterol Compositions. U.S. Patent 20200038412A, 6 February 2020. [Google Scholar]
  21. Barbut, D.; Zasloff, M. Methods of Treating Parkinson’s Disease Using Aminosterol Compositions. U.S. Patent 20200038413A1, 6 February 2020. [Google Scholar]
  22. Barbut, D.; Zasloff, M. Methods of Treating Constipation Using Aminosterol Compositions. U.S. Patent 20200038414A1, 6 February 2020. [Google Scholar]
  23. Barbut, D.; Zasloff, M. Aminosterol Compositions and Methods of Using the Same for Treating Erectile Dysfunction. U.S. Patent 20200038415A1, 6 February 2020. [Google Scholar]
  24. Barbut, D.; Zasloff, M. Methods of Treating Cardiac Conduction Defects Using Aminosterol Compositions. U.S. Patent 20200038416A1, 6 February 2020. [Google Scholar]
  25. Barbut, D.; Zasloff, M. Methods and Compositions for Treating Cognitive Impairment. U.S. Patent 20200038417A1, 6 February 2020. [Google Scholar]
  26. Barbut, D.; Zasloff, M. Methods of Treating Autism Spectrum Disorder Using Aminosterol Compositions. U.S. Patent 20200038418A1, 6 February 2020. [Google Scholar]
  27. Barbut, D.; Zasloff, M. Methods of Treating Multiple System Atrophy Using Aminosterol Compositions. U.S. Patent 20200038419A1, 6 February 2020. [Google Scholar]
  28. Barbut, D.; Zasloff, M. Aminosterol Compositions and Methods of Using the Same for Treating Depression. U.S. Patent 20200038420A1, 6 February 2020. [Google Scholar]
  29. Barbut, D.; Zasloff, M. Aminosterol Compositions and Methods of Using the Same for Treating Schizophrenia. U.S. Patent 20200155574A1, 21 May 2020. [Google Scholar]
  30. Zasloff, M. Methods for Treating and Preventing Viral Infections. U.S. Patent 20200323883A1, 15 October 2020. [Google Scholar]
  31. Selinsky, B.S.; Zhou, Z.; Fojtik, K.G.; Jones, S.R.; Dollahon, N.R.; Shinnar, A.E. The aminosterol antibiotic squalamine permeabilizes large unilamellar phospholipid vesicles. Biochim. Biophys. Acta-Biomembr. 1998, 1370, 218–234. [Google Scholar] [CrossRef]
  32. Williams, J.I. Squalamine: A new angiostatic steroid. Antiangiogenic Agents Cancer Ther. 1999, 1, 153–174. [Google Scholar] [CrossRef]
  33. Savage, P.B.; Li, C. Cholic acid derivatives: Novel antimicrobials. Expert Opin. Investig. Drugs 2000, 9, 263–272. [Google Scholar] [CrossRef]
  34. Shu, Y.; Jones, S.R.; Kinney, W.A.; Selinsky, B.S. The synthesis of spermine analogs of the shark aminosterol squalamine. Steroids 2002, 67, 291–304. [Google Scholar] [CrossRef]
  35. Savage, P.B. Cationic steroid antibiotics. Curr. Med. Chem.–Anti-Infect. Agents 2002, 1, 293–304. [Google Scholar] [CrossRef]
  36. Salunke, D.B.; Hazra, B.G.; Pore, V.S. Bile acide-polyamine conugates as synthetic ionophores. Archivoc 2003, 9, 115–125. [Google Scholar]
  37. Choucair, B.; Dherbomez, M.; Roussakis, C.; El Kihel, L. Synthesis of spermidinylcholestanol and spermidinylcholesterol, squalamine analogues. Tetrahedron 2004, 60, 11477–11486. [Google Scholar] [CrossRef]
  38. Alhanout, K.; M Rolain, J.; M Brunel, J. Squalamine as an Example of a New Potent Antimicrobial Agents Class: A Critical Review. Curr. Med. Chem. 2010, 17, 3909–3917. [Google Scholar] [CrossRef]
  39. Bourguet-Kondracki, M.-L.; Brunel, J.-M. Promises of the Unprecedented Aminosterol Squalamine. Outstanding Marine Molecules: Chemistry, Biology, Analysis, 1st ed.; Wiley-VCH Verlag GmbH&Co., KGaA: Weinheim, Germany, 2014; pp. 265–283, Print ISBN: 9783527334650, Online ISBN: 9783527681501. [Google Scholar] [CrossRef]
  40. Djouhri-Bouktab, L.; Rolain, J.M.; Brunel, J.M. Mini-Review: Polyamines Metabolism, Toxicity and Potent Therapeutical Use. Anti-Infect. Agents 2014, 12, 95–103. [Google Scholar] [CrossRef]
  41. Blanchet, M.; Brunel, J.M. Bile acid derivatives: From old molecules to a new potent therapeutic use: An overview. Curr. Med. Chem. 2018, 25, 3613–3636. [Google Scholar] [CrossRef] [PubMed]
  42. Négrel, S.; Brunel, J.-M. Synthesis and biological activities of naturally functionalized polyamines: An overview. Curr. Med. Chem. 2021, 28, 3406–3448. [Google Scholar] [CrossRef] [PubMed]
  43. Kinney, W.A.; Zhang, X.; Williams, J.I.; Johnston, S.; Michalak, R.S.; Deshpande, M.; Dostal, L.; Rosazza, J.P.N. A short formal synthesis of squalamine from a microbial metabolite. Org. Lett. 2000, 2, 2921–2922. [Google Scholar] [CrossRef]
  44. Weis, A.L.; Bakos, T.; Alferiev, I.; Zhang, X.; Shao, B.; Kinney, W.A. Synthesis of an azido spermidine equivalent. Tetrahedron Lett. 1999, 40, 4863–4864. [Google Scholar] [CrossRef]
  45. Wehrli, S.L.; Moore, K.S.; Roder, H.; Durell, S.; Zasloff, M. Structure of the novel steroidal antibiotic squalamine determined by two-dimensional NMR spectroscopy. Steroids 1993, 58, 370–378. [Google Scholar] [CrossRef]
  46. Pearson, A.J.; Chen, Y.S.; Han, G.R.; Hsu, S.Y.; Ray, T. A new method for the oxidation of alkenes to enones. An efficient synthesis of Δ5-7-oxo steroids. J. Chem. Soc. Perkin Trans. 1 1985, 267–273. [Google Scholar] [CrossRef]
  47. Tal, D.M.; Frisch, G.D.; Elliott, W.H. Bile acids LXIX. Selective K-selectride reduction of 3,7-diketo steroids. Tetrahedron 1984, 40, 851–854. [Google Scholar] [CrossRef]
  48. Arnostova, L.M.; Pouzar, V.; Drasar, P. Preparation of steroid hydroxy sulfates. Synth. Commun. 1990, 20, 1521–1529. [Google Scholar] [CrossRef]
  49. McGill, J.M.; LaBell, E.S.; Williams, M. Hydride reagents for stereoselective reductive amination. An improved preparation of 3-endo-tropanamine. Tetrahedron Lett. 1996, 37, 3977–3980. [Google Scholar] [CrossRef]
  50. Li, C.; Budge, L.P.; Driscoll, C.D.; Willardson, B.M.; Allman, G.W.; Savage, P.B. Incremental conversion of outer-membrane permeabilizers into potent antibiotics for gram-negative bacteria. J. Am. Chem. Soc. 1999, 121, 931–940. [Google Scholar] [CrossRef]
  51. Zhang, X.; Rao, M.N.; Jones, S.R.; Shao, B.; Feibush, P.; McGuigan, M.; Tzodikov, N.; Feibush, B.; Sharkansky, I.; Snyder, B.; et al. Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J. Org. Chem. 1998, 63, 8599–8603. [Google Scholar] [CrossRef]
  52. Liang, F.; Wan, S.; Li, Z.; Xiong, X.; Yang, L.; Zhou, X.; Wu, C. Medical applications of macrocyclic polyamines. Curr. Med. Chem. 2006, 13, 711–727. [Google Scholar] [CrossRef] [PubMed]
  53. Zhou, X.D.; Cai, F.; Zhou, W.S. A new highly stereoselective construction of the sidechain of squalamine through improved Sharpless catalytic asymmetric dihydroxylation. Tetrahedron Lett. 2001, 42, 2537–2539. [Google Scholar] [CrossRef]
  54. Zhou, X.-D.; Cai, F.; Zhou, W.-S. A stereoselective synthesis of squalamine. Tetrahedron 2002, 58, 10293–10299. [Google Scholar] [CrossRef]
  55. Zhang, D.-H.; Cai, F.; Zhou, X.-D.; Zhou, W.-S. A concise and stereoselective synthesis of squalamine. Org. Lett. 2003, 5, 3257–3259. [Google Scholar] [CrossRef]
  56. Kolb, H.C.; VanNieuwenhze, M.S.; Sharpless, K.B. Catalytic asymmetric dihidroxylation. Chem. Rev. 1994, 94, 2483–2549. [Google Scholar] [CrossRef]
  57. Iida, T.; Nishida, S.; Chang, F.C.; Niwa, T.; Goto, J.; Nambara, T. Potential bile acid metabolites. 19. The epimeric 3alpha,6,7beta-trihydroxy- and 3alpha,6,7beta,12alpha-tetrahydroxy-5alpha-cholanoic acids. Cherm. Pharm. Bull. 1993, 41, 763–765. [Google Scholar] [CrossRef]
  58. Huang, L.F.; Zhou, W.S.; Sun, L.Q.; Pan, X.F. Studies on steroidal plant-growth regulators. Part 29. Osmium tetroxide-catalysed asymmetric dihydroxylation of the (22E,24R)- and the (22E,24S)-24-alkyl steroidal unsaturated side chain. J. Chem. Soc. Perkin Trans. 1 1993, 1683–1686. [Google Scholar] [CrossRef]
  59. Corey, E.J.; Grogan, M.J. Stereocontrolled syntheses of 24(S),25-epoxycholesterol and related oxysterols for studies on the activation of LXR receptors. Tetrahedron Lett. 1998, 39, 9351–9354. [Google Scholar] [CrossRef]
  60. Yadav, J.S.; Mysorekar, S.V. A facile conversion of tertiary alcohols to olefins. Synth. Commun. 1989, 19, 1057–1060. [Google Scholar] [CrossRef]
  61. Goodnow, R., Jr.; Konno, K.; Niwa, M.; Kallimopoulos, T.; Bukownic, R.; Lenares, D.; Nakanishi, K. Synthesis of glutamate receptor antagonist philanthotoxin-433 (PhTX-433) and its analogs. Tetrahedron 1990, 46, 3267–3286. [Google Scholar] [CrossRef]
  62. Okumura, K.; Nakamura, Y.; Takeuchi, S.; Kato, I.; Fujimoto, Y.; Ikekawa, N. Formal synthesis of squalamine from desmosterol. Chem. Pharm. Bull. 2003, 51, 1177–1182. [Google Scholar] [CrossRef]
  63. Jones, S.R.; Selinsky, B.S.; Rao, M.N.; Zhang, X.N.; Kinney, W.A.; Tham, F.S. Efficient route to 7α-(benzoyloxy)-3-dioxolane cholestan-24(R)-ol, a key intermediate in the synthesis of squalamine. J. Org. Chem. 1998, 63, 3786–3789. [Google Scholar] [CrossRef]
  64. Foricher, J.; Furbringer, C.; Pfoertner, K. Process for the Catalytic Oxidation of Isoprenoids Having Allylic Groups. U.S. Patent 5,030,739, 9 July 1991. [Google Scholar]
  65. Shen, J.M.; Zhou, X.D.; Zhou, W.S. Formal synthesis of squalamine from methylhyodeoxycholanate. Acta Chim. Sin. 2006, 64, 1513–1516. [Google Scholar]
  66. Zasloff, M. Use of Squalamine for the Manufacture of a Medicament for Inhibiting NHE. Europe Patent 0831837B1, 2 May 2003. [Google Scholar]
  67. Jones, S.R.; Kinney, W.A.; Zhang, X.; Jones, L.M.; Selinsky, B.S. The synthesis and characterization of analogs of the antimicrobial compound squalamine: 6β-hydroxy-3-aminosterols synthesized from hyodeoxycholic acid. Steroids 1996, 61, 565–571. [Google Scholar] [CrossRef]
  68. Aher, N.G.; Pore, V.S.; Mishra, N.N.; Shukla, P.K.; Gonnade, R.G. Design and synthesis of bile acid-based amino sterols as antimicrobial agents. Bioorg. Med. Chem. Lett. 2009, 19, 5411–5414. [Google Scholar] [CrossRef] [PubMed]
  69. Brunel, J.M.; Marc, J.P. Compounds That Are Analogs of Squalamine, Used as Antibacterial Agents. U.S. Patent 10729701B2, 4 August 2020. [Google Scholar]
  70. Kim, H.S.; Choi, B.S.; Kwon, K.S.; Lee, S.O.; Kwak, H.J.; Lee, C.H. Synthesis and antimicrobial activity of squalamine analogue. Bioorg. Med. Chem. 2000, 8, 2059–2065. [Google Scholar] [CrossRef]
  71. Choucair, B.; Dherbomez, M.; Roussakis, C.; El Kihel, L. Synthesis of 7α- and 7β-spermidinylcholesterol, squalamine analogues. Bioorg. Med. Chem. Lett. 2004, 14, 4213–4216. [Google Scholar] [CrossRef]
  72. Kim, H.-S.; Khan, S.N.; Jadhav, J.R.; Jeong, J.-W.; Jung, K.; Kwak, J.-H. A concise synthesis and antimicrobial activities of 3-polyamino-23,24-bisnorcholanes as steroid–polyamine conjugates. Bioorg. Med. Chem. Lett. 2011, 21, 3861–3865. [Google Scholar] [CrossRef]
  73. Salmi, C.; Loncle, C.; Vidal, N.; Letourneux, Y.; Brunel, J.M. New stereoselective titanium reductive amination synthesis of 3-amino and polyaminosterol derivatives possessing antimicrobial activities. Eur. J. Med. Chem. 2008, 43, 540–547. [Google Scholar] [CrossRef] [PubMed]
  74. Salmi, C.; Loncle, C.; Vidal, N.; Laget, M.; Letourneux, Y.; Brunel, J. New 3-aminosteroid derivatives as a new family of topical antibacterial agents active against methicillin-resistant staphylococcus aureus (MRSA). Lett. Drug Des. Discov. 2008, 5, 169–172. [Google Scholar] [CrossRef]
  75. Salmi, C.; Loncle, C.; Vidal, N.; Laget, M.; Letourneux, Y.; Brunel, J.M. Antimicrobial activities of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine. J. Inzyme Inhib. Med. Chem. 2008, 23, 860–865. [Google Scholar] [CrossRef]
  76. Boes, A.; Brunel, J.M.; Derouaux, A.; Kerff, F.; Bouhss, A.; Touze, T.; Breukink, E.; Terrak, M. Squalamine and aminosterol mimics inhibit the peptidoglycan glycosyltransferase activity of PBP1B. Antibiotics 2020, 9, 373. [Google Scholar] [CrossRef] [PubMed]
  77. Loncle, C.; Salmi, C.; Letourneux, Y.; Brunel, J.M. Synthesis of new 7-aminosterol squalamine analogues with high antimicrobial activities through a stereoselective titanium reductive amination reaction. Tetrahedron 2007, 63, 12968–12974. [Google Scholar] [CrossRef]
  78. Alhanout, K.; Brunel, J.M.; Raoult, D.; Rolain, J.M. In vitro antibacterial activity of aminosterols against multidrug-resistant bacteria from patients with cystic fibrosis. J. Antimicrob. Chemother. 2009, 64, 810–814. [Google Scholar] [CrossRef]
  79. Alhanout, K.; Brunel, J.M.; Ranque, S.; Rolain, J.M. In vitro antifungal activity of aminosterols against moulds isolated from cystic fibrosis patients. J. Antimicrob. Chemother. 2010, 65, 1307–1309. [Google Scholar] [CrossRef]
  80. Blanchet, M.; Borselli, D.; Brunel, J.M. Polyamine derivatives: A revival of an old neglected scaffold to fight resistant Gram-negative bacteria? Future Med. Chem. 2016, 8, 963–973. [Google Scholar] [CrossRef]
  81. Djouhri, L.; Vidal, N.; Rolain, J.M.; Brunel, J.M. Synthesis of new 3,20-bispolyaminosteroid squalamine analogues and evaluation of their antimicrobial activities. J. Med. Chem. 2011, 54, 7417–7421. [Google Scholar] [CrossRef]
  82. Sakr, A.; Laurent, F.; Brunel, J.-M.; Dagher, T.N.; Blin, O.; Rolain, J.-M. Polyaminosteroid Analogues as Potent Antibacterial Agents Against Mupirocin- Resistant Staphylococcus aureus Strains. Anti-Infect. Agents 2020, 18, 239–244. [Google Scholar] [CrossRef]
  83. Khan, S.N.; Kim, B.J.; Kim, H.-S. Synthesis and antimicrobial activity of 7-fluoro-3-aminosteroids. Bioorg. Med. Chem. Lett. 2007, 17, 5139–5142. [Google Scholar] [CrossRef]
  84. Khabnadideh, S.; Tan, C.L.; Croft, S.L.; Kendrick, H.; Yardley, V.; Gilbert, I.H. Squalamine analogues as potential anti-trypanosomal and anti-leishmanial compounds. Bioorg. Med. Chem. Lett. 2000, 10, 1237–1239. [Google Scholar] [CrossRef]
  85. Dvorken, L.V.; Smyth, R.B.; Mislow, K. Stereochemistry of the 1,2,3,4-dibenz-1,3-cyclooctadiene system. J. Am. Chem. Soc. 1958, 80, 486–492. [Google Scholar] [CrossRef]
  86. Blagbrough, I.S.; Al-Hadithi, D.; Geall, A.J. DNA condensation by bile acid conjugates of thermine and spermine. Pharm. Pharmacol. Commun. 1999, 5, 139–144. [Google Scholar] [CrossRef]
  87. Vida, N.; Svobodová, H.; Rárová, L.; Drašar, P.; Šaman, D.; Cvačka, J.; Wimmer, Z. Polyamine conjugates of stigmasterol. Steroids 2012, 77, 1212–1218. [Google Scholar] [CrossRef] [PubMed]
  88. Randazzo, R.A.S.; Bucki, R.; Janmey, P.A.; Diamond, S.L. A series of cationic sterol lipids with gene transfer and bactericidal activity. Bioorg. Med. Chem. 2009, 17, 3257–3265. [Google Scholar] [CrossRef] [PubMed]
  89. Blagbrough, I.S.; Geall, A.J.; Neal, A.P. Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy. Biochem. Soc. Trans. 2003, 31, 397–406. [Google Scholar] [CrossRef] [PubMed]
  90. Geall, A.J.; Taylor, R.J.; Earll, M.E.; Eaton, M.A.W.; Blagbrough, I.S. Synthesis of cholesteryl polyamine carbamates: pKa studies and condensation of calf thymus DNA. Bioconjug. Chem. 2000, 11, 314–326. [Google Scholar] [CrossRef]
  91. Kim, H.-S.; Kwon, K.-C.; Kim, K.S.; Lee, C.H. Synthesis and antimicrobial activity of new 3α-Hydroxy-23,24-bisnorcholane polyamine carbamates. Bioorg. Med. Chem. Lett. 2001, 11, 3065–3068. [Google Scholar] [CrossRef]
  92. Savage, P.B. Design, synthesis and characterization of cationic peptide and steroid antibiotics. Eur. J. Org. Chem. 2002, 2002, 759–768. [Google Scholar] [CrossRef]
  93. Lai, X.Z.; Feng, Y.; Pollard, J.; Chin, J.N.; Rybak, M.J.; Bucki, R.; Epand, R.F.; Epand, R.M.; Savage, P.B. Ceragenins: Cholic acidbased mimics of antimicrobial peptides. Acc. Chem. Res. 2008, 41, 1233–1240. [Google Scholar] [CrossRef] [PubMed]
  94. Epand, R.M.; Epand, R.F.; Savage, P.B. Ceragenins (cationic steroid compounds), a novel class of antimicrobial agents. Drug News Perspect. 2008, 21, 307–311. [Google Scholar] [CrossRef]
  95. Leszczyńska, K.; Namiot, A.; Fein, D.E.; Wen, Q.; Namiot, Z.; Savage, P.B.; Diamond, S.; Janmey, P.A.; Bucki, R. Bactericidal activities of the cationic steroid CSA-13 and the cathelicidin peptide LL-37 against Helicobacter pylori in simulated gastric juice. BMC Microbiol. 2009, 9, 187. [Google Scholar] [CrossRef]
  96. Bucki, R.; Sostarecz, A.G.; Byfield, F.J.; Savage, P.B.; Janmey, P.A. Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum. J. Antimicrob. Chemother. 2007, 60, 535–545. [Google Scholar] [CrossRef]
  97. Bucki, R.; Namiot, D.B.; Namiot, Z.; Savage, P.B.; Janmey, P.A. Salivary mucins inhibit antibacterial activity of the cathelicidin-derived LL-37 peptide but not the cationic steroid CSA-13. J. Antimicrob. Chemother. 2008, 62, 329–335. [Google Scholar] [CrossRef] [PubMed]
  98. Leszczyńska, K.; Namiot, A.; Cruz, K.; Byfield, F.J.; Won, E.; Mendez, G.; Sokołowski, W.; Savage, P.B.; Bucki, R.; Janmey, P.A. Potential of ceragenin CSA-13 and its mixture with pluronic F-127 as treatment of topical bacterial infections. J. Appl. Microbiol. 2011, 110, 229–238. [Google Scholar] [CrossRef] [PubMed]
  99. Hoppenes, M.A.; Sylvester, C.B.; Qureshi, A.T.; Scherr, T.; Czapski, D.R.; Duran, R.S.; Savage, P.B.; Hayes, D. Ceragenin mediated selectivity of antimicrobial silver nanoparticles. ACS Appl. Mater. Interfaces 2014, 6, 13900–13908. [Google Scholar] [CrossRef] [PubMed]
  100. Niemirowicz, K.; Surel, U.; Wilczewska, A.Z.; Mystkowska, J.; Piktel, E.; Gu, X.; Namiot, Z.; Kułakowska, A.; Savage, P.B.; Bucki, R. Bactericidal activity and biocompatibility of ceragenin-coated magnetic nanoparticles. J. Nanobiotechnol. 2015, 13, 32. [Google Scholar] [CrossRef] [PubMed]
  101. Kikuchi, K.; Bernard, E.M.; Sadownik, A.; Regen, S.L.; Armstrong, D. Antimicrobial activities of squalamine mimics. Antimicrob. Agents Chemother. 1997, 41, 1433–1438. [Google Scholar] [CrossRef]
  102. Saha, S.; Savage, P.B.; Bal, M. Enhancement of the efficacy of erythromycin in multiple antibiotic-resistant gram-negative bacterial pathogens. J. Appl. Microbiol. 2008, 105, 822–828. [Google Scholar] [CrossRef] [PubMed]
  103. Lavigne, J.-P.; Brunel, J.-M.; Chevalier, J.; Pages, J.-M. Squalamine, an original chemosensitizer to combat antibiotic-resistant Gram-negative bacteria. J. Antimicrob. Chemother. 2010, 65, 799–801. [Google Scholar] [CrossRef] [PubMed]
  104. Ding, B.; Yin, N.; Liu, Y.; Cardenas-Garcia, J.; Evanson, R.; Orsak, T.; Fan, M.; Turin, G.; Savage, P.B. Origins of cell selectivity of cationic steroid antibiotics. J. Am. Chem. Soc. 2004, 126, 13642–13648. [Google Scholar] [CrossRef]
  105. Zasloff, M. Formulations Comprising Aminosterols. U.S. Patent 8623416B2, 7 January 2014. [Google Scholar]
  106. Vicens, M.; Medarde, M.; Macias, R.I.R.; Larena, M.G.; Villafaina, A.; Serrano, M.A.; Marin, J.J.G. Novel cationic and neutral glycocholic acid and polyamine conjugates able to inhibit transporters involved in hepatic and intestinal bile acid uptake. Bioorg. Med. Chem. 2007, 15, 2359–2367. [Google Scholar] [CrossRef]
  107. Blagbrough, I.S.; Geall, A.J. Practical synthesis of unsymmetrical polyamine amides. Tetrahedron Lett. 1998, 39, 439–442. [Google Scholar] [CrossRef]
  108. Chen, W.-H.; Shao, X.-B.; Moellering, R.; Wennersten, C.; Regen, S.L. A bioconjugate approach toward squalamine mimics: Insight into the mechanism of biological action. Bioconjug. Chem. 2006, 17, 1582–1591. [Google Scholar] [CrossRef]
  109. Chen, W.-H.; Wennersten, C.; Moellering, R.C.; Regen, S.L. Towards squalamine mimics: Synthesis and antibacterial activities of head-to-tail dimeric sterol-polyamine conjugates. Chem. Biodivers. 2013, 10, 385–393. [Google Scholar] [CrossRef]
  110. Xiao, Q.; Sun, J.; Ju, Y.; Zhao, Y.; Cui, Y. Facile synthesis of 3β-cholesterol H-phosphonates. Chem. Lett. 2003, 32, 522–523. [Google Scholar] [CrossRef]
  111. Xiao, Q.; Sun, J.; Sun, Q.; Ju, Y.; Zhao, Y.F.; Cui, Y.X. Synthesis of AZT 5′-O-hydrogen phospholipids and their derivatives. Synthesis 2003, 2003, 107–112. [Google Scholar] [CrossRef]
  112. Ji, S.H.; Xiao, Q.; Ju, Y.; Zhao, Y. Synthesis of novel dimeric steroidal-nucleoside phosphoramidates. Chem. Lett. 2005, 34, 944–945. [Google Scholar] [CrossRef]
  113. Wu, D.; Ji, S.; Wu, Y.; Ju, Y.; Zhao, Y. Design, synthesis, and antitumor activity of bile acid-polyamine-nucleoside conjugates. Bioorg. Med. Chem. Lett. 2007, 17, 2983–2986. [Google Scholar] [CrossRef] [PubMed]
  114. Shawakfeh, K.Q.; Al-Said, N.H.; Abboushi, E.K. Synthesis of new di- and triamine diosgenin dimers. Tetrahedron 2010, 66, 1420–1423. [Google Scholar] [CrossRef]
  115. Bajaj, A.; Kondaiah, P.; Bhattacharya, S. Synthesis and gene transfection efficacies of PEI-cholesterol-based lipopolymers. Bioconjug. Chem. 2008, 19, 1640–1651. [Google Scholar] [CrossRef]
  116. Mishra, R.; Mishra, S. Updates in bile acid-bioactive molecule conjugates and their applications. Steroids 2020, 159, 108639–108654. [Google Scholar] [CrossRef]
  117. Errico, S.; Lucchesi, G.; Odino, D.; Muscat, S.; Capitini, C.; Bugelli, C.; Canale, C.; Ferrando, R.; Grasso, G.; Barbut, D.; et al. Making biological membrane resistant to the toxicity of misfolded protein oligomers: A lesson from trodusquemine. Nanoscale 2020, 12, 22596–22614. [Google Scholar] [CrossRef]
  118. Govers, R.M.T.; Brunel, J.M. Anti-Diabetic Aminosteroid. Derivatives. Patent WO2013057422A1, 25 April 2013. [Google Scholar]
  119. Pandey, Z.N.R.; Zhou, X.; Zaman, T.; Cruz, S.A.; Qin, Z.; Lu, M.; Keyhanian, K.; Brunel, J.M.; Stewart, A.F.R.; Chen, H.H. LMO4 is required to maintain hypothalamic insulin signaling. Biochem. Biophys. Res. Commun. 2014, 450, 666–672. [Google Scholar] [CrossRef]
  120. Blanchet, M.; Borselli, D.; Rodallec, A.; Peiretti, F.; Vidal, N.; Bolla, J.-M.M.; Digiorgio, C.; Morrison, K.R.; Wuest, W.M.; Brunel, J.M. Claramines: A New Class of Broad-Spectrum Antimicrobial Agents with Bimodal Activity. ChemMedChem 2018, 13, 1018–1027. [Google Scholar] [CrossRef]
  121. Mancini, I.; Defant, A.; Guella, G. Recent synthesis of marine natural products with antibacterial activities. Anti-Infect. Agents Med. Chem. 2007, 6, 17–48. [Google Scholar] [CrossRef]
  122. Pietras, R.J.; Weinberg, O.K. Antiangiogenic Steroids in Human Cancer Therapy. Evid. Based Complement. Alternat. Med. 2005, 2, 49–57. [Google Scholar] [CrossRef]
  123. Wnorowska, U.; Fiedoruk, K.; Piktel, E.; Prasad, S.V.; Sulik, M.; Janion, M.; Daniluk, T.; Savage, P.B.; Bucki, R. Nanoantibiotics containing membrane-active human cathelicidin LL-37 or synthetic ceragenins attached to the surface of magnetic nanoparticles as novel and innovative therapeutic tools: Current status and potential future applications. J. Nanobiotechnol. 2020, 18, 3. [Google Scholar] [CrossRef] [PubMed]
  124. Dias, C.; Rauter, A.P. Membrane-targeting antibiotics: Recent developments outside the peptide space. Future Med. Chem. 2019, 11, 211–228. [Google Scholar] [CrossRef]
  125. Butler, M.W.; Stahlschmidt, Z.R.; Ardia, D.R.; Davies, S.; Davis, J.; Guillette, L.J.; Johnson, N.; McCormick, S.D.; McGraw, K.J.; DeNardo, D.F. Thermal sensitivity of immune function: Evidence against a generalist-specialist trade-off among endothermic and ectothermic vertebrates. Am. Nat. 2013, 181, 761–774. [Google Scholar] [CrossRef] [PubMed]
  126. Savage, P.B.; Li, C.; Taotafa, U.; Ding, B.; Guan, Q. Antibacterial properties of cationic steroid antibiotics. FEMS Microbiol. Lett. 2002, 217, 1–7. [Google Scholar] [CrossRef] [PubMed]
  127. Alhanout, K.; Giorgio, C.D.; Meo, M.D.; Brunel, J.M. Non-Genotoxic Assessment of a Natural Antimicrobial Agent: Squalamine. Anti-Infect. Agents 2014, 12, 75–79. [Google Scholar] [CrossRef]
  128. Salmi, C.; Loncle, C.; Vidal, N.; Letourneux, Y.; Fantini, J.; Maresca, M.; Taïeb, N.; Pagès, J.M.; Brunel, J.M.; Page, J. Squalamine: An Appropriate Strategy against the Emergence of Multidrug Resistant Gram-Negative Bacteria? PLoS ONE 2008, 3, e2765. [Google Scholar] [CrossRef]
  129. Alhanout, K.; Djouhri, L.; Vidal, N.; Brunel, J.M.; Piarroux, R.; Ranque, S. In vitro activity of aminosterols against yeasts involved in blood stream infections. Med. Mycol. 2011, 49, 121–125. [Google Scholar] [CrossRef] [PubMed]
  130. Khelaifia, S.; Brunel, J.M.; Michel, J.B.; Drancourt, M. In-vitro archaeacidal activity of biocides against human-associated archaea. PLoS ONE 2013, 8, e62738. [Google Scholar] [CrossRef]
  131. Khelaifia, S.; Drancourt, M. Susceptibility of archaea to antimicrobial agents: Applications to clinical microbiology. Clin. Microbiol. Infect. 2012, 18, 841–848. [Google Scholar] [CrossRef]
  132. Nicol, M.; Mlouka, M.A.B.; Berthe, T.; Di Martino, P.; Jouenne, T.; Brunel, J.M.; Dé, E. Anti-persister activity of squalamine against Acinetobacter baumannii. Int. J. Antimicrob. Agents 2019, 53, 337–342. [Google Scholar] [CrossRef]
  133. Coulibaly, O.; Alhanout, K.; L’ollivier, C.; Brunel, J.M.; Thera, M.A.; Djimdé, A.A.; Doumbo, O.K.; Piarroux, R.; Ranque, S. In vitro activity of aminosterols against dermatophytes. Med. Mycol. 2013, 51, 309–312. [Google Scholar] [CrossRef]
  134. Kwon, D.H.; Lu, C.D. Polyamines increase antibiotic susceptibility in pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2006, 50, 1623–1627. [Google Scholar] [CrossRef] [PubMed]
  135. Kwon, D.H.; Lu, C.D. Polyamine effects on antibiotic susceptibility in bacteria. Antimicrob. Agents Chemother. 2007, 51, 2070–2077. [Google Scholar] [CrossRef]
  136. Alhanout, K.; Malesinki, S.; Vidal, N.; Peyrot, V.; Rolain, J.M.; Brunel, J.M. New insights into the antibacterial mechanism of action of squalamine. J. Antimicrob. Chemother. 2010, 65, 1688–1693. [Google Scholar] [CrossRef]
  137. Di Pasquale, E.; Salmi-Smail, C.; Brunel, J.M.; Sanchez, P.; Fantini, J.; Maresca, M. Biophysical studies of the interaction of squalamine and other cationic amphiphilic molecules with bacterial and eukaryotic membranes: Importance of the distribution coefficient in membrane selectivity. Chem. Phys. Lipids 2010, 163, 131–140. [Google Scholar] [CrossRef]
  138. Selinsky, B.S.; Smith, R.; Frangiosi, A.; Vonbaur, B.; Pedersen, L. Squalamine is not a proton ionophore. Biochim. Biophys. Acta-Biomembr. 2000, 1464, 135–141. [Google Scholar] [CrossRef]
  139. Russo, T.A.; Mylotte, D. Expression of the K54 and O4 specific antigen has opposite effects on the bactericidal activity of squalamine against an extraintestinal isolate of Escherichia coli. FEMS Microbiol. Lett. 1998, 162, 311–315. [Google Scholar] [CrossRef] [PubMed]
  140. Ghodbane, R.; Ameen, S.M.; Drancourt, M.; Brunel, J.M. In vitro antimicrobial activity of squalamine derivatives against mycobacteria. Tuberculosis 2013, 93, 565–566. [Google Scholar] [CrossRef]
  141. Asmar, S.; Drancourt, M. Chlorhexidine decontamination of sputum for culturing Mycobacterium tuberculosis. BMC Microbiol. 2015, 15, 155. [Google Scholar] [CrossRef]
  142. Djouhri-Bouktab, L.; Alhanout, K.; Andrieu, V.; Raoult, D.; Rolain, J.M.; Brunel, J.M. Squalamine ointment for Staphylococcus aureus skin decolonization in a mouse model. J. Antimicrob. Chemother. 2011, 66, 1306–1310. [Google Scholar] [CrossRef] [PubMed]
  143. Djouhri-Bouktab, L.; Alhanout, K.; Andrieu, V.; Stremler, N.; Dubus, J.C.; Raoult, D.; Rolain, J.M.; Brunel, J.M. Soluble squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients. J. Cyst. Fibros. 2012, 11, 555–559. [Google Scholar] [CrossRef]
  144. Hraiech, S.; Brégeon, F.; Brunel, J.M.; Rolain, J.M.; Lepidi, H.; Andrieu, V.; Raoult, D.; Papazian, L.; Roch, A. Antibacterial efficacy of inhaled squalamine in a rat model of chronic Pseudomonas aeruginosa pneumonia. J. Antimicrob. Chemother. 2012, 67, 2452–2458. [Google Scholar] [CrossRef] [PubMed]
  145. Coulibaly, O.; Thera, M.A.; Koné, A.K.; Siaka, G.; Traoré, P.; Djimdé, A.A.; Brunel, J.M.; Gaudart, J.; Piarroux, R.; Doumbo, O.K.; et al. A double-blind randomized placebo-controlled clinical trial of squalamine ointment for tinea capitis treatment. Mycopathologia 2015, 179, 187–193. [Google Scholar] [CrossRef]
  146. Zasloff, M.; Adams, A.P.; Beckerman, B.; Campbell, A.; Han, Z.; Luijten, E.; Meza, I.; Julander, J.; Mishra, A.; Qu, W.; et al. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential. Proc. Natl. Acad. Sci. USA 2011, 108, 15978–15983. [Google Scholar] [CrossRef]
  147. Ozaslan, M. Squalamine: May be an effective viral control. Int. J. Virol. 2012, 8, 285–287. [Google Scholar] [CrossRef]
  148. Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M.B.D.; Challa, P.K.; Kirkegaard, J.B.; Flagmeier, P.; Cohen, S.I.A.; Cascella, R.; et al. A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc. Natl. Acad. Sci. USA 2017, 114, E1009–E1017. [Google Scholar] [CrossRef]
  149. Limbocker, R.; Staats, R.; Chia, S.; Ruggeri, F.S.; Mannini, B.; Xu, C.K.; Perni, M.; Cascella, R.; Bigi, A.; Sasser, L.R.; et al. Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers. Front. Neurosci. 2021, 15, 541–558. [Google Scholar] [CrossRef] [PubMed]
  150. Perni, M.; Flagmeier, P.; Limbocker, R.; Cascella, R.; Aprile, F.A.; Galvagnion, C.; Heller, G.T.; Meisl, G.; Chen, S.W.; Kumita, J.R.; et al. Multistep inhibition of α-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine. ACS Chem. Biol. 2018, 13, 2308–2319. [Google Scholar] [CrossRef]
  151. Limbocker, R.; Mannini, B.; Ruggeri, F.S.; Cascella, R.; Xu, C.K.; Perni, M.; Chia, S.; Chen, S.W.; Habchi, J.; Bigi, A.; et al. Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism. Commun. Biol. 2020, 3, 435. [Google Scholar] [CrossRef] [PubMed]
  152. Errico, S.; Ramshini, H.; Capitini, C.; Canale, C.; Spaziano, M.; Barbut, D.; Calamai, M.; Zasloff, M.; Oropesa-Nuñez, R.; Vendruscolo, M.; et al. Quantitative Measurement of the Affinity of Toxic and Nontoxic Misfolded Protein Oligomers for Lipid Bilayers and of Its Modulation by Lipid Composition and Trodusquemine. ACS Chem. Neurosci. 2021, 12, 3189–3202. [Google Scholar] [CrossRef]
  153. Perni, M.; van der Goot, A.; Limbocker, R.; van Ham, T.J.; Aprile, F.A.; Xu, C.K.; Flagmeier, P.; Thijssen, K.; Sormanni, P.; Fusco, G.; et al. Comparative Studies in the A30P and A53T α-Synuclein C. Elegans Strains to Investigate the Molecular Origins of Parkinson’s Disease. Front. Cell Dev. Biol. 2021, 9, 492–502. [Google Scholar] [CrossRef]
  154. Limbocker, R.; Chia, S.; Ruggeri, F.S.; Perni, M.; Cascella, R.; Heller, G.T.; Meisl, G.; Mannini, B.; Habchi, J.; Michaels, T.C.T.; et al. Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes. Nat. Commun. 2019, 10, 225. [Google Scholar] [CrossRef] [PubMed]
  155. Odino, D.; Errico, S.; Canale, C.; Ferrando, R.; Chiti, F.; Relini, A. Interaction between Biomimetic Lipid Membranes and Trodusquemine: An Atomic Force Microscopy Study. Biophys. J. 2021, 120, 325a. [Google Scholar] [CrossRef]
  156. Zhang, L.; Qin, Z.; Sharmin, F.; Lin, W.; Ricke, K.M.; Zasloff, M.A.; Stewart, A.F.R.; Chen, H.-H. Tyrosine Phosphatase PTP1B Impairs Presynaptic NMDA Receptor-Mediated Plasticity in a Mouse Model of Alzheimer’s Disease. Neurobiol. Dis. 2021, 156, 105402. [Google Scholar] [CrossRef]
  157. Ricke, K.M.; Cruz, S.A.; Qin, Z.; Farrokhi, K.; Sharmin, F.; Zhang, L.; Zasloff, M.A.; Stewart, A.F.R.; Chen, H.-H. Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer’s Disease in Mice. J. Neurosci. 2020, 40, 1581–1593. [Google Scholar] [CrossRef]
  158. Limbocker, R.; Errico, S.; Barbut, D.; Knowles, T.P.J.; Vendruscolo, M.; Chiti, F.; Zasloff, M. Squalamine and Trodusquemine: Two natural products for neurodegenerative diseases, from physical chemistry to the clinic. Nat. Prod. Rep. 2021, 38. [Google Scholar] [CrossRef]
  159. Li, D.; Williams, J.I.; Pietras, R.J. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene 2002, 21, 2805–2814. [Google Scholar] [CrossRef]
  160. Akhter, S.; Nath, S.K.; Tse, G.M.; Williams, J.; Zasloff, M.; Donowitz, M. Squalamine, a novel cationic steroid, specifically inhibits the brush- border NA+/H+exchanger isoform NHE3. Am. J. Physiol.-Cell Physiol. 1999, 276, 136–144. [Google Scholar] [CrossRef]
  161. Williams, J.I.; Weitman, S.; Gonzalez, C.M.; Jundt, C.H.; Marty, J.; Stringer, S.D.; Holroyd, K.J.; Mclane, M.P.; Chen, Q.; Zasloff, M.; et al. Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies. Clin. Cancer Res. 2001, 7, 724–733. [Google Scholar]
  162. Teicher, B.A.; Williams, J.I.; Takeuchi, H.; Ara, G.; Herbst, R.S.; Buxton, D. Potential of the aminosterol, squalamine in combination therapy in the rat 13,762 mammary carcinoma and the murine Lewis lung carcinoma. Anticancer Res. 1998, 18, 2567–2573. [Google Scholar]
  163. Márquez-Garbán, D.C.; Gorrín-Rivas, M.; Chen, H.W.; Sterling, C.; Elashoff, D.; Hamilton, N.; Pietras, R.J. Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer cells with or without HER-2/neu overexpression. Cancer Lett. 2019, 449, 66–75. [Google Scholar] [CrossRef]
  164. Higgins, R.D.; Yan, Y.; Geng, Y.; Zasloff, M.; Williams, J.I. Regression of retinopathy by squalamine in a mouse model. Pediatr. Res. 2004, 56, 144–149. [Google Scholar] [CrossRef] [PubMed]
  165. Ciulla, T.A.; Criswell, M.H.; Danis, R.P.; Williams, J.I.; McLane, M.P.; Holroyd, K.J. Squalamine lactate reduces choroidal neovascularization in a laser-injury model in the rat. Retina 2003, 23, 808–814. [Google Scholar] [CrossRef]
  166. Genaidy, M.; Kazi, A.A.; Peyman, G.A.; Passos-Machado, E.; Farahat, H.G.; Williams, J.I.; Holroyd, K.J.; Blake, D.A. Effect of squalamine on iris neovascularization in monkeys. Retina 2002, 22, 772–778. [Google Scholar] [CrossRef] [PubMed]
  167. Kinter, A.; Hardy, E.; Kinney, W.J.; Chao, T.; Zasloff, M.; Fauci, A. MSI-1436, a novel aminosterol, inhibits HIV replication in vitro and in vivo infected mononuclear cells. In Proceedings of the 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, USA, 22–26 January 1997; p. 231. [Google Scholar]
  168. Alper, S.L.; Chernova, M.N.; Williams, J.; Zasloff, M.; Law, F.Y.; Knauf, P.A. Differential inhibition of AE1 and AE2 anion exchangers by oxonol dyes and by novel polyaminosterol analogs of the shark antibiotic squalamine. Biochem. Cell Biol. 1998, 76, 799–806. [Google Scholar] [CrossRef] [PubMed]
  169. Chernova, M.N.; Vandorpe, D.H.; Clark, J.S.; Williams, J.I.; Zasloff, M.A.; Jiang, L.; Alper, S.L. Apparent receptor-mediated activation of Ca2+-dependent conductive Cl transport by shark-derived polyaminosterols. Am. J. Physiol. Integr. Comp. Physiol. 2005, 289, R1644–R1658. [Google Scholar] [CrossRef]
  170. Zasloff, M.; Williams, J.; Kinney, W.; Anderson, M.; McLane, M. Therapeutic Uses for an Aminosterol. Compound. Patent WO9744044, 27 November 1997. [Google Scholar]
  171. Zasloff, M.; Williams, J.; Chen, Q.; Anderson, M.; Maeder, T.; Holroyd, K.; Jones, S.; Kinney, W.; Cheshire, K.; McLane, M. A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. Int. J. Obes. 2001, 25, 689–697. [Google Scholar] [CrossRef] [PubMed]
  172. Ahima, R.S.; Patel, H.R.; Takahashi, N.; Qi, Y.; Hileman, S.M.; Zasloff, M.A. Appetite suppression and weight reduction by a centrally active aminosterol. Diabetes 2002, 51, 2099–2104. [Google Scholar] [CrossRef]
  173. Roitman, M.F.; Wescott, S.; Cone, J.J.; McLane, M.P.; Wolfe, H.R. MSI-1436 reduces acute food intake without affecting dopamine transporter activity. Pharmacol. Biochem. Behav. 2010, 97, 138–143. [Google Scholar] [CrossRef] [PubMed]
  174. Cho, H. Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitam. Horm. 2013, 91, 405–424. [Google Scholar] [CrossRef]
  175. Bence, K.K.; Delibegovic, M.; Xue, B.; Gorgun, C.Z.; Hotamisligil, G.S.; Neel, B.G.; Kahn, B.B. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 2006, 12, 917–924. [Google Scholar] [CrossRef] [PubMed]
  176. Haj, F.G.; Zabolotny, J.M.; Kim, Y.B.; Kahn, B.B.; Neel, B.G. Liver-specific Protein-tyrosine Phosphatase 1B (PTP1B) Re-expression Alters Glucose Homeostasis of PTP1B–/–Mice. J. Biol. Chem. 2005, 280, 15038–15046. [Google Scholar] [CrossRef]
  177. Delibegovic, M.; Zimmer, D.; Kauffman, C.; Rak, K.; Hong, E.G.; Cho, Y.R.; Kim, J.K.; Kahn, B.B.; Neel, B.G.; Bence, K.K. Liver-specific deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes 2009, 58, 590–599. [Google Scholar] [CrossRef] [PubMed]
  178. Goldstein, B.J. Protein-tyrosine phosphatase 1B (PTP1B): A novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2001, 1, 265–275. [Google Scholar] [CrossRef]
  179. Koren, S.; Fantus, I.G. Inhibition of the protein tyrosine phosphatase PTP1B: Potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Pract. Res. Clin. Endocrinol. Metab. 2007, 21, 621–640. [Google Scholar] [CrossRef]
  180. Taylor, S. Inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B). Curr. Top. Med. Chem. 2003, 3, 759–782. [Google Scholar] [CrossRef]
  181. Lantz, K.A.; Hart, S.G.E.E.; Planey, S.L.; Roitman, M.F.; Ruiz-White, I.A.; Wolfe, H.R.; Mclane, M.P. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity 2010, 18, 1516–1523. [Google Scholar] [CrossRef]
  182. Pandey, N.R.; Zhou, X.; Qin, Z.; Zaman, T.; Gomez-Smith, M.; Keyhanian, K.; Anisman, H.; Brunel, J.M.; Stewart, A.F.R.; Chen, H.-H. The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling. J. Neurosci. 2013, 33, 12647–12655. [Google Scholar] [CrossRef] [PubMed]
  183. Krishnan, N.; Koveal, D.; Miller, D.H.; Xue, B.; Akshinthala, S.D.; Kragelj, J.; Jensen, M.R.; Gauss, C.-M.; Page, R.; Blackledge, M.; et al. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat. Chem. Biol. 2014, 10, 558–566. [Google Scholar] [CrossRef]
  184. Tonks, N.K. Protein tyrosine phosphatases—From housekeeping enzymes to master regulators of signal transduction. FEBS J. 2013, 280, 346–378. [Google Scholar] [CrossRef] [PubMed]
  185. Liu, H.; Wu, Y.; Zhu, S.; Liang, W.; Wang, Z.; Wang, Y.; Lv, T.; Yao, Y.; Yuan, D.; Song, Y. PTP1B promotes cell proliferation and metastasis through activating src and ERK1/2 in non-small cell lung cancer. Cancer Lett. 2015, 359, 218–225. [Google Scholar] [CrossRef]
  186. Lessard, L.; Labbé, D.P.; Deblois, G.; Beǵin, L.R.; Hardy, S.; Mes-Masson, A.M.; Saad, F.; Trotman, L.C.; Giguére, V.; Tremblay, M.L. PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer. Cancer Res. 2012, 72, 1529–1537. [Google Scholar] [CrossRef]
  187. Wang, J.; Liu, B.; Chen, X.; Su, L.; Wu, P.; Wu, J.; Zhu, Z. PTP1B expression contributes to gastric cancer progression. Med. Oncol. 2012, 29, 948–956. [Google Scholar] [CrossRef]
  188. Zhu, S.; Bjorge, J.D.; Fujita, D.J. PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation. Cancer Res. 2007, 67, 10129–10137. [Google Scholar] [CrossRef]
  189. Stuible, M.; Doody, K.M.; Tremblay, M.L. PTP1B and TC-PTP: Regulators of transformation and tumorigenesis. Cancer Metastasis Rev. 2008, 27, 215–230. [Google Scholar] [CrossRef] [PubMed]
  190. Julien, S.G.; Dubé, N.; Read, M.; Penney, J.; Paquet, M.; Han, Y.; Kennedy, B.P.; Muller, W.J.; Tremblay, M.L. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat. Genet. 2007, 39, 338–346. [Google Scholar] [CrossRef]
  191. Easty, D.; Gallagher, W.; Bennett, D.C. Protein tyrosine phosphatases, new targets for cancer therapy. Curr. Cancer Drug Targets 2006, 6, 519–532. [Google Scholar] [CrossRef] [PubMed]
  192. Fan, G.; Lin, G.; Lucito, R.; Tonks, N.K. Protein-tyrosine Phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells. J. Biol. Chem. 2013, 288, 24923–24934. [Google Scholar] [CrossRef] [PubMed]
  193. Stern, M.P. Diabetes and cardiovascular disease: The “common soil” hypothesis. Diabetes 1995, 44, 369–374. [Google Scholar] [CrossRef]
  194. Halcox, J.; Misra, A. Type 2 diabetes mellitus, metabolic syndrome, and mixed dyslipidemia: How similar, how different, and how to treat? Metab. Syndr. Relat. Disord. 2015, 13, 1–21. [Google Scholar] [CrossRef] [PubMed]
  195. Hamilton, S.J.; Watts, G.F. Endothelial dysfunction in diabetes: Pathogenesis, significance, and treatment. Rev. Diabet. Stud. 2013, 10, 133–156. [Google Scholar] [CrossRef]
  196. Bornfeldt, K.E.; Tabas, I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011, 14, 575–585. [Google Scholar] [CrossRef]
  197. Pansuria, M.; Xi, H.; Li, L.; Yang, X.F.; Wang, H. Insulin resistance, metabolic stress, and atherosclerosis. Front. Biosci. (Sch. Ed.) 2012, 4, 916–931. [Google Scholar] [CrossRef]
  198. Rask-Madsen, C.; Li, Q.; Freund, B.; Feather, D.; Abramov, R.; Wu, I.H.; Chen, K.; Yamamoto-Hiraoka, J.; Goldenbogen, J.; Sotiropoulos, K.B.; et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein e null mice. Cell Metab. 2010, 11, 379–389. [Google Scholar] [CrossRef]
  199. Thompson, D.; Morrice, N.; Grant, L.; Le Sommer, S.; Lees, E.K.; Mody, N.; Wilson, H.M.; Delibegovic, M. Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis. Clin. Sci. 2017, 131, 2489–2501. [Google Scholar] [CrossRef]
  200. Lu, B.; Atala, A. Small molecules and small molecule drugs in regenerative medicine. Drug Discov. Today 2014, 19, 801–808. [Google Scholar] [CrossRef]
  201. Smith, A.M.; Maguire-Nguyen, K.K.; Rando, T.A.; Zasloff, M.A.; Strange, K.B.; Yin, V.P. The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues. NPJ Regen. Med. 2017, 2, 4. [Google Scholar] [CrossRef] [PubMed]
  202. Khoury, Z.H.; Salameh, F. Trodusquemine: Potential Utility in Wound Regeneration. Regen. Eng. Transl. Med. 2021, 7, 118–119. [Google Scholar] [CrossRef]
  203. Griebel, G.; Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat. Rev. Drug Discov. 2013, 12, 667–687. [Google Scholar] [CrossRef] [PubMed]
  204. Qin, Z.; Zhou, X.; Pandey, N.R.; Vecchiarelli, H.A.; Stewart, C.A.; Zhang, X.; Lagace, D.C.; Brunel, J.M.; Béïque, J.C.; Stewart, A.F.R.; et al. Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 2015, 85, 1319–1331. [Google Scholar] [CrossRef]
  205. Krishnan, N.; Tonks, N.K. Anxious moments for the protein tyrosine phosphatase PTP1B. Trends Neurosci. 2015, 38, 462–465. [Google Scholar] [CrossRef] [PubMed]
  206. Qin, Z.; Zhang, L.; Cruz, S.A.; Stewart, A.F.R.; Chen, H.-H. Activation of Tyrosine Phosphatase PTP1B in Pyramidal Neurons Impairs Endocannabinoid Signaling by Tyrosine Receptor Kinase TrkB and Causes Schizophrenia-like Behaviors in Mice. Neuropsychopharmacology 2020, 45, 1884–1895. [Google Scholar] [CrossRef]
  207. Bhargava, P.; Marshall, J.L.; Dahut, W.; Rizvi, N.; Trocky, N.; Williams, J.I.; Hait, H.; Song, S.; Holroyd, K.J.; Hawkins, M.J. A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers. Clin. Cancer Res. 2001, 7, 3912–3919. [Google Scholar] [PubMed]
  208. Hao, D.; Hammond, L.A.; Eckhardt, S.G.; Patnaik, A.; Takimoto, C.H.; Schwartz, G.H.; Goetz, A.D.; Tolcher, A.W.; McCreery, H.A.; Mamun, K.; et al. A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor. Clin. Cancer Res. 2003, 9, 2465–2471. [Google Scholar] [PubMed]
  209. Herbst, R.S.; Hammond, L.A.; Carbone, D.P.; Tran, H.T.; Holroyd, K.J.; Desai, A.; Williams, J.I.; Bekele, B.N.; Hait, H.; Allgood, V.; et al. A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 2003, 9, 4108–4115. [Google Scholar]
  210. Ciulla, T.; Oliver, A.; Gast, M.J.; Evizon, S. Squalamine lactate for the treatment of age-related macular degeneration. Expert Rev. Ophthalmol. 2007, 2, 165–175. [Google Scholar] [CrossRef]
  211. Wroblewski, J.J.; Hu, A.Y. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study. Ophthalmic Surg. Lasers Imaging Retin. 2016, 47, 914–923. [Google Scholar] [CrossRef]
  212. Zeitz, O.; Joussen, A.M. Eye drops instead of intravitreal injections? The dream of treating macular diseases by topically administered drugs. Klin. Monbl. Augenheilkd. 2017, 234, 1088–1093. [Google Scholar] [CrossRef]
  213. Rosenfeld, P.J.; Feuer, W.J. Lessons from recent phase III trial failures: Don’t design phase III trials based on retrospective subgroup analyses from phase II trials. Ophthalmology 2018, 125, 1488–1491. [Google Scholar] [CrossRef]
  214. Kesen, M.R.; Cousins, S.W. Encyclopedia of the Eye, 1st ed.; Academic Press: New York, NY, USA, 2010; pp. 257–265. ISBN 9780123742032. [Google Scholar] [CrossRef]
  215. Deng, G.; Dewa, T.; Regen, S.L. A synthetic ionophore that recognizes negatively charged phospholipid membranes. J. Am. Chem. Soc. 1996, 118, 8975–8976. [Google Scholar] [CrossRef]
  216. Tessema, T.D.; Gassler, F.; Shu, Y.; Jones, S.; Selinsky, B.S. Structure-activity relationships in aminosterol antibiotics: The effect of stereochemistry at the 7-OH group. Bioorg. Med. Chem. Lett. 2013, 23, 3377–3381. [Google Scholar] [CrossRef]
  217. Brunel, J.M.; Blanchet, M.; Marc, J.P. Amide Derivatives of Squalamine for the Treatment of Infections. U.S. Patent 0780101B2, 22 September 2020. [Google Scholar]
  218. Qin, Z.; Pandey, N.R.; Zhou, X.; Stewart, C.A.; Hari, A.; Huang, H.; Stewart, A.F.R.; Brunel, J.M.; Chen, H.-H. Functional properties of Claramine: A novel PTP1B inhibitor and insulin-mimetic compound. Biochem. Biophys. Res. Commun. 2015, 458, 21–27. [Google Scholar] [CrossRef] [PubMed]
  219. Bartolomé, R.A.; Martín-Regalado, Á.; Jaén, M.; Zannikou, M.; Zhang, P.; de los Ríos, V.; Balyasnikova, I.V.; Casal, J.I. Protein Tyrosine Phosphatase-1B inhibition disrupts IL13Rα2-promoted invasion and metastasis in cancer cells. Cancers 2020, 12, 500. [Google Scholar] [CrossRef] [PubMed]
  220. Krishnan, N.; Konidaris, K.F.; Gasser, G.; Tonks, N.K. A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models. J. Biol. Chem. 2018, 293, 1517–1525. [Google Scholar] [CrossRef]
  221. Lou, Y.; Schapman, D.; Mercier, D.; Alexandre, S.; Dé, E.; Brunel, J.-M.; Kébir, N.; Thébault, P. Modification of poly(dimethyl siloxane) surfaces with an antibacterial claramine-derivative through click-chemistry grafting. React. Funct. Polym. 2022, 170, 105102. [Google Scholar] [CrossRef]
  222. Birteksoz-Tan, A.S.; Zeybek, Z.; Hacioglu, M.; Savage, P.B.; Bozkurt-Guzel, C. In vitro activities of antimicrobial peptides and ceragenins against Legionella pneumophila. J. Antibiot. 2019, 72, 291–297. [Google Scholar] [CrossRef]
  223. Hashemi, M.M.; Holden, B.S.; Durnas, B.; Buck, R.; Savage, P.B. Ceragenins as mimics of endogenous antimicrobial peptides. J. Antimicrob. Agents 2017, 3, 1–11. [Google Scholar] [CrossRef]
  224. Howell, M.D.; Streib, J.E.; Kim, B.E.; Lesley, L.J.; Dunlap, A.P.; Geng, D.; Feng, Y.; Savage, P.B.; Leung, D.Y.M. Ceragenins: A class of antiviral compounds to treat orthopox infections. J. Investig. Dermatol. 2009, 129, 2668–2675. [Google Scholar] [CrossRef]
  225. Moscoso, M.; Esteban-Torres, M.; Menéndez, M.; García, E. In vitro bactericidal and bacteriolytic activity of ceragenin CSA-13 against planktonic cultures and biofilms of Streptococcus pneumoniae and other pathogenic Streptococci. PLoS ONE 2014, 9, e101037. [Google Scholar] [CrossRef]
  226. Li, C.; Peters, A.S.; Meredith, E.L.; Allman, G.W.; Savage, P.B. Design and synthesis of potent sensitizers of gram-negative bacteria based on a cholic acid scaffolding. J. Am. Chem. Soc. 1998, 120, 2961–2962. [Google Scholar] [CrossRef]
  227. Oyardi, O.; Savage, P.B.; Akcali, A.; Erturan, Z.; Bozkurt-Guzel, C. Ceragenins exhibiting promising antimicrobial activity against various multidrug resistant Gram negative bacteria. Istanbul J. Pharm. 2019, 48, 68–72. [Google Scholar] [CrossRef]
  228. Dao, A.; Mills, R.J.; Kamble, S.; Savage, P.B.; Little, D.G.; Schindeler, A. The application of ceragenins to orthopedic surgery and medicine. J. Orthop. Res. 2020, 38, 1883–1894. [Google Scholar] [CrossRef]
  229. Mills, R.J.; Boyling, A.; Cheng, T.L.; Peacock, L.; Savage, P.B.; Tägil, M.; Little, D.G.; Schindeler, A. CSA-90 reduces periprosthetic joint infection in a novel rat model challenged with local and systemic Staphylococcus aureus. J. Orthop. Res. 2020, 38, 2065–2073. [Google Scholar] [CrossRef]
  230. Williams, D.L.; Sinclair, K.D.; Jeyapalina, S.; Bloebaum, R.D. Characterization of a novel active release coating to prevent biofilm implant-related infections. J. Biomed. Mater. Res. Part B Appl. Biomater. 2013, 101, 1078–1089. [Google Scholar] [CrossRef]
  231. Sinclair, K.D.; Pham, T.X.; Williams, D.L.; Farnsworth, R.W.; Loc-Carrillo, C.M.; Bloebaum, R.D. Model development for determining the efficacy of a combination coating for the prevention of perioperative device related infections: A pilot study. J. Biomed. Mater. Res. Part B Appl. Biomater. 2013, 101, 1143–1153. [Google Scholar] [CrossRef]
  232. Sinclair, K.D.; Pham, T.X.; Farnsworth, R.W.; Williams, D.L.; Loc-Carrillo, C.; Horne, L.A.; Ingebretsen, S.H.; Bloebaum, R.D. Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections. J. Biomed. Mater. Res. Part A 2012, 100, 2732–2738. [Google Scholar] [CrossRef] [PubMed]
  233. Gu, X.; Jennings, J.D.; Snarr, J.; Chaudhary, V.; Pollard, J.E.; Savage, P.B. Optimization of ceragenins for prevention of bacterial colonization of hydrogel contact lenses. Investig. Opthalmol. Vis. Sci. 2013, 54, 6217–6223. [Google Scholar] [CrossRef]
  234. Jueati, R.; Jittikoon, J.; Vajragupta, O.; Pimthon, J. Molecular dynamics and experimental investigations of membrane perturbation by ceragenin CSA-13. Mahidol Univ. J. Pharm. Sci. 2012, 39, 25–32. [Google Scholar]
  235. Bozkurt-Guzel, C.; Savage, P.B.; Gerceker, A.A. In vitro activities of the novel ceragenin CSA-13, alone or in combination with colistin, tobramycin, and ciprofloxacin, against Pseudomonas aeruginosa strains isolated from cystic fibrosis patients. Chemotherapy 2011, 57, 505–510. [Google Scholar] [CrossRef]
  236. Mitchell, G.; Silvis, M.R.; Talkington, K.C.; Budzik, J.M.; Dodd, C.E.; PbBuba, J.; Oki, E.A.; Trotta, K.L.; Licht, D.; Jimenez-Morales, D.; et al. Ceragenins and antimicrobial peptides kill bacteria through distinct mechanisms. bioRxiv 2020. [Google Scholar] [CrossRef]
  237. Damar-Çelik, D.; Mataracı-Kara, E.; Savage, P.B.; Özbek-Çelik, B. Antibacterial and antibiofilm activities of ceragenins against Achromobacter species isolated from cystic fibrosis patients. J. Chemother. 2021, 33, 216–227. [Google Scholar] [CrossRef] [PubMed]
  238. Hashemi, M.; Mmuoegbulam, A.; Holden, B.; Coburn, J.; Wilson, J.; Taylor, M.; Reiley, J.; Baradaran, D.; Stenquist, T.; Deng, S.; et al. Susceptibility of Multidrug-Resistant Bacteria, isolated from water and plants in Nigeria, to Ceragenins. Int. J. Environ. Res. Public Health 2018, 15, 2758. [Google Scholar] [CrossRef] [PubMed]
  239. Hashemi, M.M.; Holden, B.S.; Coburn, J.; Taylor, M.F.; Weber, S.; Hilton, B.; Zaugg, A.L.; McEwan, C.; Carson, R.; Andersen, J.L.; et al. Proteomic analysis of resistance of gram-negative bacteria to chlorhexidine and impacts on susceptibility to colistin, antimicrobial peptides, and ceragenins. Front. Microbiol. 2019, 10, 210. [Google Scholar] [CrossRef]
  240. Hacioglu, M.; Oyardi, O.; Bozkurt-Guzel, C.; Savage, P.B. Antibiofilm activities of ceragenins and antimicrobial peptides against fungal-bacterial mono and multispecies biofilms. J. Antibiot. 2020, 73, 455–462. [Google Scholar] [CrossRef]
  241. Hacioglu, M.; Haciosmanoglu, E.; Birteksoz-Tan, A.S.; Bozkurt-Guzel, C.; Savage, P.B. Effects of ceragenins and conventional antimicrobials on Candida albicans and Staphylococcus aureus mono and multispecies biofilms. Diagn. Microbiol. Infect. Dis. 2019, 95, 114863. [Google Scholar] [CrossRef] [PubMed]
  242. Olekson, M.A.; You, T.; Savage, P.B.; Leung, K.P. Antimicrobial ceragenins inhibit biofilms and affect mammalian cell viability and migration in vitro. FEBS Open Bio 2017, 7, 953–967. [Google Scholar] [CrossRef]
  243. Savage, P.B. 846 Effects of Ceragenins on Pseudomonas Aeruginosa biofilm formation in burn wounds in a porcine model. J. Burn Care Res. 2020, 41, S262–S263. [Google Scholar] [CrossRef]
  244. Piktel, E.; Pogoda, K.; Roman, M.; Niemirowicz, K.; Tokajuk, G.; Wróblewska, M.; Szynaka, B.; Kwiatek, W.M.; Savage, P.B.; Bucki, R. Sporicidal activity of ceragenin CSA-13 against Bacillus subtilis. Sci. Rep. 2017, 7, 44452. [Google Scholar] [CrossRef] [PubMed]
  245. Ghosh, S.; Joseph, G.; Korza, G.; He, L.; Yuan, J.H.; Dong, W.; Setlow, B.; Li, Y.Q.; Savage, P.B.; Setlow, P. Effects of the microbicide ceragenin CSA-13 on and properties of Bacillus subtilis spores prepared on two very different media. J. Appl. Microbiol. 2019, 127, 109–120. [Google Scholar] [CrossRef] [PubMed]
  246. Chmielewska, S.J.; Skłodowski, K.; Piktel, E.; Suprewicz, Ł.; Fiedoruk, K.; Daniluk, T.; Wolak, P.; Savage, P.B.; Bucki, R. NDM-1 carbapenemase-producing Enterobacteriaceae are highly susceptible to ceragenins CSA-13, CSA-44, and CSA-131. Infect. Drug Resist. 2020, 13, 3277–3294. [Google Scholar] [CrossRef]
  247. Bozkurt-Guzel, C.; Inci, G.; Oyardi, O.; Savage, P.B. Synergistic activity of ceragenins against carbapenem-resistant Acinetobacter baumannii strains in both checkerboard and dynamic time-kill assays. Curr. Microbiol. 2020, 77, 1419–1428. [Google Scholar] [CrossRef]
  248. Wnorowska, U.; Piktel, E.; Durnaś, B.; Fiedoruk, K.; Savage, P.B.; Bucki, R.; Durna, B.; Fiedoruk, K.; Savage, P.B.; Bucki, R. Use of ceragenins as a potential treatment for urinary tract infections. BMC Infect. Dis. 2019, 19, 369. [Google Scholar] [CrossRef]
  249. Ozbek-Celik, B.; Damar-Celik, D.; Mataraci-Kara, E.; Bozkurt-Guzel, C.; Savage, P.B. Comparative in vitro activities of first and second-generation ceragenins alone and in combination with antibiotics against Multidrug-Resistant Klebsiella pneumoniae strains. Antibiotics 2019, 8, 130. [Google Scholar] [CrossRef]
  250. Durnaś, B.; Wnorowska, U.; Pogoda, K.; Deptuła, P.; Wątek, M.; Piktel, E.; Głuszek, S.; Gu, X.; Savage, P.B.; Niemirowicz, K.; et al. Candidacidal activity of selected ceragenins and human cathelicidin LL-37 in experimental settings mimicking infection sites. PLoS ONE 2016, 11, e0157242. [Google Scholar] [CrossRef]
  251. Hashemi, M.M.; Rovig, J.; Holden, B.S.; Taylor, M.F.; Weber, S.; Wilson, J.; Hilton, B.; Zaugg, A.L.; Ellis, S.W.; Yost, C.D.; et al. Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms. J. Antimicrob. Chemother. 2018, 73, 1537–1545. [Google Scholar] [CrossRef]
  252. Hacioglu, M.; Guzel, C.B.; Savage, P.B.; Tan, A.S.B. Antifungal susceptibilities, in vitro production of virulence factors and activities of ceragenins against Candida spp. isolated from vulvovaginal candidiasis. Med. Mycol. 2019, 57, 291–299. [Google Scholar] [CrossRef]
  253. Niemirowicz, K.; Piktel, E.; Wilczewska, A.; Markiewicz, K.; Durnaś, B.; Wątek, M.; Puszkarz, I.; Wróblewska, M.; Niklińska, W.; Savage, P.B.; et al. Core–shell magnetic nanoparticles display synergistic antibacterial effects against Pseudomonas aeruginosa and Staphylococcus aureus when combined with cathelicidin LL-37 or selected ceragenins. Int. J. Nanomed. 2016, 11, 5443–5455. [Google Scholar] [CrossRef]
  254. Durnaś, B.; Piktel, E.; Wątek, M.; Wollny, T.; Góźdź, S.; Smok-Kalwat, J.; Niemirowicz, K.; Savage, P.B.; Bucki, R. Anaerobic bacteria growth in the presence of cathelicidin LL-37 and selected ceragenins delivered as magnetic nanoparticles cargo. BMC Microbiol. 2017, 17, 167. [Google Scholar] [CrossRef]
  255. Niemirowicz, K.; Durnaś, B.; Tokajuk, G.; Piktel, E.; Michalak, G.; Gu, X.; Kułakowska, A.; Savage, P.B.; Bucki, R. Formulation and candidacidal activity of magnetic nanoparticles coated with cathelicidin LL-37 and ceragenin CSA-13. Sci. Rep. 2017, 7, 4610. [Google Scholar] [CrossRef]
  256. Hashemi, M.; Holden, B.; Taylor, M.; Wilson, J.; Coburn, J.; Hilton, B.; Nance, T.; Gubler, S.; Genberg, C.; Deng, S.; et al. Antibacterial and antifungal activities of poloxamer Mmicelles containing ceragenin CSA-131 on ciliated tissues. Molecules 2018, 23, 596. [Google Scholar] [CrossRef] [PubMed]
  257. Piktel, E.; Bucki, R. Therapeutic potential of ceragenins and nanosystems containing membrane active compounds in the anti-cancer therapies. Postępy Pol. Med. Farm. 2019, 6, 21–32. [Google Scholar] [CrossRef]
  258. Kuroda, K.; Fukuda, T.; Okumura, K.; Yoneyama, H.; Isogai, H.; Savage, P.B.; Isogai, E. Ceragenin CSA-13 induces cell cycle arrest and antiproliferative effects in wild-type and p53 null mutant HCT116 colon cancer cells. Anticancer Drugs 2013, 24, 826–834. [Google Scholar] [CrossRef]
  259. Piktel, E.; Prokop, I.; Wnorowska, U.; Król, G.; Cieśluk, M.; Niemirowicz, K.; Savage, P.B.; Bucki, R. Ceragenin CSA-13 as free molecules and attached to magnetic nanoparticle surfaces induce caspase-dependent apoptosis in human breast cancer cells via disruption of cell oxidative balance. Oncotarget 2018, 9, 21904–21920. [Google Scholar] [CrossRef] [PubMed]
  260. Niemirowicz, K.; Prokop, I.; Wilczewska, A.; Wnorowska, U.; Piktel, E.; Wątek, M.; Savage, P.; Bucki, R. Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells. Int. J. Nanomed. 2015, 10, 3843–3853. [Google Scholar] [CrossRef] [PubMed]
  261. Piktel, E.; Markiewicz, K.H.; Wilczewska, A.Z.; Daniluk, T.; Chmielewska, S.; Niemirowicz-Laskowska, K.; Mystkowska, J.; Paprocka, P.; Savage, P.B.; Bucki, R. Quantification of synergistic effects of ceragenin CSA-131 combined with iron oxide magnetic nanoparticles against cancer cells. Int. J. Nanomed. 2020, 15, 4573–4589. [Google Scholar] [CrossRef]
  262. Kazakova, O.B.; Giniyatullina, G.V.; Medvedeva, N.I.; Tolstikov, G.A. Synthesis of a triterpene-spermidine conjugate. Russ. J. Org. Chem. 2012, 48, 1366–1369. [Google Scholar] [CrossRef]
  263. Kazakova, O.B.; Giniyatullina, G.V.; Tolstikov, G.A.; Baikova, I.P.; Zaprutko, L.; Apryshko, G.N. Synthesis and antitumor activity of aminopropoxy derivatives of betulin, erythrodiol, and uvaol. Russ. J. Bioorg. Chem. 2011, 37, 369–379. [Google Scholar] [CrossRef]
  264. Giniyatullina, G.V.; Smirnova, I.E.; Kazakova, O.B.; Yavorskaya, N.P.; Golubeva, I.S.; Zhukova, O.S.; Pugacheva, R.B.; Apryshko, G.N.; Poroikov, V.V. Synthesis and anticancer activity of aminopropoxytriterpenoids. Med. Chem. Res. 2015, 24, 3423–3436. [Google Scholar] [CrossRef]
  265. Kazakova, O.B.; Giniyatullina, G.V.; Mustafin, A.G.; Babkov, D.A.; Sokolova, E.V.; Spasov, A.A. Evaluation of cytotoxicity and α-glucosidase inhibitory activity of amide and polyamino-derivatives of lupane triterpenoids. Molecules 2020, 25, 4833–4856. [Google Scholar] [CrossRef]
  266. Giniyatullina, G.V.; Flekhter, O.B.; Tolstikov, G.A. Synthesis of squalamine analogues on the basis of lupane triterpenoids. Mendeleev Commun. 2009, 19, 32–33. [Google Scholar] [CrossRef]
  267. Giniyatullina, G.V.; Kazakova, O.B. Synthesis of O- and N-aminopropyltriterpenoids based on messagenin. Chem. Nat. Compd. 2018, 54, 913–916. [Google Scholar] [CrossRef]
  268. Giniyatullina, G.V.; Kazakova, O.B. Synthesis and cytotoxicity of lupane mono- and bis-piperazinylamides. Chem. Nat. Compd. 2021, 57, 698–705. [Google Scholar] [CrossRef]
  269. Giniyatullina, G.V.; Kazakova, O.B.; Sorokina, I.V.; Zhukova, N.A.; Tolstikova, T.G.; Tolstikov, G.A. Synthesis of aminopropylamino derivatives of betulinic and oleanolic acids. Russ. J. Bioorg. Chem. 2013, 39, 329–337. [Google Scholar] [CrossRef]
  270. Kazakova, O.B.; Giniyatullina, G.V.; Tolstikov, G.A. Synthesis of A-secomethylenamino- and substituted amidoximotriterpenoids. Russ. J. Bioorg. Chem. 2011, 37, 619–625. [Google Scholar] [CrossRef]
  271. Borselli, D.; Lieutaud, A.; Thefenne, H.; Garnotel, J.; Pagès, E.M.; Brunel, J.M.; Bolla, J.M. Polyamino-isoprenic derivatives block intrinsic resistance of P. aeruginosa to doxycycline and chloramphenicol in vitro. PLoS ONE 2016, 11, e0154490. [Google Scholar] [CrossRef]
  272. Berti, L.; Bolla, J.M.; Brunel, J.M.; Casanova, J.P.F.; Lorenzi, V. Use of Polyaminoisoprenyl Derivatives in Antibiotic or Antiseptic. Treatment. Patent WO2012113891Al, 30 August 2012. [Google Scholar]
  273. Lieutaud, A.; Pieri, C.; Bolla, J.M.; Brunel, J.M. New polyaminoisoprenyl antibiotics enhancers against two multidrug-resistant gram-negative bacteria from Enterobacter and Salmonella species. J. Med. Chem. 2020, 63, 10496–10508. [Google Scholar] [CrossRef] [PubMed]
  274. Heller, L.; Knorrscheidt, A.; Flemming, F.; Wiemann, J.; Sommerwerk, S.; Pavel, I.Z.; Al-Harrasi, A.; Csuk, R. Synthesis and proapoptotic activity of oleanolic acid derived amides. Bioorg. Chem. 2016, 68, 137–151. [Google Scholar] [CrossRef] [PubMed]
  275. Giniyatullina, G.V.; Kazakova, O.B.; Salimova, E.V.; Tolstikov, G.A. Synthesis of new betulonic and oleanonic acid amides. Chem. Nat. Compd. 2011, 47, 68–72. [Google Scholar] [CrossRef]
  276. Emmerich, D.; Vanchanagiri, K.; Baratto, L.C.; Schmidt, H.; Paschke, R. Synthesis and studies of anticancer properties of lupane-type triterpenoid derivatives containing a cisplatin fragment. Eur. J. Med. Chem. 2014, 2014, 460–466. [Google Scholar] [CrossRef]
  277. Csuk, R.; Schwarz, S.; Kluge, R.; Ströhl, D. Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid. Eur. J. Med. Chem. 2010, 45, 5718–5723. [Google Scholar] [CrossRef] [PubMed]
  278. Kazakova, O.B.; Giniyatullina, G.V.; Medvedeva, N.I.; Tolstikov, G.A.; Apryshko, G.N. Synthesis and cytotoxicity of triterpene seven-membered cyclic amines. Russ. J. Bioorg. Chem. 2014, 40, 198–205. [Google Scholar] [CrossRef] [PubMed]
  279. Medvedeva, N.I.; Kazakova, O.B.; Lopatina, T.V.; Smirnova, I.E.; Giniyatullina, G.V.; Baikova, I.P.; Kataev, V.E. Synthesis and antimycobacterial activity of triterpenic A-ring azepanes. Eur. J. Med. Chem. 2018, 143, 464–472. [Google Scholar] [CrossRef] [PubMed]
  280. Lia, T.; Fana, P.; Ye, Y.; Luo, Q.; Lou, H. Ring A-modified derivatives from the natural triterpene 3-O-acetyl-11-keto-β-boswellic acid and their cytotoxic activity. Anti-Cancer Agents Med. Chem. 2017, 17, 1153–1167. [Google Scholar] [CrossRef]
  281. Antimonova, A.N.; Uzenkova, N.V.; Petrenko, N.I.; Shakirov, M.M.; Shul’ts, E.E.; Tolstikov, G.A. Synthesis of betulonic acid amides. Chem. Nat. Compd. 2008, 44, 327–333. [Google Scholar] [CrossRef]
  282. Bai, K.K.; Yu, Z.; Chen, F.L.; Li, F.; Li, W.Y.; Guo, Y.H. Synthesis and evaluation of ursolic acid derivatives as potent cytotoxic agents. Bioorg. Med. Chem. Lett. 2012, 22, 2488–2493. [Google Scholar] [CrossRef]
  283. Ma, C.M.; Cai, S.Q.; Cui, J.R.; Wang, R.Q.; Tu, P.F.; Hattori, M.; Daneshtalab, M. The cytotoxic activity of ursolic acid derivatives. Eur. J. Med. Chem. 2005, 40, 582–589. [Google Scholar] [CrossRef]
  284. Schwarz, S.; Lucas, S.D.; Sommerwerk, S.; Csuk, R. Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases. Bioorg. Med. Chem. 2014, 22, 3370–3378. [Google Scholar] [CrossRef] [PubMed]
  285. Cheng, S.Y.; Wang, C.M.; Cheng, H.L.; Chen, H.J.; Hsu, Y.M.; Lin, Y.C.; Chou, C.-H. Biological activity of oleanane triterpene derivatives obtained by chemical derivatization. Molecules 2013, 18, 13003–13019. [Google Scholar] [CrossRef] [PubMed]
  286. Gu, W.; Hao, Y.; Zhang, G.; Wang, S.F.; Miao, T.T.; Zhang, K.P. Synthesis, in vitro antimicrobial and cytotoxic activities of new carbazole derivatives of ursolic acid. Bioorg. Med. Chem. Lett. 2015, 25, 554–557. [Google Scholar] [CrossRef]
  287. Liang, Z.; Zhang, L.; Li, L.; Liu, J.; Li, H.; Zhang, L.; Chen, L.; Cheng, K.; Zheng, M.; Wen, X.; et al. Identification of pentacyclic triterpenes derivatives as potent inhibitors against glycogen phosphorylase based on 3D-QSAR studies. Eur. J. Med. Chem. 2011, 46, 2011–2021. [Google Scholar] [CrossRef] [PubMed]
  288. Lan, P.; Wang, J.; Zhang, D.M.; Shu, C.; Cao, H.H.; Sun, P.H.; Wu, X.M.; Ye, W.C.; Chen, W.M. Synthesis and antiproliferative evaluation of 23-hydroxybetulinic acid derivatives. Eur. J. Med. Chem. 2011, 46, 2490–2502. [Google Scholar] [CrossRef]
  289. Tian, T.; Liu, X.; Lee, E.S.; Sun, J.; Feng, Z.; Zhao, L.; Zhao, C. Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents. Arch. Pharm. Res. 2017, 40, 458–468. [Google Scholar] [CrossRef]
  290. Urano, E.; Ablan, S.D.; Mandt, R.; Pauly, G.T.; Sigano, D.M.; Schneider, J.P.; Martin, D.E.; Nitz, T.J.; Wild, C.T.; Freed, E.O. Alkyl amine bevirimat derivatives are potent and broadly active HIV-1 maturation inhibitors. Antimicrob. Agents Chemother. 2016, 60, 190–197. [Google Scholar] [CrossRef]
  291. Salvador, J.A.R.; Leal, A.S.; Valdeira, A.S.; Gonçalves, B.M.F.; Alho, D.P.S.; Figueiredo, S.A.C.; Silvestre, S.M.; Mendes, V.I.S. Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment. Eur. J. Med. Chem. 2017, 142, 95–130. [Google Scholar] [CrossRef]
  292. Luo, S.; Li, P.; Li, S.; Du, Z.; Hu, X.; Fu, Y.; Zhang, Z. N, N-Dimethyl tertiary amino group mediated dual pancreas- and lung-targeting therapy against acute pancreatitis. Mol. Pharm. 2017, 14, 1771–1781. [Google Scholar] [CrossRef]
  293. Rodŕigues-Hernández, D.; Demuner, A.J.; Barbosa, L.C.A.; Csuk, R.; Heller, L. Hederagenin as a triterpene template for the development of new antitumor compounds. Eur. J. Med. Chem. 2015, 105, 57–62. [Google Scholar] [CrossRef]
  294. Ortiz, A.; Soumeillant, M.; Savage, S.A.; Strotman, N.A.; Haley, M.; Benkovics, T.; Nye, J.; Xu, Z.; Tan, Y.; Ayers, S.; et al. Synthesis of HIV-maturation inhibitor BMS-955176 from betulin by an enabling oxidation strategy. J. Org. Chem. 2017, 82, 4958–4963. [Google Scholar] [CrossRef]
  295. Spivak, A.; Khalitova, R.; Nedopekina, D.; Dzhemileva, L.; Yunusbaeva, M.; Odinokov, V.; D’yakonov, V.; Dzhemilev, U. Synthesis and evaluation of anticancer activities of novel C-28 guanidine-functionalized triterpene acid derivatives. Molecules 2018, 23, 3000. [Google Scholar] [CrossRef] [PubMed]
  296. Kahnt, M.; Hoenke, S.; Fischer, L.; Al-Harrasi, A.; Csuk, R. Synthesis and cytotoxicity evaluation of DOTA-conjugates of ursolic acid. Molecules 2019, 24, 2254–2273. [Google Scholar] [CrossRef] [PubMed]
  297. Cao, M.; Gao, Y.; Zhan, M.; Qiu, N.; Piao, Y.; Zhou, Z.; Shen, Y. Glycyrrhizin acid and glycyrrhetinic acid modified polyethyleneimine for targeted DNA delivery to hepatocellular carcinoma. Int. J. Mol. Sci. 2019, 20, 5074–5098. [Google Scholar] [CrossRef]
  298. Bildziukevich, U.; Malík, M.; Özdemir, Z.; Rárová, L.; Janovská, L.; Šlouf, M.; Šaman, D.; Šarek, J.; Wimmer, Z. Spermine amides of selected triterpenoid acids: Dynamic supramolecular systems formation influences cytotoxicity of the drugs. J. Mater. Chem. B 2020, 8, 484–491. [Google Scholar] [CrossRef] [PubMed]
  299. Spivak, A.Y.; Khalitova, R.R.; Nedopekina, D.A.; Gubaidullin, R.R. Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation. Steroids 2020, 154, 108530–108542. [Google Scholar] [CrossRef]
  300. Bildziukevich, U.; Vida, N.; Rárová, L.; Kolár, M.; Šaman, D.; Havlíček, L.; Drašar, P.; Wimmer, Z. Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation. Steroids 2015, 100, 27–35. [Google Scholar] [CrossRef] [PubMed]
  301. Bildziukevich, U.; Kaletová, E.; Šaman, D.; Sievänen, E.; Kolehmainen, E.T.; Šlouf, M.; Wimmer, Z. Spectral and microscopic study of self-assembly of novel cationic spermine amides of betulinic acid. Steroids 2017, 117, 90–96. [Google Scholar] [CrossRef]
  302. Kazakova, O.B.; Brunel, J.M.; Khusnutdinova, E.F.; Negrel, S.; Giniyatullina, G.V.; Lopatina, T.V.; Petrova, A.V. A-ring modified triterpenoids and their spermidine-aldimines with strong antibacterial activity. Molbank 2019, 2019, M1078–M1086. [Google Scholar] [CrossRef]
  303. Qian, K.; Kuo, R.; Chen, C.; Huang, L.; Morris-Natschke, S.L.; Lee, K. Anti-AIDS agents 81. Design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors. J. Med. Chem. 2010, 53, 3133–3141. [Google Scholar] [CrossRef]
  304. Rodríguez-Hernández, D.; Barbosa, L.C.A.; Demuner, A.J.; Martins, J.P.A.; Fischer (nee Heller), L.; Csuk, R. Hederagenin amide derivatives as potential antiproliferative agents. Eur. J. Med. Chem. 2019, 168, 436–446. [Google Scholar] [CrossRef] [PubMed]
  305. Özdemir, Z.; Saman, D.; Bertula, K.; Lahtinen, M.; Bednarova, L.; Pazderkova, M.; Rarova, L.; Nonappa; Wimmer, Z. Rapid self-healing and thixotropic organogelation of amphiphilic oleanolic acid−spermine conjugates. Langmuir 2021, 37, 2693–2706. [Google Scholar] [CrossRef] [PubMed]
  306. Kazakova, O.; Rubanik, L.; Smirnova, I.; Poleschuk, N.; Petrova, A.; Kapustsina, Y.; Baikova, I.; Tret’yakova, E.; Khusnutdinova, E. Synthesis and in vitro activity of oleanolic acid derivatives against Chlamydia trachomatis and Staphylococcus aureus. Med. Chem. Res. 2021, 30, 1408–1418. [Google Scholar] [CrossRef]
  307. Khusnutdinova, E.F.; Sinou, V.; Babkov, D.A.; Kazakova, O.B.; Brunel, J.M. Development of new antimicrobial oleanonic acid polyamine conjugates. Antibiotics 2022, 11, 94. [Google Scholar] [CrossRef]
Figure 1. The structures of squalamine 1, trodusquemine 2 and steroid polyamines 3–9.
Figure 1. The structures of squalamine 1, trodusquemine 2 and steroid polyamines 3–9.
Ijms 23 01075 g001
Scheme 1. Reagents and conditions: (a) 1. (COCl)2, CH2Cl2, 40 °C, 2 h; 2. (CH3)2CHCdBr, benzene, 25 °C, 1 h; 3. Ca(BH4)2, THF, 25 °C, 5 h; 4. TBDMsCl, imidazol, CH2Cl2, 16 °C, 16 h; 5. Cr(CO)6, t-BuOOH, CH3CN, 50 °C, 12 h; 6. Li, NH3, Et2O, −78 °C, 10 min; (b) 1. K-selectride, THF, −50 °C, 5 h; 2. NaCN, MeOH, 60 °C, 8 h; 3. (t-BuO)3Al, hexane, toluene, 110 °C, 20 h; (c) 1. C6H5CH2ONH2 HCl, Py, 115 °C, 16 h; 2. LiAlH4, Et2O, 35 °C, 16 h; (d) K2CO3, CH3CN, 50 °C, 20 h; (e) 1. C6H5CH2OCOCl, NaOH, THF, 0–25 °C, 4 h; 2. Na, NH3, THF, −78 °C, 18 h; 3. LiAlH4, Et2O, 35 °C, 6 h; 3. HCl, EtOH, 25 °C, 3 h; 4. SO3-Py, Py, 75 °C, 2 h.
Scheme 1. Reagents and conditions: (a) 1. (COCl)2, CH2Cl2, 40 °C, 2 h; 2. (CH3)2CHCdBr, benzene, 25 °C, 1 h; 3. Ca(BH4)2, THF, 25 °C, 5 h; 4. TBDMsCl, imidazol, CH2Cl2, 16 °C, 16 h; 5. Cr(CO)6, t-BuOOH, CH3CN, 50 °C, 12 h; 6. Li, NH3, Et2O, −78 °C, 10 min; (b) 1. K-selectride, THF, −50 °C, 5 h; 2. NaCN, MeOH, 60 °C, 8 h; 3. (t-BuO)3Al, hexane, toluene, 110 °C, 20 h; (c) 1. C6H5CH2ONH2 HCl, Py, 115 °C, 16 h; 2. LiAlH4, Et2O, 35 °C, 16 h; (d) K2CO3, CH3CN, 50 °C, 20 h; (e) 1. C6H5CH2OCOCl, NaOH, THF, 0–25 °C, 4 h; 2. Na, NH3, THF, −78 °C, 18 h; 3. LiAlH4, Et2O, 35 °C, 6 h; 3. HCl, EtOH, 25 °C, 3 h; 4. SO3-Py, Py, 75 °C, 2 h.
Ijms 23 01075 sch001
Scheme 2. Reagents and conditions: (a) 1. TsCl, Py, 14 h, 25 °C; 2. AcOK, MeOH, 4 h, 25 °C; 3. O3, MeOH, −78 °C; (b) 1. NaBH4, MeOH, 0–25 °C; 2. CH3SO2Cl, Et3N, CH2Cl2, 2 h, 0 °C; 3. NaI, acetone, 17 h, 25 °C; 4. PhSO2Na, DMF, 32 h, 25 °C; (c) 1. n-BuLi, 2 h, −78 °C; 2. Li, NH3, 30 min, −78 °C; 3. TsOH, dioxane/H2O, (7:3), 1 h, 80 °C; (d) 1. Ac2O, Py, 14 h, 25 °C; 2. CrO3, DMAP, CH2Cl2, 24 h, −20 °C; 3. Li, NH3, 10 min, −78 °C; 4. KB[CH(CH3)C2H5]3H, THF, 6 h, −50 °C; 5. Ac2O, DMAP, CH2Cl2, 14 h, 25 °C; (e) 1. CrO3, H2SO4, H2O, 7 h, 25 °C; 2. BocNH(CH2)4N(Boc)(CH2)3NH2, NaBH3CN, MeOH, 14 h, 25 °C; 3. HCl, MeOH, 11 h, 25 °C; 4. SO3-Py, Py, 6 h, 25 °C.
Scheme 2. Reagents and conditions: (a) 1. TsCl, Py, 14 h, 25 °C; 2. AcOK, MeOH, 4 h, 25 °C; 3. O3, MeOH, −78 °C; (b) 1. NaBH4, MeOH, 0–25 °C; 2. CH3SO2Cl, Et3N, CH2Cl2, 2 h, 0 °C; 3. NaI, acetone, 17 h, 25 °C; 4. PhSO2Na, DMF, 32 h, 25 °C; (c) 1. n-BuLi, 2 h, −78 °C; 2. Li, NH3, 30 min, −78 °C; 3. TsOH, dioxane/H2O, (7:3), 1 h, 80 °C; (d) 1. Ac2O, Py, 14 h, 25 °C; 2. CrO3, DMAP, CH2Cl2, 24 h, −20 °C; 3. Li, NH3, 10 min, −78 °C; 4. KB[CH(CH3)C2H5]3H, THF, 6 h, −50 °C; 5. Ac2O, DMAP, CH2Cl2, 14 h, 25 °C; (e) 1. CrO3, H2SO4, H2O, 7 h, 25 °C; 2. BocNH(CH2)4N(Boc)(CH2)3NH2, NaBH3CN, MeOH, 14 h, 25 °C; 3. HCl, MeOH, 11 h, 25 °C; 4. SO3-Py, Py, 6 h, 25 °C.
Ijms 23 01075 sch002
Scheme 3. Reagents and conditions: (a) 1. Amberlist 15, acetone; 2. SO3-Py, Py, 6 h, 80 °C; (b) KOH, MeOH, 60 °C; (c) 1. NaBH4, CH(OCH3)3, MeOH, −78 °C; 2. Pt2O, CF3COOH, EtOH.
Scheme 3. Reagents and conditions: (a) 1. Amberlist 15, acetone; 2. SO3-Py, Py, 6 h, 80 °C; (b) KOH, MeOH, 60 °C; (c) 1. NaBH4, CH(OCH3)3, MeOH, −78 °C; 2. Pt2O, CF3COOH, EtOH.
Ijms 23 01075 sch003
Scheme 4. Reagents and conditions: (a) 4-chlorobutanol, H2O, 140–150 °C; (b) 1. Boc2O, EtOH, 48 h; 2. Et3N, MsCl, CH2Cl2, 16 h; (c) 1. NaN3, DMF, 48 h; 2. HCl, dioxane, 16 h; (d) 1. 31, NaOMe, MeOH, 24 h, −78 °C, NaBH4; 2. H2, Ni-Raney.
Scheme 4. Reagents and conditions: (a) 4-chlorobutanol, H2O, 140–150 °C; (b) 1. Boc2O, EtOH, 48 h; 2. Et3N, MsCl, CH2Cl2, 16 h; (c) 1. NaN3, DMF, 48 h; 2. HCl, dioxane, 16 h; (d) 1. 31, NaOMe, MeOH, 24 h, −78 °C, NaBH4; 2. H2, Ni-Raney.
Ijms 23 01075 sch004
Scheme 5. Reagents and conditions: (a) D. gossipina; (b) Li, NH3, THF; (c) TMSCl, OH(CH2)2OH; (d) NaOCl, TEMPO, NaBr, CH2Cl2; (e) P(O)CH2C(O)CH(CH3)2, Et2O, t-BuONa, THF; (f) 1. (R)-MeCBS, BH3 THF, toluene; 2. Et3N, toluene; 3. H2, Pt/C; (g) 1. p-TsOH, H2O, acetone; 2. SO3-Py, Py.
Scheme 5. Reagents and conditions: (a) D. gossipina; (b) Li, NH3, THF; (c) TMSCl, OH(CH2)2OH; (d) NaOCl, TEMPO, NaBr, CH2Cl2; (e) P(O)CH2C(O)CH(CH3)2, Et2O, t-BuONa, THF; (f) 1. (R)-MeCBS, BH3 THF, toluene; 2. Et3N, toluene; 3. H2, Pt/C; (g) 1. p-TsOH, H2O, acetone; 2. SO3-Py, Py.
Ijms 23 01075 sch005
Scheme 6. Reagents and conditions: (a) 1. CH3OCH2OCH3, P2O5, CHCl3, 25 °C; 2. OH(CH2)2OH, PTSA, benzene, 70 °C; 3. LiAlH4, THF, 25 °C; 4. (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, BuLi, Ph3PCH+(CH3)2I, THF; (b) (DHQD)2PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, CH3SO2NH2, t-BuOH/t-BuOMe/H2O (2.5:3:2.5); (c) Ac2O, Py; (d) 1. CH3SO2Cl, DMAP, Et3N, CH2Cl2, 0–20 °C; 2. Pd/C, EtOAc, DMF, KOH, MeOH, 95 °C; (e) PPTS, t-BuOH; (f) BocNH(CH2)4NBoc(CH2)3NH2, NaBH3CN, 25 °C.
Scheme 6. Reagents and conditions: (a) 1. CH3OCH2OCH3, P2O5, CHCl3, 25 °C; 2. OH(CH2)2OH, PTSA, benzene, 70 °C; 3. LiAlH4, THF, 25 °C; 4. (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, BuLi, Ph3PCH+(CH3)2I, THF; (b) (DHQD)2PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, CH3SO2NH2, t-BuOH/t-BuOMe/H2O (2.5:3:2.5); (c) Ac2O, Py; (d) 1. CH3SO2Cl, DMAP, Et3N, CH2Cl2, 0–20 °C; 2. Pd/C, EtOAc, DMF, KOH, MeOH, 95 °C; (e) PPTS, t-BuOH; (f) BocNH(CH2)4NBoc(CH2)3NH2, NaBH3CN, 25 °C.
Ijms 23 01075 sch006
Scheme 7. Reagents and conditions: (a) 1. Ac2O, Py, 110 °C, 4 h; 2. AD-mix-β, t-BuOH/H2O; 3. BzCl, Py, 0 °C, 24 h; (b) POCl3, Py, 25 °C, 12 h; (c) H2, 10% Pd-C, EtOAc, 25 °C, 4 h; (d) N-hydroxyphthalamide, EtOAc-acetone, C7H5O2, 25 °C, 4 h; (e) H2, PtO2, EtOAc, 25 °C, 3 h; (f) PCC, CH2Cl2, 25 °C, 12 h; (g) K2CO3, MeOH-CHCl3, 25 °C, 12 h; (h) K[CH(CH3)CH2CH3]3BH, THF, H2O2, −20 °C, 3 h; (i) Ag2CO3-ceolite, toluene, 25 °C, 8 h; (j) KOH, HO(CH2)2OH, 120 °C, 3 h; (k) SO3-Py, Py, 80 °C, 4 h; (l) NaOMe, H2N(CH2)3NH(CH2)4NH2 2HCl, NaBH3CN, H2, PtO2, 25 °C, 18 h.
Scheme 7. Reagents and conditions: (a) 1. Ac2O, Py, 110 °C, 4 h; 2. AD-mix-β, t-BuOH/H2O; 3. BzCl, Py, 0 °C, 24 h; (b) POCl3, Py, 25 °C, 12 h; (c) H2, 10% Pd-C, EtOAc, 25 °C, 4 h; (d) N-hydroxyphthalamide, EtOAc-acetone, C7H5O2, 25 °C, 4 h; (e) H2, PtO2, EtOAc, 25 °C, 3 h; (f) PCC, CH2Cl2, 25 °C, 12 h; (g) K2CO3, MeOH-CHCl3, 25 °C, 12 h; (h) K[CH(CH3)CH2CH3]3BH, THF, H2O2, −20 °C, 3 h; (i) Ag2CO3-ceolite, toluene, 25 °C, 8 h; (j) KOH, HO(CH2)2OH, 120 °C, 3 h; (k) SO3-Py, Py, 80 °C, 4 h; (l) NaOMe, H2N(CH2)3NH(CH2)4NH2 2HCl, NaBH3CN, H2, PtO2, 25 °C, 18 h.
Ijms 23 01075 sch007
Scheme 8. Reagents and conditions: (a) TsCl, Py; (b) 1. KOAc, H2O, DMF; 2. Ac2O-Py; (c) PDC, TBHP, benzene; (d) 1. Pd/C, H2; 2. L-selectride, THF; (e) MOMCl, i-Pr2NEt, CH2Cl2; (f) LiAlH4, THF; (g) CrO3, Py, CH2Cl2.
Scheme 8. Reagents and conditions: (a) TsCl, Py; (b) 1. KOAc, H2O, DMF; 2. Ac2O-Py; (c) PDC, TBHP, benzene; (d) 1. Pd/C, H2; 2. L-selectride, THF; (e) MOMCl, i-Pr2NEt, CH2Cl2; (f) LiAlH4, THF; (g) CrO3, Py, CH2Cl2.
Ijms 23 01075 sch008
Scheme 9. Reagents and conditions: (a) LiAlH4, Et2O, 3Å, 12 h, 0–25 °C; (b) NaBH3CN, MeOH, 24 h, 25 °C; (c) CF3COOH, CHCl3, 25 °C; (d) SO3-Py, Py, 114 °C; (e) KOH, MeOH, 7 h, 60 °C.
Scheme 9. Reagents and conditions: (a) LiAlH4, Et2O, 3Å, 12 h, 0–25 °C; (b) NaBH3CN, MeOH, 24 h, 25 °C; (c) CF3COOH, CHCl3, 25 °C; (d) SO3-Py, Py, 114 °C; (e) KOH, MeOH, 7 h, 60 °C.
Ijms 23 01075 sch009
Scheme 10. Reagents and conditions: (a) PCC, CH2Cl2; (b) HO(CH2)2OH, TsOH, benzene; (c) 1. NaBH4, MeOH; 2. HCl, acetone; (d) 1. NaBH3CN, NH2(CH2)2NH2, NH2(CH2)4NH(CH2)3NH2, N,N-NH2(CH2)3NC2H4N(CH2)3NH2, THF, MeOH; 2. NaOH, THF.
Scheme 10. Reagents and conditions: (a) PCC, CH2Cl2; (b) HO(CH2)2OH, TsOH, benzene; (c) 1. NaBH4, MeOH; 2. HCl, acetone; (d) 1. NaBH3CN, NH2(CH2)2NH2, NH2(CH2)4NH(CH2)3NH2, N,N-NH2(CH2)3NC2H4N(CH2)3NH2, THF, MeOH; 2. NaOH, THF.
Ijms 23 01075 sch010
Scheme 11. Reagents and conditions: (a) trimethylsulfoxonium iodide, NaH, DMSO–THF, 2 h; (b) 1. NH2(CH2)2NHBoc, MeOH, 64 °C, 2 h; 2. 50% CF3COOH/CH2Cl2; 3. 50% DIPEA/CH2Cl2.
Scheme 11. Reagents and conditions: (a) trimethylsulfoxonium iodide, NaH, DMSO–THF, 2 h; (b) 1. NH2(CH2)2NHBoc, MeOH, 64 °C, 2 h; 2. 50% CF3COOH/CH2Cl2; 3. 50% DIPEA/CH2Cl2.
Ijms 23 01075 sch011
Scheme 12. Reagents and conditions: (a) 1. HOBT/DCC/BOP/ methyl chloroformate, CHC12/THF/dioxane, −20 °C to 20 °C; 2. aluminum tri-tert-butoxide/aluminum triisopropoxide/Ag2CO3, benzene, toluene, cyclohexane, trifluorotoluene; (b) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 12. Reagents and conditions: (a) 1. HOBT/DCC/BOP/ methyl chloroformate, CHC12/THF/dioxane, −20 °C to 20 °C; 2. aluminum tri-tert-butoxide/aluminum triisopropoxide/Ag2CO3, benzene, toluene, cyclohexane, trifluorotoluene; (b) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Ijms 23 01075 sch012
Scheme 13. Reagents and conditions: (a) 1. OH(CH2)2OH, PTSA, benzene; 2. Imidazole, TBDMSCl, DMAP, CH2Cl2; (b) 1. RuCl3, TBHP, cyclohexane; 2. H2, 5% Pt/C, EtOAc; (c) K-selectride, THF; (d) 1N HCl, THF; (e) BnONH2 HCl, Py, EtOH; (f) LiAlH4, Et2O; (g) 1. NaBH(OAc)3, CH2Cl2; 2. 10% HCl, MeOH; 3. SO3-Py, MeOH.
Scheme 13. Reagents and conditions: (a) 1. OH(CH2)2OH, PTSA, benzene; 2. Imidazole, TBDMSCl, DMAP, CH2Cl2; (b) 1. RuCl3, TBHP, cyclohexane; 2. H2, 5% Pt/C, EtOAc; (c) K-selectride, THF; (d) 1N HCl, THF; (e) BnONH2 HCl, Py, EtOH; (f) LiAlH4, Et2O; (g) 1. NaBH(OAc)3, CH2Cl2; 2. 10% HCl, MeOH; 3. SO3-Py, MeOH.
Ijms 23 01075 sch013
Scheme 14. Reagents and conditions: (a) NH2(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (b) NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (c) SOCl2-MeOH, CH2Cl2.
Scheme 14. Reagents and conditions: (a) NH2(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (b) NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, NaBH(OAc)3, THF; (c) SOCl2-MeOH, CH2Cl2.
Ijms 23 01075 sch014
Scheme 15. Reagents and conditions: (a) RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; (b) NaBH4, MeOH, −78 °C, 2 h.
Scheme 15. Reagents and conditions: (a) RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; (b) NaBH4, MeOH, −78 °C, 2 h.
Ijms 23 01075 sch015
Scheme 16. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 16. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Ijms 23 01075 sch016
Scheme 17. Reagents and conditions: (a) 1. Dihydropyran, TsOH, CH2Cl2, 1.5 h; 2. CrO3-Py, CH2Cl2; (b) 1. NH2(CH2)3NHBoc or NH2(CH2)4NHBoc, NaBH3CN, AcOH pH 5–6; 2. CF3COOH, CH2Cl2; (c) 1. Br(CH2)3CN, DMF, 60 °C; 2. LiAlH4, NiCl2 6H2O, THF; (d) 1. Amine, Ti(OiPr)4, MeOH, 20 °C, 5–6 h; 2. NaBH4, −78 °C, 2 h.
Scheme 17. Reagents and conditions: (a) 1. Dihydropyran, TsOH, CH2Cl2, 1.5 h; 2. CrO3-Py, CH2Cl2; (b) 1. NH2(CH2)3NHBoc or NH2(CH2)4NHBoc, NaBH3CN, AcOH pH 5–6; 2. CF3COOH, CH2Cl2; (c) 1. Br(CH2)3CN, DMF, 60 °C; 2. LiAlH4, NiCl2 6H2O, THF; (d) 1. Amine, Ti(OiPr)4, MeOH, 20 °C, 5–6 h; 2. NaBH4, −78 °C, 2 h.
Ijms 23 01075 sch017
Scheme 18. Reagents and conditions: (a) 1. (AcO)4Pb, (CH3)3SiN3, CH2Cl2; 2. LiAlH4, THF, 66 °C; (b) 1. CH2CHCN, MeOH; 2. LiAlH4,/NiCl2 6H2O, THF, 66 °C; 3. Br(CH2)3CN, DMF, 60 °C, 72 h; 4. LiAlH4,/NiCl2 6H2O, THF, 66 °C; (c) 1. AcOH, HNO3; 2. AcOH/Zn; 3. NH2OH HCl, Py.
Scheme 18. Reagents and conditions: (a) 1. (AcO)4Pb, (CH3)3SiN3, CH2Cl2; 2. LiAlH4, THF, 66 °C; (b) 1. CH2CHCN, MeOH; 2. LiAlH4,/NiCl2 6H2O, THF, 66 °C; 3. Br(CH2)3CN, DMF, 60 °C, 72 h; 4. LiAlH4,/NiCl2 6H2O, THF, 66 °C; (c) 1. AcOH, HNO3; 2. AcOH/Zn; 3. NH2OH HCl, Py.
Ijms 23 01075 sch018
Scheme 19. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, −78 °C, 2 h.
Scheme 19. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, −78 °C, 2 h.
Ijms 23 01075 sch019
Scheme 20. Reagents and conditions: (a) 1. HOCH2CH2OH, PTSA, benzene; TBSCl, imidazole, DMAP, CH2Cl2; 2. Li/NH3, THF; 3. LiAlH4, THF; (b) DAST, n-C5H12; 2. p-TsOH, acetone; (c) 1. NH2(CH2)4NBoc(CH2)3NHBoc, NaBH3CN, THF-MeOH; 2. SO3-Py, Py; 3. SOCl2, MeOH, CH2Cl2.
Scheme 20. Reagents and conditions: (a) 1. HOCH2CH2OH, PTSA, benzene; TBSCl, imidazole, DMAP, CH2Cl2; 2. Li/NH3, THF; 3. LiAlH4, THF; (b) DAST, n-C5H12; 2. p-TsOH, acetone; (c) 1. NH2(CH2)4NBoc(CH2)3NHBoc, NaBH3CN, THF-MeOH; 2. SO3-Py, Py; 3. SOCl2, MeOH, CH2Cl2.
Ijms 23 01075 sch020
Scheme 21. Reagents and conditions: (a) 1. NH2(CH2)4NH(CH2)3NH2, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, Et3N, 7 h, 25 °C; 2. LiAlH4, THF, 6 h; 3. SO3-Py, Py, 5 h, 75 °C; 4. CF3COOH, CH2Cl2, 1 h, 25 °C.
Scheme 21. Reagents and conditions: (a) 1. NH2(CH2)4NH(CH2)3NH2, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, Et3N, 7 h, 25 °C; 2. LiAlH4, THF, 6 h; 3. SO3-Py, Py, 5 h, 75 °C; 4. CF3COOH, CH2Cl2, 1 h, 25 °C.
Ijms 23 01075 sch021
Scheme 22. Reagents and conditions: (a) 1. DCC, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NH2(CH2)4NH2, NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2, CHCl3, 14 h, 25 °C; 2. SO3-Py, DMF.
Scheme 22. Reagents and conditions: (a) 1. DCC, NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NH2(CH2)4NH2, NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2, CHCl3, 14 h, 25 °C; 2. SO3-Py, DMF.
Ijms 23 01075 sch022
Scheme 23. Reagents and conditions: (a) bis(pentafluorophenyl)carbonate, 4-methylformalin, DMF, 1.5 h; (b) NH2(CH2)4NHBoc (n = 2, 4), NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, C8H19N, DMF, 2 days.
Scheme 23. Reagents and conditions: (a) bis(pentafluorophenyl)carbonate, 4-methylformalin, DMF, 1.5 h; (b) NH2(CH2)4NHBoc (n = 2, 4), NH2(CH2)3NBoc(CH2)4NBoc(CH2)3NHBoc, C8H19N, DMF, 2 days.
Ijms 23 01075 sch023
Scheme 24. Reagents and conditions: (a) NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, BuOH, THF.
Scheme 24. Reagents and conditions: (a) NH2(CH2)3NH(CH2)4NH(CH2)3NH2, DCC, BuOH, THF.
Ijms 23 01075 sch024
Figure 2. The structures of compounds 178–181.
Figure 2. The structures of compounds 178–181.
Ijms 23 01075 g002
Scheme 25. Reagents and conditions: (a) RNH2, CH2Cl2, Et3N, 0 °C, 10 min/25 °C, 12 h.
Scheme 25. Reagents and conditions: (a) RNH2, CH2Cl2, Et3N, 0 °C, 10 min/25 °C, 12 h.
Ijms 23 01075 sch025
Figure 3. The structures of compounds 184, 185.
Figure 3. The structures of compounds 184, 185.
Ijms 23 01075 g003
Figure 4. The structure of ceragenins 186a and 186b [60,103].
Figure 4. The structure of ceragenins 186a and 186b [60,103].
Ijms 23 01075 g004
Figure 5. The structure of squalamine phosphate 187.
Figure 5. The structure of squalamine phosphate 187.
Ijms 23 01075 g005
Scheme 26. Reagents and conditions: (a) NH2(CH2)3NH(CH2)3NH2, EEDQ, DMF, 60 °C, 4 h.
Scheme 26. Reagents and conditions: (a) NH2(CH2)3NH(CH2)3NH2, EEDQ, DMF, 60 °C, 4 h.
Ijms 23 01075 sch026
Scheme 27. Reagents and conditions: (a) DSC, Et3N, CHCl3, acetonitrile, 50 °C, 3 h.
Scheme 27. Reagents and conditions: (a) DSC, Et3N, CHCl3, acetonitrile, 50 °C, 3 h.
Ijms 23 01075 sch027
Scheme 28. Reagents and conditions: (a) Succinimidyl ester of deoxycholic acid, CHCl3, r.t.
Scheme 28. Reagents and conditions: (a) Succinimidyl ester of deoxycholic acid, CHCl3, r.t.
Ijms 23 01075 sch028
Scheme 29. Reagents and conditions: (a) 1. Ac2O, Et3N, DMAP, CH2Cl2, 24 h; 2. NaBH3CN, AcOH, 48 h; 3. PCC, CaCO3, SiO2, CH2Cl2, 12 h; (b) 1. 1 eq. 4 DCE, AcOH, 1 eq diamine; 2. AcOH, NaBH(OAc)3, 4 days. (c) 1. 1 eq 4 in DCE, AcOH, 0.5 eq spermidine; 2. AcOH, NaBH(OAc)3, 4 days.
Scheme 29. Reagents and conditions: (a) 1. Ac2O, Et3N, DMAP, CH2Cl2, 24 h; 2. NaBH3CN, AcOH, 48 h; 3. PCC, CaCO3, SiO2, CH2Cl2, 12 h; (b) 1. 1 eq. 4 DCE, AcOH, 1 eq diamine; 2. AcOH, NaBH(OAc)3, 4 days. (c) 1. 1 eq 4 in DCE, AcOH, 0.5 eq spermidine; 2. AcOH, NaBH(OAc)3, 4 days.
Ijms 23 01075 sch029
Figure 6. The structures of compounds 202, 203.
Figure 6. The structures of compounds 202, 203.
Ijms 23 01075 g006
Figure 7. The structures of compounds 204206.
Figure 7. The structures of compounds 204206.
Ijms 23 01075 g007
Scheme 30. Reagents and conditions: (a) 1. p-TsCl/Py/CHCl3, 0 °C, 6 h; 2. HO(CH2)2OH, 1,4-dioxane, reflux, 4 h; 3. p-TsCl/Py/CHCl3, 0 °C, 6 h; (b) MeOH, toluene, reflux.
Scheme 30. Reagents and conditions: (a) 1. p-TsCl/Py/CHCl3, 0 °C, 6 h; 2. HO(CH2)2OH, 1,4-dioxane, reflux, 4 h; 3. p-TsCl/Py/CHCl3, 0 °C, 6 h; (b) MeOH, toluene, reflux.
Ijms 23 01075 sch030
Scheme 31. Reagents and conditions: (a) NaBH3CN, NH4OAc, MeOH; (b) 1. HCl, acetone; 2. NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, MeOH; (c) NaBH4, MeOH, 96%.
Scheme 31. Reagents and conditions: (a) NaBH3CN, NH4OAc, MeOH; (b) 1. HCl, acetone; 2. NH2(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, MeOH; (c) NaBH4, MeOH, 96%.
Ijms 23 01075 sch031
Scheme 32. Reagents and conditions: (a) H2, Pd/C, MeOH, 90%; (b) NaBH3CN, NH4OAc, MeOH, 72%; (c) HCl, acetone, 68%; (d) NH(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, 81%; € NaBH4, MeOH, 87%; (f) BnONH2 HCl, DMAP, Py, 90%; (g) SO3-Py, Py, 84%; (h) NH2(CH2)3NH(CH2)4NH2, NaBH3CN, LiOH, 76%.
Scheme 32. Reagents and conditions: (a) H2, Pd/C, MeOH, 90%; (b) NaBH3CN, NH4OAc, MeOH, 72%; (c) HCl, acetone, 68%; (d) NH(CH2)3NH(CH2)4NH(CH2)3NH2, NaBH3CN, 81%; € NaBH4, MeOH, 87%; (f) BnONH2 HCl, DMAP, Py, 90%; (g) SO3-Py, Py, 84%; (h) NH2(CH2)3NH(CH2)4NH2, NaBH3CN, LiOH, 76%.
Ijms 23 01075 sch032
Scheme 33. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Scheme 33. Reagents and conditions: (a) 1. RNH2, Ti(OiPr)4, MeOH, 20 °C, 12 h; 2. NaBH4, MeOH, −78 °C, 2 h.
Ijms 23 01075 sch033
Scheme 34. Reagents and conditions: (a) 1. R1OH, PTSA, CH2Cl2, 60 °C, 8 h; 2. Al(OBu)3, acetone, toluene, 110 °C; 3. NH(CH2)3NH(CH2)4NH(CH2)3NH2, Ti(OiPr)4, MeOH, 20 °C, 24 h; 4. NaBH4, −78 °C.
Scheme 34. Reagents and conditions: (a) 1. R1OH, PTSA, CH2Cl2, 60 °C, 8 h; 2. Al(OBu)3, acetone, toluene, 110 °C; 3. NH(CH2)3NH(CH2)4NH(CH2)3NH2, Ti(OiPr)4, MeOH, 20 °C, 24 h; 4. NaBH4, −78 °C.
Ijms 23 01075 sch034
Figure 8. The structures of compounds 223 and 224.
Figure 8. The structures of compounds 223 and 224.
Ijms 23 01075 g008
Figure 9. The structures of compounds 225 and 226.
Figure 9. The structures of compounds 225 and 226.
Ijms 23 01075 g009
Figure 10. The structures of ceragenins 186ac.
Figure 10. The structures of ceragenins 186ac.
Ijms 23 01075 g010
Scheme 35. Reagents and conditions: (a) NC(CH2)3N(Boc)(CH2)3I 228, 95% HCOOH, LiAlH4, THF, 66 °C; (b) H2N(CH2)4N(Boc)(CH2)2CHO 230, benzene, Ti(OiPr)4, 80 °C; (c) NH2OH HCl, Py, 114 °C; (d) NaBH3CN, NH4OH, 15% TiCl3, MeOH, 25 °C; (e) H2N(CH2)3NH(CH2)4NH2, Ti(OiPr)4, 80 °C, benzene.
Scheme 35. Reagents and conditions: (a) NC(CH2)3N(Boc)(CH2)3I 228, 95% HCOOH, LiAlH4, THF, 66 °C; (b) H2N(CH2)4N(Boc)(CH2)2CHO 230, benzene, Ti(OiPr)4, 80 °C; (c) NH2OH HCl, Py, 114 °C; (d) NaBH3CN, NH4OH, 15% TiCl3, MeOH, 25 °C; (e) H2N(CH2)3NH(CH2)4NH2, Ti(OiPr)4, 80 °C, benzene.
Ijms 23 01075 sch035
Scheme 36. Reagents and conditions: (a) 1. CH2=CHCN, TEBAC, dioxane, 40% KOH, 25 °C, 26–36 h; 2. H2, Raney-Ni, MeOH, 100 °C, 100 atm, 19 h.
Scheme 36. Reagents and conditions: (a) 1. CH2=CHCN, TEBAC, dioxane, 40% KOH, 25 °C, 26–36 h; 2. H2, Raney-Ni, MeOH, 100 °C, 100 atm, 19 h.
Ijms 23 01075 sch036
Scheme 37. Reagents and conditions: (a) 1. (COCl)2, CHCl3, 2 h, 25 °C; 2. NH3 or NH2(CH2)6NH2, Et3N, CHCl3, 60 °C, 3 h; (b) CH2=CHCN, 40% KOH, dioxane, TEBAC, 14 h; (c) LiAlH4, THF; (d) NaBH4, i-PrOH, 0 °C, 2 h; (e) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 8 h; (f) H2SO4, Ac2O, Py, 55 °C, 1 h, then 0 °C, 15 min.
Scheme 37. Reagents and conditions: (a) 1. (COCl)2, CHCl3, 2 h, 25 °C; 2. NH3 or NH2(CH2)6NH2, Et3N, CHCl3, 60 °C, 3 h; (b) CH2=CHCN, 40% KOH, dioxane, TEBAC, 14 h; (c) LiAlH4, THF; (d) NaBH4, i-PrOH, 0 °C, 2 h; (e) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 8 h; (f) H2SO4, Ac2O, Py, 55 °C, 1 h, then 0 °C, 15 min.
Ijms 23 01075 sch037
Scheme 38. Reagents and conditions: (a) CH2=CHCN, dioxane, 40% KOH, 25 °C, 2 h; (b) NH2OH HCl, NaHCO3, i-PrOH, 77 °C, 8 h; (c) NaBH4, BF3 Et2O, THF, 65 °C, 6 h; (d) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 9 h.
Scheme 38. Reagents and conditions: (a) CH2=CHCN, dioxane, 40% KOH, 25 °C, 2 h; (b) NH2OH HCl, NaHCO3, i-PrOH, 77 °C, 8 h; (c) NaBH4, BF3 Et2O, THF, 65 °C, 6 h; (d) H2, Raney-Ni, MeOH, 100 °C, 100 atm, 9 h.
Ijms 23 01075 sch038
Scheme 39. Reagents and conditions: (a) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), H2O, 0 °C, 2 h.
Scheme 39. Reagents and conditions: (a) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), H2O, 0 °C, 2 h.
Ijms 23 01075 sch039
Scheme 40. Reagents and conditions: (i) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), −78 °C, 2 h.
Scheme 40. Reagents and conditions: (i) R-NH2, Ti(OiPr)4 (1 eq.), MeOH, 20 °C, 12 h; NaBH4 (2 eq.), −78 °C, 2 h.
Ijms 23 01075 sch040
Figure 11. The structures of triterpene conjugates with polyamines 267 [265,275], 268 [281], 269 [265], 270, 271 [300], 272, 273, 290 [298], 275, 299 [299], 276 [294,303], 277 [258], 278 [259], 279 [260], 280 [295,299], 281, 292 [302], 282 [289], 283 [274], 284 [304], 285 [287], 286 [291], 287 [284], 288 [277], 289 [285], 291 [283], 293 [296], 294 [280], 295 [297], 296 [279], 297 [274].
Figure 11. The structures of triterpene conjugates with polyamines 267 [265,275], 268 [281], 269 [265], 270, 271 [300], 272, 273, 290 [298], 275, 299 [299], 276 [294,303], 277 [258], 278 [259], 279 [260], 280 [295,299], 281, 292 [302], 282 [289], 283 [274], 284 [304], 285 [287], 286 [291], 287 [284], 288 [277], 289 [285], 291 [283], 293 [296], 294 [280], 295 [297], 296 [279], 297 [274].
Ijms 23 01075 g011aIjms 23 01075 g011b
Figure 12. Conjugates of oleanolic acid with spermine 300 and 301.
Figure 12. Conjugates of oleanolic acid with spermine 300 and 301.
Ijms 23 01075 g012
Figure 13. Conjugates of oleanolic acid with diethylenetriamine 302, triethylenetriamine 303, oleanonic acid conjugate with spermine spacered through propargylamide 304, and N-methyl-norspermidine 305.
Figure 13. Conjugates of oleanolic acid with diethylenetriamine 302, triethylenetriamine 303, oleanonic acid conjugate with spermine spacered through propargylamide 304, and N-methyl-norspermidine 305.
Ijms 23 01075 g013
Figure 14. Polyamine steroids exhibit diverse biological activity via several distinct mechanisms: permeabilization of bacterial and fungal membranes kills pathogens (A); modification of eukaryotic cell membranes renders them resistant to virions and misfolded proteins (B); inhibition of pathological angiogenesis hampers development of macular edema and tumors (C); PTP1B inhibition improves insulin sensitivity, decreases food intake and directly suppresses cancer cells proliferation (D).
Figure 14. Polyamine steroids exhibit diverse biological activity via several distinct mechanisms: permeabilization of bacterial and fungal membranes kills pathogens (A); modification of eukaryotic cell membranes renders them resistant to virions and misfolded proteins (B); inhibition of pathological angiogenesis hampers development of macular edema and tumors (C); PTP1B inhibition improves insulin sensitivity, decreases food intake and directly suppresses cancer cells proliferation (D).
Ijms 23 01075 g014
Table 1. Therapeutic profiles of squalamine, trodusquemine, claramine, and ceragenins.
Table 1. Therapeutic profiles of squalamine, trodusquemine, claramine, and ceragenins.
Primary TargetPharmacological ActionEvidence Level
SqualamineTrodusquemineClaramineCeragenins
Phospholipid membranesAntibacterialIn vitro MIC 1–8 μg/mL: E. coli, P. aeruginosa, S. aureus, S. faecalis, P. vulgaris, K. pneumoniae [38], A. baumannii [132]; MIC 0.5–1 μg/mL Methanobrevibacter spp. [130,131]; in animal studies as monotherapy or as sensitizer for conventional antibiotics against resistant strains of S. aureus, E. coli, P. aeruginosa, E. aerogenes, K. pneumoniae [103,128,142]In vitro MIC 1–4 μg/mL: S. aureus, P. aeruginosa, C. albicans [7]In vitro MIC 2–16 μg/mL: E. coli, E. aerogenes, E. cloacae, P. aeruginosa, K. pneumoniae, A. baumannii [120], and as an adjuvant for doxycycline against P. aeruginosa PAO1 and E. aerogenes EA28 [121]In vitro MIC 2–4 μg/mL: E. coli, S. aureus, S. pneumoniae, S. pyogenes, H. influenza, P. aeruginosa, N. meningitides, K. pneumoniae, L. pneumophila, B. subtilis [226,227,229,230,231,239,242,248,249,250,251,252,253]; in animal studies as sensitizer for conventional antibiotics [99,228,229,235,243]
AntifungalIn vitro MIC 12.6–25 μM: C. albicans, C. krusei, C. glabrata, A. fumigatus, A. niger, Fusarium spp.) and protozoa (P. caudatum) [127] In vitro MIC in 0.5–4 µg/mL: Candida spp., C. neoformans, A. fumigatus [245,254,255,256]
AntiviralIn vitro: Dengue virus, hepatitis B, yellow fever, herpesviruses [146,147]; in animal models: yellow fever, eastern equine encephalitis, cytomegalovirus [30]In vitro: HIV [167] In vitro: vaccinia virus [224]
Misfolded proteinsNeuroprotectiveIn vitro: alpha-synuclein, amyloid-beta [148,149]; in animal models of Parkinson’s disease [15,153]; phase 2 clinical trilas of squalamine phosphate for Parkinson’s disease [22,158]In vitro: alpha-synuclein, amyloid-beta, HypF-N [119,152,153,154,155,157]
In animal models of Parkinson’s and Alzheimer’s diseases (presumably PTP1B is also involved) [157,159,160,161]
NHE3 and mitogen signallingAntiangiogenicAs an adjuvant to cytostatic drugs in animal tumor models [14,152,164,165,166]; as a monotherapy in animal retinopathy models [167,168,169]; squalamine lactate as monotherapy or in combination with mAb to VEGF in phase 2 clinical trilas for age-related macular edema [210,211,212,213,214]; combinatorial therapy in phase 2 clinical trilas for non-small cell lung cancer [210,211,212]
PTP1BAntidiabetic via insulin and leptin receptors signalling As monotherapy in diabetic ob/ob and db/db mice [173,174,175] and DIO mice [181,220]; as monotherapy in phase 1 clinical study for type 2 diabetes mellitus (NCT00606112, NCT00806338)As monotherapy in diabetic CaMK2aCre/LMO4flox mice [218]
Anticancer via growth factor receptors signalling As monotherapy in animal models of solid tumors [180,186,188,189,190,191,192,193,194,195]; as monotherapy in phase 1 clinical study for HER-2 positive metastatic breast cancer (NCT02524951)As monotherapy in animal models of glioblastoma and colorectal carcinoma [219]
Atherosclerosis In animal models of LDLR−/− atherosclerosis [199]; phase 1 study has been announced
Anxiolytic In animal models of anxiety and schizophrenia [205,206]
Regenerative In animal models of trauma and myocardial infarction [201,202]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop