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14 pages, 5116 KiB  
Article
Enhanced Bioactivity of Quercetin–Tetrahydroisoquinoline Derivatives: Effect on Lipophilicity, Enzymes Inhibition, Antioxidant Potential, and Cytotoxicity
by Marija Vučkovski, Ana Filipović, Milka Jadranin, Lela Korićanac, Jelena Žakula, Bojan P. Bondžić and Aleksandra M. Bondžić
Int. J. Mol. Sci. 2024, 25(23), 13076; https://doi.org/10.3390/ijms252313076 - 5 Dec 2024
Cited by 2 | Viewed by 1666
Abstract
Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, [...] Read more.
Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, and P-glycoprotein substrate affinity, were assessed theoretically using the SwissADME software. The metal-chelating ability of the new compounds was evaluated on metal ions Fe2+, Zn2+, and Cu2+, whose homeostasis disruption is linked to the development of Alzheimer’s disease. Inhibition potential was tested on the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase, as well as Na+, K+-ATPase, an enzyme commonly overexpressed in tumours. Antioxidant potential was assessed using the DPPH assay. Cytotoxicity studies were conducted on healthy MRC-5 cells and three cancer cell lines: HeLa, MDA-231, and MDA-468. The results indicated that derivatization of quercetin with THIQ yielded compounds with lower toxicity, preserved chelating ability, improved antioxidant potential, increased selectivity toward the cholinergic enzyme butyrylcholinesterase, and enhanced inhibition potential toward Na+, K+-ATPase and butyrylcholinesterase compared to quercetin alone. Therefore, the synthesized derivatives represent compounds with an improved profile and could be promising candidates for further optimization in developing drugs for neurodegenerative and cancer diseases. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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33 pages, 24572 KiB  
Review
Recent Advances in the Synthesis of Chiral Tetrahydroisoquinolines via Asymmetric Reduction
by Yue Ji, Qiang Gao, Weiwei Han and Baizeng Fang
Catalysts 2024, 14(12), 884; https://doi.org/10.3390/catal14120884 - 3 Dec 2024
Cited by 2 | Viewed by 1813
Abstract
Enantiopure tetrahydroisoquinolines (THIQs), recognized as privileged skeletal structures in natural alkaloids, have attracted considerable attention from chemists due to their biological and pharmacological activities. Synthetic strategies for optically active THIQs have been rapidly and extensively developed in the past decades. In view of [...] Read more.
Enantiopure tetrahydroisoquinolines (THIQs), recognized as privileged skeletal structures in natural alkaloids, have attracted considerable attention from chemists due to their biological and pharmacological activities. Synthetic strategies for optically active THIQs have been rapidly and extensively developed in the past decades. In view of simplicity and atom economy, asymmetric reduction of N-heteroaromatics, imines, enamines, and iminium salts containing an isoquinoline (IQ) moiety should be the preferred approaches to obtain chiral THIQs. This review focuses on recent advances in the catalytic asymmetric synthesis of enantiopure THIQs via asymmetric reduction, including asymmetric hydrogenation, transfer hydrogenation, reductive amination, and deracemization. Highly enantioselective synthesis of THIQs was achieved via transition-metal-catalyzed asymmetric reduction and organocatalytic asymmetric reduction utilizing either catalyst activation or substrate activation strategy. Despite much progress in the enantioselective synthesis of THIQs, there still remain considerable opportunities and challenges for progress and developments in this field of research, particularly in the development of asymmetric catalytic systems for the direct reduction of IQs. Full article
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
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2 pages, 150 KiB  
Abstract
Synthesis of N-Flurbiprofen-Substituted 1,2,3,4-Tetrahydroisoquinolines
by Diyana Dimitrova, Stanimir Manolov, Iliyan Ivanov and Dimitar Bojilov
Proceedings 2024, 105(1), 44; https://doi.org/10.3390/proceedings2024105044 - 28 May 2024
Viewed by 576
Abstract
Isoquinoline alkaloids constitute a substantial category of natural products, among which 1,2,3,4-tetrahydroisoquinoline (THIQ) holds significance. THIQ-based compounds, whether natural or synthetic, showcase a wide array of biological activities, demonstrating efficacy against diverse infectious pathogens and neurodegenerative disorders. Consequently, THIQ heterocyclic structures have garnered [...] Read more.
Isoquinoline alkaloids constitute a substantial category of natural products, among which 1,2,3,4-tetrahydroisoquinoline (THIQ) holds significance. THIQ-based compounds, whether natural or synthetic, showcase a wide array of biological activities, demonstrating efficacy against diverse infectious pathogens and neurodegenerative disorders. Consequently, THIQ heterocyclic structures have garnered considerable interest within the scientific realm, driving the exploration and synthesis of novel THIQ derivatives with notable biological potential. In contrast, flurbiprofen falls under the category of nonsteroidal anti-inflammatory drugs (NSAIDs) and demonstrates both antipyretic and analgesic effects. Its potential extends beyond mere pain relief; it has been suggested for both local and systemic applications, such as inhibiting colon tumor growth and platelet aggregation. In our research, we focus on synthesizing novel N-flurbiprofen-substituted 1,2,3,4-tetrahydroisoquinolines. We explore novel methods for the amide cyclization, investigating the feasibility of utilizing new environmentally friendly reagents. Specifically, we examine the efficacy of strong protic acids that are immobilized on a silica gel as heterogeneous acid catalysts in intramolecular α-amidoalkylation reactions. These acid-supported silica gel systems are pivotal in acid-catalyzed synthetic processes, emerging as preferred options for producing novel organic compounds, aligning with eco-friendly practices. Our interest lies in applying this heterogeneous acid system on a silica gel as a “heterogeneous catalyst” to synthesize isoquinoline derivatives of flurbiprofen and elucidate the relationship between their structure and activity. When investigating the intramolecular α-amidoalkylation reaction, we conduct multiple experiments to determine the ideal reaction conditions. This involves altering solvents and acid reagents while considering the acid-catalyzed nature of the reaction. The novel compounds were successfully synthesized through an intramolecular α-amidoalkylation reaction. This synthesis method involved heating the reactants at 80 °C in dichloroethane, supplemented with a heterogeneous acid catalyst, PPA/SiO2. The obtained compounds underwent full spectral characterization using 1H and 13C NMR, IR spectroscopy, and mass analysis. Full article
22 pages, 2086 KiB  
Article
Diastereoselective Three-Component 1,3-Dipolar Cycloaddition to Access Functionalized β-Tetrahydrocarboline- and Tetrahydroisoquinoline-Fused Spirooxindoles
by Yongchao Wang, Yu Chen, Shengli Duan, Yiyang Cao, Wenjin Sun, Mei Zhang, Delin Zhao, Donghua Hu and Jianwei Dong
Molecules 2024, 29(8), 1790; https://doi.org/10.3390/molecules29081790 - 15 Apr 2024
Cited by 2 | Viewed by 1495
Abstract
A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized β-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60–94% of yields with excellent diastereoselectivities (10: 1−>99: 1 dr). [...] Read more.
A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized β-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60–94% of yields with excellent diastereoselectivities (10: 1−>99: 1 dr). This reaction not only realizes a concise THPI- or THIQs-based 1,3-dipolar cycloaddition, but also provides a practical strategy for the construction of two distinctive spirooxindole skeletons. Full article
(This article belongs to the Special Issue Multicomponent Reactions in Organic Synthesis)
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20 pages, 7816 KiB  
Article
Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates
by Dunja Jovanović, Ana Filipović, Goran Janjić, Tamara Lazarević-Pašti, Zdravko Džambaski, Bojan P. Bondžić and Aleksandra M. Bondžić
Int. J. Mol. Sci. 2024, 25(2), 1033; https://doi.org/10.3390/ijms25021033 - 14 Jan 2024
Cited by 6 | Viewed by 2063
Abstract
We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. [...] Read more.
We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes’ inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB. Full article
(This article belongs to the Special Issue Molecular Insights into Drug Development for Alzheimer’s Disease)
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14 pages, 2290 KiB  
Review
Lipase-Catalyzed Strategies for the Preparation of Enantiomeric THIQ and THβC Derivatives: Green Aspects
by György Orsy and Enikő Forró
Molecules 2023, 28(17), 6362; https://doi.org/10.3390/molecules28176362 - 30 Aug 2023
Cited by 2 | Viewed by 2222
Abstract
This report reviews the most important lipase-catalyzed strategies for the preparation of pharmaceutically and chemically important tetrahydroisoquinoline and tetrahydro-β-carboline enantiomers through O-acylation of the primary hydroxy group, N-acylation of the secondary amino group, and COOEt hydrolysis of the [...] Read more.
This report reviews the most important lipase-catalyzed strategies for the preparation of pharmaceutically and chemically important tetrahydroisoquinoline and tetrahydro-β-carboline enantiomers through O-acylation of the primary hydroxy group, N-acylation of the secondary amino group, and COOEt hydrolysis of the corresponding racemic compounds with simple molecular structure, which have been reported during the last decade. A brief introduction describes the importance and synthesis of tetrahydroisoquinoline and tetrahydro-β-carboline derivatives, and it formulates the objectives of this compilation. The strategies are presented in chronological order, classified according to function of the reaction type, as kinetic and dynamic kinetic resolutions, in the main text. These reactions result in the desired products with excellent ee values. The pharmacological importance of the products together with their synthesis is given in the main text. The enzymatic hydrolysis of the hydrochloride salts as racemates of the starting amino carboxylic esters furnished the desired enantiomeric amino carboxylic acids quantitatively. The enzymatic reactions, performed in tBuOMe or H2O as usable solvents, and the transformations carried out in a continuous-flow system, indicate clear advantages, including atom economy, reproducibility, safer solvents, short reaction time, rapid heating and compression vs. shaker reactions. These features are highlighted in the main text. Full article
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22 pages, 12114 KiB  
Article
An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists
by Rita Citraro, Francesca Bosco, Gianfranco Di Gennaro, Martina Tallarico, Lorenza Guarnieri, Luca Gallelli, Vincenzo Rania, Antonio Siniscalchi, Giovambattista De Sarro and Antonio Leo
Pharmaceutics 2023, 15(7), 2006; https://doi.org/10.3390/pharmaceutics15072006 - 22 Jul 2023
Cited by 5 | Viewed by 2131
Abstract
Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the [...] Read more.
Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague–Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. Results: In Sprague–Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors. Full article
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23 pages, 3522 KiB  
Article
Synthesis of Novel 1-Oxo-2,3,4-trisubstituted Tetrahydroisoquinoline Derivatives, Bearing Other Heterocyclic Moieties and Comparative Preliminary Study of Anti-Coronavirus Activity of Selected Compounds
by Meglena I. Kandinska, Nikola T. Burdzhiev, Diana V. Cheshmedzhieva, Sonia V. Ilieva, Peter P. Grozdanov, Neli Vilhelmova-Ilieva, Nadya Nikolova, Vesela V. Lozanova and Ivanka Nikolova
Molecules 2023, 28(3), 1495; https://doi.org/10.3390/molecules28031495 - 3 Feb 2023
Cited by 4 | Viewed by 2895
Abstract
A series of novel 1-oxo-2,3,4-trisubstituted tetrahydroisoquinoline (THIQ) derivatives bearing other heterocyclic moieties in their structure were synthesized based on the reaction between homophthalic anhydride and imines. Initial studies were carried out to establish the anti-coronavirus activity of some of the newly obtained THIQ-derivatives [...] Read more.
A series of novel 1-oxo-2,3,4-trisubstituted tetrahydroisoquinoline (THIQ) derivatives bearing other heterocyclic moieties in their structure were synthesized based on the reaction between homophthalic anhydride and imines. Initial studies were carried out to establish the anti-coronavirus activity of some of the newly obtained THIQ-derivatives against two strains of human coronavirus-229E and OC-43. Their antiviral activity was compared with that of their close analogues, piperidinones and thiomorpholinones, previously synthesized in our group, with aim to expand the range of the tested representative sample and to obtain valuable preliminary information about biological properties of a wider variety of compounds. Full article
(This article belongs to the Special Issue Synthesis of Tetrahydroisoquinoline and Protoberberine Derivatives)
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25 pages, 6444 KiB  
Article
Endogenous Synthesis of Tetrahydroisoquinoline Derivatives from Dietary Factors: Neurotoxicity Assessment on a 3D Neurosphere Culture
by Rania Aro, Amandine Nachtergael, Claudio Palmieri, Laurence Ris and Pierre Duez
Molecules 2022, 27(21), 7443; https://doi.org/10.3390/molecules27217443 - 2 Nov 2022
Viewed by 2392
Abstract
Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume [...] Read more.
Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume that an acute or chronic exposure to some THIQs might lead to neurodegenerative diseases including essential tremor (ET). We developed a method to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to study their reactivity with endogenous amines and identify the reaction products. Then, we predicted in silico their pharmacokinetic and toxicological properties toward the central nervous system. Finally, their possible neurological effects on a novel in vitro 3D neurosphere model were assessed. The obtained data indicate that meat is an alkaloid precursor, and we identified the alkaloid 1-benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol (1-benz-6,7-diol THIQ) as the condensation product of phenylacetaldehyde with dopamine; in silico study of 1-benz-6,7-diol-THIQ reveals modulation of dopamine receptor D1 and D2; and in vitro study of 1-benz-6,7-diol-THIQ for cytotoxicity and oxidative stress induction does not show any difference after 24 h contact for all tested concentrations. To conclude, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol-THIQ. Full article
(This article belongs to the Special Issue Recent Advances and Future Challenges in Food Analysis)
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24 pages, 6939 KiB  
Article
Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy
by Yixuan Tang, Shihui Huang, Xingxing Chen, Junzhang Huang, Qianwen Lin, Lei Huang, Shuping Wang, Qihua Zhu, Yungen Xu and Yi Zou
Molecules 2022, 27(19), 6637; https://doi.org/10.3390/molecules27196637 - 6 Oct 2022
Cited by 3 | Viewed by 2926
Abstract
Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet [...] Read more.
Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet need to discover novel and structurally diverse PRMT5 inhibitors with characterized therapeutic utility. Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound. Among them, compound 20 (IC50: 4.2 nM) exhibits more potent PRMT5 inhibitory activity than GSK-3326595 (IC50: 9.2 nM). In addition, compound 20 shows high anti-proliferative effects on MV-4-11 and MDA-MB-468 tumor cells and low cytotoxicity on AML-12 hepatocytes. Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study. Full article
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23 pages, 5616 KiB  
Article
Cell Fate following Irradiation of MDA-MB-231 and MCF-7 Breast Cancer Cells Pre-Exposed to the Tetrahydroisoquinoline Sulfamate Microtubule Disruptor STX3451
by Scott D. Hargrave, Anna M. Joubert, Barry V. L. Potter, Wolfgang Dohle, Sumari Marais and Anne E. Mercier
Molecules 2022, 27(12), 3819; https://doi.org/10.3390/molecules27123819 - 14 Jun 2022
Cited by 4 | Viewed by 3273
Abstract
A tetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by [...] Read more.
A tetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by sulfamoylation. The non-steroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radiation biology. We investigated whether 24 h pre-treatment with STX3451 could pre-sensitize MCF-7 and MDA-MB-231 breast cancer cells to radiation. This regimen showed a clear increase in cytotoxicity compared to the individual modalities, results that were contiguous in spectrophotometric analysis, flow cytometric quantification of apoptosis induction, clonogenic studies and microscopy techniques. Drug pre-treatment increased radiation-induced DNA damage, with statistically more double-strand (ds) DNA breaks demonstrated. The latter could be due to the induction of a radiation-sensitive metaphase block or the increased levels of reactive oxygen species, both evident after compound exposure. STX3451 pre-exposure may also delay DNA repair mechanisms, as the DNA damage response element ataxia telangiectasia mutated (ATM) was depressed. These in vitro findings may translate into in vivo models, with the ultimate aim of reducing both radiation and drug doses for maximal clinical effect with minimal adverse effects. Full article
(This article belongs to the Special Issue Synthesis of Tetrahydroisoquinoline and Protoberberine Derivatives)
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11 pages, 2884 KiB  
Article
Stereoelectronic Features of a Complex Ketene Dimerization Reaction
by Robert D. Barrows, Mark J. Dresel, Thomas J. Emge, Paul R. Rablen and Spencer Knapp
Molecules 2022, 27(1), 66; https://doi.org/10.3390/molecules27010066 - 23 Dec 2021
Viewed by 3964
Abstract
The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective [...] Read more.
The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed. Full article
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19 pages, 4885 KiB  
Article
Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel
by Madhavi Gangapuram, Elizabeth A. Mazzio, Kinfe K. Redda and Karam F. A. Soliman
Int. J. Mol. Sci. 2021, 22(14), 7694; https://doi.org/10.3390/ijms22147694 - 19 Jul 2021
Cited by 3 | Viewed by 3452
Abstract
The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug [...] Read more.
The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change −2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-β (TGF-β) signaling. Of interest, both drugs effectively downregulated “inhibitor of DNA binding, dominant negative helix-loop-helix” (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models. Full article
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18 pages, 2777 KiB  
Article
p-Aminophenylalanine Involved in the Biosynthesis of Antitumor Dnacin B1 for Quinone Moiety Formation
by Xiaojing Hu, Xing Li, Yong Sheng, Hengyu Wang, Xiaobin Li, Yixin Ou, Zixin Deng, Linquan Bai and Qianjin Kang
Molecules 2020, 25(18), 4186; https://doi.org/10.3390/molecules25184186 - 12 Sep 2020
Cited by 3 | Viewed by 3619
Abstract
Actinosynnema species produce diverse natural products with important biological activities, which represent an important resource of antibiotic discovery. Advances in genome sequencing and bioinformatics tools have accelerated the exploration of the biosynthetic gene clusters (BGCs) encoding natural products. Herein, the completed BGCs of [...] Read more.
Actinosynnema species produce diverse natural products with important biological activities, which represent an important resource of antibiotic discovery. Advances in genome sequencing and bioinformatics tools have accelerated the exploration of the biosynthetic gene clusters (BGCs) encoding natural products. Herein, the completed BGCs of dnacin B1 were first discovered in two Actinosynnema pretiosum subsp. auranticum strains DSM 44131T (hereafter abbreviated as strain DSM 44131T) and X47 by comparative genome mining strategy. The BGC for dnacin B1 contains 41 ORFs and spans a 66.9 kb DNA region in strain DSM 44131T. Its involvement in dnacin B1 biosynthesis was identified through the deletion of a 9.7 kb region. Based on the functional gene analysis, we proposed the biosynthetic pathway for dnacin B1. Moreover, p-amino-phenylalanine (PAPA) unit was found to be the dnacin B1 precursor for the quinone moiety formation, and this was confirmed by heterologous expression of dinV, dinE and dinF in Escherichia coli. Furthermore, nine potential PAPA aminotransferases (APAT) from the genome of strain DSM 44131T were explored and expressed. Biochemical evaluation of their amino group transformation ability was carried out with p-amino-phenylpyruvic acid (PAPP) or PAPA as the substrate for the final product formation. Two of those, APAT4 and APAT9, displayed intriguing aminotransferase ability for the formation of PAPA. The proposed dnacin B1 biosynthetic machinery and PAPA biosynthetic investigations not only enriched the knowledge of tetrahydroisoquinoline (THIQ) biosynthesis, but also provided PAPA building blocks to generate their structurally unique homologues. Full article
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82 pages, 37510 KiB  
Review
The Pictet-Spengler Reaction Updates Its Habits
by Andrea Calcaterra, Laura Mangiardi, Giuliano Delle Monache, Deborah Quaglio, Silvia Balducci, Simone Berardozzi, Antonia Iazzetti, Roberta Franzini, Bruno Botta and Francesca Ghirga
Molecules 2020, 25(2), 414; https://doi.org/10.3390/molecules25020414 - 19 Jan 2020
Cited by 66 | Viewed by 15204
Abstract
The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did [...] Read more.
The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations. Full article
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