Molecules: Natural Products: Alkaloids

Molecules, Vol. 17, Pages 191-206: Chromone and Flavonoid Alkaloids: Occurrence and Bioactivity

Shahriar Khadem — Tue, 27 Dec 2011 00:00:00 CET

The chromone and flavonoid alkaloids represent an unusual group of structurally diverse secondary metabolites, derived from the convergence of multiple biosynthetic pathways that are widely distributed through the plant and animal kingdoms. Many of them have been discovered through bioassay-guided chemical investigations of traditional medicines, suggesting potential therapeutic significance. Their unique structures and varied pharmacological activities may provide important new leads for the discovery of drugs with novel mechanisms of action. Potential therapeutic indications are as diverse as cancer and viral infections, inflammation and immunomodulation, neurological and psychiatric conditions, and diabetes.

Molecules, Vol. 16, Pages 9665-9696: A Journey Under the Sea: The Quest for Marine Anti-Cancer Alkaloids

Rita Tohme — Wed, 23 Nov 2011 00:00:00 CET

The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action.

Molecules, Vol. 16, Pages 9520-9533: Acetylcholinesterase-inhibiting Alkaloids from Zephyranthes concolor

Ricardo Reyes-Chilpa — Tue, 15 Nov 2011 00:00:00 CET

The bulbs and aerial parts of Zephyranthes concolor (Lindl.) Benth. & Hook. f. (Amaryllidaceae), an endemic species to Mexico, were found to contain the alkaloids chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. Since currently only partial and low resolution 1H-NMR data for chlidanthine acetate are available, and none for chlidanthine, its 1D and 2D high resolution 1H- and 13C-NMR spectra were recorded. Unambiguous assignations were achieved with HMBC, and HSQC experiments, and its structure was corroborated by X-ray diffraction. Minimum energy conformation for structures of chlidanthine, and its positional isomer galanthamine, were calculated by molecular modelling. Galanthamine is a well known acetylcholinesterase inhibitor; therefore, the isolated alkaloids were tested for this activity. Chlidanthine and galanthamine N-oxide inhibited electric eel acetylcholinesterase (2.4 and 2.6 × 10−5 M, respectively), indicating they are about five times less potent than galanthamine, while galwesine was inactive at 10−3 M. Inhibitory activity of HIV-1 replication, and cytotoxicity of the isolated alkaloids were evaluated in human MT-4 cells; however, the alkaloids showed poor activity as compared with standard anti-HIV drugs, but most of them were not cytotoxic.

Molecules, Vol. 16, Pages 9153-9160: Polar Compounds Isolated from the Leaves of Albertisia delagoensis (Menispermaceae)

Geoffrey E. Hawkes — Wed, 02 Nov 2011 00:00:00 CET

Aqueous infusions of the leaves of the shrub Albertisia delagoensis (Menispermaceae) are used in South Africa in traditional Zulu medicine to alleviate a variety of symptoms, including fever, and intestinal problems. We report the analysis of such an aqueous extract using the HPLC-NMR technique. A number of polar compounds were identified, including proto-quercitol, nicotinic acid, allantoic acid, 3,4-dihydroxy-benzoic acid, phthalic acid and the aporphine alkaloid derivative roemrefidine. Allantoic acid and roemrefidine have been fully characterised by 1H- and 13C-NMR and mass spectrometry. Earlier reports of antiplasmodial activity of roemrefidine and of A. delagoensis extracts are correlated with this study and with the antipyretic properties of neutral aqueous extracts.

Molecules, Vol. 16, Pages 8515-8534: Anti-Inflammatory Activity of Alkaloids: An Update from 2000 to 2010

Augusto Lopes Souto — Tue, 11 Oct 2011 00:00:00 CEST

Many natural substances with proven anti-inflammatory activity have been isolated throughout the years. The aim of this review is to review naturally sourced alkaloids with anti-inflammatory effects reported from 2000 to 2010. The assays were conducted mostly in vivo, and carrageenan-induced pedal edema was the most used experimental model. Of the 49 alkaloids evaluated, 40 demonstrated anti-inflammatory activity. Of these the most studied type were the isoquinolines. This review was based on NAPRALERT data bank, Web of Science and Chemical Abstracts. In this review, 95 references are cited.

Molecules, Vol. 16, Pages 8020-8032: The Potential of Tetrandrine as a Protective Agent for Ischemic Stroke

Yun Chen — Fri, 16 Sep 2011 00:00:00 CEST

Stroke is one of the leading causes of mortality, with a high incidence of severe morbidity in survivors. The treatment to minimize tissue injury after stroke is still unsatisfactory and it is mandatory to develop effective treatment strategies for stroke. The pathophysiology of ischemic stroke is complex and involves many processes including energy failure, loss of ion homeostasis, increased intracellular calcium level, platelet aggregation, production of reactive oxygen species, disruption of blood brain barrier, and inflammation and leukocyte infiltration, etc. Tetrandrine, a bisbenzylisoquinoline alkaloid, has many pharmacologic effects including anti-inflammatory and cytoprotective effects. In addition, tetrandrine has been found to protect the liver, heart, small bowel and brain from ischemia/reperfusion injury. It is a calcium channel blocker, and can inhibit lipid peroxidation, reduce generation of reactive oxygen species, suppress the production of cytokines and inflammatory mediators, inhibit neutrophil recruitment and platelet aggregation, which are all devastating factors during ischemia/reperfusion injury of the brain. Because tetrandrine can counteract these important pathophysiological processes of ischemic stroke, it has the potential to be a protective agent for ischemic stroke.

Molecules, Vol. 16, Pages 7480-7487: Application of Preparative High-Speed Counter-Current Chromatography for the Separation of Two Alkaloids from the Roots of Tabernaemontana catharinensis (Apocynaceae)

Milena S. Gonçalves — Fri, 02 Sep 2011 00:00:00 CEST

The methanolic extract of Tabernaemontana catharinensis (Apocynaceae) roots, which contains alkaloids with several biological activities, was separated on a preparative scale using high-speed counter-current chromatography. The optimum solvent system was found to be a mixture of CHCl3-MeOH-H2O [5:10:6 (v/v/v)] and led to a successful separation of two monoterpenic indole alkaloids, voachalotine (1) and 12-methoxy-Nb-methylvoachalotine (2) in approximately 4.0 hours. The alkaloids were all isolated at purities over 95%, and their structures were established on the basis of spectroscopic methods, including 1D and 2D NMR and EI/MS.

Molecules, Vol. 16, Pages 7344-7356: Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay

Wai Mun Kong — Mon, 29 Aug 2011 00:00:00 CEST

The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC50) values of 0.78 µg/mL and 0.636 µg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC50 of 39 µg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be determined, however, because inhibition was < 50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.

Molecules, Vol. 16, Pages 7199-7209: Chirality and Numbering of Substituted Tropane Alkaloids

Munir Humam — Thu, 25 Aug 2011 00:00:00 CEST

The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based on NMR and MS data, without taking into account the absolute configuration of these two carbons. This paper discusses the problem and the relevance of CD and NMR to determine molecular configurations. We report on the use of 1H-NMR anisochrony (Δd) induced by the Mosher’s chiral auxiliary reagents (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of (3R,6R)-3α-hydroxy-6b-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial parts of Schizanthus grahamii (Solanaceae). These analytical tools should help future works in correctly assigning the configuration of additional 3, 6/7 disubstituted tropane derivatives.

Molecules, Vol. 16, Pages 7155-7170: The Growth Suppressing Effects of Girinimbine on Hepg2 Involve Induction of Apoptosis and Cell Cycle Arrest

Suvitha Syam — Tue, 23 Aug 2011 00:00:00 CEST

Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G0/G1 peak (hypodiploid) and caused G0/G1-phase arrest. Together, these results demonstrated for the first time that girinimbine could effectively induce programmed cell death in HepG2 cells and suggests the importance of conducting further investigations in preclinical human hepatocellular carcinoma models, especially on in vivo efficacy, to promote girinimbine for use as an anticancer agent against hepatocellular carcinoma.

Molecules, Vol. 16, Pages 7125-7131: Azaphenanthrene Alkaloids with Antitumoral Activity from Anaxagorea dolichocarpa Sprague & Sandwith (Annonaceae)

Ana Silvia Suassuna Carneiro Lúcio — Mon, 22 Aug 2011 00:00:00 CEST

Phytochemical investigation of Anaxagorea dolichocarpa Sprague & Sandwith led to isolation of three azaphenanthrene alkaloids: eupolauramine, sampangine and imbiline 1. Their chemical structures were established on the basis of spectroscopic data from IR, HR-ESI-MS, NMR (including 2D experiments) and comparison with the literature. Sampangine and imbiline 1 are being described in the Anaxagorea genus for the first time. Eupolauramine and sampangine show concentration-dependent antitumoral activity in leukemic cells K562 with IC50 of 18.97 and 10.95 µg/mL, respectively.

Molecules, Vol. 16, Pages 7097-7104: Alkaloids from Hippeastrum papilio

Jean Paulo de Andrade — Thu, 18 Aug 2011 00:00:00 CEST

Galanthamine, an acetylcholinesterase inhibitor marketed as a hydrobromide salt (Razadyne®, Reminyl®) for the treatment of Alzheimer’s disease (AD), is obtained from Amaryllidaceae plants, especially those belonging to the genera Leucojum, Narcissus, Lycoris and Ungernia. The growing demand for galanthamine has prompted searches for new sources of this compound, as well as other bioactive alkaloids for the treatment of AD. In this paper we report the isolation of the new alkaloid 11β-hydroxygalanthamine, an epimer of the previously isolated alkaloid habranthine, which was identified using NMR techniques. It has been shown that 11β-hydroxygalanthamine has an important in vitro acetylcholinesterase inhibitory activity. Additionally, Hippeastrum papilio yielded substantial quantities of galanthamine.

Molecules, Vol. 16, Pages 6541-6548: Rauniticine-allo-Oxindole B and Rauniticinic-allo Acid B, New Heteroyohimbine-Type Oxindole Alkaloids from the Stems of Malaysian Uncaria longiflora var. pteropoda

Fatimah Salim — Thu, 04 Aug 2011 00:00:00 CEST

Two new heteroyohimbine-type oxindole alkaloids, rauniticine-allo-oxindole B and rauniticinic-allo acid B, have been successfully isolated from the stems extract of Malaysian Uncaria longiflora var. pteropoda. The structures of the two new alkaloids were determined by spectroscopic analysis.

Molecules, Vol. 16, Pages 5268-5282: Acute Oral Toxicity of Methanolic Seed Extract of Cassia fistula in Mice

Subramanion L. Jothy — Thu, 23 Jun 2011 00:00:00 CEST

Background and objective: Cassia fistula is widely used in traditional medicine to treat various types of ailments. The evaluation of toxic properties of C. fistula is crucial when considering public health protection because exposure to plant extracts can result in undesirable effects on consumers. Hence, in this study the acute oral toxicity of C. fistula seeds extract was investigated in mice. Results: Oral administration of crude extract at the highest dose of 5000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that C. fistula in nontoxic. Throughout 14 days of the treatment no changes in behavioural pattern, clinical sign and body weight of mice in both control and treatment groups. Also there were no any significant elevations observed in the biochemical analysis of the blood serum. Further, histopathological examination revealed normal architecture and no significant adverse effects observed on the kidney, heart, liver, lung and spleen. Conclusions: Overall, the results suggest that, the oral administration of C. fistula methanolic seeds extract did not produce any significant toxic effect in mice. Hence, the extract can be utilized for pharmaceutical formulations.

Molecules, Vol. 16, Pages 3345-3350: Identification of Diterpenoid Alkaloids from the Roots of Aconitum kusnezoffii Reihcb.

Ning Xu — Tue, 19 Apr 2011 00:00:00 CEST

Three diterpenoid alkaloids, including an unreported compound, were isolated from the roots of Aconitum kusnezoffii Reichb. On the basis of spectral analysis, these three compounds were determined to be 1,15-dimethoxy-3-hydroxy-14-benzoyl-16-ketoneoline, benzoylaconine and aconitine.

Molecules, Vol. 13, Pages 3198-3223: Gastric and Duodenal Antiulcer Activity of Alkaloids: A Review

Heloina De Sousa Falcão — Wed, 17 Dec 2008 00:00:00 CET

Peptic ulcer disease is a deep gastrointestinal erosion disorder that involves the entire mucosal thickness and can even penetrate the muscular mucosa. Numerous natural products have been evaluated as therapeutics for the treatment of a variety of diseases, including this one. These products usually derive from plant and animal sources that contain active constituents such as alkaloids, flavonoids, terpenoids, tannins and others. The alkaloids are natural nitrogen-containing secondary metabolites mostly derived from amino acids and found in about 20% of plants. There has been considerable pharmacological research into the antiulcer activity of these compounds. In this work we review the literature on alkaloids with antiulcer activity, which covers about sixty-one alkaloids, fifty-five of which have activity against this disease when induced in animals.

Molecules, Vol. 13, Pages 2462-2473: Alkaloids Induce Programmed Cell Death in Bloodstream Forms of Trypanosomes (Trypanosoma b. brucei)

Vera Rosenkranz — Fri, 03 Oct 2008 00:00:00 CEST

The potential induction of a programmed cell death (PCD) in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the induction of apoptosis by the same alkaloids in human leukemia cells (Jurkat APO-S) was tested. Several alkaloids of the isoquinoline, quinoline, indole and steroidal type (berberine, chelerythrine, emetine, sanguinarine, quinine, ajmalicine, ergotamine, harmine, vinblastine, vincristine, colchicine, chaconine, demissidine and veratridine) induced programmed cell death, whereas quinolizidine, tropane, terpene and piperidine alkaloids were mostly inactive. Effective PCD induction (EC50 below 10 µM) was caused in T. brucei by chelerythrine, emetine, sanguinarine, and chaconine. The active alkaloids can be characterized by their general property to inhibit protein biosynthesis, to intercalate DNA, to disturb membrane fluidity or to inhibit microtubule formation.

Molecules, Vol. 13, Pages 1875-1896: Rigorous Biogenetic Network for a Group of Indole Alkaloids Derived from Strictosidine

László F. Szabó — Wed, 27 Aug 2008 00:00:00 CEST

Strictosidine, the precursor of more than 2,500 indole alkaloids, was isolated from four species of three plant families. By searching the Dictionary of Natural Products on DVD it was found that about 150 indole alkaloids were obtained from the same species (coalkaloids), which is a direct proof of their common origin. On the base of their threedimensional structure, taxonomic properties and standard reaction mechanisms an extended network was established which involved the four fundamental skeletons, the three types of carbon framework in the secologanin subunit and all major groups of indole alkaloids derived from secologanin and tryptamine (except a few minor groups, in which only less then 10 alkaloids were known). The system was extended to the heterodimer indole alkaloids and the quinoindole alkaloids as well.

Molecules, Vol. 13, Pages 1722-1742: Application of Metabolic Engineering to the Production of Scopolamine

Javier Palazón — Mon, 18 Aug 2008 00:00:00 CEST

Scopolamine is an alkaloid widely used in medicine for its anticholinergic activity. The aim of this review is to show that metabolic engineering techniques constitute a suitable tool to improve the production of tropane alkaloids, focusing in particular on scopolamine. We present an overview of results obtained by various research groups, including our own, who have studied the overexpression of genes involved in the biosynthesis of scopolamine in different plant species that produce tropane alkaloids. Experiments carried out to improve production in hairy root cultures will also be described, as well as those attempting to biotransform hyoscyamine into scopolamine in roots and transgenic tobacco cells.

Molecules, Vol. 13, Pages 1584-1598: A Simple, Rapid and Mild One Pot Synthesis of Benzene Ring Acylated and Demethylated Analogues of Harmine under Solvent-free Conditions

Sabira Begum — Wed, 06 Aug 2008 00:00:00 CEST

A simple, rapid, solvent-free, room temperature one pot synthesis of benzene ring acylated and demethylated analogues of harmine using acyl halides/acid anhydrides and AlCl3 has been developed. Eight different acyl halides/acid anhydrides were used in the synthesis. The resulting mixture of products was separated by column chromatography to afford 10- and 12-monoacyl analogues, along with 10,12-diacyl-11-hydroxy products. In five cases the corresponding 10-acyl-11-hydroxy analogues were also obtained. Yields from the eight syntheses (29 products in total) were in the 6-34% range and all compounds were fully characterized.

Molecules, Vol. 13, Pages 1518-1529: HPLC-ESI-MS/MS of Imidazole Alkaloids in Pilocarpus microphyllus

Alexandra Sawaya — Wed, 30 Jul 2008 00:00:00 CEST

Pilocarpine, an important imidazole alkaloid, is extracted from the leaves of Pilocarpus microphyllus (Rutaceae), known in Brazil as jaborandi and used mainly for the treatment of glaucoma. Jaborandi leaves also contain other imidazole alkaloids, whose pharmacological and physiological properties are unknown, and whose biosynthetic pathways are under investigation. In the present study, a HPLC method coupled with ESI-MSn was developed for their qualitative and quantitative analysis. This method permits the chromatographic separation of the imidazole alkaloids found in extracts of jaborandi, as well as the MS/MS analysis of the individual compounds. Thus two samples: leaves of P. microphyllus and a paste that is left over after the industrial extraction of pilocarpine; were compared. The paste was found to contain significant amounts of pilocarpine and other imidazole alkaloids, but had a slightly different alkaloid profile than the leaf extract. The method is suitable for the routine analysis of samples containing these alkaloids, as well as for the separation and identification of known and novel alkaloids from this family, and may be applied to further studies of the biosynthetic pathway of pilocarpine in P. microphyllus.

Molecules, Vol. 13, Pages 1465-1471: Simplexidine, a 4-Alkylpyridinium Alkaloid from the Caribbean Sponge Plakortis simplex

Ernesto Fattorusso — Thu, 17 Jul 2008 00:00:00 CEST

Chemical analysis of the secondary metabolites of the Caribbean sponge Plakortis simplex, a source of many bioactive compounds, showed the presence of the new metabolite simplexidine (4), belonging to the extremely rare class of 4-alkyl-pyridinium alkaloids. The structural characterization of this molecule, based on spectroscopic methods, is reported.

Molecules, Vol. 13, Pages 475-487: Effects of Anonaine on Dopamine Biosynthesis and L-DOPA-Induced Cytotoxicity in PC12 Cells

Jae Joon Lee — Wed, 27 Feb 2008 00:00:00 CET

The effects of anonaine, an aporphine isoquinoline alkaloid, on dopaminebiosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaineat concentration ranges of 0.01-0.2 μM showed a significant inhibition of dopaminecontent at 24 h, with an IC50 value of 0.05 μM. Anonaine at 0.05 μM inhibited tyrosinehydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) activities to 38.4-40.2% and 78.4-90.2% of control levels at 12-24 h and 3-6 h, respectively. TH activity wasmore influenced than AADC activity. Anonaine also decreased intracellular cyclic AMPlevels, but not intracellular Ca2+ concentrations. In addition, anonaine (0.05 μM) reducedL-DOPA (50 μM and 100 μM)-induced increases in dopamine content at 24 h. However,anonaine (0.05 μM) did not enhance L-DOPA (50 μM and 100 μM)-induced cell death 476after 24 h. These results suggest that anonaine inhibits dopamine biosynthesis by mainlyreducing TH activity without aggravating L-DOPA-induced cytotoxicity in PC12 cells.

Molecules, Vol. 13, Pages 272-300: Progress in the Studies on Rutaecarpine

Seung Ho Lee — Wed, 06 Feb 2008 00:00:00 CET

Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodiarutaecarpa and related herbs, which has shown a variety of intriguing biological propertiessuch as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity andthermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular andendocrine systems. Recent progress in the studies on the isolation, synthesis, structureactivityrelationship studies, biological activities and metabolism of rutaecarpine arereviewed.

Molecules, Vol. 13, Pages 3-10: NMR Spectra of Sparteine N1-oxide and α-Isosparteine N-oxide

Beata Jasiewicz — Wed, 09 Jan 2008 00:00:00 CET

Sparteine N1-oxide and α-isosparteine N-oxide were prepared and theirstructures determined for the first time by 1H- and 13C-NMR spectroscopy using twodimensionaltechniques. The N-oxide effects were also calculated.