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Synthetic study toward the misassigned (±)-tronoharine

Zhong X, Li Y, Zhang J, Han FS

Org. Lett., 2015 Feb 6;17(3):720-3.

The synthesis of a pentacyclic indole compound corresponding to the core structure of the misassigned indole alkaloid, tronoharine (1), is presented. The key reactions were a formal [3 + 3] cycloaddition of an indol-2-yl carbinol with an azadiene for the construction of the 6/5/6/6 tetracyclic system containing an all-carbon quaternary center and an intramolecular substitution reaction of an amine and a triflate for the creation of the bridged azepine ring. In addition, some other interesting transformations discovered during the synthetic studies are also discussed.

Matched MeSH terms: Tabernaemontana/chemistry

Voatinggine and tabertinggine, pentacyclic indole alkaloids derived from an iboga precursor via a common cleavamine-type intermediate

Nge CE, Gan CY, Low YY, Thomas NF, Kam TS

Org. Lett., 2013 Sep 20;15(18):4774-7.

PMID: 23991636 DOI: 10.1021/ol4021404

Two new indole alkaloids, voatinggine (1) and tabertinggine (2), which are characterized by previously unencountered natural product skeletons, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined using NMR and MS analysis, and X-ray diffraction analysis. A possible biogenetic pathway to these novel alkaloids from an iboga precursor, and via a common cleavamine-type intermediate, is presented.

Matched MeSH terms: Tabernaemontana/chemistry*

Four tetracyclic oxindole alkaloids and a taberpsychine derivative from a Malayan Tabernaemontana

Lim KH, Sim KM, Tan GH, Kam TS

Phytochemistry, 2009 Jun;70(9):1182-1186.

PMID: 19643450 DOI: 10.1016/j.phytochem.2009.06.010

Four tetracyclic oxindole alkaloids, 7(R)- and 7(S)-geissoschizol oxindole (1 and 2), 7(R),16(R)- and 7(S),16(R)-19(E)-isositsirikine oxindole (3 and 4), in addition to a taberpsychine derivative, N(4)-demethyltaberpsychine (5), were isolated from the Malayan Tabernaemontana corymbosa and the structures were established using NMR and MS analysis.

Matched MeSH terms: Tabernaemontana/chemistry*

Biologically active indole and bisindole alkaloids from Tabernaemontana divaricata

Kam TS, Pang HS, Lim TM

Org Biomol Chem, 2003 Apr 21;1(8):1292-7.

PMID: 12929658

The ethanol extract of the leaves of Tabernaemontana divaricata (double flower variety) provided a total of 23 alkaloids, including the new aspidosperma alkaloids, taberhanine, voafinine, N-methylvoafinine, voafinidine, voalenine and the new bisindole alkaloid, conophyllinine in addition to the previously known, biologically active bisindole, conophylline and its congener, conofoline. The structures of the new alkaloids were established by spectroscopic methods. The preparation and characterization of the corresponding quinones of the biologically active bisindoles are also described in relation to a structure-activity study of these compounds with respect to their action in stimulating insulin expression.

Matched MeSH terms: Tabernaemontana/chemistry*

A Hexacyclic, Iboga-Derived Monoterpenoid Indole with a Contracted Tetrahydroazepine C-Ring and Incorporation of an Isoxazolidine Moiety, a Seco-Corynanthean, an Aspidosperma-Aspidosperma Bisindole with Anticancer Properties, and the Absolute Configuration of the Pyridopyrimidine Indole Alkaloid, Vernavosine

Nge CE, Sim KS, Lim SH, Thomas NF, Low YY, Kam TS

J Nat Prod, 2016 10 28;79(10):2709-2717.

PMID: 27759387

Examination of the EtOH extract of the Malayan Tabernaemontana corymbosa resulted in the isolation of three new alkaloids, viz., cononuridine (1), an unusual hexacyclic, iboga-derived, monoterpenoid indole characterized by contraction of the tetrahydroazepine C-ring and incorporation of an additional isoxazolidine ring, taberisidine (2), a seco-corynanthean alkaloid, and conofolidine (3), an Aspidosperma-Aspidosperma bisindole that showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, and HCT 116 cells. The structures and absolute configurations of 1 and 3 and the absolute configuration of the novel pyridopyrimidine indole alkaloid vernavosine (4) were confirmed by X-ray diffraction analysis. A reasonable biosynthesis route to cononuridine starting from an iboga precursor is presented.

Matched MeSH terms: Tabernaemontana/chemistry

Criofolinine and vernavosine, new pentacyclic indole alkaloids incorporating pyrroloazepine and pyridopyrimidine moieties derived from a common yohimbine precursor

Nge CE, Gan CY, Lim KH, Ting KN, Low YY, Kam TS

Org. Lett., 2014 Dec 19;16(24):6330-3.

PMID: 25454201 DOI: 10.1021/ol503072g

Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.

Matched MeSH terms: Tabernaemontana/chemistry*

Jerantinines A-G, cytotoxic Aspidosperma alkaloids from Tabernaemontana corymbosa

Lim KH, Hiraku O, Komiyama K, Kam TS

J Nat Prod, 2008 Sep;71(9):1591-4.

PMID: 18778099 DOI: 10.1021/np800435c

Seven new indole alkaloids of the Aspidosperma type, jerantinines A-G (1-7), were isolated from a leaf extract of the Malayan Tabernaemontana corymbosa. The structures were established using NMR and MS analysis. Five of the alkaloids isolated and two derivatives (1-5, 8, 9) displayed pronounced in vitro cytotoxicity against human KB cells (IC50 < 1 microg/mL).

Matched MeSH terms: Tabernaemontana/chemistry*

Seco-tabersonine alkaloids from Tabernaemontana corymbosa

Lim KH, Thomas NF, Abdullah Z, Kam TS

Phytochemistry, 2009 Feb;70(3):424-9.

PMID: 19217125 DOI: 10.1016/j.phytochem.2009.01.001

Two seco-tabersonine alkaloids, jerantiphyllines A and B, in addition to a tabersonine hydroxyindolenine, jerantinine H, and a recently reported vincamine alkaloid 7, were isolated from the leaf extract of the Malayan Tabernaemontana corymbosa and the structures were established using NMR and MS analysis. Biomimetic conversion of jerantinines A and E to their respective vincamine and 16-epivincamine derivatives were also carried out.

Matched MeSH terms: Tabernaemontana/chemistry*

Conodurine, conoduramine, and ervahanine derivatives from Tabernaemontana corymbosa

Kam TS, Sim KM

Phytochemistry, 2003 Jul;63(5):625-9.

PMID: 12809725

Four bisindole alkaloids, viz., 19'(S)-hydroxyconodurine, conodurinine, 19'(S)-hydroxyconoduramine, and 19'(S)-hydroxyervahanine A, in addition to conodurine and ervahanine A, were obtained from the leaf and stem-bark extracts of Tabernaemontana corymbosa. The structures of the new alkaloids were determined using NMR and MS analysis.

Matched MeSH terms: Tabernaemontana/chemistry*

Five new iboga alkaloids from Tabernaemontana corymbosa

Kam TS, Sim KM

J Nat Prod, 2002 May;65(5):669-72.

PMID: 12027738

Five new indole alkaloids of the ibogan type (1-5), in addition to 12 other known iboga alkaloids, were obtained from the leaf and stem-bark extract of the Malayan species Tabernaemontana corymbosa, viz., 19(S)-hydroxyibogamine (1), 19-epi-isovoacristine (2), isovoacryptine (3), 3R/S-ethoxyheyneanine (4), and 3R/S-ethoxy-19-epi-heyneanine (5). The structures were determined using NMR and MS analysis and comparison with known related compounds.

Matched MeSH terms: Tabernaemontana/chemistry*

New bisindole alkaloids from Tabernaemontana corymbosa

Kam TS, Sim KM, Pang HS

J Nat Prod, 2003 Jan;66(1):11-6.

PMID: 12542336

Ten new bisindole alkaloids of the vobasinyl-ibogan type, viz., conodiparines A-F (1-6), conodutarines A and B (7, 8), and cononitarines A and B (9, 10), were obtained from the leaf extract of the Malayan species Tabernaemontana corymbosa. The structures were determined using NMR and MS analysis.

Matched MeSH terms: Tabernaemontana/chemistry*

Conolodinines A-D, Aspidosperma- Aspidosperma Bisindole Alkaloids with Antiproliferative Activity from Tabernaemontana corymbosa

Sim DS, Navanesan S, Sim KS, Gurusamy S, Lim SH, Low YY, et al.

J Nat Prod, 2019 04 26;82(4):850-858.

PMID: 30869890 DOI: 10.1021/acs.jnatprod.8b00919

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1-4) and two known bisindole alkaloids (5, 6) of the Aspidosperma- Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). X-ray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1-8) and the related conophylline-type bisindoles (9-13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC50 values for the active compounds in the 0.01-5 μM range.

Matched MeSH terms: Tabernaemontana/chemistry*

Fulltext Antituberculosis activity, phytochemical identification of Costus speciosus (J. Koenig) Sm., Cymbopogon citratus (DC. Ex Nees) Stapf., and Tabernaemontana coronaria (L.) Willd. and their effects on the growth kinetics and cellular integrity of Mycobacterium tuberculosis H37Rv

Mohamad S, Ismail NN, Parumasivam T, Ibrahim P, Osman H, A Wahab H

BMC Complement Altern Med, 2018 Jan 08;18(1):5.

PMID: 29310671 DOI: 10.1186/s12906-017-2077-5

BACKGROUND: Costus speciosus, Cymbopogon citratus, and Tabernaemontana coronaria are herbal plants traditionally used as remedies for symptoms of tuberculosis (TB) including cough. The aims of the present study were to evaluate the in vitro anti-TB activity of different solvent partitions of these plants, to identify the phytochemical compounds, and to assess the effects of the most active partitions on the growth kinetics and cellular integrity of the tubercle organism.

METHODS: The in vitro anti-TB activity of different solvent partitions of the plant materials was determined against M. tuberculosis H37Rv using a tetrazolium colorimetric microdilution assay. The phytochemical compounds in the most active partition of each plant were identified using gas chromatography-mass spectrometry (GC-MS) analysis. The effects of these partitions on the growth kinetics of the mycobacteria were evaluated over 7-day treatment period in a batch culture system. Their effects on the mycobacterial cellular integrity were observed under a scanning electron microscope (SEM).

RESULTS: The respective n-hexane partition of C. speciosus, C. citratus, and T. coronaria exhibited the highest anti-TB activity with minimum inhibitory concentrations (MICs) of 100-200 μg/mL and minimum bactericidal concentration (MBC) of 200 μg/mL. GC-MS phytochemical analysis of these active partitions revealed that majority of the identified compounds belonged to lipophilic fatty acid groups. The active partitions of C. speciosus and T. coronaria exhibited high cidal activity in relation to time, killing more than 99% of the cell population. SEM observations showed that these active plant partitions caused multiple structural changes indicating massive cellular damages.

CONCLUSIONS: The n-hexane partition of the plant materials exhibited promising in vitro anti-TB activity against M. tuberculosis H37Rv. Their anti-TB activity was supported by their destructive effects on the integrity of the mycobacterial cellular structure.

Matched MeSH terms: Tabernaemontana/chemistry*

A review on ethnobotany, pharmacology and phytochemistry of Tabernaemontana corymbosa

Abubakar IB, Loh HS

J Pharm Pharmacol, 2016 Apr;68(4):423-32.

PMID: 26887962 DOI: 10.1111/jphp.12523

OBJECTIVES: Tabernaemontana is a genus from the plant family, Apocynaceae with vast medicinal application and widespread distribution in the tropics and subtropics of Africa, Americas and Asia. The objective of this study is to critically evaluate the ethnobotany, medicinal uses, pharmacology and phytochemistry of the species, Tabernaemontana corymbosa (Roxb. ex Wall.) and provide information on the potential future application of alkaloids isolated from different parts of the plant.

KEY FINDINGS: T. corymbosa (Roxb. ex Wall.) parts are used as poultice, boiled juice, decoctions and infusions for treatment against ulceration, fracture, post-natal recovery, syphilis, fever, tumours and orchitis in Malaysia, China, Thailand and Bangladesh. Studies recorded alkaloids as the predominant phytochemicals in addition to phenols, saponins and sterols with vast bioactivities such as antimicrobial, analgesic, anthelmintic, vasorelaxation, antiviral and cytotoxicity.

SUMMARY: An evaluation of scientific data and traditional medicine revealed the medicinal uses of different parts of T. corymbosa (Roxb. ex Wall.) across Asia. Future studies exploring the structure-bioactivity relationship of alkaloids such as jerantinine and vincamajicine among others could potentially improve the future application towards reversing anticancer drug resistance.

Matched MeSH terms: Tabernaemontana/chemistry*

Cytotoxic vobasine, tacaman, and corynanthe-tryptamine bisindole alkaloids from Tabernaemontana and structure revision of tronoharine

Sim DS, Chong KW, Nge CE, Low YY, Sim KS, Kam TS

J Nat Prod, 2014 Nov 26;77(11):2504-12.

PMID: 25333996 DOI: 10.1021/np500589u

Seven new indole alkaloids (1-7) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan Tabernaemontana. Two of the new vobasine alkaloids (1, 3), as well as 16-epivobasine (15) and 16-epivobasenal (17), showed appreciable cytotoxicity toward KB cells (IC50 ca. 5 μg/mL). The structure of the known Tabernaemontana alkaloid tronoharine (8) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis.

Matched MeSH terms: Tabernaemontana/chemistry*

Fulltext Prostaglandin analogous and antioxidant activity mediated gastroprotective action of Tabernaemontana divaricata (L.) R. Br. flower methanolic extract against chemically induced gastric ulcers in rats

Ali Khan MS, Mat Jais AM, Afreen A

Biomed Res Int, 2013;2013:185476.

PMID: 24350249 DOI: 10.1155/2013/185476

The present study was conducted to evaluate the antiulcerogenic effect and recognize the basic mechanism of action of Tabernaemontana divaricata (L.) R. Br. flowers. T. divaricata flower methanolic extract (TDFME) was screened for antiulcer activity versus aspirin and ethanol induced gastric ulcers at three doses--125, 250, and 500 mg/kg--orally using misoprostol as a standard. Besides histopathological examination, seven parameters, that is, ulcer index, total protein, nonprotein sulphhydryls, mucin, catalase, malondialdehyde, and superoxide dismutase levels, were estimated. In addition to HPLC profiling, GC-MS analysis and electrospray ionization--high resolution mass spectral (ESI-HRMS) analysis of crude TDFME were carried out in an attempt to identify known phytochemicals present in the extract on the basis of m/z value. The results revealed a significant increase in the levels of catalase, superoxide dismutase, mucin, and nonprotein sulphhydryls, while they revealed a reduction in ulcer index, the levels of total protein, and malondialdehyde. Histopathological observations also demonstrated the protective effect. Though all the doses of TDFME exhibited gastroprotective function, higher doses were found to be more effective. Mass spectral analysis gave a few characteristic m/z values suggesting the presence of a few known indole alkaloids, while HPLC profiling highlighted the complexity of the extract. TDFME was found to exhibit its gastroprotective effect through antioxidant mechanism and by enhancing the production of gastric mucous.

Matched MeSH terms: Tabernaemontana/chemistry*

Ibogan, Aspidosperman, Vincamine, and Bisindole Alkaloids from a Malayan Tabernaemontana corymbosa: Iboga Alkaloids with C-20α Substitution

Nge CE, Chong KW, Thomas NF, Lim SH, Low YY, Kam TS

J Nat Prod, 2016 05 27;79(5):1388-99.

PMID: 27077800 DOI: 10.1021/acs.jnatprod.6b00129

Ten new indole alkaloids (1-10) comprising five ibogan, two aspidosperman, one vincamine, and two bisindole alkaloids, in addition to 32 known alkaloids, were isolated from the stem-bark extract of a Malayan Tabernaemontana corymbosa. The structures of these alkaloids were determined based on analysis of the NMR and MS data and, in five instances (1, 3, 5, 6, 8), confirmed by X-ray diffraction analysis. Two of the iboga alkaloids, conodusines B (2) and C (3), and the iboga-containing bisindole tabernamidine B (10) are notable for the presence of an α-substituted acetyl group at C-20 of the iboga carbon skeleton. The iboga alkaloid (+)-conodusine E (5) had MS and NMR data that were identical to those of (-)-ervatamine I, recently isolated from Ervatamia hainanensis. Establishment of the absolute configuration of (+)-conodusine E (5) was based on analysis of the ECD data, correlation with (-)-heyneanine, and X-ray analysis, which showed that (+)-5 belongs to the same enantiomeric series as exemplified by (-)-coronaridine. The configuration at C-20' of the previously reported Tabernaemontana bisindole alkaloid 19'-oxotabernamine (renamed tabernamidine B) required revision based on the present results. Several of the bisindoles showed pronounced in vitro growth inhibitory activity against drug-sensitive and vincristine-resistant KB cells.

Matched MeSH terms: Tabernaemontana/chemistry

Ibogan, tacaman, and cytotoxic bisindole alkaloids from tabernaemontana. Cononusine, an iboga alkaloid with unusual incorporation of a pyrrolidone moiety

Lim KH, Raja VJ, Bradshaw TD, Lim SH, Low YY, Kam TS

J Nat Prod, 2015 May 22;78(5):1129-38.

PMID: 25919190 DOI: 10.1021/acs.jnatprod.5b00117

Six new indole alkaloids, viz., cononusine (1, a rare example of an iboga-pyrrolidone conjugate), ervaluteine (2), vincamajicine (3), tacamonidine (4), 6-oxoibogaine (5), and N(4)-chloromethylnorfluorocurarine chloride (6), and two new vobasinyl-iboga bisindole alkaloids, ervatensines A (7) and B (8), in addition to other known alkaloids, were isolated from the stem-bark extract of the Malayan Tabernaemontana corymbosa. The structures of these alkaloids were established on the basis of NMR and MS analyses and, in one instance (7), confirmed by X-ray diffraction analysis. Vincamajicine (3) showed appreciable activity in reversing multidrug resistance in vincristine-resistant KB cells (IC50 2.62 μM), while ervatensines A (7) and B (8) and two other known bisindoles displayed pronounced in vitro growth inhibitory activity against human KB cells (IC50 < 2 μM). Compounds 7 and 8 also showed good growth inhibitory activity against A549, MCF-7, MDA-468, HCT-116, and HT-29 cells (IC50 0.70-4.19 μM). Cell cycle and annexin V-FITC apoptosis assays indicated that compounds 7 and 8 inhibited proliferation of HCT-116 and MDA-468 cells, evoking apoptotic and necrotic cell death.

Matched MeSH terms: Tabernaemontana/chemistry*

Fulltext Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site

Smedley CJ, Stanley PA, Qazzaz ME, Prota AE, Olieric N, Collins H, et al.

Sci Rep, 2018 Jul 13;8(1):10617.

PMID: 30006510 DOI: 10.1038/s41598-018-28880-2

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

Matched MeSH terms: Tabernaemontana/chemistry

Anti-infective activities of 11 plants species used in traditional medicine in Malaysia

Nor Azman NS, Hossan MS, Nissapatorn V, Uthaipibull C, Prommana P, Jin KT, et al.

Exp Parasitol, 2018 Nov;194:67-78.

PMID: 30268422 DOI: 10.1016/j.exppara.2018.09.020

Treatment of drug resistant protozoa, bacteria, and viruses requires new drugs with alternative chemotypes. Such compounds could be found from Southeast Asian medicinal plants. The present study examines the cytotoxic, antileishmanial, and antiplasmodial effects of 11 ethnopharmacologically important plant species in Malaysia. Chloroform extracts were tested for their toxicity against MRC-5 cells and Leishmania donovani by MTT, and chloroquine-resistant Plasmodium falciparum K1 strain by Histidine-Rich Protein II ELISA assays. None of the extract tested was cytotoxic to MRC-5 cells. Extracts of Uvaria grandiflora, Chilocarpus costatus, Tabernaemontana peduncularis, and Leuconotis eugenifolius had good activities against L. donovani with IC50 

Matched MeSH terms: Tabernaemontana/chemistry

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