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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.

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).

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.

Synergistic cytotoxic effects of combined δ-tocotrienol and jerantinine B on human brain and colon cancers

Abubakar IB, Lim KH, Kam TS, Loh HS

J Ethnopharmacol, 2016 May 26;184:107-18.

PMID: 26947901 DOI: 10.1016/j.jep.2016.03.004

The genus Tabernaemontana has widespread distribution throughout tropical and subtropical parts of the world, i.e. Africa, Asia and America which has long been used for treatments of different disease conditions including tumours, wounds, syphilis, stomach ache and headache. Some Tabernaemontana species are used for treatment of piles, spleen and abdominal tumours in India. In particular, the leaf of Tabernaemontana corymbosa is used for treatment of tumours in Bangladesh. Parts of the plant or whole plants are used as decoctions, steam bath, powder and ointments.

Cardiovascular effects of aspidofractinine-type alkaloids from Kopsia

Mok SL, Yoganathan K, Lim TM, Kam TS

J Nat Prod, 1998 Mar;61(3):328-32.

PMID: 9544563

Intravenous injection of the aspidofractinine alkaloid, kopsingine (1, 0.2-10.0 mg/kg) from Kopsia teoi, produced dose-related decreases in the mean arterial blood pressure and heart rate in anesthetized spontaneously hypertensive rats, which were similar to those seen in normotensive controls. Minor modifications in the molecular structure of kopsingine, as in kopsaporine (2, the 12-demethoxy derivative of kopsingine) and 14,15-dihydrokopsingine (4), did not significantly alter the hypotensive responses, whereas a more drastic change in the structure, as in the heptacyclic kopsidine A (3) and the 3-to-17 oxo-bridged compound 5, resulted in an increase in blood pressure. The antihypertensive effects of kopsingine (1) and its congeners (2 and 4) along with the pressor effects produced by the heptacyclic oxo-bridged compounds (5 and 3) could be ascribed to central as well as peripheral actions.

Cytotoxic and leishmanicidal aminoglycosteroids and aminosteroids from Holarrhena curtisii

Kam TS, Sim KM, Koyano T, Toyoshima M, Hayashi M, Komiyama K

J Nat Prod, 1998 Nov;61(11):1332-6.

PMID: 9834146

The EtOH extract of the leaves of Holarrhena curtisii yielded five new steroidal alkaloids: 17-epi-holacurtine (3), 17-epi-N-demethylholacurtine (4), holacurtinol (5), 3alpha-amino-14beta-hydroxypregnan-20-one (7), and 15alpha-hydroxyholamine (8), in addition to the known compounds, holacurtine (1), N-demethylholacurtine (2), and holamine (6). All eight compounds showed significant cytotoxic and leishmanicidal activities.

Cardiovascular responses in the normotensive rat produced by intravenous injection of gambirine isolated from Uncaria callophylla B1. ex Korth

Mok JS, Chang P, Lee KH, Kam TS, Goh SH

J Ethnopharmacol, 1992 Jun;36(3):219-23.

PMID: 1434680

Among several alkaloids, including dimeric indoles, isolated from Uncaria callophylla, gambirine which is an alkaloid unique to this plant, has been found to be another hypotensive principle from the plant. Intravenous injections of gambirine in the dose range of 0.2 to 10.0 mg/kg caused a dose-related fall in both systolic and diastolic blood pressures as well as heart rate. At all doses gambirine showed a prompt onset of action and at the higher doses (5.0-10 mg/kg), marked persistence of hypotension accompanied by severe bradycardia were observed. In addition, higher doses of gambirine produced a more marked decrease in diastolic than systolic pressure while at lower doses both decreased equally. It is suggested that the hypotensive effect of gambirine may be peripheral in origin and is associated, at least in part, with a cardiac action.

Conodiparines A-D, new bisindoles from Tabernaemontana. Reversal of vincristine-resistance with cultured cells

Kam TS, Sim KM, Koyano T, Toyoshima M, Hayashi M, Komiyama K

Bioorg Med Chem Lett, 1998 Jul 07;8(13):1693-6.

PMID: 9873417

Four new bisindoles of the vobasine-iboga type, conodiparines A-D were obtained from Tabernaemontana corymbosa which showed appreciable activity in reversing resistance in vincristine-resistant KB cells.

Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata

Kam TS, Pang HS, Choo YM, Komiyama K

Chem Biodivers, 2004 Apr;1(4):646-56.

PMID: 17191876

Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line.

Enhancement of apoptotic activities on brain cancer cells via the combination of γ-tocotrienol and jerantinine A

Abubakar IB, Lim KH, Kam TS, Loh HS

Phytomedicine, 2017 Jul 01;30:74-84.

PMID: 28545672 DOI: 10.1016/j.phymed.2017.03.004

BACKGROUND: γ-Tocotrienol, a vitamin E isomer possesses pronounced in vitro anticancer activities. However, the in vivo potency has been limited by hardly achievable therapeutic levels owing to inefficient high-dose oral delivery which leads to subsequent metabolic degradation. Jerantinine A, an Aspidosperma alkaloid, originally isolated from Tabernaemontana corymbosa, has proved to possess interesting anticancer activities. However, jerantinine A also induces toxicity to non-cancerous cells.

PURPOSE: We adopted a combinatorial approach with the joint application of γ-tocotrienol and jerantinine A at lower concentrations in order to minimize toxicity towards non-cancerous cells while improving the potency on brain cancer cells.

METHODS: The antiproliferative potency of individual γ-tocotrienol and jerantinine A as well as combined in low-concentration was firstly evaluated on U87MG cancer and MRC5 normal cells. Morphological changes, DNA damage patterns, cell cycle arrests and the effects of individual and combined low-concentration compounds on microtubules were then investigated. Finally, the potential roles of caspase enzymes and apoptosis-related proteins in mediating the apoptotic mechanisms were investigated using apoptosis antibody array, ELISA and Western blotting analysis.

RESULTS: Combinatorial study between γ-tocotrienol at a concentration range (0-24µg/ml) and fixed IC20 concentration of jerantinine A (0.16µg/ml) induced a potent antiproliferative effect on U87MG cells and led to a reduction on the new half maximal inhibitory concentration of γ-tocotrienol (i.e.tIC50=1.29µg/ml) as compared to that of individual γ-tocotrienol (i.e. IC50=3.17µg/ml). A reduction on undesirable toxicity to MRC5 normal cells was also observed. G0/G1 cell cycle arrest was evident on U87MG cells receiving IC50 of individual γ-tocotrienol and combined low-concentration compounds (1.29µg/ml γ-tocotrienol + 0.16µg/ml jerantinine A), whereas, a profound G2/M arrest was evident on cells treated with IC50 of individual jerantinine A. Additionally, individual jerantinine A and combined compounds (except individual γ-tocotrienol) caused a disruption of microtubule networks triggering Fas- and p53-induced apoptosis mediated via the death receptor and mitochondrial pathways.

CONCLUSIONS: These findings demonstrated that the combined use of lower concentrations of γ-tocotrienol and jerantinine A induced potent cytotoxic effects on U87MG cancer cells resulting in a reduction on the required individual concentrations and thereby minimizing toxicity of jerantinine A towards non-cancerous MRC5 cells as well as probably overcoming the high-dose limiting application of γ-tocotrienol. The multi-targeted mechanisms of action of the combination approach have shown a therapeutic potential against brain cancer in vitro and therefore, further in vivo investigations using a suitable animal model should be the way forward.

Reactions of Anodically Generated Methoxystilbene Cation Radicals: The Influence of Ortho-Substituted Vinyl and Formyl Groups

Chong KW, Thomas NF, Low YY, Kam TS

J Org Chem, 2019 Jun 07;84(11):7279-7290.

PMID: 31056921 DOI: 10.1021/acs.joc.9b00939

The present investigation represents a continuation of studies on the effect of ortho'-substitution on the reactivity of anodically generated methoxystilbene cation radicals. Whereas previous studies have focused on the effect of ortho'-substituted nucleophilic groups such as OH, NH2, CH2OH, CH2NH2, and COOH, the present study extends the investigation to ortho'-substituted vinyl and formyl groups. The results show that when the ortho'-substituent is a vinyl group, the products include a bisdihydronaphthalene derivative and a doubly bridged, dibenzofused cyclononane from direct trapping of a bis carbocation intermediate. In the presence of an additional 3-methoxy substituent, the products are the tetracyclic chrysene derivatives. When the ortho'-substituent is a nonnucleophilic formyl group, the products include fused indanylnaphthalenes and indanylbenzopyran aldehydes. When an additional 3-methoxy group is present, an unusual fused benzofluorene-dibenzoannulene product is obtained. Mechanistic rationalization for the formation of the various products is presented. The results have contributed to a deeper understanding of how the reactivity of the methoxystilbene cation radicals is affected by the nature of the ortho'-substituents.

Reactivity of Anodically Generated 4-Methoxystilbene Cation Radicals: The Influence of Ortho-Substituted Hydroxymethyl, Aminomethyl, and Carboxylic Acid Groups

Chong KW, Thomas NF, Low YY, Kam TS

J Org Chem, 2018 Dec 21;83(24):15087-15100.

PMID: 30488699 DOI: 10.1021/acs.joc.8b02360

The effect of ortho'-substituted side chains bearing nucleophilic groups such as CH2OH, CH2NHR, and CO2H on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals was investigated, and results were compared with those of substrates where the nucleophilic groups such as OH and NHR are directly attached to the aromatic ring. It was found that when ortho'-substituted groups such as CH2OH or CH2NHR are present in the other ring, only direct intramolecular cation-nucleophile reactions occur to give bisbenzopyrans or bisisoquinolines. Crossover products (previously obtained when the ortho' substituents were OH and NH2) such as the fused benzoxepanes/fused benzoazepanes were not formed. When the ortho' substituent is COOH, direct intramolecular cation-nucleophile reaction occurs to give the corresponding bis-δ-lactones in high yield. The presence of an additional 3-methoxy substituent resulted in the formation of other fused polycyclic products due to competing aromatic substitution reactions. Reaction pathways leading to the different products and reasons for the difference in behavior shown by the present stilbenes are presented. The results have provided additional insight into the reactivity and behavior of anodically generated stilbene cation radicals.

Aspidofractinine and Eburnane Alkaloids from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused, and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora

Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS

J Nat Prod, 2016 Jan 22;79(1):230-9.

PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992

Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.

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.

Corynanthean, eburnan, secoleuconoxine, and pauciflorine alkaloids from Kopsia pauciflora

Gan CY, Yoganathan K, Sim KS, Low YY, Lim SH, Kam TS

Phytochemistry, 2014 Dec;108:234-42.

PMID: 25442910 DOI: 10.1016/j.phytochem.2014.09.014

Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine-resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo.

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.

Oxidized derivatives of macroline, sarpagine, and pleiocarpamine alkaloids from Alstonia angustifolia

Tan SJ, Lim JL, Low YY, Sim KS, Lim SH, Kam TS

J Nat Prod, 2014 Sep 26;77(9):2068-80.

PMID: 25211145 DOI: 10.1021/np500439u

A total of 20 new indole alkaloids comprising mainly oxidized derivatives of macroline- (including alstofonidine, a macroline indole incorporating a butyrolactone ring-F), pleiocarpamine-, and sarpagine-type alkaloids were isolated from the bark and leaf extracts of Alstonia angustifolia. The structures and relative configurations of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 3, 7, 35, and 41 showed moderate to weak activity, while 21 showed strong activity in reversing multidrug resistance in vincristine-resistant KB cells.

Transformations of the 2,7-Seco Aspidosperma alkaloid leuconolam, structure revision of epi-leuconolam, and partial syntheses of leuconoxine and leuconodines A and F

Low YY, Hong FJ, Lim KH, Thomas NF, Kam TS

J Nat Prod, 2014 Feb 28;77(2):327-38.

PMID: 24428198 DOI: 10.1021/np400922x

Several transformations of the seco Aspidosperma alkaloid leuconolam were carried out. The based-induced reaction resulted in cyclization to yield two epimers, the major product corresponding to the optical antipode of a (+)-meloscine derivative. The structures and relative configuration of the products were confirmed by X-ray diffraction analysis. Reaction of leuconolam and epi-leuconolam with various acids, molecular bromine, and hydrogen gave results that indicated that the structure of the alkaloid, previously assigned as epi-leuconolam, was incorrect. This was confirmed by an X-ray diffraction analysis, which revealed that epi-leuconolam is in fact 6,7-dehydroleuconoxine. Short partial syntheses of the diazaspiro indole alkaloid leuconoxine and the new leuconoxine-type alkaloids leuconodines A and F were carried out.

Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla

Lim SH, Low YY, Sinniah SK, Yong KT, Sim KS, Kam TS

Phytochemistry, 2014 Feb;98:204-15.

PMID: 24342109 DOI: 10.1016/j.phytochem.2013.11.014

A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells.

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.

Perhentidines A-C: macroline-macroline bisindoles from Alstonia and the absolute configuration of perhentinine and macralstonine

Lim SH, Low YY, Tan SJ, Lim KH, Thomas NF, Kam TS

J Nat Prod, 2012 May 25;75(5):942-50.

PMID: 22559995 DOI: 10.1021/np300120p

Three new bisindole alkaloids of the macroline-macroline type, perhentidines A-C (1-3), were isolated from the stem-bark extract of Alstonia macrophylla and Alstonia angustifolia. The structures of these alkaloids were established on the basis of NMR and MS analyses. The absolute configurations of perhentinine (4) and macralstonine (5) were established by X-ray diffraction analyses, which facilitated assignment of the configuration at C-20 in the regioisomeric bisindole alkaloids perhentidines A-C (1-3). A potentially useful method for the determination of the configuration at C-20 based on comparison of the NMR chemical shifts of the bisindoles and their acetate derivatives, in these and related bisindoles with similar constitution and branching of the monomeric units, is also presented.

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