Two new bisindole alkaloids, bisnicalaterines B and C (1 and 2) consisting of an eburnane and a corynanthe type of skeletons, were isolated from the bark of Hunteria zeylanica. Their absolute structures were determined by combination of NMR, CD, and computational methods, and each of them was shown to be in an atropisomeric relationship. Bisnicalaterines B and C (1 and 2) showed potent vasorelaxant activity on isolated rat aorta.
The tryptamine-derived polycyclic bridged bioactive indole alkaloids subincanadines A-G were isolated in 2002 by Ohsaki and coworkers from the bark of the Brazilian medicinal plant Aspidosperma subincanum. Kobayashi proposed that subincanadines D-F could be biosynthetically resulting from stemmadenine via two different pathways and, furthermore, that the subincanadines A-C could be biogenetically resulting from subincanadines D and E. Kam and coworkers, in their focused efforts, isolated five indole alkaloids from Malaysian Kopsia arborea species, namely valparicine, apparicine, arboridinine, arborisidine, and arbornamine in combination with subincanadine E. On the basis of structural features, it has been proposed and proved in some examples that subincanadine E is a biogenetic precursor of these five different bioactive indole alkaloids bearing complex structural architectures. All important information on isolation, characterization, bioactivity, probable biogenetic pathways, and more specifically racemic and enantioselective total synthesis of subincanadine alkaloids and their biogenetic congeners are summarized in the present chapter. Special importance is given to the total synthesis and the synthetic strategies intended therein, comprising a set of main reactions.
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.
In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.
Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the β-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.
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.
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.
Nine bisindole alkaloids, comprising four belonging to the macroline-sarpagine group, and five belonging to the macroline-pleiocarpamine group, were isolated from the stem-bark extracts of Alstonia angustifolia (Apocynacea). Their structures were established using NMR and MS analyses.
A total of 20 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia angustiloba, of which two are hitherto unknown. One is an alkaloid of the angustilobine type (angustilobine C), while the other is a bisindole alkaloid angustiphylline, derived from the union of uleine and secovallesamine moieties. The structures of these alkaloids were established using NMR and MS analysis. Angustilobine C showed moderate cytotoxicity towards KB cells.
Leucofoline and leuconoline, representing the first members of the aspidospermatan-aspidospermatan and eburnane-sarpagine subclasses of the bisindole alkaloids, respectively, were isolated from the Malayan Leuconotis griffithii. The structures of these bisindole alkaloids were established using NMR and MS analysis, and in the case of leuconoline, confirmed by X-ray diffraction analysis. Both alkaloids showed weak cytotoxicity towards human KB cells.
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.
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.
Lumusidines A-D, bisindole alkaloids of the macroline-macroline type, and one of the macroline-pleiocarpamine type, villalstonidine F, were isolated from the stem-bark extract of Alstonia macrophylla (Apocynaceae). The structures and absolute configurations of these alkaloids were established using NMR, MS, and X-ray diffraction analyses.
Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.
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.
Eight undescribed iboga alkaloids, polyneurines A-H, were isolated from the bark of Tabernaemontana polyneura. The structures of these alkaloids were established by interpretation of the MS and NMR data, while the configurations were determined using GIAO NMR calculations and DP4+ probability analysis, TDDFT-ECD method, or X-ray diffraction analysis. Polyneurine A possesses a γ-lactone unit embedded within the iboga skeleton, while polyneurines D and E incorporate a formylmethyl moiety at C-3 of the iboga skeleton. Biosynthetic pathways towards the formation of polyneurines A, C, D, and E were proposed.
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.
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.
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.