Vincristine-resistant KB Research Articles

Arbolodinines A−C, biologically-active aspidofractinine-aspidofractinine, aspidofractinine-strychnan, and kopsine-strychnan bisindole alkaloids from Kopsia arborea

Three new bisindole alkaloids, arbolodinines A−C, comprising aspidofractinine-aspidofractinine, aspidofractinine-strychnan, and kopsine-strychnan alkaloids, respectively, were isolated from the stem bark extract of the Malayan Kopsia arborea . The structures of the alkaloids were elucidated based on analysis of the spectroscopic data while the absolute configurations were established based on experimental and calculated ECD data. Arbolodinine A is characterized by the union of two aspidofractinine halves with rare and unusual branching from C-5′ of an iminium/carboxylate zwitterion of one aspidofractinine half to the olefinic C-14 of the other aspidofractinine half, while arbolodinines B and C represent first examples of aspidofractinine-strychnan and kopsine-strychnan bisindoles, respectively. Arbolodinine B displayed pronounced cytotoxic effects against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, HCT 116, HT-29, MDA-MB-231, MCF7 and A549 cells with IC 50 values ranging from 1.3 to 9.6 μM. • Three new bisindole alkaloids, arbolodinines A−C were isolated from Kopsia arborea. • Arbolodinine A is an aspidofractinine-aspidofractinine type bisindole. • Arbolodinine B is an aspidofractinine-strychnan type bisindole. • Arbolodinine C is a kopsine-strychnan type bisindole. • Arbolodinine B showed strong cytotoxicity against an array of human cancer cells.

Macroline-Sarpagine Bisindole Alkaloids with Antiproliferative Activity from Alstonia penangiana.

A methanol extract of the stem bark of the Malayan Alstonia penangiana provided seven new bisindole alkaloids, comprising six macroline-sarpagine alkaloids (angustilongines E-K, 1-6) and one macroline-pleiocarpamine bisindole alkaloid (angustilongine L, 7). Analysis of the spectroscopic data (NMR and MS) of these compounds led to the proposed structures of these alkaloids. The macroline-sarpagine alkaloids (1-6) showed in vitro growth inhibitory activity against a panel of human cancer cell lines, inclusive of KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, HCT 116, and A549 cells (IC50 values: 0.02-9.0 μM).

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

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.

Ajmaline, Oxindole, and Cytotoxic Macroline-Akuammiline Bisindole Alkaloids from Alstonia penangiana.

Examination of the EtOH extract of the Malayan Alstonia penangiana resulted in the isolation of 10 new alkaloids, comprising two ajmaline (1, 2), four macroline oxindole (3-6), and four macroline-akuammiline bisindole alkaloids (7-10). The structures of these alkaloids were determined based on analysis of the spectroscopic data and, in the case of the oxindole 6 and the bisindole alkaloid 7, also confirmed by X-ray diffraction analysis. The bisindole alkaloids 7 and 8 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, HCT 116, and A549 cells with IC50 values in the 0.3-8.3 μM range.

Tabercorymines A and B, Two Vobasinyl-Ibogan-Type Bisindole Alkaloids from Tabernaemontana corymbosa.

Tabercorymines A (1) and B (2), two new vobasinyl-ibogan-type bisindole alkaloids with an unprecedented skeleton, were isolated from Tabernaemontana corymbosa. Their structures were established by a combination of spectroscopic data, chemical transformation, single-crystal X-ray diffraction, and ECD calculation. Compound 1 represents a novel bisindole alkaloid, characterized by a caged heteropentacyclic ring system incorporating an unprecedented C-7/C-20 bond in the vobasinyl unit. Alkaloids 1 and 2 showed potent antiproliferative activity against several human cancer cell lines, including vincristine-resistant KB.

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.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Rhazinilam–Leuconolam–Leuconoxine Alkaloids from Leuconotis griffithii

Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.

Grandilodines A−C, Biologically Active Indole Alkaloids from Kopsia grandifolia

Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.

Strychnan and Secoangustilobine A Type Alkaloids from Alstonia spatulata. Revision of the C-20 Configuration of Scholaricine

A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.

Leucoridines A−D, Cytotoxic Strychnos−Strychnos Bisindole Alkaloids from Leuconotis

Four new bisindole alkaloids of the Strychnos-Strychnos type, leucoridines A-D (1-4), were isolated from the stem-bark extract of Leuconotis griffithii. Alkaloids 1-4 showed moderate cytotoxicity against drug-sensitive and vincristine-resistant human KB cells.

Cytotoxic Polyisoprenyl Benzophenonoids from Garcinia subelliptica

Six new polyisoprenyl benzophenonoids, (+/-)-garcinialiptone A (1, 2), garcinialiptone B (3), (-)-cycloxanthochymol (4), garcinialiptone C (5), and garcinialiptone D (6), along with three known compounds, xanthochymol (7), isoxanthochymol (8), and cycloxanthochymol (9), were isolated from the fruits of Garcinia subelliptica. The structures of 1-6 were elucidated by spectroscopic analysis. Biological evaluation showed that all compounds 1-9 exhibited cytotoxic activity against a small panel of human tumor cell lines (A549, DU145, KB, vincristine-resistant KB).

Benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6 H-imidazo[3′,4′:1,2]pyridin[3,4- b]indole-2-substituted acetates: One-pot-preparation, anti-tumor activity, docking toward DNA and 3D QSAR analysis

To discover the anti-tumoral indoles a series of benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6 H-imidazo[3′,4′:1,2]pyridin[3,4- b]indole-2-substituted acetates ( 2a– n) are prepared via one-pot-preparation. The IC 50 values of 2a– n in vitro against human lung carcinoma, prostate cancer, nasopharyngeal carcinoma, vincristine-resistant KB subline and human breast carcinoma cells range from 40 nM to 60 μM. On Sarcoma 180 (S180) tumor-bearing mouse model four of them ( 2e, g, h, i) significantly inhibited the tumor growth. At the dose of 0.1 mg/kg the efficacy of the most potent 2h was equal to that of 1.0 mg/kg of doxorubicin. In contrast to doxorubicin, at 1.0 mg/kg of dose 2e, g, h, i did not induce the treated S180 mice to have organ atrophy and body emaciation. The healthy mice receiving 10, 100 and 500 mg/kg of 2e, g, h, i gave no any neurotoxic response. Even up to the dose of 500 mg/kg the healthy mice occurred no death. The interaction of 2a– n with DNA was confirmed by the fluorescence quenching experiments and automated flexible ligand docking. By 3D QSAR analysis the IC 50 values of 2a– n against prostate cancer cells were correlated with the structures and conformations of their side chains. To increase the data related to their physical-chemical properties the experimental Log P values were also provided.

Leuconicines A−G and (−)-Eburnamaline, Biologically Active Strychnan and Eburnan Alkaloids from Leuconotis

Seven new indole alkaloids of the Strychnos type, leuconicines A-G (1-7), and a new eburnan alkaloid, (-)-eburnamaline (8), were isolated from the stem-bark extract of two Malayan Leuconotis species. The structures of these alkaloids were established using NMR and MS analysis and in the case of 8 also by partial synthesis. Alkaloids 1-5 reversed multidrug resistance in vincristine-resistant KB cells.

Structure, biological activity, and a biomimetic partial synthesis of the lirofolines, novel pentacylic indole alkaloids from Tabernaemontana

Two new pentacyclic indole alkaloids, lirofolines A and B, possessing a novel rearranged ibogan ring system, are obtained from two Malayan Tabernaemontana species ( Tabernaemontana corymbosa and Tabernaemontana divaricata) and the structures are established by analysis of the spectroscopic data. A biomimetic partial synthesis of lirofoline A from ibogaine via the Polonovski reaction is carried out. Lirofolines A and B showed significant activity in reversing multidrug resistance in vincristine-resistant KB cells (IC 50 3.4 and 7.5 μg/ml, respectively).