RESUMEN
A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-ß-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1-14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR) study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/química , Carbolinas/síntesis química , Carbolinas/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Células KB , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Mana-Hox is a synthetic analog of manzamines, which are beta-carboline alkaloids isolated from marine sponges. Mana-Hox exhibited cytotoxicity against various tumor cell lines with the IC(50) range from 1 to 5 microM. Cell cycle synchronization and flow cytometric analysis showed that Mana-Hox delayed cell cycle progression at mitosis. At the concentration that delayed mitotic progression, bipolar spindle with lagged chromosomes and multipolar spindle with disorganized chromosomes were detected. The presence of such aberrant mitotic cells accompanied by the activation of spindle checkpoint that delayed cells exit from mitosis. However, after a short delay, lagged chromosomes were able to display in the abnormal metaphase plates, and subsequent cell division resulting in chromosome missegregation. Furthermore, the aberrant mitotic cells showed lower viability, indicating that Mana-Hox-induced cell death resulting from chromosome missegregation. This study is the first to explore cytotoxic mechanism of a manzamine-related compound and understand its potential as a lead compound for the development of future anticancer agents.
Asunto(s)
Alcaloides/química , Alcaloides/toxicidad , Carbolinas/química , Carbolinas/toxicidad , Citotoxinas/química , Citotoxinas/toxicidad , Indoles/química , Pirroles/química , Carbazoles , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cromosomas Humanos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Nocodazol/farmacología , Huso Acromático/efectos de los fármacosRESUMEN
Phytochemical investigation of taxane diterpenoidal content of an acetone extract of the leaves and twigs of Taxus sumatrana has resulted in the isolation of three new taxoid compounds, tasumatrols E (1), F (2), and G (3) together with 13 known taxanes (5-16). The structures of these taxanes as well as their derivatives were established on the basis of spectroscopic analyses, especially 1D and 2D NMR. Compounds 1, 2, 12, and 16 exhibited significant cytotoxicity against human A-498, NCI-H226, A549, and PC-3 tumor cells.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Plantas Medicinales/química , Taxoides/aislamiento & purificación , Taxus/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Hojas de la Planta/química , Taiwán , Taxoides/química , Taxoides/farmacología , Células Tumorales CultivadasRESUMEN
Five new taxane diterpenoids, taxumairols G (1), H (2), I (3), J (4), and L (5) were isolated from extracts of the roots of Taiwanese Taxus mairei (LEMEE & LEVL.) S. Y. Hu. Compounds 1-4 belong to the new 11(15-->1)-abeo-taxene system, having a tetrahydrofuran ring along carbons C-2, C-3, C-4 and C-20. Compounds 3 and 4 contain an isopropenyl group at C-1 while compounds 1 and 2 are attached with a benzoxyl group at C-15. The structures of compounds 1-5 were determined on the basis of two-dimensional (2D)-NMR techniques including correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC), and nuclear Overhauser effect spectroscopy (NOESY) experiments.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/aislamiento & purificación , Diterpenos/aislamiento & purificación , Taxoides , Taxus/química , Hidrocarburos Aromáticos con Puentes/química , Diterpenos/química , Raíces de Plantas/química , TaiwánRESUMEN
In addition to 19-dydroxybaccatin III, 1beta-hydroxy-5 alpha-deacetylbaccatin I, taxayuntin G and 13-O-deacetyltaxumairol Z (4), three new taxane diterpenoids, taxumairols X (1), Y (2), Z (3) have been isolated from extracts of the Formosan Taxus mairei (LEMEE & LEVL.) S. Y. HU. Compounds 1-2 belong to the 11(15-->1)-abeo-taxane system, having a tetrahydrofuran ring at C-2, C-3, C-4 and C-20. The new compound 3 and 4, which was misidentified previously are derivatives of 11(15-->1)-abeo-taxane with an intact oxirane system. The structures of compounds 1-4 were elucidated on the basis of extensive two dimensional (2D)-NMR analysis.
Asunto(s)
Paclitaxel/aislamiento & purificación , Taxoides , Taxus/química , Espectroscopía de Resonancia Magnética , Paclitaxel/análogos & derivados , Componentes Aéreos de las Plantas/química , Raíces de Plantas/química , Plantas Medicinales/química , TaiwánRESUMEN
Two new taxane diterpenoids, tasumatrols A (1) and B (2), have been isolated from extracts of the leaves and twigs of Taiwanese Taxus sumatrana. Tasumatrol A is a rare 5/6/6 taxene system, having a novel gamma-lactone at C-10 and C-19. The structures of compounds 1 and 2 were determined on the basis of two dimensional (2D)-NMR techniques, including correlation spectroscopy (COSY), 1H-detected heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond connectivity (HMBC) experiments.