RESUMEN
A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines (~60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunction. Moreover, the compounds induced a concentration-dependent accumulation of cells in the subG0/G1phase, while confined viable cells in G2/M phase.
Asunto(s)
Antineoplásicos/síntesis química , Diseño de Fármacos , Imidazoles/síntesis química , Indoles/síntesis química , Neoplasias/tratamiento farmacológico , Piridinas/síntesis química , Pirroles/síntesis química , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fase G2/efectos de los fármacos , Halogenación , Humanos , Imidazoles/química , Imidazoles/farmacología , Indoles/química , Indoles/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metilación , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estructura Molecular , Neoplasias/patología , Piridinas/química , Piridinas/farmacología , Pirroles/química , Pirroles/farmacología , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2'-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivatives, methoxy substituents at positions 3 and 8 or/and 9 were especially effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were associated to IIQ-mediated impairment of tubulin polymerization at pharmacologically significant concentrations of tested compounds. In addition, impaired DNA topoisomerase I functions and perturbation in telomere architecture were observed in cells exposed to micromolar concentrations of IIQ derivatives. The above results suggest that IIQ derivatives exhibit multi-target cytotoxic activities.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Iminas/química , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Quinoxalinas/química , Solubilidad , Tubulina (Proteína)/metabolismo , AguaRESUMEN
Using a phenotypic screening and SAR optimization approach, a phenyl-bis-oxazole derivative has been identified with anti-proliferative activity, optimized with the use of a panel of cancer cell lines. The lead compound was synthesized by means of a short and effective two-step synthesis using Pd-catalyzed direct arylation. The compound stabilizes several quadruplex DNA sequences including a human telomeric DNA and one from the promoter of the HSP90 gene, although the structure-activity relationships of the series are not obviously related to the quadruplex binding.
Asunto(s)
G-Cuádruplex , Compuestos Heterocíclicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Concentración 50 Inhibidora , Ligandos , Relación Estructura-ActividadRESUMEN
A series of substituted ethyl 1-[(tert-butoxycarbonyl)amino]-2-methyl-5- (1-methyl-1H-indol-3-yl)-4-[(1-methyl-1H-indol-3-yl)carbonyl]-1H-pyrrole-3-carboxylates were prepared in excellent yields (82-98%) by one-pot reactions between ß-dicarbonyl compounds 12a-e and 1,2-diaza-1,3-diene (DD) 13. Derivatives 10a,c-e, deazaanalogues of the bis-indole alkaloid topsentin, screened by the National Cancer Institute (Bethesda, MD, USA) in the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity, with the exception of compound 9e, which showed moderate activity against the HOP-92 cell line of the non small cell lung cancer sub-panel and the SNB-75 cell line of the CNS sub-panel.