RESUMEN
Pyrano[3,2- c]pyridone and pyrano[3,2- c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Proliferación Celular/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Quinolonas/química , Quinolonas/farmacología , Tubulina (Proteína)/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/síntesis química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Piridonas/síntesis química , Quinolonas/síntesis química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
4-Arylpyrano-[3,2-c]-pyridones have been prepared by a one-step cyclocondensation of 4-hydroxy-1,6-dimethylpyridin-2(1H)-one with various substituted benzaldehydes and malononitrile. These heterocycles exhibit micromolar and submicromolar antiproliferative activity in HeLa and induce apoptosis in Jurkat cell lines. Structure-activity studies performed on a small library of these compounds show a pronounced cytotoxicity enhancing effect of the bromo substituent at the meta position of the C4 aromatic moiety.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Piridonas/farmacología , Humanos , Células Jurkat , Relación Estructura-ActividadRESUMEN
Plants used in folklore medicine continue to be an important source of discovery and development of novel therapeutic agents. In the present study, we determined the effects of crude aqueous extracts of a panel of medicinal plants on the growth and invasion of cancer cells. Our results showed that extracts of L. tridentata (Creosote Bush) and J. communis L. (Juniper Berry) significantly decreased the growth of MCF-7/AZ breast cancer cells. The latter as well as A. californica (Yerba Mansa) inhibited invasion into the collagen type I gel layer. Furthermore, the phosphorylation levels of extracellular signal-regulated kinase 1 and 2 (ERK1/2) decreased when the cells were exposed to aqueous extracts of L. tridentata, J. communis L. and A. californica. This study provides original scientific data on the anticancer activity of selected aqueous medicinal plant extracts used in traditional medicine.