RESUMEN
Microtubules are among the most successful targets for development of compounds useful for anticancer therapy. Continuing our project to develop new small molecule antitumor agents, two new series of derivatives based on the 2-aroyl-4-phenylbenzofuran molecular skeleton were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. SAR were elucidated with various substitutions on the benzoyl moiety at the 2-position of the benzofuran ring. The most promising compound in this series, the (5-hydroxy-4-phenylbenzofuran-2-yl)(4-methoxyphenyl)methanone derivative (3d), has significant growth inhibitory activity in the submicromolar range against the Molt4, CEM and HeLa cancer cell lines and interacts with tubulin by binding to the colchicine site. Exposure to 3d led to the arrest of K562 cells in the G2-M phase of the cell cycle and to the induction of apoptosis.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzofuranos/síntesis química , Benzofuranos/farmacología , Microtúbulos/efectos de los fármacos , Tubulina (Proteína)/efectos de los fármacos , Animales , Benzofuranos/química , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Citometría de Flujo , Fase G2/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Tubulina (Proteína)/biosíntesisRESUMEN
Allosteric enhancers at the adenosine A(1) receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, allosteric modulators at the adenosine A(1) receptor have therapeutic potential as analgesics and neuroprotective agents. In particular, the compounds with improved potency as enhancers and reduced antagonist properties are mentioned.