RESUMEN
A series of syn-restricted polymethoxylated 4-heteroarylcoumarins--the isostuctural analogs of combretastatin A-4--was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiproliferative activity. The 4-(1-methyl-1H-indol-5-yl)chromen-2-ones exhibit a potent cytotoxicity against HBL100 epithelial cell line with an IC(50) value amounting to 0.098 and 0.078 microM, respectively. The two compounds, having an indolyl moiety, potent inhibit in vitro microtubule assembly with a substoichiometric mode of action. A structure-activity relationship was discussed and the indolyl moiety was proved to be a good surrogate for the 3-hydroxy-4-methoxyphenyl ring of CA-4.
Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Estilbenos/farmacología , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Sitios de Unión , Neoplasias de la Mama , Línea Celular Tumoral , Cumarinas/síntesis química , Reactivos de Enlaces Cruzados/química , Humanos , Concentración 50 Inhibidora , Estilbenos/síntesis química , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Ensayo de Tumor de Célula MadreRESUMEN
2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.