RESUMEN
Inspired by potent antiproliferative xanthone natural products and so far limited examples of derived bioactive agents, a structure activity study of architecturally novel types of xanthones is reported. Their preparation was enabled in a short and divergent manner by a modular chlorination in combination with optimized protocols for a polar condensation and a hetero-cyclization. Application of these procedures allowed for the synthesis of various polyhalogenated representatives (including mixed bromo/chloro xanthones) that were obtained in up to fourfold improved yields as compared to previous procedures. Subsequent Suzuki coupling of either halide enabled access to phenyl- and chloro-bearing xanthones, which may be functionalized at four out of five non-hydroxylated positions. Antiproliferative assays against breast cancer cell lines revealed potent activities of some of these simplified analogs that are in the range of pharmaceutically used anticancer drug doxorubicin.
Asunto(s)
Antineoplásicos , Proliferación Celular , Doxorrubicina , Ensayos de Selección de Medicamentos Antitumorales , Xantonas , Xantonas/química , Xantonas/síntesis química , Xantonas/farmacología , Humanos , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Estructura Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
A versatile strategy to halogenated xanthones was developed that relies on a modular coupling of vanillin derivatives with a dibromoquinone. Depending on the reaction conditions, either the 6- or the 7-bromo heterocycles may be obtained in a divergent manner. These heterocycles may be readily further elaborated by sequential Sonogashira couplings, and the sequence may be successfully applied to substructures of the antibiotic lysolipin.
