Potent but ill researched. Despite promising antiproliferative data of substituted xanthones, their structure-activity relationship remains largely unknown. We systematically synthesized previously inaccessible phenyl- and chloro-bearing xanthones through a modular chlorination followed by a concise and optimized sequence of polar condensation, cyclization and Suzuki coupling. Despite their simplicity several of these xanthones exhibited antiproliferative activities comparable to anticancer drug doxorubicin.

Abstract

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.