Synthesis and cancer cell cytotoxicity of substituted xanthenes

A series of substituted xanthenes was synthesized and screened for activity using DU-145, MCF-7, and HeLa cancer cell growth inhibition assays. The most potent compound, 9g ([N, N-diethyl]-9-hydroxy-9( 3-methoxyphenyl)-9H-xanthene-3-carboxamide), was found to inhibit cancer cell growth with IC50 values ranging from 36 to 50 mu M across all three cancer cell lines. Structure-activity relationship (SAR) data is presented that indicates additional gains in potency may be realized through further derivatization of the compounds (e. g., the incorporation of a 7-fluoro substituent to 9g). Results are also presented that suggest the compounds function through a unique mechanism of action as compared to that of related acridine and xanthone anticancer agents (which have been shown to intercalate into DNA and inhibit topoisomerase II activity). A structural comparison of these compounds suggests the differences in function may be due to the structure of the xanthene heterocycle which adopts a nonplanar conformation about the pyran ring. (C) 2010 Elsevier Ltd. All rights reserved.