Chiral resolution of a caged xanthone and evaluation across a broad spectrum of breast cancer subtypes

Enantiomerically pure or racemic mixtures of (+/−)-MAD28 show increased cytotoxicity against triple negative, metastatic and chemorefractant breast cancer subtypes. [Display omitted] •Racemic resolution of a caged xanthone was performed with a resolving agent.•(+)-,(−)-, and (+/−)- MAD28 are equipotent in a panel of breast cancer cell lines.•(+/−)- MAD28 exhibits higher cytotoxicity against triple negative breast cancer cell lines.•Caged xanthones are promising leads as breast cancer-targeting therapeutics. Racemic resolution of (+/−)-MAD28, a representative caged xanthone, was accomplished using (1S, 4R)-(−)-camphanic chloride as the chiral agent. Selective crystallization of the resulting diastereomers in acetonitrile produced, after hydrolysis, the pure enantiomers. Screening of racemic MAD28 and both enantiomers across a broad spectrum of breast cancer cell lines revealed that they: (a) are equipotent in each of the breast cancer subtypes examined; and (b) exhibit a higher degree of cytotoxicity against breast cancer cell lines of basal-like subtype and triple negative receptor status. The results support the notion that MAD28 and related caged xanthones are promising drug leads against chemoresistant and metastatic cancers.