Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

Inflammatory breast cancer (IBC) is a highly metastatic, lethal form of breast cancer that lacks targeted therapeutic strategies. Inspired by the promising cytotoxicity of gambogic acid and related caged xanthones in spheroidsMARY-X, an in vitro preclinical IBC model, we constructed a library of synthetic analogs and performed structure-activity relationship studies. The studies revealed that functionalizing the A-ring of the caged xanthone framework can significantly affect potency. Specifically, introduction of hydroxyl or fluorine groups at discrete positions of the A-ring leads to enhanced cytotoxicity at submicromolar concentrations. These compounds induce complete dissolution of spheroidsMARY-X with subsequent apoptosis of both the peripherally- and centrally-located cells, proliferative and quiescent-prone (e.g. hypoxic), respectively. These results highlight the structural flexibility and pharmacological potential of the caged xanthone motif for the design of IBC-targeting therapeutics. [Display omitted] •Inflammatory breast cancer (IBC) is a lethal subtype of breast cancer with no known pharmacological treatment.•A synthetic library of caged xanthones allows structure-activity studies in an IBC model.•A-ring modified caged xanthones are potent against spheroidsMARY-X, an in vitro model of IBC.•Synthetic caged xanthones induce complete dissolution of spheroidsMARY-X and cell apoptosis.•The caged xanthone motif represents a potent drug lead for the design of IBC-targeting therapeutics.