Research Grants Program Office (RGPO)
Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer.
- Author(s): Chantarasriwong, Oraphin
- Milcarek, Andrew T
- Morales, Theodore Habarth
- Settle, Aspen L
- Rezende, Celso O
- Althufairi, Bashayer D
- Theodoraki, Maria A
- Alpaugh, Mary L
- Theodorakis, Emmanuel A
- et al.
Published Web Locationhttps://doi.org/10.1016/j.ejmech.2019.02.047
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.