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

Oraphin Chantarasriwong, Andrew T. Milcarek, Theodore Habarth Morales, Aspen L. Settle, Celso O. Rezende, Bashayer D. Althufairi, Maria A. Theodoraki, Mary L. Alpaugh, Emmanuel A. Theodorakis

    Research output: Contribution to journalArticlepeer-review

    6 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)405-413
    Number of pages9
    JournalEuropean Journal of Medicinal Chemistry
    Volume168
    DOIs
    StatePublished - Apr 15 2019

    All Science Journal Classification (ASJC) codes

    • Pharmacology
    • Drug Discovery
    • Organic Chemistry

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