Design and Synthesis of Androgen Receptor Antagonists with Bulky Side Chains for Overcoming Antiandrogen Resistance

Incorporation of curcumin and beta-ionone into one chemical entity led to identification of a novel antiandrogen with two bulky side chains, 6, which is a pure antagonist of the wild-type and the T877A, W741C, and H874Y mutated androgen receptors (AR), showing no cross-reactivity with progesterone receptor and low micromolar cytotoxicity in LNCaP, PCa-2b, 22Rv1, and C4-2B prostate cancer cells. Molecular modeling indicates 6 adopts a Y-shape conformation and forms multiple hydrogen bonds with AR backbone.