Design and synthesis of androgen receptor antagonists with bulky side chains for overcoming antiandrogen resistance

  • J Med Chem. 2009 Sep 10;52(17):5546-50. doi: 10.1021/jm801218k.
Jinming Zhou  1 ,  Guoyan Geng ,  Qingwen Shi ,  Francoise Sauriol ,  Jian Hui Wu
Affiliations
  • 1. Montreal Centre for Experimental Therapeutics in Cancer, Segal Cancer Center, McGill University, Montreal, Quebec, Canada.
PMID: 19725582 DOI: 10.1021/jm801218k
Abstract

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.