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.
Zhou
Jinming
J
Montreal Centre for Experimental Therapeutics in Cancer, Segal Cancer Center, McGill University, Montreal, Quebec, Canada.
Geng
Guoyan
G
Shi
Qingwen
Q
Sauriol
Francoise
F
Wu
Jian Hui
JH
D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry; D013196:Dihydrotestosterone / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D045792:Norisoprenoids / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D008024:Ligands; D045792:Norisoprenoids; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D003474:Curcumin