Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants.

Abstract	A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used antiandrogens. We aim to identify novel antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.
Authors	Jinming Zhou, Guoyan Geng, Jian Hui Wu
Journal	Investigational new drugs (Invest New Drugs) Vol. 28 Issue 3 Pg. 291-8 (Jun 2010) ISSN: 1573-0646 [Electronic] United States
PMID	19390783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Androgen Antagonists Androgen Receptor Antagonists Antineoplastic Agents, Hormonal Chalcones Norisoprenoids Receptors, Androgen
Topics	Androgen Antagonists (chemical synthesis, pharmacology, therapeutic use) Androgen Receptor Antagonists Antineoplastic Agents, Hormonal (chemical synthesis, pharmacology, therapeutic use) Cell Line, Tumor Cell Proliferation (drug effects) Chalcones (chemical synthesis, pharmacology, therapeutic use) Drug Design Drug Resistance, Neoplasm (genetics) Drug Screening Assays, Antitumor Humans Male Molecular Structure Mutation (drug effects) Norisoprenoids (chemical synthesis, pharmacology, therapeutic use) Receptors, Androgen (genetics) Structure-Activity Relationship

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