Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants.
Jinming Zhou, Guoyan Geng, Jian Hui Wu
文献索引:Invest. New Drugs 28 , 291, (2010)
全文:HTML全文
摘要
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.
相关化合物
相关文献:
2011-08-11
[J. Med. Chem. 54 , 5320, (2011)]
2010-06-01
[Eur. J. Med. Chem. 45 , 2307, (2010)]
2011-04-28
[Med. Chem. 54 , 2668, (2011)]
2011-05-01
[Eur. J. Med. Chem. 46 , 1874, (2011)]
2011-04-07
[Org. Biomol. Chem. 9 , 2142, (2011)]