developmentofaminocarbonylcompoundsasandrogenreceptorantagonists

	developmentofaminocarbonylcompoundsasandrogenreceptorantagonists
	Zhang Zhiyun; Zhu Yanhui; Zhou Caihong; Liu Qing; Lu Huili; Ge Yunjun; Wang Mingwei
刊名	actapharmacologicasinica
	2014
卷号	35 期号:5 页码:664
关键词	prostate cancer structural modification androgen receptor antagonist molecular docking β-amino-carbonyl compound
ISSN号	1671-4083
英文摘要	Aim: Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist. Methods: Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts. Results: Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH_2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S). Conclusion: Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/284088]
专题	中国科学院上海药物研究所
作者单位	中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Zhang Zhiyun,Zhu Yanhui,Zhou Caihong,et al. developmentofaminocarbonylcompoundsasandrogenreceptorantagonists[J]. actapharmacologicasinica,2014,35(5):664.
APA	Zhang Zhiyun.,Zhu Yanhui.,Zhou Caihong.,Liu Qing.,Lu Huili.,...&Wang Mingwei.(2014).developmentofaminocarbonylcompoundsasandrogenreceptorantagonists.actapharmacologicasinica,35(5),664.
MLA	Zhang Zhiyun,et al."developmentofaminocarbonylcompoundsasandrogenreceptorantagonists".actapharmacologicasinica 35.5(2014):664.