Zhang Zhi-yun, Zhu Yan-hui, Zhou Cai-hong, Liu Qing, Lu Hui-li, Ge Yun-jun, Wang Ming-wei
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
1] The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
Acta Pharmacol Sin. 2014 May;35(5):664-73. doi: 10.1038/aps.2013.201.
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.
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.
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, NH2- 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).
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.
雄激素受体（AR）拮抗剂已被证明在前列腺癌的早期控制中有用。本研究的目的是鉴定和表征一种新型的基于β-氨基羰基的雄激素受体拮抗剂。
通过手性分离获得β-氨基羰基化合物的不同异构体。通过AR核转位、哺乳动物双杂交、竞争性受体结合和细胞增殖试验评估异构体的生物活性。用实时PCR分析AR下游基因的表达。在携带LNCaP异种移植瘤的雄性SCID小鼠中观察对体内肿瘤生长的治疗效果。
化合物21先前通过对多种化合物文库的高通量筛选被鉴定为AR调节剂。在本研究中，化合物21的两种异构体，称为化合物21-1和21-2，在雄激素诱导的AR核转位、前列腺特异性抗原表达和细胞增殖方面被表征为部分AR激动剂。进一步的结构修饰导致发现了一种雄激素受体拮抗剂（化合物6012），它阻断雄激素受体核转位、雄激素反应性基因表达和雄激素依赖性LNCaP细胞增殖。分离出化合物6012的四种立体异构体，并评估了它们的生物活性。6012的药理作用，包括AR结合、雄激素诱导的AR转位、NH2-和COOH-末端相互作用、体外LNCaP细胞生长抑制和裸鼠中LNCaP异种移植瘤生长，主要限于异构体6012-4（1R，3S）。
化合物6012-4被确定为一种新型雄激素受体拮抗剂，其在体外和体内对前列腺癌的抑制活性与比卡鲁胺相当。
