Development of beta-amino-carbonyl compounds as androgen receptor antagonists
文献类型：期刊论文
| 作者 | Zhang, Zhi-yun1,3; Zhu, Yan-hui1,3; Zhou, Cai-hong1,3; Liu, Qing1,3; Lu, Hui-li1,3; Ge, Yun-jun1,3; Wang, Ming-wei1,2,3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2014-05 |
| 卷号 | 35期号:5页码:664-673 |
| 关键词 | prostate cancer structural modification androgen receptor antagonist molecular docking beta-amino-carbonyl compound |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.201 |
| 文献子类 | Article |
| 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 beta-amino-carbonyl-based androgen receptor antagonist. Methods: Different isomers of the beta-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, 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). 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. |
| WOS关键词 | ADVANCED PROSTATE-CANCER ; STRUCTURAL BASIS ; CELL-GROWTH ; ANTIANDROGEN ; INVOLVEMENT |
| 资助项目 | Ministry of Health[2012ZX09304-011] ; Ministry of Health[2013ZX09401003-005] ; Ministry of Health[2013ZX09507001] ; Ministry of Health[2013ZX09507002] ; Shanghai Science and Technology Development Fund[13DZ2290300] ; Thousand Talents Program in China[00000000] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000335447000011 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277100]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Wang, Ming-wei |
| 作者单位 | 1.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.S China Univ Technol, Sch Biosci & Bioengn, Guangzhou 510006, Guangdong, Peoples R China 3.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Zhi-yun,Zhu, Yan-hui,Zhou, Cai-hong,et al. Development of beta-amino-carbonyl compounds as androgen receptor antagonists[J]. ACTA PHARMACOLOGICA SINICA,2014,35(5):664-673. |
| APA | Zhang, Zhi-yun.,Zhu, Yan-hui.,Zhou, Cai-hong.,Liu, Qing.,Lu, Hui-li.,...&Wang, Ming-wei.(2014).Development of beta-amino-carbonyl compounds as androgen receptor antagonists.ACTA PHARMACOLOGICA SINICA,35(5),664-673. |
| MLA | Zhang, Zhi-yun,et al."Development of beta-amino-carbonyl compounds as androgen receptor antagonists".ACTA PHARMACOLOGICA SINICA 35.5(2014):664-673. |
入库方式： OAI收割
来源：上海药物研究所
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