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Discovery of novel 5‐methyl‐1H‐pyrazole derivatives as potential antiprostate cancer agents: Design, synthesis, molecular modeling, and biological evaluation
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2018-03-01 , DOI: 10.1111/cbdd.13173
Daoguang Zhang 1 , Solomon Asnake 2 , Jingya Zhang 1 , Per-Erik Olsson 2 , Guisen Zhao 1
Affiliation  

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration‐resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5‐methyl‐1H‐pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability compared with 10e in human liver microsomes.

中文翻译:

发现新型5-甲基-1H-吡唑衍生物作为潜在的抗前列腺癌药物:设计,合成,分子建模和生物学评估

雄激素受体(AR)信号传导是前列腺癌(PCa)病情发展的核心驱动力,而且AR被证明甚至是去势抵抗性前列腺癌(CRPC)的有效治疗靶标。在此,基于两个前导化合物T310e通过片段剪接策略进行结构修饰,从而发现了一系列5-甲基-1 H-吡唑衍生物。AR报道基因检测表明,化合物A13A14是有效的AR拮抗剂。该系列中的某些化合物比恩杂鲁胺更有效地抑制PCa LNCaP细胞的生长。A13A14与人肝微粒体中的10e相比,还显示出改善的代谢稳定性。
更新日期:2018-03-01
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