新型四氢苯并噻唑化合物作为雄激素受体调节剂的合成与构效关系（英文）  

Synthesis and Structure-activity Relationship of Novel Tetrahydrobenzo[d]thiazole as Androgen Receptor Modulator

作　　者：王明博 曾凡勋 刘鹏飞[1] 肖新哲 夏爽 邓小康 黄瑾[1,2] 徐晓勇[1,3] WANG Ming-Bo;ZENG Fan-Xun;LIU Peng-Fei;XIAO Xin-Zhe;XIA Shuang;DENG Xiao-Kang;HUANG Jin;XU Xiao-Yong(Shanghai Key Laboratory of Chemical Biology,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;Shanghai Collaborative Innovation Center for Biomanufacturing Technology,130 Meilong Road,Shanghai 200237,China)

机构地区：[1]华东理工大学药学院上海生物化学重点实验室,上海200237 [2]华东理工大学药学院上海新药设计重点实验室,上海200237 [3]华东理工大学药学院上海生物制造技术协同创新中心,上海200237

出　　处：《中国生物化学与分子生物学报》2018年第9期962-971,共10页Chinese Journal of Biochemistry and Molecular Biology

基　　金：Supported by National Natural Science Foundation of China(No.81773775);Project of Science and Technology Commission of Shanghai Municipality(No.15431902000);Special Funding for Basic Scientific Research in Central Universities~~

摘　　要：前列腺癌是男性最常被诊断出的癌症之一,而雄激素受体(androgen receptor,AR)是前列腺癌治疗的重要靶标。现有的AR拮抗剂在长期使用后通常由于多种原因而失效。因此,新型AR拮抗剂的开发仍具有重要的意义。一系列四氢苯并噻唑类化合物,通过α,β-环氧环己酮与适当的硫脲的缩合反应被合成。其中,多个化合物在酵母双杂交系统中表现出强于或相当于氟他胺的雄激素受体拮抗活性(IC50≤2. 48 mmol/L)。进一步的细胞活力试验表明,这些活性化合物有效地抑制了雄激素敏感的LNCa P细胞的增殖(IC50值17. 1～41. 4 mmol/L)。分子对接研究提供了化合物与受体相互作用的可能模型,较好地符合了初步的构效关系研究。总之,本文的研究证明,四氢苯并噻唑可以作为有效的AR调节剂,可能代表了一种有前景的先导化合物,有助于进一步开发出新型的更加强效的雄激素受体拮抗剂。Prostate cancer is one of the most commonly diagnosed cancer in men,and androgen receptor（ AR） is an important target for the treatment of prostate cancer. For many reasons,existing AR antagonists fail to treat prostate cancer after long-term use. Therefore,the development of novel AR antagonists is still of great significance. A series of tetrahydrobenzo [d]thiazole compounds were synthesized by condensation reaction of α,β-epoxycyclohexanones and appropriate substituted thioureas8,which were obtained from the corresponding anilines 7. Their antiandrogenic activities were tested using an yeast two-hybrid（ Y2 H） system,and several compounds exhibited androgen receptor（ AR）antagonistic behavior equal or stronger than that of flutamide（ IC50≤ 2. 48 mmol/L）. Further cell viability assay demonstrated that some active compounds effectively inhibited the proliferation of androgensensitive LNCa P cells values with IC50 values of 17. 1 ～ 41. 4 mmol/L. Molecular docking study provide a possible model of ligand receptor interactions,which was consistent with the initial structure-activity relationship（ SAR） studies. Taken together,tetrahydrobenzo[d]thiazoles act as effective AR modulators may represent promising leads for further development of novel and improved AR antagonists.

关 键 词：噻唑 雄激素受体 前列腺癌 构效关系 

分 类 号：R914[医药卫生—药物化学]