受比卡鲁胺启发的新型1,2,3-三唑衍生雄激素受体拮抗剂的合成与初步研究

Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

作者信息

Altimari Jarrad M, Niranjan Birunthi, Risbridger Gail P, Schweiker Stephanie S, Lohning Anna E, Henderson Luke C

机构信息

Strategic Research Center for Chemistry and Biotechnology, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia; Institute for Frontier Materials, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia.

Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia.

出版信息

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4948-53. doi: 10.1016/j.bmcl.2014.09.036. Epub 2014 Sep 19.

DOI:10.1016/j.bmcl.2014.09.036

PMID:25301770

Abstract

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 μM and 29-151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

摘要

本文介绍了一种通用且高产率的新型雄激素受体（AR）拮抗剂合成方法。采用该方法，通过五步合成了六种1,4-取代-1,2,3-三唑衍生的比卡鲁胺类似物，分离总产率为41%至85%。评估这些化合物对雄激素依赖性（LNCaP）和非依赖性（PC-3）细胞的抗增殖特性，其IC50值分别为34 - 45 μM和29 - 151 μM，结果令人满意。数据表明，后一类化合物可能是开发针对雄激素依赖性和非依赖性前列腺癌治疗药物的极佳起点。还对这些化合物（每种对映体）进行了计算机模拟对接，使其与LNCaP细胞所具有的T877A突变雄激素受体结合。