Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
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探索四氢异喹啉硫代乙内酰脲支架阻断雄激素受体作为有效的抗前列腺癌药物
DOI：
10.1016/j.ejmech.2017.10.031
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Bian, Jinlei
中科院分区：
文献类型：
--
作者：
Xu, Xi;Ge, Raoling;Bian, Jinlei
前列腺癌（PC）是世界范围内癌症相关男性死亡的主要原因，并且不断需要鉴定新的和改进的有效抗PC分子。基于恩杂鲁胺的结构和我们的前期工作，合理设计了一种新型的四氢异喹啉硫代乙内酰脲支架，从而发现了一系列新的抗增殖化合物。与enzalutamide相比，几种新的类似物显示出改善的雄激素受体（AR）拮抗活性，同时保持对LNCaP细胞（富含AR）的选择性毒性高于DU 145细胞（AR缺乏）。事实上，化合物55通过损害AR不透明易位而显示出有希望的体外抗肿瘤活性。更重要的是，与我们前期工作中报道的化合物1相比，55显示出更好的药代动力学性质。这些结果证明了朝着开发新的和改进的AR拮抗剂迈出了一步。(C)2017 Elsevier Masson SAS。All rights reserved.
Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists. (C) 2017 Elsevier Masson SAS. All rights reserved.