Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo
Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo
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二氢吡唑衍生物作为端粒酶抑制剂：基于结构的设计、合成、SAR 和体外和体内抗癌评价
DOI：
10.1016/j.ejmech.2016.02.009
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发表时间：
2016-04-13
影响因子：
6.7
通讯作者：
Liu, Xin Hua
中科院分区：
文献类型：
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作者：
Wang, Yang;Cheng, Fei Xiong;Liu, Xin Hua
因此，开发和鉴定具有端粒酶活性的新化合物用于肿瘤的治疗是我们的研究重点。为了进行更合理的设计，本论文基于基于结构的药物设计，设计并合成了几个系列的N-取代二氢吡唑类化合物，共78个具有潜在的人端粒酶抑制剂活性的化合物。结果表明，部分化合物对4种肿瘤细胞具有较强的抗肿瘤活性，且对肿瘤细胞的选择性优于体细胞。通过改良的TRAP测定，化合物13 i显示出最有效的抗端粒酶活性，IC 50值为0.98 μ M。体内评价结果表明，化合物13 i对S180和HepG 2荷瘤小鼠的生长有抑制作用，对EAC荷瘤小鼠的生存率也有显著提高。进一步的体内实验结果证实，它能明显改善N，N-二乙基亚硝胺（DEN）诱发的大鼠肝癌的病理变化。这些数据支持进一步的研究，以评估更有效的端粒酶抑制剂在未来的合理设计。(C)2016 Elsevier Masson SAS。All rights reserved.
It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. In order to carry out more rational design, based on structure-based drug design, several series of N-substituted-dihydropyrazole derivatives, totally 78 compounds as potential human telomerase inhibitors were designed and synthesized. The results demonstrated that some compounds had potent anticancer activity against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells. By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity against telomerase with an IC50 value of 0.98 mu M. In vivo evaluation results indicated that compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further studies to assess rational design of more efficient telomerase inhibitors in the future. (C) 2016 Elsevier Masson SAS. All rights reserved.