School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Technology, Shanghai 200237, PR China.
Eur J Med Chem. 2016 Apr 13;112:231-251. doi: 10.1016/j.ejmech.2016.02.009. Epub 2016 Feb 6.
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 μM. 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.
我们有兴趣生成和识别具有调节端粒酶的新型化合物，用于癌症治疗。为了进行更合理的设计，基于基于结构的药物设计，我们设计并合成了几类 N-取代二氢吡唑衍生物，总共 78 种潜在的人类端粒酶抑制剂。结果表明，一些化合物对四种肿瘤细胞系具有很强的抗癌活性，并在肿瘤细胞与体细胞之间表现出良好的选择性。通过改良的 TRAP 测定，化合物 13i 对端粒酶表现出最强的抑制活性，IC50 值为 0.98 μM。体内评价结果表明，化合物 13i 能抑制 S180 和 HepG2 荷瘤小鼠的生长，显著提高 EAC 荷瘤小鼠的存活率。进一步的体内结果证实，它能显著改善 N,N-二乙基亚硝胺（DEN）诱导的大鼠肝肿瘤的病理变化。这些数据支持进一步的研究，以评估未来更有效的端粒酶抑制剂的合理设计。
