Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo

作者：Wang, Yang; Cheng, Fei Xiong; Yuan, Xiao Long; Tang, Wen Jian; Shi, Jing Bo; Liao, Chen Zhong; Liu, Xin Hua^*

来源：European Journal of Medicinal Chemistry, 2016, 112: 231-251.

DOI：10.1016/j.ejmech.2016.02.009

• Dihydropyrazole
• Selective anticancer activity
• Telomerase
• Inhibitor

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.

• 出版日期2016-4-13
• 单位华东理工大学; 安徽医科大学