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

• Published in: European journal of medicinal chemistry 2016-04, Vol.112, p.231-251
• Main Authors: Wang, Yang, Cheng, Fei Xiong, Yuan, Xiao Long, Tang, Wen Jian, Shi, Jing Bo, Liao, Chen Zhong, Liu, Xin Hua
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Dihydropyrazole; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Hep G2 Cells; Humans; Inhibitor; Male; Mice; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats; Rats, Sprague-Dawley; Selective anticancer activity; Telomerase; Telomerase - antagonists & inhibitors; Telomerase - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.02.009

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. Based on structure-based drug design, 78 compounds as potential human telomerase inhibitors were designed. In vivo studies showed that compound 13i displayed potent anticancer activity with inhibition tumor growth of S180 and HepG2 tumor-bearing mice. It also significantly enhanced the survival rate of EAC tumor-bearing mice. [Display omitted] •Structure-based design used as the new coumarin telomerase inhibitors.•Based on 78 new compounds, the rational SAR was analyzed.•In vivo studies showed that compound 13i displayed potent anticancer activity.