title: Dihydropyrazole derivatives as telomerase inhibitors: Structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo.
abstract: 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.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Technology, Shanghai 200237, PR China.
authors.forename: Fei Xiong
authors.initials: FX
authors.lastname: Cheng
authors.affiliation: The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China.
authors.forename: Xiao Long
authors.initials: XL
authors.lastname: Yuan
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors.forename: Wen Jian
authors.initials: WJ
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors.forename: Jing Bo
authors.initials: JB
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors.forename: Chen Zhong
authors.initials: CZ
authors.lastname: Liao
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. Electronic address: xhliuhx@163.com.
authors.forename: Xin Hua
authors.initials: XH
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D019098:Telomerase
keywords: Dihydropyrazole; Inhibitor; Selective anticancer activity; Telomerase