Synthesis, biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (4), p.1091-1095
• Main Authors: Luo, Yin, Zhang, Shuai, Qiu, Ke-Ming, Liu, Zhi-Jun, Yang, Yu-Shun, Fu, Jie, Zhong, Wei-Qing, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: 3D-QSAR; active sites; Antiproliferative; Aryl-2H-pyrazole; Binding Sites; Cell Growth Processes - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; inhibitory concentration 50; melanoma; Models, Molecular; pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Quantitative Structure-Activity Relationship; stomach neoplasms; telomerase; Telomerase - antagonists & inhibitors; Telomerase - chemistry; Telomerase - metabolism; Telomerase inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.12.010

A series of aryl-2H-pyrazole derivatives have been designed and synthesized, and their biological activities were also evaluated for telomerase inhibitory activity. Compound 16A possessed the most potent enzyme inhibition activities (IC50=0.9μM for telomerase) and anticancer activities (IC50=5.34μM for B16-F10 and IC50=18.07μM for SGC-7901). Docking simulation was performed to explore the binding model of compound 16A with telomerase. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity. A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC50 value of 0.9μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC50 values of 18.07 and 5.34μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity.