Design, synthesis and antitumor activity of Novel Sorafenib derivatives bearing pyrazole scaffold

作者：Wang, Min; Xu, Shan; Lei, Huajun; Wang, Caolin; Xiao, Zhen; Jia, Shuang; Zhi, Jia; Zheng, Pengwu^*; Zhu, Wufu^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(20): 5754-5763.

DOI：10.1016/j.bmc.2017.09.003

• Sorafenib derivatives
• Pyrazole
• VEGFR-2/KDR kinase inhibitors
• Anticancer activity

Four series of Sorafenib derivatives bearing pyrazole scaffold (8a-m, 9a-c, 10a-e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0.56 mu M. And compound 8b exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, c-Met, EGFR, Flt-3 kinases. Eleven of the target compounds exhibited moderate to good antitumor activities. The most promising compound 8b showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC50 values of 2.84 +/- 0.78 mu M, 1.85 +/- 0.03 mu M and 1.96 +/- 0.28 mu M, which were equivalent to Sorafenib (2.92 +/- 0.68 mu M, 3.44 +/- 0.50 mu M and 3.18 +/- 0.18 mu M). Structure-activity relationships (SARs) and docking studies indicated that the pyrazole scaffolds exerted key effect on antitumor activities of target compounds. Substitutions of aryl group at C-3 positions had a significant impact on the antitumor activities, and 3-Br substitution produced the best potency.

• 出版日期2017-10-15
• 单位江西科技师范大学