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

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 0.56μM. 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±0.78μM, 1.85±0.03μM and 1.96±0.28μM, which were equivalent to Sorafenib (2.92±0.68μM, 3.44±0.50μM and 3.18±0.18μM). 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.