Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit

Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) 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 and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0.56 +/- 0.83 mu M, 3.88 +/- 1.03 mu M and 3.15 +/- 0.81 mu M, which were 1.03-6.14-fold more active than sorafenib (3.44 +/- 1.50 mu M, 3.18 +/- 1.43 mu M, 3.24 +/- 0.45 mu M), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50 value was 0.72 mu M. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity. (C) 2016 Elsevier Ltd. All rights reserved.