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

Article abstract of DOI:10.1016/j.bmcl.2016.10.029

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 IC₅₀values of 0.56?±?0.83?μM, 3.88?±?1.03?μM and 3.15?±?0.81?μM, which were 1.03–6.14-fold more active than sorafenib (3.44?±?1.50?μM, 3.18?±?1.43?μM, 3.24?±?0.45?μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC₅₀value was 0.72?μM. 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.