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/VEGFR2/KDR/Flk-1 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±0.83μM, 3.88±1.03μM and 3.15±0.81μM, which were 1.03-6.14-fold more active than sorafenib (3.44±1.50μM, 3.18±1.43μM, 3.24±0.45μM), respectively. The compound 5b showed good activity on VEGFR-2/VEGFR2/KDR/Flk-1 kinase, and its IC₅₀ value was 0.72μM. 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.

(N-Methylpicolinamide-4-oxy) chalcones; Anticancer activity; Sorafenib derivatives; VEGFR-2/KDR kinase inhibitors.