Synthesis,characterization and biological activities of nitrogen-containing Combretastatin A-4 derivatives

A series of new combretastatin A4 derivatives (6a-6c, 9a-12c) containing nitrogen atoms and nitrogen heterocycles were synthesized by condensation reaction, reduction reaction, hydrolysis reaction and Crutius rearrangement, and the structures were confirmed by 1 H NMR, 13 C NMR and Mass spectrum. The antitumor cytotoxicity of a series of newly synthesized compounds were evaluated in vitro toward the cell line of hepatoma cell with erianin as positive control. Amoung all the compound, 6b exhibit the most antitumor activity against HepG2 (Human hepatoellular carcinomas) cell line with the inhibition rate 93.85%, and the other compounds also showed moderate to potent antitumor activity. To understand the interaction of series with active binding site of receptor, docking study was performed with VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2) kinase domain in complex with axitinib using Sybyl. The compound with the highest total score was 9c, reaching 8.92, which was higher than that of the positive control erianin This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery. Graphical abstract