| To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein
kinase signaling pathway new compounds based on sorafenib were designed, synthesized and
biologically evaluated. Using de novo design method, a library of new ligands was generated
and expanded. Considering in silico binding affinity towards VEGFR2, synthetic feasibility,
and drug-likeness property, some of the designed ligands were selected for synthesis and
screening for their in vitro antiproliferative activities against two cancer cell lines (HT-29 and
A549). Four compounds (13a, 14a, 14l and 15b) exhibited stronger antiproliferative activity
(with IC50 values of 13.27, 6.62, 12.74, 3.38 µM, respectively) against HT-29 cells compared
to that of the positive reference drug sorafenib (IC50 = 17.28 µM). Notably, compound 15b
demonstrated the highest activity, and in particular, it induced HT-29 apoptosis, increased
intracellular reactive oxygen species level, arrested cell cycle at G0/G1 phase, and influenced
the expression of apoptosis- and cell cycle-related proteins. 15b compound can effectively
block the Raf/MEK/ERK pathway and inhibit VEGFR2 phosphorylation. Molecular docking
revealed that 15b can bind well to the active site of VEGFR2 receptor. Collectively, 15b may
be considered as a promising compound amenable for further investigation for the
development of new anticancer agents. |