New derivatives of 2-phenylquinazolin-4(3H)-one were designed, synthesized, and biologically evaluated as potent allosteric kinase inhibitors with in situ cytotoxicity against MCF-7 and HepG2 cells. Compounds 15 and 18 among the proposed compounds showed promising antiproliferative activity against MCF-7 (IC50 = 1.35 µM) and HepG2 cells (IC50 = 3.24 µM), comparable to sorafenib, with IC50 values of 3.04, 2.93 µM, respectively, according to in situ cytotoxicity testing. Comparing compounds 15 and 18 to sorafenib, the in vitro VEGFR-2 inhibitory activity displayed encouraging selective efficacy with IC50 values of 13, 67, and 30 nM, respectively. Results of VEGFR-2 inhibition at various ATP concentrations proved that there was no statistically significant difference between the IC50 values, which improved the non-ATP competitive binding. Compound 15 caused apoptotic breast cancer cell death with 55.11-fold cell-cycle arrest at the S-phase, where it affected the apoptosis-mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the antiapoptotic gene Bcl-2. A molecular docking study was conducted to confirm the binding of the designed compounds to the allosteric site of VEGFR-2 in DFG-out mode, leaving the ATP-binding pocket unoccupied when superimposed to the pose of sorafenib. The designed molecules showed resealable binding affinity toward the DFG loop and the allosteric site. Hence, the 2-phenylquinazolin-4(3H)-one derivative constitutes intriguing starting points for designing apoptotic-inducing drugs.
Keywords: 2-phenylquinazolin-4(3H)-one; VEGFR-2 allosteric inhibitor; apoptosis; breast and liver cancer; cytotoxicity.
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