2‐Phenylquinazolin‐4(3H)‐one scaffold as newly designed, synthesized VEGFR‐2 allosteric inhibitors with potent cytotoxicity through apoptosis

Abstract

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 (IC 50 = 1.35 µM) and HepG2 cells (IC 50 = 3.24 µM), comparable to sorafenib, with IC 50 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 IC 50 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 IC 50 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.

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

“…An in vitro VEGFR-2 enzyme assay showed that the latter five compounds, 29, 30, 31, 32a, and 32b significantly suppressed VEGFR-2 (IC50 = 0.290 ± 0.05, 0.517 ± 0.07, 0.380 ± 0.04, 0.377 ± 0.04, and 0.415 ± 0.03 µg/mL, respectively) compared to sorafenib, with an IC50 value of 0.588 µg/mL (Figure 13) [53]. In a recent study conducted by Elrayess et al [54], novel derivatives of 2-phenylquinazolin-4(3H)-one were developed. Their cytotoxic effects were assessed in situ against MCF-7 and HepG2 cells, revealing promising results.…”

“…In a recent study conducted by Elrayess et al [ 54 ], novel derivatives of 2-phenylquinazolin-4(3 H )-one were developed. Their cytotoxic effects were assessed in situ against MCF-7 and HepG2 cells, revealing promising results.…”

“…In a recent study conducted by Elrayess et al [54], novel derivatives of 2-phenylquinazolin-4(3H)-one were Their cytotoxic effects were assessed in situ against MCF-7 and HepG2 cells, revealing promising results. Derivatives 33 and 34 (Figure 14) exhibited notable antiproliferative effects against MCF-7 (IC 50 = 1.35 µM) and HepG2 cells (IC 50 = 3.24 µM), which were equivalent to those of sorafenib (IC 50 values of 3.04 and 2.93 µM, respectively).…”