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Abstract
Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5–17 and 4-(2-(2-(substituted-1H-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 18–24 were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5, to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds 5–24, were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds 9, 20, 22 and 23, showed excellent VEGFR-2 inhibitory activity with IC50 ranging from 0.64 to 1.04 µm. Being the most potent, compound 9 was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound 9 boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound 9 showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC50 = 29.41 µm, respectively) in normal breast cells MCF-12 A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme.
Graphical Abstract
Acknowledgements
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project No. RGP-302.
Disclosure statement
No potential conflict of interest was reported by the authors.