VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety

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-1 H -pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[ g ]quinazolin-3(4 H )-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 IC 50 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 (IC 50 = 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.

Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

“…The synthesis of the target compounds 5–18 was described in Scheme 1. The starting compound 4-(2-mercapto-4-oxobenzo[ g ]quinazolin-3(4 H )-yl) benzenesulfonamide 4 29 was prepared from the reaction of 3-amino-2-naphthoic acid 3 with 4-isothiocyanatobenzenesulfonamide 2 22 . The reaction of 4 with 2-chloro- N -substituted acetamide derivatives in dry acetone containing an equimolar amount of anhydrous K 2 CO 3 yielded the appropriate N -(substituted)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[ g ]quinazolin-2-yl)thio]acetamides 5–18 (Scheme 1).…”

“…In this context, we desire to exploit newer leads with tuneable anticancer activity and low toxicity 14 , 29 . A series of substituted benzo[g]quinazolinone benzenesulfonamide hybrids were designed, synthesized, and evaluated as dual EGFR/HER2 inhibitors.…”

Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies

“…VEGFR-2 is a key player that is credited with angiogenesis and cancer growth [46,47]. The ATP binding pocket of VEGFR-2 acts as active site for small molecule inhibitors that are largely competitive inhibitors to the ATP [15,48]. Generally, the kinase inhibitors are of four different types; type 1 inhibitors bind to the active form of the kinases, while the type II interact with the inactive form of the kinases and bind with the residues located at the ATP binding site and the allosteric site.…”

<p>Novel <em>N</em>-(Substituted) Thioacetamide Quinazolinone Benzenesulfonamides as Antimicrobial Agents</p>

“…4,30 So, sulfonamides were integrated with quinazolin-4(3H)-ones in order to obtain more potent candidates. As a continuation of our previous efforts, 12,[31][32][33][34][35] we synthesized new quinazolinone derivatives bearing benzenesulfonamide in order to study their antimicrobial activity. The synthesized compounds were tested against Gram-positive bacteria, Gramnegative bacteria, MRSA and Candida.…”