Novel methoxyquinazoline sulfonamide derivatives as angiogenesis inhibitors and radiosensitizers

A library of new methoxyquinazoline sulfonamide derivatives was synthesized through two main structural modifications: either by introducing methoxy groups at the quinazoline ring, or S-alkylation with acetamide moieties bearing differently substituted aromatic groups to explore the structure-activity relationship. The synthesized compounds were assessed for their cytotoxic effects against A549, MDA-MB-231 and HepG-2 Cancer cell lines, as well as WI-38 and MCF-10A normal cell lines. Among these derivatives, the trimethoxy-substituted quinazolines 9a-c showed the highest cytotoxic potency, with compound 9a emerging as the lead candidate. Compound 9a displayed strong inhibitory activity against VEGFR-2, with an IC₅₀ value of 0.23 ± 0.03 μM, comparable to that of sorafenib. It inhibited HepG-2 cell migration in a wound healing assay, which correlated with a reduction in Akt phosphorylation (p-Akt), suggesting its potential to modulate VEGFR-2-mediated signaling pathways involved in angiogenesis. Compound 9a induced Apoptosis, evidenced by Caspase-3 activation, upregulation of Bax, downregulation of Bcl-2 and a marked increase in Bax/Bcl-2 ratio. Cell cycle analysis demonstrated G2/M phase arrest, supporting its antiproliferative activity. It also revealed enhanced radiation-induced cytotoxicity when combined with a single 8 Gy dose of gamma radiation. Docking within the VEGFR-2 active site supported the biological findings by revealing promising binding interactions. Besides, ADME analysis supports the design strategy and suggests that these derivatives possess promising pharmacokinetic properties.