Antiproliferative, antiangiogenic and apoptotic effect of new hybrids of quinazoline-4(3H)-ones and sulfachloropyridazine

Three new sets of quinazolinones bearing sulfachloropyridazine 4a-f, 6a-i and 8a-i were designed and synthesized. All the synthesized compounds were screened for their in vitro cytotoxicity against a panel of 60 Cancer cell lines. The most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were evaluated as VEGFR-2 inhibitors. Compounds 8f, 8c and 6f were the most active with IC₅₀ = 66 ± 0.002, 108 ± 0.004 and 146 ± 0.006 nM, respectively. Compound 8f showed also moderate inhibition against PDGFR (IC₅₀ = 180 ± 0.009 nM), EGFR (IC₅₀ = 98 ± 0.004 nM), FGFR-1 (IC₅₀ = 82 ± 0.004 nM) and ability to reduce migration of cells in wound healing assay. Compound 8f showed cell cycle arrest at S-phase and induced early and late Apoptosis in Annexien V-FITC assay. In addition, compound 8f increased the level of Caspase-3 and up regulate Bax expression and down regulate Bcl-2 in UO-31 cells. The cytotoxicity of compounds 6f, 6g and 8f against UO-31 and melanoma cells was slightly affected by combination with γ-radiation. Also, compound 8f showed low toxicity against human normal renal (RPTEC) cell line. Docking studies of the most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were performed to have more insights on their binging mode within VEGFR-2 active site.

Apoptosis; Cytotoxic; Quinazolinone; Sulfachloropyridazine; VEGFR-2.