Novel differently substituted pyrazole derivatives were designed, synthesized and evaluated for their anticancer activity. All compounds selectively inhibited COX-2 enzyme (IC50 = 0.043-0.56 μM). Compounds 11, 12 and 15 showed superior potency (IC50 = 0.043-0.049 μM) and screened for their antiproliferative effect against MCF-7 and HT-29 cancer cell lines using doxorubicin and 5-FU as reference drugs. Compounds 11, 12 and 15 showed good potency against MCF-7 (IC50 = 2.85-23.99 μM) and HT-29 (IC50 = 2.12-69.37 μM) cell lines. Also, compounds 11, 12 and 15 displayed (IC50 = 56.61-115.75 μM) against non-cancerous WI-38 cells compared to doxorubicin (IC50 = 13.32 μM). Compound 11 showed superior cytotoxicity against both MCF-7 (IC50 = 2.85) and HT-29 (IC50 = 2.12 μM) and was more potent than 5-FU (HT-29: IC50 = 8.77 μM). Besides, it displayed IC50 of 115.75 μM against normal WI-38 cells regarding it as a safe cytotoxic agent. In addition, compound 11 displayed IC50 values of 63.44 μM and 98.60 μM against resistant HT-29 and resistant MCF-7 cancer cell lines sequentially. The most potent compound arrested cell cycle at G1/S phase in HT-29 treated cells displaying accumulation of cells in G0 phase and increase in percentage of cells in both early and late apoptotic stages. Apoptotic induction ability was confirmed via up-regulation of BAX, down-regulation of Bcl-2 and activation of caspase-3/9 protein levels. Compound 11 inhibited both EGFR (IC50 = 0.083 μM) and Topo-1 (IC50 = 0.020 μM) enzymes. Also, compound 11 decreased both total and phosphorylated EGFR concentration in HT-29 cells. Finally, molecular docking study showed good binding interactions between novel compounds and target receptors.
Keywords: Apoptosis; COX-2; Cancer; EGFR; Pyrazole; Topo-1.
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