Synthesis, in vitro antiproliferative and antiinflammatory activities, and kinase inhibitory effects of new 1,3,4-triarylpyrazole derivatives

Background: Pyrazole derSivatives have been reported as both anticancer and antiinflammatory agents. Objective'. This study was conducted to develop new pyrazole derivatives as potential anticancer and/or antiinflammatory agents. Their molecular mechanisms of action have been investigated. Method', a series of new triarylpyrazole derivatives were synthesized. Their in vitro anticancer activity was tested against NCI-58 cancer cell line panel of nine cancer types. The most active compound la was tested against sixteen kinases, many of them are known to be over-expressed in leukemia and breast cancer. The most sensitive kinases were V600E-B-RAF, C-RAF, FLT3, and P38α/MAPK14. Compound la was further tested for caspase-3/7 activity and LDH release assay as measures of its apoptotic and necrotic activities against RPMI-8226. Moreover, the ability of compounds la, lb, and lg to inhibit nitric oxide and prostaglandin E2 production in LPS-induced RAW 264.7 macrophages was also examined. Results: Compounds la, lc, and lg showed the highest activities against the cancer cell line panel, with more inhibitory effects against leukemia and breast cancer subpanels. The highest activity was exerted by compound la. Its IC₅₀ values against RPMI-8226, K-562 leukemia cell lines, and MDA-MB-468 breast cancer cell line were 1.71 μM, 3.42 μM, and 6.70 μM, respectively. The IC₅₀ of compound la against P38α/MAPK14 kinase was 0.515 μM. The caspase activity was increased by 72% and 170% at 1.23 μM and 3.70 μM concentrations of compound la, respectively. Furthermore, compound lb inhibited 80.26% and 95.31% of NO and PGE2 productions, respectively, at 50 μM concentration in the LPS-induced RAW 264.7 macrophages. Conclusion: Compound la could kill the cells through induction of apoptosis rather than necrosis. Compound la was more selective against cancer cells than non-cancerous cells. In addition, the hydroxyl analogue lb was the most active as antiinflammatory agent.