Background: Pyrazole derivatives 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 1a 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 1a 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 1a, 1b, and 1g to inhibit nitric oxide and prostaglandin E2production in LPS-induced RAW 264.7
macrophages was also examined.
Results: Compounds 1a, 1c, and 1g 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 1a. 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 1a 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 1a,
respectively. Furthermore, compound 1b 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 1a could kill the cells through induction of apoptosis rather than necrosis. Compound 1a was
more selective against cancer cells than non-cancerous cells. In addition, the hydroxyl analogue 1b was the most active
as antiinflammatory agent.