El-Gamal, Mohammed I. Abdel-Maksoud, Mohammed S. El-Din, Mahmoud M. Gamal Shin, Ji-Sun Lee, Kyung-Tae Yoo, Kyung Ho Oh, Chang-Hyun 2024-01-20T02:04:25Z 2024-01-20T02:04:25Z 2022-01-10 2017-02 1871-5206 https://pubs.kist.re.kr/handle/201004/123107 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 P38 alpha/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 E2 production 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 mu M, 3.42 mu M, and 6.70 mu M, respectively. The IC50 of compound 1a against P38a/MAPK14 kinase was 0.515 mu M. The caspase activity was increased by 72% and 170% at 1.23 mu M and 3.70 mu M concentrations of compound 1a, respectively. Furthermore, compound 1b inhibited 80.26% and 95.31% of NO and PGE(2) productions, respectively, at 50 mu M 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. English BENTHAM SCIENCE PUBL LTD RAW 264.7 MACROPHAGES MELANOMA-CELL LINE NITRIC-OXIDE BIOLOGICAL EVALUATION PGE(2) PRODUCTIONS PYRAZOLE DESIGN CANCER AGENTS COX-2 Synthesis, in vitro Antiproliferative and Antiinflammatory Activities, and Kinase Inhibitory effects of New 1,3,4-triarylpyrazole Derivatives Article 10.2174/1871520616666160620074534 1 ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v.17, no.1, pp.75 - 84 ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY 17 1 75 84 scie scopus 000397225500010 2-s2.0-85015080171 Oncology Chemistry, Medicinal Oncology Pharmacology & Pharmacy Article RAW 264.7 MACROPHAGES MELANOMA-CELL LINE NITRIC-OXIDE BIOLOGICAL EVALUATION PGE(2) PRODUCTIONS PYRAZOLE DESIGN CANCER AGENTS COX-2 Antiinflammatory antiproliferative nitric oxide P38 alpha/MAPK14 kinase PGE(2) 1,3,4-triarylpyrazole