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Synthesis, in vitro Antiproliferative and Antiinflammatory Activities, and Kinase Inhibitory effects of New 1,3,4-triarylpyrazole Derivatives.

Abstract：

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 Eproduction 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.

journal_name

Anticancer Agents Med Chem

journal_title

Anti-cancer agents in medicinal chemistry

authors

El-Gamal MI,Abdel-Maksoud MS,Gamal El-Din MM,Shin JS,Lee KT,Yoo KH,Oh CH

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

75-84

issue

eissn

1871-5206

issn

1875-5992

pii

ACAMC-EPUB-76674

journal_volume

pub_type

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Synthesis, in vitro Antiproliferative and Antiinflammatory Activities, and Kinase Inhibitory effects of New 1,3,4-triarylpyrazole Derivatives.