Synthesis, in vitro antiproliferative activity, and kinase inhibitory effects of pyrazole-containing diarylureas and diarylamides
- Synthesis, in vitro antiproliferative activity, and kinase inhibitory effects of pyrazole-containing diarylureas and diarylamides
- 오창현; 박병준; 모하메드엘가말
- Antiproliferative; Caspase; Kinase; Pyrazole
- Issue Date
- European journal of medicinal chemistry
- VOL 156-239
- Twenty pyrazole-containing diarylureas and diarylamides were designed and synthesized. They were tested for in vitro antiproliferative activity over a 58-cancer cell line panel at the NCI, USA. The diarylurea derivatives 1b-e and 1g exerted the strongest antiproliferative activity. Among them, compound 1e possessing 3,5-bis(trifluoromethyl)phenyl terminal ring and 3`-methoxy-5`-chlorophenyl ring attached to the central pyrazole ring was the most potent. Its IC50 values were in sub-micromolar range against most of the tested cell lines. It showed superior potency than sorafenib, a reference diarylurea drug, over all the tested cell lines. It was also extremely selective towards cancer cells than non-cancerous cells (IC50 against RAW 264.7 macrophages was higher than 100  μM). At molecular level, compound 1e selectively inhibited V600E mutated B-RAF kinase (IC50  =  0.39  μM). It also stimulated caspase 3/7 enzymes in RPMI-8226 leukemia cells (2.79 fold increase at 10  μM concentration, EC50  1.52  μM). So compound 1e may kill cancer cells through induction of apoptosis. This promising candidate can be considered further for development of new efficient anticancer agents.
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