Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

Title
Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents
Authors
유경호오창현Mahmoud Mohamed Gamal El-Din엘가말사미르백대진최정승이희성
Keywords
Antiproliferative activity; arylsulfonamide,; 1,3,4-triarylpyrazole,; RAF kinases
Issue Date
2017-01
Publisher
Journal of enzyme inhibition and medicinal chemistry
Citation
VOL 31, NO S2-122
Abstract
A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10  μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10  μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.
URI
http://pubs.kist.re.kr/handle/201004/68496
ISSN
1475-6366
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KIST Publication > Article
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