Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors.
Bioorg Chem
; 93: 103349, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31627060
ABSTRACT
In the present work, a novel series of B-RAF kinase inhibitors having imidazo[2,1-b]oxazole scaffold was designed and synthesized based on the structures of the well-known B-RAF inhibitors. The twenty two final compounds were tested over A375 and SKMEL28 cell lines to determine the primary cytotoxic activity of these compounds, and their activities were compared with that of sorafenib as a standard. Compounds 11c, 11e, 11o, 11q, 11r, and 11u exhibited higher cellular activity compared to sorafenib with IC50 values of 7.25, 8.03, 9.81, 8.47, 4.70, and 9.04⯵M, respectively and 10.38⯵M for sorafenib. In addition, the target compounds were screened for their anticancer activity by the NCI-60 cell line assay. Compounds 11v and 11u were the most active compounds with percent inhibition reached 95.99% for 11v and 87.03% for 11u over K562 cell line at 10⯵M concentration. Compound 11v was selected for 5-dose test mode. Furthermore, the kinase inhibitory activities of 11a, 11c, 11e, 11i, 11o, 11q, 11r, 11u, and 11v were determined against wild-type B-RAF, V600E-B-RAF, and RAF1. Compound 11o was the most potent against V600E-B-RAF with IC50 34â¯nM followed by 11q and 11u with IC50 92 and 93â¯nM, respectively.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxazóis
/
Desenho de Fármacos
/
Quinases raf
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Imidazóis
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Egito