Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors.
Bioorg Med Chem
; 26(1): 245-256, 2018 01 01.
Article
em En
| MEDLINE
| ID: mdl-29203143
ABSTRACT
Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58⯱â¯0.15⯵M, 0.47⯱â¯0.06⯵M and 0.74⯱â¯0.12⯵M, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16â¯nM, which showed equal activity to Foretinib (14â¯nM) and better than the compound 5 (90â¯nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Picolínicos
/
Pirimidinas
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Proteínas Proto-Oncogênicas c-met
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Inibidores de Proteínas Quinases
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article