New quinoxalin-2(1H)-one-derived VEGFR-2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies.
Arch Pharm (Weinheim)
; 355(7): e2200048, 2022 Jul.
Article
em En
| MEDLINE
| ID: mdl-35437829
ABSTRACT
More than 70% of cancer patients who are treated with chemotherapeutics do not show a durable response. As part of the global plan seeking new effective chemotherapeutics, here, we report the synthesis and in vitro and computational studies of new lenvatinib and sorafenib analog quinoxalines as vascular endothelial growth factor receptor II (VEGFR-2) tyrosine kinase inhibitors. The central quinolone and pyridine moieties of the Food and Drug Administration-approved anticancer agents lenvatinib and sorafenib were replaced with the versatile quinoxaline scaffold that has been exploited for developing potent cytotoxic agents. With some minor structural optimizations, all the other pharmacophoric features of lenvatinib and sorafenib were maintained. Accordingly, three new sets of quinoxalines were synthesized to evaluate their activity against liver, colorectal, and breast malignancies. The results obtained in the in vitro cytotoxicity evaluation study revealed the superior activity of three derivatives (20, 25, and 29) compared with that of doxorubicin and sorafenib. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling and docking of 20, 25, and 29 into the VEGFR-2 receptor were also performed. Results of in silico studies showed the potential of the designed compounds to bind effectively with a number of key residues. The obtained in vitro cytotoxic activity and ADMET profiles of compounds 20, 25, and 29 suggested that they should be subjected to further structural optimizations to develop new candidates in cancer treatment protocols.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptor 2 de Fatores de Crescimento do Endotélio Vascular
/
Antineoplásicos
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article