Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases.
J Nat Prod
; 82(1): 16-26, 2019 01 25.
Article
em En
| MEDLINE
| ID: mdl-30620194
Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptor 2 de Fatores de Crescimento do Endotélio Vascular
/
Inibidores de Proteínas Quinases
/
Duocarmicinas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Nat Prod
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha
País de publicação:
Estados Unidos