Novel 4-(piperazin-1-yl)quinolin-2(1H)-one bearing thiazoles with antiproliferative activity through VEGFR-2-TK inhibition.
Bioorg Med Chem
; 40: 116168, 2021 06 15.
Article
en En
| MEDLINE
| ID: mdl-33962153
ABSTRACT
A new series of 2-(4-(2-oxo-1,2-dihydroquinolin-4-yl)piperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide derivatives were synthesized and evaluated for anticancer activity. All target compounds showed anticancer activity higher than that of their 2-oxo-4-piperazinyl-1,2-dihydroquinolin-2(1H)-one precursors. Multidose testing of target compounds was performed against breast cancer T-47D cell line. Five compounds showed higher cytotoxic activity than Staurosporine. The dihalogenated derivative showed the best cytotoxic activity with IC50 2.73 ± 0.16 µM. In addition, the VEGFR-2 inhibitory activity of all synthetic compounds was evaluated. Two compounds of 6-fluoro-4-(piperazin-1-yl)quinolin-2(1H)-ones showed inhibitory activity comparable to sorafenib with IC50 46.83 ± 2.4, 51.09 ± 2.6 and 51.41 ± 2.3 nM, respectively. The cell cycle analysis of two compounds namely, 2-(4-(6-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)piperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide and N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(4-(2-oxo-1-phenyl-1,2-dihydroquinolin-4-yl)piperazin-1-yl)acetamide revealed that the arrest of cell cycle occurred at S phase. In apoptosis assay, the same two compounds were able to induce significant levels of early and late apoptosis. In a similar manner to Sorafenib, docking of target compounds with VEGFR-2 protein 4ASD showed HB with Cys919 in hinge region of enzyme and HB with both Glu885 and Asp1046 in gate area. Using SwissADME, all target compounds were predicted to be highly absorbed from gastrointestinal tract with no BBB permeability. It is clear that the two compounds are promising antiproliferative candidates that require further optimization.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tiazoles
/
Receptor 2 de Factores de Crecimiento Endotelial Vascular
/
Inhibidores de Proteínas Quinasas
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Egipto