Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition.
J Enzyme Inhib Med Chem
; 34(1): 1347-1367, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-31322015
ABSTRACT
In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 µM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 µM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ftalazinas
/
Desenho de Fármacos
/
Receptor 2 de Fatores de Crescimento do Endotélio Vascular
/
Inibidores de Proteínas Quinases
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article