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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.
Artigo em Inglês | MEDLINE | ID: mdl-31322015
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.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Ftalazinas / Desenho de Drogas / Receptor 2 de Fatores de Crescimento do Endotélio Vascular / Inibidores de Proteínas Quinases / Antineoplásicos Limite: Humanos Idioma: Inglês Revista: J Enzyme Inhib Med Chem Assunto da revista: Bioquímica / Química Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Egito