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Eur J Med Chem ; 183: 111697, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536891

RESUMO

A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 µM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 µM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was evaluated on HepG2 cells. The anilide 5r showed a remarkable tubulin inhibition compared to CA-4. Moreover, flow cytometry studies showed that HepG2 cells treated with the most potent compounds 5b and 5r were arrested in the G2/M phase of the cell cycle. This effect was accompanied by cellular apoptosis and activation of caspase-3. Molecular modeling showed several hydrogen bonding and van der Waals interactions with several important amino acids inside the colchicine binding site of tubulin.


Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Estilbenos/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
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