RESUMO
A series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibited potent antiproliferative activities against MCF-7, Bewo and HL-60 cells and c-Met kinase inhibitory activities. Three compounds were highly effective against MCF-7, Bewo and HL-60 cells with IC50 values in 1.09-2.24µM. Molecular docking was further performed to study the inhibitor-c-Met kinase interactions, and the results show that compound 4j was potently bound to the c-Met kinase with three hydrogen bonds. The further research on acute toxicity and in vivo antitumor activity of compound 4j to ICR (Institute of Cancer Research) mice were carried out, and found 4j with a certain toxicity but good efficacy in vivo. Based on the preliminary results, it is deduced that compound 4j with potent c-Met kinase inhibitory activity may be a potential anticancer agent.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Sítios de Ligação , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Humanos , Concentração Inibidora 50 , Células MCF-7 , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Estaurosporina/farmacologia , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/síntese química , Triazóis/toxicidadeRESUMO
A series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and their structures were confirmed by single-crystal X-ray diffraction. Compared to some reported structures of 1,6-dihydro-1,2,4,5-tetrazine, these compounds can't be considered as having homoaromaticity. Their antiproliferative activities were evaluated against MCF-7, Bewo and HL-60 cells in vitro. Two compounds were highly effective against MCF-7, Bewo and HL-60 cells with IC50 values in 0.63-13.12µM. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 51 [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives with antiproliferative activity against MCF-7 cell. Models with good predictive abilities were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.716 and 0.723, respectively. Conventional r(2) values were 0.985 and 0.976, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.