RESUMO
It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. In order to carry out more rational design, based on structure-based drug design, several series of N-substituted-dihydropyrazole derivatives, totally 78 compounds as potential human telomerase inhibitors were designed and synthesized. The results demonstrated that some compounds had potent anticancer activity against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells. By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity against telomerase with an IC50 value of 0.98 µM. In vivo evaluation results indicated that compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further studies to assess rational design of more efficient telomerase inhibitors in the future.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Telomerase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Células Hep G2 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Telomerase/metabolismoRESUMO
Aromatase is a key enzyme responsible for in vivo estrogen biosynthesis. Inhibition of the activity of the aromatase has become an alterative way for treatment of breast cancer. In this review, the structure and catalytic mechanism of the aromatase is briefly introduced followed by thorough review of the progress in the study of the steroidal and non-steroidal aromatase inhibitors. This review is focused on the natural compounds that exhibit the aromatase inhibition, which include flavonoids, xanthones, coumarins, and sesquiterpenes. The structure-activity relationship of these compounds is also discussed.