RESUMEN
Resveratrol has been extensively studied as the anti-cancer agent. A variety of resveratrol analogues have been developed with structural modification to improve its bioactivity. In this work, resveratrol analogues, compound 1-4, were designed and synthesized with the Stille-Heck reaction. These results showed compound 1-4 had better anticancer effect than that of parent resveratrol. Especially compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3-methylphenol)) displayed the excellent cytotoxicity and high selectivity. The mechanism research indicated compound 1 inhibited cell proliferation by binary paths of cell cycle arrest in S phase regulated by cyclin A1/A2 and apoptosis induction mediated by Bax/Bcl2 in a prooxidant manner.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias/patología , Resveratrol/análogos & derivados , Resveratrol/farmacología , Apoptosis/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células HeLa , Humanos , Células MCF-7 , Fenómenos Químicos Orgánicos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resveratrol/síntesis química , Resveratrol/química , Relación Estructura-Actividad , Proteína X Asociada a bcl-2/metabolismoRESUMEN
With the improvement and advance in cancer diagnosis and treatment, the cancer is still a major cause of morbidity and mortality throughout the world. Obviously, new breakthroughs in therapies remain be urgent needed. In this work, we designed and synthesized the compound 1-4, namely resveratrol analogues with methylation of hydroxy distyrene, to further explore its new anti-cancer potential. Encouragingly, compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3,5-dimethylphenol)) exhibited cytotoxicity superior to resveratrol in MCF 7 cells. More importantly, the compound 1 showed greater toxicity to tumor cells than that to normal cells, which proved that it could selectively kill tumor cells. The favorable results encouraged us to explore the inhibitory mechanism of compound 1 on MCF 7 cells. The research finding indicated the compound 1 inhibited tumor cell proliferation by both arresting cell cycle in S phase and apoptosis via a prooxidant manner. In addition, the results further verified compound 1 caused cell cycle arrest in S phase and apoptosis by down-regulation of the cycling A1/cycling A2 expression and the rise of Bax/Bcl-2 ratio in a p21-dependant pathway in MCF 7 cells. Therefore, these results are helpful for the effective design of anticancer reagents and the better understanding of their mechanism of action.