Novel Curcumin Analogue Hybrids:Synthesis And Anticancer Activity

Mammalian thioredoxin reductase(TrxR)is a homodimeric flavonase containing selenocysteine that catalyzes nadph-dependent reduction of oxidized thioredoxin.In recent years,a large amount of evidence has shown that over-activation of TrxR is closely related to various diseases,especially in the process of tumor development.Meanwhile,more and more evidences show that TrxR is a potential target of anticancer drug development.Now,researchers are keen to develop anti-tumor drugs that target TrxR.Studies have shown that curcumin and myricetin have significant anti-tumor activities,partly due to the inhibition of high levels of thioredoxin reductase expression in tumor cells.Based on these experimental findings and the previous experimental accumulation of the research group,our research group designed and synthesized 20 curcumin derivatives to inhibit the proliferation activity of tumor cells by regulating the activity of thioredoxin reductase.Compounds(4a-4f)were obtained by incorporation of the active structure of curcumin into diarylpentadienone.The active structure of myricetin was incorporated into diarylpentadienone to obtain compounds(7a-7n).Results of anticancer activity showed that 5,7-dimethoxy-3-(3-(2-((1E,4E)-3-oxo-5-(pyridin-2-yl)penta-1,4-dien-1-yl)phenoxy)propoxy)-2-(3,4,5-trimethoxyphenyl)-4Hchromen-4-one(compound 7d)could induce gastric cancer cells apoptosis by arresting cell cycle,inducing the accumulation of ROS,breaking mitochondria function and inhibiting TrxR activity.Meanwhile,western blot revealed that this compound could dramatically up expression of Bax/Bcl-2 ratio and high expression of TrxR oxidation.These results preliminarily show that the important role of ROS mediated activation of ASK1/MAPK signaling pathways by this title compound.