Synthesis and Antioxidant Activities of Ferrocenyl-containing Curcumin Analogues

Background: Metal organic compounds have attracted considerable attention since the advent of Salvarsan, a metal organic compound for the treatment of syphilis. Ferrocene as an effective phenyl bioisostere is becoming a viable platform for drug design by virtue of its redox properties, high lipophilicity and three-dimensional metallocene unit, which may lead to some changes in selectivity toward biological targets compared with phenyl or alkyl groups. Therefore, ferrocene seems to an appropriate candidate for improving the antioxidant activity of drugs. Methods: We synthesized four ferrocenyl-containing curcumin analogues by introducing ferrocenyl groups into the active methylene groups to obtain higher antioxidant activity than the parent ferrocene-substituted curcumin analogues, and their antioxidant activities were evaluated in 2, 2'-azobis (2-amidinopropane hydrochloride) (AAPH) and Cu2+/glutathione(GSH)-induced oxidation of DNA, and in trapping 2, 2'-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azinobis(3-ethylbenzothiazoline-6- sulfonate) cationic radicals (ABTS+.) and galvinoxyl radicals. Results: These ferrocenyl-containing curcumin analogues can protect DNA against Cu2+/GSH-induced oxidation, and scavenge 5.7, 6.9, 5.5 and 5.3 radicals in protecting DNA against AAPH-induced oxidation. Compounds (3)similar to(5) can trap more DPPH, ABTS+. and galvinoxyl radicals than compound (6). The substituents and iron atoms play an antioxidant role in ferrocenyl-containing curcumin analogues. Conclusion: The introduction of ferrocenyl group results in a higher antioxidant activity than the traditional hydroxyl-involved curcumin analogues. The ferrocenyl group is a powerful antioxidative group that could be used to modify natural antioxidants. The electron-accepting group attaching to the phenyl-group could further increase the antioxidant activity. Ferrocene-containing curcumin analogues show higher activities in quenching radicals and protecting DNA against radical-induced oxidation. Therefore, the introduction of ferrocenyl group into the natural antioxidant may contribute to increase the antioxidant activity.