Construction of 3D Antioxidants with Nucleosides as the Core: Inhibition of DNA Oxidation

Abstract

We herein attach ferulic and caffeic acids to −OH and −NH 2 in cytidine, uridine, adenosine, or guanosine for achieving antioxidative hybrids with three-dimensional (3D) configuration. In the case of molecular docking computation, the nucleoside antioxidants with 3D configuration facilitate to bind with the groove of DNA and to cover the surface of a DNA helix. Experimentally, the antioxidative effects of nucleoside hybrids are measured in the inhibition of DNA oxidation caused by 2,2′-azobis(2-amidinopropane dihydrochloride) (AAPH), and the stoichiometric factor (n, the number of free radical propagations terminated by one molecule of antioxidant) can be selected as a quantitative index for expressing antioxidative effects. It is found that the effect of cytidine tetraferulate against AAPH-induced DNA oxidation is seven times better than that of ferulic acid, even though four ferulic acid moieties are involved and cytidine itself does not exhibit activity. Moreover, the antioxidative effect of cytidine tetracaffeate is almost 20 times higher than that of caffeic acid. The n values of nucleoside antioxidants against AAPH-induced DNA oxidation are found to correlate proportionally with the rate constants for quenching 2,2′-diphenyl-1-picrylhydrazyl and galvinoxyl radicals. Therefore, nucleoside linking with antioxidative carboxylic acid might be a promising way for constructing antioxidants against peroxyl radical-induced oxidation of DNA.

Multicomponent Reactions for Integrating Multiple Functional Groups into an Antioxidant

“…Recently, we have found that four caffeic acids attaching to three -OHs and one -NH 2 of cytidine exhibit antioxidative effect more than 4-fold higher than a single caffeic acid in the protection of DNA against radicalmediated oxidation. [49] Therefore, three-dimensional configuration is beneficial for the antioxidant being recognized by the DNA strand. Along with our findings on the antioxidative effects resulting from the Ugi 4CR and Passerini 3CR products, it is reasonable to expect that antioxidants constructed by MCRs with steric configuration will take advantage of being recognized by biological microenvironments, and thus, become the most promising candidates for pharmacological screening.…”

“…Hence, the steric configurations of biological issue should be taken into consideration in the designing of antioxidative structures. Recently, we have found that four caffeic acids attaching to three ‐OHs and one ‐NH 2 of cytidine exhibit antioxidative effect more than 4‐fold higher than a single caffeic acid in the protection of DNA against radical‐mediated oxidation [49] . Therefore, three‐dimensional configuration is beneficial for the antioxidant being recognized by the DNA strand.…”