Glutathione conjugates of 2- or 6-substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives: formation and structure

Thirty-four glutathione conjugates of 5,8-dimethoxy-1,4-naphthoquinones (DMNQ) were synthesized and their structure was determined. The yield of GSH conjugate was dependent on size of alkyl group; the longer the size of alkyl group was, the lower was the yield. It was also found that the length of alkyl side chain influenced the chemical shift of quinonoid protons; the quinonoid protons of 2-glutathionyl DMNQ derivatives with R=H to propyl, 6.51-6.59 ppm vs. other ones with R=butyl to heptyl, 6.64-6.68 ppm. This was explained to be due to a folding effect of longer alkyl group. Glutathione (GSH) reacted with DMNQ derivative first to form a 1,4-adduct (2- or 3-glutathionyl-1,4-dihydroxy-5,8-dimethoxynaphthalenes) and then, the adduct was autooxidized to 2- or 3-glutathionyl-DMNQ derivatives. Moreover, GSH reduced DMNQ derivatives to their hydrogenated products. It was suggested that such an organic reaction might play an important role for a study of metabolism or toxicity of DMNQ derivatives in the living cells.