Chemical reactivity and biological activity of dihydro-1,4-dithiin tetraoxides

Certain dihydro-1,4-dithiin tetraoxides such as dimethipin, a commercial plant growth regulant, have been reported to exhibit highly selective biological activities depending on the type and number of substitutions on the α,β-unsaturated bond in the dithiin ring. Despite the abundant reports on this class of compounds, the study of chemical reactivity of the α,β-unsaturated bond in the dithiin ring has not been reported and the factors governing the biological selectivity of these compounds are still unknown. In this study, the reactivity of eight dithiin compounds substituted in varying degrees at the α,β-unsaturated bond towards biologically important nucleophilic groups at pH 7.4 were investigated using UV-vis, fluorescence, and 1 H NMR spectroscopies. Their reactivity towards glutathione correlated strongly with their cell growth inhibitory activity and inhibition of DNA topoisomerase II, an enzyme containing critical sulfhydryl groups. On this basis, the mechanism by which these dithiins achieve the biological selectivity previously reported was proposed. Excellent correlations between glutathione reactivity and Taft’s polar substituent constants or electrostatic atomic charges of the dithiins were also demonstrated, suggesting that these descriptors might be useful for predicting the reactivity of other dithiins towards sulfhydryl nucleophiles.