Mono and dihydroxy coumarin derivatives: Copper chelation and reduction ability

Abstract

Due to the limited array of the currently available copper chelators, research of such compounds continues to be of clinical interest. Notably, o-dihydroxycoumarins have been previously shown to be potent iron chelators under neutral conditions. Within this study, the interaction of a series of natural coumarins and their synthetic analogs with copper has been evaluated in order to obtain structure-activity relationships under different pathophysiological pH conditions. Both competitive and non-competitive methods have been employed. Analysis of cupric ion reduction has also been performed.Under mildly competitive conditions, cupric chelation was observed for o-dihydroxycoumarins, and partially for o-diacetoxycoumarin. Non-competitive studies showed that cuprous ions are not chelated at all and that the stoichiometries of the most active 6,7- and 7,8-dihydroxycoumarins to cupric ions ranged from 1:1 to 2:1 depending on pH and concentration. Interestingly, under highly competitive conditions, coumarins were not capable of chelating cupric ions, either. Reduction experiments have shown that 13 out of the 15 coumarins included in this study reduced cupric ions. However, significant differences depending on their structures were apparent in their potencies. O-dihydroxycoumarins were the most potent ones again. ConclusionO-dihydroxycoumarins are moderately active cupric ion chelators with potent copper reducing properties.