Detoxifying polyhalogenated catechols through a copper-chelating agent by forming stable and redox-inactive hydrogen-bonded complexes with an unusual perpendicular structure

Abstract

The use of selective metal chelating agents with preference for binding of a specific metal ion to investigate its biological role is becoming increasingly common. We found recently that a well-known copper-specific chelator 2,9-dimethyl-1,10-phenanthroline (2,9-Me2OP) could completely inhibit the synergistic toxicity induced by tetrachlorocatechol (TCC) and sodium azide (NaN3). However, its underlying molecular mechanism is still not clear. Here, we show that the protection by 2,9-Me2OP is not due to its classic copper-chelating property, but rather due to formation of a multiple hydrogen-bonded complex between 2,9-Me2OP and TCC, featuring an unusual perpendicular arrangement of the two binding partners. The two methyl groups at the 2,9 positions in 2,9-Me2OP were found to be critical to stabilize the 2,9-Me2OP/TCC complex due to steric hindrance, and therefore completely prevents the generation of the reactive and toxic semiquinone radicals by TCC/NaN3. This represents the first report showing that an unexpected new protective mode of action for the copper "specific" chelating agent 2,9-Me2OP by using its steric hindrance effect of the two CH3 groups not only to chelate copper, but also to "chelate" a catechol through multiple H-bonding. These findings may have broad biological implications for future research of this widely used copper-chelating agent and the ubiquitous catecholic compounds.

Keywords: chelates; hydrogen bonds; radical reactions; reaction mechanisms; steric hindrance.