Oxidation of CuII to CuIII, free radical production, and DNA cleavage by hydroxy-salen-copper complexes.: Isomeric effects studied by ESR and electrochemistry

A series of copper complexes of bis(hydroxysalicylidene)ethylenediamine (hydroxy-salens) have been synthesized. The hydroxy group in the ortho, meta, or para position on each salicylidene unit was added to reinforce the stability of the copper complex and to create a hydroquinone system cooperating with the copper redox system to facilitate the spontaneous formation of oxidizing Cu-III species. Cyclic voltammetry and ESR spectroscopy in combination with electrochemistry and spin trapping experiments have been used to characterize the structure and the redox state of the hydroxy-salen-copper complexes and to evidence the production of oxygen-based free radicals. A complete set of magnetic values were determined. In addition, we studied the capacity of complexes 3a,b,c to cleave DNA in the absence of activating agents. The meta isomer 3b does not generate oxygen radicals, and as a result it cannot cleave DNA. In sharp contrast, the para isomer 3c and to a lower extent the ortho isomer 3a exhibit nuclease activities in relation to their capacities to produce oxygen radicals. Electrochemistry provides unequivocal evidence for the formation of Cu-III species with compounds 3a and 3c, but not with 3b. The nuclease activity correlates well with the ability of the hydroxy-salens to form the oxidizing Cu-III species. The redox properties and therefore the DNA cleaving activities of the complexes depend crucially on the position of the OH groups which contribute significantly to stabilize the square planar copper complexes. The present work supports the hypothesis that a hydroquinone system can cooperate with a redox metal system to trigger DNA cleavage. The design of metallo(hydroxy-salens) provides an original route for the development of self-activated chemical nucleases.