Anaerobic Photocleavage of DNA in Red Light by Dicopper(II) Complexes of 3,3′-Dithiodipropionic Acid

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Abstract
Binuclear copper(II) complexes [{(phen)CuII}2(μ-dtdp)2] (1), [{(dpq)CuII}2(μ-dtdp)2] (2), [{(phen)CuII}2(μ-az)2] (3), and [{(dpq)CuII}2(μ-az)2] (4) and a zinc(II) complex [{(phen)ZnII}2(μ-dtdp)2] (5), having 3,3′-dithiodipropionic acid (H2dtdp), azelaic acid (nonanedioic acid), 1,10-phenanthroline (phen), and dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), were prepared and characterized by physicochemical methods. Complex 1 has been structurally characterized by X-ray crystallography. The complexes have each metal center bound to a chelating phenanthroline base and two bridging carboxylate ligands giving a square-planar MN2O2 coordination geometry. The molecular structure of complex 1 shows two sterically constrained disulfide moieties of the dtdp ligands. The complexes show good binding propensity to calf thymus DNA in the major groove. The photoinduced DNA cleavage activity of the complexes has been studied using 365 nm UV light and 647.1 nm and >750 nm red light under both aerobic and anaerobic conditions. The phen complex 1, having dtdp ligand, cleaves supercoiled (SC) DNA to its nicked circular (NC) form. The dpq analogue 2 shows formation of a significant quantity of linear DNA resulting from double-strand breaks (dsb) in air. Mechanistic studies reveal the involvement of HO• and 1O2 as the reactive species under an aerobic medium. The dsb of DNA is rationalized from the docking studies on 2, showing a close proximity of two photosensitizers, namely, the disulfide moiety of dtdp and the quinoxaline ring of dpq to the complementary strands of DNA. The copper(II) complexes of the dtdp ligand cleave SC DNA to its NC form upon exposure to UV or red light under an argon atmosphere. An enhancement of the DNA cleavage activity under argon has been observed upon increasing the concentration of the DMF solvent in the DMF−Tris buffer medium. Theoretical studies suggest the possibility of sulfide anion radical formation from a copper(II)-bound dtdp ligand in >750 nm red light, which further cleaves the DNA. The copper(II) azelate complexes are inactive under similar reaction conditions. The azelate complex of the dpq ligand cleaves DNA in air following the 1O2 pathway. The zinc(II) complex of the dtdp ligand (5) does not show any photoinduced DNA cleavage activity in red light.

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