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

Abstract

Binuclear copper(II) complexes [{(phen)Cu(II)}(2)(mu-dtdp)(2)] (1), [{(dpq)Cu(II)}(2)(mu-dtdp)(2)] (2), [{(phen)Cu(II)}(2)(mu-az)(2)] (3), and [{(dpq)Cu(II)}(2)(mu-az)(2)] (4) and a zinc(II) complex [{(phen)Zn(II)}(2)(mu-dtdp)(2)] (5), having 3,3'-dithiodipropionic acid (H(2)dtdp), 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 MN(2)O(2) 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 (1)O(2) 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 (1)O(2) pathway. The zinc(II) complex of the dtdp ligand (5) does not show any photoinduced DNA cleavage activity in red light.

Remarkable photocytotoxicity in hypoxic HeLa cells by a dipyridophenazine copper(II) Schiff base thiolate

“…Dirhodium(II,II) complexes are reported to cleave DNA on photoexposure to visible light via both oxygen dependent and independent pathways [15,16]. The present work stems from our interest to design and develop 3d-metal complexes that could photocleave DNA in an oxygen independent pathway in red light [17][18][19]. The use of red light is essential for phototherapeutic applications since red light has greater tissue penetration ability than blue or green light [1].…”

Anaerobic DNA cleavage in red light by dicopper(II) complexes on disulphide bond activation

“…It has also been observed that copper(II) complexes having a disulphide moiety show significantly enhanced DNA photo-cleavage activity under anaerobic medium in comparison to the complexes lacking the disulphide bond. 52 In air, it presumably reacts with the dissolved oxygen in the solvent to produce hydroxyl radical. 53 The anaerobic DNA cleavage by sulphide anion radical (RS •− ) presumably proceeds via formation of nucleobase radical anion (B •− ) that could activate the sugar moiety by hydrogen abstraction and leading to DNA cleavage.…”

Synthesis, DNA binding, photo-induced DNA cleavage, cytotoxicity and apoptosis studies of copper(II) complexes

“…Planar heterocyclic bases complexes have been at the forefront of these investigations because of their unusual electronic properties, diverse chemical reactivity, and peculiar structure, which result in noncovalent interactions with DNA [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Recent reports have shown that d 9 -copper(II) complexes having a DNA binder and a photosensitizer are capable of cleaving plasmid DNA on photo-induced [37][38][39][40][41][42][43][44][45][46][47][48][49][50]. The choice of dpq and dppz ligands is based on the fact that quinoxalines are known to generate photo-induced 3 (n-π) and/or 3 (π-π) states which transfers its excited state energy to molecular oxygen in a type-II process forming singlet oxygen that causes oxidative cellular damage [51].…”