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.
Lanthanide complexes of formulation [La(B)(2)(NO(3))(3)] (1-3) and [Gd(B)(2)(NO(3))(3)] (4-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2, 5) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3, 6), have been prepared, characterized from physicochemical data, and their photoinduced DNA and protein cleavage activity studied. The photocytotoxicity of the dppz complexes 3 and 6 has been studied using HeLa cancer cells. The complexes exhibit ligand centered bands in the UV region. The dppz complexes show the lowest energy band at 380 nm in N,N-dimethylformamide (DMF). The La(III) complexes are diamagnetic. The Gd(III) complexes (4-6) have magnetic moments that correspond to seven unpaired electrons. The complexes are 1:1 electrolytic in aqueous DMF. The dpq and dppz complexes in DMF show ligand-based reductions. The complexes display moderate binding propensity to calf thymus DNA giving binding constant values in the range of 5.7 x 10(4)-5.8 x 10(5) M(-1) with a relative order: 3, 6 (dppz) > 2, 5 (dpq) > 1, 4 (phen). The binding data suggest DNA surface and/or groove binding nature of the complexes. The complexes do not show any hydrolytic cleavage of plasmid supercoiled pUC19 DNA. The dpq and dppz complexes efficiently cleave SC DNA to its nicked circular form on exposure to UV-A light of 365 nm at nanomolar complex concentration. Mechanistic studies reveal the involvement of singlet oxygen ((1)O(2)) and hydroxyl radical (HO*) as the cleavage active species. The complexes show binding propensity to bovine serum albumin (BSA) protein giving K(BSA) values of approximately 10(5) M(-1). The dppz complexes 3 and 6 show BSA protein cleavage activity in UV-A light of 365 nm. The dppz complexes 3 and 6 exhibit significant photocytotoxicity in HeLa cells giving respective IC(50) values of 341 nM and 573 nM in UV-A light of 365 nm for an exposure time of 15 min (IC(50) > 100 microM in dark for both the complexes). Control experiments show significant dark and phototoxicity of the dppz base alone (IC(50) = 413 nM in light with 4 h incubation in dark and 11.6 microM in dark with 24 h incubation). A significant decrease in the dark toxicity of the dppz base is observed on binding to the lanthanide ions while retaining similar phototoxicity.
Cobalt(iii) complexes [Co(pnt)(B)(2)](NO(3))(2) (1-3) of pyridine-2-thiol (pnt) and phenanthroline bases (B), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in ) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3), have been prepared, characterized and their photo-induced anaerobic DNA cleavage activity studied. The crystal structure of 1a as mixed ClO(4)(-) and PF(6)(-) salt of 1 shows a Co(III)N(5)S coordination geometry in which the pnt and phen showed N,S- and N,N-donor binding modes, respectively. The complexes exhibit Co(iii)/Co(ii) redox couple near -0.3 V (vs. SCE) in 20% DMF-Tris-HCl buffer having 0.1 M TBAP. The complexes show binding propensity to calf thymus DNA giving K(b) values within 2.2 x 10(4)-7.3 x 10(5) M(-1). Thermal melting and viscosity data suggest DNA surface and/or groove binding of the complexes. The complexes show significant anaerobic DNA cleavage activity in red light under argon atmosphere possibly involving sulfide anion radical or thiyl radical species. The DNA cleavage reaction under aerobic medium in red light is found to involve both singlet oxygen and hydroxyl radical pathways. The dppz complex shows non-specific BSA and lysozyme protein cleavage activity in UV-A light of 365 nm via both hydroxyl and singlet oxygen pathways. The dppz complex exhibits photocytotoxicity in HeLa cervical cancer cells giving IC(50) values of 767 nM and 19.38 microM in UV-A light of 365 nm and in the dark, respectively. A significant reduction of the dark toxicity of the dppz base (IC(50) = 8.34 microM in dark) is observed on binding to the cobalt(iii) center.
(3) and dpq (4) complexes were structurally characterized by X-ray data analysis. Their DNA binding, oxidative cleavage and antibactirial activities were studied. The dpq (4) and dppz (5) complexes are avid binders to the Calf thymus DNA (CT-DNA). The phen (3), dpq (4) and dppz (5) complexes show efficient oxidative cleavage of supercoiled DNA (SC DNA) through hydroxyl radical ( Å OH) pathway in the presence of Mercaptopropionic acid (MPA).
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