Metal-assisted red light-induced efficient DNA cleavage by dipyridoquinoxaline-copper(II) complex

Complete cleavage of double stranded pUC19 DNA by the complex [Cu(dpq)2(H2O)](ClO4)2 (dpq, dipyridoquinoxaline) has been observed on irradiation at 694 nm from a pulsed ruby laser, assisted by the metal d-band transition as well as the quinoxaline triplet states in the absence of any external additives.     

Reactivity of mononuclear alkylperoxo copper(II) complex. O-O bond cleavage and C-H bond activation

A detailed reactivity study has been carried out for the first time on a new mononuclear alkylperoxo copper(II) complex, which is generated by the reaction of copper(II) complex supported by the bis(pyridylmethyl)amine tridentate ligand containing a phenyl group at the 6-position of the pyridine donor groups and cumene hydroperoxide (CmOOH) in CH3CN. The cumylperoxo copper(II) complex thus obtained has been found to undergo homolytic cleavage of the O-O bond and induce C-H bond activation of exogenous substrates, providing important insights into the catalytic mechanism of copper monooxygenases.     

Metal-assisted red light-induced DNA cleavage by ternary L-methionine copper(II) complexes of planar heterocyclic bases

Ternary copper(II) complexes [Cu(l-met)B(Solv)](ClO4) (1-4), where B is a N,N-donor heterocyclic base like 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2'],3'-c]phenazene (dppz, 4), are prepared and their DNA binding and photo-induced DNA cleavage activity studied (L-Hmet =L-methionine). Complex 2, structurally characterized by X-ray crystallography, shows a square pyramidal (4 + 1) coordination geometry in which the N,O-donor L-methionine and N,N-donor heterocyclic base bind at the basal plane and a solvent molecule is coordinated at the axial site. The complexes display a d-d band at approximately 600 nm in DMF and exhibit a cyclic voltammetric response due to the Cu(II)/Cu(I) couple near -0.1 V in DMF-Tris-HCl buffer. The complexes display significant binding propensity to the calf thymus DNA in the order: 4(dppz) > 3(dpq) > 2(phen> 1(bpy). Control cleavage experiments using pUC19 supercoiled DNA and distamycin suggest major groove binding for the dppz and minor groove binding for the other complexes. Complexes 2-4 show efficient DNA cleavage activity on UV (365 nm) or red light (632.8 nm) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The DNA cleavage activity of the dpq complex is found to be significantly more than its dppz and phen analogues.     

Disulfide bond cleavage induced by a platinum(II) methionine complex

The cleavage of a disulfide bond and the redox equilibrium of thiol/disulfide are strongly related to the levels of glutathione (GSH)/oxidized glutathione (GSSG) or mixed disulfides in vivo. In this work, the cleavage of a disulfide bond in GSSG induced by a platinum(II) complex [Pt(Met)Cl2] (where Met = methionine) was studied and the cleavage fragments or their platinated adducts were identified by means of electrospray mass spectrometry, high-performance liquid chromatography, and ultraviolet techniques. The second-order rate constant for the reaction between [Pt(Met)Cl2] and GSSG was determined to be 0.4 M(-1) s(-1) at 310 K and pH 7.4, which is 100- and 12-fold faster than those of cisplatin and its monoaqua species, respectively. Different complexes were formed in the reaction of [Pt(Met)Cl2] with GSSG, mainly mono- and dinuclear platinum complexes with the cleavage fragments of GSSG. This study demonstrated that [Pt(Met)Cl2] can promote the cleavage of disulfide bonds. The mechanistic insight obtained from this study may provide a deeper understanding on the potential involvement of platinum complexes in the intracellular GSH/GSSG systems.     

Ferrocene-conjugated copper(II) dipyridophenazine complex as a multifunctional model nuclease showing DNA cleavage in red light

The copper(II) complex [Cu(L)(dppz)](ClO₄)₂ (1) having a tripodal ligand ferrocenylmethylbis(2-pyridylmethylamine) (L) with a pendant ferrocenyl unit and a planar NN-donor dipyrido-[3,2-a:2′,3′-c]-phenazine (dppz) base is prepared and its DNA binding and cleavage properties studied. The complex is redox active showing cyclic voltammetric responses at 0.52 and –0.01 V vs. SCE due to Fe(III)/Fe(II) and Cu(II)/Cu(I) couples, respectively. The complex that binds to the major groove of DNA shows dual chemical nuclease activity involving both the metal centres. The complex displays efficient photo-induced DNA cleavage activity in visible laser light of 458 and 568 nm wavelengths forming cleavage active hydroxyl radicals. Significant DNA cleavage is also observed in red light of 647 nm within the photodynamic therapy (PDT) window.     

Comparing a mononuclear Zn(II) complex with hydrogen bond donors with a dinuclear Zn(II) complex for catalysing phosphate ester cleavage

Introducing ligand based hydrogen bond donors to increase the activity of a mononuclear Zn(II) complex for catalysing phosphate ester cleavage can be a more effective strategy than making the dinuclear analogue.     

Catalytic promiscuity in biomimetic systems: catecholase-like activity, phosphatase-like activity, and hydrolytic DNA cleavage promoted by a new dicopper(II) hydroxo-bridged complex

Presented in this Communication are the structure, physicochemical properties, and catalytic promiscuity of a new dinuclear CuII(mu-OH)CuII complex containing a novel N,O-donor symmetric dinucleating ligand.     

Efficient plasmid DNA cleavage by a mononuclear copper(II) complex

The Cu(II) complex of the ligand all-cis-2,4,6-triamino-1,3,5-trihydroxycyclohexane (TACI) is a very efficient catalyst of the cleavage of plasmid DNA in the absence of any added cofactor. The maximum rate of degradation of the supercoiled plasmid DNA form, obtained at pH 8.1 and 37 degrees C, in the presence of 48 microM TACI.Cu(II), is 2.3 x 10(-3) s(-1), corresponding to a half-life time of only 5 min for the cleavage of form I (supercoiled) to form II (relaxed circular). The dependence of the rate of plasmid DNA cleavage from the TACI.Cu(II) complex concentration follows an unusual and very narrow bell-like profile, which suggests an high DNA affinity of the complexes but also a great tendency to form unreactive dimers. The reactivity of the TACI.Cu(II) complexes is not affected by the presence of several scavengers for reactive oxygen species or when measured under anaerobic conditions. Moreover, no degradation of the radical reporter Rhodamine B is observed in the presence of such complexes. These results are consistent with the operation of a prevailing hydrolytic pathway under the normal conditions used, although the failure to obtain enzymatic religation of the linearized DNA does not allow one to rule out the occurrence of a nonhydrolytic oxygen-independent cleavage. A concurrent oxidative mechanism becomes competitive upon addition of reductants or in the presence of high levels of molecular oxygen: under such conditions, in fact, a remarkable increase in the rate of DNA cleavage is observed.     

Hydrolytic cleavage of DNA by a ruthenium(II) polypyridyl complex

The complex [Ru(bpy)2(BPG)]Cl2 (1) containing hydrogen-bond donor (N-H atoms) and acceptor (O atoms) groups mediates hydrolytic cleavage of plasmid pBR322 DNA in an enzyme-like manner. The kinetic aspects of DNA cleavage under pseudo- and true-Michaelis-Menten conditions are detailed.     

Collision-activated cleavage of a peptide/antibiotic disulfide linkage: possible evidence for intramolecular disulfide bond rearrangement upon collisional activation

Ceftiofur is an important veterinary beta-lactam antibiotic whose bioactive metabolite, desfuroylceftiofur, has a free thiol group. Desfuroylceftiofur (DFC) was reacted with two peptides, [Arg8]-vasopressin and reduced glutathione, both of which have cysteine residues to form disulfide-linked peptide/antibiotic complexes. The products of the reaction, [vasopressin + (DFC-H) + (DFC-H) + H]+, [(vasopressin+H) + (DFC-H) + H]+ and [(glutathione-H) + (DFC-H) + H]+, were analyzed using collision-activated dissociation (CAD) with a quadrupole ion trap tandem mass spectrometer. MS/MS of [vasopressin + (DFC-H) + (DFC-H) + H]+ resulted in facile dissociative loss of one and two covalently bound DFC moieties. Loss of one DFC resulted from either homolytic or heterolytic dissociation of the peptide/antibiotic disulfide bond with equal or unequal partitioning of the two sulfur atoms between the fragment ion and neutral loss. Hydrogen migration preceded heterolytic dissociation. Loss of two DFC moieties from [vasopressin + (DFC-H) + (DFC-H) + H]+ appears to result from collision-activated intramolecular disulfide bond rearrangement (IDBR) to produce cyclic [vasopressin + H]+ (at m/z 1084) as well as other cyclic fragment ions at m/z 1084 +/- 32 and +64. The cyclic structure of these ions could only be inferred as MS/MS may result in rearrangement to non-cyclic structures prior to dissociative loss. IDBR was also detected from MS(3) experiments of [vasopressin + (DFC-H) + (DFC-H) + H]+ fragment ions. MS/MS of [(glutathione-H) + (DFC-H) + H]+ resulted in cleavage of the peptide backbone with retention of the DFC moiety as well as heterolytic cleavage of the peptide/antibiotic disulfide bond to produce the fragment ion: [(DFC-2H) + H]+. These results demonstrate the facile dissociative loss by CAD of DFC moieties covalently attached to peptides through disulfide bonds. Published in 2004 by John Wiley & Sons, Ltd.     

Effect of 1,10-phenanthroline on DNA binding,DNA cleavage,cytotoxic and lactate dehydrogenase inhibition properties of Robson type macrocyclic dicopper(II) complex

DNA targeting macrocyclic dicopper(II) complex, [Cu₂L(H₂O)₂](phen)₂(ClO₄)₂ (L = μ-11,23-dimethyl-3,7,15,19-tetraazatricyclo-[19.3.1.1^9,13,21] he p t a c o s a-1(24), 2, 7, 9, 11, 13(26), 14, 19, 21(25), 22-decaene-25,26-diol) (2), has been synthesized and characterized. This has been synthesized by reacting a Robson type macrocyclic precursor dicopper(II) complex [Cu₂L(H₂O)₂](ClO₄)₂ (1) and 1,10-phenanthroline in ethanol. Solution ESR, electronic, and ESI-MS spectral studies suggest that 1,10-phenanthroline replaces coordinated water in 1, giving 2. The influence of the phenanthroline on DNA binding, cleavage, and anticancer properties of 2 have been investigated. Complex 2 displays better DNA binding and cleavage than 1. The dicopper(II) complexes 1 and 2 show cytotoxicity in human cervical HeLa cancer cells, giving IC₅₀ values of 79.41 and 15.82 μM, respectively. Antiproliferative properties of 1 and 2 were confirmed by Trypan Blue exclusive assay and lactate dehydrogenase enzyme level in HeLa cancer cell lysate and content media.     

Supramolecular assembly and DNA cleavage activity of a nickel(II) complex

A new mononuclear nickel(II) complex, [NiL₂] (HL = ((2-(5-fluoro-2-hydroxybenzyl)(2-(imidazole-2-yl)ethyl))imine), has been synthesized and characterized by IR, UV–vis and X-ray diffraction technique. The X-ray crystal structure of the complex shows that the coordination environment around Ni(II) ion is an approximate octahedron. Each molecule connects with four adjacent neighbors through strong hydrogen bonding interactions (N–H···O, d(N–O) = 2.687 Å and ∠N–H···O = 158.3(1)°), forming a supramolecular network. The interaction of the complex with DNA was monitored using agarose gel electrophoresis. The results show that the complex has DNA cleavage activity. The cyclic voltammogram shows one pair of anodic and cathodic peaks with E_1/2 = ?1.06 V, assigned to the Ni(II)/Ni(I) couple.     

Potential-modulated DNA cleavage by (N-salicylideneglycinato)copper(II) complex.

The interaction of aqua (N-salicylideneglycinato)copper(II) (Cu(salgly)2+) complex with calf thymus DNA has been investigated by cyclic voltammetry. Potential-modulated DNA cleavage in the presence of Cu(salgly)2+ complex was performed at a gold electrode in a thin layer cell. DNA can be efficiently cleaved by electrochemically reducing Cu(salgly)2+ complex to Cu(salgly)+ complex at -0.7 V (vs. Ag/AgCl). When the solution was aerated with a small flow of O2 during electrolysis, the extent of DNA cleavage was dramatically enhanced, and hydroxyl radical scavengers inhibited DNA cleavage. These results suggested that O2 and hydroxyl radical were involved in potential-modulated DNA cleavage reaction. The percentage of DNA cleavage was enhanced as the working potential was shifted to more negative values and the electrolysis time was increased. It was also dependent on the ratio of Cu(salgly)2+ complex to DNA concentration. The cleaved DNA fragments were separated by high performance liquid chromatography (HPLC). The experimental results indicated that the method for potential-modulated DNA cleavage by Cu(salgly)2+ complex was simple and efficient.     

Intramolecular nucleophilic activation promoting efficient hydrolytic cleavage of DNA by (aqua)bis(dipyridoquinoxaline)copper(II) complex

The axial aqua bound copper(II) complex [Cu(dpq)2(H2O)](ClO4)2, having a planar NN-donor heterocyclic base dipyridoquinoxaline (dpq) as the DNA minor groove binder, shows efficient hydrolytic cleavage of supercoiled DNA in the dark and in the absence of any external reagents, as evidenced from T4 ligase experiments, with a rate of 5.58 +/- 0.4 h(-1) and a rate enhancement of 1.55 x 10(8).     

Synthesis of new dinuclear dicopper(II) and dinickel(II) complexes. The kinetics of catechol oxidase and electrochemistry of a dicopper(II) complex

A new dinuclear ligand L, ethylene[OO-bis-salicylidene--diketone] bearing two symmetrical coordination sites was synthesized by the condensation of salicylaldehyde and acetylacetone, L, with 1,2-dibromoethane under reflux. The ligand L in a 1:1 ratio was treated with CuCl₂ and NiCl₂ to yield the complexes, tetrachloro bis[OO-bis- salicylidene--diketone copper(II)] and bis[OO-bis-salicylidene--diketone nickel(II)] chloride. The complexes were subsequently characterized by spectroscopic techniques, elemental analysis, i.r., ¹H-n.m.r., ¹³C-n.m.r., u.v.–vis., e.p.r. spectroscopy, and conductance measurements. The conductance measurements in DMF reveal that the Cu^II complex is covalent while the Ni^II complex is ionic and the spectral data support the Cu^II complex to be distorted octahedral whereas the Ni^II complex has square-planar geometry. The dioxygen binding was studied spectrophotometrically by the oxidation of tetrachloro bis[OO-bis-salicylidene--diketone copper(II)] with pyrocatechol in the presence of oxygen. The kinetic experiments were performed with the copper complex in DMF by monitoring the increase in absorbance over time at pH 8.0 in the presence of pyrocatechol at 25 °C. The kinetic parameters V_max and K_M were determined on the Michaelis–Menten Approach. Redox behavior of the dinuclear copper(II) complex was investigated by cyclic voltammetry in the presence of O₂ with the pyrocatechol (substrate) and also without the substrate. The large difference in potentials E⁰ is indicative of reversible oxygen binding of the complex and distinct catalytic activity.     

Oxygen activation and intramolecular C-H bond activation by an amidate-bridged diiron(II) complex

A diiron(II) complex containing two μ-1,3-(κN:κO)-amidate linkages has been synthesized using the 2,2',2'-tris(isobutyrylamido)triphenylamine (H(3)L(iPr)) ligand. The resulting diiron complex, 1, reacts with dioxygen (or iodosylbenzene) to effect intramolecular C-H bond activation at the methine position of the ligand isopropyl group. The ligand-activated product, 2, has been isolated and characterized by a variety of methods including X-ray crystallography. Electrospray ionization mass spectroscopy of 2 prepared from(18)O(2) was used to confirm that the oxygen atom incorporated into the ligand framework is derived from molecular oxygen.     

Self-activated DNA cleavage of a water-soluble mononuclear Cu(II) complex with polyquinolinyl ligand

The synthesis and characterization of a water-soluble mononuclear Cu(II) complex, [CuLCl₂]·2CH₃CH₂OH, where L = bis(2-quinolinyl methyl)benzyl-amine has been reported. L is a tridentate polyquinolinyl ligand, coordinated to Cu(II) via NNN donors. The central copper ion of 1 has N₃Cl₂ donor set in a distorted trigonal-bipyramidal geometry. The dimer existing in the solid state resulted from hydrogen bonds and π–π accumulation between two mononuclear units. The interaction of 1 with CT-DNA has been explored by absorption and emission titration methods, revealing partial intercalation between 1 and CT-DNA. Moreover, 1 could make pBR322 plasmid DNA cleaved by a self-activated oxidative process; hydroxyl radical and singlet oxygen may be the main reactive oxygen species species in the process. Complex 1 may quench the intrinsic fluorescence of bovine serum albumin in a static quenching process, which has been investigated by UV–visible and fluorescence spectroscopic methods. 1 also demonstrates potent cytotoxity against Hela cells with IC₅₀ value of 2.84 μM, which shows it to be a potential candidate as an anticancer metal-based drug.