DNA cleavage activity of VIVO(acac)2 and derivatives

Inorganic Chemistry, 2005

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°C, in the presence of 48 µM TACI‚Cu II , is 2.3 × 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.

Polyhedron, 2009

A new series of unsymmetrical macrocyclic binuclear bis-phenoxo bridged oxidovanadium(IV) complexes have been synthesized and characterized by elemental and spectral techniques. A cyclic voltammetric investigation of these binuclear V IV O complexes evidenced that two successive quasi-reversible one electron transfer reduction waves (E 1 pc = À0.54 to À0.67 V, E 2 pc = À0.80 to À0.85 V) are obtained. In the positive potential region (+0.50 to +1.00 V) two quasi-reversible oxidation couples are observed for all the complexes. The first one electron oxidation is observed around (E 1 pc ) +0.63 to +0.78 V and the second around (E 2 pc ) +0.82 to +0.97 V. The ESR spectra of all the binuclear V IV O complexes showed a single broad-band resonance at ca. g = 1.97-2.11 with the half field signal at 1500G (M = ±2), which suggest magnetic interactions between two V IV O ions through the phenolate bridge. DNA binding experiments show that the aromatic diimine containing macrocyclic V IV O complexes display better DNA interactions than the aliphatic diimine containing V IV O analogues. These complexes significantly promote the oxidative cleavage of supercoiled plasmid DNA under physiological conditions in the presence of H 2 O 2 . All the complexes show noticeable growth inhibition of some plant pathogenic fungal species and human pathogenic bacterial species.

Inorganic Chemistry, 2007

Oxovanadium(IV) complexes [VO(salmet)(B)] (1−3) and [VO(saltrp)(B)] (4−6), where salmet and saltrp are N-salicylidene-L-methionate and N-salicylidene-L-tryptophanate, respectively, and B is a N,N-donor heterocyclic base (viz. 1,10-phenanthroline (phen, 1, 4), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, 2, 5), and dipyrido[3,2-a:2′,3′c]phenazine (dppz, 3, 6)) are prepared and characterized and their DNA binding and photoinduced DNA cleavage activity studied. Complexes 1, 2, and 4 are structurally characterized by single-crystal X-ray crystallography. The molecular structure shows the presence of a vanadyl group in the VO 3 N 3 coordination geometry. The dianionic R-amino acid Schiff base acts as a tridentate O,N,O-donor ligand in a meridional binding mode. The N,N-donor heterocyclic base displays a chelating mode of bonding with a N-donor site trans to the oxo group. The complexes show a d−d band in the range of 680−710 nm in DMF with a shoulder near 840 nm. They exhibit an irreversible oxidative cyclic voltammetric response near 0.8 V assignable to the V(V)/V(IV) couple and a quasi-reversible V(IV)/ V(III) redox couple near −1.1 V vs SCE in DMF−0.1 M TBAP. The complexes show good binding propensity to calf thymus DNA giving binding constant values in the range from 5.2 × 10 4 to 7.2 × 10 5 M-1. The binding site size, thermal melting, and viscosity data suggest DNA surface and/or groove binding nature of the complexes. The complexes show poor "chemical nuclease" activity in the dark in the presence of 3-mercaptopropionic acid or hydrogen peroxide. The dpq and dppz complexes show efficient DNA cleavage activity on irradiation with UV-A light of 365 nm via a mechanistic pathway involving formation of singlet oxygen as the reactive species. They also show significant DNA cleavage activity on photoexcitation in red light (>750 nm) by 1 O 2 species. Observation of red-light-induced cleavage of DNA is unprecedented in the vanadium chemistry. The DNA cleavage activity is metal promoted as the ligands or vanadyl sulfate alone are cleavage inactive on photoirradiation at these wavelengths.

Inorganic Chemistry, 2007

Oxovanadium(IV) complexes [VO(salmet)(B)] (1−3) and [VO(saltrp)(B)] (4−6), where salmet and saltrp are N-salicylidene-L-methionate and N-salicylidene-L-tryptophanate, respectively, and B is a N,N-donor heterocyclic base (viz. 1,10-phenanthroline (phen, 1, 4), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, 2, 5), and dipyrido[3,2-a:2′,3′c]phenazine (dppz, 3, 6)) are prepared and characterized and their DNA binding and photoinduced DNA cleavage activity studied. Complexes 1, 2, and 4 are structurally characterized by single-crystal X-ray crystallography. The molecular structure shows the presence of a vanadyl group in the VO 3 N 3 coordination geometry. The dianionic R-amino acid Schiff base acts as a tridentate O,N,O-donor ligand in a meridional binding mode. The N,N-donor heterocyclic base displays a chelating mode of bonding with a N-donor site trans to the oxo group. The complexes show a d−d band in the range of 680−710 nm in DMF with a shoulder near 840 nm. They exhibit an irreversible oxidative cyclic voltammetric response near 0.8 V assignable to the V(V)/V(IV) couple and a quasi-reversible V(IV)/ V(III) redox couple near −1.1 V vs SCE in DMF−0.1 M TBAP. The complexes show good binding propensity to calf thymus DNA giving binding constant values in the range from 5.2 × 10 4 to 7.2 × 10 5 M-1. The binding site size, thermal melting, and viscosity data suggest DNA surface and/or groove binding nature of the complexes. The complexes show poor "chemical nuclease" activity in the dark in the presence of 3-mercaptopropionic acid or hydrogen peroxide. The dpq and dppz complexes show efficient DNA cleavage activity on irradiation with UV-A light of 365 nm via a mechanistic pathway involving formation of singlet oxygen as the reactive species. They also show significant DNA cleavage activity on photoexcitation in red light (>750 nm) by 1 O 2 species. Observation of red-light-induced cleavage of DNA is unprecedented in the vanadium chemistry. The DNA cleavage activity is metal promoted as the ligands or vanadyl sulfate alone are cleavage inactive on photoirradiation at these wavelengths.

J Am Chem Soc, 2001

Significant effort has been made to develop synthetic metal complexes that hydrolyze DNA. Here we report a new dicerium complex, Ce 2 (HXTA) (HXTA) 5-methyl-2-hydroxy-1,3-xylene-R,R-diamine-N,N,N′,N′-tetraacetic acid), which can hydrolyze DNA at pH 8 and 37°C. This complex hydrolyzes DNA restriction fragments to give products with high regioselectivity, affording >90% 5′-OPO 3 and 3′-OH ends, like the products of DNA hydrolyzing enzymes. Ce 2 (HXTA) also hydrolyzes Litmus 29 plasmid DNA to afford both nicked and linear DNA. Analysis of the relative amounts of supercoiled, nicked, and linear DNA present show that there is one double-strand cleavage per ten single-strand cleavages, indicating that the linear DNA formed cannot be the result of two random single-strand cleavage events. The kinetics of nicked and linear DNA formation are comparable, both being associated with apparent first-order rate constants of approximately 1 × 10-4 s-1 for complex concentrations of 10-5-10-4 M. These observations suggest that similar factors affect the hydrolysis of the first and second DNA strands and that cleaving the phosphodiester bond is likely the rate determining step in both cases. This is the first detailed study of a metal complex shown to mimic DNA hydrolases in their capability to effect double-strand DNA hydrolysis regioselectively at the 3′-O-P bond.

Org. Lett, 2004

Inorganic …, 2008

Two binuclear Cu(II) complexes of N-functionalized macrocycle ligands, namely 1,3-bis(1,4,7-triaza-1-cyclonomyl)propane and 1-(3-(1,4,7-triazonan-1-yl)propyl)-1,4,7,10-tetraazacyclo-dodecane, were synthesized and their ability to hydrolyze the cleavage of supercoiled plasmid DNA (pBR322) was compared with that of structurally related non-functionalized mononuclear Cu(II) complexes. The former, binuclear Cu(II) complex with the symmetrical ligand exhibited enhanced double-strand cleavage activity compared to the other three complexes at the same [Cu 2+ ] concentration. In contrast, the latter binuclear complex with unsymmetrical macrocylic ligand did not give rise to double-strand DNA cleavage. The linear DNA formation induced by the mononuclear Cu(II) 1,4,7,10-tetraazacyclo-dodecane complex was realized via a non-random double-stranded scission process. The differential cleavage activity is discussed in relation to dimer formation, effective cooperation and coordination environment of the metal center. The hydrolytic cleavage by the copper complexes without H 2 O 2 is supported by evidence from an anaerobic reaction, free radical quenching, and nitro blue tetrazolium assay. In contrast, both the binuclear complexes cleaved supercoiled DNA efficiently to Form III (linearized DNA) in the presence of H 2 O 2 , indicating that nuclearity is a crucial parameter in oxidative cleavage. The radical scavenger inhibition study and nitro blue tetrazolium assay suggested the involvement of H 2 O 2 and superoxide ions in the oxidative cleavage of DNA by the binuclear complexes.

1999

ion of an H atom from sugar units and predict the release of specific chemical residues arising from transformed sugars, depending on the position from which the H atom is removed 17 • It has been shown earlierx that the cleavage is inhibited by free radical scavengers implying that hydroxyl radical or peroxy derivatives mediate the cleavage reaction . Further, the reaction is modulated by a metallo complex bound hydroxyl radical or a peroxo species generated from the coreactant H 2 0 2 . Thi s results in oxidative attack on the deoxyribose moiety at C-\ hydrogen leading to a series of elimination reactions that ruptures the phospho di este r backbone and yields 3' and 5' pho sphomonoe s ter termini, free bases and 5methylene-2 furanone. A key question in elucidating mechanisms of nucleic acid damages is which of hydrogen atom is abstracted in the formation of a st rand break . Further work is in progress to characterise the structure of metal complexes and in the identifica...

Chemistry-a European Journal, 2003

A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently linked to viologen by an alkylidene spacer was synthesized, and their photophysical properties and interactions with DNA, including DNA cleaving properties, were investigated. The fluorescence quantum yields of the viologen-linked acridines were found to be lower than that of the model compound 9-methylacridine (MA). The changes in free energy for the electron transfer reactions were found to be favorable, and the fluorescence quenching observed in these systems is explained by an electron transfer mechanism. Intramolecular electron transfer rate constants were calculated from the observed fluorescence quantum yields and singlet lifetime of MA and are in the range from 1.06×1010 s−1 for 1 a (n=1) to 6×108 s−1 for 1 c (n=11), that is, the rate decreases with increasing spacer length. Nanosecond laser flash photolysis of these systems in aqueous solutions showed no transient absorption, but in the presence of guanosine or calf thymus DNA, transient absorption due to the reduced viologen radical cation was observed. Studies on DNA binding demonstrated that the viologen-linked acridines bind effectively to DNA in both intercalative and electrostatic modes. Results of PM2 DNA cleavage studies indicate that, on photoexcitation, these molecules induce DNA damage that is sensitive to formamidopyrimidine DNA glycosylase. These viologen-linked acridines are quite stable in aqueous solutions and oxidize DNA efficiently and hence can be useful as photoactivated DNA-cleaving agents which function purely by the co-sensitization mechanism.