Elucidating DNA damage and repair processes by independently generating reactive and metastable intermediates

DNA damage is a double-edged sword. The modifications produced in the biopolymer are associated with aging, and give rise to a variety of diseases, including cancer. DNA is also the target of anti-tumor agents and the most generally used nonsurgical treatment of cancer, ionizing radiation. Agents that damage DNA produce a variety of radicals. Elucidating the chemistry of individual DNA radicals is challenging due to the availability of multiple reactive pathways and complexities inherent with carrying out mechanistic studies on a heterogeneous polymer. The ability to independently generate radicals and their metastable products at defined sites in DNA has greatly facilitated understanding this biologically important chemistry.     

Activation barriers for DNA alkylation by carcinogenic methane diazonium ions

Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.     

Tailoring the separation selectivity of metal complexes and organometallic compounds resolved by capillary electrophoresis using auxiliary separation processes

The use of auxiliary separation mechanisms to manipulate the separation selectivity of metal complexes and organometallic species is reviewed. Auxiliary separation mechanisms included in the review are micellar electrokinetic capillary chromatography, ion-pairing and ion-exchange electrokinetic chromatography. This paper discusses how these secondary mechanisms can be effectively employed to tailor separation selectivity.     

Exploring the DNA binding mode of transition metal based biologically active compounds

Few novel 4-aminoantipyrine derived Schiff bases and their metal complexes were synthesized and characterized. Their structural features and other properties were deduced from the elemental analysis, magnetic susceptibility and molar conductivity as well as from mass, IR, UV-vis, (1)H NMR and EPR spectral studies. The binding of the complexes with CT-DNA was analyzed by electronic absorption spectroscopy, viscosity measurement, and cyclic voltammetry. The interaction of the metal complexes with DNA was also studied by molecular modeling with special reference to docking. The experimental and docking results revealed that the complexes have the ability of interaction with DNA of minor groove binding mode. The intrinsic binding constants (K(b)) of the complexes with CT-DNA were found out which show that they are minor groove binders. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pUC19 DNA in the presence of AH(2) (ascorbic acid). Moreover, the oxidative cleavage studies using distamycin revealed the minor groove binding for the newly synthesized 4-aminoantipyrine derived Schiff bases and their metal complexes. Evaluation of antibacterial activity of the complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, and Klebsiella pneumoniae exhibited that the complexes have potent biocidal activity than the free ligands.     

Nanostructured metal sulfide surfaces by ion exchange processes

A scalable preparation procedure for structured semiconducting sulfide films from zinc oxide by means of subsequent anion and cation exchange processes is described, which is low in cost and waste production. The starting material was columnar ZnO films, which were grown in electrodeposition by O₂ reduction. Here, their detailed morphology depends on the substrate and the process parameters. These films were converted to ZnS by reaction with H₂S gas or sulfur vapour at temperatures around 450 °C. In this process the columnar morphology of the ZnO is preserved. A partial conversion is also possible and leads to tubular ZnS films. Then the ZnS films were reacted in metal salt solutions to convert them further to Ag₂S, Cu₂S, Bi₂S₃ and Sb₂S₃ films. Here the columnar or tubular morphology was, in general, also reproduced, but its outer quality depends on the interaction of the involved processes, namely dissolution, precipitation and exchange inside the solid. This was further examined by a series of Ag₂S films from modified solutions.Presented at the 3rd International Symposium on Electrochemical Processing of Tailored Materials held at the 53rd Annual Meeting of the International Society of Electrochemistry, 15–20 September 2002, Düsseldorf, Germany     

Alkylation of DNA bases by carcinogenic N-nitrosamine metabolites: A theoretical study

N-Nitrosamines are believed to act as carcinogens by alkylating DNA in their ultimate carcinogenic forms which are produced by metabolic activation. Alkylation at certain oxygen sites in DNA, described as “promutagenic,” appears to be of particular significance for mutagenesis and cancer, as indicated by experimental findings. This theoretical study deals with two factors involved in the alkylation of these promutagenic oxygen sites by N-nitrosamine ultimate carcinogens. The first is the competition between alkylation at the promutagenic O⁶-guanine and O⁴-thymine sites and that at the nonmutagenic N⁷-guanine site, which is here related to the degree of participation of cationic ultimate carcinogens as compared with neutral ultimate carcinogens. Parent dialkylnitrosamines are classified structurally according to their degree of cationic ultimate carcinogen participation and preference for promutagenic alkylation. The second factor is the thermodynamic facileness of alkylation at the O⁶-guanine and O⁴-thymine sites. Heats of alkylation by candidate ultimate carcinogens are calculated here for numerous parent dialkylnitrosamines. Finally, these two factors are jointly considered in an attempt to correlate them with experimental carcinogenic potency of the parent nitrosamines. Out of the patterns of correlation observed, light is shed on mechanistic factors likely to be involved in the modulation of parent carcinogenic potency.     

DNA liquid-crystalline gel as adsorbent of carcinogenic agent

DNA liquid crystalline gel (LCG) has been newly prepared by a dialysis of concentrated DNA solutions into concentrated metal cation solutions. The condition for forming DNA LCG is examined by means of the insolubilization reaction. The shrinking ratio and the ratio of the thickness of LCG layer, delta, and the diameter of the dialysis tube, d0, do not depend on d0. The adsorption of one of carcinogenic agents, acridine orange is demonstrated. From the experimental results, the mechanism for forming DNALCG is discussed.     

Selectivity and sensitivity of metal determination by co-ordination compounds

Quantum chemical structure calculations for metal co-ordination compounds with various organic ligands allow choice of generalized parameters of chelate electronic structures, to form a basis for systematization and prediction of analytical properties. The extent of the co-ordinative saturation of a metal is measured as the sum of the covalent bonding energies of the two-centre metal interactions with the ligand atoms. The concept of "valence state of the ligand" is considered and characterized by the energy sum of the covalent components of two-centre interactions in the ligand. It is shown that the ligand structure can be correlated with the complex stability and this provides a new mechanism for assessing the influence of substituents in ligands. The calculated data make it possible to predict compound stability in solutions and synergic action, and therefore such analytical properties as sensitivity and selectivity. For the azo dyes as an example, it is shown that quantum chemical calculations can explain many of the experimental data on the use of azo dyes in photometry, and suggest directions of search for new analytical reagents.     

Selective isomerization of 1-alkenes by binary metal carbonyl compounds

An efficient and selective isomerization of 1-alkenes to their corresponding 2-alkenes is achieved by using binary metal carbonyls such as Ru₃(CO)₁₂ as catalysts. Possible mechanisms are discussed. Substituents on the 1-alkene have a significant effect on the isomerization.     

Radiative-thermal modification of dispersed and fibrous adsorbents by metal compounds

The investigation of solid-phase reaction in salt-oxide systems has a promising future for radiative modification of the surface by metallic clusters and oxides.     

Direct repair of the exocyclic DNA adduct 1,N6-ethenoadenine by the DNA repair AlkB proteins

The exocyclic DNA base adduct 1,N6-ethenoadenine (epsilonA) is directly repaired by the AlkB proteins in vitro.     

Disruption processes in films grown and reduced electrochemically on metals

New aspects characterizing the disruption process are discussed, based on an analysis of a proposed disruption model and on a review of previously reported voltammetric and galvanostatic anodic growths of films on metals and their consequent reduction. For voltammetric cases of Pb and Zn, it is shown that the formation charge is not always recoverable, leading to irreversible processes. The total formation charge of Zn can never be totally recovered, but that of Pb is totally recoverable if the reduction rate trends to zero, rendering the process reversible. Furthermore, disruption always causes part of the film to remain adhered to the metal, which is why it is only partially disrupted. Increasing the reduction rate causes the disruption process to increase and the remaining film adhered to the metal to trend toward a minimum constant value, which differs in Pb and Zn but is equal in voltammetric and galvanostatic experiments with Pb. The conclusions are the same with regard to the galvanostatic results for Pb, except that the film charge density is always totally reversibly recovered if the reduction rate is lower than the formation rate. Moreover, the reduction rate does not necessarily have to trend to zero in this case. It needs only to be lower than or equal to the formation rate. All these facts are discussed based on the disruption model. The paper also discusses in detail how to experimentally obtain highly reproducible measurements, which are fundamental for the conclusion’s validity. These experimental discussions and propositions are also based on the disruption model. High reproducibility is achieved even in the case of Pb, a metal whose reproducibility is notoriously difficult. This paper is dedicated to Professor Francisco Carlos Nart, in memoriam.     

Photoredox processes in coordination compounds

Transition metal complexes display a number of charge-transfer bands in the absorption spectra. Optical excitation of the metal complexes produces a variety of products depending upon the nature of the excited state. Cobalt (III) ammine complexes on excitation in the CTTM bands produce cobalt(II) and oxidised ligand. Ruthenium(II) complexes on excitation in the cm. band leads to the oxidation of the metal centre. In certain reactions participation of the solvent in the primary photoredox reactions has also been reported. In recent years extensive investigations have been undertaken to utilize the photoredox systems of coordination compounds to convert solar energy to electricity or hydrogen.     

Highly efficient formation of metal and metal alloy particles from methyl metal compounds by a single pulse laser irradiation

Highly efficient processes for fine particle formation of metal alloys and metal oxides were developed using a high-power laser. In these processes, laser light was used only for the ignition of a thermal chain reaction. This reaction was suppressed by adding inert gases, and the suppression effect was in the order C₃H₈ > C₂H₆ > CH₄ > He > Ar > Xe. Oxygen accelerated the reaction because of the large exothermicity of the reaction of oxygen with methyl metal compounds.     

DNA structural distortions induced by ruthenium-arene anticancer compounds

Organometallic ruthenium(II)-arene (RA) compounds combine a rich structural diversity with the potential to overcome existing chemotherapeutic limitations. In particular, the two classes of compounds [Ru(II)(eta(6)-arene)X(en)] and [Ru(II)(eta(6)-arene)(X)2(pta)] (RA-en and RA-pta, respectively; X = leaving group, en = ethylenediamine, pta = 1,3,5-triaza-7-phosphaadamantane) have become the focus of recent anticancer research. In vitro and in vivo studies have shown that they exhibit promising new activity profiles, for which their interactions with DNA are suspected to be a crucial factor. In the present study, we investigate the binding processes of monofunctional RA-en and bifunctional RA-pta to double-stranded DNA and characterize the resulting structural perturbations by means of ab initio and classical molecular dynamics simulations. We find that both RA complexes bind easily through their ruthenium center to the N7 atom of guanine bases. The high flexibility of DNA allows for fast accommodation of the ruthenium complexes into the major groove. Once bound to the host, however, the two complexes induce different DNA structural distortions. Strain induced in the DNA backbone from RA-en complexation is released by a local break of a Watson-Crick base-pair, consistent with the experimentally observed local denaturation. The bulkier RA-pta, on the other hand, bends the DNA helix toward its major groove, resembling the characteristic DNA distortion induced by the classic anticancer drug cisplatin. The atomistic details of the interactions of RA complexes with DNA gained in the present study shed light on some of the anticancer properties of these compounds and should assist future rational compound design.     

Nitrogen fixation by transition metal compounds: Results and prospects

The reaction of H₂PtCl_σ with benzene, toluene, ethylbenzene, xylenes, anisole and chlorobenzene affords the new anionic σ-aryl complexes of Pt^IV. In the cases of monosubstituted benzenes mixtures of meta- and para-platinated isomers were prepared. No examples of the ortho-isomer were found. These complexes are intermediates in the chlorination and dimerization of aromatic compounds by H₂PtCl_σ.     

Superconductivity of some transition metal compounds

Single crystals of niobium carbonitride were made by zone melting growth methods and single crystals of γ-NbN and δ-NbN by zone annealing crystal growth. The crystals are nonstoichiometric in contrast to the niobium carbonitride or niobium nitride prepared in reaction with nitrogen gas and niobium-niobium carbide mixtures and niobium metal, respectively. The transition temperature for superconductivity (T_c) decreases with increasing deviation from stoichiometry, and a determination of T_c is a nondestructive determination of this deviation. An instrument using the Wheatstone bridge principle is described and T_c values are listed for some nonstoichiometric single crystals of niobium carbonitride and niobium nitride.