Disruption of DNA repair processes by carcinogenic metal compounds

Based on pronounced enhancing effects in combination with other DNA-damaging agents the potentials of Ni(II), Cd(II) and As(III) to interfere with DNA repair processes in HeLa cells was investigated. With respect to oxidative DNA damage, Ni(II) and Cd(II) induced DNA strand breaks starting at concentrations of 250 μM and 5 μM, respectively. The induction of oxidative DNA base modifications like 8-hydroxyguanine was restricted to the cytotoxic concentration of 750 μM Ni(II) and not observed after treatment with Cd(II). In contrast, the removal of oxidative DNA base modifications was inhibited at concentrations as low as 50 μM Ni(II) and 0.5 μM Cd(II). Regarding nucleotide excision repair, Ni(II) and Cd(II) disturbed the DNA-protein interactions involved in the damage recognition step when applying HeLa nuclear protein extracts and a UV-damaged oligonucleotide, while As(III) inhibited the actual incision event. In the case of Ni(II) and Cd(II), this effect was reversible by the addition of Mg(II) and Zn(II), respectively. Furthermore, Cd(II) inactivated the isolated bacterial Fpg protein, most likely by the displacement of Zn(II) from its zinc finger structure. Since DNA is continuously damaged by exogenous and endogenous sources, an impaired repair capacity might well account for the carcinogenic action of the metal compounds. Received: 30 July 1997 / Revised: 6 October 1997 / Accepted: 10 October 1997     

Generating M-Indeterminate Probability Densities by Way of Quantum Mechanics

Probability densities that are not uniquely determined by their moments are said to be “moment-indeterminate,” or “M-indeterminate.” Determining whether or not a density is M-indeterminate, or how to generate an M-indeterminate density, is a challenging problem with a long history. Quantum mechanics is inherently probabilistic, yet the way in which probability densities are obtained is dramatically different in comparison with standard probability theory, involving complex wave functions and operators, among other aspects. Nevertheless, the end results are standard probabilistic quantities, such as expectation values, moments and probability density functions. We show that the quantum mechanics procedure to obtain densities leads to a simple method to generate an infinite number of M-indeterminate densities. Different self-adjoint operators can lead to new classes of M-indeterminate densities. Depending on the operator, the method can produce densities that are of the Stieltjes class or new formulations that are not of the Stieltjes class. As such, the method complements and extends existing approaches and opens up new avenues for further development. The method applies to continuous and discrete probability densities. A number of examples are given.

     

Molecular orbital calculations of iron(II) complexes of diimine ligands

Summary Molecular orbital calculations using-, the INDO method have been carried out fm the [FeL(CN)₄]² and [FeLH(CN)₄] complexes, as well as for the tree ligands, with L 2 × pyridine, 1,10-phenanthroline.2,2-bipyridyl. 2,2-rimidine, 2, 3,3-bipyridazine and 4.4-bipyrimidine. Calculations of residual charge at carbon atoms in the ligand rings. correlating with relative nucleophilicity of the compounds, corresponds with observed differences of rate of reaction of the complex [FeI;]² With nucleophiles.     

SCF and MC–SCF Study of CO2 with bond angle variation

Multiconfiguration (MC ) SCF calculations are reported for CO₂ for bond angles between 60° and 180°. The ground state configuration is found to be …?5a4b∣b∣a for small bending angles and …?6a3b∣b∣a for large bending angles, the change in ground state character occurring at a bond angle of about 100°. The force constant for bending obtained from the MC –SCF function is about 8.0% lower than the corresponding SCF value, and in considerably better agreement with experiment.     

An unexpected P-cluster like intermediate en route to the nitrogenase FeMo-co

The nitrogenase MoFe protein contains two different FeS centers, the P-cluster and the iron–molybdenum cofactor (FeMo-co). The former is a [Fe₈S₇] center responsible for conveying electrons to the latter, a [MoFe₇S₉C-(R)-homocitrate] species, where N₂ reduction takes place. NifB is arguably the key enzyme in FeMo-co assembly as it catalyzes the fusion of two [Fe₄S₄] clusters and the insertion of carbide and sulfide ions to build NifB-co, a [Fe₈S₉C] precursor to FeMo-co. Recently, two crystal structures of NifB proteins were reported, one containing two out of three [Fe₄S₄] clusters coordinated by the protein which is likely to correspond to an early stage of the reaction mechanism. The other one was fully complemented with the three [Fe₄S₄] clusters (RS, K1 and K2), but was obtained at lower resolution and a satisfactory model was not obtained. Here we report improved processing of this crystallographic data. At odds with what was previously reported, this structure contains a unique [Fe₈S₈] cluster, likely to be a NifB-co precursor resulting from the fusion of K1- and K2-clusters. Strikingly, this new [Fe₈S₈] cluster has both a structure and coordination sphere geometry reminiscent of the fully reduced P-cluster (P^N-state) with an additional μ²-bridging sulfide ion pointing toward the RS cluster. Comparison of available NifB structures further unveils the plasticity of this protein and suggests how ligand reorganization would accommodate cluster loading and fusion in the time-course of NifB-co synthesis.

The K-cluster of NifB as a key intermediate in the synthesis of the nitrogenase active site supports [Fe₄S₄] cluster fusion occurs before carbide and sulfide insertion and displays ligand spatial arrangement reminiscent to that of the P-cluster.     

An efficient approach towards the convergent synthesis of "fully-carbohydrate" mannodendrimers

Glycosylation of sugar trityl ethers with sugar 1,2-O-(1-cyano)ethylidene derivatives (the trityl-cyanoethylidene condensation) has been applied to the synthesis of highly branched (dendritic) mannooligosaccharides incorporating a Manalpha1-->3(Manalpha1-->6)Man structural motif. The convergent synthetic strategy used to assemble these oligosaccharides was based on the use of glycosyl acceptors and/or a glycosyl donor already bearing this structural motif. The former were represented by mono- and ditrityl ethers of ManalphaOMe, Manalpha1-->3ManalphaOMe, and Manalpha1-->3(Manalpha1-->6)ManalphaX, where X=OMe or SEt. The pivotal glycosyl donor was the peracetylated 1,2-O-(1-cyano)ethylidene-3,6-di-O-(alpha-D-mannopyranosyl)-beta-D-mannopyranose (1), prepared by orthogonal Helferich glycosylation of the known 1,2-O-(1-cyano)ethylidene-beta-D-mannopyranose with tetra-O-acetyl-alpha-D-mannopyranosyl bromide followed by O-acetylation. Glycosylation of acetates of methyl 6-O-trityl-alpha-D-mannopyranoside and methyl 3,6-di-O-trityl-alpha-D-mannopyranoside with one equivalent of the donor 1 gave rise to the isomeric tetrasaccharide derivatives, Manalpha1-->3(Manalpha1-->6)Manalpha1-->6ManalphaOMe and Manalpha1-->3(Manalpha1-->6)Manalpha1-->3ManalphaOMe, respectively. The latter derivative was further mannosylated at the remaining 6-O-trityl acceptor site to give the protected pentasaccharide Manalpha1-->3(Manalpha1-->6)Manalpha1-->3(Manalpha1-->6)ManalphaOMe. The isomeric pentasaccharide, Manalpha1-->3(Manalpha1-->6)Manalpha1-->6(Manalpha1-->3)ManalphaOMe, was prepared by reaction of 1 with the 6-O-trityl derivative of (Manalpha1-->3)ManalphaOMe. In a similar fashion, 6'- and 6"-O-trityl derivatives of the branched trisaccharide Manalpha1-->3(Manalpha1-->6)ManalphaOMe served as precursors for two isomeric mannohexaosides. The 3,6-di-O-trityl ether of ManalphaOMe and the 6',6"-di-O-trityl ether of Manalpha1-->3(Manalpha1-->6)ManalphaX (X=OMe or SEt) were efficiently bis-glycosylated with the donor 1 to give the corresponding protected mannoheptaoside and mannononaoside. The yields of these glycosylations with the donor 1 ranged from 50 to 66 %. Final deprotection of all the oligosaccharides was straightforward and afforded the target products in high yields. Both the acylated and deprotected products were characterized, and the intersaccharide connectivities were elucidated by extensive one- and two-dimensional NMR spectroscopy. The described blockwise convergent approach allows assembly of a variety of 3,6-branched mannooligosaccharides.     

Formation of M2+(O2)(C3H8) species in alkaline-earth-exchanged Y zeolite during propane selective oxidation

The adsorption of oxygen and d2-propane (CH3CD2CH3) on a series of alkaline-earth-exchanged Y zeolite at room temperature was studied with in situ infrared spectroscopy. Surprisingly at room temperature, oxygen adsorption led to the formation of supercage M2+(O2) species. Further, at low propane coverage, propane was found to adsorb linearly on Mg2+ cations, but a ring-adsorption structure was observed for propane adsorbing on Ca2+, Sr2+, and Ba2+ cations. It is demonstrated that O2 and propane can simultaneously attach to one active center (M2+) to form a M2+(O2)(C3H8) species, which is proposed to be the precursor in thermal propane selective oxidation. Selectivity to acetone in the propane oxidation reaction decreases with increasing temperature and cation size due to the formation of 2-propanol and carboxylate ions. An extended reaction scheme for the selective oxidation of propane over alkaline earth exchanged Y zeolites is proposed.     

Hyperfine field calculations: Search for muon stopping sites in Fe3O4

Muon Spin Rotation (SR) results for magnetite (Fe₃O₄) are analyzed and discussed. At room temperature, a SR signal is observed due to the presence of an internal magnetic field (B_int) at the muon site. External transverse field measurements show that B_int is parallel to the magnetic spin direction, the <111> direction in zero applied field. Calculations of the hyperfine field to pinpoint muon stopping sites in magnetite show that the local field contains supertransfer (covalent) and dipolar field contributions. The implanted muons appear to stop at sites structurally similar to those reported for hematite (-Fe₃O₄), where muon-oxygen bond formation was strongly indicated.Research partially supported by US Department of Energy     

A systematic study of the interactions between chemical partners (metal, ligands, counterions, and support) involved in the design of Al2O3-supported nickel catalysts from diamine-Ni(II) chelates

1.5 Ni wt %/Al2O3 catalysts have been prepared by incipient wetness impregnation using [Ni(diamine)x(H2O)(6-2x)]Y2 precursors (diamine = 1,2-ethanediamine (en) and trans-1,2-cyclohexanediamine (tc); x = 0, 1, and 2; Y = NO3- and Cl-), to avoid the formation, during calcination, of difficult-to-reduce nickel aluminate. N2 was chosen for thermal treatment to help reveal and take advantage of the reactions occurring between Ni2+, ligands, counterions, and support. In the case of [Ni(en)2(H2O)2]Y2 salts used as precursors, in situ UV-vis and DRIFT spectroscopies show that after treatment at 230 degrees C Ni(II) ions are grafted to alumina via two OAl bonds and that the diamine ligands still remain coordinated to grafted nickel ions but in a monodentate way, bridging the cation with the alumina surface. With Y = Cl-, the chloride counterions desorb as hydrogen chloride, and hydrogen released upon decomposition of the en ligands is able to reduce a fraction of nickel ions into metal as evidenced by XPS. In contrast, with Y = NO3-, compounds such as CO or NO are formed during thermal treatment, indicating that nitrate ions burn the en ligands. After thermal treatment at 500 degrees C, a surface phase containing Ni(II) ions forms, characterized by XPS and UV-vis spectroscopy. Temperature-programmed reduction shows that these ions can be quantitatively reduced to the metallic state at 500 degrees C, in contrast with the aluminate obtained when the preparation is carried out from [Ni(H2O)6]2+, which is reduced only partly at 950 degrees C. On the other hand, a total self-reduction of nickel complexes leading to 2-5-nm metal particles is obtained upon thermal treatment via the hydrogen released by a hydrogen-rich ligand such as tc, whatever the Y counterion. An appropriate choice of the ligand and the counterion allows then to obtain selectively Ni(II) ions or a dispersed reduced nickel phase after treatment in N2, as a result of the reactions occurring between the chemical partners present on alumina.