Distinguishing rate-limiting electron versus H-atom transfers in Cu2O2-mediated oxidative N-dealkylations: application of inter- versus intramolecular kinetic isotope effects

Copper-dioxygen adducts are important biological oxidants. To gain a better understanding of the underlying chemistries of such species, we report on a series of Cu2II-O2 complexes, [{CuII(MePY2)R'}2(O2)](B(C6F5)4)2 (1R') (where (MePY2)R' is a 4-pyridyl substituted bis[2-(2-(4-R'-pyridyl)ethyl]methylamine; R' = H, MeO, Me2N; Zhang, C. X.; et al. J. Am. Chem. Soc. 2003, 125, 634-635), which readily oxidize exogenous substrates. In this study, we explore the mechanism by which 1R' facilitates the oxidative N-dealkylation of para-substituted N,N-dimethylanilines (R-DMA; R = MeO, Me, H, CN). In the case of 1H, the linear free-energy correlation plot (rho = -2.1) and intramolecular deuterium kinetic isotope effect (KIEintra, using p-R-(C6H4)-N(CH3)(CD3)) profile suggest that R-DMA oxidation occurs through rate-limiting electron transfer (ET). This mechanism was further enforced by comparison of KIEintra versus the intermolecular KIE (KIEinter, using p-R-(C6H4)-N(CH3)2 versus p-R-(C6H4)-N(CD3)2). It was found that KIEinter < KIEintra, suggesting an ET process. In the case of both 1MeO and 1Me2N, the KIEintra profile and linear free-energy correlation plots (rho = -0.49 and -0.99 for 1Me2N and 1MeO with especially poor fitting for the latter) are inconclusive in distinguishing between a rate-limiting ET or hydrogen atom transfer (HAT) pathway. Comparisons of KIEinter versus KIEintra demonstrate a switch in mechanism from ET to HAT for 1Me2N and 1MeO oxidation of R-DMA as R-DMA is made less reducing. In the case of 1Me2N, MeO-DMA and Me-DMA are oxidized via a rate-limiting ET (KIEinter < KIEintra), while H-DMA and CN-DMA are oxidized through a HAT pathway (KIEinter approximately KIEintra). For 1MeO, oxidation occurs through an ET pathway for MeO-, Me-, and H-DMA (KIEinter < KIEintra), while CN-DMA is oxidized though a HAT process (KIEinter approximately KIEintra). Copper complex attributes, which may contribute to the mechanistic observations, are suggested.     

Identification of nuclear proteins that interact with platinum-modified DNA by photoaffinity labeling

Interactions between cellular proteins and cisplatin-modified DNA are important in determining the anticancer activity of the drug. To develop a general approach for identifying proteins that mediate cellular responses to cisplatin, photoreactive cisplatin analogues having a tethered benzophenone moiety were prepared and used to form the major 1,2-intrastrand platinum-DNA cross-links. Upon irradiation of the platinated DNA dissolved in a HeLa nuclear extract, the appended photolabile benzophenone group generates a highly reactive species that binds irreversibly to cellular proteins that interact with the probe. Several DNA-protein cross-linked adducts were identified that may function in the cellular processing of cisplatin-DNA adducts. Of these, PARP-1 had not previously been demonstrated directly to contact Pt-DNA cross-links in human cells.     

Electrochemical Studies of an Iron Porphyrin Immobilized on Nb2O5/SiO2 and Its Application for Simultaneous Determination of Dopamine and Ascorbic Acid Using Multivariate Calibration Methodology

This paper shows an application of a first generation porphyrin, FeTPPCl 5,10,25,20‐tetraphenylporphyrin iron(III) chloride (FeTPPCl or FeTPP⁺) immobilized on a inorganic matrix, SiO₂/Nb₂O₅ (niobium oxide grafted on silica gel surface, designated as SiNb) to the preparation of a carbon paste electrode (CPE). The carbon paste modified with a FeTPP⁺ immobilized on SiO₂/Nb₂O₅ (SiNb), designated as CPE/SiNb/FeTPP, was applied for simultaneous electrochemical determination of dopamine (DA) and ascorbic acid (AA). Because of the overlapping of the voltammetric peaks of DA and AA, the multivariate calibration methodology based on partial least square regression (PLSR) was proposed. The data pre‐treatment used in this process was mean centering and to choose the principal components number a cross validation procedure was used (leave‐one‐out). Five principal components were necessary to obtain the lowest PRESS (prediction residual error sum of squares). The statistics showed that this model explains approximately 95.2% of the variance from the data set. Using this model, high correlation between actual and predicted concentrations was observed, mainly for higher dopamine (maximum relative error of 8%) and ascorbic acid (maximum relative error of 10%) concentrations. For low analytes concentrations the relative error increases to 35% for AA. Considering the similarity of the voltammetric response of the analytes, the results obtained were satisfactory and showed the promissory capability of the CPE/SiNb/FeTPP coupled multivariate calibration methods for simultaneous voltammetric analysis of DA and AA.     

Carbon ceramic electrodes modified with mixed oxides SiO<Subscript>2</Subscript>/SnO<Subscript>2</Subscript> for determination of levofloxacin

The preparation of a carbon ceramic electrode modified with SnO₂ (CCE/SnO₂) using tin dibutyl diacetate as precursor was optimized by a 2³ factorial design. The factors analyzed were catalyst (HCl), graphite/organic precursor ratio, and inorganic precursor (dibutyltin diacetate). The statistical treatment of the data showed that only the second-order interaction effect, catalyst × inorganic precursor, was significant at 95% confidence level, for the electrochemical response of the system. The obtained material was characterized by scanning electron microscopy (MEV), X-ray diffraction (XRD), RAMAN spectroscopy, XPS spectra, and voltammetric techniques. From the XPS spectra, it was confirmed the formation of the Si–O–Sn bond by the shift in the binding energy values referred to Sn 3d3/2 due to the interaction of Sn with SiOH species. The incorporation of SnO₂ provided an increment of the electrode response for levofloxacin, with Ipa = 147.0 μA for the ECC and Ipa = 228.8 μA for ECC/SnO₂, indicating that SnO₂ when incorporated into the silica network enhances the electron transfer process. Under the optimized working conditions, the peak current increased linearly with the levofloxacin concentration in the range from 6.21×10^?5 to 6.97×10^?4 mol L^?1 with quantification and detection limits of 3.80×10^?5 mol L^?1 (14.07 mg L^?1) and 1.13×10^?5 mol L^?1 (4.18 mg L^?1), respectively.     

1-Ethyl-1H-3-nitrobenzopyrano[4,3,2-cd]isoindole: a novel heterocyclic ring system bearing an unusually labile deuterium-exchangeable aromatic proton

The ease of deuterium exchange of the aromatic H2 of the novel heterocycle 1-ethyl-1H-3-nitrobenzopyrano[4,3,2-cd]isoindole was studied by NMR and theoretical calculations.     

Copper(I)-dioxygen reactivity of [(L)Cu(I)](+) (L = tris(2-pyridylmethyl)amine): kinetic/thermodynamic and spectroscopic studies concerning the formation of Cu-O2 and Cu2-O2 adducts as a function of solvent medium and 4-pyridyl ligand substituent variations

The kinetic and thermodynamic behavior of O(2)-binding to Cu(I) complexes can provide fundamental understanding of copper(I)/dioxygen chemistry, which is of interest in chemical and biological systems. Here we report stopped-flow kinetic investigations of the oxygenation reactions of a series of tetradentate copper(I) complexes [(L(R))Cu(I)(MeCN)](+) (1(R), R=H, Me, tBu, MeO, Me(2)N) in propionitrile (EtCN), tetrahydrofuran (THF), and acetone. The syntheses of 4-pyridyl substituted tris(2-pyridylmethyl)amine ligands (L(R)) and copper(I) complexes are detailed. Variations of ligand electronic properties are manifested in the electrochemistry of 1(R) and nu(CO) of [(L(R))Cu(I)-CO](+) complexes. The kinetic studies in EtCN and THF show that the O(2)-reactions of 1(R) follow the reaction mechanism established for oxygenation of 1(H) in EtCN (J. Am. Chem. Soc. 1993, 115, 9506), involving reversible formation (k(1)/k(-1)) of [(L(R))Cu(II)(O(2-))](+) (2(R)), which further reacts (k(2)/k(-2)) with 1(R) to form the 2:1 Cu(2)O(2) complex [[(L(R))Cu(II)](2)(O(2)(2-))](2+) (3(R)). In EtCN, the rate constants for formation of 2(R) (k(1)) are not dramatically affected by the ligand electronic variations. For R = Me and tBu, the kinetic and thermodynamic parameters are very similar to those of the parent complex (1(H)); e.g., k(1) is in the range 1.2 x 10(4) to 3.1 x 10(4) M(-1) s(-1) at 183 K. With the stronger donors R = MeO and Me(2)N, more significant effects were observed, with the expected increase in thermodynamic stability of resultant 2(R) and 3(R) complexes, and decreased dissociation rates. The modest ligand electronic effects manifested in EtCN are due to the competitive binding of solvent and dioxygen to the copper centers. In THF, a weakly coordinating solvent, the formation rate for 2(H) is much faster (>/=100 times) than that in EtCN, and the thermodynamic stabilities of both the 1:1 (K(1)) and 2:1 (beta = K(1)K(2)) copper-dioxygen species are much higher than those in EtCN (e.g., for 2(H), deltaH(o) (K(1))=-41 kJ mol(-1) in THF versus -29.8 kJ mol(-1) in EtCN; for 3(H), deltaH(o) (beta)=-94 kJ mol(-1) in THF versus -77 kJ mol(-1) in EtCN). In addition, a more significant ligand electronic effect is seen for the oxygenation reactions of 1(MeO) in THF compared to that in EtCN; the thermal stability of superoxo- and peroxocopper complexes are considerably enhanced using L(MeO) compared to L(H). In acetone as solvent, a different reaction mechanism involving dimeric copper(I) species [(L(R))(2)Cu(I)(2)](2+) is proposed for the oxygenation reactions, supported by kinetic analyses, electrical conductivity measurements, and variable-temperature NMR spectroscopic studies. The present study is the first systematic study investigating both solvent medium and ligand electronic effects in reactions forming copper-dioxygen adducts.     

Mononuclear gallium(III) complexes based on salicylaldoximes: Synthesis,structure and spectroscopic characterization

The reactions of Ga(acac)₃ with salicylaldoxime (saoH₂) and methyl-salicylaldoxime (Me-saoH₂) in dichloromethane/hexane afforded the complexes [Ga(acac)(saoH)₂] (1) and [Ga(acac)₃][Ga(acac)(MesaoH)₂] (2), respectively, in high yields. The crystal structures of 1 and 2 have been determined by single-crystal X-ray crystallography. Both complexes are mononuclear with the Ga(III) atoms being in octahedral environments surrounded by two bidentate chelate R-saoH⁻ and one bidentate chelate acac⁻ ligands. A [Ga(acac)₃] moiety has co-crystallized along with the methylsalicylaldoximato complex. Characteristic IR as well as NMR data are discussed in terms of the nature of bonding in the structures of the two complexes. ¹H and ¹³C NMR data in CDCl₃ indicate that the salicylaldoximato complexes isomerize in solution.     

Influence of eicosapentaenoic acid, an omega-3 fatty acid, on ultraviolet-B generation of prostaglandin-E2 and proinflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6 and interleukin-8 in human skin in vivo

Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA) reduce sunburn, an acute inflammatory response, in humans. We assessed whether this may be mediated by reduced ultraviolet-B (UV-B) induction of proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6, IL-8 and prostaglandin (PG)E(2) in healthy skin. In a double-blind, randomized study, 28 humans received 4 g daily of 95% ethyl esters of eicosapentaenoic acid (EPA) or oleic acid (OA) orally for 3 months. Skin biopsies and suction blister fluid were taken from unexposed and UV-B-exposed skin and examined for mediator expression immunohistochemically and quantitatively by immunoassay; plasma levels were also assayed. The subjects taking EPA, but not OA, showed a significant rise in their minimal erythemal dose (MED) (data reported elsewhere). Before supplementation, irradiation with 3x MED UV-B increased blister fluid TNF-alpha, IL-6, IL-8 and PGE(2) at 16 h (all P < 0.001). No significant change occurred in baseline or UV-B-induced skin levels of cytokines after either supplement, whereas UV-B induction of PGE(2) was abolished after EPA but not OA. Immunohistochemical expression of the cytokines at baseline and after UV-B was unaltered by EPA and OA; circulating cytokine and PGE(2) levels were also unchanged. Hence, in healthy skin in vivo, there was no evidence that reduction of the sunburn response by EPA is mediated by the proinflammatory cytokines examined; abrogation of UV-B-generated PGE(2) may play a role.