The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury

Background  

Stromal cell-derived factor 1 (SDF-1 or CXCL12) is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI) injury in neonatal brain.     

Transposition des cycles satures en spectrometrie de masse II–Ethylene acetals derives de cyclopentanones et de cyclohexanones

The detailed study of the mass spectra of cyclopentanone and cyclohexanone acetals produces new evidences for the rearrangement of the corresponding molecular ions. The rearrangement was quantitatively studied with the help of a simple model. The influence of different structural features is discussed.     

Charge state effect on the zwitterion influence on stability of non-covalent interaction of single-stranded DNA with peptides

Negative ion ESI mass spectrometry was used to study the gas-phase stability and dissociation pathways of peptide-DNA complexes. We show that bradykinin and three modified peptides containing the basic residue arginine or lysine form stable interactions with single-stranded oligonucleotides. ESI-MS/MS of complexes of T(8) with PPGFSPFRR resulted in a major dissociation pathway through cleavage of the peptide covalent bond. The stability of the complex is due to electrostatic interaction between the negatively charged phosphate group and the basic side chain of the arginine and lysine residues as demonstrated by Vertes et al. and Woods et al. In fact, the present work establishes the role played by zwitterions on complex stabilisation. The presence of protons in nucleobase and/or amino acid contributes in reinforcing the strength of the salt bridge (SB) interaction. The zwitterionic form of the most basic of amino acid residues, arginine, is assumed to form a strong SB interaction to the negatively charged phosphate groups of DNA. This non-covalent complex is stable enough to withstand disruption of the non-covalent interaction and to first break the covalent bond. Moreover, the dependence of fragmentation patterns upon the complex charge state is explained by the fact that the net number of negative charges modulates the number of zwitterionic sites, which stabilise the complexes. Finally, the weak influence of the nucleobase is assumed by the existence of competition for proton addition between the nucleobase and the R/K side chain leading to a decrease in the stabilisation of the SB interaction.     

An enyne cycloisomerization approach to the triple reuptake inhibitor GSK1360707F

The triple reuptake inhibitor GSK1360707F was synthesized via an efficient and scalable route that features an enyne cycloisomerization reaction catalyzed by either Pt(II) or Au(I). Key aspects of this work such as the choice of the nitrogen protecting group and initial enantioselectivity studies are discussed.     

Effects of nitrogen and alkene substitution on the PtCl2 catalyzed cycloisomerization of N-tethered 1,6-enyne precursors to the triple reuptake inhibitor GSK1360707

The effects of nitrogen and alkene substitution on the cycloisomerization of N-tethered 1,6-enynes into 3-azabicyclo[4.1.0]heptene precursors to the triple reuptake inhibitor GSK1360707 are described. In general, electron donating substituents proved beneficial both in terms of the reaction rate and chemoselectivity.     

Gas‐phase doubly charged complexes of cyclic peptides with copper in +1, +2 and +3 formal oxidation states: formation,structures and electron capture dissociation

Copper complexes with a cyclic D‐His‐β‐Ala‐L‐His‐L‐Lys and all‐L‐His‐β‐Ala‐His‐Lys peptides were generated by electrospray which were doubly charged ions that had different formal oxidation states of Cu(I), Cu(II) and Cu(III) and different protonation states of the peptide ligands. Electron capture dissociation showed no substantial differences between the D‐His and L‐His complexes. All complexes underwent peptide cross‐ring cleavages upon electron capture. The modes of ring cleavage depended on the formal oxidation state of the Cu ion and peptide protonation. Density functional theory (DFT) calculations, using the B3LYP with an effective core potential at Cu and M06‐2X functionals, identified several precursor ion structures in which the Cu ion was threecoordinated to pentacoordinated by the His and Lys side‐chain groups and the peptide amide or enolimine groups. The electronic structure of the formally Cu(III) complexes pointed to an effective Cu(I) oxidation state with the other charge residing in the peptide ligand. The relative energies of isomeric complexes of the [Cu(c‐HAHK + H)]²⁺ and [Cu(c‐HAHK ? H)]²⁺ type with closed electronic shells followed similar orders when treated by the B3LYP and M06‐2X functionals. Large differences between relative energies calculated by these methods were obtained for open‐shell complexes of the [Cu(c‐HAHK)]²⁺ type. Charge reduction resulted in lowering the coordination numbers for some Cu complexes that depended on the singlet or triplet spin state being formed. For [Cu(c‐HAHK ? H)]²⁺ complexes, solution H/D exchange involved only the N–H protons, resulting in the exchange of up to seven protons, as established by ultra‐high mass resolution measurements. Contrasting the experiments, DFT calculations found the lowest energy structures for the gas‐phase ions that were deprotonated at the peptide C_α positions. Copyright © 2012 John Wiley & Sons, Ltd.     

High-resolution mass spectrometry and hydrogen/deuterium exchange study of mitorubrin azaphilones and nitrogenized analogues

Azaphilones represent numerous groups of wild fungal secondary metabolites that exhibit exceptional tendency to bind to nitrogen atoms in various molecules, especially those containing the amine group. Nitrogenized analogues of mitorubrin azaphilones, natural secondary metabolites of Hypoxylon fragiforme fungus, have been detected in the fungal methanol extract in very low concentrations. Positive electrospray ionization interfaced with high-resolution mass spectrometry was applied for confirmation of the elemental composition of protonated species. Collision-induced dissociation (CID) experiments have been performed, and fragmentation mechanisms have been proposed. Additional information regarding both secondary metabolite analogue families has been reached by application of gas-phase proton/deuterium (H/D) exchanges performed in the collision cell of a triple quadrupole mass spectrometer. An incomplete H/D exchange with one proton less than expected was observed for both protonated mitorubrin azaphilones and their nitrogenized analogues. By means of the density functional theory, an appropriate explanation of this behavior was provided, and it revealed some information concerning gas-phase H/D exchange mechanism and protonation sites. Copyright ? 2012 John Wiley & Sons, Ltd.