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  • 1. Borg, O. Anders
    et al.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Durbeej, Bo
    Electron-transfer induced repair of 6-4 photoproducts in DNA: a computational study.2007In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 111, no 12, p. 2351-2361Article in journal (Refereed)
    Abstract [en]

    The mechanism employed by DNA photolyase to repair 6-4 photoproducts in UV-damaged DNA is explored by means of quantum chemical calculations. Considering the repair of both oxetane and azetidine lesions, it is demonstrated that reduction as well as oxidation enables a reversion reaction by creating anionic or cationic radicals that readily fragment into monomeric pyrimidines. However, on the basis of calculated reaction energies indicating that electron transfer from the enzyme to the lesion is a much more favorable process than electron transfer in the opposite direction, it is suggested that the photoenzymic repair can only occur by way of an anionic mechanism. Furthermore, it is shown that reduction of the oxetane facilitates a mechanism involving cleavage of the C−O bond followed by cleavage of the C−C bond, whereas reductive fragmentation of the azetidine may proceed with either of the intermonomeric C−N and C−C bonds cleaved as the first step. From calculations on neutral azetidine radicals, a significant increase in the free-energy barrier for the initial fragmentation step upon protonation of the carbonylic oxygens is predicted. This effect can be attributed to protonation serving to stabilize reactant complexes more than transition structures.

  • 2. Bunta, Juraj
    et al.
    Dahlberg, Martin
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Korolev, Nikolai
    Laaksonen, Aatto
    Lohikoski, Raimo
    Lyubartsev, Alexander
    Pinak, Miroslav
    Schyman, Patric
    Solvating, manipulating, damaging, and repairing DNA in a computer2007In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 107, no 2, p. 279-291Article in journal (Refereed)
    Abstract [en]

    This work highlights four different topics in modeling of DNA: (i) the importance of water and ions together with the structure and function of DNA; the hydration structure around the ions appears to be the determining factor in the ion coordination to DNA, as demonstrated in the results of our MD simulations; (ii) how MD simulations can be used to simulate single molecule manipulation experiments as a complement to reveal the structural dynamics of the studied biomolecules; (iii) how damaged DNA can be studied in computer simulations; and (iv) how repair of damaged DNA can be studied theoretically.

  • 3.
    Bushnell, Eric A. C.
    et al.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Erdtman, Edvin
    Örebro University, School of Science and Technology.
    Llano, Jorge
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase2011In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 5, p. 822-834Article in journal (Refereed)
    Abstract [en]

    In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.

  • 4.
    Czégény, Gyula
    et al.
    Institute of Biology, University of Pécs, Pécs, Hungary; Institute of Plant Biology, Biological Research Centre, Szeged, Hungary.
    Wu, Min
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Dér, András
    Institute of Biophysics, Biological Research Centre, Szeged, Hungary.
    Eriksson, Leif A
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Hideg, Éva
    Institute of Biology, University of Pécs, Pécs, Hungary.
    Hydrogen peroxide contributes to the ultraviolet-B (280-315 nm) induced oxidative stress of plant leaves through multiple pathways2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 14, p. 2255-2261Article in journal (Refereed)
    Abstract [en]

    Solar UV-B (280-315 nm) radiation is a developmental signal in plants but may also cause oxidative stress when combined with other environmental factors. Using computer modelling and in solution experiments we show that UV-B is capable of photosensitizing hydroxyl radical production from hydrogen peroxide. We present evidence that the oxidative effect of UV-B in leaves is at least two-fold: (i) it increases cellular hydrogen peroxide concentrations, to a larger extent in pyridoxine antioxidant mutant pdx1.3-1 Arabidopsis and (ii) is capable of a partial photo-conversion of both ‘natural’ and ‘extra’ hydrogen peroxide to hydroxyl radicals. As stress conditions other than UV can increase cellular hydrogen peroxide levels, synergistic deleterious effects of various stresses may be expected already under ambient solar UV-B.

  • 5. dos Santos, Daniel
    et al.
    Scherbak, Nikolai
    Örebro University, Department of Natural Sciences.
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Modelling Pisum sativum short-chain dehydrogenase/reductase enzymesManuscript (Other academic)
  • 6.
    Elmabsout, Ali
    et al.
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences.
    Karlsson, Magnus
    Örebro University, School of Science and Technology.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Hans, Törmä
    Uppsala universitet, Uppsala, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Eriksson, Leif A
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Cloning and functional studies of a splice variant of CYP26B1: a cellular storage protein for all-trans retinoic acid2010In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 3, p. 345-346Article in journal (Refereed)
    Abstract [en]

    Background

    All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

    Methodology/Principal Findings

    The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

    Conclusions/Significance

    Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 7.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    dos Santos, Daniel J. V. A.
    Löfgren, Lennart
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer2008In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 178-182Article in journal (Refereed)
    Abstract [en]

    5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

  • 8.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    dos Santos, Daniel J. V. A.
    Örebro University, School of Science and Technology.
    Löfgren, Lennart
    Orebro Univ Hosp, Head & Neck Oncol Ctr, S-70185 Orebro, Sweden.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer (vol 463, pg 178, 2008)2009In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 470, no 4-6, p. 369-369Article in journal (Refereed)
  • 9.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives2007In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, no 1-3, p. 101-106Article in journal (Refereed)
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

  • 10.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, p. 4367-4374Article in journal (Refereed)
    Abstract [en]

    5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

  • 11.
    Eriksson, Emma S. E.
    et al.
    Örebro University, Department of Natural Sciences.
    Guedes, Rita C.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Redox and debromination reactions of brominated hypericin2008In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 108, no 11, p. 1921-1929Article in journal (Refereed)
    Abstract [en]

    Phototoxic and radical-generating debromination reactions of monobrominated hypericin with bromine at one of four possible positions were investigated using density functional theory. The study was performed on two closely lying conformational isomers, differing in the relative orientations of the two anthracene units of the hypericin core. Calculated adiabatic electron affinities show that the molecules have the ability to, in aqueous solution, extract an electron from the surrounding. The electron might then be passed on to molecular oxygen, forming reactive superoxide radical anions. If electron extraction from the molecule does not occur in this step, the molecule might dissociate, generating a negatively charged bromine as a leaving group and a hypericin radical capable of forming direct binding to biological molecules. This reaction was found possible for those species substituted by Br at two of the four positions, with barriers of 13 kcal/mol in aqueous solution. Debromination was not found energetically possible for neither the neutral ground state compounds nor the bay-deprotonated species.

  • 12.
    Eriksson, Leif A.
    et al.
    Örebro University, Department of Natural Sciences.
    Russo, Nino
    Ugalde, Jesus M.
    Second International Theoretical Biophysics Symposium, Örebro University, Sweden, June 28–July 1, 20052007In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 107, no 2, p. 66p. 259-260Article in journal (Refereed)
  • 13.
    Gao, Li
    et al.
    Örebro University, School of Science and Technology.
    Tu, Yaoquan
    Örebro University, School of Science and Technology.
    Wegman [Palmebäck-Wegman], Pia
    Örebro University, School of Science and Technology.
    Wingren, Sten
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives2011In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 2, p. 306-314Article in journal (Refereed)
    Abstract [en]

    The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.

  • 14. Grand, André
    et al.
    Morell, C
    Labet, Vanessa
    Cadet, Jean
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    *H and *OH radical reactions with 5-methylcytosine2007In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 111, no 37, p. 8968-8972Article in journal (Refereed)
  • 15. Guedes, Rita Cardoso
    et al.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Photophysics, photochemistry, and reactivity: Molecular aspects of perylenequinone reactions2007In: Photochemical and Photobiological Sciences, ISSN 1474-905X, E-ISSN 1474-9092, Vol. 6, no 10, p. 1089-1096Article in journal (Refereed)
    Abstract [en]

    Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used to elucidate the photochemistry and photophysics of eight different perylenequinones (PQ). The objective of this work has been to quantitatively investigate the photodynamic therapeutic potential of this family of compounds and give an overview of their photoreactivity. The effects of solvation were evaluated through single-point calculations using the integral equation formalism of the polarised continuum model. It is concluded that the eight studied perylenequinones can generate singlet oxygen (in aqueous solution) and superoxide radical anions, and that the autoionisation of two nearby PQ molecules is possible.

  • 16. Jarikote, Dilip V.
    et al.
    Li, Wei
    Jiang, Tao
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Murphy, Paul V.
    Towards echinomycin mimetics by grafting quinoxaline residues on glycophane scaffolds2011In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 2, p. 826-835Article in journal (Refereed)
    Abstract [en]

    Echinomycin is a natural depsipeptide, which is a bisintercalator, inserting quinoxaline units preferentially adjacent to CG base pairs of DNA. Herein the design and synthesis of echinomycin mimetics based on grafting of two quinoxaline residues onto a macrocyclic scaffold (glycophane) is addressed. Binding of the compounds to calf-thymus DNA was studied using UV-vis and steady state fluorescence spectroscopy, as well as thermal denaturation. An interesting observation was enhancement of fluorescence emission for the peptidomimetics on binding to DNA, which contrasted with observations for echinomycin. Molecular dynamics simulations were exploited to explore in more detail if bis-intercalation to DNA was possible for one of the glycophanes. Bis-intercalating echinomycin complexes with DNA were found to be stable during 20 ns simulations at 298 K. However, the MD simulations of a glycophane complexed with a DNA octamer displayed very different behaviour to echinomycin and its quinoxaline units were found to rapidly migrate out from the intercalation site. Release of bis-intercalation strain occurred with only one of the quinoxaline chromophores remaining intercalated throughout the simulation. The distance between the quinoxaline residues in the glycophane at the end of the MD simulation was 7.3-7.5 angstrom, whereas in echinomycin, the distance between the residues was similar to 11 angstrom, suggesting that longer glycophane scaffolds would be required to generate bis-intercalating echinomycin mimetics. (C) 2010 Elsevier Ltd. All rights reserved.

  • 17.
    Jönsson, Sofie
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A
    Örebro University, School of Science and Technology.
    van Bavel, Bert
    Örebro University, School of Science and Technology.
    Multivariate characterisation and quantitative structure-property relationship modelling of nitroaromatic compounds2008In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 621, no 2, p. 155-162Article in journal (Refereed)
    Abstract [en]

    A multivariate model to characterise nitroaromatics and related compounds based on molecular descriptors was calculated. Descriptors were collected from literature and through empirical, semi-empirical and density functional theory-based calculations. Principal components were used to describe the distribution of the compounds in a multidimensional space. Four components described 76% of the variation in the dataset. PC1 separated the compounds due to molecular weight, PC2 separated the different isomers, PC3 arranged the compounds according to different functional groups such as nitrobenzoic acids, nitrobenzenes, nitrotoluenes and nitroesters and PC4 differentiated the compounds containing chlorine from other compounds. Quantitative structure-property relationship models were calculated using partial least squares (PLS) projection to latent structures to predict gas chromatographic (GC) retention times and the distribution between the water phase and air using solid-phase microextraction (SPME). GC retention time was found to be dependent on the presence of polar amine groups, electronic descriptors including highest occupied molecular orbital, dipole moments and the melting point. The model of GC retention time was good, but the precision was not precise enough for practical use. An important environmental parameter was measured using SPME, the distribution between headspace (air) and the water phase. This parameter was mainly dependent on Henry's law constant, vapour pressure, logP, content of hydroxyl groups and atmospheric OH rate constant. The predictive capacity of the model substantially improved when recalculating a model using these five descriptors only.

  • 18.
    Karlsson, Magnus
    et al.
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Homology Models and Molecular Modeling of Human Retinoic Acid Metabolizing Enzymes Cytochrome P450 26A1 (CYP26A1) and P450 26B1 (CYP26B1)2008In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, no 6, p. 1021-1027Article in journal (Refereed)
    Abstract [en]

    Homology models of cytochrome P450 26A1 and cytochrome P450 26B1 were constructed using the crystal structures of human, CYP2C8, CYP2C9, and CYP3A4 as templates for the model building. The homology models generated were investigated for their docking capacities against the natural substrate all-trans-retinoic acid (atRA), five different tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and R115866. Interaction energies (IE) and linear interaction energies (LIE) were calculated for all inhibitors in both homology models after molecular dynamics (MD) simulation of the enzyme-ligand complexes. The results revealed that the homologues had the capacity to distinguish between strong and weak inhibitors. Important residues in the active site were identified from the CYP26A1/B1-atRA complexes. Residues involved in hydrophobic interactions with atRA were Pro113, Phe222, Phe299, Val370,

    Pro371, and Phe374 in CYP26A1 and Leu88, Pro118, Phe222, Phe295, Ile368, and Tyr272 in CYP26B1. Hydrogen bonding interactions were observed between the atRA carboxylate group and Arg 90 in CYP26A1 and with Arg76, Arg95, and Ser369 in CYP26B1.

  • 19. Labet, Vanessa
    et al.
    Grand, Andre
    Morell, Christophe
    Cadet, Jean
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Mechanism of nitric oxide induced deamination of cytosine2009In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 14, p. 2379-2386Article in journal (Refereed)
    Abstract [en]

    A five-step mechanism is proposed for the NO center dot-induced deamination of cytosine. It has been investigated using DFT calculations, including both explicit water molecules and a bulk solvent model to mimic an aqueous environment. According to this mechanism, cytosine first undergoes tautomerization with the assistance of a water molecule from the bulk. A NO+ cation produced by the autooxidation of NO center dot is subsequently added to the exocyclic imino group of the cytosine imine tautomer. The resulting adduct is able to undergo a tautomerization step with the participation of a water molecule to produce a cytosine in which a -N2OH group is attached to carbon C4. Protonation of the oxygen of the latter gives a water molecule which dissociates instantaneously, leading to a pyrimidinic diazonium cation. This constitutes the rate-determining step of the mechanism with an activation free energy of 92.6 kJ mol(-1). The last step, which is highly exergonic, represents the driving force of the reaction. It is the substitution of the -N-2(+) terminal group by a water molecule which simultaneously allows the transfer of one of the two hydrogens to the bulk. Thus, the two products of the reaction consist of a nitrogen molecule and the enol tautomer of uracil in equilibrium with the keto form.

  • 20. Labet, Vanessa
    et al.
    Grand, André
    Cadet, Jean
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Deamination of the radical cation of the base moiety of 2’deoxycytidine: A theoretical study2008In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 9, no 8, p. 1195-1203Article in journal (Refereed)
    Abstract [en]

    Five pathways leading to the deamination of cytosine (to uracil) after formation of its deprotonated radical cation are investigated in the gas phase, at the UB3LYP/6-311GACHTUNGTRENUNG(d,p) level of theory, and in bulk aqueous solvent. The most favorable pathway involves hydrogen-atom transfer from a water molecule to the N3 nitrogen of the deprotonated radical cation, followed by addition of the resulting hydroxyl radical to the C4 carbon of the cytosine derivative. Following protonation of the amino group (N4), the C4 N4 bond is broken with elimination of the NH3 ·+ radical and formation of a protonated uracil. The rate-determining step of this mechanism is hydrogen-atom transfer from a water molecule to the cytosine derivative. The associated free energy barrier is 70.2 kJmol 1.

  • 21. Labet, Vanessa
    et al.
    Grand, André
    Morell, Christophe
    Cadet, Jean
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Proton catalyzed hydrolytic deamination of cytosine: a computational study2008In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 120, no 4-6, p. 429-435Article in journal (Refereed)
    Abstract [en]

    Two pathways involving proton catalyzed hydrolytic deamination of cytosine (to uracil) are investigated at the PCM-corrected B3LYP/6-311G(d,p) level of theory, in the presence of an additional catalyzing water molecule. It is concluded that the pathway involving initial protonation at nitrogen in position 3 of the ring, followed by water addition at C4 and proton transfer to the amino group, is a likely route to hydrolytic deamination. The rate determining step is the addition of water to the cytosine, with a calculated free energy barrier in aqueous solution of G==140 kJ/mol. The current mechanism provides a lower barrier to deamination than previous work based on OH− catalyzed reactions, and lies closer to the experimental barrier derived from rate constants (Ea = 117 ± 4kJ/mol).

  • 22. Labet, Vanessa
    et al.
    Morell, Christophe
    Cadet, Jean
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Grand, Andre
    Hydrolytic Deamination of 5-Methylcytosine in Protic Medium: A Theoretical Study2009In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 11, p. 2524-2533Article in journal (Refereed)
    Abstract [en]

    The mechanism for the deamination reaction of 5-methylcytosine with H2O in protic medium was investigated using DFT calculations at the B3LYP/6-311G(d,p) level of theory. Two pathways were found. Pathway 5mA is a two-step mechanism where the N3-protonated 5-MeCyt undergoes a nucleophilic attack to carbon C4 by a water dimer before the elimination of an ammonium cation. Pathway 5mB is a three-step mechanism where neutral 5-MeCyt is directly attacked by a water dimer. The resulting intermediate is then protonated to allow the elimination of an ammonium cation. Both pathways lead to the formation of thymine in interaction with an ammonium cation and a water molecule. Pathway 5mA can explain the spontaneous deamination of 5-MeCyt in protic medium at acidic pH, whereas pathway 5mB is more representative of the deamination in protic medium at neutral pH. The nucleophilic addition of the water dimer is rate-determining in both pathways and is associated with an activation free energy in aqueous solution of 137.4 kJ/mol for pathway 5mA and 134.1 kJ/mol for pathway 5mB. This latter value is in agreement with the experimental observation that 5-MeCyt deaminates four- to fivefold faster than Cyt at neutral pH. Both electrostatic and electron-transfer contributions appear to have significant importance. In vacuum, the former one dominates when the substrate is positively charged and the latter one when it is neutral.

  • 23.
    Labet, Vanessa
    et al.
    CEA, UJF, Lab Les Acides Nucle,INAC,SCIB,UMR E 3, CEA Grenoble, Grenoble, France.
    Morell, Christophe
    CEA, UJF, Lab Les Acides Nucle,INAC,SCIB,UMR E 3, CEA Grenoble, Grenoble, France.
    Douki, Thierry
    CEA, UJF, Lab Les Acides Nucle,INAC,SCIB,UMR E 3, CEA Grenoble, Grenoble, France.
    Cadet, Jean
    CEA, UJF, Lab Les Acides Nucle,INAC,SCIB,UMR E 3, CEA Grenoble, Grenoble, France.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Grand, Andre
    CEA, UJF, Lab Les Acides Nucle,INAC,SCIB,UMR E 3, CEA Grenoble, Grenoble, France.
    Hydrolytic Deamination of 5,6-Dihydrocytosine in a Protic Medium: A Theoretical Study2010In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 114, no 4, p. 1826-1834Article in journal (Refereed)
    Abstract [en]

    The mechanism for the deamination reaction of 5,6-dihydrocytosine with H2O in a protic medium was investigated by DFT calculations at the B3LYP/6-311G(d,p) level of theory as a model reaction for the deamination reaction of 5,6-saturated cytosine derivatives. Two pathways were found. Pathway dhA, which can explain the deamination in it protic Medium at acidic pH, and pathway dhBt, more representative of the reaction in a protic medium at neutral pH. Pathway dhA is a two-step mechanism initiated by the nucleophilic addition of a water molecule to carbon C4 of N3-protonated 5,6-dihydrocytosine with the assistance of a second water molecule, followed by elimination of ail ammonium cation to form 5.6-dihydrouracil. The nucleophilic addition is rate-determining, with ail activation free energy of 116.0 kJ/mol in aqueous solution. Pathway dhBt is a four-step mechanism which starts with the water-assisted tautomerization of 5,6-dihydrocytosine to form the imino tautomer. This intermediate undergoes nucleophilic addition of water to carbon C4, which after protonation eliminates ail ammonium cation, as in pathway dhA. The nucleophilic addition is again rate-determining, with ail activation free energy of 113.3 kJ/mol in aqueous solution. The latter value is about 25 kJ/mol lower than its Counterpart for cytosine, in agreement with the experimental observation that 5,6-saturated cytosine derivatives exhibit a much shorter lifetime in aqueous solution than their unsaturated Counterparts. The evaluation of reactivity indices derived from conceptual DFT leads to the conclusion that this lower activation free energy can be attributed to a larger local electrophilic power of carbon C4 in 5.6-saturated derivatives.

  • 24.
    Larsson, Anders
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Andersson, Patrik L.
    Ivarson, Per
    Olsson, Per-Erik
    Örebro University, Department of Natural Sciences.
    Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist2006In: Journal of medicinal chemistry, ISSN 0022-2623, Vol. 49, no 25, p. 7366-7372Article in journal (Refereed)
    Abstract [en]

    To investigate androgen receptor (AR) activation by exogenous compounds, we used a combination of experimental analysis and theoretical modeling to compare a set of brominated flame retardants (BFRs) to dihydrotestosterone (DHT) with regard to ligand docking, AR binding, and AR activation in human hepatocellular liver carcinoma cells, as well as interacting energy analysis. Modeling of receptor docking was found to be a useful first step in predicting the potential to translocate to the ligand pocket of the receptor, and the computed interaction energy was found to correlate with the observed binding affinity. Flexible alignment studies of the BFR compounds demonstrated that 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (BCH) closely overlap DHT. Combining the theoretical modeling with in vitro ligand-binding and receptor-activation assays, we show that BCH binds to and activates the human AR. The remaining BFRs did not successfully interact with the ligand pocket, were not able to replace a synthetic androgen from the receptor, and failed to activate the receptor.

  • 25.
    MacIntyre, Meghan M.
    et al.
    Dept Chem, Cape Breton Univ, Sydney NS, Canada.
    Martell, Jaime M.
    Dept Chem, Cape Breton Univ, Sydney NS, Canada.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology. Sch Chem, Natl Univ Ireland Galway, Galway, Ireland.
    DFT study of five naphthalimide derivatives: Structures and redox properties2010In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 941, no 1-3, p. 133-137Article in journal (Refereed)
    Abstract [en]

    Geometries for five naphthalimide (NI) derivatives proposed as photoactive redox units in cancer treatment, have been optimized in the ground state, reduced and oxidized states using density functional theory (DFT) with the B3LYP hybrid functional and the 6-31G (d,p) basis set. The bond lengths of the N-[3-(dimethylamino)propyl]-1,8-naphthalimide derivative showed the most variation from the other four NI derivatives due to the nature of its substituent. An examination of atomic charges and spin densities shows in general that the ring carbons are most significant, except in the N-(propyl)-1,8-naphthalimide,3'-phosphoric acid derivative, where charges and densities are localized in the phosphate group. Single point energy calculations, both in vacuum and solution were performed for each NI derivative. The adiabatic and vertical electron affinities and ionization potentials are given for each of the NI derivatives in the ground state. The results suggest that none of the five NI derivatives studied can oxidize DNA nucleobases via direct electron transfer from the ground states, and that the dark toxicity of the compounds is thus most likely very low. (C)0 2009 Elsevier B.V. All rights reserved.

  • 26.
    Matxain, Jon M.
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Formoso, Elena
    Piris, Mario
    Ugalde, Jesus M.
    Endohedral (X@ZniSi)i=4-160,± Nanoclusters, X = Li, Na, K, Cl, Br2007In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 111, no 9, p. 3560-3565Article in journal (Refereed)
    Abstract [en]

    Endohedral (X@ZniSi)q structures have been characterized, with X being alkali metals such as Li, Na, and K or halogens such as Cl and Br, 4 > i > 16, and q = -1, 0, 1. In these structures, the atoms are trapped inside previously characterized spheroid hollow structures with positively charged Zn atoms and negatively charged S atoms. Moreover, although the radii of all atoms are similar, Zn atoms are located more inside the structure. The alkali metals are found to be trapped inside a larger number of spheroid structures than the halogens. The parameters determining the stability of the endohedral structures are the charge and size of the trapped atom, along with the sphericity of the cluster.

  • 27.
    Matxain, Jon M
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A
    Örebro University, Department of Natural Sciences.
    Mercero, Jose M
    Lopez, Xabier
    Piris, Mario
    Ugalde, Jesus M
    Poater, Jordi
    Matito, E
    Solá, Miguel
    New solids based on B12N12 fullerenes2007In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 111, no 36, p. 13354-60Article in journal (Refereed)
    Abstract [en]

    In recent years, BN fullerenes have been synthesized experimentally. As their carbon counterparts, these BN fullerenes could be assembled in molecular solids, but this possibility has been studied little in the literature. In this work, we focus on the smallest synthesized BN fullerene, B12N12, which is built by squares and hexagons. First, the interaction between two of these fullerenes has been analyzed, using the hybrid B3LYP and MPW1PW91 density functional methods. Two different interactions have been studied in the dimer, a square facing a square (S−S) and a hexagon facing a hexagon (H−H). In both cases, a B is facing a N. The most stable dimer was found to be S−S facing, with covalent interactions between the monomers, but other dimers with weak interactions have been found as well, which opens possibilities of new systems, as in the case of fullerene dimers and solids. The solids resulting from the infinite repetition of the characterized dimers were optimized, finding two different solids, with covalent and weak interactions between monomers, respectively. The solid with covalent interactions is a nanoporous material that is more stable by around 12 eV. Because of the nanoporous character of this solid, it could be used for heterogeneous catalysis, molecular transport, and so forth. The SIESTA code with the GGA-PBE density functional method has been used for the solid-state calculations.

  • 28.
    Matxain, Jon M.
    et al.
    Euskal Herriko Unibertsitatea.
    Padro, Daniel
    Euskal Herriko Unibertsitatea.
    Ristilä, Mikael
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Evidence of High dot OH Radical Quenching Efficiency by Vitamin B-62009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 29, p. 9629-9632Article in journal (Refereed)
    Abstract [en]

    Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of the utmost importance in the living cell. The antioxidative properties of pyridoxine (vitamin B6) have recently been discovered. Previous theoretical calculations have shown a high reactivity of pyridoxine toward hydroxyl radicals, where the latter preferably abstract H from either carbon of the two methanol substituents (C8 or C9). In this study, we have explored the reactivity of pyridoxine toward further hydroxyl radicals, considering as the first step the H abstraction from either C8 or C9, also including addition reactions and cyclization. Many of the reactions display similar ΔG, and hence, the quenching of hydroxyl radicals by pyridoxine may undergo different pathways leading to a mix of products. In addition, we observe that pyridoxine, under high hydroxyl radical concentrations, may scavenge up to eight radicals, supporting its observed high antioxidant activity.

  • 29.
    Matxain, Jon M.
    et al.
    Örebro University, Department of Natural Sciences.
    Ristilä, Mikael
    Örebro University, Department of Natural Sciences.
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of the antioxidant properties of pyridoxine2006In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 110, no 48, p. 13068-13072Article in journal (Refereed)
    Abstract [en]

    Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. The antioxidative properties of pyridoxine (vitamin B6) have recently been discovered. In this study, we have analyzed the reactivity of pyridoxine toward the ROS .OH, .OOH, and .O2- at the density functional theory level (functionals B3LYP and MPW1B95). Two reaction types have been studied as follows: addition to the aromatic ring atoms and hydrogen/proton abstraction. Our results show that .OH is the most reactive species, while .OOH displays low reactivity and .O2- does not react at all with pyridoxine. The most exergonic reactions are those where .H is removed from the CH2OH groups or the ring-bound OH group and range from -33 to -39 kcal/mol. The most exergonic addition reactions occur by attacking the carbon atoms bonded to nitrogen but with an energy gain of only 6 kcal/mol.

  • 30.
    Matxain, Jon M
    et al.
    Örebro University, Department of Natural Sciences.
    Ristilä, Mikael
    Örebro University, Department of Natural Sciences.
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A
    Örebro University, Department of Natural Sciences.
    Theoretical study of the reaction of vitamin B6 with 1O22007In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 13, no 16, p. 4636-42Article in journal (Refereed)
    Abstract [en]

    Singlet oxygen is known to cause oxidative stress in cells, leading to severe damage (e.g., lipid peroxidation, membrane degradation, mutagenic alterations to DNA, protein misfunctionality). Recently, pyridoxine has been discovered to be capable of quenching singlet oxygen, however, the mechanism of this reaction remains essentially unknown. In this work, we have investigated four sets of reactions: 1) 1,3-addition to a double bond connected to a hydrogen-carrying group,resulting in the formation of allylic hydroperoxides; 2) [p2+p2] 1,2-cycloaddition to an isolated double bond, resulting in the formation of 1,2-peroxides; 3) 1,4-cycloaddition to a system containing at least two conjugated double bonds, resulting in the formation of the so-called 1,4-peroxides;4) 1,4-addition to phenols and naphthols with the formation of hydroperoxide ketones. Thermodynamically, reaction 4 and the 6(9), 3(8), and 5(8) cases of reaction 1 are the most exergonic ones, with energies ranging from 16 to 18 kcalmol 1. Furthermore, reaction 4 shows the lowest barrier through the reaction path, and is predicted to be the preferred mechanism

    for the pyridoxine + singlet-oxygen reaction, which is in agreement with previous experimental results.

  • 31.
    Musa, Klefah A. K.
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties: Suprofen and Tiaprofenic Acid2009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 32, p. 11306-11313Article in journal (Refereed)
    Abstract [en]

    The photodegradation of nonsteroid anti-inflammatory drugs suprofen, 2-[4-(2-thienoyl)phenyl]propionic acid, and tiaprofenic acid, 2-(5-benzoyl-2-thienyl)propanoic acid, is studied by means of density functional theory. Besides the redox properties of the neutral species, we report on absorption spectra and degradation pathways involving excitation, intersystem crossing to the T-1 state. and spontaneous decarboxylation of the deprotonated species of each drug. The energetics and properties of the suprofen and tiaprofenic acid systems are found to be very similar to those of the highly photolabile benzyl analogue ketoprofen. Mechanisms leading to the formation of a closed-shell decarboxylated ethyl species, as well as peroxyl radicals capable of initiating lipid peroxidation reactions, are discussed.

  • 32.
    Musa, Klefah A. K.
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct2009In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 22, p. 4601-4610Article in journal (Refereed)
    Abstract [en]

    Diclofenac (DF) is a widely used non-steroid anti-inflammatory drug, associated with a range of side effects. The phototoxicity of DF is studied herein employing computational quantum chemistry at the B3LYP/6-31G(d,p) level of theory. The results show that the drug readily absorbs radiation from the UV-region. The deprotonated form spontaneously dechlorinates from its triplet state leading to ring closure and formation of an active photoproduct: chlorocarbazole acetic acid, CCA. The formed CCA is also photodegraded easily from its deprotonated triplet state. Photodegradation routes of deprotonated CCA are decarboxylation (barrier less than 4.5 kcal mol(-1)) and dechlorination (barrier around 6.2 kcal mol(-1)). The energy barrier required for dechlorination to take place from the neutral from is about 20 kcal mol(-1). The differences between the molecular orbitals of the neutral and the deprotonated forms of DF and CCA and spectra obtained using time-dependent density-functional theory (TD-DFT), in addition to the different radical and oxygenated intermediate species formed during the photodegradation mechanism, are discussed in more detail. The theoretical results obtained herein are in line with the experimental results available to date.

  • 33.
    Musa, Klefah A. K.
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical assessment of naphazoline redoxchemistry and photochemistry2007In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 15, p. 3977-3981Article in journal (Refereed)
    Abstract [en]

    The imidazoline derivative naphazoline (2-(1-naphtylmethyl)-2-imidazoline) is an α2-adrenergic agonist used as non-prescription eye and nasal preparations. Besides its functionality in generating vascoconstriction and decongestion in the patient, the toxicity, ROS generating capability, and recently also possible antioxidant capacity of the compound have been reported in the literature. In the current work the structural and electronic features of the drug are explored, using computational chemical tools. Electron affinities, ionization potentials, and excitation energies are reported, as well as charge and spin distributions of various forms of the drug. The difference in photochemical behavior between the protonated and unprotonated (basic) species is explained by the molecular orbital distributions, allowing for efficient excitation quenching in the basic structure but clear naphthalene to imidazolene charge transfer upon HOMO→ LUMO excitation in the protonated form, enabling larger intersystem crossing capability to the imidazole localized excited triplet and a resulting higher singlet oxygen quantum yield.

  • 34.
    Musa, Klefah A. K.
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Theoretical assessment of norfloxacin redox and photochemistry2009In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 40, p. 10803-10810Article in journal (Refereed)
    Abstract [en]

    Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydo-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli c acid, NOR, is an antibiotic drug from the fluoroquinoline family. The different protonation states of this drug formed throughout the pH range is studied by means of density functional theory (DFT) and the spectra of the NOR species computed using time-dependent DFT. Details about their photochemistry are obtained from investigating the highest occupied and lowest unoccupied molecular orbitals. The predominant species under physiological pH, the zwitterion, is the most photoliable one, capable of producing singlet oxygen or/and superoxide radical anions from its triplet state. In addition, the main photodegradation step, defluorination, occurs more easily from this species compared with the other forms. The defluorination from the excited triplet state requires passing a barrier of 16.3 kcal/mol in the case of the zwitterion. The neutral and cationic forms display higher transition barriers, whereas the reaction path of defluorination is completely endothermic for the anionic species. The theoretical results obtained herein are in line with previous experimental data.

  • 35.
    Musa, Klefah A. K.
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical Study of Ibuprofen Phototoxicity2007In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 46, p. 13345-13352Article in journal (Refereed)
    Abstract [en]

    The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C−C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

  • 36.
    Musa, Klefah A K
    et al.
    Örebro University, Department of Natural Sciences.
    Matxain, Jon M
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A
    Örebro University, Department of Natural Sciences.
    Mechanism of Photoinduced Decomposition of Ketoprofen2007In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 8, p. 1735-1743Article in journal (Refereed)
    Abstract [en]

    UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.

  • 37.
    Musa, Klefah A. K.
    et al.
    Örebro University, School of Science and Technology.
    Palwai, Viraja R.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity2011In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 111, no 6, p. 1184-1195Article in journal (Refereed)
    Abstract [en]

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic, analgesic, and anti-inflammatory agents. However, they are also associated with a range of side effects, from phototoxicity due to excited state induced decarboxylation to severe conditions in the gastrointestinal tract caused by inhibition of the COX-1 isoform of the target cyclooxygenase enzyme. In the current work, new derivatives of the three NSAIDs ketoprofen, ibuprofen, and naproxen were designed. Their photochemistry was explored using hybrid-density functional theory (B3LYP/6-31G(d,p)) and time-dependent (TD) DFT, showing that the compounds will have significantly reduced propensity to decarboxylate from the first excited triplet state. In addition, docking studies were carried out for these new molecules to explore their activity and selectivity toward the two isoforms of the COX enzyme. The results show that most compounds have increased activity toward the COX enzymes, and in general are more selective toward the COX-2 target isoform. The results from this study suggest that the new modified molecules could be used in the future as NSAIDs with considerably reduced side effects.

  • 38.
    Musa, Klefah A.K.
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen2009In: Journal of Photochemistry and Photobiology A: Chemistry, ISSN 1010-6030, E-ISSN 1873-2666, Vol. 202, no 1, p. 48-56Article in journal (Refereed)
    Abstract [en]

    The photodegradation mechanism of the widely used non-steroidal anti-inflammatory drug 2-(4-phenyl-3-fluorophenyl) propanoic acid, Flurbiprofen, and its photochemical and photophysical properties have been investigated by means of computational quantum chemistry at the DFT-B3LYP/6-31G(d,p) level. Comparison of computed and experimental singlet and triplet–triplet absorption spectra point to that most experiments, using a range of different solvents, are conducted on the neutral, protonated form of Flurbiprofen. The deprotonated acid, which should dominate at physiological pH, shows no sign of decarboxylation from the lowest singlet excited states, whereas from its first excited triplet state this should readily occur by passing over an energy barrier of <0.5 kcal/mol. Further reactions in the proposed photodegradation mechanism, after decarboxylation, as well as the probability for reactive oxygen species formation are discussed in detail. The generation of the corresponding peroxyl radical from the decarboxylated radical and molecular oxygen is strictly exergonic and occurs without barrier under aerobic conditions. The thus formed peroxyl radical will in turn be capable of initiating propagating lipid peroxidation processes.

  • 39.
    Musa, Klefah A.K.
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Theoretical Study of the Phototoxicity of Naproxen and the Active Form of Nabumetone2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 43, p. 10921-10930Article in journal (Refereed)
  • 40.
    Omar, Salama
    et al.
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Computational study of khellin excited states and photobinding to DNA2009In: Photochemical and Photobiological Sciences, ISSN 1474-905X, E-ISSN 1474-9092, Vol. 8, no 8, p. 1179-1186Article in journal (Refereed)
    Abstract [en]

    A theoretical investigation of the formation and spectroscopic properties of the furan and pyrone monoadducts between the photosensitizer khellin and DNA base thymine is reported. The thermal reaction pathways involve very high barriers, whereas the excited state surfaces display low barriers in regions leading to the ground state TS structures and potential wells at the ground state TS geometries. Computed UV absorption spectra are interpreted with the support of molecular orbital calculations, and the role of solvent effects on the spectra is discussed. The red-shift in the khellin spectra upon intercalation in DNA is excellently reproduced by the computational methodology, as is the solvent induced spectral shift. The data also provides an explanation to why khellin predominantly forms furan monoadducts in DNA, as opposed to the closely related psoralen compounds.

  • 41. Omar, Salama
    et al.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Interaction and photobinding between 8-methoxypsoralen and thymine2009In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 471, no 1-3, p. 128-132Article in journal (Refereed)
    Abstract [en]

    The intercalation and photobinding of 8-methoxypsoralen with thymine in DNA is studied by computational chemistry techniques. Photochemical [2+2] cycloadditions at the S-1 surface display barriers of approximately 20 kcal/mol. The lowest lying excited surface has a defined potential well at the ground state TS, enabling for efficient decay. Avoided crossings between the S-1 and S-2 surfaces are also observed, which may influence the photochemical reactivity. The further reactions leading to crosslink formation from furan monoadducts but not from pyrone ones are fully explained by the excitation energies of the monoadducts, whereas the predominance of furan over pyrone monoadduct formation is not explained looking at the excitation energy surfaces alone. (C) 2009 Elsevier B.V. All rights reserved.

  • 42.
    Ristilä, Mikael
    et al.
    Örebro University, Department of Natural Sciences.
    Matxain, Jon M.
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    pH-dependent electronic and spectroscopic properties of pyridoxine (vitamin B6)2006In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 33, p. 16774-16780Article in journal (Refereed)
    Abstract [en]

    The key electronic and spectroscopic properties of vitamin B6 (pyridoxine) and some of its main charged and protonated/deprotonated species are explored using hybrid density functional theory (DFT) methods including polarized solvation models. It is found that the dominant species at low pH is the N1-protonated form and, at high pH, the O3¢-deprotonated compound. Computed and experimental UV-spectra for these species (experimental spectra recorded at pH 1.7 and 11.1, respectively) show a very close resemblance. At pH 4.3, the protonated species dominates, but with onset of the zwitterionic oxo form which is also the dominant species at neutral pH. The computational studies furthermore show that neither a polarized continuum model of the polar aqueous solvent or explicit hydrogen bonding through additional water molecules are sufficient to describe accurately the spectrum at physiological pH. Instead, Na+ and Cl- counterions were required to give a blue-shift of approximately 0.15 eV.

  • 43. Saenz Méndez, P.
    et al.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Ventura, O. N.
    Theoretical study of the structure of neutral, radical and anionic monoperoxo carbonic acid2009In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 913, no 1-3, p. 131-138Article in journal (Refereed)
    Abstract [en]

    Bicarbonate ion reacts with aqueous hydrogen peroxide, yielding monoperoxocarbonate (HCO4-, PCA-). This species is a better oxidizing agent than hydrogen peroxide itself and has been shown to lead to double bond epoxidation of alkenes under mild conditions. The structure of this anion as well as that of the parent monoperoxocarbonic acid (H2CO4, HPCA) are not known experimentally. The structures of the neutral, anionic and radical species derived from H2CO4 are reported in this paper employing DFT and MP2 methods, both in gas phase and simulating the bulk water solvent using the PCM method. Several conformers are found, of which the most stable one in gas phase has a planar, hydrogen-bonded structure similar to the one observed for peroxyformic acid (PFA). However, optimization of this structure in the bulk solvent leads to a non-planar conformation with a gauche disposition of the bonds in the COOH group. It is furthermore shown that the barriers separating the conformers are much smaller in solution, thus allowing easy interconversion.

  • 44.
    Saenz-Mendez, Patricia
    et al.
    Örebro University, Department of Natural Sciences.
    Guedes, Rita C.
    dos Santos, Daniel J.V.A.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical prediction of binding modes and hot sequences for allopsoralen-DNA interaction2007In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 450, no 1-3, p. 127-131Article in journal (Refereed)
    Abstract [en]

    Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as ligand were performed. The calculated interaction energies showed that the ligand can be docked into the minor groove as well as become intercalated. However, unlike psoralen, allopsoralen preferred binding mode for non-poly-TA sequences is minor groove binding. Calculated energies for intercalation between different base pairs suggest that the predicted sequence selectivity for allopsoralen is analogous to that observed for psoralen. Intercalation is favored in 5'-TpA sites in poly-TA sequences.

  • 45.
    Saenz-Mendez, Patricia
    et al.
    Örebro University, Department of Natural Sciences.
    Guedes, Rita C.
    dos Santos, Daniel J.V.A.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of sequence selectivity and preferred binding mode of psoralen with DNA2007In: Research Letters in Physical Chemistry, ISSN 1687-6873, p. Article number 60623-Article in journal (Refereed)
    Abstract [en]

    Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand.We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5'-TpA in (AT)n sequences.

  • 46.
    Scherbak, Nikolai
    et al.
    Örebro University, Department of Natural Sciences.
    Brosché, Mikael
    Ala-Häivälä, Anneli
    Olsson, Annika
    Enroth, Cristofer
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Nilsson, Fredrik
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Plant SAD proteins: characterization of the tetrameric Pisum sativum proteinManuscript (preprint) (Other academic)
  • 47.
    Scherbak, Nikolai
    et al.
    Örebro University, Department of Natural Sciences.
    Strid, Åke
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Non-enzymatic oxidation of NADH by quinones2005In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 414, no 1-3, p. 243-247Article in journal (Refereed)
    Abstract [en]

    Non-enzymatic oxidation of NADH by a large number of different quinones has been explored both theoretically and experimentally. It is concluded that the smaller benzo- and naphtho-quinones are capable of oxidising NADH in aqueous solution, whereas the larger anthraquinone is not. The mechanisms of stepwise electron and proton transfers are explored, and ruled out in favour of direct hydride transfer. For menadione (2-methyl-1,4-naphthoquinone), no reaction is observed experimentally; theoretically we find that there is a very close balance between the energetic cost of hydride removal from NADH and the energy gain of formation of the menadione semiquinone radical anion.

  • 48. Schyman, Patric
    et al.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Laaksonen, Aatto
    Hydrogen Abstraction from Deoxyribose by a Neighboring 3 '-Uracil Peroxyl Radical2009In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 18, p. 6574-6578Article in journal (Refereed)
    Abstract [en]

    Theoretical examination of the reactivity of the uracil-5-peroxyl radical when abstracting a hydrogen atom from a neighboring 5'-deoxyribose in 5'-ApU-5-peroxyl-3' has been performed using density functional theory with the MPWB1K functional. Halogenated uracils are often used as radiosensitizers in DNA since the reactive uracil-5-yl radical is formed upon radiation and is known to create strand break and alkali-labile sites. Under aerobic conditions, such as in the cell, it has been proposed that the uracil-5-peroxyl radical is formed and would be the damaging agent. Our results show low reactivity for the uracil-5-peroxyl radical, determined by calculating the activation and reaction energies for the plausible hydrogen abstraction sites C1', C2' and C3' of the neighboring 5'-deoxyribose. These findings support the hypothesis that hydrogen abstraction primarily occurs by the uracil-5-yl radical, also under aerobic conditions, prior to formation of the peroxyl radical.

  • 49. Schyman, Patric
    et al.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Zhang, Ru bo
    Laaksonen, Aatto
    Hydroxyl radical - thymine adduct induced DNA damages2008In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 458, no 1-3, p. 186-189Article in journal (Refereed)
    Abstract [en]

    DNA damages caused by a 5-hydroxy-5,6-dihydrothymine-6-yl radical (5-OHT-6yl) abstracting a C20 hydrogen from a neighboring sugar (inter-H abstraction) have been theoretically investigated using hybrid DFT in gas phase and in water solution. The inter-H abstraction was here shown to be comparable in energy (24 kcal mol 1) with the intra-H abstraction in which the 5-OHT-6yl abstracts a C20 hydrogen from its own sugar. The effect of a neutrally or a negatively charged phosphate group was also studied and the results show no significant impact on the activation energy of the hydrogen abstraction whereas base release and strand break reactions are affected.

  • 50. Schyman, Patric
    et al.
    Zhang, Ru bo
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Laaksonen, Aatto
    Hydrogen Abstraction from Deoxyribose by a Neighbouring Uracil-5-yl Radical2007In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 9, p. 5975-5979Article in journal (Refereed)
    Abstract [en]

    Hydrogen abstraction from the C1 and C2 positions of deoxyadenosine by a neighbouring uracil-5-yl radical in the 5-AU-3 DNA sequence is explored using DFT. This hydrogen abstraction is the first step in a sequence leading to single or double strand break in DNA. The uracil-5-yl radical can be the result of photolysis or low-energy electron (LEE) attachment. If the radical is produced by photolysis the neighbouring adenine will become a cation radical and if it is produced by LEE the adenine will remain neutral. The hydrogen abstraction reactions for both cases were investigated. It is concluded that it is possible for the uracil-5-yl to abstract hydrogen from C1 and C2. When adenine is neutral there is a preference for the C1 site and when the adenine is a radical cation the C2 site is the preferred. If adenine is positively charged, the rate-limiting step when abstracting hydrogen from C1 is the formation of an intermediate crosslink between uracil and adenine. This crosslink might be avoided in dsDNA, making C1 the preferred site for abstraction.

12 1 - 50 of 63
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