Béla Fiser

Antioxidant Potential of Glutathione: A Theoretical Study

All possible X-H (where X can be C, N, O or S) bond dissociation energies (BDEs) of glutathione (γ-L-glutamyl-L-cysteinyl-glycine, GSH) and its fragments have been calculated by first principle methods, and the antioxidant potential of GSH was revealed to be higher than expected in earlier studies. Electron delocalization was found to have an important influence on the antioxidant potential. All structures were optimized and their harmonic vibrational frequencies were calculated in the gas phase at the B3LYP/6-31G(d) level of theory. Solvent effects were taken into account for optimizations at the same level of theory by applying the conductor-like polarizable continuum model (CPCM). Hydrogen cleavage from glutathione proved that the G3MP2B3 composite method provides results consistent with the experimental values for bond dissociation enthalpies (DH(298)) of S-H, O-H, C-H, and N-H bonds. In order to replace the G3MP2B3 energies with accurate single point calculations, six density functionals, namely, MPWKCIS, MPWKCIS1K, M06, TPSS1KCIS, TPSSh, and B3LYP, were tested against G3MP2B3 for obtaining accurate bond dissociation energies. The MPWKCIS1K/6-311++G(3df,2p)//B3LYP/6-31G(d) level of theory provides the best correlation with the G3MP2B3 method for BDEs in both phases, and therefore, it is recommended for similar calculations. Gas phase results showed that the O-H bond was the weakest, while in aqueous phase the N-H bond in the ammonium group proved to have the smallest BDE value in the studied system. In both cases, the cleavage of the X-H bond was followed by decarboxylation which was responsible for the energetic preference of these processes over the S-H dissociation, which was regarded as the most favorable one until now. The calculated BDE values showed that in aqueous phase the most preferred H-abstraction site is at the weakest N-H bond (BDE(aq) = 349.3 kJ mol(-1)) in the glutamine fragment near the α-carbon. In water, the formation of N-centered radicals compared to S-centered ones (BDE(aq) = 351.7 kJ mol(-1)) is more endothermic by 2.54 kJ mol(-1), due to decarboxylation. Hydrogen dissociation energies from the α-carbons are also comparable in energy with those of the thiol hydrogen, within computational error. The higher stability of the radicals--except the S-centered ones--is due to various degrees of electron delocalization. In aqueous phase, four quasi-equivalent stable radical centers (the α-carbons, the N-centered radical of the NH(2) group, and the S-centered radical) were found which provide the antioxidant behavior of glutathione.

Cu-promoted sydnone cycloadditions of alkynes: scope and mechanism studies.

Cu salts have been found to promote the cycloaddition reaction of sydnones and terminal alkynes, providing significant reduction in reaction times. Specifically, the use of Cu(OTf)2 is found to provide 1,3-disubstituted pyrazoles, whereas simply switching the promoter system to Cu(OAc)2 allows the corresponding 1,4-isomers to be produced. The mechanism of the Cu-effect in each case has been investigated by experimental and theoretical studies, and they suggest that Cu(OTf)2 functions by Lewis acid activation of the sydnone, whereas Cu(OAc)2 promotes formation of reactive Cu(I) acetylides.

Construction of Cyclopenta[b]indol-1-ones by a Tandem Gold(I)-Catalyzed Rearrangement/Nazarov Reaction and Application to the Synthesis of Bruceolline H

A tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates which efficiently provides cyclopenta[b]indol-1-ones as useful precursors for the synthesis of natural and bioactive compounds is described. The synthetic potential of the methodology is demonstrated by the first total synthesis of bruceolline H.

Approach to cis-Phlegmarine Alkaloids via Stereodivergent Reduction: Total Synthesis of (+)-Serratezomine E and Putative Structure of (−)-Huperzine N

A unified strategy for the synthesis of the cis-phlegmarine group of alkaloids is presented, leading to the first synthesis of serratezomine E (1) as well as the putative structure of huperzine N (2). A contrasteric hydrogenation method was developed based on the use of Wilkinsons catalyst, which allowed the facial selectivity of standard hydrogenation to be completely overturned. Calculations were performed to determine the mechanism, and structures for huperzines M and N are reassigned.

A Modular Class of Fluorescent Difluoroboranes: Synthesis, Structure, Optical Properties, Theoretical Calculations and Applications for Biological Imaging

Ten borylated bipyridines (BOBIPYs) have been synthesized and selected structural modifications have been made that allow useful structure-optical property relationships to be gathered. These systems have been further investigated using DFT calculations and spectroscopic measurements, showing blue to green fluorescence with quantum yields up to 41 %. They allow full mapping of the structure to determine where selected functionalities can be implemented, to tune the optical properties or to incorporate linking groups. The best derivative was thus functionalised with an alkyne linker, which would enable further applications through click chemistry and in this optic, the stability of the fluorophores has been evaluated.

Pd-Catalyzed Hydroamination of Alkoxyallenes with Azole Heterocycles: Examples and Mechanistic Proposal

Palladium-catalyzed regio- and enantioselective addition of azole heterocycles to alkoxyallenes was developed (up to 92% yields and up to 94% ee). DFT calculations suggest a new Pd(0)-driven mechanistic pathway proceeding through protonation of the Pd-coordinated allene (4-PdL2), which develops a strongly nucleophilic character at the central C atom.

Glutathione as a prebiotic answer to α-peptide based life.

The energetics of peptide bond formation is an important factor not only in the design of chemical peptide synthesis, but it also has a role in protein biosynthesis. In this work, quantum chemical calculations at 10 different levels of theory including G3MP2B3 were performed on the energetics of glutathione formation. The strength of the peptide bond is found to be closely related to the acid strength of the to-be N-terminal and the basicity of the to-be C-terminal amino acid. It is shown that the formation of the first peptide activates the amino acid for the next condensation step, manifested in bacterial protein synthesis where the first step is the formation of an N-formylmethionine dipeptide. The possible role of glutathione in prebiotic molecular evolution is also analyzed. The implications of the thermodynamics of peptide bond formation in prebiotic peptide formation as well as in the preference of α- instead of β- or γ-amino acids are discussed. An empirical correction is proposed for the compensation of the error due to the incapability of continuum solvation models in describing the change of the first solvation shell when a peptide bond is formed from two zwitterions accompanied by the disappearance of one ion pair.

Structure and binding efficiency relations of QB site inhibitors of photosynthetic reaction centres.

Many herbicides employed in agriculture and also some antibiotics bind to a specific site of the reaction centre protein (RC) blocking the photosynthetic electron transport. Crystal structures showed that all these compounds bind at the secondary ubiquinone (QB) site albeit to slightly different places. Different herbicide molecules have different binding affinities (evaluated as inhibition constants, KI, and binding enthalpy values, ΔHbind). The action of inhibitors depends on the following parameters: (i) herbicide molecular structure; (ii) interactions between herbicide and quinone binding site; (iii) protein environment. In our investigations KI and ΔHbind were determined for several inhibitors. Bound herbicide structures were optimized and their intramolecular charge distributions were calculated. Experimental and calculated data were compared to those available from databank crystal structures. We can state that the herbicide inhibition efficiency depends on steric and electronic, i.e. geometry of binding with the protein and molecular charge distribution, respectively. Apolar bulky groups on N-7 atom of the inhibitor molecule (like t-buthyl in terbutryn) are preferable for establishing stronger interactions with QB site, while such substituents are not recommended on N-8. The N-4,7,8 nitrogen atoms maintain a larger electron density so that more effective H-bonds are formed between the inhibitor and the surrounding amino acids of the protein.

Molecular ageing: Free radical initiated epimerization of thymopentin – A case study

The epimerization of amino acid residues increases with age in living organisms. In the present study, the structural consequences and thermodynamic functions of the epimerization of thymopentin (TP-5), the active site of the thymic hormone thymopoietin, were studied using molecular dynamics and density functional theory methods. The results show that free radical-initiated D-amino acid formation is energetically favoured (-130 kJmol(-1)) for each residue and induces significant changes to the peptide structure. In comparison to the wild-type (each residue in the L-configuration), the radius of gyration of the D-Asp(3) epimer of the peptide decreased by 0.5 Å, and disrupted the intramolecular hydrogen bonding of the native peptide. Beyond establishing important structural, energetic and thermodynamic benchmarks and reference data for the structure of TP-5, these results disseminate the understanding of molecular ageing, the epimerization of amino acid residues.