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Renaud Hardré

Publications and source records attributed to Renaud Hardré.

8 recordsLinked to original sources
PubMed2006

Pathway for the stereocontrolled Z and E production of alpha,alpha-difluorine-substituted phenyl butenoates.

An efficient preparation of pure ethyl Z- and E-alpha,alpha-difluoro-4-phenyl-3-butenoate 1a and 1b together with the corresponding acids 2a and 2b is described. The procedures involve stereocontrolled additions of *CF2CO2Et to phenylacetylene or beta-bromostyrene. Compound 1a is easily obtained by addition of *CF2CO2Et to phenylacetylene via a mechanism where the stereochemistry is controlled by an electron-transfer process to produce predominantly the Z vinyl anion. The product 1b is obtained by *CF2CO2Et addition-elimination to Z- or E-beta-bromostyrenes via a mechanism where the stereochemistry is controlled by steric factors in the conformational equilibration of the intermediates.

Acetylene↗
PubMed2006

Mono, di and tri-mannopyranosyl phosphates as mannose-1-phosphate prodrugs for potential CDG-Ia therapy.

An efficient and convergent method for the synthesis of mannose-1-phosphate prodrugs is described as a potential therapy for congenital disorders of glycosylation-Ia (CDG-Ia). The key feature of the proposed approach is the silver assisted nucleophilic substitution of 2,3,4,6-tetra-O-protected-alpha-d-mannopyranosyl bromides with various silver phosphate salts to afford mono, di, and tri-mannopyranosyl phosphates. A preliminary biological evaluation of the synthesized phosphate prodrugs has been carried out.

Carbohydrate Sequence↗
PubMed2005

The impact of pyrrolidine hydroxylation on the conformation of proline-containing peptides.

[structure: see text] A series of eight dipeptides of the general formula Ac-Phe-Pro-NHMe was synthesized and the thermodynamics of the cis --> trans isomerization about the central amide bond were studied by NMR. Pro* represents the following prolines: l-proline (Pro), l-trans-4-hydroxyproline (Hyp), l-cis-4-hydroxyproline (hyp), l-cis-4-methoxyproline (hyp[OMe]), l-trans-3-hydroxyproline (3-Hyp), l-cis-3-hydroxyproline (3-hyp), l-2,3-trans-3,4-cis-3,4-dihydroxyproline (DHP), and l-2,3-cis-3,4-trans-3,4-dihydroxyproline (dhp). The conformation of the pyrrolidine ring in each case is discussed in light of previous structural studies, analysis of potential stereoelectronic effects, and NMR data. Hydroxy substituents at C-4 have a greater impact on cis --> trans isomerization than analogous substituents at C-3 as a result of the intervening bond distances and bridging groups. The position of the equilibrium and its dependence on temperature are a reflection of both enthalpic and entropic factors, the latter being complicated in this study by an Ar-Pro interaction in the cis conformation. The substituents on the pyrrolidine ring determine the conformation of the five-membered ring, which in turn influences the strength of the Ar-Pro interaction, backbone dihedral angles, and the relative energy of the cis and trans species. The ultimate position of the equilibrium depends on a complex blend of steric, electronic, and conformational factors.

Dipeptides↗
PubMed2004

The structures of inhibitor complexes of Pyrococcus furiosus phosphoglucose isomerase provide insights into substrate binding and catalysis.

Pyrococcus furiosus phosphoglucose isomerase (PfPGI) is a metal-containing enzyme that catalyses the interconversion of glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P). The recent structure of PfPGI has confirmed the hypothesis that the enzyme belongs to the cupin superfamily and identified the position of the active site. This fold is distinct from the alphabetaalpha sandwich fold commonly seen in phosphoglucose isomerases (PGIs) that are found in bacteria, eukaryotes and some archaea. Whilst the mechanism of the latter family is thought to proceed through a cis-enediol intermediate, analysis of the structure of PfPGI in the presence of inhibitors has led to the suggestion that the mechanism of this enzyme involves the metal-dependent direct transfer of a hydride between C1 and C2 atoms of the substrate. To gain further insight in the reaction mechanism of PfPGI, the structures of the free enzyme and the complexes with the inhibitor, 5-phospho-d-arabinonate (5PAA) in the presence and absence of metal have been determined. Comparison of these structures with those of equivalent complexes of the eukaryotic PGIs reveals similarities at the active site in the disposition of possible catalytic residues. These include the presence of a glutamic acid residue, Glu97 in PfPGI, which occupies the same position relative to the inhibitor as that of the glutamate that is thought to function as the catalytic base in the eukaryal-type PGIs. These similarities suggest that aspects of the catalytic mechanisms of these two structurally unrelated PGIs may be similar and based on an enediol intermediate.

Archaeal Proteins↗
PubMed2004

Leishmania mexicana mexicana glucose-6-phosphate isomerase: crystallization, molecular-replacement solution and inhibition.

Glucose-6-phosphate isomerase (PGI; EC 5.3.1.9; also often called by its old nomenclature phosphoglucose isomerase) is an intracellular enzyme that catalyses the reversible conversion of D-glucose 6-phosphate (G6P) to D-fructose 6-phosphate (F6P). The native Leishmania PGI is a homodimeric molecule of 60 kDa per monomer with 47% sequence identity to human PGI. It has been shown to be present in both the cytosol and the glycosome of Leishmania promastigotes and represents a potential target for rational drug design. The present work describes the crystallization of two bacterially expressed Leishmania PGI constructs, one corresponding to the natural protein and the other to an N-terminally deleted form. Crystals of both forms are identical and present a large c unit-cell parameter. A complete data set was collected from the N-terminally deleted PGI to a resolution of 3.3 A in space group P6(1), with unit-cell parameters a = b = 87.0, c = 354.7 A, alpha = beta = 90, gamma = 120 degrees. A preliminary study of the first inhibitors to be evaluated on the Leishmania enzyme is also reported.

Amino Acid Sequence↗
PubMed2003

Factors affecting conformation in proline-containing peptides.

[reaction: see text] NMR was used to study the thermodynamics of the cis --> trans isomerization for prolyl amide bonds in the compounds shown. The magnitude of K(t/c) for C-terminal esters is greater than for the corresponding amides, signifying stronger backbone stereoelectronic effects in esters. Increasing the steric bulk of the N-terminal residue from Ac- to Ac-Gly- favors the trans conformation. Incorporation of a Phe residue N-terminal to Pro, however, shifts the equilibrium in favor of the cis conformation, via a stabilizing aromatic-proline interaction.

Peptides↗
PubMed2003

Sugar derivatives as new 6-phosphogluconate dehydrogenase inhibitors selective for the parasite Trypanosoma brucei.

Sugar derivatives mimicking compounds which take part in the catalysed reaction have been assayed as alternative substrates and/or competitive inhibitors of 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Phosphonate analogues have been synthesised and the new compound 5-deoxy-5-phosphono-D-arabinonate shows good selectivity towards the parasite enzyme. A number of 4-carbon and 5-carbon aldonates are strong inhibitors of the parasite enzyme with K(i) values below the substrate K(m) and some acyl derivatives are also potent inhibitors. At least five of the compounds showing a significant selectivity for the parasite enzyme represent leads for trypanocidal drugs against this recently validated target.

Animals↗