Gérald Villeneuve

A comprehensive thermodynamic investigation of water-ethylene glycol mixtures at 5, 25, and 45°C

A detailed thermodynamic study of water (W)-ethylene glycol (EG) mixtures has been carried out as function of temperature (5, 25 and 45°C) and over the entire composition range. The data comprise heats of mixing, densities, heat capacities and compression coefficients. Using excess free energy data from earlier work, molar excess functions were calculated for free energies GE, enthalpies HE and entropies TSE, volumes VE, isobaric and isochoric heat capacities CPE, CVE, adiabatic and isothermal compression KE, KTE and thermal expansion EE, as well as the temperature derivatives of K, C and E functions. The corresponding partial molar quantities were also calculated except for G, H and S and are reported for both EG and W. Also calculated were cohesive energy density, internal pressure and Kirkwood-Buff integrals. The data reported here for EG-W mixtures are compared with similar data for other mixtures as available in order to gain insight into: 1) the relative discriminating ability of various thermodynamic coefficients towards weak cooperative intermolecular interactions in liquids; 2) the quantitative similarities and differences between liquid water and ethylene glycol; 3) the intermolecular phenomena which dominate the properties of EG-W mixtures of varying composition; 4) the usefulness of a qualtitative description of liquid water proposed by Lumry et al. which involves hydrogen-bonding interactions, hydrogen-bonding connectivity and small cooperative fluctuation units.

Efficient parallel synthesis of macrocyclic peptidomimetics.

A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.

A proposal for the molecular basis of μ and δ opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid

SummaryThe molecular basis underlying the divergent receptor selectivity of two cyclic opioid peptides Tyr-c[Nδ-d-Orn2-Gly-Phe-Leu-] (c-ORN) and [d-Pen2, l-Cys5]-enkephalinamide (c-PEN) was investigated using a molecular modeling approach. Ring closure and conformational searching procedures were used to determine low-energy cyclic backbone conformers. Following reinsertion of amino acid side chains, the narcotic alkaloid 7α-[(1R)-1-methyl-1-hydroxy-3-phenylpropyl]-6,14-endoethenotetrahydro oripavine (PEO) was used as a flexible template for bimolecular superpositions with each of the determined peptide ring conformers using the coplanarity and cocentricity of the phenolic rings as the minimum constraint. A vector space of PEO, accounting for all possible orientations for the C21-aromatic ring of PEO served as a geometrical locus for the aromatic ring of the Phe4 residue in the opioid peptides. Although a vast number of polypeptide conformations satisfied the criteria of the opiate pharmacophore, they could be grouped into three classes differing in magnitude and sign of the torsional angle values of the tyrosyl side chain. Only class III conformers for both c-ORN and c-PEN, having tyramine dihedral angles χ1 =−150° ± 30° and χ2=−155° ± 20°, had significant structural and conformational properties that were mutually compatible while respecting the PEO vector space. Comparison of these properties in the context of the divergent receptor selectivity of the studied opioid peptides suggests that the increased distortion of the peptide backbone in the closure region of c-PEN together with the pendant β,β-dimethyl group, combine to generate a steric volume which is absent in c-ORN and that may be incompatible with a restrictive topography of the μ receptor. The nature and stereo-chemistry of substituents adjacent to the closure region of the peptides could also modulate receptor selection by interacting with a charged (δ) or neutral (μ) subsite.

Rigidified acetylcholine mimics: conformational requirements for binding to neuronal nicotinic receptors.

Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60 degrees, C-C-O-C=180 degrees ) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low microM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the alpha-bungarotoxin sensitive subclass. We also report few compounds with microM affinity for the alpha-bungarotoxin sensitive subclass.

Insertion of the methylene-oxy surrogate of the amide bond into Boc-Val-Leu-OH: X-ray crystal structure, solution conformation and molecular modelling study

The conformational features associated with the introduction of the methylene-oxy surrogate of the amide bond were explored by studying the crystal and solution conformation of the related model peptides Boc-Val-Leu-OH (1) and Boc-Val-ψ(CH2O)-Leu-OH (2). Two independent molecular conformations were found for 1 in the crystal state whereas one was found for its congener 2. In compound 2 the dihedral angle defined by Cα–CH2–O–Cα(ω′) adopts a value of –165.7(3)°, close to the situation encountered in the classical amide bond. 2D NOE NMR studies suggest that the preferred backbone conformation of 2 in [2H6]DMSO correlates with the crystal structure whereas the preferred backbone conformation of 1 in [2H6]DMSO showed a departure from its crystalline conformation. Molecular mechanics computations demonstrate the effect of the short C(sp3)–O(sp3) bond in compound 2 in dictating the preferred dihedral angle values adopted by ω′ and φLeu.

S-p-methylbenzyl-β-phenylcysteine: a potential tool for probing receptor topologies

erythro and threo N-Acetyl-S-p-methylbenzyl-β-phenyl-DL-cysteine methyl esters were obtained by addition of p-methyltoluene-α-thiol to 4-benzylidene-2-methyloxazol-5-one in methanol–tetrahydrofuran under basic conditions. The diastereoisomers were separated as their methyl esters by fractional crystallization and the relative configuration assigned by X-ray crystallography. Both diastereoisomers were converted into their N-trifluoroacetyl derivatives and resolved using Carboxypeptidase A. Hydrazinolysis of the unchanged N-trifluoroacetyl amino acids gave the other enantiomers of the free amino-acids. Optical purity was determined using Eu(hfc)3 chemical shift reagent on N-trifluoroacetyl-D-amino acid methyl ester by both 1H and 19F NMR spectra. We discuss the conformation of this unique amino acid based on X-ray data and molecular mechanics calculations. Its usefulness in probing the opiate receptor site is also demonstrated.