C-3 branched δ-3,5-cis- and trans-THF sugar amino acids: synthesis of the first generation of branched homooligomers.

This article describes the efficient synthesis of the first generation of branched sugar amino acid (SAA) oligomers in solution phase via two main routes: by the use of a standard coupling reagent and via the use of active ester intermediates. Benzyl-protected dimeric carbopeptoid and methyl-protected dimeric and tetrameric, hexameric and octameric carbopeptoids were obtained from a branched δ-3,5-trans-tetrahydrofuran (THF) SAA and methyl-protected dimeric and tetrameric carbopeptoids were synthesised from a branched δ-3,5-cis-THF SAA. These systems are of interest because of their potential to display foldameric properties reminiscent of those observed in α-peptides and proteins.

Penta-fluoro-phenyl (3R,4R,5S)-5-{[(3R,4R,5S)-5-azido-methyl-3,4-dimeth-oxy-2,3,4,5-tetra-hydro-furan-3-carboxamido]-meth-yl}-3,4-dimeth-oxy-2,3,4,5-tetra-hydro-furan-3-carboxyl-ate.

The title compound, C(22)H(25)F(5)N(4)O(9), is a stable penta-fluoro-phenyl ester inter-mediate in the synthesis of novel homo-oligomeric structures containing branched carbon chains. The structure is epimeric to the previously characterized dimeric penta-fluoro-phenyl ester with stereochemistry (3R,4R,5R), which was synthesized using d-ribose as starting material. The crystal structure of the title mol-ecule removes any ambiguities arising from the relative stereochemistries of the six chiral centres.

Spectroscopic studies of oligomers containing 2,5-trans furanoid sugar amino acids.

Sugar amino acids and their oligomers, known as carbopeptoids, are commonly studied as foldamers. However, study of their conformational preference is often challenging when the adopted conformations are extended and/or disordered. This study is the first to explore the disordered nature of such carbopeptoids by utilizing a family of 2,5-trans carbopeptoids.

Raman optical activity and circular dichroism reveal dramatic differences in the influence of divalent copper and manganese ions on prion protein folding.

The binding of divalent copper ions to the full-length recombinant murine prion protein PrP23-231 at neutral pH was studied using vibrational Raman optical activity (ROA) and ultraviolet circular dichroism (UV CD). The effect of the Cu2+ ions on PrP structure depends on whether they are added after refolding of the protein in water or are present during the refolding process. In the first case ROA reveals that the hydrated alpha-helix is lost, with UV CD revealing a drop from approximately 25% to approximately 18% in the total alpha-helix content.

Residual structure in disordered peptides and unfolded proteins from multivariate analysis and ab initio simulation of Raman optical activity data.

Vibrational Raman optical activity (ROA), measured as a small difference in the intensity of Raman scattering from chiral molecules in right- and left-circularly polarized incident light, or as the intensity of a small circularly polarized component in the scattered light, is a powerful probe of the aqueous solution structure of proteins. The large number of structure-sensitive bands in protein ROA spectra makes multivariate analysis techniques such as nonlinear mapping (NLM) especially favorable for determining structural relationships between different proteins. We have previously used NLM to map a large dataset of peptide, protein, and virus ROA spectra into a readily visualizable two-dimensional space in which points close to or distant from each other, respectively, represent similar or dissimilar structures.

Delineation of protein structure classes from multivariate analysis of protein Raman optical activity data.

Vibrational Raman optical activity (ROA), measured as a small difference in the intensity of Raman scattering from chiral molecules in right and left-circularly polarized incident light, or as the intensity of a small circularly polarized component in the scattered light, is a powerful probe of the aqueous solution structure of proteins. On account of the large number of structure-sensitive bands in protein ROA spectra, multivariate analysis techniques such as non-linear mapping (NLM) are especially favourable for determining structural relationships between different proteins. Here NLM is used to map a dataset of 80 polypeptide, protein and virus ROA spectra, considered as points in a multidimensional space with axes representing the digitized wavenumbers, into readily visualizable two and three-dimensional spaces in which points close to or distant from each other, respectively, represent similar or dissimilar structures.

Classification of conformation for sugar amino acid systems using chiroptical spectroscopy.

A number of structurally related sugar amino acid systems have been examined by chiroptical methods to aid interpretation of their conformational preference. The use of circular dichroism, in addition to NMR and solution IR, has enabled classification of the conformations adopted by sugar amino acid systems as hydrogen-bonded regular, non-hydrogen-bonded regular, and non-hydrogen-bonded irregular. A set of tetrameric SAAs are examined and the effect of change in primary structure related to conformation.

Raman optical activity of proteins, carbohydrates and glycoproteins.

On account of its sensitivity to chirality, Raman optical activity (ROA), which may be measured as a small difference in the intensity of vibrational Raman scattering from chiral molecules in right- and left-circularly polarized incident light, or as the intensity of a small circularly polarized component in the scattered light, is a powerful probe of the structure of biomolecules. Protein ROA spectra provide information on secondary and tertiary structures of polypeptide backbones, backbone hydration and side-chain conformations, and on structural elements present in unfolded states. Carbohydrate ROA spectra provide information on the central features of carbohydrate stereochemistry, especially that of the glycosidic link.

Conformational studies of oligomeric oxetane-based dipeptide isosteres derived from L-rhamnose or D-xylose.

Conformational investigations have been undertaken on oligomers (dimers, tetramers, hexamers) of five closely related oxetane-based dipeptide isosteres. All the oligomers were subjected to a range of studies by NMR, FT-IR and CD spectroscopy. The oligomers derived from methyl 2,4-anhydro-5-azido-3-O-tert-butyldimethylsilyl-5-deoxy-L-rhamnonate 'monomer' all exhibited evidence of ordered conformations in chloroform and 2,2,2-trifluoroethanol (TFE) solution.

Structure, electronic circular dichroism and Raman optical activity in the gas phase and in solution: a computational and experimental investigation.

A computational (ab initio and molecular dynamics) and experimental exploration of the relative importance of molecular conformation and explicit solvent effects on the electronic circular dichroism (ECD) of chiral molecules, is presented. The exploration includes an assessment of the validity of angular correlation (sector) rules linking ECD to molecular conformation. It is based upon studies of 1-(R) phenylethanol (including its Raman optical activity spectrum), the corresponding 'benchmark' base, 1-(R)-phenylethylamine and its protonated cation; their hydrated clusters in the gas phase; and their non-polar and aqueous solutions.

Circular dichroism studies of carbopeptoid-cyclodextrins.

A series of sugar amino acids, based on open chain sugars, have been oligomerised and cyclised. The resulting cyclic carbopeptoids have been examined for desirable properties such as host-guest chemistry (as in cyclodextrins) or self-assembling properties (e.g.

Helix-forming carbohydrate amino acids.

[reaction: see text] The solution-phase conformational properties of tetrameric and octameric chains of C-glycosyl alpha-d-lyxofuranose configured tetrahydrofuran amino acids (where the C-2 and C-5 substituents on the tetrahydrofuran ring are trans to each other) were examined using NMR and IR and CD in organic solvents. Studies by NMR and IR demonstrated that in chloroform solution, the tetramer 7 does not adopt a hydrogen-bonded conformation whereas the octamer 10 populates a well-defined helical secondary structure stabilized by 16-membered (i, i - 3) interresidue hydrogen bonds, similar to a pi-helix. Circular dichroism studies in trifluoroethanol are consistent with this conformation for the octamer 10, and also indicate that the tetramer 7 adopts a rigid conformation not stabilized by hydrogen bonds.

Determination of drug-plasma protein binding kinetics and equilibria by chromatographic profiling: exemplification of the method using L-tryptophan and albumin.

Drug-plasma protein binding may greatly influence the bioavailability and metabolism of a plasma-borne drug, the bound form being partially protected from the metabolic fate of the unbound drug. Traditionally, equilibrium values (e.g.