Cristina Vicent

A Synthetic Lectin for O-Linked β-N-Acetylglucosamine†

Changing employment: Receptor 1 binds beta-N-acetylglucosaminyl (beta-GlcNAc) up to 100 times more strongly than it does glucose. This synthetic lectin shows affinities similar to wheat germ agglutinin (WGA), a natural lectin used to bind GlcNAc. Remarkably, 1 is more selective than WGA. It favors especially the glycoside unit in glycopeptide 2, a model of the serine-O-GlcNAc posttranslational protein modification.

Carbohydrate Hydrogen‐Bonding Cooperativity − Intramolecular Hydrogen Bonds and Their Cooperative Effect on Intermolecular Processes − Binding to a Hydrogen‐Bond Acceptor Molecule

The high hydroxy (OH) group content in carbohydrates makes the study of carbohydrate OH···XH and OH···X H-bond energetics fundamental to understanding of carbohydrate recognition. There is, however, a relative lack of knowledge concerning the factors that allow a carbohydrate to participate in recognition events stabilised by intermolecular H bonds. We therefore present here a systematic study on the factors that determine the formation of a well-defined intramolecular H-bonding network between carbohydrate hydroxy groups, and its cooperative or anti-cooperative influence on selected intermolecular processes mediated by H bonds. With this in mind, we first determined the H-bonding networks of a series of carbohydrate derivatives − monoalcohols, 1,2- and 1,3-diols and amidoalcohols − by 1H NMR and FT-IR spectroscopy. The hydroxy groups of these compounds showed different abilities to form intramolecular H bonds, depending on their relative positions and configurations on the pyranose ring, and on the nature of the adjacent functional groups. It has also been shown that both the directionality and strength of the intramolecular H-bonding network of a carbohydrate govern the formation of cooperative or anti-cooperative H-bond centres, with consequent repercussions on the thermodynamics of the intermolecular H-bonding interactions of the carbohydrate in question. From this study, some general rules for the prediction of the intramolecular H-bonding network characteristics of a given carbohydrate and its influence on the energetics of intended intermolecular recognition processes have been inferred. The results presented here give a new perspective over understanding of the role of the H-bonding interactions in carbohydrate recognition and have fundamental implications for the rational design of glycoconjugates incorporating H-bonding motifs with geometrical and electronic complementarity to given receptor molecules.

Investigation of the Hydrogen Bonding Properties of a Series of Monosaccharides in Aqueous Media by 1H NMR and IR Spectroscopy

A technique, based on 1H NMR and IR experiments, to characterise intramolecular hydrogen bonds in aqueous medium in a series of amino, amido and ammonium sugar derivatives has been established. Three groups of molecules, representing amides (4, 5 and 6), amines (7 and 8) and ammonium salts (chlorides 9 and 10, and phosphates 11 and 12), with different relative configurations of their functional groups, have been investigated to assess the effect of the nature and the stereochemistry of these groups on the hydrogen-bonding features of the sugar. The deduced features in water solution are compared to those obtained previously in nonpolar solvents. The phosphate salts of amines 7 and 8 (11 and 12) were also prepared, in order to evaluate the influence of the OH groups on the binding of the phosphate counterion, and the possibility of establishing cooperative hydrogen bonds involving the phosphate group. The data presented here indicate that the 1,3-cis-diaxial-type configuration in sugar diols and amino alcohols produces an intramolecular six-membered-ring hydrogen bond that survives in water and, moreover, offers the possibility to establish cooperative intermolecular hydrogen bonds. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Experimental Evidence for the Existence of Non-exo-Anomeric Conformations in Branched Oligosaccharides: NMR Analysis of the Structure and Dynamics of Aminoglycosides of the Neomycin Family

It is commonly known that the exo-anomeric effect is a major factor governing the conformational behavior of naturally occurring oligosaccharides. Conformational flexibility in these molecules mainly concerns the aglycon psi angle since phi is restricted by this stereo-electronic effect. In fact, to the best of our knowledge no case of a natural glycoside adopting a non-exo-anomeric conformation in solution has yet been reported. With respect to the flexibility among naturally occurring carbohydrates, branched type oligosaccharides including sugar residues glycosidated at contiguous positions (such as blood type carbohydrate antigens Lewis X) have been considered as the paradigm of rigid saccharides--the rigidity being enhanced by van der Waals interactions. Herein, we demonstrate unambiguously that both common beliefs are not to be generalized. For example in neomycin B, a branched oligosaccharide antibiotic, a large number of non-exo-anomeric conformations was detected in solution for the first time in naturally occurring sugars. This unusual behavior is attributed to branching. Here, polar contacts between non-vicinal sugar units lead to an enhanced flexibility of the ribose glycosidic torsion phi. The influence of sugar flexibility on RNA recognition will also be discussed.

New synthetic strategy to highly symmetric chiral macrocycles from carbohydrate derivatives

Abstract A simple strategy for the synthesis of highly symmetric macrocycles incorporating carbohydrates is presented. The application of this strategy to the synthesis of optically active tetra-gluco-24-crown-8 (1), bis-gluco-15-crown-5 (3), and bis-gluco-21-crown-8 (5) is described. Preliminary studies showed that macrocycles 1, 3 and 5 complex ammonium salts. These macrocyclic compounds have been used as catalysts in the asymmetric Michael addition of methyl α-phenylacetate to methyl acrylate.

The Relevance of Carbohydrate Hydrogen‐Bonding Cooperativity Effects: A Cooperative 1,2‐trans‐Diaxial Diol and Amido Alcohol Hydrogen‐Bonding Array as an Efficient Carbohydrate–Phosphate Binding Motif in Nonpolar Media

Carbohydrates with suitably positioned intramolecularly hydrogen-bonded hydroxyl and amide groups have the potential to act as efficient bidentate phosphate binders by taking advantage of sigma- and/or ,sigma,pi-H-bonding cooperativity in nonpolar solvents. Donor-donor 1,2-trans-diaxial amido alcohol (1) and diol (3), in which one of the donor centres is cooperative, are very efficient carbohydrate-phosphate binding motifs. We have proven and quantified the key role of hydrogen-bonding centres indirectly involved in complexation, which serve to generate an intramolecular H-bond (six-membered cis H-bond) in 1 and 3. This motif enhances the donor nature of the H-bonding centres that are directly involved in complexation. A comparison of the thermodynamic parameters of the complexes formed between phosphate and a cooperative (1-Phos) or anti-cooperative (2-Phos) bidentate H-bonded motif of a carbohydrate has allowed us to quantify the energetic advantage of H-bonding cooperativity in CDCl3 and CDCl3/CCl4 (1:1.3) (Delta Delta G degrees=-2.2 and -2.0 kcal mol(-1), respectively). The solvent dependences of the entropy and enthalpy contributions to binding provide a valuable example of the delicate balance between entropy and enthalpy that can arise for a single process, providing effective cooperative binding in terms of Delta G degrees.

Sugar–Oligoamides: Synthesis of DNA Minor Groove Binders

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-minor groove DNA interactions. Here we report an efficient solution-phase synthetic strategy to obtain two broad families of sugar-oligoamides. The first type, structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group present as a substituent on the nitrogen of pyrrole B, connected to the C terminal of the oligoamide fragment. The second type, structure vector B (-Py[(CH(2))(11)OH]-γ-Py-Ind), has an alkyl chain present on the nitrogen of pyrrole B connected to the C terminal of the oligoamide fragment and has been designed to access to di- and multivalent sugar-oligoamides. By using sequential DIPC/HOBt coupling reactions, the oligoamide fragment -Py[R]-γ-Py-Ind has been constructed. The last coupling reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a BtO- ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and two types of water-soluble sugar-oligoamide ligands, with vector A structure (compounds 3-7) and with vector B structure (compound 8), was carried out.

Carbohydrate Recognition at the Minor‐Groove of the Self‐Complementary Duplex d(CGCGAATTCGCG)2 by a Synthetic Glyco‐oligoamide

The structure of a neutral glyco-conjugate β-Gal-Py-γ-Py-Ind (1), designed as a probe for analyzing sugar-DNA interactions, when bound to a self-complementary oligonucleotide duplex d(CGCG AATT CGCG)(2) has been deduced by employing (1)H NMR techniques. Analysis of the formed 1:1 complex demonstrated that the glycol ligand is bound in a hairpin-like conformation in which both pyrrole amino acid moieties are stacked, whereas the indole and the sugar residues are spatially close. The binding site is defined by the minor groove formed by the -AATT- stretch. In particular, the -Py-γ-Py- region of the ligand is sited near the A5-A6 oligonucleotide residues, whereas the indole and the sugar rings are next to the T7-T8 base pairs. More relevant, the existence of a variety of intermolecular NOE correlations permitted the close proximity of the sugar to the minor groove to be assessed, thus showing that the binding of the glycoconjugate at the minor groove is the origin of the specificity of the glycoconjugate-DNA interaction. The experimental NMR data have been combined with restrained and unrestrained molecular dynamics calculations, to provide the 3D structure of the complex.

Cooperative Hydrogen Bonding in Glyco–Oligoamides: DNA Minor Groove Binders in Aqueous Media

A strategy to create cooperative hydrogen-bonding centers by using strong and directional intramolecular hydrogen-bonding motifs that can survive in aqueous media is presented. In particular, glyco-oligoamides, a family of DNA minor groove binders, with cooperative and non-cooperative hydrogen-bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by means of NMR spectroscopy and molecular modeling methods. Indeed, two different sugar moieties, namely, β-D-Man-Py-γ-Py-Ind (1; Ind=indole, Man=mannose, Py=pyrrole) and β-D-Tal-Py-γ-Py-Ind (2; Tal=talose), were chosen according to our design. These sugar molecules should present one- or two-directional intramolecular hydrogen bonds. The challenge has been to study the conformation of the glyco-oligoamides at low temperature in physiological media by detecting the exchangeable protons (amide NH and OH resonances) by means of NMR spectroscopic analysis. In addition, two more glyco-oligoamides with non-cooperative hydrogen-bonding centers, that is, β-D-Glc-Py-γ-Py-Ind (3; Glc=glucose), β-D-Gal-Py-γ-Py-Ind (4; Gal=galactose), and the model compounds β-D-Man-Py-NHAc (5) and β-D-Tal-Py-NHAc (6) were synthesized and studied for comparison. We have demonstrated the existence of directional intramolecular hydrogen bonds in 1 and 2 in aqueous media. The unexpected differences in terms of stabilization of the intramolecular hydrogen bonds in 1 and 2 relative to 5 and 6 promoted us to evaluate the influence of CH-π interactions on the establishment of intramolecular hydrogen bonds by using computational methods. Initial binding studies of 1 and 2 with calf-thymus DNA and poly(dA-dT)2 by NMR spectroscopic analysis and molecular dynamics simulations were also carried out. Both new sugar-oligoamides are bound in the minor groove of DNA, thus keeping a stable hairpin structure, as in the free state, in which both intramolecular hydrogen-bonding and CH-π interactions are present.

Towards a molecular abacus

The solid state and solution structures of the 1 : 1 complex formed between the cyclobis(paraquat-p-phenylene) tetracationic cyclophane and 1,5-dimethoxynaphthalene has led to the successful design and characterisation by X-ray crystallography of a prototype for the construction of a molecular abacus in the shape of a 2 : 1 complex between the same cyclophane and 1,3-bis(5-hydroxy-1-naphthyloxy) propane.