Non-conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-bond Glycosidic Connections

Abstract

Thiooligosaccharides display inhibitory activity against glycoside hydrolases and they constitute a valuable tool for structural biology. The construction of the interglycosidic linkage, in which the oxygen atom is replaced by sulfur, usually involves one of the following reactions: i) nucleophilic displacement of good leaving groups in a carbohydrate moiety by a sugar thiol, ii) Michael and Michael-type additions of sugar thiols to unsaturated acceptors, iii) ring-opening of aziridines and oxiranes by thiosugars, iv) enzyme-catalyzed couplings of thiosugar moieties. The application of these reactions for the syntheses of thiooligosaccharides are surveyed, and the biological activities of the resulting products briefly described. Carbohydrate structures incorporating three-bond glycosidic linkages with two heteroatoms are uncommon in Nature. The -N-O-interglycosidic bond in the oligosaccharide part of enediyne antibiotics is partly responsible for their potent antitumor activities. The disulfide bond which plays an essential role in proteins has recently been introduced as an interglycosidic connecting motif. The sulfenamide functionality is the sulfur analog of the hydroxylamine type glycosidic linkages in calicheamicins. Novel glycosylation strategies have recently been developed by taking advantage of unconventional, three-bond glycosidic linkages to construct neoglycoproteins and other glycoconjugates which are increasingly important tools in glycobiology and drug discovery. To explore conformational preferences and molecular flexibility in these structures NMR spectroscopy, chiroptical methods and X-ray crystallography are being used, supplemented by molecular modelling calculations. The structural features will be briefly discussed with relevance to biological interactions such as enzyme binding.

Circular dichroism of diglycosyl dichalcogenides in solution and solid state

“…The solution and solidstate CD spectra of the symmetrical disulfide Ac 4 GalSSGalAc 4 (8) also showed the same pattern as those of 1-4 indicating the same helicity of these disulfides. It is noteworthy that the corresponding transitions have the same signs both in the solution and solid-state CD spectra of the disulfides 1-4 and 8, and except for some wavelength shift (n 1 ?r* of Ac 4 interglycosidic linkage and its longest wavelength transition is at 207 nm.…”

“…[1][2][3] The disulfide bond may, on the other hand, be regarded as a representative of a special connection between two sugar units via a three-bond interglycosidic linkage incorporating two heteroatoms. 4 The importance of such unusual type of glycosidic linkage was emphasized by the example of the calicheamicin-esperamicin family of antibiotics incorporating a hydroxylamine bond as an interglycosidic connection in the oligosaccharide part of the molecules. These molecules are endowed with potent antitumor activity which is due to specific cleavage of double-stranded DNA.…”

Thio-click approach to the synthesis of stable glycomimetics

“…The best-documented stable glycomimetics are the C-and S-glycosides, in which the glycosidic oxygen is replaced by a methylene group or a sulfur atom (Liu et al, 2001;Szilágyi & Varela, 2006;Witczak et al, 2007). Research efforts have also been directed toward the incorporation of a novel, stable linker comprising two or three bridging atoms in place of a native O-glycosidic bond.…”

Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics

“…S-glycosides can readily be produced either chemically [10,12,13] or enzymatically with glycoligases for thiosugars [11,14], or by using dynamic combinatorial libraries for glycosyldisulfides [15]. Interestingly, lectin-binding properties for a plant toxin and adhesion/growth-regulatory galectins have recently been revealed for digalactosyldisulfide [15].…”