Synthesis of Enantiopure Constrained α,ß-Cycloaliphatic Cystines via Diels-Alder Reaction with Homochiral Thiazolines.

The behavior of homochiral 2,3-dihydrothiazoles, easily available from l-cysteine in Diels-Alder reaction with different dienes, "en route" to sterically constrained modified cystines, has been studied. The oxidation level of the sulfur atom of the heterocyclic ring was crucial for the course of the reaction. Whereas 2,3-dihydrothiazoles did not lead to Diels-Alder adducts, 1-oxide and 1,1-dioxide derivatives afforded the exo adduct enantiopurely in high yields and diastereoselectivities. Further elaboration of the resulting adducts provided conformationally restricted quaternary cystines. DFT calculations correctly predict both the reactivity and stereoselectivity observed experimentally.

Glycomimetics Targeting Glycosyltransferases: Synthetic, Computational and Structural Studies of Less-Polar Conjugates.

The Leloir donors are nucleotide sugars essential for a variety of glycosyltransferases (GTs) involved in the transfer of a carbohydrate to an acceptor substrate, typically a protein or an oligosaccharide. A series of less-polar nucleotide sugar analogues derived from uridine have been prepared by replacing one phosphate unit with an alkyl chain. The methodology is based on the radical hydrophosphonylation of alkenes, which allows coupling of allyl glycosyl compounds with a phosphate unit suitable for conjugation to uridine. Two of these compounds, the GalNAc and galactose derivatives, were further tested on a model GT, such as GalNAc-T2 (an important GT widely distributed in human tissues), to probe that both compounds bound in the medium-high micromolar range. The crystal structure of GalNAc-T2 with the galactose derivative traps the enzyme in an inactive form; this suggests that compounds only containing the ß-phosphate could be efficient ligands for the enzyme. Computational studies with GalNAc-T2 corroborate these findings and provide further insights into the mechanism of the catalytic cycle of this family of enzymes.

Rational Design of Glycomimetic Compounds Targeting the Saccharomyces cerevisiae Transglycosylase Gas2.

The transglycosylase Saccharomyces cerevisiae Gas2 (ScGas2) belongs to a large family of enzymes that are key players in yeast cell wall remodeling. Despite its biologic importance, no studies on the synthesis of substrate-based compounds as potential inhibitors have been reported. We have synthesized a series of docking-guided glycomimetics that were evaluated by fluorescence spectroscopy and saturation-transfer difference (STD) NMR experiments, revealing that a minimum of three glucose units linked via a ß-(1,3) linkage are required for achieving molecular recognition at the binding donor site. The binding mode of our compounds is further supported by STD-NMR experiments using the active site-mutants Y107Q and Y244Q. Our results are important for both understanding of ScGas2-substrate interactions and setting up the basis for future design of glycomimetics as new antifungal agents.

Revealing Stepwise Mechanisms in Dipolar Cycloaddition Reactions: Computational Study of the Reaction between Nitrones and Isocyanates.

The mechanism of cycloaddition reactions of nitrones with isocyanates has been studied using density functional theory (DFT) methods at the M06-2X/cc-pVTZ level of theory. The exploration of the potential energy surfaces associated with two reactive channels leading to 1,2,4-oxadiazolidin-5-ones and 1,4,2-dioxazolidines revealed that the cycloaddition reaction takes place through a concerted mechanism in gas phase and in apolar solvents but a stepwise mechanism in polar solvents. In stepwise mechanisms, the first step of the reaction is a rare case in which the nitrone oxygen acts as a nucleophile by attacking the central carbon atom of the isocyanate (interacting with the π-system of the C═O bond) to give an intermediate. The corresponding transition structure is stabilized by an attractive electrostatic interaction favored in a polar medium. The second step of the reaction is the rate-limiting one in which the formation of 1,2,4-oxadiazolidin-5-ones or 1,4,2-dioxazolidines is decided. Calculations indicate that formation of 1,2,4-oxadiazolidin-5-ones is favored both kinetically and thermodynamically independently of the solvent, in agreement with experimental observations. Noncovalent interactions (NCI) and topological analysis of the gradient field of electron localization function (ELF) bonding confirmed the observed interactions.

Recent progress on fucosyltransferase inhibitors.

Fucosyltransferases (FucTs) are enzymes that transfer L-fucose from GDP-fucose to a glycoside or a peptide. They have important roles in a variety of diseases including cancer and autoimmune disorders, viral and bacterial infections and inflammatory processes, and thus they represent important drug targets for the development of agents for the treatment of such disorders. This review highlights recent developments regarding carbohydrate mimics as inhibitors of FucTs. The most recent and relevant synthetic strategies are described.

Current developments in the synthesis and biological activity of aza-C-nucleosides: immucillins and related compounds.

This review will describe the recent advances in the field of aza-C-nucleosides with a particular emphasis on immucillins and related compounds. The review will cover both chemical and biological aspects concerning their preparation and/or occurrence in Nature as well as their biological properties which include glycosidase, glycosyl transferase, and nucleoside hydrolase and phosphorylase inhibition, among others. These enzymatic inhibitory properties are the basis for the potential use of the title compounds in viral and parasitic infections, cancer and genetic disorders.