RESUMO
Monosaccharide derivatives having a double bond conjugated to a carbonyl (sugar enones or enuloses) are relevant synthetic tools. They are also suitable starting materials, or versatile intermediates, for the synthesis of a wide variety of natural or synthetic compounds with a broad spectrum of biological and pharmacological activities. The preparation of enones is mainly focused on the search for more efficient and diastereoselective synthetic methodologies. The usefulness of enuloses relies on the diverse reaction possibilities offered by alkene and carbonyl double bonds, which are prone to undergo varied reactions such as halogenation, nitration, epoxidation, reduction, addition, etc. The addition of thiol groups that led to sulfur glycomimetics, such as thiooligosaccharides, is particularly relevant. Therefore, the synthesis of enuloses and the Michael addition of sulfur nucleophiles to give thiosugars or thiodisaccharides are discussed here. Chemical modifications of the conjugate addition products to afford biologically active compounds are also reported.
Assuntos
Açúcares , Tioaçúcares , Carboidratos , AlcenosRESUMO
Fluoroalkyl-substituted carbohydrates play relevant roles in diverse areas such as supramolecular chemistry, glycoconjugation, liquid crystals, and surfactants, with direct applications as wetting, antifreeze, and coating agents. In light of these promising applications, new methodologies for the late-stage incorporation of fluoroalkyl RF groups into carbohydrates and derivatives are herein presented as they are relevant to the synthetic carbohydrate community. Previously reviewed protocols for the installation of RF groups onto carbohydrates and derivatives will be succinctly summarized in the light of the new achievements. Fluoroalkyl-substituted iminosugars, on the other hand, are also interesting glycomimetic derivatives with prominent roles as glycosidases and glycosyltransferases inhibitors, as has recently been demonstrated. Also, they positively contribute to the study of sugar-protein interactions and enzyme mechanisms. New advances in the syntheses of fluoroalkyl-substituted iminosugars will also be presented here.
Assuntos
Fluorocarbonos , Tioaçúcares , Carboidratos , Glicosídeo Hidrolases , PiranosRESUMO
The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-ß-D-galactopyranose (7) as a nucleophile led to (1 â 3)- and (1 â 4)-thiodisaccharides. High regio- and diastereoselectivities were achieved in the synthesis of the per-O-acetyl derivative of the ß-D-Galp-S-(1 â 4)-4-thio-α-D-Glcp-O-iPr (10). Analogues of the 4-thiolactoside 10 have been prepared, with the ß-D-Galp non-reducing end S-linked to D-Glcp, D-Gulp and D-Idop. A similar regioselective attack of 7 on C-4 of 2-propyl 3,6-di-O-acetyl-3,4-epithio-α-D-galactopyranoside (6) led to 2-propyl 3,4-dithiolactoside derivative 15. During this reaction the free 3-SH group of 15 underwent oxidative dimerization or oxidative coupling with the SH function of 7 to give the respective disulfides. Glycosylation of the thiol group of 15 using trichloroacetimidate derivatives of ß-D-Galp or ß-D-Galf afforded the corresponding branched dithiotrisaccharides. The free compounds were evaluated as inhibitors of the E. coli ß-galactoside. The bis(2-propyl 3,4-dithiolactosid-3-yl)-disulfide, obtained from 15, displayed the strongest inhibitory activity in these series of glycomimetics and proved to be a non-competitive inhibitor (K(i) = 95 µM).
Assuntos
Escherichia coli/enzimologia , Lactose/análogos & derivados , Lactose/farmacologia , Tioaçúcares/química , Tioaçúcares/farmacologia , beta-Galactosidase/antagonistas & inibidores , Dissulfetos/síntese química , Dissulfetos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Lactose/síntese química , Modelos Moleculares , Tioaçúcares/síntese químicaRESUMO
The synthesis of multivalent glycoclusters, designed to be compatible with biological systems, is reported. A variety of 1-thio-ß-D-galactosides linked to a terminal triple bond through oligoethyleneglycol chains of variable lengths has been synthesized. Also, azide-containing oligosaccharide scaffolds were prepared from trehalose, maltose, and maltotriose by direct azidation with NaN(3)/PPh(3)/CBr(4). Click reaction between the thiogalactoside residues and the azide scaffolds under microwave irradiation afforded a family of glycoclusters containing 1 to 4 residues of 1-thio-ß-D-galactose. The yields went from moderate to excellent, depending on the valency of the desired product. Deacetylation with Et(3)N/MeOH/H(2)O led to the final products. Complete characterization of the products was performed by NMR spectroscopy and HR-MS techniques. Their activities as inhibitors of ß-galactosidase from E. coli were determined by using the Lineweaver-Burk method. The use of hydrophilic carbohydrate scaffolds for the synthesis of multivalent galactosides represents an interesting approach to improve their pharmacokinetics and bioavailability. In addition, the presence of the thioglycosidic bond will improve their stability in biological fluids.