RESUMO
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.