Convenient synthesis of 4-thiolactose, 3,4-dithiolactose and related thiooligosaccharides and disulfides. Inhibitory activity of the glycomimetics against a β-galactosidase.
The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranose (7) as a nucleophile led to (1 → 3)- and (1 → 4)-thiodisaccharides. High regio- and diastereoselectivities were achieved in the synthesis of the per-O-acetyl derivative of the β-D-Galp-S-(1 → 4)-4-thio-α-D-Glcp-O-iPr (10). Analogues of the 4-thiolactoside 10 have been prepared, with the β-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 β-D-Galp or β-D-Galf afforded the corresponding branched dithiotrisaccharides. The free compounds were evaluated as inhibitors of the E. coli β-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).
CIHIDECAR-CONICET-UBA, Departamento de Química Orgánica, FCEN, Universidad de Buenos Aires, Pabellón II, Ciudad Universitaria, 1428-Buenos Aires, Argentina.
Verónica E
VE
Manzano
María Laura
ML
Uhrig
Oscar
O
Varela
D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D007785:Lactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D054330:Thiosugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors*
D004220:Disulfides; D004791:Enzyme Inhibitors; D054330:Thiosugars; D001616:beta-Galactosidase; D007785:Lactose