Convenient synthesis of 4-thiolactose, 3,4-dithiolactose and related thiooligosaccharides and disulfides. Inhibitory activity of the glycomimetics against a ß-galactosidase

VERÓNICA E. MANZANO; MARÍA LAURA UHRIG; OSCAR VARELA

ORGANIC & BIOMOLECULAR CHEMISTRY

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2012 vol. 10 p. 8884 - 8888

1477-0520

The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranose (7) as 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. Similar regioselective attack of 7 to 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 1-SH 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 glycomimetics were evaluated as inhibitors of the E. coli β-galactoside. The symmetric disulfide bis-(2-propyl 3,4-dithiolactosid-3-yl)-disulfide, obtained from 15, displayed the stronger inhibitory activity of these series of thioglycomimetics and proved to be a non-competitive inhibitor of the enzyme (Ki = 95 microM).