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

V. E. MANZANO; M.L. UHRIG; O. VARELA

ORGANIC & BIOMOLECULAR CHEMISTRY

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2012 vol. 10 p. 8884 - 8894

1477-0520

The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-b-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 b-D-Galp-S-(1-4)-4-thio-a-D-Glcp-O-iPr (10). Analogues of the 4-thiolactoside 10 have been prepared, with the b-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-Oacetyl-3,4-epithio-a-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 b-D-Galp or b-D-Galf afforded the corresponding branched dithiotrisaccharides. The free compounds were evaluated as inhibitors of the E. coli b-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 (Ki = 95 μM).