Synthesis of pentopyranosyl-containing thiodisaccharides. Inhibitory activity against β-glycosidases

ALEJANDRO J. CAGNONI; MARÍA LAURA UHRIG; OSCAR VARELA

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2009 vol. 17 p. 6203 - 6212

0968-0896

β-(1→4)-Thiodisaccharides formed by a pentopyranose unit as reducing or non reducing end have been synthesized using a sugar enone derived from a hexose or pentose as Michael acceptor of a 1-thiopentopyranose or 1-thiohexopyranose derivatives. Thus, 2-propyl per-O-acetyl-3-deoxy-4-S-(β-D-Xylp)-4-thiohexopyranosid-2-ulose (3) and benzyl per-O-acetyl-3-deoxy-4-S-(β-D-Galp)-4-thiopentopyranosid-2-ulose (11) were obtained in almost quantitative yields. The carbonyl function of these uloses was reduced with NaBH4 or K-Selectride, and the stereochemical course of the reduction was highly dependent on the reaction temperature, reducing agent and solvent. Unexpectedly, reduction of 3 with NaBH4-THF at 0 °C gave a 3-deoxy-4-S-(β-D-Xylp)-4-thio-α-D-ribo-hexopyranoside derivative (6) as major product (74% yield), with isomerization of the sulfur-substituted C-4 stereocenter of the pyranone. Reduction of 11 gave always as major product the benzyl 3-deoxy-4-S-(Galp)-4-thio-β-D-threo-pentopyranoside derivative 14, which was the only product isolated (80% yield) in the reduction with K-Selectride in THF at -78 °C. Deprotection of 14 and its epimer at C-2 (13) afforded respectively the free thiodisaccharides 19 and 18. They displayed strong inhibitory activity against the β-galactosidase from E. coli. Thus, compound 18 proved to be a non-competitive inhibitor of the enzyme (Ki = 0.80 mM), whereas 19 was a mixed-type inhibitor (Ki = 32 M).