Synthesis of pentopyranosyl-containing thiodisaccharides. Inhibitory activity against beta-glycosidases.
Beta-(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-(beta-D-Xylp)-4-thiohexopyranosid-2-ulose (3) and benzyl per-O-acetyl-3-deoxy-4-S-(beta-D-Galp)-4-thiopentopyranosid-2-ulose (11) were obtained in almost quantitative yields. The carbonyl function of these uloses was reduced with NaBH(4) 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 NaBH(4)-THF at 0 degrees C gave a 3-deoxy-4-S-(beta-D-Xylp)-4-thio-alpha-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-beta-D-threo-pentopyranoside derivative 14, which was the only product isolated (80% yield) in the reduction with K-Selectride in THF at -78 degrees 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 beta-galactosidase from Escherichia coli. Thus, compound 18 proved to be a non-competitive inhibitor of the enzyme (K(i)=0.80 mM), whereas 19 was a mixed-type inhibitor (K(i)=32 microM).
Cagnoni
Alejandro J
AJ
CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428-Buenos Aires, Argentina.
Uhrig
María Laura
ML
Varela
Oscar
O
D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013696:Temperature; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004187:Disaccharides; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D001617:beta-Glucosidase; D001616:beta-Galactosidase