Thiasugars: potential glycosidase inhibitors.
The inhibitory activities against glycosidases of synthetic thiasugars, the ring sulfur analogs of carbohydrate, were surveyed with a special emphasis on our own studies. 5-Thio-L-fucose, the ring sulfur analog of L-fucose, was the first thiopyran that shows a K(i) value in the micromolar range against a glycosidase. The structure-activity relationship studies for the fucosidase inhibition by 5-thio-L-fucose disclosed that a hydrophobic interaction between the ring sulfur atom and the enzyme is responsible for the strong binding. The syntheses and activities of di- and trisaccharide analogs incorporating thiasugars are also outlined. These oligosaccharide analogs are glycosidase-resistant and some of them show strong binding to antibodies or lectins. We created a sulfylimine compound having a thiafuran structure as a transition-state analog inhibitor of glucosidases and found that it has a weak inhibition against a glucosidase. The same thiafuran structure could be found in a natural product, salacinol, which was isolated and elucidated to be a strong glucosidase inhibitor by another group. A study of the structure-activity relationship using the synthetic analogs of salacinol indicated the relevance of both the sulfonium ion in the thiafuran ring and its intramolecular counter anion, sulfate, to the inhibition activity.
Yuasa
Hideya
H
Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Midoriku, Yokohama, Japan. hyuasa@bio.titech.ac.jp
Izumi
Masayuki
M
Hashimoto
Hironobu
H
D002240:Carbohydrate Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005643:Fucose / Q000031:analogs & derivatives* / Q000737:chemistry; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry*
C119490:5-thiofucose; D004791:Enzyme Inhibitors; D013457:Sulfur Compounds; D005643:Fucose; D006026:Glycoside Hydrolases