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New synthetic routes to chain-extended selenium, sulfur, and nitrogen analogues of the naturally occurring glucosidase inhibitor salacinol and their inhibitory activities against recombinant human maltase glucoamylase.
- Source :
-
The Journal of organic chemistry [J Org Chem] 2007 Aug 17; Vol. 72 (17), pp. 6562-72. Date of Electronic Publication: 2007 Jul 21. - Publication Year :
- 2007
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Abstract
- Six heteroanalogues (X = S, Se, NH) of the naturally occurring glucosidase inhibitor salacinol, containing polyhydroxylated, acyclic chains of 6-carbons, were synthesized for structure-activity studies with different glycosidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-seleno-, 1,4-anhydro-4-thio-, and 1,4-anhydro-4-imino-D-arabinitols at the least hindered carbon atom of 1,3-cyclic sulfates. These 1,3-cyclic sulfates were derived from D-glucose and D-galactose, and significantly, they utilized butane diacetal as the protecting groups for the trans 2,3-diequatorial positions. Deprotection of the coupled products proceeded smoothly, unlike in previous attempts with different protecting groups, and afforded the target selenonium, sulfonium, and ammonium sulfates with different stereochemistry at the stereogenic centers. The four new heterosubstituted compounds (X = Se, NH) inhibited recombinant human maltase glucoamylase (MGA), one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine. The two selenium derivatives each had Ki values of 0.10 microM, giving the most active compounds to date in this general series of zwitterionic glycosidase inhibitors. The two nitrogen compounds also inhibited MGA but were less active, with Ki values of 0.8 and 35 microM. The compounds in which X = S showed Ki values of 0.25 and 0.17 microM. Comparison of these data with those reported previously for related compounds reinforces the requirements for an effective inhibitor of MGA. With respect to chain extension, the configurations at C-2' and C-4' are critical for activity, the configuration at C-3', bearing the sulfate moiety, being unimportant. It would also appear that the configuration at C-5' is important but the relationship is dependent on the heteroatom.
- Subjects :
- Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Humans
Magnetic Resonance Spectroscopy
Recombinant Proteins antagonists & inhibitors
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Sugar Alcohols chemistry
Sugar Alcohols pharmacology
Sulfates chemistry
Sulfates pharmacology
Enzyme Inhibitors chemical synthesis
Glycoside Hydrolase Inhibitors
Nitrogen chemistry
Selenium chemistry
Sugar Alcohols chemical synthesis
Sulfates chemical synthesis
Sulfur chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3263
- Volume :
- 72
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- The Journal of organic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17658854
- Full Text :
- https://doi.org/10.1021/jo071045m