Spirocyclopropyl pyrrolidines as a new series of α- l-fucosidase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 12; pp. 4047 - 4054
• Main Authors: Laroche, Christophe, Behr, Jean-Bernard, Szymoniak, Jan, Bertus, Philippe, Schütz, Catherine, Vogel, Pierre, Plantier-Royon, Richard
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2006; Elsevier Science
• Subjects: alpha-L-Fucosidase - antagonists & inhibitors; Analytical, structural and metabolic biochemistry; Animals; Azasugars; Biological and medical sciences; Cattle; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glycosidases; Hydrolases; Inhibition; Kidney - enzymology; Medical sciences; Miscellaneous; Molecular Conformation; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Spiro compounds; Spiro Compounds - chemistry; Stereoisomerism; Structure-Activity Relationship; Inhibition; Glycosidases; Spiro compounds; Azasugars; Nitrogen heterocycle; Selectivity; Kidney; Structure activity relation; Iminoalditol; Bicyclic compound; α-L-Fucosidase; Chemical synthesis; Ungulata; Bovine; Enzyme; Enzyme inhibitor; In vitro; Spiran; Vertebrata; Mammalia; Animal; Azasugar; Hydrolases; Artiodactyla; O-Glycosidases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.02.005

Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of α- l-fucosidase from bovine kidney ( K i = 1.6 μM, competitive).