Spirocyclopropyl pyrrolidines as a new series of alpha-L-fucosidase inhibitors.
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 alpha-L-fucosidase from bovine kidney (Ki=1.6 microM, competitive).
Laroche
Christophe
C
Laboratoire Réactions Sélectives et Applications, Université de Reims Champagne-Ardenne, UMR URCA/CNRS 6519, UFR Sciences, BP 1039, F-51687 Reims Cedex 2, France.
Behr
Jean-Bernard
JB
Szymoniak
Jan
J
Bertus
Philippe
P
Schütz
Catherine
C
Vogel
Pierre
P
Plantier-Royon
Richard
R
D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013141:Spiro Compounds; D005644:alpha-L-Fucosidase