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).
Laboratoire Réactions Sélectives et Applications, Université de Reims Champagne-Ardenne, UMR URCA/CNRS 6519, UFR Sciences, BP 1039, F-51687 Reims Cedex 2, France.
Christophe
C
Laroche
Jean-Bernard
JB
Behr
Jan
J
Szymoniak
Philippe
P
Bertus
Catherine
C
Schütz
Pierre
P
Vogel
Richard
R
Plantier-Royon
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