The first synthesis of substituted azepanes mimicking monosaccharides: a new class of potent glycosidase inhibitors.
The synthesis of the first examples of seven-membered ring iminoalditols, molecules displaying an extra hydroxymethyl substituent on their seven-membered ring compared to the previously reported polyhydroxylated azepanes, has been achieved from d-arabinose in 10 steps using RCM of a protected N-allyl-aminohexenitol as a key step. While the (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxy-azepane 10, a seven-membered ring analogue of fagomine, is a weak inhibitor of glycosidases, the (2R,3R,4R,5S,6S)-2-hydroxymethyl-3,4,5,6-tetrahydroxy-azepane 9 selectively inhibits green coffee bean alpha-galactosidase in the low micromolar range (Ki = 2.2 muM) despite a D-gluco relative configuration.
Li
Hongqing
H
Ecole Normale Supérieure, Département de Chimie, UMR 8642, 24 rue Lhomond, 75231 Paris 05, France.
Blériot
Yves
Y
Chantereau
Caroline
C
Mallet
Jean-Maurice
JM
Sollogoub
Matthieu
M
Zhang
Yongmin
Y
Rodríguez-García
Eliazar
E
Vogel
Pierre
P
Jiménez-Barbero
Jesús
J
Sinaÿ
Pierre
P
D001089:Arabinose / Q000737:chemistry; D044602:Cellulases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007097:Imines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009005:Monosaccharides / Q000737:chemistry; D013402:Sugar Alcohols / Q000737:chemistry; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D007097:Imines; D009005:Monosaccharides; D013402:Sugar Alcohols; D001089:Arabinose; D044602:Cellulases; D006026:Glycoside Hydrolases; D000520:alpha-Glucosidases; D000519:alpha-Galactosidase; D001616:beta-Galactosidase