title: Isofagomine lactams, synthesis and enzyme inhibition.
abstract: The synthesis of isofagomine lactams (2-oxoisofagomines) corresponding to the biologically important hexoses is presented. The D-glucose/D-mannose analogue (3S,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (9) was synthesised in 9 steps from D-arabinose, the D-galactose analogue (3S,4S,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (10) was synthesised in 11 steps from D-arabinose and the L-fucose analogue (3R,4R,5R)-3,4-dihydroxy-5-methylpiperidin-2-one (11) was synthesised in 12 steps from L-arabinose. The three lactams 9-11 were found to be glycosidase inhibitors with micro- to nanomolar inhibition constants. The lactam 10 showed slow onset inhibition of beta-galactosidase from A. Oryzae. The rate constants for this process were determined to be k(on) = 2.55 x 10(4) M-1 s-1 and k(off) = 1.7 x 10(-3) s-1. The activation energies and standard thermodynamic functions were also determined.
authors.affiliation: Department of Chemistry, University of Aarhus, Langelandsgade 140, DK-8000 Aarhus, Denmark.
authors.forename: Vinni H
authors.initials: VH
authors.lastname: Lillelund
authors.forename: Huizhen
authors.initials: H
authors.lastname: Liu
authors.forename: Xifu
authors.initials: X
authors.lastname: Liang
authors.forename: Helmer
authors.initials: H
authors.lastname: Søhoel
authors.forename: Mikael
authors.initials: M
authors.lastname: Bols
mesh_terms: D001089:Arabinose / Q000737:chemistry; D001236:Aspergillus oryzae / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005643:Fucose / Q000737:chemistry; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D050112:Imino Pyranoses; D007700:Kinetics; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D007769:Lactams; D010880:Piperidines; C098432:isofagomine; D005643:Fucose; D001089:Arabinose; D006026:Glycoside Hydrolases