Isofagomine lactams, synthesis and enzyme inhibition

Org Biomol Chem. 2003 Jan 21;1(2):282-7. doi: 10.1039/b208784g.

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.

MeSH terms

  • Arabinose / chemistry
  • Aspergillus oryzae / enzymology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Fucose / chemistry
  • Glycoside Hydrolases / antagonists & inhibitors
  • Imino Pyranoses
  • Kinetics
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Models, Molecular
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Thermodynamics

Substances

  • Enzyme Inhibitors
  • Imino Pyranoses
  • Lactams
  • Piperidines
  • isofagomine
  • Fucose
  • Arabinose
  • Glycoside Hydrolases