Biological Properties of D- And L-1-deoxyazasugars

J Med Chem. 2005 Mar 24;48(6):2036-44. doi: 10.1021/jm0495881.

Abstract

L-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyidonojirimycin (ido-DNJ) were prepared according to prior methods for the d-enantiomers. These enantiospecific syntheses established unambiguously the absolute configuration of naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, and gulo-DNJ. Although d-DNJ and d-galacto-DNJ are known to be powerful competitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the nM range, l-DNJ and l-galacto-DNJ were noncompetitive inhibitors of alpha-glucosidase and alpha-galactosidase, respectively, with K(i) values in the muM range. However, the azasugar mimicking the structure of the terminal sugar moiety of the natural substrate is not always an inhibitor of the glycosidase responsible for the hydrolysis. d-manno-DNJ is known as a much better inhibitor of alpha-l-fucosidase than alpha-mannosidase, while l-allo-DNJ was a better inhibitor than d-manno-DNJ of alpha-mannosidase. l-galacto-DNJ can be regarded as the 6-hydroxylated derivative of deoxyfuconojirimycin (DFJ), which is a powerful inhibitor of alpha-l-fucosidase with a K(i) value in the nM range. However, this replacement of the methyl group in DFJ by a hydroxymethyl group reduced its affinity by about 50-fold. This suggests that there is a hydrophobic region in or around the active site of alpha-l-fucosidase. It has been found that inhibitors of human lysosomal glycosidases have therapeutic potential for the corresponding lysosomal storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition of human lysosomal glycosidases by the 1-deoxyazasugars synthesized was investigated. d-galacto-DNJ is a potent inhibitor of lysosomal alpha-galactosidase (IC(50) = 90 nM) and is now being evaluated preclinically for its potential use in Fabry disease, while d-DNJ inhibiting alpha-glucosidase (IC(50) = 40 nM) potently does not appear to become a potential therapeutic agent because of additional inhibitory activity toward glycoprotein processing alpha-glucosidases. On the other hand, although l-allo-DNJ is a moderate inhibitor of alpha-mannosidase (IC(50) = 64 microM), it may become a key compound for the drug design of potential therapeutic agents for alpha-mannosidosis.

MeSH terms

  • 1-Deoxynojirimycin / chemical synthesis*
  • 1-Deoxynojirimycin / chemistry
  • 1-Deoxynojirimycin / pharmacology
  • Animals
  • Cattle
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glucan 1,4-alpha-Glucosidase / antagonists & inhibitors
  • Glucan 1,4-alpha-Glucosidase / chemistry
  • Humans
  • In Vitro Techniques
  • Lysosomes / enzymology
  • Male
  • Molecular Mimicry
  • Rats
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • alpha-Galactosidase / antagonists & inhibitors
  • alpha-Galactosidase / chemistry
  • alpha-L-Fucosidase / antagonists & inhibitors
  • alpha-L-Fucosidase / chemistry
  • alpha-Mannosidase / antagonists & inhibitors
  • alpha-Mannosidase / chemistry
  • beta-Galactosidase / antagonists & inhibitors
  • beta-Galactosidase / chemistry
  • beta-Glucosidase / antagonists & inhibitors
  • beta-Glucosidase / chemistry
  • beta-Mannosidase / antagonists & inhibitors
  • beta-Mannosidase / chemistry

Substances

  • Enzyme Inhibitors
  • 1-Deoxynojirimycin
  • beta-Glucosidase
  • alpha-Galactosidase
  • beta-Galactosidase
  • alpha-Mannosidase
  • beta-Mannosidase
  • Glucan 1,4-alpha-Glucosidase
  • alpha-L-Fucosidase