Efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc) and sp(2)-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme

Eur J Med Chem. 2016 Oct 4:121:926-938. doi: 10.1016/j.ejmech.2015.10.038. Epub 2015 Oct 26.

Abstract

Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-iminosugars have been widely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta β-N-acetylglucosaminidase (β-hexosaminidase) among the epimeric series, is here described. This novel procedure can be easily scaled up, providing enough material for structural modifications and further biological tests. Thus, two series of sp(2)-iminosugar conjugates derived from DAJNAc have been prepared, namely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory activity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic strategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory potencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of the compounds towards β-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor form) were encountered. The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase.

Keywords: Hexosaminidase inhibitors; Pharmacological chaperones; Stereoselective synthesis; Tay-Sachs disease; sp(2)-iminosugars.

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / chemical synthesis
  • 1-Deoxynojirimycin / chemistry
  • 1-Deoxynojirimycin / pharmacology
  • Chemistry Techniques, Synthetic
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hexosaminidases / antagonists & inhibitors*
  • Humans
  • Imino Sugars / chemistry*
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Stereoisomerism

Substances

  • 2-acetamido-1,2-dideoxyallonojirimycin
  • Enzyme Inhibitors
  • Imino Sugars
  • 1-Deoxynojirimycin
  • Hexosaminidases