Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4- epi-Isofagomine

Molecules. 2020 Sep 3;25(17):4025. doi: 10.3390/molecules25174025.


Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

Keywords: 4-epi-isofagomine; GM1-gangliosidosis; aminocyclopentane; carbasugar; galactosidase inhibitor; iminoalditol; pharmacological chaperone.

MeSH terms

  • Crystallization
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Galactosidases / antagonists & inhibitors
  • Galactosidases / metabolism*
  • Humans
  • Imino Pyranoses / chemical synthesis
  • Imino Pyranoses / chemistry
  • Imino Pyranoses / pharmacology*
  • Ligands
  • Lysosomes / drug effects
  • Lysosomes / enzymology*
  • Molecular Chaperones / metabolism*
  • Molecular Conformation
  • Mutant Proteins / metabolism


  • Cyclopentanes
  • Enzyme Inhibitors
  • Imino Pyranoses
  • Ligands
  • Molecular Chaperones
  • Mutant Proteins
  • isofagomine
  • Galactosidases