1-Deoxy-D-galactonojirimycins with dansyl capped N-substituents as β-galactosidase inhibitors and potential probes for GM1 gangliosidosis affected cell lines

Carbohydr Res. 2011 Sep 6;346(12):1592-8. doi: 10.1016/j.carres.2011.05.010. Epub 2011 May 24.

Abstract

Two simple and reliably accessible intermediates, N-carboxypentyl- and N-aminohexyl-1-deoxy-D-galactonojirimycin were employed for the synthesis of a set of terminally N-dansyl substituted derivatives. Reaction of the terminal carboxylic acid of N-carboxypentyl-1-deoxy-D-galactonojirimycin with N-dansyl-1,6-diaminohexane provided the chain-extended fluorescent derivative. Employing bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained. Partially protected N-aminohexyl-1-deoxy-D-galactonojirimycin served as intermediate for two additional chain-extended fluorescent 1-deoxy-D-galactonojirimycin (1-DGJ) derivatives featuring terminal dansyl groups in the N-alkyl substituent. These new compounds are strong inhibitors of d-galactosidases and may serve as leads en route to pharmacological chaperones for GM1-gangliosidosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / chemical synthesis
  • 1-Deoxynojirimycin / pharmacology
  • Animals
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Cats
  • Cell Line
  • Dansyl Compounds / chemistry*
  • Diamines / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / pharmacology
  • Gangliosidosis, GM1 / drug therapy
  • Gangliosidosis, GM1 / enzymology*
  • Gangliosidosis, GM1 / physiopathology
  • Humans
  • Imines / chemistry
  • Kinetics
  • Lysosomes / metabolism
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / pharmacology
  • Molecular Probes / chemical synthesis
  • Molecular Probes / pharmacology
  • Molecular Targeted Therapy
  • Phosphatidylcholines / chemistry*
  • Plant Proteins / antagonists & inhibitors
  • Plant Proteins / chemistry
  • Plant Proteins / metabolism*
  • Sugar Alcohols / chemistry
  • beta-Galactosidase* / antagonists & inhibitors
  • beta-Galactosidase* / chemistry
  • beta-Galactosidase* / metabolism

Substances

  • 1-deoxy-D-galactohomonojirimycin
  • 1-myristoyl-2-(12-((5-dimethylamino-1-naphthalenesulfonyl)amino)dodecanoyl)-sn-glycero-3-phosphocholine
  • Bacterial Proteins
  • Dansyl Compounds
  • Diamines
  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Imines
  • Molecular Chaperones
  • Molecular Probes
  • Phosphatidylcholines
  • Plant Proteins
  • Sugar Alcohols
  • 1-Deoxynojirimycin
  • beta-Galactosidase
  • 1,6-diaminohexane