Combinatorial approach to N-substituted aminocyclitol libraries by solution-phase parallel synthesis and preliminary evaluation as glucocerebrosidase inhibitors

J Comb Chem. 2007 Jan-Feb;9(1):43-52. doi: 10.1021/cc060080o.

Abstract

Libraries of N-substituted aminocyclitol derivatives of the scyllo and racemic chiro series by means of parallel solution-phase methodology with the help of robotic technology are described. Chemical diversity has been introduced by reaction of selected scaffolds with a set of aldehydes, acyl chlorides, sulfonyl chlorides, chloroformates, and amines to afford the corresponding amines, amides, sulfonamides, carbamates and ureas, respectively. The optimized methodology has proven excellent, in terms of overall purities of the resulting libraries, for the production of amides. Sulfonamides and carbamates have been obtained in slightly lower purities, while amines afforded modest results. Selected library members have been evaluated as inhibitors of recombinant glucocerebrosidase with K(i) values ranging in the low micromolar scale for the most active members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohols / chemical synthesis*
  • Alcohols / pharmacology
  • Carbamates / chemical synthesis
  • Carbamates / pharmacology
  • Combinatorial Chemistry Techniques / methods
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Glucosylceramidase / antagonists & inhibitors*
  • Hexosamines / chemical synthesis*
  • Hexosamines / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Spectrophotometry, Infrared
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology
  • Urea / analogs & derivatives
  • Urea / chemical synthesis
  • Urea / pharmacology

Substances

  • Alcohols
  • Carbamates
  • Cyclohexanes
  • Enzyme Inhibitors
  • Hexosamines
  • Sulfonamides
  • Urea
  • Glucosylceramidase
  • imiglucerase