3,8-Diazabicyclo[3.2.1]octan-2-one peptide mimetics: synthesis of a conformationally restricted inhibitor of farnesyltransferase

Org Lett. 2001 Mar 22;3(6):865-8. doi: 10.1021/ol015504w.

Abstract

A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Farnesyltranstransferase
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Peptides / chemistry*
  • Thermodynamics

Substances

  • 3,8-diazabicyclo(3.2.1)octan-2-one
  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Peptides
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase