Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I

Bioorg Med Chem Lett. 2004 Feb 9;14(3):639-43. doi: 10.1016/j.bmcl.2003.11.051.

Abstract

A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Prenylation
  • Structure-Activity Relationship
  • Tumor Cells, Cultured / drug effects*
  • Tumor Cells, Cultured / enzymology

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Piperazines
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase