Synthesis and evaluation of hydroxyproline-derived isoprenyltransferase inhibitors

Bioorg Med Chem Lett. 1999 Jul 19;9(14):2095-100. doi: 10.1016/s0960-894x(99)00342-x.

Abstract

A series of peptidomimetics based on a hydroxyproline scaffold was prepared and evaluated for inhibition of farnesyltransferase and geranylgeranyltransferase I in both enzymatic and cell-based assays. A number of analogs were potent and selective inhibitors of FTase, while one compound (22) was nonselective in the enzymatic assays but eight-fold selective for inhibition of GGTase in the cellular assay (IC50 = 0.39 microM).

MeSH terms

  • 3T3 Cells / drug effects
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Hydroxyproline / chemistry*
  • Inhibitory Concentration 50
  • Methionine / analogs & derivatives
  • Methionine / pharmacology
  • Mice
  • Molecular Mimicry
  • Peptides / chemistry*
  • Structure-Activity Relationship

Substances

  • B 956
  • Enzyme Inhibitors
  • Peptides
  • Methionine
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • Hydroxyproline