Farnesyltransferase inhibitors: CAAX mimetics based on different biaryl scaffolds

Valentina Straniero, Marco Pallavicini, Giuseppe Chiodini, Paola Ruggeri, Laura Fumagalli, Cristiano Bolchi, Alberto Corsini, Nicola Ferri, Chiara Ricci, Ermanno Valoti

Research output: Contribution to journalArticlepeer-review

Abstract

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed as farnesyltransferase (FTase) inhibitors (FTIs) by replacing AA with o-aryl or o-heteroaryl substituted p-hydroxy- or p-aminobenzoic acid, while maintaining the replacement of C with 1,4-benzodioxan-2-ylmethyl or 2-amino-4- thiazolylacetyl residue as in previous CAAX mimetics. Both FTase inhibition and antiproliferative effect were showed by two thiazole derivatives, namely those with 1-naphthyl (10 and 10a) or 3-furanyl (15 and 15a) in the central spacer, and by the benzodioxane derivative with 2-thienyl (6 and 6a) in the same position. Accumulation of unprenylated RAS was demonstrated in cells incubated with 15a. Consistently with FTIs literature, such results delineate the biaryl scaffold not only as a spacer but also as a sensible area of these mimetic molecules, where modifications at the branching aromatic ring are not indifferent and should be matter of further investigation.

Original languageEnglish
Pages (from-to)2924-2927
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number13
DOIs
Publication statusPublished - Jul 1 2014

Keywords

  • 2-Aminothiazole
  • Benzodioxane
  • FTase inhibitor
  • Mimetic
  • RAS protein

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

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