New Ras CAAX mimetics: Design, synthesis, antiproliferative activity, and RAS prenylation inhibition

Cristiano Bolchi, Marco Pallavicini, Laura Fumagalli, Nicola Ferri, Alberto Corsini, Chiara Rusconi, Ermanno Valoti

Research output: Contribution to journalArticle

Abstract

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing cysteine (C) by 2-hydroxymethylbenzodioxane or 2-aminomethylbenzodioxane, respectively etherified and amidified with 2′-methyl or 2′-methoxy substituted 2-carboxy-4-hydroxybiphenyl and 2,4-dicarboxybiphenyl. These pluri-substituted biphenyl systems, used as internal spacer and AA dipeptide bioisoster, were linked to the methyl ester of l-methionine, glycine or l-leucine by an amide bond. The resultant twelve pairs of stereoisomers at the dioxane C-2 were tested for antiproliferative effect finding the maximum activity for derivatives with methyleneoxy linker between benzodioxane and 2′-methylbiphenyl. Of these compounds, the one with terminal methionine and S configuration proved a good Ras prenylation inhibitor in a cell-based assay.

Original languageEnglish
Pages (from-to)5500-5504
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number18
DOIs
Publication statusPublished - Sep 15 2009

Keywords

  • Antiproliferative agents
  • Antitumors
  • Peptidomimetic inhibitors
  • Prenylation inhibitors

ASJC Scopus subject areas

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

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  • Cite this

    Bolchi, C., Pallavicini, M., Fumagalli, L., Ferri, N., Corsini, A., Rusconi, C., & Valoti, E. (2009). New Ras CAAX mimetics: Design, synthesis, antiproliferative activity, and RAS prenylation inhibition. Bioorganic and Medicinal Chemistry Letters, 19(18), 5500-5504. https://doi.org/10.1016/j.bmcl.2009.07.065