Solution/solid-phase synthesis of partially modified retro- and retro-inverso-ψ[NHCH(CF3)]-peptidyl hydroxamates and their evaluation as MMP-9 inhibitors

Alessandro Volonterio, Stefano Bellosta, Pierfrancesco Bravo, Monica Canavesi, Eleonora Corradi, Stefano V. Meille, Mara Monetti, Nathalie Moussier, Matteo Zanda

Research output: Contribution to journalArticle

Abstract

The synthesis of a novel family of partially modified (PM) retro-and retro-inverso-peptidyl hydroxamates, each incorporating a [CH(CF3)CH2CO] unit as a surrogate for the conventional malonyl group, has been accomplished both in solution and in solid phase. The key step is the Michael-type N-addition of free or polymer-bound α-amino hydroxamates to 3-[(E)-enoyl]-1,3-oxazolidin-2-ones, which takes place in high yields, although with low stereocontrol. This method is suitable for the preparation of combinatorial libraries of PM retro-ψNHCH(CF3)]-peptidyl hydroxamates for screening as metalloprotease inhibitors. A number of tri- and tetrapeptidyl hydroxamates were indeed obtained either in diastereomerically pure form by solution-phase synthesis followed by chromatographic purification, or as mixtures of two epimers by solid-phase synthesis and release from the resin. X-ray diffraction of a Tfm-retropeptidyl hydroxamate showed an interesting turn-like conformation with an intramolecularly hydrogen-bonded nine-membered ring, and a nearly planar geometry of the NH group bound to the CH(CF3) group. Three retro-peptidyl hydroxamates were submitted to bioassays, and displayed the capacity to reduce MMP-9 (Gelatinase B) gelatinolytic activity.

Original languageEnglish
Pages (from-to)428-438
Number of pages11
JournalEuropean Journal of Organic Chemistry
Issue number3
Publication statusPublished - 2002

Keywords

  • Fluorine
  • Matrix metalloproteinases
  • Michael additions
  • Peptidomimetics
  • Solid-phase synthesis

ASJC Scopus subject areas

  • Organic Chemistry

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    Volonterio, A., Bellosta, S., Bravo, P., Canavesi, M., Corradi, E., Meille, S. V., Monetti, M., Moussier, N., & Zanda, M. (2002). Solution/solid-phase synthesis of partially modified retro- and retro-inverso-ψ[NHCH(CF3)]-peptidyl hydroxamates and their evaluation as MMP-9 inhibitors. European Journal of Organic Chemistry, (3), 428-438.