Solid-Phase Synthesis of C-Terminal Peptide Hydroxamic Acids

摘要

Hydroxamic acids are strong metal ion chelators and represent a wide spectrum of bioactive agents with antibacterial, antifungal, and anticancer properties. In particular, they have been identified as potent inhibitors of matrix metallo-proteinases (MMPs), a family of zinc-dependent endopro-teinases involved in extracellular matrix remodeling. Hydroxamic acids have generally been synthesized in solution from nitro compounds or by acylation of hydroxylamine and its derivatives with activated carboxylic acids. Recently, solid-phase synthesis has become an important tool for production of combinatorial libraries and lead generation, and there have been several reports describing solid-phase syntheses of hydroxamic acid derivatives. In principle, hydroxamic acids may be obtained by direct cleavage of resin-bound esters with hydroxylamine derivatives; however, it has been reported that this approach does not give reproducible results. Therefore, solid-phase synthesis of hydroxamic acid derivatives generally involves either immobilization of the hydroxylamine group through a special N- or O-linkage or formation of a protected resin-bound hydroxamate. In the current report, we describe a facile approach for the synthesis of peptide hydroxamic acids based on cleavage of resin-bound thioesters. During the preparation of this manuscript, Muir et al. described preliminary results of thioester resin cleavage by different nucleophiles including hydroxylamine.