Alpha-keto amide peptides: a synthetic strategy to resin-bound peptide isosteres for protease inhibitor screening on solid support.
A synthetic strategy for the formation of resin-bound internal alpha-keto amide peptides suitable for protease inhibitor screening on solid support is presented. This general approach is based on the incorporation of alpha-keto amide building blocks during solid-phase peptide synthesis (SPPS). Such dipeptidyl building blocks were accessible using the acylcyanophosphorane methodology. The acid-labile alpha-keto carbonyl functionality was protected as a 1,3-dithiolane derivative. This protective group is fully compatible with standard SPPS reaction conditions and can be efficiently removed with N-bromosuccinimide in 10% aqueous acetone. The alpha-keto amide peptides were assembled on SPOCC-1500 resin and were characterized with high-resolution magic angle spinning (HR-MAS) NMR on bead. The methodology was evaluated and tested with a variety of building blocks containing natural and nonnatural amino acid moieties.
Carlsberg Laboratory, Department of Chemistry, Center for Solid-Phase Organic Combinatorial Chemistry, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark.
Alexandra
A
Papanikos
Morten
M
Meldal
D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry; D007651:Keto Acids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010455:Peptides / Q000138:chemical synthesis*; D011480:Protease Inhibitors / Q000032:analysis*; D012117:Resins, Synthetic / Q000737:chemistry
D000577:Amides; D000596:Amino Acids; D006571:Heterocyclic Compounds; D007651:Keto Acids; D010455:Peptides; D011480:Protease Inhibitors; D012117:Resins, Synthetic; C012948:1,3-dithiolane