alpha-Keto Amide Peptides:A Synthetic Strategy to Resin-Bound Peptide Isosteres for Protease Inhibitor Screening on Solid Support

摘要

A synthetic strategy for the formation of resin-bound internal a-keto amide peptides suitable for protease inhibitor screening on solid support is presented.This general approach is based on the incorporation of a-keto amide building blocks during solid-phase peptide synthesis (SPPS).Such dipeptidyl building blocks were accessible using the acylcyanophosphorane methodology.The acid-labile a-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 ,/V-bromosuccinimide in 10% aqueous acetone.The a-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.