Studies on novel peptidomimetics having bi-directional dispositions of hydroxylated D-Pro-Gly motifs anchored on a C₂-symmetric iminosugar-based foundation

Abstract

A rigid pyrrolidine based scaffold comprising of 2,5-dideoxy-2,5-imino-D-idaric acid (1) is developed. Attachment of peptide strands to the carboxylic groups at both ends of this novel template led to the peptidomimetics 2 and 3. Conformational analysis by NMR studies revealed that compounds 2b, 3b and 2c, 3c take interesting turn structures (C₂ symmetric for 2c and 3c) in DMSO-d₆ consisting of identical intramolecular hydrogen bonds at two ends between LeuNH → sugar-OH as depicted in structure A, whereas 2a and 3a display structures with regular β-turns with hydrogen bonds between LeuNH → Boc·C=O in one-half of their molecular frameworks (structure B), characteristic of the turn structures commonly observed in "D-Pro-Gly"-containing peptides. These results suggest that a cis hydroxyl group at the 3-position of the proline residue favors a pseudo β-turn-like nine-membered ring structure in hydroxyproline-containing peptides involving an intramolecular hydrogen bond between the hydroxyl and the i + 2 backbone amide.