Conformational studies of 3,4-dideoxy furanoid sugar amino acid containing analogs of the receptor binding inhibitor of vasoactive intestinal peptide

Conformational analysis of vasoactive intestinal peptide (VIP) receptor binding inhibitor Leu(1)-Met(2)-Tyr(3) -Pro(4)-Thr(5)-Tyr(6)-Leu(7)-Lys(8) 1 by various NMR techniques and constrained molecular dynamics (MD) simulation studies revealed that the molecule had a turn structure involving its Tyr(3)-Pro(4)-Thr(5)-Tyr(6) moiety with intramolecular hydrogen bond between Tyr(6)NH-->Tyr(3)CO. In order to mimic the structure of 1, peptidomimetic analogs 2-4 were synthesized using conformationally constrained scaffolds of 3,4-dideoxy furanoid sugar amino acids (2S,5R)-ddSaa1 5 and its enantiomer (2R,5S)-ddSaa2 6. All these analogs displayed well defined three-dimensional structures akin to that found in 1. Peptides 2 and 3, which differed only in the sugar amino acid stereochemistry, show propensity of structures with identical intramolecular hydrogen bonds between ThrNH --> MetCO. A similar structure with a hydrogen bond between TyrNH --> MetCO was observed in 4. (C) 2004 Elsevier Ltd. All rights reserved.