Synthesis and conformational analysis of small peptides containing 6-endo-BT(t)L scaffolds as reverse turn mimetics.

Abstract

Two new dipeptide isosteres derived from L-leucine and meso-tartaric acid derivatives, named 6-endo-BTL and 6-endo-BtL, were inserted in a small peptide by means of SPPS, and the conformational features of the resulting peptides 3 and 4 were studied by NMR, IR, and molecular modeling techniques. The presence of a reverse turn conformation was observed in all the structures, suggesting the key role of the scaffolds as reverse turn promoters. Peptides 3 and 4 did not adopt a preferred conformation as indicated by the presence of equilibria between open turn and intramolecular hydrogen-bonded structures. 6-endo-BTL-peptide 3 showed a 3:1 mixture of conformers. The major conformer adopted mainly an open turn structure in equilibrium with hydrogen-bonded structures. The minor conformer displayed a better organized structure with a 14-membered ring hydrogen-bond typical of a beta-hairpin-like structure, in equilibrium with a gamma-turn, too. 6-endo-BtL-peptide 4 showed a unique conformer, and did not adopt as good a conformation as 3, due to the bulky equatorial substituent at C-2. Thus, marked structural differences between peptides containing 6-endo-BTL and 6-endo-BtL scaffolds as reverse turn inducers exist.