Synthesis of a type-VIβ-turn peptide mimetic and its incorporation into a high-affinity somatostatin receptor ligand

Article abstract of DOI:10.1002/hlca.19950780614

The synthesis of a cis-Phe-Pro dipeptide mimetic is described, which adopts a type-VIβ-turn conformation. In this mimetic, the α-positions of Phe and Pro are joined by a CH₂CH₂ bridge, thereby forming a fused bicyclic system, and fixing a geometry similar to that seen in cis-Phe-Pro units in protein crystal structures. The dipeptide mimetic 20 was synthesized in optically pure form starting from (R)-α-allylproline, with a free carboxylic acid and an Fmoc-protected N-terminus, thereby allowing its incorporation into linear and cyclic peptides using standard solid-phase methods. The mimetic 20 was incorporated into the cyclic somatostatin analogue cyclo(-Phe = Pro-Phe-D-Trp-Lys-Thr-), where Phe = Pro represents the mimetic. This analogue shows a high affinity (pIC₅₀ 8.6) for somatostatin receptors on rat-brain cortex membranes. Based on NMR studies in aqueous solution, likely low-energy conformations for this analogue were deduced using restrained dynamic simulated annealing. The conformations found, which include a distorted type-II' turn at D-Trp-Lys, are similar to low-energy conformations deduced elsewhere for cyclo(-Phe-Pro-Phe-D-Trp-Lys-Thr-), as well as to those seen in crystal structures of the somatostatin analogue octreotide.