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Synthesis of a Type‐VIβ‐Turn Peptide Mimetic and Its Incorporation into a High‐Affinity Somatostatin Receptor Ligand
Author(s) -
Gramberg Dieter,
Weber Christoph,
Beeli Reto,
Inglis Janice,
Bruns Christian,
Robinson John A.
Publication year - 1995
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19950780614
Subject(s) - chemistry , dipeptide , stereochemistry , turn (biochemistry) , peptide , cyclic peptide , ligand (biochemistry) , peptide synthesis , somatostatin , receptor , crystallography , biochemistry , neuroscience , biology
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 CH 2 CH 2 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 ( 6 ; Schemes 1, 3 , and 4 ), 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 (p IC 50 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.