Synthesis of cyclic dipeptide templates, their incorporation into peptides and studies on their conformational and biological properties.
This study investigated the diastereoselective synthesis of three dipeptide templates 1, 2 and 3, which may be regarded as conformationally restricted analogs of H-Gly-Xaa-OH, in which Xaa constitutes an aromatic amino acid. Bond formation between alpha-C of Gly and the aromatic moiety was achieved by proton-catalyzed intramolecular electrophilic aromatic substitution. The absolute configuration of the dipeptide templates was determined by single-crystal X-ray crystallography or by nuclear Overhauser enhancement measurements. A protective group strategy was elaborated to allow their incorporation into peptide sequences by liquid phase as well as by solid-phase peptide synthesis. The templates were used to generate an enkephalin analog 15, a modified peptidic neurokinin antagonist 20 and two dermorphin derivatives (24 and 33). Molecular dynamic simulations with 15 and 20 revealed the preference for a turn-like motif for 15. The biological activity, as investigated by respective receptor binding and functional assays, was strongly diminished with all four derivatives, indicating that their receptor-relevant molecular geometries lie outside the examined conformational space.
Asche
G
G
Department of Medicinal Chemistry, Boehringer Ingelheim, Ingelheim, Germany.
Kunz
H
H
Nar
H
H
Köppen
H
H
Briem
H
H
Pook
K H
KH
Schiller
P W
PW
Chung
N N
NN
Lemieux
C
C
Esser
F
F
D018360:Crystallography, X-Ray; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013698:Templates, Genetic
D010456:Peptides, Cyclic