title: Synthesis of cyclic dipeptide templates, their incorporation into peptides and studies on their conformational and biological properties.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Asche
authors.forename: H
authors.initials: H
authors.lastname: Kunz
authors.forename: H
authors.initials: H
authors.lastname: Nar
authors.forename: H
authors.initials: H
authors.lastname: Köppen
authors.forename: H
authors.initials: H
authors.lastname: Briem
authors.forename: K H
authors.initials: KH
authors.lastname: Pook
authors.forename: P W
authors.initials: PW
authors.lastname: Schiller
authors.forename: N N
authors.initials: NN
authors.lastname: Chung
authors.forename: C
authors.initials: C
authors.lastname: Lemieux
authors.forename: F
authors.initials: F
authors.lastname: Esser
mesh_terms: D018360:Crystallography, X-Ray; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013698:Templates, Genetic
chemical_list: D010456:Peptides, Cyclic