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 dipe ptide templates 1, 2 and 3, which may be regarded as conformationally restricted analogs of H-Gly-Xaa-OH, in which Xaa constitutes an aromat ic amino acid. Bond formation between alpha-C of Gly and the aromatic moiety was achieved by proton-catalyzed intramolecular electrophilic a romatic substitution. The absolute configuration of the dipeptide temp lates was determined by single-crystal X-ray crystallography or by nuc lear 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 template s were used to generate an enkephalin analog 15, a modified peptidic n eurokinin antagonist 20 and two dermorphin derivatives (24 and 33). Mo lecular 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 dimin ished with all four derivatives, indicating that their receptor-releva nt molecular geometries lie outside the examined conformational space. (C) Munksgaard 1998.