APPROACHES TO PEPTIDOMIMETICS WHICH SERVE AS SURROGATES FOR THE CIS AMIDE BOND - NOVEL DISULFIDE-CONSTRAINED BICYCLIC HEXAPEPTIDE ANALOGS OF SOMATOSTATIN

In testing and refining our model of the receptor-bound conformation of the potent small-ring somatostain analog cyclo-(Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11), we have investigated structures constrained within bicyclic systems. Specifically, we have incorporated the 8-membered -Cys-Cys-unit in place of the -Phe11-Pro6-segment, thus achieving two aims: 1) constraint of the 11->6 amide bond to the cis geometry established for the cyclic hexapeptide; 2) positioning of the disulfide in place of the position-11 phenyl group, to act as surrogate for phenyl in receptor binding. Synthetic methodology which provides ready access to this class of compounds is presented, along with results of NMR spectral studies of the bicyclic systems. Biological assays show retention of high potency, in confirmation of our view of cyclo-cystine as a good mimetic for cis amide. Other reported mimetics for the cis amide bond are reviewed from the perspectives of comparative ease of accessibility and approximation of various amide bond parameters.