DE-NOVO DESIGN AND SYNTHESIS OF SOMATOSTATIN NONPEPTIDE PEPTIDOMIMETICS UTILIZING BETA-D-GLUCOSE AS A NOVEL SCAFFOLDING

Non-peptide peptidomimetics of the peptide hormone somatostatin (SRIF) were designed and synthesized, utilizing beta-D-glucose as a novel scaffolding. Such compounds resemble conventional peptide analogs in that they retain critical amino acid side chains but differ in that they are devoid of both the peptide backbone and amide surrogates. Structure-activity relationships resulting from systematic deletion or modification of the side chains of 4a were consistent with expectations, with the exception that analogs 8a and gb, lacking an indole side chain, bound to the SRIF receptor. A possible explanation for this unexpected result and its potential implications are discussed. Unexpectedly we also found that the primary amino group of Lys9 is not required for SRIF receptor binding or activation. Taken together, the results reported herein, and those described elsewhere, 1,2 support the validity of the concept of non-peptide scaffolding and also demonstrate that non-peptidal peptidomimetics can provide unexpected biological information not previously available from natural ligands or their peptidal analogs.