Synthesis and biological evaluation of C-terminal hydroxamide analogues ofbombesin

Bombesin pseudo-peptide analogues containing a hydroxamide function on the C-terminal part of the molecule, e.g. H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-N HOBzl and H-D-Phe-Gln-Trp-Ala-Val-GIy-His-Leu-NHOH 2 were synthesized. Thes e compounds were tested for their ability to recognize the bombesin recepto r on rat pancreatic acini and on STS cells, to stimulate (i) amylase secret ion from rat pancreatic acini and (ii) accumulation of tritiated thymidine in 3T3 cells. Compounds 1 and 2 were able to recognize bombesin receptors o n both models with high affinity (K-i =7 +/- 2 and 5.8 +/- 0.9 nM on rat pa ncreatic acini, and K-i = 4.1 +/- 1.2 and 7.7 +/- 1.9 nM on 3T3 cells, resp ectively). Interestingly, compound 1 behaved as a potent agonist in stimula ting amylase secretion from rat pancreatic acini and is able to stimulate t hymidine accumulation in 3T3 cells, while compound 2 was able to potently a ntagonize bombesin-stimulated amylase secretion (K-i= 22 +/- 5 nM) in rat p ancreatic acini and had no proper effect on 3T3 cells: however, it was able to inhibit bombesin-stimulated thymidine accumulation in 3T3 cells with hi gh potency (K-i = 1.6 +/- 0.6 nM). Copyright (C) 1999 European Peptide Soci ety: and John Wiley & Sons, Ltd.