Synthesis and biological evaluation of C-terminal hydroxamide analogues of bombesin.

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-NHOBzl 1 and H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH 2 were synthesized. These compounds were tested for their ability to recognize the bombesin receptor on rat pancreatic acini and on 3T3 cells, to stimulate (i) amylase secretion from rat pancreatic acini and (ii) accumulation of tritiated thymidine in 3T3 cells. Compounds 1 and 2 were able to recognize bombesin receptors on both models with high affinity (Ki = 7 +/- 2 and 5.8 +/- 0.9 nM on rat pancreatic acini, and Ki = 4.1 +/- 1.2 and 7.7 +/- 1.9 nM on 3T3 cells, respectively). Interestingly, compound 1 behaved as a potent agonist in stimulating amylase secretion from rat pancreatic acini and is able to stimulate thymidine accumulation in 3T3 cells, while compound 2 was able to potently antagonize bombesin-stimulated amylase secretion (Ki = 22 +/- 5 nM) in rat pancreatic acini and had no proper effect on 3T3 cells; however, it was able to inhibit bombesin-stimulated thymidine accumulation in 3T3 cells with high potency (Ki = 1.6 +/- 0.6 nM).