In the search for selective and long-acting analogs of somatostatin, nearly 200 compounds were synthesized by solid-phase methods, purified, and tested biologically. Among these octapeptides, some contained N-terminal D-Phe, Ac-D-Phe, or AcPhe followed by hexapeptide showed a prolonged duration of action and were able to inhibit growth hormone release for at least 3 hr. Analogs of both Phe-3/Thr-6 and Tyr-3/Val-6 classes also suppressed the release of insulin and glucagon in rats and pentagastrin-induced secretion of gastric acid in dogs, but their potencies in these tests were much smaller than the growth-hormone-release inhibitory activity. Some of these analogs possessed antitutnor activities as shown by the inhibition of growth of animal models of prostate, mammary, and ductal pancreatic tumors.The tetradecapeptide somatostatin (also called somatostatin -14) is of little therapeutic value since it has a broad spectrum of biological actions and a short half-life (1). Conformational analyses and structure-function studies on somatostatin analogs indicate that the sequence required for biological activity consists of the B-turn fragment Phe-Trp-Lys-Thr corresponding to the residues 7-10 of somatostatin (2, 3). Many somatostatin analogs with smaller and more rigid rings have been designed and synthesized in the search for compounds with selective, enhanced, and prolonged activity (2-6). Veber and co-workers (3, 4) reported that cyclic hexapeptide analogs cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) and cyclo(N-MeAla-Phe-D-Trp-Lys-Thr-Phe) were highly active in tests on the inhibition of growth hormone (GH), insulin, and glucagon release. More recently, the same group synthesized a new hexapeptide, cyclo(N-MeAla-Tyr-D-Trp-LysVal-Phe), containing tyrosine and valine in positions corresponding to the residues 7 and 10, respectively, of somatostatin, and found it to be 50-100 times more potent than the parent molecule (5). Bauer et al. (6) synthesized another series of highly potent octapeptide analogs of somatostatin. They retained the sequence of residues 7-10 of somatostatin, Phe-Trp-Lys-Thr, and incorporated this sequence with the tryptophan residue in the D configuration into a series of cystine-bridged analogs of which D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (code no. SMS 201-995) containing a C-terminal amino alcohol was the most active (6). This analog has been subjected to careful clinical evaluation (7,8).Recently, nearly 200 octapeptide amide analogs of somatostatin related to compound SMS 201-995 made by Bauer et al. (6) have been synthesized by solid-phase methods in our laboratory (9, 10). This paper reports the synthesis and the evaluation of biological activities of some of these analogs.
MATERIALS AND METHODSSynthesis. The analogs were synthesized in a Beckman model 990 automatic peptide synthesizer using standard solid-phase procedures (11). Benzhydrylamine resin (0.50 mmol/g) was used as starting material. Amino acids were coupled as their NV-tert-butoxycarbonyl (Boc) derivatives, and reactive side ch...