We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) of a few analogues of the cyclic octapeptide octreotide (1), where the disulfide bridge was replaced by a dicarba group. These analogues were prepared by on-resin RCM of linear hepta-peptides containing two allylglycine residues; first- and second-generation Grubbs catalyst efficiencies were compared. The C=C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by (1)H NMR spectroscopy. Conformation-affinity relationships confirmed the importance of D-Phe(2) orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)(10) favored the formation of a 3(10)-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.

Somatostatin (SS) is a cyclic tetradecapeptide able to inhibit the release of growth hormone (GH) mainly through the binding to two G‐protein coupled receptor (GPCR) subtypes, SSTR2 and SSTR5. These receptors are overexpressed in approximately 90% of carcinoid tumors. However, the clinical use of somatostatin is limited by its short half‐life in vivo. In order to overcome this severe drawback, a huge number of analogs have been prepared, leading to the development of Octreotide, which is currently used in the clinic, among other applications, to treat various neuroendocrine tumors and, radiolabeled by, for example, 111In, 11C, and 68Ga, for imaging SS‐secreting tumors. Despite the success of Octreotide, there is an unmet need for the development of novel, more stable and selective Octreotide‐derived radiotherapeutics. To this end, the Cu(I)‐catalyzed azide‐alkyne 1,3‐dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to replace the susceptible disulfide bridge with a durable [1,2,3]triazolyl containing bridge and to introduce conformational constraints increasing specific receptor binding. Herein we report the design and synthesis of a series of i‐to‐i + 5 1,4‐ and 4,1‐disubstituted [1,2,3]triazolyl‐bridged cyclopeptides derived from the Octreotide scaffold and their detailed conformational analysis via NMR spectroscopy.

No abstract