Octreotide Analogs

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.

Researchers in the Papini Group, published in Peptide Science, 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.

Design, Synthesis, and Conformational Studies of [DOTA]‐Octreotide Analogs Containing [1,2,3]Triazolyl as a Disulfide Mimetic
Chiara Testa, Debora D'Addona, Mario Scrima, Anna Maria Tedeschi, Anna Maria D'Ursi, Claire Bernhard, Franck Denat, Claudia Bello, Paolo Rovero, Michael Chorev, Anna Maria Papini
Peptide Science, Volume 110, Issue 5, Special Issue: Emerging Peptide Science in Italy, September 2018