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Design, synthesis, and conformational studies of [DOTA]‐Octreotide analogs containing [1,2,3]triazolyl as a disulfide mimetic
Author(s) -
Testa Chiara,
D'Addona Debora,
Scrima Mario,
Tedeschi Anna Maria,
D'Ursi Anna Maria,
Bernhard Claire,
Denat Franck,
Bello Claudia,
Rovero Paolo,
Chorev Michael,
Papini Anna Maria
Publication year - 2018
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.533
H-Index - 7
ISSN - 2475-8817
DOI - 10.1002/pep2.24071
Subject(s) - octreotide , click chemistry , somatostatin receptor , somatostatin , chemistry , combinatorial chemistry , neuroendocrine tumors , in vivo , receptor , disulfide bond , stereochemistry , biochemistry , medicine , biology , microbiology and biotechnology
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, SSTR 2 and SSTR 5 . 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, 111 In, 11 C, and 68 Ga, 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.