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Bioactive Unnatural Somatostatin Analogues through Bioorthogonal Iodo‐ and Ethynyl‐Disulfide Intercalators
Author(s) -
Pfisterer Anne,
Eisele Klaus,
Chen Xi,
Wagner Manfred,
Müllen Klaus,
Weil Tanja
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201100287
Subject(s) - bioconjugation , chemistry , bioorthogonal chemistry , combinatorial chemistry , peptide , somatostatin , peptidomimetic , cycloaddition , reagent , stereochemistry , click chemistry , biochemistry , organic chemistry , neuroscience , biology , catalysis
Abstract Iodo‐ and ethynyl‐containing bisalkylating bioconjugation agents 5 and 8 were achieved and allow the introduction of reactive unnatural substituents into proteins and peptides whilst the bioactive 3D structure is retained. Derivatives of the peptide hormone somatostatin bearing a single iodo or ethynyl group were prepared through intercalation into the disulfide bridge. For the first time, the exact reaction mechanism of the intercalation was elucidated by applying 2D NMR experiments and it was shown that, during the reaction, somatostatin diastereomers were formed. Site‐directed modification of the ethynyl‐modified peptide with a coumarin chromophore was achieved through a [1,3] dipolar Huisgen cycloaddition reaction; this suggests that such a derivative could serve as an attractive platform to prepare artificial somatostatin compound libraries. The biological activity and specificity of a representative modified somatostatin derivative was demonstrated and efficient receptor‐mediated cell uptake occurred in a dose‐dependent manner into receptor positive cells only. The iodo and ethynyl bioconjugation reagents presented herein could be applied for introducing such substituents into alternative peptides and proteins and, in principle, could facilitate the efficient design of a broad variety of artificial protein and peptide analogues with previously unknown bioactivities.