title: Bioactive unnatural somatostatin analogues through bioorthogonal iodo- and ethynyl-disulfide intercalators.
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.
authors: Max Planck Institute for Polymer Research, Mainz, Germany.
authors: Anne
authors: A
authors: Pfisterer
authors: Klaus
authors: K
authors: Eisele
authors: Xi
authors: X
authors: Chen
authors: Manfred
authors: M
authors: Wagner
authors: Klaus
authors: K
authors: Müllen
authors: Tanja
authors: T
authors: Weil
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D007202:Indicators and Reagents / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D004220:Disulfides; D007202:Indicators and Reagents; D007364:Intercalating Agents; D010455:Peptides; D013004:Somatostatin