Synthesis and reactivity of 6,7-dihydrogeranylazides: reagents for primary azide incorporation into peptides and subsequent staudinger ligation
| Autor: | Benjamin P. Duckworth, Mark D. Distefano, Emily C. Jenson, Stepan Lenevich, Juhua Xu, Simon J. Gruber, Cheng Min Tann, George Barany, Amanda J. DeGraw |
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| Rok vydání: | 2006 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Azides Organic Chemistry Peptide Biochemistry Combinatorial chemistry chemistry.chemical_compound chemistry Reagent Drug Discovery Spectroscopy Fourier Transform Infrared Molecular Medicine Moiety Reactivity (chemistry) Azide Chemical ligation Staudinger reaction Triphenylphosphine Peptides Nuclear Magnetic Resonance Biomolecular |
| Zdroj: | Chemical biologydrug design. 68(2) |
| ISSN: | 1747-0277 |
| Popis: | Protein farnesyltransferase (PFTase) catalyzes the attachment of a geranylazide moiety to a peptide substrate, N-dansyl-GCVIA. Because geranylazide is actually a mixture of isomeric, interconverting primary and secondary azides, incorporation of this isoprenoid into peptides can potentially result in a corresponding mixture of prenylated peptides. Here, we first examined the reactivity of geranyl azide in a model Staudinger reaction and determined that a mixture of products is formed. We then describe the synthesis of 6,7-dihydrogeranylazide diphosphate and demonstrate that this compound allows exclusive incorporation of a primary azide into a peptide. The resulting azide-containing peptide was derivatized with a triphenylphosphine-based reagent to generate an O-alkyl imidate-linked product. Finally, we show, using a series of model reactions, that the Staudinger ligation frequently produces small amounts of O-alkyl imidate products in addition to the major amide-linked products. Thus, the alkoxyimidates we have observed as the exclusive products in the reactions of peptides containing prenylated azides also appear to be a common type of product formed using other azide-containing reactants, although at greatly reduced levels. This method for chemical modification of the C-terminus of a protein should be useful for a variety of applications in protein chemistry. |
| Databáze: | OpenAIRE |
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