3-Thiopropionic acid as a highly versatile multidetachable thioester resin linker |
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Authors: | Camarero Julio A Adeva Alberto Muir Tom W |
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Institution: | (1) Laboratory of Synthetic Protein Chemistry, The Rockefeller University, 1230 York Avenue, Box 223, 10021 New York, NY, U.S.A. |
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Abstract: | Summary This paper describes a practical new use of 3-mercaptopropionic acid as a highly versatile multidetachable linker for solid-phase
synthesis. Our approach is based on the stability of the alkylthioester functionality to optimized Boc-SPPS protocols and
HF treatment, as well as on the mild activation of the thioester functionality toward nucleophilic or reductive displacement.
This allows several C-terminal modifications to be introduced into a synthetic molecule during the cleavage step. We have
shown that unprotected peptides can be efficiently cleaved from a propyl thioester-polyethylene glycol-poly-(N,N-dimethylacrylamide) copolymer resin using a great variety of nucleophiles to give the corresponding C-terminally modified
peptides (esters, thioesters, carboxylic acids, thioacids, amides, hydroxamic acids, hydrazides, alcohols). The nucleophilic
cleavage reaction is both rapid and exceptionally clean in all the cases tested.
Abbreviations: HBTU,N-(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphateN-oxide); DIEA,N,N-diisopropylethylamine; DMF,N,N-dimethyl formamide; ES-MS, electrospray mass spectrometry; FAB-MS, fast atom bombardment mass spectrometry; HMBA, hydroxymethylbenzoic
acid; HPLC, high performance liquid chromatography; PBS: phosphate buffer saline; PEGA, polyethylene glycolpoly-(N,N-dimethylacrylamide); TFA, trifluoroacetic acid; SPPS, solid-phase peptide synthesis. Standard IUPAC single and triple letter
codes for amino acids are used throughout |
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Keywords: | C-terminal modified peptides hydrazides hydroxamates multidetachable resin solid-phase peptide synthesis thioester handle |
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