Convergent Site-Selective Carbohydrate-Peptide Ligations With Dehydroalanine and Aziridine -2 -Carboxylic Acid-Containing Peptides
Galonic, Danica
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https://hdl.handle.net/2142/87884
Description
Title
Convergent Site-Selective Carbohydrate-Peptide Ligations With Dehydroalanine and Aziridine -2 -Carboxylic Acid-Containing Peptides
Author(s)
Galonic, Danica
Issue Date
2005
Doctoral Committee Chair(s)
Gin, David Y.
van der Donk, Wilfred A.
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
The development of two convergent strategies for site-selective peptide modification and their application to the preparation of alpha-thio analogs of mucin related glycoconjugates is described. Chemoselectivity in these reactions was realized through the incorporation of dehydroalanine and aziridine-2-carboxylic acid residues into peptides and subsequent conjugation of the resulting peptide electrophiles with various thiols. Oligosaccharides incorporating a suitable anomeric thio-functionality were prepared via dehydrative glycosylation and glycolamide-auxiliary controlled sialylation reactions. The efficiency of the dehydroalanine ligation approach was demonstrated by the preparation of thio-isosteres of the four tumor-associated carbohydrate antigens, T N, T, STN, and 2,6-ST, as a pair of diastereoisomers at the newly formed cysteine stereocenter. This 1,4-conjugate addition ligation proceeded in high yield and with retention of alpha-anomeric configuration of the carbohydrate donor. In addition, site- and stereoselective peptide modification of aziridine-2-carboxylic acid-containing peptides was achieved. A solid-phase peptide synthesis methodology that allows for the rapid generation of peptides incorporating the aziridine residue was developed. The resulting peptides were conjugated with various thiol nucleophiles, such as anomeric carbohydrate thiols, farnesyl thiol, and biochemical tags, both in solution and on solid support. This ligation proceeds with the retention of the anomeric configuration of carbohydrate nucleophiles, and (R) configuration at the alpha-carbon of the newly formed cysteine derivative. This strategy, combined with native chemical ligation, provided convergent and rapid access to complex glycoconjugates. The developed convergent peptide modification approaches should allow for the construction of a variety of glycopeptide and lipopeptide conjugates for biological evaluations.
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