title: Toward homogeneous erythropoietin: fine tuning of the C-terminal acyl donor in the chemical synthesis of the Cys29-Gly77 glycopeptide domain.
abstract: Described herein is the chemical synthesis of the Cys(29)-Gly(77) glycopeptide domain (22) of erythropoietin. Our initial ligation strategy targeted a C --> N termini condensation between glycopeptide 3 and peptide 4. However, the reaction was hindered by the "unattainable" reactivity, mismatched polarity, and severe aggregation of the (glyco)peptide substrates. In contrast, by tuning the C-terminal acyl donor and using smaller peptide fragments, the Cys(29)-Gly(77) glycopeptide domain of erythropoietin was prepared through unconventional N --> C termini condensation reactions. The use of a p-cyanonitrophenyl ester and the development of a masked thiophenyl ester as acyl donors enabled us to promptly access glycopeptides bearing complex carbohydrates and offer potential synthetic applications beyond our current work.
authors.affiliation: Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Wan
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Tan
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Cindy
authors.initials: C
authors.lastname: Kan
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000215:Acylation; D004921:Erythropoietin / Q000138:chemical synthesis*; D006020:Glycopeptides / Q000138:chemical synthesis*; D010446:Peptide Fragments / Q000138:chemical synthesis*; D010648:Phenylacetates; D011134:Polysaccharides; D017434:Protein Structure, Tertiary
chemical_list: D006020:Glycopeptides; D010446:Peptide Fragments; D010648:Phenylacetates; D011134:Polysaccharides; D004921:Erythropoietin; C012577:thiophenyl acetate