Synthesis of novel triazole-derived glycopeptides as analogs of alpha-dystroglycan mucins

Author(s)

Marchiori, Marcelo Fiori ^[1] ; Iossi, Giulia Pompolo ^[1] ; Bortot, Leandro Oliveira ^[1] ; Dias-Baruffi, Marcelo ^[1] ; Campo, Vanessa Leiria ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Barao Maua Univ Ctr, 423 Ramos Azevedo St, BR-14090180 Ribeirao Preto, SP - Brazil

• Document type: Review article
• Source: Carbohydrate Research; v. 472, p. 23-32, JAN 15 2019.
• Web of Science Citations: 1

Abstract

alpha-Dystroglycan (alpha-DG) mucins are essential for maintenance of the structural and functional stability of the muscle fiber and, when hypoglycosylated, they are directly involved in pathological processes such as dystroglycanopathies. Thus, this work reports the synthesis of the novel 1,2,3-triazole-derived glycosyl amino acids alpha GlcNAc-1-O-triazol-2Man alpha-ThrOH (1) and Gal-beta 1,4-alpha GlcNAc-1-O-triazol-2Man alpha-ThrOH (2), followed by solid-phase assembly to get the corresponding glycopeptides NHAcThrVal{[}alpha GlcNAc-1-triazol-2Man alpha]ThrIleArgGlyOH (3) and NHAcThrVal{[}Gal-beta 1,4-alpha GlcNAc-1-triazol-2Man alpha]ThrIleArgGlyOH (4) as analogs of alpha-DG mucins. The glycosyl amino acids 1 (72%) and 2 (35%) were synthesized by Cu(I)-assisted 1,3-dipolar azide-alkyne cycloaddition reactions (CuAAC) between the azide-glycosyl amino acid alpha ManN(3)-FmocThrOBn (5) and the corresponding alkyne-functionalyzed sugars 2'-propynyl-alpha GlcNAc (6) and 2'-propynyl-Gal-beta 1,4-alpha GlcNAc (7), followed by hydrogenation reactions. Subsequently, glycopeptides 3 (23%) and 4 (12%) were obtained by solid phase synthesis, involving sequential couplings of Fmoc-protected amino acids or the glycosyl amino acids 1 and 2, followed by cleavage from resin, N-acetylation and O-deacetylation (NaOMe) reactions. Lastly, enzymatic galactosylation of glycopeptide 3 with bovine beta-1,4-GalT showed that it was not a substrate for this enzyme, which could be better elucidated by docking simulations with beta-1,4-GalT. (AU)

• FAPESP's process: 12/19390-0 - Development of mucin glycoconjugates with diagnostic and therapeutic applications in muscular dystrophies and cancer
• Grantee: Vanessa Leiria Campo
• Support Opportunities: Research Grants - Young Investigators Grants