Synthesis of novel triazole-derived glycopeptides as analogs of α-dystroglycan mucins.


Faculty of Pharmaceutical Sciences of Ribeirão Preto - USP, Av. do Café S/N, CEP 14040-903, Ribeirão Preto, SP, Brazil; Barão de Mauá University Centre, 423 Ramos de Azevedo Street, Jardim Paulista, CEP 14090-180, Ribeirão Preto, SP, Brazil. Electronic address: [Email]


α-Dystroglycan (α-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 αGlcNAc-1-O-triazol-2Manα-ThrOH (1) and Gal-β1,4-αGlcNAc-1-O-triazol-2Manα-ThrOH (2), followed by solid-phase assembly to get the corresponding glycopeptides NHAcThrVal[αGlcNAc-1-triazol-2Manα]ThrIleArgGlyOH (3) and NHAcThrVal[Gal-β1,4-αGlcNAc-1-triazol-2Manα]ThrIleArgGlyOH (4) as analogs of α-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 αManN3-FmocThrOBn (5) and the corresponding alkyne-functionalyzed sugars 2'-propynyl-αGlcNAc (6) and 2'-propynyl-Gal-β1,4-αGlcNAc (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 β-1,4-GalT showed that it was not a substrate for this enzyme, which could be better elucidated by docking simulations with β-1,4-GalT.