title: α-Selective glycosylation affords mucin-related GalNAc amino acids and diketopiperazines active on Trypanosoma cruzi.
abstract: This work addresses the synthesis and biological evaluation of glycosyl diketopiperazines (DKPs) cyclo[Asp-(αGalNAc)Ser] 3 and cyclo[Asp-(αGalNAc)Thr] 4 for the development of novel anti-trypanosomal agents and Trypanosoma cruzi trans-sialidase (TcTS) inhibitors. The target compounds were synthetized by coupling reactions between glycosyl amino acids αGalNAc-Ser 7 or αGalNAc-Thr 8 and the amino acid (O-tBu)-Asp 17, followed by one-pot deprotection-cyclisation reaction in the presence of 20% piperidine in DMF. The protected glycosyl amino acid intermediates 7 and 8 were, in turn, obtained by α-selective, HgBr2-catalysed glycosylation reactions of Fmoc-Ser/Thr benzyl esters 12/14 with αGalN3Cl 11, being, subsequently, fully deprotected for comparative biological assays. The DKPs 3 and 4 showed relevant anti-trypanosomal effects (IC50 282-124 μM), whereas glycosyl amino acids 1 and 2 showed better TcTS inhibition (57-79%) than the corresponding DKPs (13-25%).
authors: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. Café s/n, Ribeirão Preto, SP 14040-930, Brazil.
authors: Maristela B
authors: MB
authors: Martins-Teixeira
authors: Vanessa L
authors: VL
authors: Campo
authors: Monica
authors: M
authors: Biondo
authors: Renata
authors: R
authors: Sesti-Costa
authors: Zumira A
authors: ZA
authors: Carneiro
authors: João S
authors: JS
authors: Silva
authors: Ivone
authors: I
authors: Carvalho
mesh_terms: D000116:Acetylgalactosamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000737:chemistry / Q000494:pharmacology; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D054659:Diketopiperazines; D006023:Glycoproteins; D009077:Mucins; D014344:Trypanocidal Agents; C069715:trans-sialidase; D009439:Neuraminidase; D000116:Acetylgalactosamine