A Synthetic MUC1 Glycopeptide Bearing ßGalNAc-Thr as a Tn Antigen Isomer Induces the Production of Antibodies against Tumor Cells.

This study presents the synthesis of the novel protected O-glycosylated amino acid derivatives 1 and 2, containing ßGalNAc-SerOBn and ßGalNAc-ThrOBn units, respectively, as mimetics of the natural Tn antigen (αGalNAc-Ser/Thr), along with the solid-phase assembly of the glycopeptides NHAcSer-Ala-Pro-Asp-Thr[αGalNAc]-Arg-Pro-Ala-Pro-Gly-BSA (3-BSA) and NHAcSer-Ala-Pro-Asp-Thr[ßGalNAc]-Arg-Pro-Ala-Pro-Gly-BSA (4-BSA), bearing αGalNAc-Thr or ßGalNAc-Thr units, respectively, as mimetics of MUC1 tumor mucin glycoproteins. According to ELISA tests, immunizations of mice with ßGalNAc-glycopeptide 4-BSA induced higher sera titers (1:320 000) than immunizations with αGalNAc-glycopeptide 3-BSA (1:40 000). Likewise, flow cytometry assays showed higher capacity of the obtained anti-glycopeptide 4-BSA antibodies to recognize MCF-7 tumor cells. Cross-recognition between immunopurified anti-ßGalNAc antibodies and αGalNAc-glycopeptide and vice versa was also verified. Lastly, molecular dynamics simulations and surface plasmon resonance (SPR) showed that ßGalNAc-glycopeptide 4 can interact with a model antitumor monoclonal antibody (SM3). Taken together, these data highlight the improved immunogenicity of the unnatural glycopeptide 4-BSA, bearing ßGalNAc-Thr as Tn antigen isomer.

α-Selective glycosylation affords mucin-related GalNAc amino acids and diketopiperazines active on Trypanosoma cruzi.

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%).

Antitumour Anthracyclines: Progress and Perspectives.

Anthracyclines are ranked among the most effective chemotherapeutics against cancer. They are glycoside drugs comprising the amino sugar daunosamine linked to a hydroxy anthraquinone aglycone, and act by DNA intercalation, oxidative stress generation and topoisomerase II poisoning. Regardless of their therapeutic value, multidrug resistance and severe cardiotoxicity are important limitations of anthracycline treatment that have prompted the discovery of novel analogues. This review covers the most clinically relevant anthracyclines and their development over decades, since the first discovered natural prototypes to recent semisynthetic and synthetic derivatives. These include registered drugs, drug candidates undergoing clinical trials, and compounds under pre-clinical investigation. The impact of the structural modifications on antitumour activity, toxicity and resistance profile is addressed.