Synthesis and activity of UDP-GlcNAc and UDP-GalNAc analogues

Abstract

UDP-GlcNAc and UDP-GalNAc are the most important Leloir substrates employed by glycosyltransferases (GTs). We are interested in two particular GTs: OGT and GalNAc-T2. The human O-GlcNAc transferase (hOGT) is a metal independent Leloir GT that transfers GlcNAc to Ser or Thr residues of intracellular proteins and peptides. hOGT is an essential enzyme for the proliferation of mammalian cells, and is an active actor in several serious illnesses, including Parkinson, Alzheimer and different types of cancer. GalNAc-T2 is an enzyme belonging to the glycosyl transferase family that catalyzes the transfer of N-acetylgalactosamine from the donor substrate UDP-GalNAc to an acceptor hydroxyl group of mucine-type proteins. In the human body it is present in twenty different isoforms and they are correlated to several metabolic disorders. In this communication we will present new synthetic approaches to different Leloir substrates analogues. We have developed new hOGT and GalNAc-T2 inhibitors by replacing the carbohydrate moiety, the pyrophosphate linker or both of them. Biological in vitro activity will be presented through different techniques, such as Kd measurements and NMR. Furthermore, we have justified by computational calculations and simulations the biological activity, obtaining a valuable feedback.