New inhibitors of human O-GlcNAc Transferase: Spectroscopic, computational and biological studies

Abstract

Resumen del trabajo presentado al 12th Spanish-Italian Symposium on Organic Chemistry (SISOC), celebrado en Ferrara (Italia) del 2 la 4 de julio de 2018.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. Two series of glycomimetics of UDP-GlcNAc have been prepared. In the first one (A) the ß-phosphate has been replaced by an alkyl chain, through a S-mediated click-chemistry procedure. In the second family (B) the -phospahte has been replaced by a phosphonate, so the pyrophosphate moiety is conserved. In both cases, the sugar moiety has been replaced by a pyrrolidine ring have been synthesized by using different procedures. Their affinity for hOGT has been evaluated and computationally studied. The binding epitopes of the best ligands have been determined in solution using saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic and computational results are in agreement, pointing out the essential role for binding of the ß-phosphate, and, on the other hand, a great enhancement of the affinity by the hydrophobic groups attached to the pyrrolidine.Peer Reviewe