Aromatic stacking in Glycochemistry: can glycosidations be tamed?

Descrizione del progetto

Quanto è dolce: ottenere un migliore controllo delle reazioni di glicosilazione

I glicani, anche conosciuti con il nome di carboidrati, saccaridi e zuccheri, sono onnipresenti nelle cellule e svolgono un ruolo cruciale nei processi cellulari. Si tratta di polimeri composti da combinazioni differenti di monomeri o monosaccaridi che formano complesse strutture tridimensionali. Spesso, i glicani sono legati ad altre molecole non zuccherine e, per farlo, si ricorre alla glicosilazione, ovvero la formazione di legami glicosidici. Dato il ruolo determinante dei glicani in fondamentali settori di applicazione, quali la biomedicina, l’energia e le biotecnologie, il progetto SWEET-PI, finanziato dall’UE, studierà alcuni percorsi per il raggiungimento di un migliore controllo sulle numerose fasi e specie coinvolte nelle reazioni di glicosilazione.

Obiettivo

Progress in chemical synthesis has provided access to a large variety of complex glycostructures, having a major impact in the expansion of Glycoscience. Central to carbohydrate chemistry is the glycosidation reaction, which involves the formation of a glycosidic bond between donor and acceptor molecules. It is commonly accepted that this process requires the formation of transient ionic species, whose stability, conformational properties and interactions determine to a large extend the reaction outcome. In principle, these elusive species are stabilized by means of inter- and intramolecular interactions, and in fact, this is a key feature for the activity of glycosidases and glycosyltransferases, typically requiring the participation of electron-rich functional groups, such as carboxylates. Interestingly, aromatic/carbohydrate interactions have too been detected and evaluated as supramolecular recognition motifs but, to the best of our knowledge, never at the reaction intermediate level, despite being frequently invoked to play a major role during enzymatic catalysis. Our hypothesis in this project revolves around the idea that stacking interactions involving electron-rich aromatic systems can be employed to stabilize the glycosyl oxocarbenium ion and to enhance the glycosyl acceptor reactivity; in the first case, these contacts might increase the life-time of the cationic intermediates, facilitating their detection and potentially allowing the modulation of the glycosidic donor in order to better control the stereochemical course of the reaction. Alternatively, CH/pi complexes involving the glycosyl acceptor could enhance the electron density of the reactive functional group, thus its nucleophilicity. This project aims to test both aspects of the carbohydrate/aromatic interaction employing a bioorganic approach based on the design, synthesis and systematic analysis of appropriate molecular models.