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Tesi etd-02172014-150854

Thesis type
Tesi di laurea specialistica LC5
Stereoselective synthesis of a Glc-NAc conjugate as potential modulator of carbohydrate metabolism and Regio- and stereoselective behaviour of carbapyranose 1,2-epoxides with α-gluco and β-manno configuration
Corso di studi
relatore Dott.ssa Di Bussolo, Valeria
Parole chiave
  • Regio- and stereoselective nucleophilic addition
  • GlcNAc conjugate
  • Glc-NAcylation
  • Lactate Dehydrogenase Inhibitor
  • Carbaepoxides
Data inizio appello
Riassunto analitico
The first part of the present work thesis concerns the synthesis of a Glc-NAc-Conjugated Lactate Dehydrogenase Inhibitor as promising anticancer agent.
It was widely demonstrated that solid tumors have an enormous consumption of glucose and are characterized by a “metabolic switch”, because tumor cells use as principal source of energy aerobic glycolysis, instead of oxidative phosphorylation. Besides, cancer cells overexpress the glucose transporter GLUT-1 and enzymes of glycolysis, including Lactate Dehydrogenase Isoform A (LDH-A), which has recently emerged as a new potential target in the anticancer therapy, because of its key role in glycolysis progression. On the basis of these evidences, N-hydroxyindole-based (NHI) LDH-A inhibitors were synthesized in our Department. Recently the research team where I carried out my thesis converted one of these NHI-based LDH-A inhibitors into the corresponding glucose-conjugate and the preliminary studies on its anticancer activity demonstrated that this activity depends on a dual-targeting mechanism, which involves both LDH-A and glucose transporter GLUT-1. On account of this, our goal was synthesizing the corresponding Glc-NAc-conjugate, since the N-acetylglucosamine group, as reported, plays a very important biological role and appears to be involved in determining some features of cancer cells.

The second part of this work thesis concerns regioselective studies of the nucleophilic addition reactions to carbapyranose-1,2-epoxide with α-gluco and β-manno configuration.
Ring-opening reactions of carbapyranose-1,2-epoxide with β-manno configuration had been widely studied because these epoxides were opened efficiently with attack at C(1) (sterically and electronically favoured) to give 1,2-trans-diaxial carba-α-manno derivatives with both oxygen and nitrogen nucleophiles. Instead carbapyranose-1,2-epoxide with α-gluco configuration did not give such good results, because nucleophiles attack was often unregioselective. Precedent studies, finalyzed to the synthesis of useful α-manno glycoconjugates confirmed these kinds of behaviour, besides in our studies on epoxides with α-gluco configuration it was observed an undesired intramolecular addition process with the internal nucleophile C(5)-CH2OR, that allows the formation of a bicyclic byproduct. The first goal of my thesis was to minimize or to avoid the formation of this bicyclic byproduct, in order to better study and direct the stereo- and regioselectivity of nucleophilic addition reaction on these substrates. For these reasons, first we introduced different bulky protecting groups on the C(6) position, then, we introduced a deoxy-methyl group on C(6) position. On the one hand, introduction of bulky protective groups on C(6) position still have not allowed to obtain regioselective results in nucleophilic addition reactions with O-nucleophiles, however reduced formation of the bicyclic compound was achieved.
On the other hand, the introduction of a methyl substituent on C(5) position completely avoids the formation of the bicyclic compound but still affords unregioselective results in nucleophilic addition reactions.
More interesting, the use of alcohols different from MeOH efficiently influences the regio- and stereoselectivity of the ring opening process. A very nice result was obtained under methanolysis using LiClO4 as the coordinating agent: in these reaction conditions we observed a completely C(1) regio- and stereoselective nucleophilic addition process.