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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. <br>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. <br><br>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.<br> 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.<br>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. <br>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. <br>