Development of compounds able to interfere with cancer metabolism.

The energetic flux in a cancer cells is mostly promoted by glycolysis rather than mitochondrial oxidative phosphorylation even in the presence of oxygen and fully functioning mitochondria (Warburg effect). Glucose metabolism comprises a predominant sequence of ten enzymatic reactions, which oxidize the hexose sugar into two three-carbon compounds, ending with the formation of pyruvate and the production of a small amount of adenosine triphosphate (ATP). Cancer cells are characterized by high pyruvate conversion into lactate by lactate dehydrogenase (LDH) enzyme. This final step is fundamental because it allows the regeneration of the oxidized cofactor NAD+, which is required for the regular progress of glycolysis. This last step of the aerobic glycolysis that involve lactate dehydrogenase (LDH) for the conversion of pyruvate into lactate is considered of great importance for targeting cancer cell proliferation. In addition to LDH targeting, the inhibition of glucose cellular uptake at the first glycolytic step, which involves glucose membrane transporters (GLUTs) as the primary nutrient-interacting target, represents another important starting point for blocking tumor progression. GLUTs are generally overexpressed in many cancer cells. Furthermore, many glucose analogues or neoglycosides can be utilized in conjugation with bioactive molecules in order to selectively deliver them in cancer cells. Therefore, a series of molecules were produced and assessed to evaluate their potential as anticancer agents, such as: EBSELEN analogues as possible LDH5 inhibitors; 4-ARYL-SALICYLKETOXIMES as GLUT1 inhibitors, which were tested in GLUT1 or GLUT3 giant vesicle assays, in addition to several crystallization attempts by using purified GLUT1 protein; H2S-DONOR GLYCOCONJUGATES as antiproliferative agents. The research project focused also on the design and synthesis of new metabolic probes useful in infrared techniques for cancer cell imaging.