Current cancer research is being increasingly focused on the study of distinctive characters of tumour metabolism, resulting in a switch from oxidative phosphorylation to glycolysis (Warburg effect). Isoform 5 of human lactate dehydrogenase (hLDH5), which catalyzes the final step in the glycolytic cascade (pyruvate to lactate), constitutes a relatively new and untapped anti-cancer target. In this study, careful design and synthesis of a selected series of aryl-substituted N-hydroxyindole-2-carboxylates (NHIs) has led to several hLDH5-inhibitors, showing "first-in-class" potency and isoform selectivity. Enzyme kinetics studies indicated that these inhibitors exhibit a competitive mode of inhibition. Some representative examples were tested against two human pancreatic carcinoma cell lines, and displayed a good anti-proliferative activity, which was even more evident under hypoxic conditions.
|Autori:||Granchi C; Roy S; De Simone A; Salvetti I; Tuccinardi T; Martinelli A; Macchia M; Lanza M; Betti L; Giannaccini G; Lucacchini A; Giovannetti E; Sciarrillo R; Peters GJ; Minutolo F|
|Titolo:||N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation|
|Anno del prodotto:||2011|
|Digital Object Identifier (DOI):||10.1016/j.ejmech.2011.08.046|
|Appare nelle tipologie:||1.1 Articolo in rivista|