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.

N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation

GRANCHI, CARLOTTA;TUCCINARDI, TIZIANO;MARTINELLI, ADRIANO;MACCHIA, MARCO;BETTI, LAURA;GIANNACCINI, GINO;LUCACCHINI, ANTONIO;MINUTOLO, FILIPPO
2011

Abstract

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.
Granchi, Carlotta; Roy, S; De Simone, A; Salvetti, I; Tuccinardi, Tiziano; Martinelli, Adriano; Macchia, Marco; Lanza, M; Betti, Laura; Giannaccini, Gino; Lucacchini, Antonio; Giovannetti, E; Sciarrillo, R; Peters, Gj; Minutolo, Filippo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/199639
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