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

Carlotta Granchi, Sarabindu Roy, Alessio De Simone, Irene Salvetti, Tiziano Tuccinardi, Adriano Martinelli, Marco Macchia, Mario Lanza, Laura Betti, Gino Giannaccini, Antonio Lucacchini, Elisa Giovannetti, Rocco Sciarrillo, Godefridus J Peters, Filippo Minutolo

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61 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5398-5407
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Issue number11
Publication statusPublished - Nov 2011


  • Antineoplastic Agents/chemical synthesis
  • Carboxylic Acids/chemistry
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Enzyme Inhibitors/chemical synthesis
  • Humans
  • Indoles/chemical synthesis
  • Inhibitory Concentration 50
  • Isoenzymes/antagonists & inhibitors
  • L-Lactate Dehydrogenase/antagonists & inhibitors
  • Molecular Dynamics Simulation
  • Protein Conformation

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