TY - JOUR
T1 - N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation
AU - Granchi, Carlotta
AU - Roy, Sarabindu
AU - De Simone, Alessio
AU - Salvetti, Irene
AU - Tuccinardi, Tiziano
AU - Martinelli, Adriano
AU - Macchia, Marco
AU - Lanza, Mario
AU - Betti, Laura
AU - Giannaccini, Gino
AU - Lucacchini, Antonio
AU - Giovannetti, Elisa
AU - Sciarrillo, Rocco
AU - Peters, Godefridus J
AU - Minutolo, Filippo
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/chemical synthesis
KW - Carboxylic Acids/chemistry
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Enzyme Inhibitors/chemical synthesis
KW - Humans
KW - Indoles/chemical synthesis
KW - Inhibitory Concentration 50
KW - Isoenzymes/antagonists & inhibitors
KW - L-Lactate Dehydrogenase/antagonists & inhibitors
KW - Molecular Dynamics Simulation
KW - Protein Conformation
U2 - https://doi.org/10.1016/j.ejmech.2011.08.046
DO - https://doi.org/10.1016/j.ejmech.2011.08.046
M3 - Article
C2 - 21944286
SN - 0223-5234
VL - 46
SP - 5398
EP - 5407
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 11
ER -