title: N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation.
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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Sarabindu
authors.initials: S
authors.lastname: Roy
authors.forename: Alessio
authors.initials: A
authors.lastname: De Simone
authors.forename: Irene
authors.initials: I
authors.lastname: Salvetti
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Mario
authors.initials: M
authors.lastname: Lanza
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Rocco
authors.initials: R
authors.lastname: Sciarrillo
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000080864:Lactate Dehydrogenase 5; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C409667:lactate dehydrogenase 1