title: Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds.
abstract: A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing the enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. filippo.minutolo@farm.unipi.it.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.forename: Emilia C
authors.initials: EC
authors.lastname: Calvaresi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Paterni
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008314:Malonates; C588170:methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5