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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)5398-5407
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number11
DOIs
Publication statusPublished - Nov 2011

Cite this

Granchi, C., Roy, S., De Simone, A., Salvetti, I., Tuccinardi, T., Martinelli, A., ... Minutolo, F. (2011). N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation. European Journal of Medicinal Chemistry, 46(11), 5398-5407. https://doi.org/10.1016/j.ejmech.2011.08.046
Granchi, Carlotta ; Roy, Sarabindu ; De Simone, Alessio ; Salvetti, Irene ; Tuccinardi, Tiziano ; Martinelli, Adriano ; Macchia, Marco ; Lanza, Mario ; Betti, Laura ; Giannaccini, Gino ; Lucacchini, Antonio ; Giovannetti, Elisa ; Sciarrillo, Rocco ; Peters, Godefridus J ; Minutolo, Filippo. / N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation. In: European Journal of Medicinal Chemistry. 2011 ; Vol. 46, No. 11. pp. 5398-5407.
@article{5e201c1f292a47f3af3560ebf3bc5354,
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.",
keywords = "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",
author = "Carlotta Granchi and Sarabindu Roy and {De Simone}, Alessio and Irene Salvetti and Tiziano Tuccinardi and Adriano Martinelli and Marco Macchia and Mario Lanza and Laura Betti and Gino Giannaccini and Antonio Lucacchini and Elisa Giovannetti and Rocco Sciarrillo and Peters, {Godefridus J} and Filippo Minutolo",
note = "Copyright {\circledC} 2011 Elsevier Masson SAS. All rights reserved.",
year = "2011",
month = "11",
doi = "10.1016/j.ejmech.2011.08.046",
language = "English",
volume = "46",
pages = "5398--5407",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
number = "11",

}

Granchi, C, Roy, S, De Simone, A, Salvetti, I, Tuccinardi, T, Martinelli, A, Macchia, M, Lanza, M, Betti, L, Giannaccini, G, Lucacchini, A, Giovannetti, E, Sciarrillo, R, Peters, GJ & Minutolo, F 2011, 'N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation' European Journal of Medicinal Chemistry, vol. 46, no. 11, pp. 5398-5407. https://doi.org/10.1016/j.ejmech.2011.08.046

N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation. / Granchi, Carlotta; Roy, Sarabindu; De Simone, Alessio; Salvetti, Irene; Tuccinardi, Tiziano; Martinelli, Adriano; Macchia, Marco; Lanza, Mario; Betti, Laura; Giannaccini, Gino; Lucacchini, Antonio; Giovannetti, Elisa; Sciarrillo, Rocco; Peters, Godefridus J; Minutolo, Filippo.

In: European Journal of Medicinal Chemistry, Vol. 46, No. 11, 11.2011, p. 5398-5407.

Research output: Contribution to journalArticleAcademicpeer-review

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

N1 - Copyright © 2011 Elsevier Masson SAS. All rights reserved.

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 - 10.1016/j.ejmech.2011.08.046

DO - 10.1016/j.ejmech.2011.08.046

M3 - Article

VL - 46

SP - 5398

EP - 5407

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

IS - 11

ER -