Synthesis of 1-Hydroxy(and 1-Alkoxy, 1-Acyloxy)-1H-indoles and evaluations of their suppressive activities against tumor growth through inhibiting lactate dehydrogenase A

Eur J Med Chem. 2025 Feb 5:283:117104. doi: 10.1016/j.ejmech.2024.117104. Epub 2024 Nov 30.

Abstract

Inhibition of lactate dehydrogenase (LDH) has emerged as a promising cancer therapy strategy due to its essential role in the metabolic transformation of cancer cells. In this study, 53 derivatives of 1-hydroxy(and 1-alkoxy, 1-acyloxy)indoles were designed, synthesized, and biologically evaluated. Several multi-substituted 1-hydroxy(and 1-alkoxy, 1-acyloxy)indole compounds exhibited inhibitory activity against the LDH-A isoform (LDHA). We confirmed that the C(3)-substituent provided additional significant hydrogen bonding and hydrophobic interactions, which enhanced the LDHA inhibitory activity with high selectivity. Our results revealed that methyl 4-bromo-3-[(n-hexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (1g), selectively inhibited LDHA (IC50 = 25 ± 1.12 nM) without affecting the LDH-B isoform (LDHB). The compound exhibited potent cytotoxic activity in several cancer cell lines, including DLD-1 colorectal cancer cells (GI50 = 27 ± 1.2 μM). Compound 1g significantly inhibited cancer cell growth by activating apoptotic pathways in a xenograft cancer model, without causing weight loss or liver and kidney damage. Therefore, compound 1g may serve as a highly specific and promising candidate for the development of LDHA inhibitors for cancer therapy.

Keywords: 1-Hydroxyindole; Anticancer; Apoptosis; DLD-1; Lactate dehydrogenase (LDH).

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor*
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Indoles* / chemical synthesis
  • Indoles* / chemistry
  • Indoles* / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase* / antagonists & inhibitors
  • L-Lactate Dehydrogenase* / metabolism
  • Lactate Dehydrogenase 5 / antagonists & inhibitors
  • Lactate Dehydrogenase 5 / metabolism
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Indoles
  • L-Lactate Dehydrogenase
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Isoenzymes
  • Lactate Dehydrogenase 5