Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells

Bioorg Chem. 2024 Sep:150:107594. doi: 10.1016/j.bioorg.2024.107594. Epub 2024 Jun 25.

Abstract

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Keywords: Cytotoxic; Ferroptosis; Lipid peroxidation; Piperine derivatives; hDHODH inhibitors.

MeSH terms

  • Alkaloids* / chemical synthesis
  • Alkaloids* / chemistry
  • Alkaloids* / pharmacology
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Benzodioxoles* / chemical synthesis
  • Benzodioxoles* / chemistry
  • Benzodioxoles* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dihydroorotate Dehydrogenase* / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Screening Assays, Antitumor*
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Ferroptosis* / drug effects
  • Humans
  • Molecular Structure
  • Piperidines* / chemical synthesis
  • Piperidines* / chemistry
  • Piperidines* / pharmacology
  • Polyunsaturated Alkamides* / chemical synthesis
  • Polyunsaturated Alkamides* / chemistry
  • Polyunsaturated Alkamides* / pharmacology
  • Structure-Activity Relationship

Substances

  • Alkaloids
  • Dihydroorotate Dehydrogenase
  • Piperidines
  • Benzodioxoles
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • piperine
  • Polyunsaturated Alkamides