Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce: In vivo tumor inhibition

Jong Hyun Kim, Samuel Ofori, Sean Parkin, Hemendra Vekaria, Patrick Sullivan, Samuel Awuah

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Expanding the chemical diversity of metal complexes provides a robust platform to generate functional bioactive reagents. To access an excellent repository of metal-based compounds for probe/drug discovery, we capitalized on the rich chemistry of gold to create organometallic gold(iii) compounds by ligand tuning. We obtained novel organogold(iii) compounds bearing a 1,2-bis(diphenylphosphino)benzene ligand, providing structural diversity with optimal physiological stability. Biological evaluation of the lead compound AuPhos-89 demonstrates mitochondrial complex I-mediated alteration of the mitochondrial electron transport chain (ETC) to drive respiration and diminish cellular energy in the form of adenosine triphosphate (ATP). Mechanism-of-action efforts, RNA-Seq, quantitative proteomics, and NCI-60 screening reveal a highly potent anticancer agent that modulates mitochondrial ETC. AuPhos-89 inhibits the tumor growth of metastatic triple negative breast cancer and represents a new strategy to study the modulation of mitochondrial respiration for the treatment of aggressive cancer and other disease states where mitochondria play a pivotal role in the pathobiology.

Original languageEnglish
Pages (from-to)7467-7479
Number of pages13
JournalChemical Science
Volume12
Issue number21
DOIs
StatePublished - Jun 7 2021

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry.

ASJC Scopus subject areas

  • General Chemistry

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