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 language | English |
|---|---|
| Pages (from-to) | 7467-7479 |
| Number of pages | 13 |
| Journal | Chemical Science |
| Volume | 12 |
| Issue number | 21 |
| DOIs | |
| State | Published - Jun 7 2021 |
Bibliographical note
Publisher Copyright:© The Royal Society of Chemistry.
Funding
We are grateful to the University of Kentucky for funding. The authors acknowledge the support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456). The work was also supported by NIH R01NS112693-01A1 (PGS). Our study was performed in compliance with the NIH guidelines (NIH Publication No. 85-23 Rev. 1985) for the care and use of laboratory animals and all experimental procedures were monitored and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Kentucky (USA). We thank the UK NMR Center supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the ow cytometry analysis, we thank Dr Greg Bauman and the UK Flow Cytometry & Immune Monitoring core facility supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center core support grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. We thank Dr Tomoko Sengoku and Mr Michael Alstott for the redox metabolism analysis and their program supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558). We sincerely thank Dr Wendy Katz and Ms Megan A. Peterson for helping with H&E staining, and their research program supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30 GM127211. We also thank Dr Thomas Lee and the University of Colorado Boulder, College of Arts and Sciences, Mass Spectrometry Facility, for analyzing HRMS samples. We thank Dr Neeraj Kapur for providing the NCM460 cell. We also thank Ms Sailajah Guka-thasan for helping with the LC-MS and Dr Steven Van Lanen of the UK College of Pharmacy, who allowed the use of the LC-MS.
| Funders | Funder number |
|---|---|
| Center for Pharmaceutical Research and Innovation | |
| Office of the Vice President for Research | |
| National Science Foundation Arctic Social Science Program | CHE-997738, CHE-1625732 |
| National Science Foundation Arctic Social Science Program | |
| National Institutes of Health (NIH) | P30 GM127211, P20 GM130456, R01NS112693-01A1 |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | P30 CA177558 |
| National Childhood Cancer Registry – National Cancer Institute | |
| National Institute of General Medical Sciences | |
| University of Kentucky | |
| University of Kentucky Markey Cancer Center |
ASJC Scopus subject areas
- General Chemistry
