Abstract
Chemical control of mitochondrial dynamics and bioenergetics can unravel fundamental biological mechanisms and therapeutics for several diseases including, diabetes and cancer. We synthesized stable, water-soluble gold(III) complexes (Auraformin) supported by biguanide metformin or phenylmetformin for efficacious inhibition of mitochondrial respiration. The new compounds were characterized following the reaction of [C N]-cyclometalated gold(III) compounds with respective biguanides. Auraformin is solution stable in a physiologically relevant environment. We show that auraformin decreases mitochondrial respiration efficiently in comparison to the clinically used metformin by 100-fold. The compound displays significant mitochondrial uptake and induces antiproliferative activity in the micromolar range. Our results shed light on the development of new scaffolds as improved inhibitors of mitochondrial respiration.
| Original language | English |
|---|---|
| Pages (from-to) | 3222-3230 |
| Number of pages | 9 |
| Journal | ChemMedChem |
| Volume | 16 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 15 2021 |
Bibliographical note
Publisher Copyright:© 2021 Wiley-VCH GmbH.
Funding
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). 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 (P30CA177558). We also thank Dr. Thomas Lee and the University of Colorado Boulder, College of Arts and Sciences, Mass Spectrometry Facility, for analyzing HRMS samples. For microscopy, we would like to thank Dr. Thomas Wilkop (UK Light Microscopy Core) for his assistance. We are grateful to the University of Kentucky for funding. The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456). 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). 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 (P30CA177558). We also thank Dr. Thomas Lee and the University of Colorado Boulder, College of Arts and Sciences, Mass Spectrometry Facility, for analyzing HRMS samples. For microscopy, we would like to thank Dr. Thomas Wilkop (UK Light Microscopy Core) for his assistance. We are grateful to the University of Kentucky for funding. The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456).
| Funders | Funder number |
|---|---|
| Center for Pharmaceutical Research and Innovation | |
| Proteomics & Mass Spectrometry Facility | |
| U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China | CHE‐997738, CHE‐1625732 |
| National Institutes of Health (NIH) | |
| National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences | P20GM130456 |
| University of Kentucky | |
| University of Colorado Boulder | |
| College of Arts and Sciences, Boston University | |
| University of Kentucky Markey Cancer Center | P30CA177558 |
Keywords
- Anticancer
- Auraformin
- Gold(III)-Metformin Complexes
- Mitochondria Inhibition
- OXPHOS
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Pharmacology
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Organic Chemistry
