Water-Soluble Gold(III)–Metformin Complex Alters Mitochondrial Bioenergetics in Breast Cancer Cells

Jong Hyun Kim; Samuel Ofori; R. Tyler Mertens; Sean Parkin; Samuel G. Awuah

doi:10.1002/cmdc.202100233

Water-Soluble Gold(III)–Metformin Complex Alters Mitochondrial Bioenergetics in Breast Cancer Cells

Jong Hyun Kim, Samuel Ofori, R. Tyler Mertens, Sean Parkin, Samuel G. Awuah

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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	https://doi.org/10.1002/cmdc.202100233
State	Published - Oct 15 2021

Bibliographical note

Funding Information:
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).

Funding Information:
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).

Publisher Copyright:
© 2021 Wiley-VCH GmbH.

Keywords

Anticancer
Auraformin
Gold(III)-Metformin Complexes
Mitochondria Inhibition
OXPHOS

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics (all)
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cmdc.202100233

Cite this

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title = "Water-Soluble Gold(III)–Metformin Complex Alters Mitochondrial Bioenergetics in Breast Cancer Cells",

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.",

keywords = "Anticancer, Auraformin, Gold(III)-Metformin Complexes, Mitochondria Inhibition, OXPHOS",

author = "{Hyun Kim}, Jong and Samuel Ofori and Mertens, {R. Tyler} and Sean Parkin and Awuah, {Samuel G.}",

note = "Funding Information: 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). Funding Information: 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). Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH.",

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doi = "10.1002/cmdc.202100233",

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AU - Parkin, Sean

AU - Awuah, Samuel G.

N1 - Funding Information: 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). Funding Information: 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). Publisher Copyright: © 2021 Wiley-VCH GmbH.

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N2 - 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.

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Water-Soluble Gold(III)–Metformin Complex Alters Mitochondrial Bioenergetics in Breast Cancer Cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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