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

Producción científica: Article › revisión exhaustiva

28 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	3222-3230
Número de páginas	9
Publicación	ChemMedChem
Volumen	16
N.º	20
DOI	https://doi.org/10.1002/cmdc.202100233
Estado	Published - oct 15 2021

Nota bibliográfica

Publisher Copyright:
© 2021 Wiley-VCH GmbH.

Financiación

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).

Financiadores	Número del financiador
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

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Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

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ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Organic Chemistry

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10.1002/cmdc.202100233

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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.",

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doi = "10.1002/cmdc.202100233",

language = "English",

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AU - Awuah, Samuel G.

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

Resumen

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Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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