Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction

Richard J. Mitchell; Anitha S. Gowda; Alexander G. Olivelli; Aron J. Huckaba; Sean Parkin; Jason Unrine; Viral Oza; Jessica Blackburn; Folami Ladipo; David K. Heidary; Edith Glazer

doi:10.1021/acs.inorgchem.3c00736

Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction

Richard J. Mitchell, Anitha S. Gowda, Alexander G. Olivelli, Aron J. Huckaba, Sean Parkin, Jason Unrine, Viral Oza, Jessica Blackburn, Folami Ladipo, David K. Heidary, Edith Glazer

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

Abstract

While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4′-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

Original language	English
Journal	Inorganic Chemistry
DOIs	https://doi.org/10.1021/acs.inorgchem.3c00736
State	Accepted/In press - 2023

Bibliographical note

Funding Information:
The authors gratefully acknowledge the National Institutes of Health (Grant GM107586) for funding this research. The UK Flow Cytometry & Immune Monitoring core facility, which was used for experiments in this study, is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was also supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry

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10.1021/acs.inorgchem.3c00736

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@article{aa78d330a0a948b4852e6ff8bae5ca34,

title = "Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction",

abstract = "While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4′-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.",

author = "Mitchell, {Richard J.} and Gowda, {Anitha S.} and Olivelli, {Alexander G.} and Huckaba, {Aron J.} and Sean Parkin and Jason Unrine and Viral Oza and Jessica Blackburn and Folami Ladipo and Heidary, {David K.} and Edith Glazer",

note = "Funding Information: The authors gratefully acknowledge the National Institutes of Health (Grant GM107586) for funding this research. The UK Flow Cytometry & Immune Monitoring core facility, which was used for experiments in this study, is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was also supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2023",

doi = "10.1021/acs.inorgchem.3c00736",

language = "English",

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TY - JOUR

T1 - Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction

AU - Mitchell, Richard J.

AU - Gowda, Anitha S.

AU - Olivelli, Alexander G.

AU - Huckaba, Aron J.

AU - Parkin, Sean

AU - Unrine, Jason

AU - Oza, Viral

AU - Blackburn, Jessica

AU - Ladipo, Folami

AU - Heidary, David K.

AU - Glazer, Edith

N1 - Funding Information: The authors gratefully acknowledge the National Institutes of Health (Grant GM107586) for funding this research. The UK Flow Cytometry & Immune Monitoring core facility, which was used for experiments in this study, is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was also supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). Publisher Copyright: © 2023 American Chemical Society.

PY - 2023

Y1 - 2023

N2 - While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4′-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

AB - While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4′-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

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U2 - 10.1021/acs.inorgchem.3c00736

DO - 10.1021/acs.inorgchem.3c00736

M3 - Article

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AN - SCOPUS:85164714043

SN - 0020-1669

JO - Inorganic Chemistry

JF - Inorganic Chemistry

ER -

Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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