Biological Investigations of Ru(II) Complexes with Diverse β-Diketone Ligands

Raphael T. Ryan; Dmytro Havrylyuk; Kimberly C. Stevens; L. Henry Moore; Sean Parkin; Jessica S. Blackburn; David K. Heidary; John P. Selegue; Edith C. Glazer

doi:10.1002/ejic.202100468

Biological Investigations of Ru(II) Complexes with Diverse β-Diketone Ligands

Raphael T. Ryan, Dmytro Havrylyuk, Kimberly C. Stevens, L. Henry Moore, Sean Parkin, Jessica S. Blackburn, David K. Heidary, John P. Selegue, Edith C. Glazer

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

2 Scopus citations

Abstract

The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ²-O,O’-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ²-O,O’-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

Original language	English
Pages (from-to)	3611-3621
Number of pages	11
Journal	European Journal of Inorganic Chemistry
Volume	2021
Issue number	35
DOIs	https://doi.org/10.1002/ejic.202100468
State	Published - Sep 21 2021

Bibliographical note

Funding Information:
We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF‐4003‐RDE‐020 to J.P.S. and E.C.G.) for the support of this research. LC‐MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for O detection. 1 2

Funding Information:
We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF-4003-RDE-020 to J.P.S. and E.C.G.) for the support of this research. LC-MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for 1O2 detection.

Publisher Copyright:
© 2021 Wiley-VCH GmbH.

Keywords

Antitumor agents
Cytotoxicity
Photophysics
Ruthenium

ASJC Scopus subject areas

Inorganic Chemistry

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10.1002/ejic.202100468

Cite this

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title = "Biological Investigations of Ru(II) Complexes with Diverse β-Diketone Ligands",

abstract = "The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2-O,O{\textquoteright}-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2-O,O{\textquoteright}-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.",

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author = "Ryan, {Raphael T.} and Dmytro Havrylyuk and Stevens, {Kimberly C.} and Moore, {L. Henry} and Sean Parkin and Blackburn, {Jessica S.} and Heidary, {David K.} and Selegue, {John P.} and Glazer, {Edith C.}",

note = "Funding Information: We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF‐4003‐RDE‐020 to J.P.S. and E.C.G.) for the support of this research. LC‐MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for O detection. 1 2 Funding Information: We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF-4003-RDE-020 to J.P.S. and E.C.G.) for the support of this research. LC-MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for 1O2 detection. Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH.",

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doi = "10.1002/ejic.202100468",

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AU - Havrylyuk, Dmytro

AU - Stevens, Kimberly C.

AU - Moore, L. Henry

AU - Parkin, Sean

AU - Blackburn, Jessica S.

AU - Heidary, David K.

AU - Selegue, John P.

AU - Glazer, Edith C.

N1 - Funding Information: We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF‐4003‐RDE‐020 to J.P.S. and E.C.G.) for the support of this research. LC‐MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for O detection. 1 2 Funding Information: We gratefully acknowledge the National Institutes of Health (Grant GM107586 to E.C.G. and DP2CA228043 to J.S.B.) and the Kentucky Science & Engineering Foundation (KSEF-4003-RDE-020 to J.P.S. and E.C.G.) for the support of this research. LC-MS data were obtained using an instrument kindly shared by Dr. Steven Van Lanen (UK College of Pharmacy) and supported in part by the University of Kentucky Vice President for Research. We thank Prof. Doo Young Kim for the use of his fluorimeter for 1O2 detection. Publisher Copyright: © 2021 Wiley-VCH GmbH.

PY - 2021/9/21

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N2 - The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2-O,O’-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2-O,O’-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

AB - The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2-O,O’-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2-O,O’-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

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KW - Photophysics

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ER -

Biological Investigations of Ru(II) Complexes with Diverse β-Diketone Ligands

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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