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

11 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

Publisher Copyright:
© 2021 Wiley-VCH GmbH.

Funding

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 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.

Funders	Funder number
National Institutes of Health (NIH)	DP2CA228043, GM107586
University of Kentucky
Kentucky Science and Engineering Foundation	KSEF‐4003‐RDE‐020

Keywords

Antitumor agents
Cytotoxicity
Photophysics
Ruthenium

ASJC Scopus subject areas

Inorganic Chemistry

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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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AU - Moore, L. Henry

AU - Parkin, Sean

AU - Blackburn, Jessica S.

AU - Heidary, David K.

AU - Selegue, John P.

AU - Glazer, Edith C.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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