Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines

Dmytro Havrylyuk; Brock S. Howerton; Leona Nease; Sean Parkin; David K. Heidary; Edith C. Glazer

doi:10.1016/j.ejmech.2018.04.044

Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines

Dmytro Havrylyuk, Brock S. Howerton, Leona Nease, Sean Parkin, David K. Heidary, Edith C. Glazer

Chemistry

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

39 Scopus citations

Abstract

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

Original language	English
Pages (from-to)	790-799
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	156
DOIs	https://doi.org/10.1016/j.ejmech.2018.04.044
State	Published - Aug 5 2018

Bibliographical note

Funding Information:
This work was supported by the American Cancer Society ( RSG-13-079-01-CDD ). Mass spectrometry analysis was performed at the University of Kentucky Environmental Research Training Laboratory (ERTL).

Publisher Copyright:
© 2018

Keywords

Cancer
Coordination chemistry
Cytotoxic
Ruthenium
Translation

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1016/j.ejmech.2018.04.044

Cite this

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title = "Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines",

abstract = "8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.",

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author = "Dmytro Havrylyuk and Howerton, {Brock S.} and Leona Nease and Sean Parkin and Heidary, {David K.} and Glazer, {Edith C.}",

note = "Funding Information: This work was supported by the American Cancer Society ( RSG-13-079-01-CDD ). Mass spectrometry analysis was performed at the University of Kentucky Environmental Research Training Laboratory (ERTL). Publisher Copyright: {\textcopyright} 2018",

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doi = "10.1016/j.ejmech.2018.04.044",

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AU - Havrylyuk, Dmytro

AU - Howerton, Brock S.

AU - Nease, Leona

AU - Parkin, Sean

AU - Heidary, David K.

AU - Glazer, Edith C.

N1 - Funding Information: This work was supported by the American Cancer Society ( RSG-13-079-01-CDD ). Mass spectrometry analysis was performed at the University of Kentucky Environmental Research Training Laboratory (ERTL). Publisher Copyright: © 2018

PY - 2018/8/5

Y1 - 2018/8/5

N2 - 8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

AB - 8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

KW - Cancer

KW - Coordination chemistry

KW - Cytotoxic

KW - Ruthenium

KW - Translation

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Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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