Ruthenium-containing P450 inhibitors for dual enzyme inhibition and DNA damage

Ana Zamora; Catherine A. Denning; David K. Heidary; Erin Wachter; Leona A. Nease; José Ruiz; Edith C. Glazer

doi:10.1039/C6DT04405K

Ruthenium-containing P450 inhibitors for dual enzyme inhibition and DNA damage

Ana Zamora, Catherine A. Denning, David K. Heidary, Erin Wachter, Leona A. Nease, José Ruiz, Edith C. Glazer

Chemistry

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

70 Scopus citations

Abstract

Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.

Original language	English
Pages (from-to)	2165-2173
Number of pages	9
Journal	Dalton Transactions
Volume	46
Issue number	7
DOIs	https://doi.org/10.1039/C6DT04405K
State	Published - 2017

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry.

Funding

This work was supported by the American Cancer Society (RSG-13-079-01-CDD). We would like to thank the University of Kentucky Environmental Research Training Laboratory (ERTL) for their assistance in some chemical analysis. A. Z. was supported by Fundación Séneca-CARM (Exp. 19020/FPI/13). The Spanish Ministerio de Economía y Competitividad and FEDER (Project CTQ2015-64319-R) is also acknowledged. E. W. was supported by the University of Kentucky Research Challenge Trust Fund Fellowship and C. A. D. by NIDA T32 Research Fellowship (NIH DA016176

Funders	Funder number
Environmental Research and Training Laboratory (ERTL)
University of Kentucky Environmental Research Training Laboratory
University of Kentucky Research Challenge Trust Fund
National Institutes of Health (NIH)	DA016176
National Institute on Drug Abuse
American Cancer Society	RSG-13-079-01-CDD
Fundación Séneca	19020/FPI/13
Ministerio de Economía y Competitividad
European Regional Development Fund	CTQ2015-64319-R

ASJC Scopus subject areas

Inorganic Chemistry

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Cite this

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abstract = "Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.",

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doi = "10.1039/C6DT04405K",

language = "English",

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AU - Zamora, Ana

AU - Denning, Catherine A.

AU - Heidary, David K.

AU - Wachter, Erin

AU - Nease, Leona A.

AU - Ruiz, José

AU - Glazer, Edith C.

PY - 2017

Y1 - 2017

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AB - Cytochrome P450s are key players in drug metabolism, and overexpression in tumors is associated with significant resistance to many medicinal agents. Consequently, inhibition of P450s could serve as a strategy to restore drug efficacy. However, the widespread expression of P450s throughout the human body and the critical roles they play in various biosynthetic pathways motivates the development of P450 inhibitors capable of controlled local administration. Ruthenium complexes containing P450 inhibitors as ligands were synthesized in order to develop pro-drugs that can be triggered to release the inhibitors in a spatially and temporally controlled fashion. Upon light activation the compounds release ligands that directly bind and inhibit P450 enzymes, while the ruthenium center is able to directly damage DNA.

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Ruthenium-containing P450 inhibitors for dual enzyme inhibition and DNA damage

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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