Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

John Roque; Dmytro Havrylyuk; Patrick C. Barrett; Tariq Sainuddin; Julia McCain; Katsuya Colón; William T. Sparks; Evan Bradner; Susan Monro; David Heidary; Colin G. Cameron; Edith C. Glazer; Sherri A. McFarland

doi:10.1111/php.13174

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

John Roque
, Dmytro Havrylyuk
, Patrick C. Barrett
, Tariq Sainuddin
, Julia McCain
, Katsuya Colón
, William T. Sparks
, Evan Bradner
, Susan Monro
, David Heidary
, Colin G. Cameron
, Edith C. Glazer
, Sherri A. McFarland

Chemistry

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

44 Scopus citations

Abstract

A series of strained Ru(II) complexes were studied for potential anticancer activity in hypoxic tissues. The complexes were constructed with methylated ligands that were photolabile and an imidizo[4,5-f][1,10]phenanthroline ligand that contained an appended aromatic group to potentially allow for contributions of ligand-centered excited states. A systematic variation of the size and energy of the aromatic group was performed using systems containing 1–4 fused rings, and the photochemical and photobiological behaviors of all complexes were assessed. The structure and nature of the aromatic group had a subtle impact on photochemistry, altering environmental sensitivity, and had a significant impact on cellular cytotoxicity and photobiology. Up to 5-fold differences in cytotoxicity were observed in the absence of light activation; this rose to 50-fold differences upon exposure to 453 nm light. Most significantly, one complex retained activity under conditions with 1% O₂, which is used to induce hypoxic changes. This system exhibited a photocytotoxicity index (PI) of 15, which is in marked contrast to most other Ru(II) complexes, including those designed for O₂-independent mechanisms of action.

Original language	English
Pages (from-to)	327-339
Number of pages	13
Journal	Photochemistry and Photobiology
Volume	96
Issue number	2
DOIs	https://doi.org/10.1111/php.13174
State	Published - Mar 1 2020

Bibliographical note

Publisher Copyright:
© 2019 American Society for Photobiology

Funding

Research reported in this publication was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under Award Number R01CA222227 (to SAM) and the National Institute of General Medical Sciences (NIGMS) of the NIH under Award Number R01GM107586 (to ECG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also acknowledge financial support from the University of North Carolina at Greensboro, the Natural Sciences and Engineering Council of Canada, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Nova Scotia Research and Innovation Trust, and Acadia University. Research reported in this publication was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under Award Number R01CA222227 (to SAM) and the National Institute of General Medical Sciences (NIGMS) of the NIH under Award Number R01GM107586 (to ECG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also acknowledge financial support from the University of North Carolina at Greensboro, the Natural Sciences and Engineering Council of Canada, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Nova Scotia Research and Innovation Trust, and Acadia University.

Funders	Funder number
Canadian Foundation for Innovation
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA222227
National Institute of General Medical Sciences	R01GM107586
University of North Carolina and North Carolina State University
Acadia University
Nova Scotia Research Innovation Trust
University of North Carolina, Greensboro
Canadian Institutes of Health Research
Natural Sciences and Engineering Research Council of Canada
Canada Foundation for Innovation

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry

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10.1111/php.13174

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title = "Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions",

abstract = "A series of strained Ru(II) complexes were studied for potential anticancer activity in hypoxic tissues. The complexes were constructed with methylated ligands that were photolabile and an imidizo[4,5-f][1,10]phenanthroline ligand that contained an appended aromatic group to potentially allow for contributions of ligand-centered excited states. A systematic variation of the size and energy of the aromatic group was performed using systems containing 1–4 fused rings, and the photochemical and photobiological behaviors of all complexes were assessed. The structure and nature of the aromatic group had a subtle impact on photochemistry, altering environmental sensitivity, and had a significant impact on cellular cytotoxicity and photobiology. Up to 5-fold differences in cytotoxicity were observed in the absence of light activation; this rose to 50-fold differences upon exposure to 453 nm light. Most significantly, one complex retained activity under conditions with 1\% O2, which is used to induce hypoxic changes. This system exhibited a photocytotoxicity index (PI) of 15, which is in marked contrast to most other Ru(II) complexes, including those designed for O2-independent mechanisms of action.",

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Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Abstract

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