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Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
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Venkatesh, Venkatesh, Berrocal-Martin, Raul, Wedge, Christopher, Romero-Canelón, Isolda, Sanchez-Cano, Carlos, Song, Ji-Inn, Coverdale, James P. C., Zhang, Pingyu, Clarkson, Guy J., Habtemariam, Abraha, Magennis, Steven W., Deeth, Robert J. and Sadler, P. J. (2017) Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. Chemical Science, 8 (12). pp. 8271-8278. doi:10.1039/C7SC03216A ISSN 2041-6520.
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WRAP-mitochondria-targeted spin-labelled-luminescent-iridium-anticancer-complexes-Sadler-2017.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2412Kb) | Preview |
Official URL: http://dx.doi.org/10.1039/C7SC03216A
Abstract
Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(III) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [C43H43N6O2Ir1·PF6]˙ (Ir-TEMPO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6]˙ (Ir-TEMPO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin–spin interactions between the TEMPO units in Ir-TEMPO2. Both Ir-TEMPO1 and Ir-TEMPO2 showed bright luminescence with long lifetimes (ca. 35–160 ns); while Ir-TEMPO1 displayed monoexponential decay kinetics, the biexponential decays measured for Ir-TEMPO2 indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of Ir-TEMPO2 towards a range of cancer cells was much greater than that of Ir-TEMPO1, and also the antioxidant activity of Ir-TEMPO2 is much higher against A2780 ovarian cancer cells when compared with Ir-TEMPO1. Most notably Ir-TEMPO2 was particularly potent towards PC3 human prostate cancer cells (IC50 = 0.53 μM), being ca. 8× more active than the clinical drug cisplatin, and ca. 15× more selective towards cancer cells versus normal cells. Confocal microscopy showed that both Ir-TEMPO1 and Ir-TEMPO2 localise in the mitochondria of cancer cells.
Item Type: | Journal Article | ||||||||||||||||||||||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Mitochondria, Ovaries -- Cancer -- Treatment | ||||||||||||||||||||||||
Journal or Publication Title: | Chemical Science | ||||||||||||||||||||||||
Publisher: | Royal Society of Chemistry | ||||||||||||||||||||||||
ISSN: | 2041-6520 | ||||||||||||||||||||||||
Official Date: | 2017 | ||||||||||||||||||||||||
Dates: |
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Volume: | 8 | ||||||||||||||||||||||||
Number: | 12 | ||||||||||||||||||||||||
Page Range: | pp. 8271-8278 | ||||||||||||||||||||||||
DOI: | 10.1039/C7SC03216A | ||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
Date of first compliant deposit: | 6 April 2018 | ||||||||||||||||||||||||
Date of first compliant Open Access: | 6 April 2018 | ||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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