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Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

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 [C(43)H(43)N(6)...

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Autores principales: Venkatesh, V., Berrocal-Martin, Raul, Wedge, Christopher J., 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., Sadler, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857930/
https://www.ncbi.nlm.nih.gov/pubmed/29568475
http://dx.doi.org/10.1039/c7sc03216a
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author Venkatesh, V.
Berrocal-Martin, Raul
Wedge, Christopher J.
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.
Sadler, Peter J.
author_facet Venkatesh, V.
Berrocal-Martin, Raul
Wedge, Christopher J.
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.
Sadler, Peter J.
author_sort Venkatesh, V.
collection PubMed
description 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 [C(43)H(43)N(6)O(2)Ir(1)·PF(6)]˙ (Ir-TEMPO1) and two TEMPO spin labels [C(52)H(58)N(8)O(4)Ir(1)·PF(6)]˙ (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 (IC(50) = 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.
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spelling pubmed-58579302018-03-22 Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes Venkatesh, V. Berrocal-Martin, Raul Wedge, Christopher J. 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. Sadler, Peter J. Chem Sci Chemistry 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 [C(43)H(43)N(6)O(2)Ir(1)·PF(6)]˙ (Ir-TEMPO1) and two TEMPO spin labels [C(52)H(58)N(8)O(4)Ir(1)·PF(6)]˙ (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 (IC(50) = 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. Royal Society of Chemistry 2017-12-01 2017-10-20 /pmc/articles/PMC5857930/ /pubmed/29568475 http://dx.doi.org/10.1039/c7sc03216a Text en This journal is © The Royal Society of Chemistry 2017 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0)
spellingShingle Chemistry
Venkatesh, V.
Berrocal-Martin, Raul
Wedge, Christopher J.
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.
Sadler, Peter J.
Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title_full Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title_fullStr Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title_full_unstemmed Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title_short Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
title_sort mitochondria-targeted spin-labelled luminescent iridium anticancer complexes
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857930/
https://www.ncbi.nlm.nih.gov/pubmed/29568475
http://dx.doi.org/10.1039/c7sc03216a
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