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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. and Sadler, Peter J. (2017) Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. Chemical Science, 8 (12). pp. 8271-8278. ISSN 2041-6520

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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: Article
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Schools: School of Applied Sciences
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Depositing User: Sharon Beastall
Date Deposited: 14 Dec 2017 11:46
Last Modified: 14 Dec 2017 22:41


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