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Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

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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.

Graphical abstract: Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

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Publication details

The article was received on 23 Jul 2017, accepted on 11 Oct 2017 and first published on 20 Oct 2017


Article type: Edge Article
DOI: 10.1039/C7SC03216A
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY license
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    Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

    V. Venkatesh, R. Berrocal-Martin, C. J. Wedge, I. Romero-Canelón, C. Sanchez-Cano, J. Song, J. P. C. Coverdale, P. Zhang, G. J. Clarkson, A. Habtemariam, S. W. Magennis, R. J. Deeth and P. J. Sadler, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C7SC03216A

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