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Chem Sci. 2017 Dec 1;8(12):8271-8278. doi: 10.1039/c7sc03216a. Epub 2017 Oct 20.

Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes.

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Department of Chemistry , University of Warwick , Coventry CV4 7AL , UK . Email:
Department of Inorganic and Physical Chemistry , Indian Institute of Science , Bangalore-560012 , India.
School of Chemistry , WestCHEM , University of Glasgow , Glasgow G12 8QQ , UK . Email:
Department of Chemical Sciences , University of Huddersfield , Huddersfield HD1 3DH , UK . Email:
School of Pharmacy , University of Birmingham , Edgbaston B15 2TT , UK.


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.

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