Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

Venkatesh, V and Berrocal-Martin, Raul and Wedge, Christopher J and Romero-Canelon, Isolda and Sanchez-Cano, Carlos and Song, Ji-Inn and Coverdale, James PC and Zhang, Pingyu and Clarkson, Guy J and Habtemariam, Abraha and Magennis, Steven W and Deeth, Robert J and Sadler, Peter J (2017) Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. In: CHEMICAL SCIENCE, 8 (12). pp. 8271-8278.

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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 mu M), being ca. 8 x more active than the clinical drug cisplatin, and ca. 15 x 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
Publication:	CHEMICAL SCIENCE
Additional Information:	Copy right for this article belongs to the ROYAL SOC CHEMISTRY, THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited:	26 Dec 2017 06:05
Last Modified:	26 Dec 2017 06:05
URI:	http://eprints.iisc.ac.in/id/eprint/58415

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