Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

V. Venkatesh; Raul Berrocal-Martin; Christopher J. Wedge; Isolda Romero-Canelón; Carlos Sanchez-Cano; Ji Inn Song; James P.C. Coverdale; Pingyu Zhang; Guy J. Clarkson; Abraha Habtemariam; Steven W. Magennis; Robert J. Deeth; Peter J. Sadler

doi:10.1039/c7sc03216a

Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

V. Venkatesh, Raul Berrocal-Martin, Christopher J. Wedge, Isolda Romero-Canelón, Carlos Sanchez-Cano, Ji Inn Song, James P.C. Coverdale, Pingyu Zhang, Guy J. Clarkson, Abraha Habtemariam, Steven W. Magennis, Robert J. Deeth, Peter J. Sadler

Research output: Contribution to journal › Article

23 Citations (Scopus)

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] (IrO1) and two TEMPO spin labels [C₅₂H₅₈N₈O₄Ir₁·PF₆] (IrO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in IrO2. Both IrO1 and IrO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while IrO1 displayed monoexponential decay kinetics, the biexponential decays measured for IrO2 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 IrO2 towards a range of cancer cells was much greater than that of IrO1, and also the antioxidant activity of IrO2 is much higher against A2780 ovarian cancer cells when compared with IrO1. Most notably IrO2 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 IrO1 and IrO2 localise in the mitochondria of cancer cells.

Original language	English
Pages (from-to)	8271-8278
Number of pages	8
Journal	Chemical Science
Volume	8
Issue number	12
DOIs	https://doi.org/10.1039/c7sc03216a
Publication status	Published - 20 Oct 2017

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Chris Wedge

C.Wedge@hud.ac.uk

Department of Chemical Sciences - Senior Lecturer in Physical Chemistry
School of Applied Sciences
Centre for Functional Materials - Member
Pharmaceutics and Drug Delivery Centre - Associate Member
Structural, Molecular and Dynamic Modelling Centre - Associate Member

Person: Academic

Cite this

Venkatesh, V., Berrocal-Martin, R., Wedge, C. J., Romero-Canelón, I., Sanchez-Cano, C., Song, J. I., ... Sadler, P. J. (2017). Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. Chemical Science, 8(12), 8271-8278. https://doi.org/10.1039/c7sc03216a

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. In: Chemical Science. 2017 ; Vol. 8, No. 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] (IrO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6] (IrO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in IrO2. Both IrO1 and IrO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while IrO1 displayed monoexponential decay kinetics, the biexponential decays measured for IrO2 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 IrO2 towards a range of cancer cells was much greater than that of IrO1, and also the antioxidant activity of IrO2 is much higher against A2780 ovarian cancer cells when compared with IrO1. Most notably IrO2 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 IrO1 and IrO2 localise in the mitochondria of cancer cells.",

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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.; Sadler, Peter J.

In: Chemical Science, Vol. 8, No. 12, 20.10.2017, p. 8271-8278.

Research output: Contribution to journal › Article

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AU - Venkatesh, V.

AU - Berrocal-Martin, Raul

AU - Wedge, Christopher J.

AU - Romero-Canelón, Isolda

AU - Sanchez-Cano, Carlos

AU - Song, Ji Inn

AU - Coverdale, James P.C.

AU - Zhang, Pingyu

AU - Clarkson, Guy J.

AU - Habtemariam, Abraha

AU - Magennis, Steven W.

AU - Deeth, Robert J.

AU - Sadler, Peter J.

PY - 2017/10/20

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N2 - 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] (IrO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6] (IrO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in IrO2. Both IrO1 and IrO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while IrO1 displayed monoexponential decay kinetics, the biexponential decays measured for IrO2 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 IrO2 towards a range of cancer cells was much greater than that of IrO1, and also the antioxidant activity of IrO2 is much higher against A2780 ovarian cancer cells when compared with IrO1. Most notably IrO2 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 IrO1 and IrO2 localise in the mitochondria of cancer cells.

AB - 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] (IrO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6] (IrO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in IrO2. Both IrO1 and IrO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while IrO1 displayed monoexponential decay kinetics, the biexponential decays measured for IrO2 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 IrO2 towards a range of cancer cells was much greater than that of IrO1, and also the antioxidant activity of IrO2 is much higher against A2780 ovarian cancer cells when compared with IrO1. Most notably IrO2 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 IrO1 and IrO2 localise in the mitochondria of cancer cells.

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