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 journalArticle

13 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.

LanguageEnglish
Pages8271-8278
Number of pages8
JournalChemical Science
Volume8
Issue number12
DOIs
Publication statusPublished - 20 Oct 2017

Fingerprint

Iridium
Mitochondria
Cells
Spin Labels
Confocal microscopy
Metabolism
Cisplatin
Density functional theory
Paramagnetic resonance
Conformations
Luminescence
Antioxidants
Spectroscopy
Kinetics
Pharmaceutical Preparations
TEMPO

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.
@article{9ddb82b7b1794057a83befb5ce62a2d4,
title = "Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes",
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.",
author = "V. Venkatesh and Raul Berrocal-Martin and Wedge, {Christopher J.} and Isolda Romero-Canel{\'o}n and Carlos Sanchez-Cano and Song, {Ji Inn} and Coverdale, {James P.C.} and Pingyu Zhang and Clarkson, {Guy J.} and Abraha Habtemariam and Magennis, {Steven W.} and Deeth, {Robert J.} and Sadler, {Peter J.}",
year = "2017",
month = "10",
day = "20",
doi = "10.1039/c7sc03216a",
language = "English",
volume = "8",
pages = "8271--8278",
journal = "Chemical Science",
issn = "2041-6520",
publisher = "Royal Society of Chemistry",
number = "12",

}

Venkatesh, V, Berrocal-Martin, R, Wedge, CJ, Romero-Canelón, I, Sanchez-Cano, C, Song, JI, Coverdale, JPC, Zhang, P, Clarkson, GJ, Habtemariam, A, Magennis, SW, Deeth, RJ & Sadler, PJ 2017, 'Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes', Chemical Science, vol. 8, no. 12, pp. 8271-8278. https://doi.org/10.1039/c7sc03216a

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 journalArticle

TY - JOUR

T1 - Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

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

Y1 - 2017/10/20

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.

UR - http://www.scopus.com/inward/record.url?scp=85034760952&partnerID=8YFLogxK

U2 - 10.1039/c7sc03216a

DO - 10.1039/c7sc03216a

M3 - Article

VL - 8

SP - 8271

EP - 8278

JO - Chemical Science

T2 - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 12

ER -

Venkatesh V, Berrocal-Martin R, Wedge CJ, Romero-Canelón I, Sanchez-Cano C, Song JI et al. Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. Chemical Science. 2017 Oct 20;8(12):8271-8278. https://doi.org/10.1039/c7sc03216a