期刊
CHEMICAL SCIENCE
卷 8, 期 12, 页码 8271-8278出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7sc03216a
关键词
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资金
- EPSRC
- CRUK [EP/F034210/1, EP/N007875/1, C53561/A19933]
- Royal Society
- Chemical Computing Group (provision of MOE)
- WCPRS
- Bruker Daltonics
- EPSRC [EP/F034210/1, EP/N007875/1] Funding Source: UKRI
- MRC [G0701062] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/F034210/1, EP/N007875/1] Funding Source: researchfish
- Medical Research Council [G0701062] Funding Source: researchfish
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.
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