Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes. Issue 12 (20th October 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Chemical science. Volume 8:Issue 12(2017)
• Page Start: 8271
• Page End: 8278
• Publication Date: 2017-10-20
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7sc03216a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. 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 [C43 H43 N6 O2 Ir1 ·PF6 ]˙ (Ir-TEMPO1 ) and two TEMPO spin labels [C52 H58 N8 O4 Ir1 ·PF6 ]˙ (Ir-TEMPO2 ). Electron paramagnetic resonance (EPR) spectroscopy revealed spin–spin interactions between the TEMPO units inIr-TEMPO2 . BothIr-TEMPO1 andIr-TEMPO2 showed bright luminescence with long lifetimes ( ca. 35–160 ns); whileIr-TEMPO1 displayed monoexponential decay kinetics, the biexponential decays measured forIr-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 ofIr-TEMPO2 towards a range of cancer cells was much greater than that ofIr-TEMPO1, and also the antioxidant activity ofIr-TEMPO2 is much higher against A2780 ovarian cancer cells when compared withIr-TEMPO1 . Most notablyIr-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 bothIr-TEMPO1 andIr-TEMPO2 localise in the mitochondria of cancer cells.