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