Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

Research output: Contribution to journalArticle

Authors

  • V. Venkatesh
  • Raul Berrocal-Martin
  • Christopher J. Wedge
  • 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

Colleges, School and Institutes

External organisations

  • Department of Chemistry, University of Warwick
  • Department of Inorganic and Physical Chemistry, Indian Institute of Science
  • University of Glasgow
  • University of Huddersfield

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]˙ (Ir-TEMPO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6]˙ (Ir-TEMPO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units inIr-TEMPO2. BothIr-TEMPO1andIr-TEMPO2showed bright luminescence with long lifetimes (ca.35-160 ns); whileIr-TEMPO1displayed monoexponential decay kinetics, the biexponential decays measured forIr-TEMPO2indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity ofIr-TEMPO2towards a range of cancer cells was much greater than that ofIr-TEMPO1, and also the antioxidant activity ofIr-TEMPO2is much higher against A2780 ovarian cancer cells when compared withIr-TEMPO1. Most notablyIr-TEMPO2was particularly potent towards PC3 human prostate cancer cells (IC50= 0.53 μM), beingca.8× more active than the clinical drug cisplatin, andca.15× more selective towards cancer cellsversusnormal cells. Confocal microscopy showed that bothIr-TEMPO1andIr-TEMPO2localise in the mitochondria of cancer cells.

Details

Original languageEnglish
Pages (from-to)8271-8278
Number of pages8
JournalChemical Science
Volume8
Issue number12
Early online date20 Oct 2017
Publication statusPublished - 1 Dec 2017