Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(iii) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS- attack on the azo bond facilitates the substitution of iodide by GS-, and leads to formation of GSSG and superoxide if O2 is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generate Ir-SG complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.
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© The Royal Society of Chemistry 2020.
This research was supported by the EPSRC (Grant No. EP/P030572/1 and EP/F500378/1 MOAC studentship for G. M. H.), CRUK/EPSRC (Grant No. C53561/A19933), a Chancellor's International PhD Scholarship from the University of Warwick (for W.-Y. Z.), and a Royal Society Newton International Fellowship (NF151429 for S. B.). H. E. B thanks Mike and Enfys Bagguley, and the EPSRC (grant no. EP/F034210/1) for PhD studentship support. We thank Dr Lijiang Song, Dr Ivan Prokes and Ian Bagley (University of Warwick) for excellent technical assistance with MS, NMR and zebrafish embryo experiments, respectively.
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