Ligand-centred redox activation of inert organoiridium anticancer catalysts.

Chemical Science
Wen-Ying ZhangPeter J Sadler

Abstract

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 th...Continue Reading

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Citations

Feb 23, 2021·Photochemistry and Photobiology·Sarah J FarleyPeter J Sadler
Oct 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Joan J Soldevila-BarredaNicolas P E Barry
Jun 15, 2021·Chemical Science·Elizabeth J AnthonyZijin Zhang
Jul 25, 2021·International Journal of Molecular Sciences·Alice De PaloFabio Marchetti
Oct 27, 2020·Inorganic Chemistry·Ana C CarrascoAna M Pizarro
Oct 29, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Liyan WangZhe Liu
Nov 4, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Yan YangHong Liang
Nov 12, 2021·Journal of Medicinal Chemistry·Robin RamosJoëlle Sobczak-Thépot

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Methods Mentioned

BETA
X-ray
NMR
electron paramagnetic resonance
flow cytometry

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