Multitarget Thiol-Activated Tetrapyridyl Gold(III) Complexes for Hypoxic Cancer Therapy
Xue‐Quan Zhou, Selda Abyar, Imma Carbo‐Bague, Lan Wang, Sebastian Türck, Maxime A. Siegler, Uttara Basu, Ingo Ott, Rongfang Liu, Adriaan P. IJzerman, Sylvestre Bonnet
Abstract
Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase (TrxR) inhibition, which disturbs the redox balance of cancer cells.However, in this model, the role of the ligand(s) coordinated to gold is often overlooked.In this work, we present a series of tetrapyridyl Au(III) complexes that exhibit thiol-induced release of a Au(I) ion and a tetrapyridyl ligand.The formation of a free Au(I) center is responsible for the expected TrxR inhibition.Additionally, the released ligand, which was visible in cells due to its intense blue fluorescence, showed excellent binding properties to the hERG potassium channel.Moreover, these ligands ended up in the lysosomes, resulting in significant lysosome damage.Altogether, the Au(III) complexes presented in this work showed broad-spectrum anticancer properties, both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(I) center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.