Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M–S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.
Supramolecular ensembles adopting ring-in-ring structures are less developed compared with catenanes featuring interlocked rings.W hile catenanes with inter-ring closedshell metallophilic interactions,s uch as d 10 -d 10 Au I -Au I interactions,h ave been well-documented, the ring-in-ring complexes featuring such metallophilic interactions remain underdeveloped. Herein is described an unprecedented ring-inring structure of aA u I -thiolate Au 12 cluster formed by recrystallization of aA u I -thiolate Au 10 [2]catenane from alkane solvents such as hexane,w ith use of ab ulky dibutylfluorene-2-thiolate ligand. The ring-in-ring Au I -thiolate Au 12 cluster features inter-ring Au I -Au I interactions and underwent cluster core change to form the thermodynamically more stable Au 10 [2]catenane structure upon dissolving in, or recrystallization from, other solvents such as CH 2 Cl 2 ,CHCl 3 ,and CH 2 Cl 2 / MeCN.T he cluster-to-cluster transformation process was monitored by 1 HNMR and ESI-MS measurements.D ensity functional theory (DFT) calculations were performed to providei nsight into the mechanism of the "ring-in-ringÐ [2]catenane" interconversions.
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