An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols

Abstract

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.

High-resolution visualization and quantification of nucleic acid–based therapeutics in cells and tissues using Nanoscale secondary ion mass spectrometry (NanoSIMS)

“…Over the past five years, we have used NanoSIMS imaging and correlative electron microscopy to visualize the trafficking of lipoprotein–derived fatty acids into cells and tissues ( 19 , 22 ); to define the distribution of cholesterol within the plasma membrane ( 46 , 47 ); and to define the cellular and subcellular distributions of pharmaceutical agents ( 20 , 27 , 32 ). Based on these studies, we suspected that it might be possible to use similar experimental approaches to refine our understanding of the trafficking and distribution of NATs in cells and tissues.…”

Correlative Light Electron Ion Microscopy revealin vivolocalisation of bedaquiline inMycobacterium tuberculosisinfected lungs

“…CLEIMiT is readily applicable to other drugs and not only for antibiotics or brominecontaining drugs but also any drugs detectable by nanoSIMS. Ion microscopy methods using nanoSIMS represents a good combination of spatial resolution and sensitivity to map drugs that contain elements other than Bromine that are low in the biological systems such as platinum [16], gold [17] and iodine [18]. What makes the approach more widely applicable is the nanoSIMS capability to detect stable isotope labelled molecules with high-resolution such as molecules that are labelled with 2 H [19,20], 13 C [19,21] and 15 N [22,23].…”

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands

“…Copyright 2015, John Wiley and Sons. (E–J) Reprinted with permission from Tong et al ( 2020 ). Copyright 2020, National Academy of Sciences.…”

“…By varying the meso -tetraphenylporphyrin ligand into quasiphysiological mesoporphyrin IX, we have uncovered a previously unknown biomolecular interaction of the gold(III) complex that can be exploited for anticancer applications (Tong et al, 2020 ). Gold complexes usually interact with cysteine thiols via M–S bond formation.…”