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.

中文翻译：

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一种抗癌金（III）活化的卟啉支架，可共价修饰蛋白质半胱氨酸硫醇。

许多与癌症相关的蛋白质的半胱氨酸硫醇是抗癌药的诱人靶标。在这里，我们明确地证明了金（III）中卟啉IX二甲基酯（AuMesoIX）的独特的巯基靶向特性及其抗癌活性。虽然半胱氨酸硫醇与金属络合物的结合通常是通过MS键的形成发生的，但AuMesoIX的独特之处在于，卟啉环的内消旋碳原子被金（III）离子激活，从而被巯基进行亲核芳香取代。已显示AuMesoIX可修饰反应性半胱氨酸残基并抑制抗癌蛋白靶标（包括硫氧还蛋白，过氧化物酶和去泛素酶）的活性。用AuMesoIX处理癌细胞导致形成金结合的富硫蛋白质聚集体，氧化应激介导的细胞毒性，和泛素化蛋白的积累 重要的是，AuMesoIX在小鼠中表现出有效的抗肿瘤活性。我们的研究发现了金（III）诱导的硫醇靶向配体支架反应性，可用于抗癌应用。