当前位置: X-MOL 学术Nat. Commun. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs
Nature Communications ( IF 16.6 ) Pub Date : 2022-08-09 , DOI: 10.1038/s41467-022-32474-y
Kui Xiao 1 , Niyuan Zhang 2 , Feifei Li 3 , Dayong Hou 2, 4, 5 , Xiaoyi Zhai 1 , Wanhai Xu 4, 5 , Gelin Wang 3 , Hao Wang 2 , Liang Zhao 1
Affiliation  

Medicinal applications of gold complexes have recently attracted attention due to their innovative antitumor mechanisms. In this work, two hypercoordinated carbon-centered gold clusters PAA4 and PAA5 are quantitatively synthesized by an intramolecular 6-exo-dig cyclization of polymetalated precursors. The on-bench and in vitro experimental studies demonstrate that the characteristic hypercarbon-tetragold(I) multi-center bonding in PAA4 and PAA5 not only guarantees their stability under common physiological conditions, but also facilitates a glutathione (GSH)-triggered prompt and synergetic release of active Au(I) ions in the GSH-overexpressed and acidic microenvironment of human bladder cancer EJ cells. The instantly massive release of coordination unsaturated Au(I) ions causes the efficient inhibition of thioredoxin reductases and then induces a rapid pro-oxidant response, consequently causing the occurrence of accelerated ferroptosis of EJ cells. As a result, these hypercarbon-centered gold(I) cluster prodrugs show high cytotoxicity to bladder cancer cell lines and thus exhibit a significant inhibition effect towards bladder tumors in vivo. Correlation of the synergetic domino dissociation of carbon-polymetal multi-center bonding in metal clusters with the accelerated ferroptosis of cancer cells provides a strategy for metallo-prodrugs and opens a broader prospect for the biological application of metal cluster compounds.



中文翻译:

高碳中心金 (I) 簇前药协同释放 Au(I) 引起的促氧化反应和加速铁死亡

金配合物的药物应用由于其创新的抗肿瘤机制最近引起了人们的关注。在这项工作中,两个超配位碳中心金簇PAA4PAA5通过多金属化前体的分子内 6 - exo - dig环化定量合成。实验室和体外实验研究表明, PAA4和PAA5中的特征性超碳四金 (I) 多中心键不仅保证了它们在常见生理条件下的稳定性,而且促进了谷胱甘肽 (GSH) 触发的活性 Au(I) 离子在人膀胱癌 EJ 细胞的 GSH 过表达和酸性微环境中的迅速和协同释放。配位不饱和Au(I)离子的瞬间大量释放导致硫氧还蛋白还原酶的有效抑制,然后诱导快速的促氧化反应,从而导致EJ细胞加速铁死亡的发生。结果,这些以高碳为中心的金(I)簇前药对膀胱癌细胞系表现出高细胞毒性,因此对体内膀胱肿瘤表现出显着的抑制作用。

更新日期:2022-08-11
down
wechat
bug