Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China.
Nat Commun. 2022 Aug 9;13(1):4669. doi: 10.1038/s41467-022-32474-y.
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.
由于其创新的抗肿瘤机制，金配合物的药用应用最近引起了关注。在这项工作中，通过多金属化前体的分子内 6-endo-dig 环化，定量合成了两个超配位的碳中心金簇 PAA4 和 PAA5。在台架和体外实验研究中，证明了 PAA4 和 PAA5 中特征性的超碳-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，而且有利于谷胱甘肽（GSH）触发在人膀胱癌 EJ 细胞中 GSH 过表达和酸性微环境下的活性 Au（I）离子的迅速和协同释放。配位不饱和的 Au（I）离子的瞬时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剂反应，从而导致 EJ 细胞发生加速的铁死亡。结果，这些超碳中心金（I）簇前药对膀胱癌细胞系表现出高细胞毒性，因此在体内对膀胱癌表现出显著的抑制作用。金属簇化合物中碳-多金属多中心键的协同级联解离与癌细胞加速铁死亡的相关性为金属前药提供了一种策略，并为金属簇化合物的生物学应用开辟了更广阔的前景。
