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  3. Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs

Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs

  • Nat Commun. 2022 Aug 9;13(1):4669. 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 6 7,  Gelin Wang 8,  Hao Wang 9,  Liang Zhao 10
Affiliations

Affiliations

  • 1 Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China.
  • 2 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.
  • 3 School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 4 Department of Urology, the Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China.
  • 5 NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
  • 6 Department of Urology, the Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China. xuwanhai@hrbmu.edu.cn.
  • 7 NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China. xuwanhai@hrbmu.edu.cn.
  • 8 School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China. gelinwang@tsinghua.edu.cn.
  • 9 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. wanghao@nanoctr.cn.
  • 10 Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China. zhaolchem@mail.tsinghua.edu.cn.
  • # Contributed equally.
PMID: 35945240 DOI: 10.1038/s41467-022-32474-y
Abstract

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.

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