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
  • 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. [email protected].
  • 7. NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China. [email protected].
  • 8. School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China. [email protected].
  • 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. [email protected].
  • 10. Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China. [email protected].
  • # 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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