A thiosemicarbazone-based dinuclear copper(II) complex: potent antiproliferative activity, distinct cell-type-specific anticancer mechanisms and robust in vivo antitumor efficacy

  • Bioorg Chem. 2026 Sep 5:179:109981. doi: 10.1016/j.bioorg.2026.109981.
Shufang Wu  1 ,  Qihan Feng  1 ,  Yan-Bo Wu  1 ,  Sisi Feng  1 ,  Zeyu Peng  2 ,  Caixia Yuan  3 ,  Xinhua Li  4 ,  Liping Lu  1 ,  Lijuan Qiu  5 ,  Ai Wang  6
Affiliations
  • 1. Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan 030006, Shanxi, China.
  • 2. State Key Laboratory of Clean and Efficient Coal Utilization, Taiyuan University of Technology, Taiyuan 030024, Shanxi, China.
  • 3. Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan 030006, Shanxi, China. Electronic address: [email protected].
  • 4. Department of Materials and Chemical Engineering, Taiyuan University, Taiyuan 030032, Shanxi, China.
  • 5. Basic Medicine School, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
  • 6. Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan 030006, Shanxi, China. Electronic address: [email protected].
PMID: 42150409 DOI: 10.1016/j.bioorg.2026.109981
Abstract

A feasible way to avoid chemoresistance in Cancer therapy is to endow a single drug with multiple Anticancer mechanisms. In this work, we propose that a multinuclear metal complex may be a promising drug candidate when its metal centers possess different coordination environments. Our proposal has been demonstrated by our studies on a dinuclear Cu(II) complex [Cu2LCl2(H2O)] (1, H2L = 2,2'-Bis[1-(2-pyrazinyl)ethylidene]carbonothioic dihydrazide), in which the two Cu centers adopt square planar tetracoordination and square pyramidal pentacoordination, respectively. Such a characteristic structure not only induces potent antiproliferative activity against multiple human Cancer cells (IC50 = 0.68-1.94 μM), but also leads to distinct cell-type-specific Anticancer mechanisms: Suppression of Proteasome activity in human colon Cancer HCT-116 cells, but inhibition of protein tyrosine Phosphatase 1B and T-cell protein tyrosine Phosphatase in the human breast Cancer MCF-7 cells. Together with the low toxicity to normal cells and high in vivo antitumor efficacy, 1 represents a promising candidate of the Anticancer metallodrugs for overcoming chemoresistance.

Keywords
Anticancer mechanism; Antiproliferative activity; Copper complex; In vivo antitumor efficacy; Metallodrug; Thiosemicarbazone derivative.
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