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Chiral SPINOL-Based Pt(II) Metallacycles For Immunogenic Cell Death
Lu Zhu1, Wenjing Du2, Yanrong Li2,3
1School of Life Sciences, Nanjing University, Nanjing 210023, China.
Inorganic Chemistry
|September 6, 2023
Summary
Chiral platinum(II) metallacycles were synthesized and tested for anticancer activity. These novel compounds induce immunogenic cell death by generating reactive oxygen species, offering a new strategy for cancer therapy.
Area of Science:
- Coordination Chemistry
- Materials Science
- Chemical Biology
Background:
- Chirality in platinum(II)-based metal-organic complexes (MOCs) offers unique properties for applications like nonlinear optics and chiral catalysis.
- The biological potential of chiral Pt(II) metallacycles is largely unexplored.
- Developing novel chiral platinum agents is crucial for advancing cancer therapy.
Purpose of the Study:
- To design and synthesize novel chiral Pt(II) metallacycles.
- To investigate their structural, photophysical, and antitumor properties.
- To explore their mechanism of action in inducing cancer cell death.
Main Methods:
- Coordination-driven self-assembly of chiral SPINOL-derived ligands with cis-Pt(PEt3)2(OTf)2.
- Structural characterization using NMR, ESI-TOF-MS, and X-ray crystallography.
- Photophysical studies including UV-vis, fluorescence, and circular dichroism (CD) spectroscopy.
- In vitro cytotoxicity assays and mechanistic studies involving mitochondrial function, glutathione (GSH)/glutathione disulfide (GSSG) levels, superoxide dismutase (SOD) activity, and reactive oxygen species (ROS) generation.
Main Results:
- Two chiral Pt(II) metallacycles, complexes 1 and 2, were successfully synthesized and characterized.
- Both complexes demonstrated significant cytotoxicity against cancer cells, particularly A549.
- Mechanistic studies revealed that complexes 1 and 2 induce cell death by disrupting mitochondrial function, inhibiting GSH/GSSG, and inactivating SOD, leading to ROS accumulation.
- This ROS overload triggered apoptotic cell death and subsequent release of damage-associated molecular patterns (DAMPs), inducing immunogenic cell death (ICD).
Conclusions:
- This study presents the first Pt(II)-based metallacycles capable of inducing immunogenic cell death.
- These chiral metallacycles offer a promising new avenue for developing immune-modulating platinum agents for cancer therapy.
- The findings provide a novel strategy for designing next-generation platinum-based anticancer drugs.
