Chiral SPINOL-Based Pt(II) Metallacycles For Immunogenic Cell Death

The incorporation of chirality endows Pt(II)-based metal-organic complexes (MOCs) with unique potentials in several fields such as nonlinear optics and chiral catalysis. However, the exploration of chiral Pt(II) metallacycles in biological responses remains underdeveloped. Herein, we designed and synthesized two chiral Pt(II) metallacycles 1 and 2 via the coordination-driven selfassembly of chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-derived ligands and cis-Pt(PEt3)(2)(OTf) (2) (90 degrees Pt). Their structures were well characterized by 1H NMR, P-31{H-1} NMR, ESI-TOF-MS, and X-ray crystallography, and their photophysical properties were investigated by UV-vis absorption, fluorescence, and circular dichroism (CD) spectroscopies. Then, the antitumor activity of the two chiral metallacycles in vitro was further tested. Complexes 1 and 2 exhibited strong cytotoxicity, especially toward the A549 cells. The destruction of the mitochondrial function, the inhibition of the glutathione (GSH)/glutathione disulfide (GSSG) level, and the inactivation of superoxide dismutase (SOD) induced by complexes 1 and 2 led to the massive accumulation of reactive oxygen species (ROS). The overloaded ROS then triggered apoptotic cell death, and the release of damage-associated molecular patterns (DAMPs) further induced immunogenic cell death (ICD). To the best of our knowledge, this is the first example of Pt(II)-based metallacycles that can induce immunogenic cell death, providing a new strategy for the future design and construction of immune-modulating platinum agents in cancer therapy.

Automated summary

In this study, two chiral Pt(II) metallacycles were designed and synthesized, and their antitumor activity was tested. The results showed that these two metallacycles exhibited strong cytotoxicity, especially against A549 cells. Mechanistic studies revealed that the metallacycles induced apoptotic cell death and immunogenic cell death, providing a new strategy for the development of immune-modulating platinum agents in cancer therapy.