Cisplatin, the first successful metallotherapy, has been utilized over the past four decades as chemotherapy treatment of a wide range of tumors. However, due to persistent side-effects and a buildup of platinum resistance in cancer cells, alternative metallotherapies have been sought after. Ferrocene is a promising scaffold alternative due to advantages such as cost, biologically stability, and iron is a biologically relevant metal. Ferrocene compound Ferroquine, has been successful clinically as an anti-malarial compound, currently going through the third phase of clinical trial.

We have synthesized para-substituted benzoyferrocene derivatives that photochemically release free iron(II). Through the group of derivatives, we have optimized highly specific photodynamic therapy (PDT) compounds that induce no cytotoxicity in the dark but do after irradiation. It is hypothesized that the observed cytotoxicity is due to the release of iron(II), which catalyzes the Fenton reaction, leading to the formation of toxic reactive oxygen species (ROS) in the cell. Through a series of in vitro experiments, we have reported that photolysis in cells incubated with 1,1`-bis(4-n-pentylbenzoyl)ferrocene leads to a dose-dependent increase in lipid peroxidation, suggesting ferroptosis as a mechanism of cell death. Additionally, we found that ferroptosis GPx4, SOD1, and VDAC are overexpressed after irradiation. Overall this work reports ferrocene derivatives function as highly specific PDT anti-cancer agents.