Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species

Elevated levels of reactive oxygen species (ROS) and deficient mitochondria are two weak points of cancer cells. Their simultaneous targeting is a valid therapeutic strategy to design highly potent anticancer drugs. The remaining challenge is to limit the drug effects to cancer cells without affecting normal ones. We have previously developed three aminoferrocene (AF)‐based derivatives, which are activated in the presence of elevated levels of ROS present in cancer cells with formation of electron‐rich compounds able to generate ROS and reduce mitochondrial membrane potential (MMP). All of them exhibit important drawbacks including either low efficacy or high unspecific toxicity that prevents their application in vivo up to date. Herein we describe unusual AF‐derivatives lacking these drawbacks. These compounds act via an alternative mechanism: they are chemically stable in the presence of ROS, generate mitochondrial ROS in cancer cells, but not normal cells and exhibit anticancer effect in vivo. An unusual aminoferrocene (AF) agent (3 d) is reported, which does not react with reactive oxygen species (ROS) in contrast to usual AF agents (e. g., 3 b) and exhibits excellent anticancer effects in a variety of cancer cells and in a murine cancer Nemeth‐Kellner lymphoma (NK/Ly) model. The mode of action relies on the increase of the level of mitochondrial ROS (mROS), whereas usual AF agents (e. g. 3 b) do not affect mROS.