Anticancer Effect of an Electronically Coupled Oligoferrocene

Abstract

The mode of anticancer activity of simple ferrocenes often relies on their intracellular oxidation with the formation of cytotoxic ferrocenium species. The former compounds should be considered as prodrugs and derived from them ferroceniums as drugs. The drugs are 17e– organometallic species. Therefore, they are chemically unstable and decompose with formation of free cyclopentadienyl ligands (which are further transformed to more stable species) and iron ions. The short lifetime of ferrocenium drugs limits the anticancer effect of ferrocene prodrugs. In this paper we prepared a series of acylated aminoferrocene monomers, dimers, and higher oligonuclear complexes FcN (where N = 1–4). Drugs [FcN]+ derived from FcN (N > 1) are more stable than monomeric [Fc]+, provided that the ferrocene units are electronically coupled. Correspondingly, we expected that FcN species will be more potent anticancer agents in comparison to the related monomers. These assumptions were confirmed for dimer 10. We observed that this prodrug has sufficient solubility in aqueous solution (100 μM) and favorable lipophilicity (log P = 2.2 ± 0.2). Ferrocene units in 10 are efficiently electronically coupled via a −C(═O)NH– linker according to cyclic voltammetry, differential pulse voltammetry, and spectroelectrochemistry. We observed that 10 is the most efficient catalyst of the production of reactive oxygen species (ROS) and the most active anticancer agent in comparison to control monomers and their mixtures.