UC San Diego

The discovery of ferrocene in 1951 and subsequent structure elucidation essentially founded the field of modern organometallic chemistry. The remarkable stability of the sandwich complex’s iron-carbon bonds and ease of derivatization have made the archetypal metallocene ubiquitous across an array of scientific disciplines. Coupled with the wealth of literature available on ferrocene functionalization and the complex’s stability in aqueous and aerobic media, it is no wonder ferrocene has gained widespread popularity among anti-cancer researchers in particular.

Our research has explored two avenues of cytotoxicity for ferrocene-based antitumor agents. First, we wished to explore selective generation of cytotoxic metals in tumor cells. To this end, we describe the preparation of a series of ferrocene derivatives that are photosensitive and undergo successive ring--slips to form cyclopentadienes and inorganic iron(II) when exposed to visible light. We proposed the photochemically generated iron(II) would form reactive oxygen species in situ by reaction with endogenous hydrogen peroxide, forming the highly toxic hydroxyl radical via the Haber Weiss Cycle. The synthesis, characterization, photochemical properties, and biological activity of the synthesized antitumor agents were examined in detail. Second we wished to take advantage of the unique photochemical properties of benzoylferrocene to selectively deliver cytotoxic enediyne ligands to tumor cells. We proposed that once the organoferrous enediynes were localized within the cell, irradiation with visible light would trigger enediyne cycloaromatization. The reactive para-benzyne diradical could abstract hydrogen atoms from DNA in a similar manner to that of the enediyne antibiotics. To this end we describe the preparation of I, which was expected to cyclize intramolecularly to form para-benzyne. Then we describe the synthesis and characterization of ferrous enediynes II-IV, which are extremely light sensitive upon irradiation. The biological activity of selected ferrous enediynes in both the light and dark is also provided and discussed.