Heterometallic Ferrocenyl Complexes and Their Application in the Treatment of Cancer

Abstract

Ferrocene, a stable 18‐electron metallocene, has been readily modified to include other functionalities by reactions such as Friedel–Crafts and Mannich. While ferrocene and its derivatives have many applications, for example, as fuel additives and materials chemistry, they have been heavily researched in the past three decades for their medicinal applications; namely, tamoxifen, a well‐known breast cancer drug, has been modified with ferrocene (ferrocifen) to improve breast cancer selectivity, and chloroquine, an antimalarial drug, was modified with ferrocene to improve its activity in chloroquine‐resistant malarial strains. In these two molecules, ferrocene imparts a metal‐specific effect, enhancing the therapeutic potential of these complexes. Ferrocifen and ferroquine are currently in phase II clinical trials and preclinical evaluation, respectively. No other ferrocene‐containing complexes have reached clinical trial stages. One strategy that could fast‐track these complexes to an advanced stage is to develop heterometallic complexes, as they often exhibit enhanced pharmacological properties and have different biological targets compared to their homometallic/mononuclear counterparts. In this article, we have highlighted the area of heterometallic ferrocenyl complexes and their applications in the treatment of cancer and look at the most promising complexes to date.

Cytotoxicity of Ruthenium(II) Arene Complexes Containing Functionalized Ferrocenyl β-Diketonate Ligands

“…18 Heterobimetallic species have the potential benefit of both metals working together, and by combining ruthenium and ferrocene into a singular complex, it is possible to have synergistic effects against cancer cells. 17,19,20 Alongside other research groups, in 2021, we reported the synthesis of heterobimetallic ruthenium−ferrocenyl complexes, [(bpy) 2 (Fc-acac)Ru][PF 6 ] (bpy = 2,2′-bipyridine; Figure 1F) 21 and highlighted their excellent nanomolar cytotoxicity against both human pancreatic carcinoma (MIA PaCa-2) and human colorectal carcinoma p53-wildtype (HCT116 p53 +/+ ) cell lines with dose-dependent double-strand DNA damage, which is correlated to their cytotoxicity. In 2022, Manikandan et al reported Ru(II) piano-stool complexes of the type [(arene)RuCl(Fc-acac)], where arene = p-cymene (p-cym) or 1,2,3,4,5-pentamethylcyclopentadiene (Cp*) and Fc-acac = a functionalized ferrocenyl β-diketonate ligand with either a methyl or trifluoromethyl group (Figure 1G).…”