Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells

Abstract

Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide–alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3′-azido-3′-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 μM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.