Antioxidant and Anticancer Properties of Functionalized Ferrocene with Hydroxycinnamate Derivatives-An Integrated Experimental and Theoretical Study.

Two ferrocenyl derivatives, Fc-CA and Fc-FA, were synthesized by a condensation reaction between the amino ferrocene and hydroxycinnamic acids, that is, caffeic acid (CA) and ferulic acid (FA). The structures and purity of all compounds were characterized by 1H- and 13C NMR spectroscopies, Mass spectrometry (MS), and elemental analysis. The antioxidant properties of Fc-CA and Fc-FA and of its ligand were studied for free radical scavenging activity toward DPPH•, superoxide anion (O2•-), NO•, and ABTS•+ by UV-vis and electron spin resonance spectroscopies. The cytotoxicity of Fc-CA and Fc-FA against MCF-7 and MDA-MB-231 breast cancer cells and MRC-5 human lung fibroblasts cell was higher than that of cisplatin. The geometry and electronic structures of all compounds were then simulated using density functional theory at M05-2X/6-311+G(d,p) level of theory. Thermodynamics of the free radical quenching reactions by common mechanisms reveal the higher antioxidant properties of the Fc-CA and Fc-FA in comparison to their ligands. An in-depth study of the free radical scavenging activity against HOO• and HO• radicals was performed for two of the most favorable and competitive mechanisms, the hydrogen transfer (either hydrogen atom transfer or proton-coupled electron transfer mechanisms) and the radical adduct formation. The in silico studies indicated that ferrocenyl derivatives exhibited prominent binding affinity to protein models in comparison to CA and FA. Their dock scores were notable at ligand binding sites of ERα, Erß, and JAK2 proteins. Dock pose analysis also shed light into the possible mechanism of action for the studied compounds.