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

Abstract

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, Erβ, and JAK2 proteins. Dock pose analysis also shed light into the possible mechanism of action for the studied compounds.

New insights into the competition between antioxidant activities and pro-oxidant risks of rosmarinic acid

“…1,3,4 This causes several diseases such as cancers, heart diseases, and Alzheimer's disease. [5][6][7][8][9][10][11] Many methods have been used to protect human health from OS. Among them, the use of antioxidant compound supplementary provided from natural products or diets is one of the most effective ways.…”

“…14 Similarly, different phenolic compounds have also been analyzed for evaluating their scavenging activities towards peroxyl radicals: propyl gallate, 15 esculetin, 16 transresveratrol, 17 capsaicin, 18 sinapinic acid, 19 piceatannol, 20 genistein, daidzein, glycitein, equol, 6-hydroxydaidzein, 8-hydroxiglycitein, 21 and dihydroxybenzoic acids. 22 The hydroxycinnamic acids, a class of polyphenol compounds, have already demonstrated their benets to human health, including antioxidant, 9,12,23 anticancer, 7,24 anti-inammatory, 25,26 and antiviral 27 activities. The antioxidant activity of hydroxycinnamic acids and their derivatives has attracted the attention of many researchers.…”

“…The antioxidant activity of hydroxycinnamic acids and their derivatives has attracted the attention of many researchers. [5][6][7][8][9][10][11][12]23,28 Owing to the presence of phenolic hydroxyl groups and the participation of large conjugated systems, many hydroxycinnamic acids are expected to have high free radical scavenging activities based on the H-atom transfer from the -OH group. 5,6 In addition, the secondary antioxidant activity via transition metal ion chelation of hydroxycinnamic acids has also been well reported.…”

“…The hydroxycinnamic acids, a class of polyphenol compounds, have already demonstrated their benefits to human health, including antioxidant, 9,12,23 anticancer, 7,24 anti-inflammatory, 25,26 and antiviral 27 activities. The antioxidant activity of hydroxycinnamic acids and their derivatives has attracted the attention of many researchers.…”

Ferrocene conjugates linked by 1,2,3‐triazole and their Zn(II) and Cu(II) complexes: Synthesis, characterization and biological activity

“…[1,[11][12][13] Ferrocene-based conjugates in which ferrocene derivatives are linked to other compounds via selected linkers have been found to exhibit antiproliferative activity with low toxic effects when compared with known anticancer agents (Figure 1). [14][15][16] The antitumour activity of ferrocene-based compounds generally depends on the oxidation state of the central iron atom. Ferrocene can undergo a one-electron oxidation process, yielding the ferrocenium cation.…”