Metal-Flavonoid Interactions-From Simple Complexes to Advanced Systems

Abstract

For many years, metal-flavonoid complexes have been widely studied as a part of drug discovery programs, but in the last decade their importance in materials science has increased significantly. A deeper understanding of the role of metal ions and flavonoids in constructing simple complexes and more advanced hybrid networks will facilitate the assembly of materials with tailored architecture and functionality. In this Review, we highlight the most essential data on metal-flavonoid systems, presenting a promising alternative in the design of hybrid inorganic-organic materials. We focus mainly on systems containing Cu^II/I and Fe^III/II ions, which are necessary in natural and industrial catalysis. We discuss two kinds of interactions that typically ensure the formation of metal-flavonoid systems, namely coordination and redox reactions. Our intention is to cover the fundamentals of metal-flavonoid systems to show how this knowledge has been already transferred from small molecules to complex materials.

Keywords: flavonoids; hybrid materials; redox; transition metals.

Figure 1

Chemical structure of basic compounds and selected flavonoids.

Figure 2

Active sites responsible for the formation of metal–flavonoid systems and structural features of major and minor importance for the antioxidant actions (Bors criteria).

Figure 3

Various substituents and their importance for the antioxidant activity of FLs.

Figure 4

Active sites responsible for the formation of metal–flavonoid systems.

Figure 5

(A) Chemical structure of naringenin Cu(II) complex (solid state) [49]. Used with permission of Springer Nature BV, from [49]; permission conveyed through Copyright Clearance Center, Inc., Danvers, MA, USA. (B) Mechanism for Cu^II translocation in Cu^II−Lut complexes resulting from changing from 5.6 to 6.6 and pH changing from 6.6 to 5.6 [52]. Reprinted (adapted) with permission from [52]. Copyright 2020 American Chemical Society. (C) Coordination of Fe²⁺ by polyphenols and subsequent electron transfer reaction in presence of oxygen generating the Fe³⁺−polyphenol complex. Used with permission from Springer Nature BV, from [53]; permission conveyed through Copyright Clearance Center, Inc. (D) Coordination of Fe³⁺ by polyphenols, subsequent iron reduction and semiquinone formation, and reduction in Fe³⁺ to form quinone species and Fe²⁺. R=H, OH [53]. Used with permission from Springer Nature BV, from [53]; permission conveyed through Copyright Clearance Center, Inc. (E) Distribution diagrams in presence of H₅Que of Fe^III (C_M = 0.5 mM and C_L = 0.7 mM) [54]. Used with permission from Elsevier Science & Technology Journals, from [54]; permission conveyed through Copyright Clearance Center, Inc.

Figure 6

Schematic view on redox activity of pre-formed (left) and in situ (right) produced Cu^II–luteolin complexes. (A) pH-dependent coordination and translocation of Cu^II between 5-OH/4-C=O and the 3′−OH/4′−OH sites based on work by Xu et al. [52] (B) Time-dependent reactivity of pre-formed Cu^II−luteolin M:L 1:1 against ABTS^•+ cation radicals. Upper plot (a): activity of species formed at pH 5.60; bottom plot (b): activity of species formed at pH of 7.20 [52]. Reproduced with permission from [52]. Copyright 2020, American Chemical Society. (C) Coordination with Cu^II affects the strength of O−H bonds. The impact of Cu^II was deduced based on DI parameters [51]. Red circles: faster proton cleavage. Blue circle: disturbed proton cleavage. (D) Time-dependent scavenging of DPPH^• radicals provided by in situ Cu^II−luteolin [85]. Reproduced with permission from [85]. Copyright 2022, Lee and Heffern. (E) Copper-catalyzed Fenton reactions. (F) EPR spin-trapping performed for in situ Cu^II−luteolin at different M:L molar ratios. DMPO was used as spin trap and H₂O₂ was applied to initiate Fenton reactions [86]. Reprinted from [86]. Copyright 2022, with permission from Elsevier. (G) Anti-Fenton activity of in situ Cu^II–luteolin verified by the ROS−catalyzed DNA cleavage experiment [86]. Reprinted from [86]. Copyright 2022, with permission from Elsevier.

Figure 7

(A) A schematic view on the concept of the coordination-driven assembly of MPNs on a templating surface. Fe^III and quercetin were used to mediate the assembly. The network was established involving three different coordination sites [8]. Used with permission from the Royal Society of Chemistry, from [8]; permission conveyed through the Copyright Clearance Center, Inc. (B) Characterization of MPN films (a); PSs are the uncoated particular substrates, and the remaining systems are the films prepared from Fe^III–quercetin and Fe^III–myricetin. From left to right: differential interference contrast (DIC) microscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) with the height profile (b) [8]. Used with permission from the Royal Society of Chemistry, from [8]; permission conveyed through the Copyright Clearance Center, Inc. FLs with multiple coordination sites enable the construction of MPNs by engaging different parts of the structures. Moreover, the control over coordination gives the possibility of constructing materials with high precision of structure and functionality. Switching the binding between catechol, carbonyl, and hydroxyl groups delivers more flexible materials. In this way, the mechanical and physicochemical properties of MPNs can be easily tuned only by directing cross-linking. The synthesis of MPNs with an approach of site-selective coordination was investigated on FLs containing the 4-C=O group, namely quercetin, chrysin, 3-hydroxyflavone, and 3′,4′-dihydroxyflavone. All these ligands served as binding modulators and Fe^II and Fe^III ions were used to trigger coordination and cross-linking [8]. In general, the coordination with Fe^III was more favorable because of the production of thermodynamically stable systems.

Figure 8

(A) The preparation of MPNs using the spray-assembly method. Solutions of FLs and metal ions are alternately sprayed onto a solid substrate [92]. Reproduced with permission [92]. Copyright 2018, American Chemical Society. (B) Coordination sites involved in the assembly of MPNs. (C) The characterization of Fe^III–quercetin films prepared onto various substrates: iron plates, glass, polystyrene (PS), polypropylene (PP), and polyurethane (PU) [92]. Reproduced with permission [92]. Copyright 2018, American Chemical Society.

Figure 9

(A) The procedure of the preparation of MPNs using a green tea (GT) infusion (a) as the source of flavonoids and rusted nails (b) as the source of metal ions. The GT infusion was prepared in hot water (c), followed by filtration and cooling to room temperature (d). PMMA microparticles were added to the GT infusion to serve as a solid template. Rusted nails were incubated in the GT infusion to initiate the assembly of Fe^III-GT networks (e–h). The DIC image (i) confirmed the formation of hollow capsules after template removal [93]. Reproduced with permission [93]. Copyright 2018, American Chemical Society. (B) The characterization of Fe^III-GT capsules. Top-left (a): UV-Vis absorption spectra of the GT infusion and Fe^III-GT capsules suspension. Top-right (b): AFM image. Bottom-left (c): TEM image. Bottom-right (d): EDX spectrum confirming the coordination with Fe^III in the formed MPN [93]. Reproduced with permission [93]. Copyright 2018, American Chemical Society.