International Journal of Molecular Sciences Review Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond ZdenˇekKejík 1,2,3 , Robert Kaplánek 1,2,3, Michal Masaˇrík 1,2,4,5, Petr Babula 4, Adam Matkowski 6 , Petr Filipenský 7, KateˇrinaVeselá 1,2,3, Jakub Gburek 8, David Sýkora 1,3 , Pavel Martásek 1 and Milan Jakubek 1,2,3,* 1 Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, CZ-121 08 Prague, Czech Republic; [email protected] (Z.K.); [email protected] (R.K.); [email protected] (M.M.); [email protected] (K.V.); [email protected] (D.S.); [email protected] (P.M.) 2 BIOCEV, First Faculty of Medicine, Charles University, Prague, CZ-252 50 Vestec, Czech Republic 3 Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, CZ-166 28 Prague, Czech Republic 4 Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; [email protected] 5 Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic 6 Department of Pharmaceutical Biology and Botany, Wroclaw Medical University, Borowska 211, 50556 Wroclaw, Poland; [email protected] 7 Department of Urology, St. Anne’s University Hospital Brno, Pekaˇrská 53, 656 91 Brno, Czech Republic; petr.fi[email protected] 8 Department of Pharmaceutical Biochemistry, Wroclaw Medical University, Borowska 211A, 50556 Wroclaw, Poland; [email protected] * Correspondence: [email protected] Abstract: Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition Citation: Kejík, Z.; Kaplánek, R.; metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. Masaˇrík,M.; Babula, P.; Matkowski, A.; Filipenský, P.; Veselá, K.; Gburek, The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by J.; Sýkora, D.; Martásek, P.; et al. Iron their interaction with transition metal ions, mainly iron. In this review, we explain the interaction Complexes of Flavonoids-Antioxidant of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of Capacity and beyond. Int. J. Mol. Sci. chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their 2021, 22, 646. https://doi.org/ iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in 10.3390/ijms22020646 this review. Received: 4 December 2020 Keywords: flavonoids; iron ions; metallocomplexes Accepted: 2 January 2021 Published: 11 January 2021 Publisher’s Note: MDPI stays neu- 1. Introduction tral with regard to jurisdictional clai- ms in published maps and institutio- Flavonoids represent a group of secondary (specialized) metabolites (approx. up to nal affiliations. 10,000) that are widely distributed in the plant kingdom. Collectively, they are a subclass of phenolics and remain the most intensively studied group of polyphenols, responsible for many health benefits attributable to high vegetable consumption and using polyphenol- rich herbs. Copyright: © 2021 by the authors. Li- They perform a variety of functions, mainly ecological (giving a characteristic colour censee MDPI, Basel, Switzerland. to plant organs, especially flowers and fruits), and they also participate in the regulation This article is an open access article of plant development and growth, as well as plant–microbe and plant–animal interac- distributed under the terms and con- tions (signalling functions) [1]. Due to strong antioxidant properties, they are involved ditions of the Creative Commons At- in UV protection. They are intensively discussed and studied thank their positive influ- tribution (CC BY) license (https:// ence on human health. Flavonoids occur both in free state and as glycosides (O- or C-). creativecommons.org/licenses/by/ The structure of flavonoids consists of a diphenylpropane (C6–C3–C6, benzo-γ-pyrone) 4.0/). Int. J. Mol. Sci. 2021, 22, 646. https://doi.org/10.3390/ijms22020646 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 21 Int. J. Mol. Sci. 2021, 22, 646 human health. Flavonoids occur both in free state and as glycosides (O- or C-). The 2 of 20 structure of flavonoids consists of a diphenylpropane (C6–C3–C6, benzo-γ-pyrone) skel- eton [2], but biosynthetically, they originate from the general phenylpropanoid pathway complemented with malonyl-CoA to form the final core structure of flavane. Further, when the B ring is moved from position 2 of the C-ring to the carbon atom in position 3, skeletonthe isoflavones [2], but biosynthetically, are formed, whereas they those originate in which the from B ring the is general linked in phenylpropanoidposition 4 are path- way complementedcalled neoflavonoids. with However, malonyl-CoA B ring remains to form in position the final 2 of corethe basic structure flavane ofskeleton flavane. Further, whenwhich the B can ring be subdivided is moved into from different position subgroups 2 of thedepending C-ring the to degree the carbonof unsaturation atom in position 3, theand isoflavones oxidation of are the formed,C ring. These whereas subgroups those are: in flavones, which flavonols, the B ring flavanones, is linked fla- in position 4 are calledvanonols, neoflavonoids. flavanols or catechins, However, and chalcones B ring (you remains can see in in Figure position 1) [3]. 2 of the basic flavane Specific flavonoids form can be represent by anthocyanidins and anthocyanins (their skeletonglycosylated which can form), be derivates subdivided of 2-phenylbe into differentnzopyrylium subgroups cation [4]. depending Unlike other the flavo- degree of unsat- urationnoids, and they oxidation are intensive of the pigments, C ring. and These are responsible subgroups for the are: red, flavones, blue and purple flavonols, color flavanones, flavanonols,of many flavanolsplant parts. or The catechins, most common and anth chalconesocyanidins (you are cancyanid seein, in delphinidin, Figure1)[ pe-3]. onidin, malvidin, petunidin, and pelargonidin. Figure 1. BasicFigure flavonoid 1. Basic structure flavonoid showing structure showing rings A, rings B and A, B C and and C theand numbering,the numbering, flavonoids flavonoids and chalcone chalcone chemical chemical structures. structures. SpecificIt has flavonoids been repeatedly form postulated can be represent that theseby compounds anthocyanidins can be beneficial and anthocyanins in the pre- (their gly- cosylatedvention form), of numerous derivates diseases, of 2-phenylbenzopyrylium particularly oncological, cardiovascular, cation [4]. Unlikemetabolic other and flavonoids, they areneurodegenerative intensive pigments, diseases and[5–11]. are responsible for the red, blue and purple color of many plant parts.Numerous The most works common proved anthocyanidinsvarious anticancer areeffects cyanidin, of flavonoids. delphinidin, For example, peonidin, quer- malvidin, cetin can reduce can activity of a nuclear factor kappa B and expression of the P-glycopro- petunidin, and pelargonidin. tein and thereby angiogenesis and multidrug resistance and cell migration [12–14]. Simi- Itlarly, has Gates been et al. repeatedly publish, that postulated kaempferol can that significantly these compounds decrease a riskcan of ovarian be beneficial can- in the preventioncer [15]. of Other numerous important diseases, benefit of particularlyflavonoid application oncological, could becardiovascular, the reduction of drug metabolic and neurodegenerativetoxicity. Mojžíšová diseases et al. found, [5– that11]. quercetin decrease daunorubicin-induced toxicity for Numerouscardiomyoblasts works [16]. proved various anticancer effects of flavonoids. For example, In this case of cardiovascular diseases, therapeutic effects of flavonoids (e.g., querce- quercetintin, or can kaempferol) reduce include can activity antihypertensive of a nuclear properties factor and kappaimproved B endothelial and expression func- of the P- glycoproteintions [17,18]. and Hang thereby et al. angiogenesisreport that patients and with multidrug rheumatoid resistance arthritis after and bajcalin cell migration treat- [12–14]. Similarly,ment Gateshave decreased et al. publish, levels of apolipoproteins, that kaempferol triglycerides, can significantly as well as total- decrease and low a den- risk of ovarian cancersity [15 lipoprotein]. Other importantcholesterol, and benefit a lower of flavonoidrisk of the corona applicationry artery disease could be[19]. the Bakker reduction et of drug al. found that Montmorency cherry supplement (235 mg/per day anthocyanins) enhanced toxicity. Mojžíšová et al. found, that quercetin decrease daunorubicin-induced toxicity for the recovery of an endothelium-dependent vasodilatation after ischemia-reperfusion in- cardiomyoblastsjury [20]. [16]. In thisFlavonoids case of cardiovascularare also promising diseases, agents for therapeuticthe treatment effectsand prevention of flavonoids of metabolic (e.g., quercetin, or kaempferol)diseases. Vital include et al. found antihypertensive that cyanidin propertiesand delphinidin and glucosides improved are endothelial potent inductors functions