molecules Review The Antioxidant Activity of Prenylflavonoids Clementina M. M. Santos 1,* and Artur M. S. Silva 2,* 1 Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal 2 QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal * Correspondence: clems@ipb.pt (C.M.M.S.); artur.silva@ua.pt (A.M.S.S.) Received: 3 January 2020; Accepted: 3 February 2020; Published: 6 February 2020 Abstract: Prenylated flavonoids combine the flavonoid moiety and the lipophilic prenyl side-chain. A great number of derivatives belonging to the class of chalcones, flavones, flavanones, isoflavones and other complex structures possessing different prenylation patterns have been studied in the past two decades for their potential as antioxidant agents. In this review, current knowledge on the natural occurrence and structural characteristics of both natural and synthetic derivatives was compiled. An exhaustive survey on the methods used to evaluate the antioxidant potential of these prenylflavonoids and the main results obtained were also presented and discussed. Whenever possible, structure-activity relationships were explored. Keywords: ABTS assay; antioxidant; chelation studies; DPPH radical; flavonoids; FRAP; lipid peroxidation; natural products; prenyl; ROS 1. Introduction Flavonoids are oxygen heterocyclic compounds widespread throughout the plant kingdom. This class of secondary metabolites are responsible for the color and aroma of many flowers, fruits, medicinal plants and plant-derived beverages and play an important protective role in plants against different biotic and abiotic stresses. Flavonoids are also known for their nutritional value and positive therapeutic effects on humans and animals [1,2]. The basic structure of a flavonoid consists of a dibenzo-γ-pyrone framework and the degree of unsaturation and oxidation of the C ring defines the subclasses of this compounds such as chalcones, flavones, isoflavones and their dehydro derivatives. Different substitution patterns that includes hydroxyl, methyl, methoxyl, prenyl and glycosyl groups can be attached to the flavonoid unit, varying the number, type and position of the substituents [3]. Over the past two decades there have been an increasing number of reports on the isolation of prenylated flavonoids, belonging to the Leguminosae and Moraceae families, with some distribution among others such as Cannabaceae, Euphorbiaceae, Guttiferae, Rutaceae, Umbelliferae, etc. [4,5]. Barron and Ibrahim reviewed more than 700 prenylated flavonoids up to the end of 1994 [5] and Botta et al. compiled it from 1995 till 2004 [6]. Most of the prenylated flavonoids have been identified as chalcones, dihydrochalcones, flavones, flavanones, flavonols and isoflavones, being C-prenyl more common than O-prenyl derivatives. In addition, prenyl side-chains can include variations in the number of carbons, oxidation, dehydration, cyclization or reduction to give a huge array of compounds with an impressive antioxidant potential [4]. Along the manuscript, “prenyl” will be used a general term to identify prenyl/isopentenyl, geranyl and farnesyl side chains as well as furano or dimethylchromano derivatives. The beneficial effects of flavonoids appear to be related to the various biological and pharmacological activities as anti-inflammatory, antimicrobial, antioxidant, antitumor, estrogenic, Molecules 2020, 25, 696; doi:10.3390/molecules25030696 www.mdpi.com/journal/molecules Molecules 2020, 25, 696 2 of 33 and immunosuppressive properties, among others. According to the literature, prenylation of flavonoids can induce an increase in their bioactivities namely as antimicrobial and anticancer agents, however, a decrease in the bioavailability and plasma absorption is recorded, when compared to related non-prenylated derivatives [7–11]. TheMolecules available 2019, 24 information, x FOR PEER REVIEW concerning the antioxidant activity of prenylated flavonoids2 of 32 is sparse, appearing some studies in a couple of review papers [7,8]. Taking into account our both interest (organicflavonoids and medicinal can induce chemistry) an increase for in the their identification bioactivities namely of prenylated as antimicrobial flavonoids and anticancer that has agents, already been tested forhowever, their antioxidanta decrease in activity,the bioavailability a systematic and pl revisionasma absorption of the literature is recorded, was when made compared using PubMedto ® related non-prenylated derivatives [7–11]. and Web of Knowledge® databases. The research was limited to the 21st century, with publications The available information concerning the antioxidant activity of prenylated flavonoids is sparse, from Januaryappearing 2000 some to Octoberstudies in 2019, a couple using of thereview terms papers “prenyl”, [7,8]. Taking “flavonoid”, into account “prenylated our both interest flavonoid” in combination(organic with and “antioxidant”, medicinal chemistry) as keywords. for the identification After a careful of prenylated analysis offlavonoids nearly one thathundred has already of papers, we excludedbeen tested many for of their them antioxidant due to the activity, absence a syst ofematic the antioxidant revision of the eff ectsliterature for thewas target made compounds,using leavingPubMed® 59 papers and to beWeb included of Knowledge and discussed® databases. in The the research present was review. limited to the 21st century, with Herein,publications it is our from propose January 2000 to organize to October and 2019, summarize using the terms the “prenyl”, structural “flavonoid”, and chemical “prenylated diversity of flavonoid” in combination with “antioxidant”, as keywords. After a careful analysis of nearly one naturalhundred and synthetic of papers, flavonoids we excluded applied many of as them antioxidants, due to the absence providing of the theantioxidant main ineffects vitro forand the in vivo methodologiestarget compounds, used in thisleaving field 59 ofpapers research. to be included This information and discussed is in very the present useful review. for organic chemists to know the trendsHerein, of it structure-antioxidant is our propose to organize activity and summa relationship,rize the structural in order and to develop chemical ediversityfficient routesof for the totalnatural synthesis and synthetic of natural flavonoids derivatives, applied to as develop antioxidants, improved providing strategies the main to in maximize vitro and in the vivo synthesis of suchmethodologies natural and syntheticused in this compoundsfield of research. or This even information in the design is very and useful synthesis for organic of chemists novel flavonoids to know the trends of structure-antioxidant activity relationship, in order to develop efficient routes for with different prenyl substituents in different positions of the main skeleton. So, the studies here the total synthesis of natural derivatives, to develop improved strategies to maximize the synthesis summarizedof such and natural the promisingand synthetic results compounds obtained or even highlights in the design the importance and synthesis of of prenylated novel flavonoids flavonoids as potentialwith antioxidant different prenyl agents. substituents in different positions of the main skeleton. So, the studies here summarized and the promising results obtained highlights the importance of prenylated flavonoids 2. Naturalas potential Occurrence antioxidant and Structuralagents. Variation of Prenylflavonoids with Antioxidant Activity From2. Natural the natural Occurrence prenylflavonoids and Structural Variation with antioxidant of Prenylflavonoids activity mostwith Antioxidant of them are Activity from Moraceae and Fabaceae families with a limited number of derivatives from Apiaceae, Asteraceae, Cannabaceae, From the natural prenylflavonoids with antioxidant activity most of them are from Moraceae and Euphorbiaceae.and Fabaceae families with a limited number of derivatives from Apiaceae, Asteraceae, Cannabaceae, Theand most Euphorbiaceae. common substitution among the flavonoid family with antioxidant properties is representedThe by most the 3,3-dimethylallylcommon substitution chain. among the l,l-Dimethylallyl, flavonoid family geranyl,with antioxidant lavandulyl properties and is farnesyl units canrepresented also be by present the 3,3-dimethylallyl in such structures. chain. l,l-Dime Theythylallyl, can be geranyl, found lavandulyl in chalcones, and farnesyl dihydrochalcones, units flavones,can flavanones, also be present isoflavones, in such structures. xanthone-type They can andbe found other in complex chalcones, molecules dihydrochalcones, (Figure flavones,1). As referred flavanones, isoflavones, xanthone-type and other complex molecules (Figure 1). As referred before, before, C-prenylated compounds are more abundant than O-prenylated ones, being most of the C-prenylated compounds are more abundant than O-prenylated ones, being most of the O- O-prenylflavonoidsprenylflavonoids obtained obtained by by synthesis. synthesis. FigureFigure 1. Chemical 1. Chemical structures structures of of some some flavonoidsflavonoids and and main main prenylation prenylation patterns. patterns. Molecules 2020, 25, 696 3 of 33 Chalcone derivatives. This is the most abundant class of prenylated flavonoids with antioxidant activity, being a great number of the natural derivatives obtained from different extracts of hops [12–17], belonging to the Cannabaceae family. A limited number of derivatives