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Journal of Industrial and Engineering Chemistry xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Journal of Industrial and Engineering Chemistry

journal homepage: www.elsevier.com/locate/jiec

1
2 Review

3 Structural implications of polyphenolic antioxidants

4 Q1 Kantappa Halake, Mallinath Birajdar, Jonghwi Lee *
5 Department of Chemical Engineering and Material Science, Chung-Ang University, 212 HeukSeok-Dong, DongJak-gu, Seoul 156-756, South Korea

A R T I C L E I N F O A B S T R A C T

Article history: Natural polyphenols have been used in foods, cosmetics, and medicines to exploit their functional
Received 12 December 2015 properties, including antioxidant, anti-inflammatory, antiviral, antidepressant, analgesic, anti-mutation,
Received in revised form 31 December 2015 and antitumor activities. Because of their protective property against reactive oxygen species in the
Accepted 2 January 2016
human body, which are associated with aging-related chronic diseases, polyphenols have been
Available online xxx
considered as useful building blocks for biomaterials development. Here, recent studies on common
polyphenols are summarized and their structural implications are discussed, providing insights into
their molecular structure and related properties and evaluating the effect of structural modifications
Polyphenols
such as functional rearrangements, substitution reactions, and polymeric conjugations. The fundamental
Flavones
Flavonols
understanding of the chemical structure of polyphenols could diversify the strategy for the development
Isoflavones of biomimetic, eco-friendly, and biocompatible materials.
Flavanones ß 2016 Published by Elsevier B.V. on behalf of The Korean Society of Industrial and Engineering
Catechol Chemistry.

6
7 Contents

8 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
9 Types of natural polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
10 Flavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
11 Flavonols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
12 Isoflavones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
13 Flavanone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
14 Polyphenol structures as building blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
15 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
16 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
18

19 Introduction their antioxidant activity; they are found in a wide variety of food 26
sources and are the most common active ingredients of phenolic- 27
20 Recently, natural antioxidants such as polyphenols have based plant constituents [15,16]. Polyphenols exhibit various 28
21 become the subject of active investigation for the development beneficial effects such as anti-inflammatory, anticancer, and 29
22 of future biomaterials because of their beneficial properties [1–14]. antioxidant activities [6–8]. Because of their characteristic 30
23 These structures have been used as valuable building blocks with phenolic OH groups, they have the ability to chelate highly 31
24 outstanding functionality and biocompatibility. Polyphenols be- redox-active metal ions, which strengthens their protective effect 32
25 long to the large group of flavonoids, which are well-known for against oxidative damage [16]. 33
Polyphenols are the most effective functional ingredients 34
with biological activities [17,18]. Polyphenolic-based com- 35
* Corresponding author. Tel.: +82 2 816 5269; fax: +82 2 824 3495. pounds are useful to mitigate oxidative stress and prevent or 36
E-mail address: jong@cau.ac.kr (J. Lee). delay oxidation processes by scavenging reactive radicals and 37

http://dx.doi.org/10.1016/j.jiec.2016.01.003
1226-086X/ß 2016 Published by Elsevier B.V. on behalf of The Korean Society of Industrial and Engineering Chemistry.

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38 by chelating iron [19–24]. Numerous studies have revealed Polyphenolic-based secondary metabolites of plants, which are 65
39 various functions, such as skin protection against biological the most commonly used antioxidants in humans, are abundant in 66
40 stressors, ultraviolet (UV) radiation, viruses, bacteria, and a wide variety of plant-derived foods, especially fruits, leaves, and 67
41 fungi, and assistance for the adaptation process to environ- seeds [27,29]. Their content in a regular diet is associated with a 68
42 mental conditions and cellular signal transduction. These good antioxidant performance, and their intake could be as high as 69
43 useful properties can be altered by chemical and enzymatic 1 g/day, which is much higher than that of all other classes of 70
44 treatments [25]. Dietary polyphenols play a considerable phytochemicals and known dietary antioxidants, 10 times higher 71
45 role in age-related human diseases and their prevention. than the intake of vitamin C, and 100 times higher than the intakes 72
46 Although these compounds have been extensively studied, of vitamin E and carotenoids. This clearly proves the biocompati- 73
47 their complex relation with diseases has not yet been bility of polyphenols. 74
48 thoroughly defined. Their importance is mainly based on their The present review article focuses on polyphenolic-based 75
49 positive contribution to cellular processes in the human body antioxidants and the dependence of their properties on their 76
50 and protective activity against oxidative damage by suppres- chemical structures. More specifically, hydroxyl groups and their 77
51 sion of reactive radicals [26]. These advantageous properties modification by glycosylation, acylation, conjugation with macro- 78
52 make polyphenols attractive building blocks for the develop- molecules, and substitution reactions will be extensively discussed 79
53 ment of novel biomaterials. to highlight the possible relationship between the presence of a 80
54 Commercial uses of polyphenols are based on their numerous C3 hydroxyl group and the antioxidant capacity. For simplicity, this 81
55 properties and include functional food ingredients, antioxidants article will discuss only four representative polyphenolic classes, 82
56 for preservation, cosmetic applications, etc. [27–29]. Plant-derived i.e., flavanones, flavonols, isoflavones, and flavones, and their 83
57 polyphenols have been receiving increasing attention as compared molecular structures, which are represented in Table 1. Attach- 84
58 with synthetic antioxidants such as butylated hydroxyanisole, ment of a sugar moiety to these natural products is under 85
59 butylated hydroxytoluene, and tert-butyl hydroquinone, widely development as one of the most promising tools for the design of 86
60 used in the food industry. Presently, the use of synthetic novel compounds with potential biological applications. 87
61 antioxidants is limited because of their carcinogenicity and liver In the last decade, since aging-linked chronic diseases were 88
62 toxicity, and the development and utilization of more beneficial associated with oxidative stress, the use of polyphenolic com- 89
63 and biocompatible antioxidants of natural origin significantly pounds in materials science and engineering, particularly in 90
64 increased [30]. biomaterials, has become more popular because of the preventive 91

Table 1
Basic structures of polyphenols and their numbering.

Classes Skeleton and carbon numbering of flavonoids Common examples

Flavones R1 = H (Apigenin)
R1 = OH (Luteolin)

Flavonols R1 = OH, R2 = H (Quercetin)

R1 = R2 = H (Kaempferol)
R1 = R2 = OH (Myricetin)
R1 = OMe, R2 = H (Isorhamnetin)

Isoflavones R1 = R2 = OH (Genistein)
R1 = OH, R2 = H (Daidzein)
R1 = OH, R2 = H (Glycitein)

Flavanone R1 = OH, R2 = OMe (Hesperetin)

R1 = H, R2 = OH (Naringenin)

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92 effects of natural polyphenols against reactive oxygen species R1 = H, the flavone is known as apigenin, and when R1 = OH it is 139
93 (ROS) in the human body [31]. Thus, the use of polyphenolic called luteolin [27]. Their structural diversity provides a broad 140
94 structures as building blocks is emerging as a very promising range of biological activities. Namely, the antioxidant and anti- 141
95 biomimetic approach. Natural polyphenolic groups can be inflammatory activities of flavones are widely applicable in the 142
96 incorporated in the polymeric backbone of poly(anhydride-ester)s, pharmaceutical and food industries. The 30 ,40 -catechol structure in 143
97 to generate non-cytotoxic antioxidant agents [3]. Chitosan has the B-ring is the most significant determinant of the scavenging 144
98 been modified by attaching various polyphenolic antioxidants to activity of ROS and reactive nitrogen species (RNS), leading to the 145
99 its side amine group [32]. Lee et al. reported the improved formation of ortho-semiquinone radicals stabilized by electron 146
100 degradation resistance of polyphenol–hyaluronic acid hydrogels delocalization. This structure is also responsible for strong 147
101 cross-linked by horseradish peroxidase [33,34]: In these com- adhesion of mussel-adhesion proteins [39]. Gomes et al. reported 148
102 pounds, amine-functionalized polyphenols were bonded to the that methylation of hydroxyl groups decreased the ROS and RNS 149
103 carboxyl groups of hyaluronic acid. Metal-binding properties of scavenging ability, especially when the methylation occurred in 150
104 polyphenols have been exploited to develop novel metal–organic the B-ring. 151
105 coordination materials. Guo et al. designed capsule carriers for A variety of functionalized derivatives prepared by chemical 152
106 active compounds using tannic acid and various metals, which modifications, including glycosylation, acylation, hydroxylation, 153
107 resulted in stimuli-responsive stable materials [4]. Recently, van and methylation, further increase the complexity of these 154
108 Lith et al. introduced antioxidant structures into polyesters, in secondary metabolites. Generally, glycosylation reactions enhance 155
109 order to attenuate oxidative stress-related disorders and improve the solubility of lipophilic secondary metabolites. Thus, most 156
110 the biocompatibility [35]. flavones exist in their glycosylated forms, exhibiting higher 157
stability, bioactivity, and solubility; nevertheless, aglycones are 158
111 Types of natural polyphenols also present in large amounts. Besides glycosylation, several other 159
modifications such as hydroxylation, malonylation, methylation, 160
112 Polyphenols are ubiquitous in plants and constitute a large class and sulfation are common reactions for the diversification of 161
113 of compounds containing various phenolic groups, which are flavones. Among the various flavonoids reported, amentoflavone is 162
114 responsible for the antioxidant activity. Polyphenols belong to the the dimeric form of apigenin and is called biflavonoid. Possible 163
115 class of flavonoids comprising 15 carbon atoms, arranged in two dimer combinations include flavanone–flavone, flavone–flavone, 164
116 aromatic rings connected by a heterocyclic three-carbon ring and and flavone–flavonol. Along with their primary properties such as 165
117 having a molecular skeleton of C6–C3–C6, as shown in Table 1. The antioxidant, antiviral, antidepressant, anti-inflammatory, and 166
118 six membered rings, which are designated as A, B, and C, contain analgesic activities, they also possess a variety of biological 167
119 several hydroxyl groups and engage in multiple intra- and functions such as enzymatic inhibition [40]. 168
120 intermolecular interactions [36]. In the C6–C3–C6 skeleton, the Flavonoids exhibited different levels of activity against 169
121 extended conjugation of the carbon–carbon double bonds with the Escherichia coli and free radicals, and their structure-activity 170
122 4-oxo functionality resulted in enhanced antioxidant activity, as relationship is critical [27]. The antibacterial and antioxidant 171
123 shown in Fig. 1. The most common subclasses of polyphenols are effects of flavonoids have been found to be related to the 172
124 flavones, flavonols, isoflavones, and flavanones, which are usually arrangement of functional groups in their molecular structures, 173
125 isolated by extraction with an appropriate solvent, selected namely the number, the position, and the substitution of the 174
126 according to the properties of the target solute [21,37]. Pure hydroxyl groups. For instance, it has been reported that methoxy- 175
127 alcohol or water–alcohol mixtures are used for the extraction of substituted moieties decrease the antibacterial activity of flavo- 176
128 more polar aglycones or flavonoid glycosides, whereas organic noids. Wu et al. revealed that tangeritin and 5,6,7,40 -tetramethox- 177
129 solvents, including chloroform, dichloromethane, diethyl ether, yflavone exhibit lower antibacterial activity than the 178
130 and ethyl acetate, and water–alcohol mixtures are used for less corresponding flavonoids, demonstrating that methoxy substitu- 179
131 polar flavonoids (isoflavones, flavanones, methylated flavones, and tion of the 5-OH group of the A-ring inhibits the growth of E. 180
132 flavonols). Polyphenols occur in both simple and polymeric forms coli. However, the methoxy group at C8 of the A-ring appears to 181
133 (e.g., tannins, which are commonly found in tea) [17]. Substitution enhance the antibacterial activity. Thus, tangeritin, which differs 182
134 of polyphenols results in various compounds, which were grouped from 5,6,7,40 -tetramethoxyflavone for the presence of a methoxy 183
135 in different classes. group at this position, showed higher activity than 5,6,7,40 - 184
tetramethoxyflavone [41]. 185
136 Flavones
Flavonols 186
137 Flavones are structurally similar to flavonols and differ only in
138 the lack of oxygenation at the C3 position (Table 1) [38]. When The basic backbone structure of flavanols consists of a 3- 187
hydroxybenzopyran and various hydroxyl groups distributed on 188
both rings A and B. They are widely found in the plant kingdom, 189
with the exception of fungi and algae. The most common flavonols 190
include kaempferol, quercetin, isorhamnetin, and myricetin, 191
illustrated in Table 1. They exhibit a characteristic conjugation 192
with the hydroxyl groups at the 5, 7, 30 , 40 , and 50 positions [38], and 193
the 3-hydroxy group is typically substituted with monosacchar- 194
ides, disaccharides, and acyl groups; the monosaccharides include 195
glucose, rhamnose, galactose, fucose, and arabinose, and the 196
disaccharides include rhamnose-glucose. In plants, the aglycone 197
quercetin occurs predominantly in the form of glycosides such as 198
isoquercetin and rutin [27]. Glycosylated quercetin and other 199
glycosylated flavonols were reported to have considerably 200
Fig. 1. Polyphenols with extended conjugation to stabilize free radicals in the C6– enhanced water solubility as compared with the corresponding 201
C3–C6 carbon skeleton. aglycones, which resulted in improved extraction yields [42]. 202

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203 Because of their bioavailability, O-glycosylated flavonols are key role in the inhibition of nitric oxide (NO), which is a typical 265
204 frequently selected for the analysis of potential effects on the anti-inflammatory biomarker [53]. Evaluation of the scavenging 266
205 antioxidant activity. activity against reactive free radicals is useful for gaining insight 267
206 Kaempferol, isolated from tea and vegetables such as broccoli, into the structural arrangement of flavanone derivatives. Investi- 268
207 grapefruit, Brussels sprouts, and apples, has been reported to have gation of the radical scavenging activity of naringin and hesperidin 269
208 antioxidant, antimutation, and anticancer activities [15]. Its showed that methoxy groups at positions 30 , 40 , and 50 enhanced 270
209 extremely poor oral bioavailability limits its use as an anticancer the activity of 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulphonic 271
210 agent [22,43]; however, the combination of kaempferol with other acid) [53]. A high inhibitory activity against NO production in 272
211 anticancer agents such as quercetin significantly enhanced the stimulated anti-inflammatory macrophages was also observed. 273
212 anticancer effects of quercetin [44]. In addition, the poor Thus, the position of the methoxy groups in flavanones is closely 274
213 bioavailability of kaempferol has been shown to increase the related to the anti-inflammatory and antioxidant activities [53]. 275
214 bioavailability of other anticancer agents. On the other hand, the aglycones of flavanones, such as 276
215 Kaempferol exhibited higher antioxidant activity than (+)-a- eriodictyol, contain adjacent dihydroxy groups on the B-ring 277
216 tocopherol and L-ascorbic acid [15]. Astragalin (kaempferol-3-O- (catechol moiety). Among flavanones, eriodictyol is a metabolite 278
217 glucoside) and kaempferol showed better cellular protective that exhibits strong activity [54,55]. Flavanone aglycones, namely 279
218 effects than (+)-a-tocopherol. Moreover, in vitro permeation hesperetin, eriodictyol, and isosakuranetin, are obtained via 280
219 experiments, kaempferol permeated deeper into the skin than various reactions such as methylation or hydroxylation 281
220 astragalin [15]. These results indicate that kaempferol and [56,57]. Naringenin and hesperetin glycosides are of particular 282
221 astragalin could be applicable to new antioxidant and antiaging interest because of their high prevalence in grapefruit and orange, 283
222 cosmeceuticals. These phytochemicals serve a wide range of respectively [58,59]. These compounds have preventive activity 284
223 physiological functions in plants, mainly related to antioxidation against cardiovascular diseases and cancer, because of their anti- 285
224 Q2 effects. Yang et al. indicated that a planar flavonol structure inflammatory, antioxidant, antimutagenic, and antitumor activi- 286
225 containing only one hydroxyl group such as that of kaempferol is ties. Upon ingestion, the flavanone glycosides typically reach the 287
226 beneficial for the inhibition of influenza B virus; namely, the C40 colon, where they are hydrolyzed to the corresponding aglycones 288
227 phenolic hydroxyl group in the B-ring was found to be necessary (naringenin, hesperetin, etc.) by microflora glycosidases. 289
228 for the anti-influenza activity [45]. The bioavailability and bioactivity are dependent on chemical 290
modifications as well as on technological processing [60]. The 291
229 Isoflavones bioavailability of hesperidin encapsulated in arabic gum particles 292
is twice that of conventional hesperdin prepared by micronization 293
230 Unlike flavones, the B-ring of isoflavones is attached to the C3 [61]. Flavanones in homogenized juices obtained by applying 294
231 rather than to the C2 position, as shown in Table 1. Isoflavones, moderate hydrolytic pressure show improved absorption as 295
232 mainly daidzein, genistein, and their glycosides, are commonly compared with those in conventionally pasteurized juices [62]. 296
233 found in leguminous plants, and are the major constituents of
234 soybean. On the other hand, because of hydrolysis, the correspond- Polyphenol structures as building blocks 297
235 ing aglycones can be found in considerable quantities in soybeans
236 and their products [38,46]. The aglycones are structurally similar The position of the hydroxyl groups on the basic C6–C3–C6 298
237 to 17-b-estradiol and are known as phytoestrogens. Hence, this carbon skeletons affects the properties of the resulting poly- 299
238 structural similarity made them more efficiently applicable for phenols [27]. The hydroxyl groups can be substituted with sugar 300
239 various pharmacological applications such as anticancer, antihy- residues, to obtain more complex structures [27,63]. Sugar 301
240 pertensive, antioxidative, and antiallergic properties [45,47]. moieties are commonly linked via O- or C-glycosylation reactions. 302
241 The components of isoflavones, i.e., aglycones (daidzein, The hydroxyl groups on the sugar rings are targets for O-acylation, 303
242 genistein, and glycitein) and their glycosides (daidzin, genistin, -methylation, -glycosylation, -sulfation, or -acylation [27]. More- 304
243 and glycitin), have recently been suggested as chemopreventive over, enzyme-catalyzed glycosylation converts flavonoids into 305
244 agents. Their intake results in decreased rates of age-related their corresponding glycosylated forms. These compounds may be 306
245 cardiovascular diseases and osteoporosis, hormone-dependent further esterified with various mono- and disaccharides [27] or 307
246 breast and prostate cancers, and a reduction in menopausal with each other, resulting in polymeric macromolecules (e.g., 308
247 symptoms [46,48–50]. Genistein has numerous health effects and tannins) [64]. 309
248 its consumption through diet is considered a safe and nontoxic In order to evaluate the chemical stability of polyphenols 310
249 pharmacological treatment [51]. In 2006, because of the dramati- obtained via chemical modifications such as hydroxylation, 311
250 cally increased demand of soy-derived products, the maximum glycosylation, and methoxylation, the early degradation time 312
251 isoflavone intake was set at 75 mg/day (30 mg/day in supple- and half-degradation time were assessed. The reactivity of flavones 313
252 ments) by the Japanese Government Food Safety Commission and flavonols toward hydroxylation follows this order: resorcinol- 314
253 (Food Safety Commission Novel Foods Expert Committee, 2006). type > catechol-type > pyrogallol-type. Along with glycosylation, 315
254 The structure-activity relationship revealed that daidzein exhibits methoxylation of flavonoids having more than three hydroxyl 316
255 the highest inhibitory effect, which proves that the addition of a groups and hydrogenation of the C25 5C3 double bond resulted in 317
256 glucoside at the C7 and C8 positions of ring A reduces the improved stability [65]. Moreover, the chemical structures and 318
257 antibacterial activity of isoflavonoids [41,48]. their modifications influence the interactions with polysacchar- 319
ides. Wang et al. reported that flavonoids with a number of 320
258 Flavanone hydroxyl groups equal to or lower than three have higher 321
adsorption than those with four or more hydroxyl groups. The 322
259 Flavanones, such as naringenin and hesperetin, are character- adsorption ability increased as follows: flavonol > flavo- 323
260 ized by the absence of the double bond between C2 and C3 and the flavone > flavanone > isoflavone [36]. 324
261 presence of a chiral center at C2. Flavanones are generally Xiao et al. reviewed the aldose reductase inhibitory activity of 325
262 glycosylated at position 7 by mono- or disaccharides, leading to polyphenols and reported that the molecular structure affects the 326
263 the corresponding flavanone glycosides [52]. These small mole- activity of flavonoids [65]. Methylation and methoxylation of the 327
264 cule-substituted flavanones containing monomeric sugars play a hydroxyl groups at the C3, C30 , and C40 positions of flavonoids 328

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329 decreased or slightly affected the inhibitory potency. Methylation radical scavenging activity, flavonoids bearing 3,4-catechol units 366
330 and methoxylation of the hydroxyl groups at C5, C6, and C8 have a wide spectrum of biological activities. The catechol unit 367
331 significantly enhanced the inhibitory activity, whereas the same stabilizes free radicals, thus improving the antioxidant activity 368
332 transformations of the C7–OH influenced the inhibitory activity [19,66]. Inspired by the reductive and adhesive properties of 369
333 depending on the substituents on the A- and B-rings of flavonoids. dopamine, catechol-containing polyphenols have been extensively 370
334 The inhibitory activity of flavonoids was significantly increased or exploited because of their low cost and high bioavailability 371
335 slightly affected by glycosylation of the C3–OH but significantly [69,70]. Cordoba et al. reported that quercetin-functionalized 372
336 decreased by glycosylation of the C7–OH and C40 –OH. The surfaces have a faster stem cell adhesion as compared with control 373
337 inhibitory activity was remarkably improved by hydroxylation surfaces, because of the presence of the catechol groups of 374
338 of the A-ring of flavones and isoflavones, especially at positions quercetin [71], which are able to transfer electrons to metal ions 375
339 5 and 7, and by hydroxylation at the C30 and C40 positions of the B- chelated by coordinate bonds [72] and to scavenge reactive oxygen 376
340 ring of flavonoids; on the other hand, the inhibitory activity was species. Catechol and caffeic acid derivatives were found to be 377
341 significantly reduced upon hydroxylation of the C-ring and potent lipoxygenase inhibitors [73]. Flavonoids bearing a catechol 378
342 hydrogenation of the C25 5C3 double bond of flavones. moiety on the B-ring, such as quercetin, luteolin, and catechins, 379
343 The grafting of natural polyphenols to macromolecules is a showed protective effects against coronary heart disease and 380
344 useful method to develop materials with particular functional oxidative stress-induced neuronal cell death [73]. 381
345 properties [32]. This synthetic strategy allowed the preparation of The metal-binding ability of catechol through chelation [25] is 382
346 selected macromolecules having the beneficial properties of due to the relatively high reduction potential and electron 383
347 polyphenols. Spizzirri et al. reported that two polyphenols, i.e., donation property of metal atoms. In the presence of polyphenols, 384
348 gallic acid and catechin, covalently bonded to gelatin enhanced the metals (M+) are reduced to stable (M0) forms by biochemical 385
349 antioxidant potential of the biomacromolecule [66]. Vittorio et al. reduction. The possible sites for metal ion-binding in specific 386
350 developed dextran-catechin conjugates, which are more effective polyphenols are elucidated in Scheme 1. Nakano et al. reported 387
351 in killing pancreatic tumor cells as compared with pure catechin that, using a specific type of tannin, Cr(VI) and Pd(II) could be 388
352 [67]. Besides chemical grafting of polyphenols, another method for reduced to Cr(III) and Pd(0), respectively [74]. In addition, 389
353 the preparation of effective antioxidants is the enzyme-catalyzed Nakajima reported that Cr(VI) and V(V) were reduced to Cr(III) 390
354 polymerization of polyphenols. Radical scavenging and ferric and V(IV), respectively, using a persimmon tannin adsorbent 391
355 reducing antioxidant assays showed that poly(pyrogallic acid), [74]. Simple and eco-friendly methods exploiting the interactions 392
356 obtained by horseradish peroxidase-catalyzed polymerization, between polyphenols and metal ions have been explored for the 393
357 exhibits superior radical scavenging capacity and ferric ion biosynthesis of metal nanoparticles [19,28]. The possible mecha- 394
358 reducing ability as compared with pyrogallic acid [68]. The nism involved the formation of metal-trapped polyphenol 395
359 oxidative coupling chemistry of horseradish peroxidase was particles, as shown in Fig. 2, leading to spherical, hexagonal, and 396
360 further exploited for hydrogel formation by cross-linking of irregular silver nanoparticles [26,28,75,76]. Hybrid particles of 397
361 polymer-phenol conjugates. Lee et al. prepared a cross-linked reduced graphene–Ag prepared using tea polyphenols showed 398
362 hydrogel from tea catechin-coupled hyaluronic acid, which enhanced catalytic activity [77]. Edayadulla et al. prepared 399
363 showed resistance toward degradation [33]. spherical nanoparticles by using palladium and Artemisia annua 400
364 Flavonoid-based antioxidants are considered to be substantial leaf extracts [74] and gold nanoparticles prepared by using 401
365 components of the human diet. Along with their fundamental Moringa oleifera flower aqueous extract [29]. Some polyphenols 402

Scheme 1. Possible metal (M) binding sites in polyphenols: (a) 3 hydroxy, 4-kito, (b) 5-hydroxy, 4-kito, (c) catechol, and (d) 3,5-dihydroxy, 4-kito groups.

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Fig. 2. Possible mechanism for metal ion binding activity of polyphenols and formation of metal ion-entrapped particles.

403 contain either one metal-binding site (flavonol, 30 ,40 -dihydroxyl- References 435
404 flavone, and chrysin) or two or three metal-binding sites (morin,
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