SAR and QSAR of the Antioxidant Activity of Flavonoids

Current Medicinal Chemistry 2007 14 827-845 827

0929-867307 $5000+00 copy 2007 Bentham Science Publishers Ltd

SAR and QSAR of the Antioxidant Activity of Flavonoids

Dragan Ami1

Du anka Davidovi -Ami1 Drago Be lo

1 Vesna Rastija

1 Bono Lu i

2 and

Nenad Trinajsti2

1Faculty of Agriculture The Josip Juraj Strossmayer University PO Box 719 HR-31107 Osijek Croatia

2The Rugjer Bo kovi Institute PO Box 180 HR-10002 Zagreb Croatia

Abstract Flavonoids are a group of naturally occurring phytochemicals abundantly present in fruits vegetables and bev-

erages such as wine and tea In the past two decades flavonoids have gained enormous interest because of their beneficial

health effects such as anti-inflammatory cardio-protective and anticancer activities These findings have contributed to

the dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavon-

oids The pharmacological effect of flavonoids is mainly due to their antioxidant activity and their inhibition of certain en-

zymes In spite of abundant data structural requirements and mechanisms underlying these effects have not been fully un-

derstood This review presents the current knowledge about structure-activity relationships (SARs) and quantitative struc-

ture-activity relationships (QSARs) of the antioxidant activity of flavonoids SAR and QSAR can provide useful tools for

revealing the nature of flavonoid antioxidant action They may also help in the design of new and efficient flavonoids

which could be used as potential therapeutic agents

Keywords SAR QSAR flavonoids antioxidant activity free radical scavenging metal chelation enzyme inhibition prooxi-dant activity mechanisms modelling molecular descriptors

INTRODUCTION

Flavonoids are a group of naturally occurring polypheno-lic compounds ubiquitously found in the plant kingdom [1 2] They are widespread in vegetables fruits flowers seeds and grains [3] The exact role of these secondary metabolites is still unclear but it is known that flavonoids are important for the survival of a plant in its environment they regulate plant growth inhibit or kill many bacterial strains inhibit major viral enzymes and destroy some pathogenic protozo-ans [4] Also they act in plants as visual attractors feeding repellents photoreceptors and as protection against UV radiation [5-7] Thus far approximately 9000 different fla-vonoids have been identified and they form the largest group of naturally occurring polyphenols [8] This list is constantly growing owing to the enormous structural diversity associ-ated with these compounds

Chemical Structure of Flavonoids

Basic structure of flavonoid has a flavan nucleus consist-ing of two benzene rings combined by an oxygen-containing pyran ring [9] The various classes of flavonoids differ in their level of oxidation of the C ring of the basic 4-oxo-flavonoid (2-phenyl-benzo- -pyrone) nucleus Common sub-families of flavonoids are flavones flavanes flavonols flavanols (catechins) anthocyanidins and isoflavones (Fig 1)

Flavonoids usually occur as glycosides in plants because the effect of glycosylation renders the flavonoid less reactive

Address correspondence to this author (DA) at the Faculty of Agriculture

The Josip Juraj Strossmayer University PO Box 719 HR-31107 Osijek

Croatia Tel ++385 31 224 200 Fax ++385 31 207 017 E-mail

damicpfoshr and to this author (NT) at the Rugjer Bo kovi Institute

PO Box 180 HR-10002 Zagreb Croatia Tel ++385 1 468 00 95 Fax

++385 1 468 02 45 E-mail trinairbhr

and more water soluble permitting its storage in the cell vacuole Structural diversity in each flavonoid family arises from the various hydroxylation methoxylation and glycosy-lation patterns of ring substitution

Health Effects of Flavonoids

Research in the field of flavonoids has increased since the discovery of the French paradox [10] The French have one of the lowest incidences of coronary heart disease de-spite their high consumption of saturated fat and smoking habits similar to those of other countries This can be ex-plained by their moderate and regular consumption of red wine The wide range of health effects of flavonoids has attracted great attention in recent years especially because of the broad prevalence of these compounds in many common fruits and vegetables [11] Flavonoids are important con-stituents of the human diet and their daily intake depending on diet can range from several hundred mg up to 1-2 g [4 12] Besides their relevance in plants it has been shown that flavonoids are pharmacologically active in humans [4] Con-sumption of fruits vegetables and certain beverages such as tea and red wine is associated with many health promoting effects [13-15] Flavonoids have recently been identified as a major cancer-preventive component of our diet [16] Re-duced risk of coronary heart disease and premature aging is also associated with a regular diet rich in flavonoids [17] In addition flavonoids exhibit a wide range of biological activi-ties including anti-inflammatory antiviral antibacterial antiulcer antiosteoporotic antiallergic and antihepatotoxic actions [18 19] These activities are mainly attributed to their powerful antioxidant activity [20 21] andor modula-tion of enzymatic activities [22 23] These effects along with epidemiological studies and animal models have led to the hypothesis that dietary flavonoids may be potential can-didates for use as drugs in illnesses such as cancer athero-sclerosis cardiovascular and coronary heart diseases diabe-

828 Current Medicinal Chemistry 2007 Vol 14 No 7 Ami et al

tes AIDS heart ailments ulcer formation bacterial infec-tions mutagenesis neurodegenerative diseases such as Park-insonrsquos and Alzheimerrsquos diseases and arthritis as well as premature body aging [24] Consumers and food manufac-tures have become increasingly interested in flavonoids for their potential beneficial role in prevention of the above-listed diseases For example flavonoids are major functional components of propolis and honey which have been used since ancient times Today hundreds of herbal supplements containing flavonoids are available on the market However the safety of these products is questionable [25] Exposure to increased levels of flavonoids can adversely affect human health due to prooxidant and promutagen activities of these compounds [26] Therefore careful evaluation of the bio-logical activity of flavonoids seems to be important for a proper determination of their safety

Flavonoids and QSAR

The multiple activities of flavonoids as well as their structural diversity make this class of compounds a rich source for modelling lead compounds with targeted pharma-

cological properties The activity of flavonoids is closely linked to their structure They are not equally physiologically active presumably because of the presence of different sub-stitutions on the carbon atoms of the basic flavonoid struc-ture and differences in lipid solubility Despite the fact that flavonoids generally occur as glycosides their bioactivity is attributed to aglycon structures rather than to sugar moieties Differentiation of flavonoids is not easy because thousands of them share a common phenyl-benzo- -pyrone skeleton and they differ from one another only in the position and number of hydroxyl andor methoxyl groups as well as the position and number of different saccharides involved in glycosylation Acylation may often occur at various posi-tions of the flavonoid nucleus as well as of the glycosyl residues These diverse substitution patterns make the fla-vonoids an ideal object of QSAR studies [27-29]

Despite the enormous interest in flavonoids and other polyphenolic compounds as potential protective agents against the development of human diseases real contribu-tions of such compounds to health maintenance and mecha-

O

A

O

O

O

OH

HO

OH

OH

OH

O

O

HO

OH

OH

OCH3

O

OH

HO

OH

OH

O

O

O

HO

OH

OH

OH

OH

O

O

HO

OH

OH

O

OCH3

OH

OCH3

OH

HO

OH

O

HOO

OH

OH

OH

OHO

OH

OCH3

OH

OCH3

O

OOH

HO

OH

2

3

4

6

5

7

8

6

5

4

3

2

flavan nucleusbasic flavonoid structure

4-oxo-flavonoid nucleus2-phenyl-benzo-γ-pyrone

(+)-Catechin (catechin flavanol)

Hesperetin (flavanone)

Taxifolin (flavanonol)

Apigenin (flavone)

Quercetin (flavonol) Malvidin (anthocyanidin)

Malvidin 3-glucoside (anthocyanin)Genistein (isoflavone)

+

+

C

B

Fig (1) Structural formulae of the main sub-classes of flavonoids

SAR and QSAR of the Antioxidant Activity of Flavonoids Current Medicinal Chemistry 2007 Vol 14 No 7 829

nisms through which they act are still unclear [30] QSARs

represent an attempt to correlate physicochemical or struc-tural descriptors of a set of structurally related compounds with their biological (pharmacological toxicological or eco-logical) activities or physical properties (quantitative struc-ture-property relationship QSPR) [31 32] Molecular de-scriptors usually include parameters accounting for elec-tronic properties hydrophobicity topology and steric ef-fects Activities include chemical measurements and biologi-cal assays A crucial factor in advancing QSAR is to find information-rich descriptors for a molecule or a fragment Once developed QSARs provide predictive models of bio-logical activity and may shed light on the mechanism of action

A number of studies have been conducted to elucidate the structural requirements of flavonoids for their biological activities in order to predict the potency of these compounds with regard to the targeted activity and to direct the synthesis of more potent analogues [33-39] Both dietary and synthetic flavonoids could be subjected to clinical trials in order to evaluate their activities The flavonoid QSAR enables pre-diction of the activities of many other untested flavonoids and directs the synthesis of flavonoid compounds with higher potency for potential clinical application

FLAVONOIDS AS ANTIOXIDANTS

The best-described activity of flavonoids is their capacity to act as antioxidants [21 40-46] Flavonoids may exert antioxidative effects as free radical scavengers hydrogen-donating compounds singlet oxygen quenchers and metal ion chelators properties attributed to the phenolic hydroxyl groups attached to ring structures [40] Free radicals are constantly generated in our body for specific metabolic pur-poses Examples of oxygen free radicals include singlet oxygen (

1O2) superoxide (O2

bull ) alkyl peroxyl (ROObull) alkoxyl (RObull) and hydroxyl (HObull) Among other functions free radicals are involved in energy production regulation of cell growth and intercellular signalling However when an imbalance between free radical generation and body defence mechanisms occurs free radicals can attack lipids in cell membranes proteins in tissues and enzymes and DNA to induce oxidations which cause membrane damage protein modifications and DNA damage This oxidative damage is considered to play a causative role in a series of human ill-nesses such as cancer heart disease and premature body aging Humans possess a wide array of antioxidant physio-logical defences to scavenge free radicals chelate metal ions involved in their formation and repair damage Diets rich in polyphenols contribute to these defences as well Many phe-

nolics such as flavonoids have antioxidant capacities that are much stronger than those of vitamins C and E [47]

Structural Criteria for the Antioxidant Action of Flavon-oids

Intensity of the antioxidant activity of a flavonoid strongly depends on its chemical structure There is a great deal of discussion and contradiction regarding the structure-antioxidant activity relationships of flavonoids [48 49] However it is well-accepted that the antioxidant activity of flavonoids is markedly influenced by the number and posi-tion of hydroxyl groups on the B and A rings and by the extent of conjugation between the B and C rings [50-59]

On the basis of many previous and recent findings [21 34 60-66] it seems that favourable general structural re-quirements for effective radical scavenging andor the anti-oxidative potential of flavonoids follow the famous three Borsrsquo criteria [33]

a) The o-dihydroxy (3rsquo4rsquo-diOH ie catechol) structure in the B ring which confers high stability to the fla-vonoid phenoxyl radicals via hydrogen bonding or by expanded electron delocalization

b) The C2-C3 double bond (in conjugation with the 4-oxo group) which determines the coplanarity of the heteroring and participates in radical stabilization via electron delocalization over all three ring systems

c) The presence of both 3-OH and 5-OH groups for the maximal radical scavenging capacity and the strong-est radical absorption

Moreover an additional criterion could be added

d) In the absence of o-dihydroxy structure in the B ring hydroxyl substituents in a catechol structure on the A ring are able to compensate and become a larger de-terminant of flavonoid antiradical activity [67-74]

According to van Acker et al [48] the basic flavonoid structure does not seem to be essential for good antioxidant activity It becomes important only when the catechol moiety is not present In addition glycosylation of flavonoids mostly decreases their antioxidant activity Blocking the hydroxy group at the C-3 position or removing the 3-OH group decreases antioxidative properties of flavonoids Fig 2 summarizes the structural criteria that modulate the antioxi-dant activity of flavonoids

Mechanisms of the Antioxidant Action of Flavonoids

Mechanisms of the antioxidant action of flavonoids can include direct scavenging of reactive free radicals chelating

O

OH

OH

OH

OH

HO

O

A

O

OH

OH

HO

O

OH

A2

3

4

6

5

7

8

6

5

4

3

2

2

3

4

6

5

7

8

6

5

4

3

2

B

C

B

C

Fig (2) Structural features of flavonoids with high antioxidant activity


of trace metal ions involved in free radical formation inhibi-tion of enzymes involved in free radical production and regeneration of membrane-bound antioxidants such as -tocopherol [24 52 75]

The antioxidant action of flavonoids can arise from direct scavenging of reactive oxygen species It is generally con-sidered that the primary mechanism of the radical scaveng-ing activity of flavonoids is hydrogen atom donation These antioxidants may also act by single-electron transfer [76]

Structural requirements for the H-donating antioxidant activ-ity include ortho-dihydroxy substitution in the B ring C2-C3 double bond and C-4 carbonyl group in the C ring [33 45] In the hydrogen atom transfer mechanism hydroxy groups donate hydrogen to a radical stabilizing it and giving rise to a relatively stable flavonoid phenoxyl radical (Fig 3) The flavonoid phenoxyl radical may react with a second radical (RObull) acquiring a stable quinone structure

The electron donation mechanism may be valid for the monohydroxyflavones where hydrogen atom donation by other hydroxyl moieties is not an option For 3-OH andor 5-OH hydroxyflavones the strong hydrogen bond of their OH moiety with the oxygen atom of the C-4 carbonyl group may prevent not only their efficient deprotonation but also their radical scavenging action by means of hydrogen atom dona-tion The proposed mechanism of the antioxidant action of C3-OH or C5-OH hydroxyflavones is shown in Fig 4

Structure A is the parent neutral molecule of 3-hydroxyflavone B is the initial radical cation (resulting from electron abstraction from the neutral molecule) and C is its more stable tautomeric form The tautomeric form C of the

radical cation results from the initial radical cation B and the proton transfer from C3-OH to the C-4 carbonyl group

A number of flavonoids efficiently chelate trace metal ions such as Fe

2+ and Cu

+ that play an important role in

oxygen metabolism and free radical formation [21] Free iron(II) and copper(I) help the formation of reactive oxygen species as exemplified by the reduction of hydrogen perox-ide (Fenton reaction) with generation of the highly aggres-sive hydroxyl radical

H2O2 + Fe2+

(Cu+) HObull + OH + Fe

3+ (Cu

2+)

The proposed binding site for trace metal ions to flavon-oids is the 3rsquo4rsquo-diOH moiety in the B ring In addition C-3 and C-5 OH groups and the 4-carbonyl group also contribute to metal ion chelation (Fig 5)

Besides scavenging free radicals directly and chelating transition metal ions by masking their prooxidant actions

flavonoids also behave as antioxidants through inhibition of prooxidant enzymes This mechanism seems to be responsi-ble for their in vivo effects [77]

Non-antioxidant mechanisms of flavonoid action such as modulation of signalling pathways and gene expression could also contribute to protective properties of flavonoids [37 45 66]

SAR AND QSAR OF THE ANTIOXIDANT ACTION

OF FLAVONOIDS

Number and Position of OH Groups

Despite the fact that numerous authors have investigated the antioxidant activity of flavonoids the relationship be-

O

O

HO

OH

OH

OH

OH

ROHO

O

HO

OH

O

OH

O

H

RO

O

O

HO

OH

O

OH

OH

O

O

O

HO

OH

OH

O

ROHRO

hydrogen-bond stabilized

flavonoid phenoxyl radical

stable quinone structure

Fig (3) Mechanism of antioxidant action of 34-diOH flavonoids

-e-O

O

O

H

B

+

O

O

O

H

C

+

O

O

O

H

A

Fig (4) Mechanism of antioxidant action of C3-OH or C5-OH hydroxyflavones [69]


O

O

HO

OH

OH

HO

HO Men+

Men+

Men+

Fig (5) Binding sites for trace elements [21]

tween their structure and antioxidant potency is not quite clear [62 78 79] Until recently elucidated SARs of flavon-oids have only been descriptive not explanatory by means of QSARs [33 48 70] Earlier SAR studies reported somewhat controversial statements regarding the role of the number and position of OH groups in the antioxidant activity of flavonoids For example Chen et al [51] emphasized that antioxidant activity of natural flavonoids is governed by the number and location of their aromatic hydroxyl groups In contrast Foti et al [68] found that in determining the level of antioxidant activity of flavonoids the number of hydroxyl groups is of negligible importance and so is their position - either in ring A or ring B Instead they found that high activ-ity is associated with flavonoids possessing an ortho-dihydroxy system in the B ring as well as with an ldquounnatu-ralrdquo ortho-hydroxylation pattern in ring A (synthetic 67- and 78-dihydroxyflavones) The report by Haenen et al [80] indicated that the catechol group in ring B and the C-3 OH group give the highest contribution to the scavenging activity of flavonoids

Seven years ago Lien et al [62] established QSARs of Trolox equivalent antioxidant capacities (TEACs) for 42 different flavonoids They found that TEACs are mainly governed by the number and position of hydroxyl groups (nOH) on the flavonoid ring system

TEAC = 0454(plusmn0088) nOH + 0402(plusmn0453)

n = 42 r2

= 0729 s = 0767 F140 = 10733 p lt 00005

By adding another indicator variable (I) being the sum of the following indicators presence of the 23-double bond (I = 1) or two of 357-OH groups (I = 1) or two of 3rsquo4rsquo5rsquo-OH groups (I = 1) or absence of the above situations (I = 0) an improved equation was derived

TEAC = 0441(plusmn0079) nOH + 0498(plusmn0293) I ndash 0320(plusmn0588)

n = 42 r2

= 0792 s = 0681 F239 = 7401 p lt 00005

In a follow-up of the Lien et al study Ami et al [38] derived a QSAR model for predicting the free radical scav-enging activity (RSA) for 28 flavonoids from the data pub-lished by Burda and Oleszek [81]

RSA = 3954(plusmn3556) + 75950(plusmn3631) I3rsquo4rsquo-diOH or 3-OH + 8499(plusmn3877) I5-OH

n = 28 r = 0974 s = 95 F = 2307

where I3rsquo4rsquo-diOH or 3-OH and I5-OH represent indicator variables If a particular flavonoid possesses 3rsquo4rsquo-diOH or 3-OH moi-ety then the value 1 is ascribed to the indicator variable I3rsquo4rsquo-

diOH or 3-OH elsewhere 0 similarly if the flavonoid bears a 5-OH group the value 1 is ascribed to I5-OH elsewhere 0 In the

data set studied the most effective free radical scavengers were flavonoids with the 3rsquo4rsquo-dihydroxy substitution pattern on the B ring andor a hydroxyl group in the C-3 position The presence of a C2-C3 double bond in the C ring does not seem to be a prerequisite for high antiradical activities while the presence of a 5-OH group enhances radical scavenging

Dugas et al [82] studied the influence of the number and position of OH andor OCH3 groups on the peroxyl radical-scavenging capacity of 7 flavonoids The results of that SAR study suggest that it is not the number but the position of OH

and OCH3 groups that is essential for the antioxidant activ-ity

SAR studies of the antioxidant activity of anthocyanins and their aglycons indicated that the activity increased with the number of hydroxyl groups on the B ring [83 84] Sub-stitution of the hydroxyl groups on the B ring with methoxyl groups resulted in decreasing the antioxidant activity De-pending on the anthocyanidin different glycosylation pat-terns either enhanced or diminished the antioxidant power Generally anthocyanidins are better antioxidants than their corresponding glycosidic forms the anthocyanins

Reaction rate constants of the superoxide anion radical (O2

bull ) scavenging by plant flavonoids were determined by Taubert et al [85] Analyzing the relations between O2

bull scavenging kinetics and structural features of flavonoids some descriptive SARs were outlined The substituents at ring B determined the superoxide scavenging kinetics whereas substituents at rings A and C had little impact on O2

bull scavenging rate constants Flavonoids with the ortho-trihydroxy (pyrogallol) group were revealed as the most rapid superoxide scavengers followed by flavonoids with the ortho-dihydroxy (catechol) group Substitution of the neighbouring OH groups at ring B by methoxyl groups caused a marked decrease in O2

bull scavenging kinetics Inter-estingly neither the existence of a C2-C3 double bond nor the existence of OH groups at C-3 and C-5 and a keto group at C-4 revealed the necessary structural features for superox-ide scavenging It seems that pyrogallol and catechol moie-ties are the main sites of the superoxide attack resulting in the formation of flavonoid phenoxyl radicals that may be stabilized by the mesomeric equilibrium to ortho-semiquinone structures without involvement of oxygen sub-stituents at C-3 C-4 and C-5 in charge delocalization Fig 6 shows a possible mesomeric equilibrium of the flavonoid phenoxyl radical The semiquinone structures incorporating the oxonium ion are also presented which has been reported to be the most stable mesomeric structures [86] (see also the note in ref 86)

Santos and Mira [87] studied protection against the per-oxynitrite oxidation of dihydrorhodamine by 13 flavonoids Correlation was observed between the number of hydroxyl groups and the oxidation efficiency (r = 080) This means that flavonoids with a large number of hydroxyl groups are more effective in preventing oxidation by peroxynitrite

The QSAR study of Rasulev et al [88] emphasized the role of OH groups such as catechol moiety in the B ring and 3-OH group The authors studied the inhibition of lipid per-oxidation (antioxidant activity) using a set of 27 flavonoids Numerous molecular descriptors were calculated by the DRAGON program To this descriptor pool a number of


quantum-chemical descriptors as well as several indicator variables were added Genetic algorithm and multiple linear regression analysis were used to select the most important molecular descriptors and to generate QSAR models The best QSAR model developed is as follows

ILPO = 0561(plusmn0059) IOH ndash 0036(plusmn0016) μ ndash 0239 (plusmn0072) IGlc +

0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171

where ILPO is the antioxidant activity expressed in percent-ages of inhibition of lipid peroxidation IOH is the indicator variable denoting the presence (IOH = 1) or absence (IOH = 0) of the 3rsquo4rsquo-dihydroxy moiety in the B ring or the OH group at the C-3 position μ is the dipole moment and IGlc is the indicator variable that denotes the presence (IGlc = 1) or ab-sence (IGlc = 0) of the O-glucose group andor the presence of the OCH3 group at the C-3rsquo position in the B ring Several QSAR models using the topological descriptor PJI3 (Petijean shape index) were also developed One of the favourable four-descriptor QSAR models is as follows

ILPO = 0526(plusmn0074) IOH + 0287(plusmn0352) PJI3 ndash 0029(plusmn0018) μ

0262 (plusmn0078) IGlc + 0028 (plusmn0313)

n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181

The obtained QSAR models show that the presence of hydroxyl or O-Rrsquo groups in relevant positions the magnitude of the dipole moment and the shape of the molecule play an important role in the inhibition of lipid peroxidation by fla-vonoids

In an SAR investigation of the tocopherol-regeneration reaction by catechins Mukai et al [89] showed that reaction rates increased remarkably with increasing the anionic char-acter of catechins that is the electron-donating capacity of catechins The mono anion from the catechol B and resorci-nol A rings and the dianion form from the pyrogallol B and G rings show the highest activity for the free radical scav-enging It has been found that catechins exert high activity in vitamin E regeneration

In the study of Di Majo et al [90] the crocin bleaching method was used to determine the antioxidant capacity of nine glycosylated flavanones and the related aglycons The results from this work demonstrate that the 3rsquo4rsquo-dihydroxy substitution in the aglycone form does not greatly influence the antioxidant activity To the contrary in the glycosylate forms the 3rsquo4rsquo-catechol structure noticeably increases the antioxidant power while O-methylation decreases the anti-oxidant activity The kind of sugar in the C-7 position and the position of the methoxyl group (C-3rsquo or C-4rsquo) perturbs the planarity of the flavanone phenoxyl radicals and influ-ences the ability to delocalize electrons

Another very recently published SAR study of flavonoids highlighted the role of ortho-dihydroxy groups Namely Cai et al [70] investigated the radical scavenging activity of 100 phenolic compounds (17 phenolic acids 41 flavonoids 6 tannins 9 stilbenes 9 lignans and 18 quinones) isolated from traditional Chinese medicinal plants The set of flavonoids encompassed 5 flavanols 11 flavonols 5 chalcones 9 fla-vones 5 flavanones and 6 isoflavones The tested flavonoids exhibited a wide variation of the radical scavenging activity Differences in the radical scavenging activity were attributed to the structural differences in hydroxylation glycosylation and methoxylation The ortho-dihydroxy groups in the basic flavonoid structure were the most important structural fea-ture of high activity Flavonoids without any hydroxyl group had no radical scavenging capacity Besides the ortho-dihydroxy groups in the B ring or in the A ring the required structural criteria of high radical scavenging activity among the investigated flavonoids included the 3-hydroxy group or the 3-galloyl group in the C ring and the C2-C3 double bond in conjugation with C-4 carbonyl group in the C ring Glyco-sylation of the hydroxyl groups diminished the antiradical capacity of the flavonoids

Pirker et al [91] studied the antioxidant behaviour of luteolin and kaempferol Antioxidant activity under the in-vestigated conditions of these two flavonoids differing only in the position of one OH group was similar However the mechanisms of action were completely different Whereas the catechol moiety of luteolin stabilizes the radical anion the initial phenoxyl radical formed by the oxidation of

O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +

Fig (6) Mesomeric equilibriums of the flavonoid phenoxyl radical [86]


kaempferol is unstable The authors concluded that the bio-logical activities of kaempferol are likely to be determined by the action of its oxidation products

In conclusion the number of OH groups on the flavonoid nucleus and especially their position implicate multiple possible meanings For example the increased number of OH groups could be related to the increased ability of H atom abstraction or electron donating capacity and increased scavenging of free radicals Flavonoid phenoxyl radicals formed by abstraction of the H atom are stabilized by hydro-gen bonding thus favourable position of OH groups like the catechol moiety in the B ring or 35-diOH substitution in conjunction with the C-4 keto group could be a prerequisite for the stability of flavonoid phenoxyl radicals Further stabilization of flavonoid phenoxyl radicals to semiquinone structures is achieved by suitable arrangement of OH groups

OxidationReduction Potential and the Number of In-volved Electrons (n Value)

Earlier SAR reports based on experimentally measured oxidationreduction potentials of flavonoids offer evidence that the catechol moiety in the B ring is the antioxidant ac-tive moiety [43 53 92] The half-peak oxidation potential (Ep2) of flavonoids has been proposed as a suitable parame-ter for evaluating the scavenging activity [48] This assumes that both the electrochemical oxidation Fl OH Fl Obull + e + H+ and the hydrogen atom donating reaction Fl OH Fl Obull + Hbull involve breaking of the same O H bond [40]

Yang et al [93] estimated the antioxidant activity of 23 flavonoids from their oxidation potentials They derived the QSAR equation

IC50(μM) = 3036 + 15150 E (V) ndash 1263 log P r = 0852

where IC50 represents the concentration for 50 inhibition of lipid peroxidation E represents the half-wave potential of the first oxidation wave measured by flow-through col-umn electrolysis and log P represents the octanolwater partition coefficient calculated by software The potential of flavonoids was shown to be strongly dependent on their structure [92 94] The antioxidant activity of flavonoids is inversely proportional to their E ie the lower the E of flavonoids the higher is their antioxidant activity [93 95] Lipophilicity of flavonoids (log P) is an important factor of their antioxidant activity in biological systems In another study Yang et al [96] disclosed a relationship between the electrochemical oxidation of catechins and their antioxidant activity in microsomal lipid peroxidation The following quantitative relationship was obtained to describe the anti-oxidant activity of catechins

log IC50(μM) = 156 + 249 E (V) ndash 029 log P r = 0907

This relationship also suggested two important character-istics determining the antioxidant activity namely the ease of oxidation and the lipophilicity

Hotta et al [97] investigated the radical scavenging ac-tivity of 34 natural polyphenolic antioxidants (14 flavonoids and 20 non-flavonoids) by electrochemical and spectropho-tometric measurements The radical scavenging activity (EC50 ndash the ratio of the antioxidant concentration necessary to decrease the initial DPPH concentration by 50 to the initial DPPH concentration) was measured by the DPPH method The electrochemical parameters of antioxidants (Epa ndash the anodic peak potential and Ipa ndash the anodic peak cur-rent) were measured by cyclic voltammetry and the n value (ie the number of electrons involved in the oxidation of a polyphenolic antioxidant) was determined by flow-column electrolysis In addition to EC50 the average stoichiometric number (nDPPH) of DPPH in reactions with each antioxidant was evaluated DPPH scavenging activities were correlated with electrochemical parameters of antioxidants The linear correlation between the DPPH radical scavenging activities (1EC50) and oxidation potentials (expEpa) was poor

1EC50 = 655 expEpa + 138 r = 073

A certain improvement was achieved by introducing Ipa as an additional variable

1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086

The n value of polyphenols has been generally found to increase with the electrolysis time Moreover for some polyphenols the n value may exceed the number of OH groups [98] This suggests that some chemical reactions (eg dimerization) following oxidations of a polyphenol regenerate the oxidizable OH moieties in the oxidation prod-uct The n values determined at a lower flow rate show a higher correlation with their DPPH scavenging activities

1EC50 = 167 n + 050 r = 094

The nDPPH values determined by the DPPH method were generally very close to the n values It seems that subsequent chemical reactions most probably enhance the antioxidant activities of the polyphenols The authors concluded that the n values should provide important information about the antioxidant activity of polyphenols These findings suggest that electrochemical properties of flavonoids contribute to their antioxidant activity and thus the n values of flavonoids can be used as descriptors of their antioxidant activities

Fujisawa et al [99] estimated the n value (number of moles of peroxy radicals trapped by one mole of flavonoid) using both kinetic measurements and theoretical calcula-tions For example PM3 calculation produced an n value of 4 for catechin (experimental value was 354) suggesting formation of the ortho-quinone product (Fig 7)

OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)

Fig (7) Catechin (n = 4) and the corresponding fully oxidized ortho-quinone product [99]


The obtained results indicate that the antioxidative mechanisms of flavonoids are not simple but multivariate and dependent on the n value Radical scavenging mecha-nisms for catechin quercetin and hesperetin were proposed However differences in reactivity towards various types of radicals may result in different experimentally determined n values [100 101]

Firuzi et al [102] evaluated antioxidant activities of 18 flavonoids by the ferric reducing antioxidant power (FRAP) assay Oxidation potentials of flavonoids were determined by cyclic voltammetry Good correlation was found between FRAP values and anodic oxidation potential (r = 0907) Hydroxyl groups and especially the catechol moiety 3-OH and the C2-C3 double bond appeared to be the most impor-tant factors in determining high antioxidant activity The correlation of nOH with oxidation potentials (r = 0960) was slightly better than with FRAP values (r = 0908)

Nagai et al [103] performed a kinetic study of the quenching reaction of singlet oxygen (

1O2) by 8 flavonoids

The result suggests that flavonoids may contribute to the protection from oxidative damage in foods and plants by quenching

1O2 The overall rate constants (kQ) for the reac-

tion of 1O2 with flavonoids increase as the number of OH

groups substituted to the flavone skeleton (ie the total elec-tron-donating capacity of flavonoids) increases The exis-tence of catechol or pyrogallol structure in the B ring is es-sential for the

1O2 quenching by flavonoids It was found that

log kQ correlates with peak oxidation potentials measured by Hotta et al [97] Flavonoids that have lower Epa values show higher reactivities For flavonoids with the C2-C3 double bond log kQ correlates well with Epa (r = 099) However flavonoids without the C2-C3 double bond deviate from the correlation line Quenching rates of

1O2 by catechins have

been studied recently [104] and a slightly lower correlation between log kQ and Epa was obtained (r = 088) Further log kQ values of flavonoids correlate well (r = 091) with the energy of the highest occupied molecular orbital EHOMO Flavonoids that have higher EHOMO values show higher reac-tivity with singlet oxygen The result is reasonable because flavonoids having higher EHOMO values will show a lower ionization potential ie lower oxidation potential Wave-lengths of absorption maximum ( max) in the UV-vis absorp-tion spectra of studied flavonoids increased with increasing the number of OH groups substituted to the flavone skeleton Good correlation (r = 096) was observed between log kQ and 1 max indicating that flavonoids with higher max values show faster

1O2 quenching rates

Butkovi et al [72] found that logarithms of reaction rate constants with stable free radicals correlate well with the reduction potential of the flavonoids They studied antiradi-cal activities of 12 flavonoids by measuring the reaction kinetics and stoichiometric factors Their results confirmed the stoichiometric factors of 1 2 and 3 for flavonoids with one two and three hydroxyl groups in the B ring respec-tively For the present series of flavonoids SAR indicated the importance of multiple OH substitutions and conjugation

The results presented in this section indicate that oxida-tion potentials (Ep2 E and Epa) and n values could be used with some success as descriptors in constructing QSAR models However even in combination with other descrip-tors the predictive power of models generated is not particu-

larly good This indicates that descriptors accounting for other driving forces of the antioxidant activity of flavonoids should be considered

Heat of Formation of the Flavonoid Radical ( Hf)

Possible explanations for some experimental antioxidant activities of flavonoids could be derived from molecular parameters related to electron distribution and structure for example the difference in heat of formation between the flavonoid and its radical Hf The Hf of a given radical represents the heat of formation difference between the par-ent flavonoid and the appropriate radical which results from the abstraction of a hydrogen atom from an assigned OH group [43] The Hf represents the relative stability of a possible phenoxyl radical with respect to its parent flavon-oid and enables comparison between the alternative posi-tions within an individual flavonoid as well as between different flavonoids Therefore the calculation of Hf for the reaction FlOH FlObull + Hbull regardless of the flavonoid sub-class or substitution pattern enables the search for a favour-able molecule with high activity The lower the Hf value the more stable the phenoxyl radical and consequently the more active the antioxidant Van Acker et al [105] consid-ered Hf as probably the best molecular descriptor for mod-elling the antioxidant activity Following this statement Zhang [106] calculated Hf using different semiempirical methods The AM1 (Austin Model 1) method was found to be best suited for Hf calculation [107] Linear correlation was found between log k3k1 (relative rate constants of scav-enging free radicals) and Hf

log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491

In another study Zhang and Chen [108] elucidated activ-ity differences of 10 flavonoid antioxidants They found a linear correlation between Hf and the logarithm of relative antioxidant efficiency (log RAE r = 07523) and no corre-lation with EHOMO

Vaya et al [109] investigated the relationship of struc-tures of 20 flavonoids to in vitro inhibition of the low-density lipoprotein (LDL) oxidation Linear correlation was found between the calculated Hf values and the experimen-tal values of antioxidant activity The following QSAR model results

inhibition = 2701 ndash 655 Hf

n = 20 r = 0883

Calculated heat of formation data ( Hf) indicated that the donation of a hydrogen atom from the OH group at C-3 was the most likely result followed by that of an OH from ring B

Modak et al [110] studied structure-antioxidant activity relationships of flavonoids using Hf and spin densities They stated that it is not possible to set forth a unique de-scriptor for correlating the antioxidant activity The most active flavonoids possess hydroxyl groups at C-4rsquo andor C-3rsquo for which the lowest Hf values were obtained The pres-ence of unsaturation at C2-C3 allows resonance stabilization of formed radicals according to the analysis of spin density maps


Sadeghipour et al [111] examined the antioxidant effects of flavonoids on the peroxynitrite oxidation reaction The ability of 11 flavonoids with different OH substitutions to inhibit peroxynitrite-induced nitration of tyrosine was inves-tigated using Hf Also the heat of the hydrogen transfer reaction from the flavonoid to the tyrosyl radical was calcu-lated ( Hf = ( Hf(flavonoid) Hf(tyrosine)) ie the heat for the reaction of tyrosyl radical repair by flavonoids TyObull + FlOH TyOH + FlObull Good correlation was observed between the calculated Hf and in vivo inhibition effects of flavonoids against tyrosine nitration Using linear regression analysis the QSAR model for predicting flavonoidsrsquo inhibi-tory activity was made

inhibition() = 10108 Hf r2 = 09056

Rackova et al [112] investigated the influence of 19 flavonoid structure-related parameters on the lipid peroxida-tion inhibition of a set of 12 flavonoids The best developed QSAR models for the antioxidant activity (pIC50) include the following molecular descriptors hydration energy (EHYDR)

Hf and energy of the lowest unoccupied molecular orbital (ELUMO)

pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234

The highest (absolute) values of EHYDR were obtained for the most potent flavonoids possessing the highest number of OH groups while the lowest (absolute) values of EHYDR were attributed to flavonoids that exerted low antioxidant activity [112] (see also the note in ref 112) The authors assumed that the parameter EHYDR reflects the hydrophilic properties of flavonoids

Seyoum et al [113] performed a SAR study where they experimentally determined the DPPH radical scavenging activity of 52 flavonoids and calculated the Hf values asso-ciated with the formation of various flavonoids and related simplified phenolic radicals Isolated para-dihydroxyl group on either A or B ring as an active hydrogen donating fea-ture was suggested Spin density of flavonoid radicals was also analyzed The authors concluded that the ease of hydro-gen atom abstraction and the ease of termination of the fla-vonoid phenoxyl radicals could be responsible for the radical scavenging activity of flavonoids However there is no QSAR model to confirm this statement This lack of model is in accord with the suggestion that it is hard to believe that only one molecular descriptor even assigned as ldquothe best molecular descriptor for modelling the antioxidant activityrdquo could generate a good predictive QSAR model Only one molecular descriptor could not embrace the manifold nature of antioxidant processes

Bond Dissociation Energy (BDE) of the O H Group and Ionization Potential (IP)

Wright et al [114 115] performed density functional theory (DFT) calculations to discern the activity of several classes of phenolic antioxidants These antioxidants act ei-

ther by hydrogen atom transfer for which the calculation of BDE is relevant or by single-electron transfer for which the calculation of IP is relevant A lower BDE value is usually attributed to a higher ability to donate a hydrogen atom from the hydroxyl group and thereby scavenge free radicals A relatively high value of IP decreases the electron-transfer rate between antioxidant and oxygen and thus reduces the pro-oxidative potency of the antioxidant In an attempt to design an optimum synthetic antioxidant eg for a given biological role Wright et al [115] suggested that BDE and IP are excellent primary descriptors of the antioxidant activ-ity This was supported by the recent SAR study on rational design of phenolic and flavonoid antioxidants by Zhang et al [116] The study revealed that the catechol moiety in ring B of flavonoids has the advantage of a relatively low BDE value for O H

Recent studies indicate that flavonoid derived anions are more active than neutral molecules to scavenge free radicals [69 117] Martins et al [118] found that the antioxidant activity of flavonoids is comparable to the ease of deprotona-tion ie to their acidity Dissociation constants absolute hardness partition coefficient and binding energy may be used as descriptors for the relationship between the acidity of hydroxyl groups and the biological activity of flavonoids [119] Zhang and Wang [120 121] pointed out that it is not the H atom abstraction but the proton coupled electron trans-fer reaction that is responsible for the enhanced radical scav-enging activity of the anionic form Therefore to select or rationally design novel antioxidants the proton dissociation process should be taken into consideration especially in polar systems [121 122]

McPhail et al [57] determined the stoichiometry and kinetics of the hydrogen-donating ability of 15 flavonoids by electron spin resonance spectroscopy The second-order rate constants (k2) of the reduction of galvinoxyl radical by fla-vonoids governed by the BDE value for O H are highly dependent on the configuration of OH groups on the flavon-oid B and C rings To have high reaction rates and high reac-tion stoichiometries flavonoids must be capable of being oxidized to ortho-quinones or extended para-quinones Moderately high correlation (r = 0818) was found between log(k2) and the reaction stoichiometry This result highlights the importance of considering reaction kinetics as well as stoichiometry when assessing the antioxidant capacity of flavonoids

Using the semiempirical quantum chemical parametric method 3 (PM3) Kondo et al [123] have calculated not only phenolic O H but also all of the BDEs for C H of catechins The calculated BDEs for C H for catechins at the C-2 posi-tion were unexpectedly low compared to BDEs of C H at phenolic sites suggesting that hydrogen at the C-2 position may be abstracted by free radicals The authors proposed tentative antioxidative mechanisms of catechins based on kinetic measurements and theoretical calculations Zhang and Wang [124] ascribed the unexpectedly low BDEs for C H in catechins to the inaccuracy of the quantum chemical method used By the Gaussian-94 program they recalculated the results of Kondo et al [123] and found that the BDEs for C H in catechins are higher than the BDEs for O H in the B ring The obtained results indicated that the C-2 hydrogen is not more abstractable than catecholic hydrogens and that the


hydrogen abstraction from C-4rsquo OH is favoured However the BDEs for C H at position C-2 in catechins are compara-ble to the BDEs for O H at position C-3rsquo implying that the C-2 hydrogen can also participate in radical scavenging Hence a high level ab initio calculation is essential in this field

A study of the effect of pH on antioxidant properties (TEAC assay) of a series of 22 hydroxyflavones was per-formed by Lemanska et al [69] They found that the pH dependent antioxidant activity is related to hydroxyl moiety deprotonation resulting in an increase of the antioxidant potential upon formation of deprotonated forms Comparison of experimental results with the calculated BDE value for O H and IP of nondeprotonated and deprotonated forms of various hydroxyflavones indicates that especially the pa-rameter reflecting the ease of electron donation IP is greatly influenced by the deprotonation These results point to the conclusion that upon deprotonation the radical scavenging capacity increases because the electron donation becomes easier Taking into account that the mechanism of radical scavenging activity of the neutral form of flavonoids is gen-erally considered to be hydrogen atom donation this implies that not only the ease of radical scavenging but also the mechanism of antioxidant activity may change upon flavon-oid deprotonation However the absence of a QSAR be-tween the IP and TEAC values of neutral hydroxyflavones indicates that electron donation is not the only mechanism by which the neutral forms of hydroxyflavones may act as anti-oxidants

Russo and coworkers [125 126] evaluated the antioxi-dant activity of a series of polyphenolic molecules com-monly present in the Mediterranean diet These authors found that the most efficient hydrogen-donor systems are characterized by the vicinal dihydroxy moiety as confirmed by their low BDE values Radicalization of their hydroxyl groups gives rise to phenoxyl radicals in which the odd electron appears to be delocalized over the whole molecule and stabilized by hydrogen bonds On the basis of the com-puted BDE and IP values taxifolin luteolin and epicatechin are expected to act as hydrogen donors Luteolin apigenin and kaempferol appear to be good candidates for the single-electron transfer mechanism Their planar conformation and the extended electron delocalization between adjacent rings determine low IP values

In their recent SAR study Trouillas et al [76] investi-gated the specificity of the 3-OH group in the antioxidant action of quercetin and taxifolin The analysis of BDE val-ues for all OH sites in these flavonoids clearly shows the importance of the 3rsquo4rsquo-diOH and 3-OH moieties only when the C2-C3 double bond is present Distribution of spin densi-ties in radicals formed by H-removal from each OH site of both flavonoids indicates that the 3-OH quercetin radical possesses a large spin density on the C-2 atom which ex-plains the C-ring opening process observed in flavonol deg-radation during metabolism [127]

Chen et al [128] performed a theoretical examination of designed four ortho-hydroxy-amino derivatives of flavon-oids The results revealed that the ortho-hydroxy-amino group plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE IP and spin density Spin density is an important de-

scriptor to characterize the stability of free radicals because the energy of a free radical can be efficiently decreased if unpaired electrons are highly delocalized through the conju-gated system Derivatives with the ortho-hydroxy-amino group show stronger antioxidant activity than derivatives with a monohydroxy or ortho-dihydroxy group The authors concluded that the ortho-hydroxy-amino group can be used as another potential functional group to synthesize novel antioxidants

In summary according to the current knowledge of the radical scavenging processes of flavonoid antioxidants H-atom donation is the dominant mechanism which involves two pathways (1) H-atom transfer and (2) electron trans-ferproton transfer

R Obull + Fl OH R OH + Fl Obull (1)

R Obull + Fl OH R O + Fl OHbull+ R OH + Fl Obull (2)

If the flavonoids tend to deprotonate then flavonoid anions should be considered H-atom transfer (1) can be characterized by BDE of OH groups Electron trans-ferproton transfer (2) can be measured by IP The lower these parameters are the stronger is the flavonoid radical scavenging ability [29] Currently besides the Hf BDE of the OH group and IP are the most considered primary de-scriptors of antioxidant activity Lack of QSAR models of antioxidant activity of flavonoids using only BDE and IP additionally reflects the complex nature of antioxidant proc-esses

Miscellaneous Molecular Descriptors

Heijnen et al [129] studied the peroxynitrite scavenging activity of substituted phenols and several flavonoids Good QSAR models were found between the peroxynitrite scav-enging activity of substituted phenols and the Hammett or the EHOMO However no unambiguous QSAR has been ob-tained for flavonoids Instead two relatively independent pharmacophores were identified located on either the catechol group (3rsquo4rsquo-diOH) in ring B or on three OH groups (357-triOH) in the AC ring In the AC ring the 3-OH group was the reactive centre and the reactivity of this group was enhanced by electron donating groups at C-5 andor C-7

Theoretical calculation of the electronic properties and reactivity of flavonoids offers valuable descriptors for QSAR analysis [130 131] Ghiotto et al [132] proposed the new electronic index EHH 1 ie energy difference between HOMO and HOMO 1 as the descriptor for modelling the antioxidant activity of flavonols Linear regression analysis between TEAC and EHH 1 resulted in the following equa-tion

TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403

Farkas et al [133] developed the PLS (partial least squares projection of latent structures) model for predicting the antioxidant activity of 36 flavonoids They found that connectivity indices (variations of the Randi index ) and two-dimensional topological indices play an important role in describing antioxidant activities Surprisingly the number of OH groups does not have a significant role in this PLS model


Estrada et al [134] developed QSAR models for predict-ing inhibitory activity of a dataset of 22 cinnamic acids and flavonoid derivatives against peroxidation of linoleic acid The models are based on the Topological Sub-Structural Molecular Design (TOPS-MODE) approach This approach permitted structural interpretation of the activityproperty of studied compounds in terms of bond contributions Descrip-tors accounting for hydrophobicpolarity electronic and steric features of the molecules were calculated and corre-lated with experimental values of the antioxidant activity expressed as log(IC50) The best model that was obtained contained three descriptors and is given by the following equation

log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v

is the valence connectivity index of order zero 4 v

p is the path valence connectivity index of order 4 and 6

ring is the ring connectivity index of order 6 However the shortcoming of that model is the absence of a clear physico-chemical meaning of the descriptors involved By the virtual structure generation procedure the authors generated a set of 192 flavonoid compounds Among them 75 designed fla-vonoids according to their calculated IC50 values exhibit more potent antioxidant activity than the most active flavon-oid from the experimental dataset Accuracy of such predic-tions is questionable due to the very limited number of com-pounds used in the dataset (only 19 compounds were used for model development) and because of limited accuracy of model (r = 09382) In addition because the authors per-formed only fitting and gave only statistical parameters of fit there is no evidence that such accuracy will be obtained in prediction on an external dataset containing compounds of higher antioxidant activity The proposed model should be additionally tested

Weber et al [135] used chemometric methods (principal component analysis (PCA) hierarchical cluster analysis (HCA) and k-nearest neighbour (KNN)) to build a model able to find a relationship between electronic features of a set of 25 flavonoid compounds and their antioxidant activity (TEAC) Quantum chemical calculations using the AM1 method were employed for the evaluation of molecular de-scriptors Four electronic descriptors were related to the antioxidant activity of the flavonoid compounds studied polarizability ( ) charge at carbon 3 (QC3) total charge at substituent 5 (QS5) and total charge at substituent 3rsquo (QS3rsquo) PCA resulted in the following equation

PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo

These variables were found to be responsible for the separation of more and less antioxidant flavonoids The results obtained with HCA and KNN agree with those from PCA Terms in the above equation were explained as fol-lows The relevance of the atomic charge at C-3rsquo lies in the fact that the oxidation occurs preferably at ring B [92 136-138] The substituent bonded to C-3 determines the planarity of the flavonoid core and the stability of the flavonoid phe-noxyl radical The role of position C-5 is relevant only for compounds lacking hydroxyls on ring B Polarizability can be related to the HOMO LUMO energy gap since the elec-tronic distribution can be easily deformed if the LUMO is close to the HOMO

In another study employing a theoretical approach Gupta et al [139] generated QSAR models for predicting the DPPH scavenging activity of 47 naturally occurring phenolic antioxidants The authors assumed that chemical reactivity is primarily determined by the properties of bonds available in a molecule (being related to the ability of bond breaking and bond making) They developed molecular maps of atom-level properties (MOLMAPs) to represent the diversity of chemical bonds existing in an antioxidant molecule Coun-terpropagation neural networks (CPG NNs) and random forests were used to model the relationship between the MOLMAP descriptors of local bond properties and the cor-responding IC50 values The IC50 values calculated by CPG NNs by performing cross-validation correlated with the experimentally observed IC50 values exhibiting a q

2 of 0712

and RMS error of 1001 Antioxidants with the presence of catechol moiety contribute to high antioxidant activity

Fan et al [140] described an effective way to explore and visualize the SARs of a set of 31 flavonoids with antioxidant activity using structure-activity maps (SAMs) SAMs are graphical maps plotting molecular descriptors such as the number of non-hydrogen atoms and bonds in a molecule or the molecular similarity index against their biological activi-ties SAMs can be used to identify important chemical struc-tural features of flavonoids with antioxidant activity and to determine the position and type of modification for improved activity

Erlejman et al [141] studied the effects of 26 flavonoids and related compounds on lipid oxidation membrane fluid-ity and membrane integrity The results presented in this work stress the importance of considering not only the chemical structure of flavonoids per se but also the nature of the interactions between these molecules and membranes when estimating the flavonoid potential antioxidant capacity The ability of flavonoids to interact with membranes at the water-lipid interface should be regarded as another factor contributing to the antioxidant activity of flavonoids

Knowledge of flavonoid interactions with membrane components seems to be necessary to predict the structure of potential flavonoid based drugs for desired biological effects [142] For this reason the lipophilicity of flavonoids is usu-ally one of their most important pharmacological features and interactions with membranes play an essential role in their biological activity The C-3 position is an excellent choice for substitution to give the flavonoid an optimum lipophilicity allowing both easy application and uptake into the membranes [53]

Kanakis et al [143] estimated the binding constants of flavonoid-DNA adducts Flavonoids are strong antioxidants that prevent DNA damage Low flavonoid concentration stabilizes the DNA duplex whereas helix destabilization can occur when DNA is incubated for a long time with high flavonoid content Among the studied compounds del-phinidin with a positive charge induces a more stabilizing effect on a DNA duplex than quercetin and kaempferol

As presented in this section many descriptors accounting for electronic properties topology steric effects and hydro-phobicity were used in the construction of QSAR models Among them there are descriptors with a clear physical meaning as well as those without a clear physical meaning It


seems reasonable to prefer construction of QSAR models using the former

Metal Ions Chelation

Examination of the antioxidant power of flavonoids is usually carried out by determining their profile as chain-breaking antioxidants by evaluating their direct free radical-scavenging activity as hydrogen- or electron-donating com-pounds [41] However this may not be the only mechanism underlying the antioxidant activity of flavonoids Another antioxidant mechanism may result from the ability of fla-vonoids to chelate metal ions rendering them inactive to participate in free radical generating reactions [21 67 95 144]

An earlier attempt to establish the SAR of iron(II)

chelation by flavonoids [53] demonstrated that 3-OH in the C ring and catechol moiety (3rsquo4rsquo-diOH) in the B ring are more important for chelation than 5-OH Catechol moiety in the B ring is shown to be important for copper(II) chelation [145] Khokhar and Owusu Apenten [146] also emphasized the role of vicinal OH groups (3rsquo4rsquo or 78 dihydroxy groups) in iron binding as well as the presence of C-5 andor C-3 OH in conjunction with the C-4 keto group

Mira and coworkers [147 148] studied the interactions of flavonoids with iron and copper ions Complexes with the range of stoichiometries of metal flavonoid 11 12 22 23 were observed The 12 stoichiometry is in general the preferred one For flavones the binding metal sites are pref-erably at 5-hydroxy and 4-oxo groups Additionally the ortho-catechol group is also a chelating site The SAR of flavonoids related to reduction of iron(III) and copper(II) ions was also investigated Moridani et al [149] showed that the initial step in superoxide radical scavenging activity involves a redox-active flavonoid-Fe

3+ complex Melidou et

al [150] performed a SAR study on the protection against nuclear DNA damage offered by flavonoids in cells exposed to hydrogen peroxide The results presented in this work support the notion that iron chelation is responsible for the DNA protection

Engelmann et al [151] determined the stability constants of ferric complexes with three differently substituted flavon-oids Hydroxy substitution pattern of three flavonoids was chosen each of which possesses one of the three most com-monly suggested sites for metal binding by flavonoids (see Fig 5) The stoichiometry for the Fe(III)-flavonoid complex formation was 11 for all three flavonoids examined and the preferred binding site was the 3rsquo4rsquo-dihydroxy moiety

The cyclic voltammetric data of de Souza and De Gio-vani [152] show a considerable decrease of the oxidation potential of the Al(III) and Zn(II) complexes with flavon-oids compared to that of free flavonoids This finding sug-

gests that flavonoid-metal complexes are more effective antioxidants than free flavonoids

The ability of flavonoids to act as chelators of transition metal ions was examined by Teixeira et al [153] In this SAR study acidity constants of catechin and taxifolin and formation constants of the corresponding copper(II) com-plexes were investigated by potentiometry andor spectro-photometry In addition partition coefficient values (log P) were determined The authors pointed out that for successful QSAR determinations different molecular descriptors of flavonoids would be of interest not only those calculated by theoretical methods but also those based on experimental physicochemical data

Russo and coworkers [154155] emphasized the role of anionic forms of flavonoids in metal chelation Loss of a proton in the flavonoid molecule is crucial for its antioxidant activity because the chelation often occurs through at least one deprotonated ligand

Inhibition of Prooxidant Enzymes

Prooxidant enzymes such as xanthine oxidase lipoxy-genase protein kinase C cyclooxygenase microsomal monooxygenase mitochondrial succinoxidase and NADPH oxidase are responsible for reactive oxygen species genera-tion [4 21 22] A better understanding of structural charac-teristics of flavonoids that promote prooxidant enzyme inhi-bition may guide the development of flavonoid compounds as potential therapeutic agents Here we are focusing on a survey of papers dealing with SAR and QSAR of xanthine oxidase and lipoxigenases inhibition by flavonoids

Xanthine Oxidase

The enzyme xanthine oxidase (XO) catalyzes the oxida-tion of hypoxanthine and xanthine to uric acid Since accu-mulation of excess uric acid in the body results in the painful disease gout (caused by crystallization of uric acid in the joints) there has been considerable interest in designing XO inhibitors As reviewed by Cotelle [156] several authors have investigated the influence of the substituent nature and position on inhibition of XO by flavonoids Hayashi et al [157] measured the inhibitory activities of 103 flavonoids against XO Their results indicate that the planar flavone core (double bond between C-2 and C-3) and the presence of free hydroxyl groups at C-5 and C-7 are important prerequi-sites for the activity

According to Costantino et al [158] and Cotelle et al [159] the OH group at position C-7 is fundamental for activ-ity Flavones with both 7-OH substitution and a catechol or pyrogallol moiety on the B ring are the most effective inhibi-tors of XO (Fig 8A)

O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH

Fig (8) Structural requirements for A) inhibition of xanthine oxidase [157159] B) lipoxygenase inhibition [173]


Anthocyanidin derivatives are less active than the corre-sponding flavones [160] Rastelli et al [161] proposed a model of interaction of flavonoids with XO Hydroxy fla-vones are active in their dissociated form Anionic oxygen at C-7 has a very strong carbonyl character because of extended delocalization of the negative charge on the entire benzopy-rone ring It enables flavones to enter hydrophobic interac-tions in the optimal region of the enzyme

Rastelli et al [162] reported the dissociation constants (pKEI) of enzyme-inhibitor complexes for 18 polyhydroxy-lated and polymethoxylated flavone inhibitors of XO Using binary (01) variables for possible hydroxyl (Hn) and methoxyl (Mn) substituents in their n positions on the fla-vone skeleton the multiple linear regression analysis re-sulted in the following QSAR model

pKEI = 269(plusmn030) + 188(plusmn023) H7 + 122(plusmn026) M4rsquo +

106(plusmn020) H5 + 071(plusmn025) H4rsquo + 055(plusmn018) H3rsquo

n = 18 r2 = 093 s = 0328 F = 3046

On the basis of additional molecular orbital calculations the authors suggest that the most active form in solution is the C-7 anionic flavone form Anions at the C-4rsquo or C-3rsquo hydroxyls are not suitable for interactions with XO

The same group of investigators [158] synthesized and tested the XO inhibitory activity of seventeen 7-hydroxyflavones carrying different substituents at the C-4rsquo position Anionic form generated by the C-7 OH group rep-resents the main species responsible for activity An excel-lent correlation between molecular refractivity (MR) and

log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873

MR is a descriptor frequently interpreted as reflecting drug-receptor dispersion interactions it describes steric and electronic properties of a molecule The authors suggest that C-4rsquo substituents are probably involved in dispersion interac-tions with the enzyme

In a study of Cos et al [163] SARs of flavonoids as inhibitors of XO and as scavengers of the superoxide radical produced by the action of this enzyme were investigated The obtained results support the findings of a study of Haya-shi et al [157] Namely these authors suggested that the planar flavonoid structure is important for XO inhibition The C2-C3 double bond makes the B ring coplanar with rings A and C due to conjugation Hydroxyl groups at C-5 and C-7 also contribute to the inhibitory activity while the presence of the hydroxyl group at C-3 slightly decreases the inhibitory activity For the superoxide scavenging activity the hydroxyl group at C-3rsquo and at C-3 were essential Fla-vonoids with both XO inhibitory activity and additional superoxide scavenging activity could be of advantage as potentially applicable compounds against gout

Ami et al [164] developed simple QSAR models of inhibitory activity of flavylium salts on XO The data set of descriptors contained Hanschrsquos hydrophobicity parameter ( values for substituents in positions C-7 and C-5 7O- and

5OH with preferably ionized C-7 OH group 5O- and 7OH with preferably ionized C-5 OH group) indicator variable I (value 1 for the presence and 0 for the absence of 57-diOH

groups) and QA descriptor (the sum of charge densities at the A ring carbons for anhydrobase form A7) Using these de-scriptors the dissociation constant of the enzyme-inhibitor complex (KEI in μM) was modelled The models presented were developed using only 16 flavylium salts and contained three or four descriptors and each model had a correlation coefficient with KEI higher than 098 However after recon-sidering the modelling process we concluded that due to its high experimental KEI value compared to experimental val-ues of other compounds in the dataset compound no 11 in Table 1 should be omitted [164] After that the best 4-descriptor model contains 5OH 7OH I and QA as descrip-tors having r = 098 rcv = 094 (correlation coefficient ob-tained by performing leave-one-out cross-validation) How-ever a model developed using only 15 compounds should not have more than two descriptors Details of the best 2-descriptor model and its statistical parameters are

KEI = 29860(plusmn5100) 398(plusmn54) I + 4959(plusmn842) QA

n = 15 r = 091 rcv = 084 s = 765 F = 2782

Nagao et al [165] evaluated the inhibitory effect of 25 flavonoids on XO The obtained SAR revealed that the pla-nar flavones and flavonols with the C-7 OH group inhibited XO activity at low concentrations while the nonplanar fla-vonoids were less inhibitory This is consistent with the presented results of other authors However contrary to the findings of Cotelle et al [159] it appears that the catechol moiety of the B ring which gives antioxidative potential to flavonoids was not related to XO inhibition This inconsis-tency was probably caused by the use of different assays

Ponce et al [166] developed a SAR topological model for predicting the activity of 22 flavonoids as XO inhibitors The inhibiting activity of XO by flavonoids is determined to a large extent by their structural properties The authors found that the J2 charge index was the best one for predicting inhibitory activity showing the following statistics r = 08495 s = 0617 F = 516 The developed model was able to classify the studied flavonoids into four groups according to their activity on XO (inactive low significant or high)

Lin et al [167] assessed the inhibition of XO by six fla-vonoids The obtained results emphasized the presence of the C2-C3 double bond OH groups at C-5 and C-7 and the car-bonyl group at C-4 as prerequisites for XO inhibition The authors presented a 3D molecular model of flavonoids bind-ing to the active site of XO

Van Hoorn et al [168] described a method for predicting the IC50 values of flavones based upon an individual contri-bution factor dependent on the location of a hydroxyl moiety in the flavone skeleton The strongest contribution towards XO inhibition results from introduction of C-5 or C-7 OH groups to a planar flavone core

Using molecular mechanics (MM+) and AM1 methods the influence of electronic steric and hydrophobic properties of seven flavonoid compounds on the inhibition of XO was studied by da Silva et al [169] The obtained results showed that geometric properties of flavonoids are the most impor-tant ones for XO inhibition When the torsion angle between C and B rings is larger than 27

o the flavonoid compound is

not able to inhibit the enzyme Small size of the flavonoid


and high hydrophobicity (log P value) enhance the inhibitory activity

A recent SAR study of XO inhibition by 26 flavonoids isolated from different plant species [170] is consistent with the statements reported by Hayashi et al [157]

Lipoxygenases

Lipoxygenases (LOXs) are prooxidant enzymes that catalyze enzymatic lipid peroxidation Additionally they are a source of free radicals initiating nonenzymatic lipid per-oxidation and other oxidative processes involved in the for-mation of atherosclerotic lesions [171-173] Consequently inhibition of LOXs may contribute to the universal antioxi-dant activities of flavonoids

Sadik et al [174] performed a SAR study of inhibition of 15-lipoxygenases (15-LOXs) by flavonoids Planar flavonoid structure with delocalized electrons (achieved by the C2-C3 double bond) seems to be a prerequisite for inhibitory activ-ity The following structural features were found to enhance the inhibitory potency (a) presence of a catechol moiety in the B or A ring (b) 4-carbonyl group in the C ring (Fig 8B) In contrast the presence of the 3-OH group in the C ring diminished the inhibition of 15-LOX While the presence of the catechol moiety is favourable an excessive number of OH groups lowers the hydrophobicity of flavonoids and diminishes intercalation in the hydrophobic cavity at the active site of the enzyme Because flavonoids possess LOX inhibitory activities as well as free radical scavenging activi-ties they could be promising compounds as therapeutic agents against cardiovascular diseases

Inhibition of 15-LOX by quercetin and quercetin mono-glucosides was reported by da Silva et al [175] The ob-tained results indicate that quercetin glycoside as well as its aglycone are capable of inhibiting the LOX induced LDL oxidation more efficiently than vitamins C and E Quercetin quercetin 3-glucoside and quercetin 7-glucoside exhibited a higher inhibitory effect than quercetin 4rsquo-glucoside The authors concluded that the catechol structure in the B ring largely contributes to the inhibition of the 15-LOX induced LDL oxidation

Redrejo-Rodriguez et al [176] performed a theoretical semiempirical SAR study of LOX inhibition by four flavon-oids The obtained results showed a clear relation between the planar character of flavonoids and the potency of these compounds as LOX inhibitors Also the ELUMO and delocali-zation of LUMO orbital are related to inhibitory potency

The ability of flavonoids to inhibit prooxidant enzymes as well as scavenge free radicals and chelate metal ions makes them very promising compounds for designing mul-

tipotent antioxidants Multipotent antioxidants are of great interest for the treatment of diseases in which multiple pa-toghenetic factors are implicated such as free radicals metal ions and prooxidant enzymes [177]

Prooxidant Activity of Flavonoids

Although the ability of flavonoids to act as antioxidants has been demonstrated there is an increasing evidence of their prooxidant activity [42 156 178-182] The presence of a different number of OH groups in the B ring of flavonols may contribute to their antioxidant activity as well as to their toxicity and may play an important role in their po-tency for biological action such as angiogenesis and im-mune-endothelial cell adhesion which respectively are important processes in the development of cancer and athe-rosclerosis [183] Bors et al [184] have suggested that the stability of flavonoid phenoxyl radical is sometimes ques-tionable and may give rise to prooxidant action This might help explain the occasional unpredictable relationships sometimes observed between the structure of some flavon-oids and their antioxidant activities Prooxidant activity is thought to be directly proportional to the total number of hydroxyl groups [54]

The flavonoid phenoxyl radical could interact with oxy-gen generating quinones and superoxide anion rather than terminating the chain reaction (Fig 9) This reaction may take place in the presence of high levels of transient metal ions and may be responsible for the undesired prooxidant effect of flavonoids [21]

The same flavonoid compound could behave both as an antioxidant and a prooxidant Van Acker et al

[53] pointed

out that the most active antioxidants are likely to be prooxi-dants This should be taken into account when designing therapeutically interesting flavonoids compounds for thera-peutic application may not be those with the highest antioxi-dant activity but those with optimum (high) antioxidant activities

Ohshima et al [185] studied the antioxidant and prooxi-

dant effects of 18 flavonoids and related phenolic com-pounds on the DNA damage induced by NO peroxynitrite and nitroxyl anion Most of the tested flavonoids inhibited DNA strand breakage Only flavonoids having an ortho-trihydroxyl group either in the B ring or in the A ring acted as prooxidants

Yoshino et al [186] found that flavonoids having a

catechol structure in the A or B ring exert prooxidant activ-ity Oxidation of catechol by a copper(II) ion bound to DNA can generate reactive oxygen species responsible for the site-specific DNA damage The mechanism of the DNA damage

O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O

Fig (9) Prooxidant activity of flavonoids


by quercetin was proposed [187] Reacting with Cu(II) quer-cetin induced extensive DNA damage but kaempferol and luteolin induced little DNA damage even in the presence of Cu(II) El Amrani et al

[188] studied the oxidative DNA

cleavage induced by an iron(III) flavonoid complex For the cleavage mechanism the authors proposed the mechanism of electron transfer in which Fe(III) takes one electron of the carbon atom vicinal to the 3-hydroxy-4-keto moiety generat-ing the iron(II) flavonoid complex (Fig 10) Then the fer-rous complex binds to DNA which results in the formation of reactive oxygen species and DNA cleavage

O

O

O

Fe(III)

O

O

O

Fe(II)

Fig (10) Proposed route for generation of the ferrous complex

from the Fe(III) flavonoid complex [188]

Nemeikaite- eniene et al [189] studied the prooxidant

cytotoxicity of 13 hydroxybenzenes and 6 flavonoids in FLK and HL-60 cells These authors demonstrated that the redox potential of phenoxyl radicalphenol couple may serve as an important tool to predict the prooxidant cytotoxicity of poly-phenols

CONCLUDING REMARKS

The potential health promoting properties of flavonoids result from their capability to decrease the risk of develop-ment of degenerative diseases such as coronary heart dis-eases some forms of cancer rheumatoid arthritis and Park-insonrsquos and Alzheimerrsquos diseases These medicinal actions of flavonoids are mostly ascribed to their antioxidant activity scavenging of free radicals metal ions chelation enzyme inhibition modulation of gene expression and interaction with the cell signalling pathways

Despite many efforts the unequivocal relationships be-tween the antioxidant activity of the flavonoids and their chemical structures are still not discovered The construction of SARQSAR of antioxidant actions of flavonoids is not an easy task The results of a number of studies analyzed and discussed in the present review provide a solid rationale for continuing efforts to improve QSAR models of flavonoid antioxidant activities Common unfavourable characteristics of available models for modelling the antioxidant activity of flavonoids are (1) a relatively small number of compounds in datasets used for model building (2) validation of developed models usually based only on the fit of statistical parameters and (3) a relatively large number of parameters (descriptors) involved in models compared to the total number of com-pounds used for models development Due to these charac-teristics such models have strong limitations and are not appropriate for real prediction of the antioxidant activity of flavonoids ie predictions by such models cannot be reli-able [190 191] An additional common characteristic of almost all developed antioxidant activity models of flavon-oids is that they are based on in vitro experimental values We must be aware that models developed based on in vitro antioxidant activity of flavonoids cannot be applied to an in

vivo situation because in vitro activity of flavonoids does not contain information about the flavonoid solubility ab-sorption metabolism and degradation in the colon and transport properties (eg whether flavonoids cross the blood-brain barrier and in which forms) [44] Only flavon-oids possessing suitable transport metabolic absorption properties as well as flavonoids that will not undergo struc-tural modifications can reach tissue in an acceptable high concentration and exert activity similar to flavonoids in vi-tro

As emphasized in a recent study by Haenen et al [59] determination of structure-activity relationships of flavon-oids is subject to many competing variables Stability of the antioxidant antioxidant effects of reaction products concen-tration of the antioxidant and concentration of the reactive species should always be evaluated critically In vitro studies can be much simpler and controllable compared to in vivo studies for screening antioxidants for the structure-activity and elucidation of the mode of action The problem is that in vitro systems usually deviate from in vivo situations Con-struction of a valid structure-activity relationship may be complicated by the fact that more that one moiety within the flavonoids can independently exert a potent activity In con-trast despite the fact that some moieties (for example the catechol group in ring B and the C-3 OH group) have an important role in metal chelating and in radical scavenging SAR for metal chelating need not be identical to SAR for radical scavenging In this case the overall SAR (comprising both metal chelating and radical scavenging) is a mixed one Even more factors are important in the in vivo activity of antioxidants eg lipophilicity activity of metabolism prod-ucts and binding to proteins As concluded by Haenen et al [59] in vitro studies reveal the initial features of a series of antioxidants These data can be transferred to the more com-plex in vivo situation Detailed investigations should be done of the actual fate of flavonoid compounds in vivo to be able to predict their effects in living cells In particular specific mechanisms explaining how these compounds act need to be discovered

Future research should be focused on at least two major areas

1 Development and application of specific and une-quivocal methods for measuring the biological activ-ity of an enlarged pool of flavonoids Uniform ana-lytical methods are needed to allow data from differ-ent sources to be compared This is most apparent in the area of antioxidant research which has been ham-pered by the lack of suitable methods to measure the antioxidant activity [59 192]

2 Improvement of the methods used in QSAR model-ling as well as the methods for designing and using suitable molecular descriptors In fact the best set of descriptors may be achieved by careful selection of several different types of molecular descriptors de-scribing the driving forces related to the activity of flavonoids The interpretability of chosen descriptors ie their chemical meaning is desirable This may help direct the synthesis and selection of new drugs with potential therapeutic applications for the treat-ment of a wide range of free radical-induced diseases


Synthesis of favourable flavonoid compounds with physiological and pharmacological activities could be achieved by different approaches Classical in vitro chemical synthesis is one of them [193-196] An alternative in vivo approach is to produce flavonoids using plant cell culture strategies [197] Also microbial and enzymatic transforma-tions of flavonoids can be used to convert abundant flavon-oids to desired products [198] Another in vivo approach to synthesizing favourable flavonoid compounds is the genetic modification of flavonoid biosynthesis Flavonoid biosynthe-sis is one of the best characterized natural product pathways in plants and is therefore an excellent target for metabolic engineering [199-201] Manipulation of flavonoid biosynthe-sis can be approached via manipulation of pathway genes modification of the expression of regulatory genes and gen-eration of novel enzymatic specificities [202] This may result in the plantrsquos ability to synthesize flavonoid bioactive natural products for human health

Reviewed SARs and QSARs demonstrate that the anti-oxidant activities of flavonoids ie free radical-scavenging metal ion chelating and enzyme inhibitor activities are de-pendent on suitable structure motifs In particular the catechol moiety makes important contributions not only to scavenging free radicals and sequestering metal ions but also to inhibiting prooxidant enzymes Integration of radical scavenging metal ion chelating and enzyme inhibiting ac-tivities into a single structure make flavonoids very promis-ing multifunctional antioxidants Flavonoids therefore seem to be a cornerstone in the exciting field of rational design of naturally occurring multipotent antioxidants

ACKNOWLEDGEMENTS

This work was supported in part by Grants 0079025 (DA DDA DB VR) and 0098034 (BL NT) awarded by the Ministry of Science Education and Sports of the Republic of Croatia The authors gratefully acknowledge the anonymous reviewers for their helpful comments on the manuscript We also thank Dr Wolf Bors for correspon-dence and help

ABBREVIATIONS

AM1 = Austin Model 1

BDE = Bond dissociation energy

DFT = Density functional theory

Hf = Heat of formation of the flavonoid radical

DPPH = 11-diphenyl-2-picrylhydrazyl

E = Half-wave potential of the first oxidation wave

EHOMO = Energy of the highest occupied molecular orbital

EHYDR = Hydration energy

ELUMO = Energy of the lowest unoccupied molecular orbital

Epa = Anodic peak potential

Ep2 = Half-peak oxidation potential

FRAP = Ferric reducing antioxidant power assay

HCA = Hierarchical cluster analysis

HOMO = Highest occupied molecular orbital

IC50 = Concentration for 50 inhibition

IP = Ionization potential

Ipa = Anodic peak current

KNN = k-nearest neighbor

kQ = Overall rate constant

LDL = Low-density lipoprotein

log P = Octanolwater partition coefficient

LOX = Lipoxygenase

LUMO = Lowest unoccupied molecular orbital

MOLMAP = Molecular maps of atom-level properties

n value = Number of electrons involved in the oxidation

PCA = Principal component analysis

QSAR = Quantitative structure-activity relationship

QSPR = Quantitative structure-property relationship

RSA = Radical scavenging activity

SAM = Structure-activity map

SAR = Structure-activity relationship

TEAC = Trolox equivalent antioxidant capacity

XO = Xanthine oxidase

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Morita N J Nat Prod 1988 51 345 [158] Costantino L Rastelli G Albasini A Eur J Med Chem 1996

31 693 [159] Cotelle N Bernier J-L Catteau J-P Pommery J Wallet J-

C Gaydou EM Free Radic Biol Med 1996 20 35 [160] Costantino L Rastelli G Albasini A Pharmazie 1995 50 573

[161] Rastelli G Costantino L Albasini A J Am Chem Soc 1997 119 3007

[162] Rastelli G Costantino L Albasini A Eur J Med Chem 1995 30 141

[163] Cos P Ying L Calomme M Hu JP Cimanga K Van Poel B Pieters L Vlietinck AJ Vanden Berghe D J Nat Prod

1998 61 71 [164] Ami D Davidovi -Ami D Be lo D Lu i B Trinajsti N

J Chem Inf Comput Sci 1998 38 815 [165] Nagao A Seki M Kobayashi H Biosci Biotechnol Biochem

1999 63 1787 [166] Ponce AM Blanco SE Molina AS Garcia-Domenech R

Galvez J J Chem Inf Comput Sci 2000 40 1039 [167] Lin C-M Chen C-S Chen C-T Liang Y-C Lin J-K

Biochem Biophys Res Commun 2002 294 167 [168] Van Hoorn DEC Nijveldt RJ Van Leeuwen PAM Hofman

Z MrsquoRabet L De Bont DBA Van Norren K Eur J Pharma-col 2002 451 111

[169] da Silva SL da Silva A Honorio KM Marangoni S Toya-ma MH da Silva ABF J Mol Struct (Theochem) 2004 684

1 [170] Montoro P Braca A Pizza C De Tommasi N Food Chem

2005 92 349 [171] Brash AR J Biol Chem 1999 274 23679

[172] Schewe T Biol Chem 2002 383 365 [173] Schewe T Sies H Research monographs Flavonoids and

prooxidant enzymes httpwwwuniklinik-duesseldorfdeimgejbfile Research_monographspdfid=280

[174] Sadik CD Sies H Schewe T Biochem Pharmacol 2003 65 773

[175] da Silva EL Tsushida T Terao J Arh Biochem Biophys 1998 349 313

[176] Redrejo-Rodriguez M Tejeda-Cano A del Carmen Pinto M Macias P J Mol Struct (Theochem) 2004 674 121


[177] Zhang H-Y Yang D-P Tang G-Y Drug Discov Today 2006

11 749 [178] Awad HM Boersma MG Boeren S van Bladeren PJ

Vervoort J Rietjens IMCM Chem Res Toxicol 2001 14 398

[179] Galati G OrsquoBrien PJ Free Radic Biol Med 2004 37 287 [180] Hodnick WF Ahmad S Pardini RS In Flavonoids in the

Living System Manthey JA Buslig B Eds Plenum Press New York 1998 pp 131-150

[181] Metodiewa D Jaiswal AK Cenas N Dickancaite E Segura-Aguilar J Free Radic Biol Med 1999 26 107

[182] Galati G Sabzevari O Wilson JX OrsquoBrien PJ Toxicology 2002 177 91

[183] Kim J-D Liu L Guo W Meydani M J Nutr Biochem 2006 17 165

[184] Bors W Michel C Schikora S Free Radic Biol Med 1995 19 45

[185] Ohshima H Yoshie Y Auriol S Gilibert I Free Radic Biol Med 1998 25 1057

[186] Yoshino M Haneda M Naruse M Murakami K Mol Genet Metab 1999 68 468

[187] Yamashita N Tanemura H Kawanishi S Mutat Res 1999 425 107

[188] El Amrani FBA Perello L Real JA Gonzalez-Alvarez M Alzuet G Borras J Garcia-Granda S Montejo-Bernardo J J

Inorg Biochem 2006 100 1208

[189] Nemeikaite- eniene A Imbrasaite A Sergediene E enas N

Arch Biochem Biophys 2005 441 182 [190] Jorgensen WL J Chem Inf Model 2006 46 937

[191] Maggiora GM J Chem Inf Model 2006 46 1535 [192] Frankel EN Meyer AS J Sci Food Agric 2000 80 1925

[193] Iacobucci GA Sweeny JG Tetrahedron 1983 39 3005 [194] van Acker FAA Hageman JA Haenen GRMM van der

Vijgh WJF Bast A Menge WMPB J Med Chem 2000 43 3752

[195] Cotelle N Vrielynck L Nowogrocki G Cotelle P Vezin H J Phys Org Chem 2004 17 226

[196] Kondo T Oyama K-i Nakamura S Yamakawa D Tokuno K Yoshida K Org Lett 2006 16 3609

[197] Lila MA In Plant Pigments and their Manipulation Davies KM Ed CRC Press Boca Raton 2004 pp 248-274

[198] Das S Rosazza JPN J Nat Prod 2006 69 499 [199] Winkel-Shirley B Plant Physiol 2001 126 485

[200] Davies KM Schwinn KE In Flavonoids Chemistry Biochem-istry and Applications Andersen OslashM Markham KR Eds

CRC Press Boca Raton 2005 pp 143-218 [201] Lepiniec L Debeaujon I Routaboul J-M Baudry A Pourcel

L Nesi N Caboche M Annu Rev Plant Biol 2006 57 405 [202] Dixon RA Steele CL Trends Plant Sci 1999 4 394

Received September 1 2006 Revised November 23 2006 Accepted November 23 2006


tes AIDS heart ailments ulcer formation bacterial infec-tions mutagenesis neurodegenerative diseases such as Park-insonrsquos and Alzheimerrsquos diseases and arthritis as well as premature body aging [24] Consumers and food manufac-tures have become increasingly interested in flavonoids for their potential beneficial role in prevention of the above-listed diseases For example flavonoids are major functional components of propolis and honey which have been used since ancient times Today hundreds of herbal supplements containing flavonoids are available on the market However the safety of these products is questionable [25] Exposure to increased levels of flavonoids can adversely affect human health due to prooxidant and promutagen activities of these compounds [26] Therefore careful evaluation of the bio-logical activity of flavonoids seems to be important for a proper determination of their safety

Flavonoids and QSAR

The multiple activities of flavonoids as well as their structural diversity make this class of compounds a rich source for modelling lead compounds with targeted pharma-

cological properties The activity of flavonoids is closely linked to their structure They are not equally physiologically active presumably because of the presence of different sub-stitutions on the carbon atoms of the basic flavonoid struc-ture and differences in lipid solubility Despite the fact that flavonoids generally occur as glycosides their bioactivity is attributed to aglycon structures rather than to sugar moieties Differentiation of flavonoids is not easy because thousands of them share a common phenyl-benzo- -pyrone skeleton and they differ from one another only in the position and number of hydroxyl andor methoxyl groups as well as the position and number of different saccharides involved in glycosylation Acylation may often occur at various posi-tions of the flavonoid nucleus as well as of the glycosyl residues These diverse substitution patterns make the fla-vonoids an ideal object of QSAR studies [27-29]

Despite the enormous interest in flavonoids and other polyphenolic compounds as potential protective agents against the development of human diseases real contribu-tions of such compounds to health maintenance and mecha-

O

A

O

O

O

OH

HO

OH

OH

OH

O

O

HO

OH

OH

OCH3

O

OH

HO

OH

OH

O

O

O

HO

OH

OH

OH

OH

O

O

HO

OH

OH

O

OCH3

OH

OCH3

OH

HO

OH

O

HOO

OH

OH

OH

OHO

OH

OCH3

OH

OCH3

O

OOH

HO

OH

2

3

4

6

5

7

8

6

5

4

3

2

flavan nucleusbasic flavonoid structure

4-oxo-flavonoid nucleus2-phenyl-benzo-γ-pyrone

(+)-Catechin (catechin flavanol)

Hesperetin (flavanone)

Taxifolin (flavanonol)

Apigenin (flavone)

Quercetin (flavonol) Malvidin (anthocyanidin)

Malvidin 3-glucoside (anthocyanin)Genistein (isoflavone)

+

+

C

B

Fig (1) Structural formulae of the main sub-classes of flavonoids







1O2) superoxide (O2














O

OH

OH

OH

OH

HO

O

A

O

OH

OH

HO

O

OH

A2

3

4

6

5

7

8

6

5

4

3

2

2

3

4

6

5

7

8

6

5

4

3

2

B

C

B

C










2+ and Cu



H2O2 + Fe2+


3+ (Cu

2+)






OF FLAVONOIDS



O

O

HO

OH

OH

OH

OH

ROHO

O

HO

OH

O

OH

O

H

RO

O

O

HO

OH

O

OH

OH

O

O

O

HO

OH

OH

O

ROHRO





-e-O

O

O

H

B

+

O

O

O

H

C

+

O

O

O

H

A



O

O

HO

OH

OH

HO

HO Men+

Men+

Men+





n = 42 r2

= 0729 s = 0767 F140 = 10733 p lt 00005



n = 42 r2

= 0792 s = 0681 F239 = 7401 p lt 00005



n = 28 r = 0974 s = 95 F = 2307

















0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171




n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181






O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +













1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466






























































































































































































1O2) superoxide (O2














O

OH

OH

OH

OH

HO

O

A

O

OH

OH

HO

O

OH

A2

3

4

6

5

7

8

6

5

4

3

2

2

3

4

6

5

7

8

6

5

4

3

2

B

C

B

C










2+ and Cu



H2O2 + Fe2+


3+ (Cu

2+)






OF FLAVONOIDS



O

O

HO

OH

OH

OH

OH

ROHO

O

HO

OH

O

OH

O

H

RO

O

O

HO

OH

O

OH

OH

O

O

O

HO

OH

OH

O

ROHRO





-e-O

O

O

H

B

+

O

O

O

H

C

+

O

O

O

H

A



O

O

HO

OH

OH

HO

HO Men+

Men+

Men+





n = 42 r2

= 0729 s = 0767 F140 = 10733 p lt 00005



n = 42 r2

= 0792 s = 0681 F239 = 7401 p lt 00005



n = 28 r = 0974 s = 95 F = 2307

















0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171




n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181






O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +













1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466
































































































































































































2+ and Cu



H2O2 + Fe2+


3+ (Cu

2+)






OF FLAVONOIDS



O

O

HO

OH

OH

OH

OH

ROHO

O

HO

OH

O

OH

O

H

RO

O

O

HO

OH

O

OH

OH

O

O

O

HO

OH

OH

O

ROHRO





-e-O

O

O

H

B

+

O

O

O

H

C

+

O

O

O

H

A



O

O

HO

OH

OH

HO

HO Men+

Men+

Men+





n = 42 r2

= 0729 s = 0767 F140 = 10733 p lt 00005



n = 42 r2

= 0792 s = 0681 F239 = 7401 p lt 00005



n = 28 r = 0974 s = 95 F = 2307

















0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171




n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181






O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +













1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466

























































































































































































O

O

HO

OH

OH

HO

HO Men+

Men+

Men+





n = 42 r2

= 0729 s = 0767 F140 = 10733 p lt 00005



n = 42 r2

= 0792 s = 0681 F239 = 7401 p lt 00005



n = 28 r = 0974 s = 95 F = 2307

















0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171




n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181






O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +













1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466



























































































































































































0273 (plusmn0081)

n = 27 r = 0933 q2 = 0821 s = 0146 F = 5142

SPRESS = 0171




n = 27 r = 0935 q2 = 0808 s = 0147 F = 3816

SPRESS = 0181






O

O

HO

OH

OH

O

OH

OO

O

O

O

OH

O

OH

OH

O

O

O

O

H

OH

O

OH

OH

O

O

O

O

O

O

OH

OH

+

+ +













1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466



































































































































































































1EC50 = 655 expEpa + 138 r = 073


1EC50 = 560 expEpa + 0294 Ipa + 947 r = 086


1EC50 = 167 n + 050 r = 094



OHO

OH

OH

OH

OH

H

HO

O

O

O

HO

OH

H

- 4 H+

- 4 e-

Catechin (n = 4)















1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466





































































































































































































1O2 quenching rates






log k3k1 = 146491 ndash 00955 Hf

n = 15 r = 09491




n = 20 r = 0883





inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466


























































































































































































inhibition() = 10108 Hf r2 = 09056



pIC50 = 00319 EHYDR + 346

n = 12 r = 0747 p lt 0005 s = 0227

pIC50 = 0035 EHYDR + 0012 Hf + 299

n = 12 r = 0756 p lt 0022 s = 0235

pIC50 = 0033 EHYDR + 029 ELUMO + 372

n = 12 r = 0759 p lt 0021 s = 0234























TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466






































































































































































































TEAC = 944797 ndash 882387 EHH 1

n = 4 r = 0972 s = 0403




log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466


























































































































































































log(1IC50) = 1863 ndash 0544 o v

+ 2536 4 v

p 85906 6

ring

n = 19 r = 09382 s = 0820 F(315) = 367

where o v





PC1 = 0517 + 0254 QC3 + 0597 QS5 0558 QS3rsquo



2 of 0712























Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466








































































































































































































Xanthine Oxidase



O

OH

OH

O

OH

A C

B

B

O

OH

OH

O

OH

A C

B

A

HO

OH







n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466





























































































































































































n = 18 r2 = 093 s = 0328 F = 3046



log IC50 is found

log IC50 = 007 MR + 451

n = 17 r = 096 F = 1873







n = 15 r = 091 rcv = 084 s = 765 F = 2782











Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466



























































































































































































Lipoxygenases











[53] pointed






O

O

O

O

O

O

O

H

H

H

H

O2 O2

-H+

O

O

O

O

O

H

H

H

O

O






O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466




























































































































































































O

O

O

Fe(III)

O

O

O

Fe(II)





CONCLUDING REMARKS











ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466



























































































































































































ACKNOWLEDGEMENTS


ABBREVIATIONS






















LOX = Lipoxygenase












REFERENCES



















New York 1996 pp 409-466
























































































































































































SAR and QSAR of the Antioxidant Activity of Flavonoids

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Transcript of SAR and QSAR of the Antioxidant Activity of Flavonoids