Electron Transfer, Radicals and Oxidative Stress - IngentaConnect

Send Orders for Reprints to [email protected] The Natural Products Journal, 2015, 5, 142-151

142

Natural Monophenols as Therapeutics, Antioxidants and Toxins; Electron Transfer, Radicals and Oxidative Stress Peter Kovacica,*, Ratnasamy Somanathana,b and Marie-Caline Z. Abadjiana a

Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA; Centro de Graduados e Investigación del Instituto Tecnológica de Tijuana, Apdo postal 1166, Tijuana, B.C. Mexico b

Abstract: Natural monophenols exhibit various properties including antioxidant, therapeutic action and toxicity. This review is unique in application of a unifying mechanistic theme comprising electron transfer, reactive oxygen species and oxidative stress. Representative phenols are as follows: salicylic acid, guaiacol, eugenol, (S)-tyrosine, vanillin, capsaicin, 6-gingerol, carvacrol, thymol, tocopherol, P. Kovacic 5-hydroxytryptamine, psilocin, sesamol, estradiol, cannabinoids, etoposide, morphine and heroin, cresols, and other related phenols, such as platensimycin and polyphenols (vancomycin and tetarimycin A). This approach to mode of action may assist in improved drug design.

Keywords: Antioxidants, electron transfer, monophenols, radicals, therapy, toxicity. ET agent

ET agent

INTRODUCTION

A prior integrating, mechanistic theme is as follows: “The preponderance of bioactive substances, usually as the metabolites, incorporate ET functionalities. We believe these play an important role in physiological responses. The main group include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). Resultant redox cycling is illustrated in Scheme 1. In vivo redox cycling with oxygen can occur, giving rise to oxidative stress (OS) through generation of reactive oxygen species (ROS), such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide) (Scheme 1). Cellular and mitochondrial enzymes can also perform catalytically in the reduction of O2.

*Address correspondence to this author at the Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA; Tel: 619-594-5595; Fax: 619-594-4534; E-mail: [email protected] 2210-3163/15 $58.00+.00

O2

O2

H

HOO

.

H

.

There is extensive literature on physiological activity of monophenols, of which a representative sample of more important ones is presented herein. The many synthetic ones are not included. A unifying mechanistic theme based on electron transfer, radicals and oxidative stress serves to rationalize therapy, antioxidant action and toxicity. The following monophenols are discussed: salicylic acid, guaiacol, eugenol, (S)-tyrosine, vanillin, capsaicin, 6-gingerol, carvacrol, thymol, tocopherol, 5-hydroxytryptamine, psilocin, sesamol, estradiol, cannabinoids, etoposide, morphine and heroin, cresols, and other related phenols, such as platensimycin and polyphenols (vancomycin and tetarimycin A). The unifying aspect may prove useful in future drug design for this class.

HOOH

e

.

HO

+

HO

Scheme 1. Redox cycling with superoxide and ROS formation.

In some cases ET results in involvement with normal electrical effects (e.g., in respiration of neurochemistry). Generally, active entities possessing ET groups display reduction potentials in the physiologically responsive range, (i.e., more positive than about -0.5 V). Hence, ET in vivo can occur resulting in production of ROS which can be beneficial in cell signaling at low concentrations, but produce toxic results at high levels. Electron donors consist of phenols, Nheterocycles or disulfides in proteins which produce relatively stable radical cations. ET, ROS and OS have been increasingly implicated in the mode of action of drugs and toxins, (e.g., antiinfective agents [1], anticancer drugs [2], carcinogens [3], reproductive toxins [4], nephrotoxins [5], hepatoxins [6], cardiovascular toxins [7], nerve toxins [8], mitochondrial toxins [8], abused drugs [9], pulmonary toxins [10] ototoxins [11] and various other categories [12]. There is a plethora of experimental evidence supporting the ET-ROS theoretical framework [1-12]. This evidence includes generation of the common ROS, lipid peroxidation, degradation products of oxidation, depletion of AOs, effect of exogenous AOs, and DNA oxidation and cleavage products, as well as electrochemical data. This comprehensive, unifying mechanism is consistent with the frequent observation that many ET substances display a variety of © 2015 Bentham Science Publishers

Natural Monophenols as Therapeutics, Antioxidants and Toxins

The Natural Products Journal, 2015, Vol. 5, No. 3

activities (e.g., multiple-drug properties), as well as toxic effects. It is important to recognize that mode of action in the biodomain is often involved with many physiological actions and is multifaceted. In addition to the ET-ROS-OS approach, other aspects may pertain, such as, enzyme inhibition, allosteric effects, receptor binding, metabolism and physical factors. A specific example involves protein binding by quinones in which protein and nucleophiles, such as amino or thiol, effect conjugate addition” [13].

OH

O

O

O OH [O]

2,3-dihydroxybenzoic acid OH

OH [O]

3-carboxy-1,2-benzoquinone O

O OH

O OH

O 2-carboxy-1,4-benzoquinone

Fig. (2). 2,3- and 2,5- Dihydroxybenzoic acid and their quinone derivatives. O

OH

HO

OH

OH

OH 2,5-dihydroxybenzoic acid

OH

O

O

HO

143

O

O

Studies point to operation of SA as an AO, which is characteristic of phenols. OS was reduced as expected, and the AO effect was greater for SA than for ASA, due to the OH group. Physiological Activity

Scheme 2. Oxidative conversion of phenol to quinones.

This review is mainly concerned with monophenols involving the unifying mode of action in physiological activity. Scheme 2 portrays oxidative conversion of a monophenol to ET quinone. Representative Monophenols Salicylic Acid Salicylic acid (SA) is an analgesic, anti-inflammatory drug [14], in addition to being a natural product, plant hormone and metabolite of acetyl salicylic acid (aspirin) (ASA) (Fig. 1). ASA undergoes enzymatic deacetylation yielding SA. The phenolic acid was hydroxylated by hydrogen peroxide to form 2,3- and 2,5- dihydroxybenzoic acid which can be further oxidized to form the quinones (Fig. 2) [15]. SA generates hydrogen peroxide in root cultures [16] leading to OS, in line with the unifying mechanism.

OH

O

O

O

O

OH

Salicylic Acid (SA)

OH

Aspirin (ASA)

Fig. (1). Chemical structure of salicylic acid (SA) and aspirin (ASA).

It also forms thiobarbituric acid substances (TBARS) which suggest involvement of ROS. The TBARS were decreased by AOs which apparently countered the ROS. Lipid peroxidation also resulted from SA indicative of OS, and produced liver damage involving mitochondrial dysfunction [14].

Rather extensive investigations of therapeutic action and toxicity have been reported. A study deals with the bacteriostatic action of SA [17]. In relation to mode of action, SA may act as an uncoupler of oxidative phosphorylation. A review provides evidence for the unifying mechanism of ET-ROS-OS in antibacterial action [1]. Clues were provided in connection with the anticancer effects of SA [18]. The drug appears to lower the tendency to develop certain cancers. The drug activated the AMPK enzyme that plays a role in cancer and diabetes. A relevant report deals with evidence supporting the ET-ROS-OS theme for anticancer agents [2]. Toxicity and Uses In addition to adverse effects present in other sections, a review deals with toxicity from topical SA [19]. The drug finds use for its keratolytic, bacteriostatic, fungicidal and additional photoprotective aspects [19]. Additional uses are for psoriasis and acne. Other indicators are nigricans, keratosis, ichthyosis, and tinea nigra. Tinnitus results from pressure and effect on hair cells. Toxicity linked to topical application includes psoriasis, ichthyosis, dermatitis and imbricata. The most severe cases involved psoriasis. Deaths occurred in connection with psoriasis, scabies, dermatitis, lupus and erythroderma. Other toxicities are necrosis, nephritis and anticoagulation. The ET-ROS-OS unifying theme has been applied to the following aspects linked to SA; antibacterial [1], antifungal [20] and dermal toxicity [21]. Other Mechanisms In accord with a multifaceted approach, other modes of action have been reported in addition to ET-ROS-OS. Inhibition of COX enzyme is involved in anti-inflammatory effects in addition to activation of protein kinases (AMPK). This action may also play a part in anticancer effects. AMPK may also be a factor in the antidiabetic effects. The ototoxic effect may entail inhibition of prestin [22]. There is evidence for involvement in Reye’s Syndrome [23].

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Kovacic et al.

Guaiacol

Vanillin

Guaiacol (2-methoxyphenol) (Fig. 3) is found in plants, like guaiacum and lignins, and commercially used to make vanillin [24] and eugenol [25]. Under oxidative stress in the presence of hydrogen peroxide, guaiacol peroxidase uses guaiacol to reduce hydrogen peroxide. This monophenolic can be converted to its quinone derivative. Guaiacol has been shown to be a good radical scavenger [26]. Although guaiacol is one of the smaller monophenols discussed, it exemplifies the unifying theme of how a relatively simple monophenol can interact in the ET-ROS-OS mechanism.

Vanillin (4-hydroxy-3-methoxybenzaldehyde) (Fig. 6) is the major component from vanilla bean and is biosynthesized from tyrosine. Several studies found that vanillin acts as a good free radical scavenger [33]. The monophenol can be converted to a hydroquinone and then a quinone which is known to interact in ET mechanisms. Vanillin has been suggested to activate antioxidative pathways under oxidative stress [34]. The compound displays antioxidant [35], antiinflammatory [35], anticancer [2, 36], and antimelanogenesis [37] properties.

HO

HO

O

H

O

Fig. (3). Guaiacol.

O

Fig. (6). Vanillin.

Eugenol Eugenol (4-allyl-2-methoxyphenol; an allyl chainsubstituted guaiacol) Fig. 4, is a fragrant compound extracted from certain plant oils, such as clove oil, nutmeg, and basil. Eugenol has been shown to possess antiseptic and anesthetic [27], antioxidant [27], and antifungal properties [28]. In relatively large quantities it is also hepatotoxic [27]. Eugenol has been shown to generate ROS upon visible light irradiation resulting in cytotoxicity [29]. Eugenol also inhibits generation of hydroxyl radicals and superoxide anion generation [30]. Eugenol inhibits lipid peroxidation in vitro, but the resulting radicals can exert cytotoxic effects to other molecular targets, such as DNA [12b]. These findings imply this monophenol is directly involved with ET-ROSOS-AO. HO

Capsaicin Capsaicin (8-methyl-N-vanillyl-6-nonenamide) (Fig. 7) is found in chili peppers and acts as a deterrent for mammal consumption, since avian species are the main target for seed dispersal. Although plants produce capsaicin as well as other capsaicinoids (for example, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, nonivamide), humans have acquired a taste for such plants. The monophenol in capsaicin can be converted via demethylation to a catechol, which is known to undergo electron transfer, presumably involving the corresponding o-quinone. There is evidence of capsaicin acting as an anti-fungal agent [38] and a transient receptor potential vanilloid receptor 1 (TRPV1) agonist [39]. Literature suggests that capsaicin is involved with ROS in the inflammation pathway [39, 40] and anticancer [41]. HO

O

O

Fig. (4). Eugenol.

H N O

(S)-Tyrosine

Fig. (7). Capsaicin.

(S)-Tyrosine (4-hydroxyphenylalanine) is a monophenol amino acid (Fig. 5). It is involved in photosynthesis in which a radical is formed that undergoes electron transfer. Under oxidative stress, it is known that tyrosine can undergo free radical hydroxylation [31]. Tyrosine can be converted to catecholamines [3] such as norepinephrine and epinephrine. It is also used to form the benzoquinone part of coenzyme Q10. There is evidence of tyrosine involved in protein tyrosine phosphorylation which regulates ROS, such as peroxides, superoxide and peroxy radicals [12, 32].

6-Gingerol

HO

6-Gingerol ((S)-5-hydroxyl-1-(4-hydroxy-3-methoxyphenyl)3-decanone) (Fig. 8) is the main component found in ginger root along with 8-gingerol, 10-gingerol and 12-gingerol. 6gingerol has an effect on rheumatoid arthritis [42], as well as anticancer properties [43]. Similar to structures previously discussed, the monophenol can be converted to its corresponding quinone which can react further with electrons. Literature has implicated 6-gingerol involving ROS to induce apoptosis [2, 44] and acting as an anti-inflammatory agent [45]. HO

NH2 OH

O O

O

Fig. (5). (S)-Tyrosine.

Fig. (8). 6-Gingerol.

OH



Carvacrol Carvacrol (5-isopropyl-2-methylphenol) (Fig. 9) is extracted from plants such as thyme and wild bergamot. It has been extensively shown to have antibacterial properties [46]. Similar to capsaicin, carvacrol influences human transient receptor potential V3 (TRPV3) and A1 (TRPA1) activating pain receptors [47]. It also exhibits anticancer properties for prostate cancer cells [2, 48]. Carvacrol appears to prime the ROS production in C6 glioma cells, which indicates a role in its antimicrobial effects [1, 49].

HO

Fig. (9). Carvacrol.

145

compound can also function as a pro-oxidant [57], evidently via metabolism to the p-quinone [58] (Scheme 3) which can act as an ET agent via formation of ROS and OS. 5-Hydroxytryptamine (5-HT) This phenol (5-HT) (Fig. 11) plays a significant role in brain chemistry. The fit within the unifying hypothesis has been addressed [13]. Evidently, 5-HT generates metabolites that can produce ROS and OS. Superoxide and hydrogen peroxide are formed by redox cycling. The oxidative processes can damage neurons, probably via the hydroxyl radical. The oxidative metabolites comprise the catechol derivative, followed by the o-quinone which can redox cycle producing ROS. Adducts of the quinone by thiols are also capable of redox cycling. The process reduces the level of AO thiols. Similar results from oxidative metabolism are reported elsewhere [59]. NH2

Thymol Thymol (2-isopropyl-5-methylphenol) (Fig. 10) is isomeric with carvacrol and found in the thyme plant. Similar to carvacrol, thymol is a monophenol involved with radical scavenging from ROS [50], making it an effective antioxidant. There is evidence of thymol inducing apoptosis and preventing oxidative stress damage by playing a role with ROS [51]. Literature strongly suggests the role of thymol in ET-ROS-OS pathways making it anti-inflammatory [52], antibacterial [53], antifungal [28], antimutagenic [54], anticancer [55], and antioxidant [52, 56] agents. OH

HO N H

Fig. (11). 5-Hydroxytryptamine (5-HT).

Psilocin This tryptamine alkaloid (Fig. 12) is structurally related to serotonin, and is formed in vivo by dephosphorylation of psilocybin [60]. It is present in certain mushrooms that exhibit psychedelic properties. Metabolism comprises enzymatic hydroxylation to a catechol derivative, followed by further oxidation to an o-quinone or iminoquinone. The end metabolite is capable of undergoing ET involving ROS and OS which may play a role in the physiological properties. The drug activates phospholipase A2.

Fig. (10). Thymol.

Sesamol Tocopherol (Vitamin E) This class of monophenol is one of the best known AOs which typically involve the phenoxy radical [12]. The

This phenol (Fig. 13) is also an ether derivative of catechol. Many therapeutic properties have been reported including cancer prevention, anti-mutagenic, anti-liver

HO

O - .H

O general tocopherol

O

3

R

R

phenoxy radical

homolytic cleavage

O

O [O]

O HO

Scheme 3. Tocopherol Metabolism.

R O

R


Kovacic et al.

central nervous system, reproductive system, kidneys, lungs, gastrointestinal tract and mammary gland. There appears to be a protective effect by ER against carcinogenesis and cell proliferation. Findings indicate that ER plays a role in AO regulated genes which control free radicals and ROS.

N HO N H

OH

Fig. (12). Psilocin. OH

O

HO

O

Fig. (13). Sesamol.

Fig. (15). Estradiol.

toxicity and numerous other reports on AO activity [61]. The drug is present in sesame oil. Much of its literature deals with AO properties. There is ability to scavenge radicals and high order potency to control lipid oxidation [62]. The antiphoto- oxidative ability was similar to that of tocopherol [63]. The AO property is related in part to the ability to scavenge singlet oxygen. Oxidation yielded cytotoxic “dimers” whose structures were elucidated [61]. One was unusual in possessing a peroxide moiety. A related study deals with cytotoxicity of “trimer” and “tetramer” formed by oxidation of sesamol [64]. There was also tetramer-induced apoptosis.

Cannabinoids

A quite significant report deals with metabolism [65]. After exposure to sesamol, examination of rat excretions revealed the presence of benzene 1,2,4-triol and 2methoxylbenzene-1,4-diol (Fig. 14). These metabolites belong to the catechol and hydroquinone families which are well known redox cyclers that generate ROS and OS. O

HO

OH

HO

OH

HO

The monophenol tetrahydrocannabinol (THC) (Fig. 16) has been a center of attention for many years, and more recently involving medical marijuana (cannabidiol, CBD (Fig. 16). CBD, a resorcinol (1,3-diol) type of phenol is the initial metabolite arising from hydrolysis of the ether portion [67]. Further extensive transformation can occur, with the product of principal interest being cannabitriol (Fig. 16), which incorporates hydroquinone and catechol entities. The subsequent steps entail conversion to the hydroxyl p-quinone (Fig. 16) (CBDHQ) which has the potential for ET and ROS formation. CBD displays various therapeutic properties including treatment of neurodisorder and dyskinesia. The AO properties may be responsible for the anti-ischemic and neuroprotective influences. ROS might play a role in anticancer action by CBD. The oxidative effects were countered by AOs. Mechanistic insight is provided by findings with the quinone product, including ROS in mouse liver. The metabolite is cytotoxic, anti-angiogenic, anticancer, apoptotic and a topoisomerase inhibitor. Evidence points to involvement of a semiquinone. The hydroxyl group can act to stabilize the radical anion as illustrated in Fig. 17.

Fig. (14). 2-Methoxylbenzene-1,4-diol and benzene 1,2,4-triol.

Etoposide Estradiol Breast cancer has received much attention in the media and in research. Data indicate that natural and synthetic estrogens play a role via metabolites [3]. Estradiol (Fig. 15), hexestrol and diethyl stilbestrol undergo oxidative metabolism to catechols, hydroquinones, semiquinones and quinones. The process involves redox cycling with formation of ROS and lipid peroxides. The AOs, GSH and catalase are affectors. ROS scavengers, such as catalase, were effective in prevention. Equilin, an oxy analog, behaved similarly in metabolism, involving redox cycling or attachment of DNA. Estrogen metabolites exhibit mutagenic and genotoxic properties [66] which may involve ROS. Adduction can occur involving the quinone metabolite and DNA. There is considerable literature on estradiol including receptor involvement. An example is a review dealing with mechanism of the estrogen receptor (ER) [66]. ER appears to be an important aspect in the mode of action involving the

Etoposide (Fig. 18) is a semisynthetic analog of podophyllotoxin which is an antitumor antibiotic [2]. The drug is activated by oxidative demethylation of the ether to a catechol type which can redox cycle with the corresponding o-quinone. Oxygen, involved in redox cycling, is a factor in cytotoxicity. Radical scavengers inhibit the DNA cleavage. ROS participation is supported by other reports. The parent model 3-methyloxy-o-quinone possesses a reduction potential favorable for electron affinity. Other possible factors that may contribute to activity are: toposisomerase inhibition, DNA intercalation and apoptosis. Morphine and Heroin Morphine (Fig. 19) has been used since ancient times to induce sleep and relieve pain. In some cases, addiction resulted. Incorporation within the ET-ROS-OS framework has been addressed including appreciable supporting evidence [13]. Formation of superoxide and nitric oxide accompanied apoptosis induced by the drug, with alleviation



OH

H H

H

147

OH

H HO

O

Cannabidiol (CBD)

Tetrahydrocannabinol (THC)

O

H

H

H HO

OH

H HO

O Cannabidiol hydroxylquinone (CBDHQ)

Cannabitriol

Fig. (16). Terahydrocannabinol (THC), cannabidiol (CBD), cannabidiol hydroxylquinine (CBDHQ) and cannabitriol.

by AOs, e.g. thiol. ROS has been linked to apoptosis in other studies. Related findings are reported for kidney insult. Redox cycling of the phenol with oxygen generated superoxide and hydrogen peroxide. Reaction with hydrogen peroxide led to nuclear hydroxylation. The resultant catechol moiety would be expected to redox cycle with the corresponding oquinone, resulting in ROS-OS. Metabolite reaction with thiols could involve the o-quinone in conjugate addition. The process would result in depletion of the thiol AO.

the generated morphine. Amounts of lipid peroxides and nitric oxide were appreciably enhanced for abusers of heroin. Oxidation and peroxidation resulted in increased injury via ROS and OS. Involvement of ROS was observed in the toxicity. Studies with heroin addicts revealed smaller quantities of AOs, e.g. vitamin C, GSH and catalase, apparently from attack by generated ROS. Hence, AO supplementation may be beneficial to abusers. O

HO

H

O

Oδ

O H

H O δ

HO

O H

N

H N

O

HO Oδ

H

Fig. (19). Morphine and heroin.

Fig. (17). Delocalized radical anion of cannabidiol hydroxylquinone (CBDHQ).

H

O

H

O

O

O

HO

H

H O

O

O H O

Cresols There are three isomers of cresol; o-, m-, and p-cresol known as methylphenols (Fig. 20). These methylphenols are unusual by being found naturally in coal tar and creosote, rather than in plants or animals. Oxidative investigations are in accord with the usual pathway entailing diol and then quinone. Catalytic oxidation with oxygen and copper acetate generated the corresponding catechol-type and oquinone derivative [68]. Bacterial oxidation led to the following conversions’ o-cresol to 3-methylcatechol and mor p- cresol to 4-methylcatechol [69]. Bacterial oxidation was used for enzymatic generation of quinone from cresol [70].

OH

O O

O

OH

Fig. (18). Etoposide. H3C

Morphine Heroin Since heroin is a metabolic precursor of morphine, the behavior of the diester derivative may well be attributed to

Fig. (20). Cresols.


Kovacic et al. HO

Related Phenols This review is based on the monophenol class. However, there are closely related types, namely, catechol, resorcinols, hydroquinones, aromatic triols and polyols. In addition, various phenol derivatives undergo metabolism to phenols such as, ethers and esters. Some other examples of bioactive phenols are found in references in the introduction in addition to the following representative list: platensimycin (Fig. 21) [71, 72]; vancomycin (Fig. 22) [73]; tetarimycin A (Fig. 23) [74-76].

OH HO

Fig. (24). Resveratrol.

OH

HO

H3CO OH O

O O

CONCLUSION

OH O

Fig. (21). Platensimycin.

HN

HO OH

O H N

OH

O H N

N H

O HO

NH2 O N H O

O

OH

HN NH

O

O

O

OH

Cl HO

O

O

O

Fig. (25). Curcumin.

O

N H OH

OCH3

O Cl

HO

There are many more natural monophenols, but the ones discussed here are representative set to show the encompassing theme of monophenols and mechanisms involved in electron transfer, reactive oxygen species and oxidative stress. The unifying mechanistic theme can be applied to most natural monophenols and polyphenols. The chemical structure of the phenol enables the conversion to a catechol by hydroxylation or demethylation. The catechol can then be further oxidized to the quinone, which is known to react with radicals, forming ROS, such as hydroxyl radicals, peroxyl radical and hydrogen peroxide.The literature presents a plethora of examples of monophenols involved in antioxidant, anti-infective, anti-bacterial, anticancer, etc activities, and this unifying mechanistic theme supports the findings with respect to monophenols. There is scant attention paid to ET in the phenol literature.

O HO

CONFLICT OF INTEREST O

The authors confirm that this article content has no conflict of interest.

H2N HO

ACKNOWLEDGEMENTS

Fig. (22). Vancomycin.

Editorial assistance by Thelma Chavez is acknowledged. LIST OF ABBREVIATIONS

O HO

OH

ET

=

Electron Transfer

ROS

=

Reactive Oxygen Species

OS

=

Oxidative Stress

AO

=

Antioxidant

SA

=

Salicyclic Acid

Polyphenols

ASA

=

Aspirin

There are other examples of this unifying theme in natural polyphenols [77, 78] such as flavonoids, stilbenes, resveratrol (Fig. 24) and curcumin (Fig. 25) lignans, which will not be discussed. It is imperative to note that monophenols and polyphenols may have similar metabolism mechanisms. For instance as shown for monophenols, polyphenols can act as radical scavengers, thereby interacting with ET and ROS and possibly reducing oxidative stress.

REFERENCES

OH

O

O

Fig. (23). Tetarimycin A.

[1]

[2] [3]

Kovacic, P.; Cooksy, A.L. Unifying mechanism for toxicity and addiction of abused drug and electron transfer and reactive oxygen species. Med. Hypotheses, 2005, 64, 357-367. Kovacic, P.; Osuna, J.A. Mechanisms of anti-cancer agnets: emphasis on oxidative stress and electron transfer. Curr. Pharmaceut. Des., 2000, 6, 277-309. Kovacic, P.; Jacintho, J.D. Mechanism of carcinogenesis. Focus on oxidative stress and electron transfer. Curr. Med. Chem., 2001, 8, 773-796.

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Watson, R.R.; Preedy, V.R.; Zibadi, S. Polyphenols in Human Health and Disease. Vol. 1; Academic Press, New York, 2013. Pandey, K.B.; Rizvi, S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cel Longev., 2009, 2, 270-278.

Accepted: July 15, 2015