Coumarins As Antioxidants

Current Medicinal Chemistry, 2011, 18, 3929-3951
3929
Coumarins as Antioxidants
I. Kostova*,1, S. Bhatia2, P. Grigorov1, S. Balkansky1, V.S. Parmar2, A.K. Prasad2 and L. Saso3
1 2 3
Department of Chemistry, Faculty of Pharmacy, Medical University, 2 Dunav St., Sofia 1000, Bulgaria Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
Abstract: Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.
Keywords: Synthetic and natural coumarins, antioxidants. INTRODUCTION Free radicals and other reactive oxygen species are derived either from normal essential metabolic processes in the human body or from external sources. Free radicals are atoms, molecules or ions with unpaired electrons, which are highly active to chemical reactions with other molecules. In the biological system, the free radicals are often derived from oxygen-, nitrogen- and sulphurcontaining molecules. These free radicals are parts of groups of molecules called reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulphur species (RSS). ROS includes free radicals such as superoxide anion, perhydroxyl radical, hydroxyl radical, nitric oxide and other species such as hydrogen peroxide, singlet oxygen, hypochlorous acid and peroxynitrite. RNS are derived from nitric oxide. RSS are easily formed from thiols by reaction with ROS. ROS are produced during cellular metabolism and functional activities, and have important roles in cell signalling, apoptosis, gene expression and ion transportation [1]. However, excessive amounts of ROS can have deleterious effects on many molecules including proteins, lipids, RNA, DNA and carbohydrates since they are very small and highly reactive. Damaged cells function wrongly, which may result in further escalation of the oxidative stress. Simultaneous ionic disbalance, mitochondrial dysfunction and activation of the caspase/calpine cascades, result in cell death [1-3]. Cells are normally able to defend themselves against ROS damage through the use of intracellular enzymes to keep the homeostasis of ROS at a low level. However, during times of environmental stress and cell dysfunction, ROS levels can increase dramatically, and cause significant cellular damage in the body. Thus, oxidative stress significantly contributes to the pathogenesis of inflammatory disease, cardiovascular disease, cancer, diabetes, Alzheimers disease, cataracts, autism and aging [4-8]. In order to prevent or reduce the ROS induced oxidative damage, the human body and other organisms have developed an antioxidant defence system that includes enzymatic, metal chelating and free radical scavenging activities to neutralize these radicals after they have formed. In addition, intake of dietary antioxidants may help to maintain an adequate antioxidant status in the body. Antioxidants may be molecules that can neutralize free radicals by accepting or donating electron(s) to eliminate the unpaired condition of the radical. The antioxidant molecules may directly react with the
*Address correspondence to this author at the Department of Chemistry, Faculty of Pharmacy, Medical University, 2 Dunav St., Sofia 1000, Bulgaria; Tel: +359 2 92 36 569; Fax: +359 2 987 987 4; E-mail: irenakostova@yahoo.com 0929-8673/11 $58.00+.00
reactive radicals and destroy them, while they may become new free radicals which are less active, longer-lived and less dangerous than those radicals they have neutralized [1]. Small molecules, such as vitamin C, vitamin E, uric acid and glutathione play important roles as cellular antioxidants. Many synthetic antioxidants have been widely used in the food industry to retard lipid oxidation. However, lots of them are not preferred for pharmacological use due to toxicological concerns. Thus, more and more interest has focused on identifying plant products and their synthetic analogs to use as dietary antioxidant supplements. In the recent years, antioxidant research has expanded dramatically due to its potential benefit in disease prevention and health promotion. Many research models have been established for the studies of mechanisms of action of antioxidants as well as identification of new antioxidants especially from natural sources. Most of the natural antioxidants come from fruits, vegetables, spices, grains and herbs which contain a wide variety of antioxidant compounds, that may help to protect cellular damages from oxidative stress and also lower the risk of chronic diseases. Coumarins (known as 1,2-benzopyrones), consisting of fused benzene and pyrone rings, are an important group of low-molecular weight phenolics and have been widely used for the prevention and treatment of many diseases. Coumarins comprise a group of natural compounds found in a variety of plant sources. The coumarins possess anti-inflammatory, antioxidant [2,3], anticancer [9,10], antiviral [11,12], anticoagulant, etc. activities. Thus, they have excellent pharmaceutical potential. Several recent reviews summarize advances in the application of coumatins, especially concerning their antioxidant properties [9-17]. The coumarins are variable in structure, due to the different types of substitutions in their basic structure, which can influence their biological activity. A careful structure -activity-relationship study of coumarins with special respect to their antioxidant and anticancer activities should be conducted. The naturally occurring coumarins as well as their synthetic analogs will be the primary focus of this review. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarin (1,2-benzopyrone, (1 )) is the simplest compound of a large class of naturally occurring phenolic substances made of fused benzene and -pyrone rings. The hydroxycoumarins, as typical phenolic compounds, act as potent metal chelators and free radical scavengers. Hydroxycoumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their antioxidant effects were extensively examined.
2011 Bentham Science Publishers Ltd.
3930 Current Medicinal Chemistry, 2011 Vol. 18, No. 25
Kostova et al.
5 6 7 8
4 3 O 1 O
In this review, plant derived coumarins and their synthetic analogues will be systematically evaluated based on their plant origin, structure-activity relationship and antioxidant efficacy. Owing to their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action has not yet been fully understood and the correlation of effects with chemical structure is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins used as antioxidant agents, because promising data have been reported for a series of these agents. In addition, their ability to bind metal ions represents an additional means of modulating their pharmacological responses. Thus, the aim of this review is to update the current approaches to study properties and mechanisms of action of coumarins-based antioxidants with emphasis on the chemical and biological systems. This review may greatly benefit researchers and scientists who are interested in the study of detailed chemical and molecular mechanisms of the antioxidant activity of coumarins. It is also helpful for physicians who are interested in alternative antioxidant therapy or prevention for certain oxidative stress related diseases or conditions. STRUCTUREACTIVITY RELATIONSHIP OF COUMARIN DERIVATIVES Natural polyphenols can be divided into several different classes depending on their basic chemical structure which ranges from simple molecules to highly polymerized compounds. Coumarin (known as 1,2-benzopyrone), consisting of fused benzene and a-pyrone rings, is an important group of low-molecular weight phenolics. Antioxidant activity of phenolic compounds was correlated to their chemical structures. Structure-activity relationship of many phenolic compounds (e.g. flavonoids, phenolic acids, coumarins, tannins, etc.) has been studied. In general, free radical scavenging and antioxidant activity of these classes of compounds mainly depends on the number and position of hydrogen-donating hydroxyl groups on the aromatic ring of the phenolic molecules, and is also affected by other factors, such as glycosylation of aglycones, other H-donating groups (-NH, -SH), etc. Very few systematic studies have been reported on structureantioxidant activity correlations in coumarins. To select or design better antioxidants, researchers have to study their structure activity relationships (SAR). In fact, there has been plenty of work devoted to this topic. The SAR and even quantitative structure activity relationships (QSAR) for most of the natural antioxidants have been elucidated by means of experimental determinations and theoretical calculations. However, there still lacks the elucidation of SAR for coumarins. Through comparing the peroxyl radicalscavenging activity of a series of coumarins in sodium dodecyl sulfate micellar system, Foti and co-workers indicated that coumarins containing a catechol moiety were stronger than the others to scavenge peroxyl radical [18], which was supported by the observations from other groups [19]. It is not surprising to see catechol moiety playing a key role in enhancing the antioxidant activity of coumarins and a large number of experimental and theoretical studies confirmed the same, revealing that the catechol group was beneficial to enhance the radical-scavenging activity of natural antioxidants. On the other hand, the ring B of coumarin, a 1,2pyrone, is unique in natural antioxidants and has also been investigated in previous studies [20]. Considering the success of density functional theory (DFT) calculations used in elucidating the SAR for a large number of antioxidants, Zhang et al. evaluated the
1,2-pyrone effect on the radical-scavenging activity. By means of density functional theory calculation on B3LYP/6-31G (d,p) level, two kinds of theoretical parameters, i.e. OH bond dissociation enthalpy (BDE) and adiabatic ionization potential, were obtained to characterize the distinct peroxyl radical-scavenging mechanisms of coumarins, i.e. H-atom transfer and proton concerted electron transfer, respectively. It was found that the former mechanism was preferred in the radical-scavenging process of coumarins, thus OH BDE was a suitable index to measure the radical-scavenging activity. As coumarins without catechol moiety have little structural factors beneficial to reduce OH BDE, they are weaker antioxidants than the counterparts containing a catechol group. The unique 1,2pyrone in ring B of coumarins is roughly an electron-withdrawing group, however, its electronic effect is rather weak. Consequently, 1,2-pyrone, being a weaker electron-withdrawing group than 1,4pyrone (a group ubiquitous in flavonoids and isoflavonoids), has little influence on the antioxidant activity of coumarins. However, this group may play an important role in determining the pharmacological effect of coumarins [20]. Xanthine oxidase (XO) is an important source of free radicals and has been reported in various physiological and pathological models. XO causes gout and is responsible for oxidative damage to living tissues. This enzyme reduces molecular oxygen. Regulation of XO activity is important during inflammation.. XO catalyses the oxidation of hypoxanthine and xanthine to uric acid yielding superoxide radicals and raises the oxidative level in an organism. Coumarins acting to inhibit XO inhibition have been reported and the structureactivity relationships (SARs) of coumarins interacting with this enzyme have also been discussed [21-23]. Lin et al. [23] employed 1,1-diphenyl-2-picrylhydrazyl hydrate (DPPH) and 5,5dimethyl-1-pyrroline-N-oxide (DMPO)electron spin resonance (ESR) to study the effects of suppression of reactive oxygen species (ROS) by eight selected coumarin derivatives under oxidative conditions and the most potent radical scavengers among the tested compounds were identified. The results suggested that the number of hydroxyl groups on the ring structure of coumarins is correlated with the effects of ROS suppression. The authors also investigated the effect of the derivatives on the inhibition of xanthine oxidase (XO) activity, and the structureactivity relationships (SARs) of these derivatives against XO activity were further examined using computer-aided molecular modeling. All determined derivatives competitively inhibited XO. The results of the structure-based molecular modeling exhibited interactions between coumarins and the molybdopterin region of XO. The carbonyl pointed toward the Arg880, and the ester O atom formed hydrogen bonds with Thr1010. Coumarins, which bear two hydroxyl moieties on its benzene rings, had the highest affinity toward the binding site of XO, and this was mainly due to the interaction of hydroxyl with the E802 residue of XO. The hypoxanthine/XO reaction in the DMPOESR technique was used to assess the combined effect on enzyme inhibition and ROS suppression by these coumarins. The authors combined the ROS-scavenging and XO inhibition roles of coumarins in order to identify which compounds are more vital for therapeutic applications. They eventually applied the results to living cells to confirm the conclusions drawn from the in vitro experiments. Up to now, a lot of mechanistic studies have been carried out on phenolic antioxidants, which have indicated that the chain reaction is controlled mainly through free radical scavenging by phenolic hydroxyl of the antioxidants. So, if a proper theoretical parameter to characterize the ability of antioxidants to scavenge free radicals can be found, it will be possible to predict their antioxidant activity, which will undoubtedly improve the selection of new antioxidants. 7-HYDROXYCOUMARINS AND THEIR DERIVATIVES Plant derived phenolic coumarins might play a role as dietary antioxidants because of their consumption in the human diet
Current Medicinal Chemistry, 2011 Vol. 18, No. 25
3931
especially in fruits and vegetables. Umbelliferone (7-hydroxycoumarin, (2), Table 1), a natural antioxidant is the main coumarin (1,2-benzopyrone) metabolite of coumarin and is a therapeutically active molecule. It exhibits antioxidant properties in vitro and may share with other coumarin derivatives vasodilator effects. It is present in the edible fruits such as golden apple (Aegle marmelos Correa) and bitter orange (Citrus aurantium ) [24]. Recently the effect of umbelliferone on glycemic control and lipids [25,26] and antioxidant properties [27-29], have been reported. Ramesh et al. [24] have also analyzed the effect of umbelliferone on fatty acid composition and histopathological studies of liver and kidney. The results showed that umbelliferone has a protective effect on membrane fatty acid composition of liver and kidney as supported by antioxidant and antihyperlipidemic effects of umbelliferone reported earlier as evidenced by improved histopathological changes, hepatic and nephritic markers, indicating recovery from the risk of diabetic complications. Furthermore, umbelliferone and its derivatives have shown to have lipid lowering potential [30,31]. The genus Heptaptera (umbelliferae) possesses ten species in the world mainly distributed from Europe to the Middle East including Italy, Balkans, Turkey, Syria, and Palestine [32]. Although limited phytochemical study has so far been carried on the Heptaptera species, the genus has been reported to be rich in coumarin derivatives; i.e. umbelliprenin derivatives. Orhan et al. screened several coumarin derivatives including umbelliferone and found some of them having moderate acetylcholinesterase inhibitory activity [33]. Although no traditional use of this genus has been reported up to date, the genus is known to contain coumarins in major amounts, which were tested for their antioxidant potential [32]. For this purpose, the ethyl acetate and methanol extracts prepared from the fruits, aerial parts, and roots of these species were tested in vitro for their acetylcholinesterase (AChE) inhibitory and antioxidant activities. Antioxidant activity of the extracts was determined by 2,2-diphenyl-1-picrylhydrazyl radical scavenging and ferrous ion-chelating power tests. The methanol extracts of the fruits and aerial parts of H. triquetra had the best scavenging effect against DPPH. All of the extracts screened displayed significant ferrous ion-chelating effect in a dose-dependent manner. It is most likely that coumarin-type of compounds in Heptaptera species could be responsible for antioxidant and mild anticholinesterase activity. The results showed that H. Triquetra showed the best radical scavenging and iron chelating effects among the extracts and could be a potential source for antioxidant compounds and this is the first report on anticholinesterase and antioxidant activities of Heptaptera species. Several linear and angular coumarins have been synthesised as possible anti-inflammatory and antioxidant agents. They were found to interact with 1,1-diphenyl-2-picryl-hydrazyl stable free radical (DPPH) [34]. The anti-inflammatory activity seemed to be connected with their reducing activity. Khan et al. [35] reported the modulatory effect of coumarin (1,2-benzopyrone) on potassium bromate (KBrO3) mediated nephrotoxicity in Wistar rats and the results showed that coumarin may be used as an effective chemopreventive agent against KBrO3-mediated renal oxidative stress, toxicity and tumor promotion response in Wistar rats. Structurally diverse coumarins were examined for their ability to inhibit lipid peroxidation induced either by Fe(II) and Fe(III) metal ions or by azo-derived peroxyl radicals in a liposomal membrane system [36]. The antioxidant effects of these compounds were evaluated on the basis of their ability to inhibit the fluorescence intensity decay of an extrinsic probe, 3-[p -(6-phenyl)-1,3,5-hexatrienyl]phenylpropionic acid (DPH-PA), caused by the free radicals generated during lipid peroxidation. All the coumarins tested exhibited higher antioxidant efficacies against metal-ion-induced peroxidations than peroxylradical-induced peroxidation, suggesting that metal chelation may play a larger role in determining the antioxidant activities of these compounds. The presence of hydroxyl substituents enhanced anti-
oxidant activity, whereas substitution by methoxy groups at the same positions diminished their activity [36]. The antioxidant effects of 7-hydroxycoumarin have been investigated in a number of studies [37]. 7-Hydroxycoumarin and esculetin (6,7-dihydroxycoumarin, (3), Table 1) were examined to determine their effect on the cellular metabolism of A431 cells over a 24-h exposure period [38]. 7-Hydroxycoumarin caused suppression of the succinate dehydrogenase activity at concentrations larger than 10 g/ml. Esculetin exerted a more serious effect with decrease in activity observed at greater than 1 g/ml. The observed effects were dose-dependent. Using the cytosensor microphysiometer to assess metabolic activities, it was observed that esculetin was more detrimental to cellular metabolism than 7-hydroxycoumarin. 7-Hydroxycoumarin (100 g/ml) caused the cellular metabolic rate to drop to 44.21 +/- 5.34% (n = 4) of the control metabolic rate, while 100 g/ml esculetin caused the metabolic rate to fall to 21.5 +/- 4.54% (n = 4) of the control rate. Connection between free radical-generating agents and inflammatory processes suggests that accumulation of reactive oxygen species can cause hepatotoxicity [39]. t-Butyl hydroperoxide (tBHP), can be metabolized to free radical intermediates by cytochrome P-450 in hepatocytes, which, in turn, can initiate lipid peroxidation, affect cell integrity and result in cell injury. Lin W. L. et al. [40] used t-BHP to induce hepatotoxicity in vitro and in vivo and determined the antioxidative bioactivity of esculetin. Pretreatment with esculetin (5-20 g/ml) significantly decreased the leakage of lactate dehydrogenase (LDH) and alanine transaminase (ALT), and also decreased the formation of malondialdehyde (MDA) in primary cultured rat hepatocytes induced by t-BHP. An in vivo study in rats showed that pretreatment with esculetin significantly lowered the serum levels of the hepatic enzyme markers (ALT and AST) and reduced oxidative stress in the liver. Histopathological evaluation of the rat livers revealed that esculetin reduced the incidence of liver lesions induced by t-BHP, including hepatocyte swelling, leukocyte infiltration, and necrosis. Thus, esculetin may play a chemopreventive role via reducing oxidative stress in living systems. Esculetin (6,7-dihydroxycoumarin) is an antioxidant coumarin derivative that inhibits the lipoxygenase and cyclooxygenase pathways of arachidonate metabolism [41,42]. Among other important pharmacological activities, esculetin promotes analgesic, immunomodulatory [43] and anti-tumoural effects [44,45]; decreases neutrophil infiltration [40], subepithelial fibrosis and TGF levels in the lung [46]; protects DNA against oxidative stress [41]; inhibits synthesis of leukotriene B4, thromboxane B2 [47], platelet aggregation [48], matrix metalloproteinases production [49,50], growth of human leukaemia cells [51] and the production of IL-6 and IL-8 [52]. The antioxidant [41], anti-inflammatory properties [47], inhibitory effect on vascular smooth muscle cells [53] and antitumour properties [54] of its derivatives have also been investigated. Based on the antioxidant and anti-inflammatory properties of esculetin and its derivatives, Witaicenis et al. [55] investigated the effects of esculetin and its substituted derivatives on the experimental model of trinitrobenzenesulphonic (TNBS) acid-induced rat colitis. For this purpose, macroscopic (diarrhoea, extension of lesion, colonic weight/length ratio and damage score) and biochemical parameters (myeloperoxidase, alkaline phosphatase and glutathione) were evaluated. They assayed the effects of the compounds in preventing the inflammatory response induced by TNBS in two different experimental settings, i.e. when the colonic mucosa is intact and when the mucosa is healing after an initial insult. In the acute colitis model, esculetin promoted a reduction in the extension of the lesion accompanied by a reduction in the incidence of diarrhoea and restoration of the glutathione content. The effect of esculetin and its derivatives on the inflammatory process may be related to their antioxidant and anti-inflammatory properties, as observed in this study. The antioxidant activity of esculetin
Kostova et al.
and its derivatives observed in [40,55], as well as their inhibitory activity on the cyclooxygenase and lipoxygenase pathways [42], suggest that these coumarins may be beneficial in the pathological inflammatory processes of the intestine. Additionally, the antiinflammatory activities of esculetin and its derivatives could be associated with their inhibition of the cyclooxygenase and lipoxygenase pathways [56,57]. These coumarins have been reported to reduce eicosanoid generation by acting on 5lipoxygenase and cyclooxygenase rather than by affecting phospholipase A2 [41]. Coumarins with two hydroxyl groups (and in some cases other substituents) present an additional interest in biological activities [41]. Conspicuously, all of the potentially active natural compounds possess at least two phenolic groups at either the 6, 7- or 6, 8-positions [9,10]. It has been found that orthodihydroxy coumarins are moderately powerful inhibitors of arachidonate metabolism via pro-inflammatory 5-lipoxygenase pathways and that 4-methylcoumarin derivatives are known to be less toxic when compared to other coumarins. Sharma et al. [58] demonstrated that the presence of adjacent phenolic hydroxyl groups is an important factor in the antioxidant and apoptosisinducing activity of dihydroxy 4-methylcoumarins. Luchini et al. [59] suggested that the presence of the hydroxyl radical at the C-4 position in the coumarin molecule improves its anti-inflammatory effect in the TNBS rat colitis model. Sekiya K. et al. have studied the effects of coumarin and its derivatives on rat platelet lipoxygenase and cyclooxygenase activities [60]. Esculetin was found to inhibit the lipoxygenase more strongly than the cyclooxygenase. The 6-glucoside of esculetin, esculin (4), Table 1 as well as umbelliferone also selectively inhibited the lipoxygenase. The mechanism of the lipoxygenase inhibition by esculetin was non-competitive. It is interesting to mention that other antioxidants (hydroquinone, gallic acid and ascorbic acid) were less inhibitory to both enzymes and showed little selectivity [60]. Zhao J. et al. [61] determined DNA damage and oxidative stress in healthy term neonates at birth. The protective activities of five natural polyphenols against H2O2induced DNA damage in mononuclear cells of umbilical blood were studied. The natural polyphenols, 7,8-Dihydroxycoumarin [(5), refer. Table 1], 7,8-dihydroxy-4-methylcoumarin [(6), refer. Table 1], quercetin (7 ) and resveratrol (8), were able to protect mononuclear cells of umbilical blood from oxidative attack, whereas other two polyphenols, rutin (9) and 7-hydroxy-4methylcoumarin [(10), refer. Table 1], did not. The protective properties of seven polyphenols against hydrogen peroxide induced DNA damage in human peripheral blood lymphocytes (PBL) were studied using single cell micro-gel electrophoresis [62]. Hydrogen
peroxide causes an increase in single cell DNA strand breakage in human PBL. Quercetin and 7,8-dihydroxy-4-methylcoumarin exhibited the strongest protection. Curcumin (11 ), resveratrol and vanillin protected against DNA damage induced by 50 M H2O2, but rutin and 7-hydroxy-4-methylcoumarin failed to provide any protection even at concentrations up to 50 M. Quercetin, 7,8dihydroxy-4-methylcoumarin, curcumin, resveratrol and vanillin were found effective in protection of human single cell DNA from oxidative attack. Kaneko et al. have examined the protective effects of coumarins against cytotoxicity induced by linoleic acid hydroperoxide [63]. Coumarins, esculetin (6,7-dihydroxycoumarin) and 4methylesculetin [(12), refer. Table 1] protected cells from injury by linoleic acid hydroperoxide. Fraxetin [(13), refer. Table 1 ] and caffeic acid showed weak, but significant, protection. Esculin, esculetin and 4-methylesculetin were effective for protecting cells against linoleic acid hydroperoxide-induced cytotoxicity in the case of pretreatment for 24 h, however fraxetin and caffeic acid showed no protection. The sugar moiety in the esculin molecule appears to be hydrolyzed during pretreatment. Coumarins containing only one hydroxyl group (umbelliferone) showed no protective effect in pretreatment or concurrent treatment. Esculetin and 4methylesculetin provided synergistic protection against cytotoxicity induced by linoleic acid hydroperoxide with alpha-tocopherol. Fraxinus species have been used as anti-inflammatory drugs, possibly due to several phenolic acids and coumarins that possess free radical-scavenging activities [64]. Cortex fraxini (CF) is a widely and traditionally used herb in Taiwan. This herb also has anti-inflammatory properties and its ingredients include coumarins, such as esculin, esculetin, fraxin (14), and fraxetin [65]. Wu et al. [66] presented the antioxidant properties of crude extract, fractions and ingredients of CF and compared the antioxidant capacities of coumarin ingredients of CF and known antioxidants, including catechin (15), quercetin, ascorbic acid, trolox and BHT. The IC50 values for CF in the DPPH and trolox equivalent antioxidant capacity (TEAC) methods were 406 and 39.3 g/ml, respectively. Among all fractions the chloroform fraction is the most active fraction in scavenging DPPH, ABTS and hydroxyl radicals, and there is a significant relationship between the antioxidant activities and the contents of the antioxidant phenolic ingredients. The amounts of esculetin and fraxetin in the chloroform fraction were 8.44 % and 11.1 %, respectively. Esculetin and fraxetin also had good radicalscavenging capacities, and esculetin was the best, among all test compounds, against the DPPH radical. Moreover, esculetin and
OH OH OH OH O HO OH OH O 7 CH3 OH C H H2 C H C O OH 8 CH3 OH OH O O-rutinose 9 HO O OH OH
C H
C O
C O
C H
11
3933
O-B-D-Glucose HO O O HO O
OH
OH OH
O 14 OH 15
fraxetin had selective scavenging activity upon hydroxyl radicals and hydrogen peroxide, and this potency was better than known antioxidants and equal to quercetin in scavenging hydrogen peroxide. These results show that CF, partitioned with chloroform, gave a phenolic coumarin-enriched fraction, and that this fraction had the best free radical-scavenging activity and inhibition of Fe2+/ascorbate-induced lipid peroxidation, mainly due to its reducing power. Some researchers [67] have indicated that glycosidic substitution decreases TEAC values of coumarins and flavonoids. Wu et al. [66] found similar results, in that there is lower free scavenging capacity in the two glycosidic coumarins, esculin and fraxin, than in their aglycones. Furthermore, esculetin and fraxetin also possess the better active oxygen-scavenging activity than do ascorbic acid and BHT, and the different potencies in scavenging various oxygen radicals, between esculetin and fraxetin, are similar to those reported earlier [14]. The active oxygen scavenging activities of two glycosidic coumarins, esculin and fraxin, were also lower than their aglycones. From these results [14,66] it may be suggested that ortho-dihydroxy substitution and the 3,4-double bond play an important role in the antioxidant property of simple coumarins that lack the B-ring of flavonoids. A hydroxyl group in the 7-position of simple coumarins is necessary for its antioxidant activity and any C6C8 substitution, including glycosidic or methoxy groups, might decrease their free radical-scavenging capacity [66]. The activity of 4-methylcoumanrin [(16), refer. Table 1], 7hydroxy-4-methylcoumarin and 7,8-dihydroxy-4-methylcoumarin in the peroxidation of human low-density lipoprotein (LDL) has been examined [68]. The peroxidation was initiated either thermally by the water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), or photochemically by a triplet sensitizer benzophenone (BP) or its water-soluble analogue disodium 3,3'disulfobenzophenonate (DSBP). Kinetic analysis of the peroxidation process demonstrated that 7,8-dihydroxy-4-methylcoumarin was a good antioxidant for both the AAPH-initiated and BP- and DSBP-photosensitized peroxidation; 7-hydroxy-4-methylcoumarin was a prooxidant for the AAPH-initiated and DSBP-photosensitized peroxidation, but an antioxidant for the BP-sensitized peroxidation; 4-methylcoumanrin was a prooxidant in all of these initiation conditions. It was suggested that he antioxidative action of the coumarin derivatives may include trapping the initiating radicals, trapping the propagating lipid peroxyl radicals, recycling alpha-tocopherol and/or deactivating the excited photosensitizer. The antioxidant activity of 4-methylcoumarin, 6-hydroxy-4methylcoumarin and 7,8-dihydroxy-4-methylcoumarin, respectively, in the inhibition of peroxidation of linoleic acid in micellar systems has been studied by Yu et al. [19]. The peroxidation was initiated either thermally by water-soluble initiator 2,2-azobis(2methylpropionamidine)dihydrochloride (AMPAD) or photochemically by a triplet sensitizer benzophenone (BP) in the anionic micelle sodium dodecyl sulfate (SDS) or in the cationic micelle cetyl trimethylammonium bromide (CTAB). It was found that 7,8dihydroxy-4-methylcoumarin is a good antioxidant for both AMPAD-initiated and BP-sensitized peroxidation in both SDS and CTAB micelles, while 6-hydroxy-4-methylcoumarin is only active for BP-sensitized peroxidation in SDS micelles. 4-Methylcoumarin was ineffective in any case. Thus, the antioxidative action of the
coumarin derivatives may include trapping the initiating radicals, trapping the propagating lipid peroxyl radicals, recycling atocopherol and/or deactivating the excited photosensitizer. Free iron participates in the production of reactive oxygen species (ROS) and plays an important role in the pathogenesis of cardiovascular diseases. Therefore, chelation of iron may attenuate some ROS consequences, but on the other hand, reduction of ferric ions to ferrous ones is unfavourable and leads to intensification of ROS production. Mladnka et al. [69] have examined the interaction of iron with coumarins which has been rarely analyzed. A series of naturally occurring and chemically synthesized 4methylcoumarins were analyzed for their ferrous and total ironchelating properties and compared with standard iron chelator deferoxamine. The authors have critically analyzed the structureactivity relationship of coumarins interaction with iron at different pH conditions. Emphasis is given not only to the potentially positive effects resulting from iron chelation but also on possible undesired involvement of coumarins in iron reduction. The study examines especially the effects of 4-methylcoumarin derivatives which are generally considered as safe substances and cannot be metabolized in human into mutagenic epoxides, in contrast to many other coumarins [70,71]. The iron chelation activity was assessed by a simple spectrophotometric approach based on the specific indicator for ferrous ions ferrozine. The methodology was also extended for the measurement of total iron. Among the tested coumarins, ortho-dihydroxy derivatives were the most potent iron chelators and 7,8-dihydroxy-4-methylcoumarin even reached the efficiency of deferoxamine in neutral pH. However, these orthodihydroxycoumarins did not bind iron firmly in acidic conditions (e.g., in acute myocardial infarction) and, moreover, they reduced ferric ions. Thus, the use of iron-chelating coumarins in acidic conditions may be disadvantageous in contrast to neutral conditions. Three dihydroxy-4-methylcoumarin derivatives, namely 7,8dihydroxy-4-methylcoumarin, 6,7- dihydroxy-4-methylcoumarin and 5,7-dihydroxy-4-methylcoumarin alone and complexed with Fe(III) and ADP have been tested for their antioxidative potential [58]. Chemical speciation studies and formation constants reveal the formation of strong dihydroxy-4-methylcoumarinFeADP (1:1:1) ternary complex. In vitro studies were done for their antioxidative property by scavenging the superoxide radicals (O 2 ) generated by xanthine + xanthine oxidase (XO) reaction. The results indicate that O 2 scavenging potential of all the three dihydroxy-4-methylcoumarins increased significantly after forming the ternary complex with Fe (III) and ADP. The structure-activity relationship studies suggest that the introduction of hydroxyl group at C-7 and C-8 positions in the coumarins, irrespective of Fe(III) ADP complexation, increases the antioxidative efficacy. No change in uric acid production in the reactions done for all studies further reveals that the coumarin derivatives and their complexes were the only causative factors for O 2 scavenging and not the suppression of the enzyme, xanthine oxidase. Fe(II) (ferrous sulphate, freshly prepared aqueous solution) in place of Fe(III) (ferric chloride) was also used in order to verify if Fe(II) has a role in antioxidative mechanism. The experiments revealed no effect in antioxidative efficacy when dihydroxy-4-methylcoumarins were complexed with Fe(II)ADP [58]. The pharmacological and biochemical properties and therapeutic usefulness of coumarins have been worked out to
Kostova et al.
be a sequel of the different substitutions in the derivatives. It is well established that the antioxidant activity of a compound is more exactly assessed by providing a microenvironment of the reaction medium and nature of the involved ROS rather than by its structure alone. Hence it is very important to assess the structure-activity relationship by trying different reactions. Coumarin derivatives have been reported as potent inhibitors of 5-hydroxy-6,8,11,14eicosatetraenoic acid (5-HETE) formation from arachidonic acid and 12-hydroxy-5,8,10-heptadecatrienoic acid in polymorphonuclear leukocytes (PMN). The presence of two adjacent phenolic hydroxyl groups at the C-6 and C-7 or C-7 and C-8 positions in coumarin structure is must for its potency for the inhibition of the 5-HETE. Monohydroxycoumarins, e,g, umbelliferone and scopoletin [(17), refer. Table 1] also inhibited the formation of 5-HETE, but not very strongly, suggestive of the essentiality of the presence of a phenolic hydroxyl group at the C-7 position for this effect [72]. Raj et al. [73] have shown that formation of ADPFeantioxidant (ligand) could assume a crucial role in the prevention of ROS. The sequestration of transition metal ions by antioxidant is one of the most powerful preventive mechanisms in vivo [74] and chelation of transition metal by antioxidant ligands can inhibit membrane lipid peroxidation. The polyphenolic structure of dihydroxy-4-methylcoumarin facilitates the inhibition of lipid peroxidation by scavenging free radicals through chelation. Raj et al. [73] reported that the chelator 7,8- dihydroxy-4-methylcoumarin is 40 times more potent than vitamin E while performing the lipid peroxidation inhibition experiments. But 6,7-dihydroxy-4methylcoumarin was found to be a weak antioxidant compared to 7,8- dihydroxy-4-methylcoumarin. Studies made with five dihydroxy derivatives of coumarin for antioxidative activity, as inhibitors of 5-lipoxygenase pathway of arachidonic metabolism revealed the high efficacy of these compounds owing to their two fold ability to chelate the iron ions and donating the electron for redox cycling of iron thus rendering the 5-lipoxygenase in catalytically inactive ferrous form [47]. Studies on chelating behavior of dihydroxycoumarin in Fe(III)-ascorbateH2O2 system revealed ortho -dihydroxycoumarin to be a strong metal chelator as compared to metal substituted compounds [75]. Different derivatives of 4-methylcoumarins have been examined by Raj et al. for their effect on the NADPH-catalysed liver-microsomal lipid peroxidation [76,77]. Dihydroxy- and diacetoxy-4-methylcoumarins produced remarkable inhibition of lipid peroxidation. 7,8Diacetoxy-4-methylcoumarin [(18), refer. Table 1] and 7,8dihydroxy-4-methylcoumarin were found to possess excellent antioxidant and radical scavenging activities. Recently, a series of selected 4-methylcoumarins were synthesised and tested for radical-scavenging ability using the stable 1,1diphenyl-2-picrylhydrazyl radical, and for reducing power ability with a test based on the reduction of ferric to ferrous cation [78]. Special attention was paid to the number and position of the functional groups attached to the benzenoid part of the coumarin molecule. The authors have examined 4-methylcoumarin possessing methyl-, methoxy- and hydroxy-, acetoxy-, and benzoxy- groups in the benzenoid ring. The majority of them are known as natural compounds. All studied compounds showed activity comparable to Trolox (6-hydroxy-2,5,7,8-tetramethylchroman2-carboxylic acid), an already known antioxidant, which is used as standard in most of the testing methods. The examined compounds showed weaker activity in reducing Fe3+ ions compared to the scavenging radicals. This might be explained by the presence of aqueous media, where coumarins were less soluble and resonance structures of resulting phenoxyl radicals are less stable. However, coumarins still showed antioxidant activity, comparable with DPPH radical-scavenging method. 7,8-Dihydroxy-4-methylcoumarin posses the strongest antioxidant activity, both in radical-scavenging and reducing power tests [78]. Since a large number of experimental and theoretical studies revealed that the catechol
group was beneficial in enhancing the radical-scavenging activity of natural antioxidants, it is not surprising to see the catechol group playing a key role in enhancing the antioxidant activity of coumarins. The results showed that the position and type of the substituent attached to the aromatic moiety of coumarin molecule have an influence on the radical-scavenging ability [78]. In general, substitution at the C-6 position gives stronger feature to coumarin for scavenging free radical than substitution at the C-7 position. The results are consistent with a previous report which proved that resonance structures of the radicals derived from coumarins with substitution at the C-6 position are especially stable because of the ortho-quinone form [23]. In addition, the type of substituent has an intense influence on the action of coumarins as antioxidants. The results indicate that the hydroxy group has the strongest influence, while the methyl group has the smallest. Previously published data indicate that the pyrone ring of the coumarin moiety has little influence on the antioxidant activity of coumarins, due to its rather weak electronic effect [20]. Observations of avar et al. [78] were made with regard to structural features that regulated the behaviour of the compounds. In general, the antioxidative effectiveness of phenolic compounds depends on the reaction activity of the phenol towards the chain-carrying peroxyl radicals and on the stability of the phenoxyl radical formed in the reaction. The reaction mechanism is based on an electron transfer (ET) reaction. Whilst the hydrogen atom abstraction is a marginal reaction pathway, because it occurs slowly in strong hydrogen-bond accepting solvents, such as methanol and ethanol, it occurs in other ET-based assays, the scavenging capacity against DPPH is strongly influenced by the solvent and the pH of reaction [69]. The steric accessibility of the DPPH is a major determinant of the reaction, since small molecules that have better access to the radical site have relatively higher antioxidant capacity. On the other hand, many large antioxidant compounds that react quickly with radicals may react slowly or may even be inert, thus introducing a benzoxy group into coumarin molecule displays relatively weak antioxidant property against the DPPH [78]. 4-Methylcoumarins having two hydroxyl groups placed ortho to each other in the benzenoid ring have shown to possess excellent antioxidant and radical scavenging properties in different experimental models [79]. In fact hydroxycoumarins can behave like classic phenol or quinol-based antioxidants, in which a hydroxyl group on an aromatic ring structure can carry out the singleelectron reduction of a free radical. The resulting phenoxyl radical or semiquinone can either be stabilized through the presence of bulky or electron-withdrawing groups on the ring system or be oxidized further through a consecutive single-electron reduction by a second hydroxyl group to produce a quinone-type end product. Furthermore, a positive property of 4-methylcoumarins is that they are not substrates for the liver P450 monoxygenases that epoxidize coumarins lacking the C4 methyl group and thus, during metabolic degradation, cannot form 3,4-coumarin epoxides, which are believed to be mutagenic and probably also have other toxic effects [80]. Morabito et al. [81] reported a study on the structure activity relationship of eight synthetic 4-methylcoumarins, carried out by employing a series of different chemical cell-free tests. These coumarins have been previously described as a promising radical scavengers in cell-based systems [58,71]. The compounds were tested by means of three assays involving one redox reaction with the oxidant (DPPH assay, ABTS + assay and FRAP) [81]. Other assays were employed to evaluate the antioxidant properties of the coumarins under investigation against NO, O2 and HClO, which are some of the major reactive oxygen and nitrogen species causing damage in the human body. Morabito et al. [81] have measured the protective capacity of these coumarins against the oxidative damage in a simple biomimetic model of phospholipid membranes. The results confirmed the good antioxidant activity of the 7,8-hydroxy4-methylcoumarin. In general, their activity was not significantly affected by the introduction of an ethoxycarbonylmethyl or an
3935
ethoxycarbonylethyl moiety at the C-3 position. A discrete antioxidant activity is retained also by the 7,8-diacetoxy-4-methylcoumarin, although they were less efficient than the corresponding 7,8-dihydroxy compounds. Two of the 4-methylcoumarins (7,8dihydroxy-4-methylcoumarin and 7,8-dihydroxy-3-ethoxycarbonylethyl-4-methylcoumarin) (19), very interestingly, showed strong scavenging activities against the superoxide anion and were also very effective in protecting the lipid bilayer against peroxidation. On the basis of these findings, these 4-methylcoumarins may be considered as potential therapeutic candidates for pathological conditions characterized by free radical overproduction [81]. Another attempt for evaluating the structureactivity relationship of different dihydroxy 4-methylcoumarins has been recently done [82]. The chain-breaking antioxidant activities of eight coumarins [7-hydroxy-4-methylcoumarin, 5,7-dihydroxy-4-methylcoumarin, 6,7-dihydroxy-4-methylcoumarin, 6,7-dihydroxycoumarin, 7,8-dihydroxy-4-methylcoumarin, ethyl-2-(7,8-dihydroxy-4-methylcoumar-3-yl)-acetate (20), 7,8-diacetoxy-4-methylcoumarin and ethyl 2-(7,8-diacetoxy-4-methylcoumar-3-yl)-acetate] (21) during bulk lipid autoxidation at 37 C and 80 C in concentrations of 0.01-1.0 mM and their radical scavenging activities at 25 C using TLC-DPPH test have been studied and compared. It was found that the o-dihydroxycoumarins demonstrated excellent activity as antioxidants and radical scavengers, much better than the m -dihydroxy analogue and the monohydroxycoumarin. The substitution at the C3 position did not show any effect either on the chain-breaking antioxidant activity or on the radical scavenging activity of the 7,8dihydroxy- and 7,8-diacetoxy-4-methylcoumarins. The comparison with DL--tocopherol (TOH), caffeic acid (CA) and p-coumaric acid (p-CumA) revealed some structure-activity correlations. Theoretical calculations and the Lipinskis Rule of Five were used for explaining the structureactivity relationships and pharmacokinetic behavior. The importance of phenolic compounds and of coumarins, in particular as potential bio-antioxidants, i.e. compounds with antioxidant and biological activity, has been theoretically demonstrated recently [82, 83]. Electrochemical and chemical oxidation of 7,8-hydroxy-4methylcoumarin and 7,8-diacetoxy-4-methylcoumarin were studied to investigate the mechanisms occurring in their antioxidant activities in acetonitrile, under electron transfer and H-atom transfer conditions [84]. Electrolysis and chemical reactions were followed online by monitoring the UV spectral changes with time. The anodic oxidation of 7,8-hydroxy-4-methylcoumarin, studied by cyclic voltammetry and controlled potential electrolysis, occurs via a reversible one-step two-electrons process, yielding the corresponding stable phenoxonium cation. Moreover, the chemical oxidation with an H-atom acceptor also follows a similar path, yielding the stable neutral quinonic product. Intermediates were never evidenced in both cases. Only in the presence of a strong base, an anodic oxidation product mono-electronic was evidenced, likely the 7,8hydroxy-4-methylcoumarin radical anion. However, the anodic oxidation of the acetoxy derivative 7,8-diacetoxy-4-methylcoumarin occurs at very high potential values, ruling out the possibility that the antioxidant activity observed in vivo might occur via an electron transfer mechanism and no reactions were evidenced with an H-atom acceptor.
As it was mentioned earlier, the unsubstituted coumarins can form 3,4-coumarin epoxides during their metabolism and these intermediates could be toxic [85]. Differently, synthetic 4methylcoumarins do not induce the formation of the epoxide, as they are not substrates for liver P450 monoxygenase [85]. For this reason, they could be better candidates for pharmacological use, particularly for their antioxidant activity. However, the great part of the structure-antioxidant activity relationship studies analyze the antioxidant activity of 4-methylcoumarins toward not physiological radicals (such as DPPH) [78,86] or in not physiological system (such as linoleic acid lipid peroxidation) [18]. One study reports on structure/antioxidant activity relation of three 4-methylcoumarins in LDL oxidation model (oxidation was initiated thermally by AAPH or photochemically by a tripler sensitizer benzophenone) [68]. Very recently, the antioxidant activity of eight synthetic 4-methylcoumarins was systematically studied [87] both in their peroxyl radicals scavenging activity and in modulating the in vitro resistance of human low-density lipoprotein (LDL) to oxidative modification initiated by 2,2-azobis (2amidinopropane) dihydrochloride (AAPH) or catalyzed by copper. The antioxidant capacity was measured using: (i) a competition kinetic test to measure the relative capacity to quench peroxyl radical; (ii) the in vitro oxidative modification of human low-density lipoprotein, initiated by AAPH or catalyzed by copper. The authors studied the effect of acetoxy and hydroxy substituents (at the position C-5,C-7; C-6,C-7 and C-7,C-8) in 4-methylcoumarins that differed also for the presence of ethoxycarbonylethyl or ethoxycarbonylmethyl chain at the C-3 position. In both models, the ortho-OH substituents were found to be better antioxidants than the meta ones [87]. The most efficient antioxidant was the 7,8dihydroxy-4-methylcoumarin and the corresponding diacetoxy derivative was unexpectedly a good antioxidant. Finally, the presence of an ethoxycarbonylethyl substituent at the C-3 position increased the antioxidant capacity of both 7,8-dihydroxy-4methylcoumarin and 7,8-diacetoxy-4-methylcoumarin. Beillerot et al. [88] investigated the antioxidant effects of some known and new coumarin derivatives on oxidative stress induced by doxorubicin (DOX) in MCF7 cells. Doxorubicin, an anthracycline antibiotic, is a potent chemotherapeutic agent, often used in the treatment of solid tumors, especially breast and ovarian cancer. However, its therapeutic use is limited by its cardiotoxicity. The DOX-induced cardiomyopathy mechanisms are not completely understood but they include formation of oxygen free radicals [89]. Different antioxidants such as vitamins A, E, and C, probucol or Nacetylcystein, and S-allylcystein do not interfere with anthracycline activity in tumor cells but their cardioprotective efficacy was limited, thus it is well established that there is, at the moment, no universal ideal antioxidant. The coumarin derivatives investigated displayed a protective antioxidant activity without affecting DOX antitumoral efficiency. A set of eighteen coumarin derivatives were synthesized and analyzed [88]. Their antioxidant power was evaluated in vitro with the FRAP (ferric reducing ability of plasma) method and in human breast adenocarcinoma MCF7 cells using H2DCFDA (2,7dichlorodihydrofluorescein diacetate) in a cytometric analysis. 4Methyl-7,8-dihydroxycoumarin was found to exhibit an important
OH OH O O O HO
OH O O OAc O O O 19 20 21 O AcO O O O
Kostova et al.
antioxidant strength, a low cytotoxicity, and could decrease ROS production generated by DOX treatment without affecting DOX cytotoxicity in MCF7 cells. The study of Goel et al. [90] examined 7,8-diacetoxy-4methylcoumarin and its thiocoumarin derivative 7,8-diacetoxy-4methylthiocoumarin (22) for their effect on human non-small cell lung cancer A549 cells. They showed that both coumarins not only inhibited cell proliferation, but also induced apoptosis with an IC50 of 160 g/ml as confirmed by morphological examination, annexinV assay and flow cytometric analysis. Interestingly, it was observed that these two coumarin compounds exhibited little cytotoxicity towards peripheral blood mononuclear cells but induced apoptosis in malignant cells. Treatment with 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin also resulted in pronounced release of apoptogenic cytochrome c from mitochondria to cytosol, alteration of mitochondrial membrane potential ( m), and activation of caspase-9 and caspase-3. Although an increase in the levels of ROS was observed, pre-treatment with antioxidant showed no protective effect against 7,8-diacetoxy-4-methylcoumarin- and 7,8-diacetoxy-4-methylthiocoumarin-induced apoptosis [90]. Results suggested that downregulation of Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulation of p53, Akt and NF-B pathway are involved in the underlying molecular mechanism of apoptosis induction by 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin in A549 cells. Goel et al. [91] have previously reported that 7,8-dihydroxy-4-methylcoumarin induces apoptosis of human lung adenocarcinoma cells by ROSindependent mitochondrial pathway through partial inhibition of ERK/MAPK signaling. As one of coumarin derivatives, daphnetin (7,8-dihydroxycoumarin) has exhibited broad biological activities, such as anti-inflammatory, antioxidant [14] as well as atitumor effects [92]. Moreover, recent studies demonstrated that daphnetin can act as a potent antiproliferative and differentiation-inducing agent in human renal cell carcinoma [93]. Esculetin (6,7-dihydroxycoumarin) showed lipoxygenase inhibitory effect on the proliferation response of cultured rabbit vascular smooth muscle cells by modulating P signal transduction pathway [94]. The structure-activity relationship of esculetin and eight other coumarin derivatives indicated that two adjacent phenolic hydroxyl groups at the C-6 and C-7 positions in the coumarin skeleton were necessary for the potent antiproliferative and antioxidant effects. Therefore, glycosylation and damage of the catechol structure (ortho-dihydroxy groups) had significant negative influence on the activity of the coumarins, for example, it considerably reduced the radical scavenging level [95]. The study of Cai et al. [96] characterized antioxidant activity and phenolic compounds of traditional Chinese medicinal plants associated with anticancer, comprising 112 species from 50 plant families. A positive, significant linear relationship between antioxidant activity and total phenolic content showed that phenolic compounds were the dominant antioxidant components in the tested medicinal herbs. Major types of phenolic compounds from most of the tested herbs were preliminarily identified and analyzed, and mainly included phenolic acids, flavonoids, tannins, coumarins and curcuminoids. These medicinal herbs exhibited far stronger antioxidant activity and contained significantly higher levels of phenolics than common vegetables and fruits. Traditional Chinese medicinal plants associated with anticancer might be potential sources of potent natural
OAc AcO S O
antioxidants and beneficial chemopreventive agents. The influence of other coumarin derivatives in induced oxidative stress has been widely studied also in vivo and ex vivo [97]. 3-HYDROXYCOUMARINS AND OTHER C-3 SUBSTITUTED COUMARINS The C-3 substituted coumarins have been extensively investigated for their antioxidant properties, for instance, 3hydroxycoumarin [(23), refer. Table 1] [98,99], as well as 3aminocoumarin [(24), refer. Table 1], 3-acetylaminocoumarin [(25), refer. Table 1 ], and coumarin-3-carboxilic acid [(26), refer. Table 1] [99]. The antioxidant capacity has been investigated with chemiluminescence measurement and by the accumulation of TBA-active products [99]. All coumarins were found to be antioxidants, with 3hydroxy-, 3-amino- and 3-acetylamino coumarins being capable of amplifying chemiluminescence. 5-Lipoxygenase and alpha-Dglucosidase inhibitory activities of coumarins greatly increased through 3-hydroxylation by 3-hydroxyscopoletin [(27), refer. Table 1] and 3-hydroxyisoscopoletin [(28), refer. Table 1 ] [100]. In these tests 3-hydroxyscopoletin and 3-hydroxyumbelliferone [(29), refer. Table 1] had a high inhibitory potency for 5-lipoxygenase and for alpha-D-glucosidase respectively. Some benzo[l]khellactone derivatives and analogues were prepared by Nicolaides et al. and their strong inhibition effect on the soybean lipoxygenase was investigate [101]. All the tested compounds were found to interact with DPPH in a concentration and time dependent manner. Some fused 1,3-dioxolocoumarins were synthesized and evaluated as antioxidants and antinflammatories [102]. The compounds were tested for their ability to interact with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH), to scavenge superoxide anion radicals, to compete with DMSO for hydroxyl radicals, and to inhibit proteolysis, -glucuronidase and soybean lipoxygenase activity in vitro . These compounds were also tested for their effect on the ferrous ion-stimulated peroxidation of linoleic acid. They showed a potent inhibitory effect (55-57 %) against inflammation induced by carrageenan in the rat paw edema model. On the contrary, their reducing ability was found to be low and no inhibition on soybean lipoxygenase was recorded. A sensitive fluorimetric assay has been used to examine whether free hydroxyl radicals (HO) were generated in the immediate vicinity of DNA by Fe(II)-bleomycin [103]. When aqueous solutions of SECCA (the succinimidyl ester of coumarin-3-carboxylic acid) were irradiated with gamma rays or incubated with Fe(II)-bleomycin or Fe (II)-EDTA in the presence of ascorbate and H2O2, 7-hydroxy-SECCA, a fluorescent product of the interaction of HO with SECCA was generated. On the contrary, Cu(II)-bleomycin complexes under similar conditions fail to induce 7-hydroxy-SECCA fluorescence. A series of coumarin analogues bearing a substituted phenyl ring on the C-3 position were synthesized via a novel methodology and the in vitro antioxidant activity of the synthesized compounds was evaluated [104]. The presence of a catechol system is well known to improve the antioxidant activity of a compound. Especially in the case of flavonoid analogues as well as in coumarin derivatives, it has been shown that the ortho-dihydroxy system forms a resonance stabilized radical which enhances the radical scavenging ability of the compound [105] and it was taken into consideration upon the synthesis in order to examine the influence of this structural feature on the biological activity of the new coumarin analogues. The in vitro antioxidant activity of the new compounds was evaluated using two antioxidant assays: the radical scavenging ability of the compounds was tested against the 1,1diphenyl-2-picryl-hydrazyl (DPPH) stable free radical and their ability to inhibit lipid peroxidation induced by the thermal free radical producer 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) was evaluated. Moreover, the ability of the synthesized coumarins to inhibit soybean lipoxygenase was determined. The interaction of the synthesized compounds with the stable free
22
3937
radical DPPH indicates their radical scavenging ability in an ironfree system. The compounds, which possessed the catechol structural feature are potent DPPH radical scavengers, showing high activity comparable to the reference compound. The corresponding methoxylated analogues had very low activity which is remarkably enhanced when the methyl groups were removed. In addition, the presence of only one free phenolic hydroxyl group does not favour activity. The catechol moiety has been identified as the structural requirement for efficient DPPH radical scavenging and lipid peroxidation activity, however it does not favour LO inhibitory ability. A facile, convenient and high yielding synthesis of a combinatorial library of 3-alkanoyl/aroyl/heteroaroyl-2H-chromene-2thiones has been developed [106]. The assessment of radical scavenging capacity of the compounds towards the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) was measured and these compounds were found to scavenge DPPH free radical efficiently. Some of the compounds were able to protect curcumin from the attack of sulfur free radical generated by radiolysis of glutathione (GSH). The newly synthesized compounds exhibited profound antioxidant activities. Reverse-phase preparative high-performance liquid chromatography (RP-HPLC) of the methanol extract of the aerial parts of Euphorbia petiolata, an endemic Iranian medicinal plant, yielded ten free radical scavengers including coumarins [107]. The free radical scavenging properties of these compounds were assessed by the 2,2-diphenyl-1-picrylhydrazyl assay. The experiments reported by Kennedy S. H. et al. [108] demonstrated that benzoyl peroxide (BP) can promote radiation-induced transformation in vitro. Benzoyl peroxide (BP) was shown to be capable of generating free radicals, determined by the kinetics of hydroxylation as measured by the fluorescence of coumarin-3carboxylic acid. Although the mechanisms involved in the BP enhancement of radiation transformation are unknown, the authors hypothesize that lipid peroxidation produced by benzoyl radicals in the vicinity of membrane associated unsaturated lipids could contribute to the promotion of transformation in vitro. Quantitative analysis for determination of hydroxyl radical generation has been performed with use of a highly specific fluorescent probe coumarin3-carboxylic acid whose hydroxylation product, 7-hydroxycoumarin-3-carboxylic acid, fluoresces intensely [109,110]. The cardioprotective effects of red wine consumption has been reported and these properties of wine have been attributed to certain polyphenolic constituents of grapes [111]. Some novel coumarin derivatives with a 7-azomethine linkage were synthesized by 7-formylcoumarin (30) [112-114] and investigated. The compounds were tested in vivo for their antiinflammatory activity and in vitro for their antioxidant ability and possessed significant protection against carrageenin induced rat paw edema. Some of the compounds were found in vitro to inhibit lipid peroxidation and to strongly scavenge superoxide radicals [113]. An attempt was made to delineate the possible mechanism of action of the studied compounds. Hydrophilicity, the presence of the free C-7OH group, and steric requirements for the substituent at the C-8 position are the most important factors in terms of SAR [114].The authors reported the in vivo antiinflammatory activity (inhibition of carrageenin rat edema) and the in vitro antioxidant effects (DPPH interaction, OH radical scavenging activity) of some new coumarin derivatives [112]. It has been established that active oxygen species are implicated in various stages of the process of inflammation, e.g. stimulation of phagocytosis, leucotriene biosynthesis. 4-HYDROXYCOUMARINS The 4-hydroxycoumarin [(31), refer. Table 1] moiety, widely spread among coumarin natural products, has been the molecular template for the synthesis of a variety of analogues exhibiting
important biological activity. The potential of 4-hydroxycoumarin derivatives as antiinflammatory and antioxidant agents, prompted researchers to design and synthesize a series of novel coumarin analogues. Some novel quinolinone-3-aminoamides bearing a methyl or phenyl group on the nitrogen heteroatom incorporating the alpha-lipoic acid (LA) moiety have been recently synthesized by Detsi et al [115] and led to compounds with combined antioxidant and anti-inflammatory activities. Incorporating alphalipoic acid to the coumarin scaffold revealed that some of the novel hybrid compounds are potent leads and may be useful in the prevention of human diseases attributed to free radical damage [116].
OHC O O
30
Coumarin derivatives including 4-hydroxycoumarin with antibacterial and antioxidant activities [117-119] have been recently synthesized. Different substituted 3,3-arylidenebis-4-hydroxycoumarins and tetrakis-4-hydroxycoumarin derivative were the final products when 4-hydroxycoumarin and aromatic aldehydes containing different groups in ortho, meta or para positions condense in boiling ethanol or acetic acid [117]. The antioxidant activity of these compounds was studied. A new family of coumarin derivatives containing a chalcone moiety was synthesized by condensation of 3-acetyl-4-difluoroboryloxycoumarin (32) with aryl and heteroaryl aldehydes with piperidine in chloroform [119] and their antioxidant activity against the stable free radical DPPH was evaluated. The antioxidant properties of five new 4-hydroxy-biscoumarins were studied and compared with 4-hydroxycoumarin [120]. It was found that compound 3,3-[(3,4-dihydroxyphenyl) methylene]bis(4-hydroxy-2H-chromen-2-one) (33) with a catecholic structure in the aromatic nucleus showed the strongest antioxidant activity. The compound demonstrated radical scavenging activity towards DPPH radical by using TLC DPPH rapid test. The other compounds did not show significant capacity as radical scavengers. The structureactivity relationship was discussed on the basis of comparable kinetic analysis of studied 4-hydroxy-biscoumarins with the known and standard antioxidants as tocopherol (TOH), caffeic acid (CA), sinapic acid (SA), ferulic acid (FA) and p-coumaric acid (p-CumA). It has been found for the first time that the substitution in the aromatic nucleus of the studied 4hydroxy-biscoumarins is responsible for their antioxidant activity. The remaining structure of 4-hydroxy-bis-coumarin moiety is not of significance for the antioxidant and antiradical activity of compounds under study. Four new 4-hydroxycoumarin derivatives, substituted with electron-donating and electron-withdrawing substituents on the third place in the coumarin ring, were synthesized by the same group [121] and were tested in vitro for antioxidant activity in hypochlorous system. The assay was based on the luminol-dependent chemiluminescence of free radicals, which decreased in the presence of 4-hydroxycoumarin derivative. Compound ethyl 2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxyphenyl)methyl]-3-oxobutanoate (34) expressed the best scavenger activity at the highest concentration. The results show that 4hydroxycoumarins with electron-donating groups on the third position and on the seventh position in the coumarin ring have the best scavenger activity. Earlier, differently substituted 4hydroxycoumarins were tested for free radical scavenger activity in the system of 1,1-diphenyl-2-picrylhydrazyl (DPPH) stable radical [122]. Structureactivity relationship of some coumarin antioxidants as protective agents against linoleic acid hydroperoxide
Kostova et al.
OH OH O O O O OH
OH
OH OH O O 34 35 O O O O
OBF2 32
OO 33
(LOOH) toxicity in cultivated human umbilical vein endothelial cells was recently explored [123]. A series of imino and amino derivatives of 4-hydroxycoumarins were synthesised and evaluated for antioxidant potential, through different in vitro models such as (DPPH) free radical-scavenging activity, linoleic acid emulsion model system, reducing power assay and phosphomolybdenum method [124,125]. All prepared compounds possessed good antioxidant activity and among them a p-nitrophenol derivative with IC50 at 25.9 M possessed radicalscavenging activity which was comparable to BHT, while the best reducing power was observed in the case of benzyl amino compound. Also, observed data indicated that compounds may serve as inhibitors of lipid peroxidation process [125]. A series of novel spiro-substituted 4-hydroxypyranocoumarins and their corresponding dihydropyrano cis-diols has been synthesized and investigated for their radical scavenging properties, in an effort to establish structureactivity relationships [126]. Among them the spiroadamantylpyranocoumarin (35) and the diols can interact with the stable free radical 1,1-diphenyl-2-picrylhydrazyl and scavenge superoxide anions generated in the xanthinexanthine oxidase system. The synthesized compounds scavenged DPPH radical in a concentration and a time-dependent manner. Their activity is comparable with that of 4-hydroxycoumarin and significantly higher than that of 7-hydroxycoumarin. OTHER SYNTHETIC COUMARINS A series of aminoalcohol derivatives of benzocoumarins from nucleophilic opening of oxirane with different amines, furnishing a variety of 2-hydroxy amino derivatives as well as simple alkyl substituted benzocoumarins were synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities [127, 128]. In terms of SAR, the simple alkyl substituted benzocoumarins exhibited interesting activity. Preliminary screening indicated that the compound, which incorporates an unbranched benzyl group, demonstrated significant lipid lowering and antioxidant activities [127]. The study revealed that such attempts on benzocoumarin-based pharmacophores which is a biologically important scaffold might result in identification of new lead for antidyslipidemia. Six novel 4-methylcoumarins bearing different functionalities such as amino, hydroxy, N -acetyl, acetoxy and nitro have been synthesized and examined for the first time for their effect on NADPH dependent liver microsomal lipid peroxidation in vitro , and the results were compared with other model 4-methylcoumarin derivatives to establish the structureactivity relationship [129]. The results demonstrated that amino group is an effective substitute for the hydroxyl group for antioxidant property and produced a dramatic inhibition of lipid peroxidation. Ortho dihydroxy and ortho hydroxy-amino coumarins were found to possess highest antioxidant and radical scavenging activities, possibly by forming a stable mixed ligand complex with ADP and Fe2+ thereby preventing the production of ADP-perferryl radical responsible for ROS formation, as postulated earlier [77, 130].
The structure of Schiff base derivatives of coumarins in addition to the biologically active coumarin nucleus, possesses amine moiety and extended conjugation that is responsible for its highly fluorescent and antioxidant nature. A series of Schiff bases have been synthesized from dicarbaldehyde of benzocoumarin, in which the reactions were regioselective and the products existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted. The compounds were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic activity for the first time and possessed significant lipid lowering and antioxidant activity [131]. Sashidhara et al. [132,133] have reported the synthesis and potential antidyslipidemic and antioxidant activity of novel Schiff bases from 7hydroxy-4-methyl-2-oxo-2H-benzo[h]chromene-8,10 dicarbaldehyde in which the reactions were regioselective and products were in the keto-enamine form and the aromaticity of the relevant ring was disrupted [132]. Further, the efforts to bring the free aldehyde at the C-4 position into reaction failed both with increasing molar ratio of the alkyl amine and also by increasing the reaction temperature to reflux [134]. Coumarin Schiff-bases (CSB) possessing different substituents on the 4-methyl-2-substituted phenyl imino-2H-chromene-7-ol molecule were evaluated for their in vitro antioxidant and plausible anti-inflammatory potential [135]. The antioxidant studies of selected CSB were carried out by determining their reducing power, OH radical scavenging activity, scavenging of stable 2,2-diphenyl-1-picrylhydrazine (DPPH) radical and inhibition of the polyphenol oxidase (PPO) enzyme. The assessment of possible anti-inflammatory potential was performed by trypsin inhibition assay and inhibition of -glucuronidase. All the CSBs under study showed significant reducing effects. The majority of the tested CSB was found to be effective scavengers of DPPH radical with moderate to low OH scavenging ability and significantly inhibited the activity of PPO. With few exceptions, results from the inhibition assay of trypsin and -glucuronidase were not encouraging, however they may be helpful in defining structure-activity relationships in further optimization of the lead molecules. Presence of electrondonating groups and/or electronegative environment may be the possible reasons for the inhibition of trypsin by some compounds, however the same cannot be said for all the CSBs showing trypsin inhibitory activity [135]. Introduction of an oxy-imino type linkage at the allylic position with respect to the biogenetic C-3, C-4 double bond in the form of oximes, amidoximes, oxadiazoles, isoxazolines, etc. has resulted in compounds with promising antiproteolytic, antioxidant, and antiinflammatory properties [136]. The coumarin nucleus incorporates the styryl carbonyl moiety into a rigid framework, the presence of which in coumarin is expected to affect the scavenging of reactive substances derived from oxygen and influence the process involving free radical mediated injury [136]. Literature review reveals the importance of pyrazoles as antioxidants by inhibiting the oxidation of LDL [137]. Keeping in view the biological importance of arylhydrazonogroup, arylazogroup, pyrazolones, pyrazoles and coumarin nucleus, design
3939
of arylazopyrazoles and arylhydrazonopyrazolones containing coumarin moiety was carried out [138]. This was followed by the synthesis of target compounds 1-(4-methylcoumarinyl-7-oxyacetyl)-3,5-dimethyl-4(arylazo)pyrazoles (36) and 1-(4-methylcoumarinyl-7-oxyacetyl)-3-methyl-4-(substituted phenyl) hydrazono2-pyrazolin-5-ones (37) and their in vitro antioxidant screening. Compound with 4-bromophenylsubstituent in the phenyl ring exhibited highest antioxidant activity from pyrazole series and pyrazolin-5-one bearing 3-nitrosubstituent in the phenyl ring exhibited enhanced antioxidant activity from the respective series [138]. Among the fused coumarins, furocoumarins are important as photochemotherapeutic agents and exhibit antioxidant and antiinflammatory activities [14]. Pyranocoumarins are used also as photoactive drugs and possess anti-inflammatory [14,101] and antioxidant [14,101] activities. Symeonidis et al. [139] reported the synthesis of angular [7,8]- and linear [6,7]-coumarins fused to dihydrofuro-, 1,3-dioxolo-, 5-membered- or 6-membered alicyclic ring. These compounds were tested in vitro for antioxidant activity and they were found to present significant scavenging activity. Many non-steroidal anti-inflammatory drugs have been reported to act either as inhibitors of free radical production or as radical scavengers. The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a well established approach to the synthesis of more potent drugs. Using this approach, several research groups have recently designed and synthesized hybrid molecules by coupling coumarins with a number of bioactive molecules including resveratrol [61,62,140] and these efforts resulted in new molecules endowed with antioxidant and other properties. Nowadays, a lot of studies report complexes of coumarin derivatives with metals, which possess biological activity. Metal ions are very promising agents, capable to induce ROS by many different ways. Cerium(III) and neodymium(III) complexes with 3,3benzylidenebis[4-hydroxycoumarin] (38) were synthesized [141]. Their cytotoxicity toward cancerous cell cultures correlated with the weakness of the coordinative bond between the cation and organic ligand and with the capability to scavenge superoxide radicals as well. The antioxidant properties of the complexes were estimated by monitoring their effects on the reduction of MTT in presence of the Xanthine/Xanthine Oxidase (X/XO) in vitro derived superoxide radical O2-. It was concluded that cerium (III) complex with 3,3-benzylidenebis[4-hydroxycoumarin] might induce intracellular acidification along with control over the extracellular oxidative stress. The high antioxidant activity of the Ce (III) complex might explain the elimination of cancerous cells via apoptotic pathway. By eliminating superoxide radicals, the Ce (III) complex would locally diminish the extra-cellular H2O2 and would increase the opportunity for apoptotic death of the cancerous cells [141]. Some
copper chelates with coumarins have been studied for their antioxidant capacity by iron-induced chemiluminescence [142]. The copper complexes were potent antioxidants, comparable to butylated hydroxytoluene. The mechanism of the antioxidant action of these copper-coumarin chelates was found similar to that of Cu-Mnsuperoxide dismutase, with a coumarin portion of the complex being involved as a free radicals trap. Considerable effort has now been given to the functionalisation of coumarins so that metalcoumarin complexes may be synthesized towards the development of artificial photosynthetic systems, chemical sensors and molecular level devices. Group-6 tetracarbonyl complexes, [M(CO)4(L)] (M= Cr, Mo, W; L= N-[(2-Pyridyl)methyliden]-6-coumarin) were synthesized and characterized [143]. The ligand and the complexes are fluorescent. The compounds showed radical scavenging activity and were investigated spectrophotometrically using 1,1-diphenyl-2picrylhydrazyl (DPPH), hydroxyl (OH), superoxide (O2-) and nitroxyl (NO) radicals. The complexes exhibited potential antioxidant property both in cell-free and in-vitro studies and highest activity is observed with [W(CO)4(L)]. NATURAL COUMARINS AS ANTIOXIDANTS Plants have formed the basis for the treatment of diseases in traditional medicine systems for thousands of years, and continue to play a major role in the primary health care of about 80 % of the World's inhabitants. While the natural products isolated as the active compounds might not be suitable for development as effective drugs, these can provide suitable leads for conversion into clinically useful agents. Coumarins are present in plants in the free form and as glycosides. In general, coumarins are characterized by great chemical diversity, mainly differing in the degree of oxygenation of their benzopyrane moiety [95]. More than 300 coumarins have been identified from natural sources, especially from green plants [144]. Most of the compounds based on the coumarin nucleus include the anticoagulants like dicoumarol (39), warfarin (40), aflatoxins and the psoralens (photosensitizing agents). In nature, most coumarins are C-7 hydroxylated [145,146]. Major coumarin constituents included simple hydroxycoumarins (e.g., aesculin, esculetin, scopoletin, and escopoletin), furocoumarins and isofurocoumarin (e.g., psoralen (41) and isopsoralen (42) from Psoralea corylifolia), pyranocoumarins (e.g., xanthyletin (43), xanthoxyletin (44), seselin (45), khellactone (46), praeuptorin A), biscoumarins, dihydroisocoumarins (e.g., bergenin (47)), and others (e.g., wedelolactone from Eclipta prostrata) [147,148]. Plants, fruits, vegetables, olive oil, and beverages (coffee, wine, and tea) are all dietary sources of coumarins; for example, seselin from fruit of Seseli indicum, khellactone from fruit of Ammi visnaga, and praeuptorin A from Peucedanum praeruptorum [149]. Cai et al. have found coumarins occurring in the medicinal herbs Umbelliferae, Asteraceae,
HN N N N O O 36 O O O N N N
NH O O O O OH OH O O O
37
38
Kostova et al.
Convolvulaceae, Leguminosae, Magnoliaceae, Oleaceae, Rutaceae, and Ranunculaceae, such as simple coumarins from A. annua, furocoumarins (5-methoxyfuranocoumarin, (48)) from Angelica sinensis, pyranocoumarins from Citrus aurantium, and isocoumarins from Agrimonia pilosa [96]. Some Indian medicinal plants (e.g., Toddalia aculeata, Murraya exotica, Foeniculum vulgare, and Carum copticum ) and dietary spices (e.g., cumin and caraway) also possess coumarins [150]. In addition, coumestans, derivatives of coumarin, including coumestrol, (49) a phytoestrogen, are found in a variety of medicinal and dietary plants such as soybeans and Pueraria mirifica. Natural phenolic compounds, including coumarins, play an important role in cancer prevention and treatment. Various bioactivities of phenolic compounds are responsible for their chemopreventive properties (e.g., antioxidant, anticarcinogenic, or antimutagenic and anti-inflammatory effects) and also contribute to their inducing apoptosis by arresting cell cycle, regulating carcinogen metabolism and oncogenesis expression, inhibiting DNA binding and cell adhesion, migration, proliferation or differentiation, and blocking signaling pathways. The review of Huang et al. [95] covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of phenolic compounds from medicinal herbs and dietary plants. Recently, there has been a great interest in natural antioxidants as bioactive components of food, nutraceuticals or potential drugs against several diseases. Chemical investigation of the EtOH extract of Morus alba L. (Moraceae), as guided by free radical scavenging activity, furnished 5-hydroxy-7-methoxycoumarin and oxyresveratrol (50) [151]. Compounds showed superoxide scavenging effects with the IC50 values of 19.1 3.6 and 3.81 0.5 M, respectively. Oxyresveratrol exhibited a DPPH free radical scavenging effect (IC50 = 23.4 1.5 M) and showed hepatoprotective effect with EC50 value of 32.3 2.62 M on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells [151]. Two new 5methylcoumarin glycosides named diosfeboside A (51) and diosfeO O O O O O
boside B (52) were isolated from the leaves of Diospyros crassiflora (Hiern). Their structures were established and in vitro cytotoxic activity of the new compounds against human carcinoma cell lines (HL-60, Bel-7402, BGC-823, and KB) was evaluated [152]. Eighty eight extracts from various parts of plants from European Asteraceae and Cichoriaceae were assayed for radical scavenging activity by means of DPPH (1,1-diphenyl-2-picryl hydrazyl radical) test using the SIA (sequential injection analysis) method developed for this purpose [153]. DPPH radical scavenging activity of all tested plant extracts was evaluated according to the IC50 parameter. Twenty nine extracts exhibited IC50 value lower than 0.1 mg/mL. The leaves of Leuzea carthamoides (IC50 = 0.046 mg/mL) were chosen as the most promising sample for a subsequent phytochemical study, which resulted in the isolation of seven natural compounds. Antioxidant activity of the isolated compounds was evaluated by DPPH test and ferric reducing antioxidant power (FRAP) test and compared with trolox and quercetin [153]. Extracts of 32 plants from the Brazilian northeastern semi-arid region called Caatinga were evaluated through DPPH radical scavenging assay, carotene bleaching, and brine shrimp lethality tests (BST) [154]. Among the extracts studied, Byrsonima cf. gardneriana, Mascagnia coriacea , Cordia globosa, Diodia apiculata and Hypenia salzmannii showed the highest activities in DPPH radical scavenging test. In the -carotene bleaching test the highest activities were observed for Passiflora cincinnata, Chamaecrista repens, B. cf. gardneriana, Rollinia leptopetala, Serjania glabrata, Diospyros gaultheriifolia, C. globosa, Mimosa ophtalmocentra, M. coriacea and Lippia cf. microphylla . In contrast, R. leptopetala, Zornia cf. brasiliensis and Leonotis nepetifolia were the most active species in the BST. The bioassay-guided fractionation of the CHCl3 extract from pigeon pea leaves led to the isolation of a new natural coumarin, named as cajanuslactone (53), together with two known phytoalexins [155]. The structure of cajanuslactone was elucidated. It was determined as 7-hydroxy-5-O-methyl-8-(3-methyl-2-butylene)-4phenyl-9,10-dihydro-benzopyran-2-one. The authors also reported
OH HO
OH
O O O 41 O O 42 OH O O
39
40
OMe
O O O
HO
Me
Me
O 43
O O 44 CH2OH OH OMe O O 47 48 OH O O O HO 49 O O O O O 45 O O 46 OH
OH MeO
HO
3941
OH
O O OH OH OH HO OH
O HO HO 50 OH O O O O O HO O OH OH HO 52 OH OMe Ph 53 OO H2C CH O C O OH 51 O O HO
CH3
CH3
the extraction, quantitative analysis and antioxidant activity test of extracts of pigeon pea leaves [156-158]. The aerial parts of several Angelica species of the Apiaceae as natural medicine, are rich sources of various coumarins with biological, to a lesser extent, toxicological activities. From the chloroform extract of the aerial parts of Angelica urumiensis MOZAFF, two new coumarins, together with six known coumarins and two known flavonoids were isolated [159]. On the basis of comprehensive spectroscopic analyses, the structures of the new compounds were established as pyranocoumarin dimer and (+)-8,9-dihydro-8(2-hydroxypropan-2-yl)-2-oxo-2H-furo[2,3-h]chromen-9-yl-3-methylbut-2-enoate. The eight known compounds were isosamidin (54), laserpitin (55), pteryxin (56), isolaserpitin(57), ciskhellactone, angelicin, genkwanin (58) and salvigenin (59), respectively. These known structures are isolated from the aerial parts of A. urumiensis for the first time. Antioxidant activities of the two new coumarins were evaluated by using 2,2-diphenyl-1picrylhydrazyl (DPPH) radical scavenging assay and exhibited a moderate antioxidant activity [159]. The dried root of Angelica gigas Nakai (Umbelliferae), Cham-Dang-Gui (the Korean name), has been traditionally used in oriental herbal medicines for thousands of years. The curative potential of A. gigas has led to efforts to isolate bioactive secondary metabolites from this plant, and several coumarin derivatives [160]. Among these coumarins, decursin (60) and decursinol (61) angelate are the most abundant components in the root of A. gigas [161] and have been shown to exhibit several pharmacological chemotherapeutic properties [161169]. The antioxidant activity of eight coumarins and two flavonols isolated from Haplopappus multifolius was studied with the DPPH radical method [170]. Results show that a high concentration of phenolic coumarins and the presence of quercetin and rhamnetin in the exudates could account for the protection of the plant against oxidative stress. The structures of the coumarins 6-hydroxy-7[(E,E )-3,7-dimethyl-2,4,7-octatrienyloxy] coumarin (62) and 7[(E)-3-methyl-4-hydroxy-2-butenyloxy] coumarin (63) are proposed on the basis of spectroscopic evidence. Antioxidant-guided fractionation of Mammea americana L. seeds resulted in the identification of three new isoprenylated coumarins, mammea B/BA hydroxycyclo F (64), mammea E/BC (65), and mammea E/BD (66) [171]. In addition, twelve known isoprenylated coumarins as well as two known flavanols, (+)-catechin and (-)-epicatechin were identified. The fifteen isoprenylated coumarins were screened for their
cytotoxicity in the SW-480, HT-29, and HCT-116 human colon cancer cell lines and antioxidant capacities in the DPPH (1,1diphenyl-2-picrylhydrazyl) free-radical assay. Compounds exhibited significant cytotoxic activities and displayed high antioxidant activity in the DPPH assay (IC50 range 86 - 135 M). The results of these assays were used to study the structure-activity relationships for this class of compounds. In the SW-480 cell line, the three new coumarins also exhibited dose-dependent increases in sub-diploid cells by flow cytometry, indicating that they induce apoptosis [171]. The fruits of wampee [Clausena lansium (Lour.) Skeels] contain a significant amount of coumarins with many health benefits [172]. The activity-guided separation of an ethyl acetate-soluble fraction on a polyamide column, followed by silica gel column and high performance liquid chromatography (HPLC) preparation afforded a pure compound, which was identified to be 8hydroxypsoralen (67) [172]. This isolate exhibited good scavenging activities against DPPH radical and superoxide anion as well as significant reducing power. It also showed potent proliferation inhibitory activity against human hepatocellular liver carcinoma cell line (HepG2), human lung adenocarcinoma epithelial cell line (A549) and human cervical carcinoma cell line (HELA). This is the first report on the antioxidant and cytotoxic properties of C . lansium fruit extract [172]. Alpinia officinarum is a rhizome belonging to the family zingeberaeceae, cultivated in South-east Asia [173]. Qualitative phytochemical analysis of the extract of Alpinia officinarum rhizome showed a majority of the compounds. The extracts showed a concentration dependent radical scavenging activity by inhibiting diphenylpicrylhydrazyl free radical. The aqueous alcoholic extract prepared by hot maceration process showed better reducing and total antioxidant activity. Four new compounds together with 16 other known compounds including coumarins were isolated from Ajania przewalskii [174]. The novel sesquiterpenolide possesses a rare carbon skeleton. Cytotoxicity of the compounds was assessed by their effects on selected cancer cell lines, K562, K562/ADM, BGC-823, and Hep-G2 cells. Radical-scavenging activities of the compounds were determined by ABTS and DPPH radical-scavenging assays. Phenols and coumarins displayed significant antioxidant properties (IC50 < 20 g/ml) [174]. The potent antioxidant activity of A. przewalskii might be attributed to the presence of the important polyphenolics, flavonoids, and coumarin compounds, which are attractive additives for the food and drug industry and are of great interest for use in complementary medicine supplements. Ryu et al. [175] isolated 18
Kostova et al.
O O O O O O OH O O O O 55 O O O O O
O OH O O O
54 OH MeO O
56 OMe O MeO O
57
O MeO OH 58 O O O OH 59 60 O HO 61 O O
n-Pr Me Me O O O O O O HO 63 64 OH O OH O O
i-Bu 62 HO
O HO O O O OH 65 O 66 OH HO
O O O
polyphenols with neuraminidase inhibitory activity from methanol extracts of the roots of Glycyrrhiza uralensis. These polyphenols consisted of four chalcones, nine flavonoids, four coumarins, and one phenylbenzofuran. Structureactivity analysis showed that the furan rings of the polyphenols were essential for neuraminidase inhibitory activity, and that this activity was enhanced by the apioside group on the chalcone and flavanone backbone. In addition, the presence of a five-membered ring between C-4 and C-2 in coumestan (68) was critical for neuraminidase inhibition. All neuraminidase inhibitors screened were found to be reversible, noncompetitive inhibitors. The antioxidant properties of methanol extracts of Ladys Bedstraw (Galium verum L., Rubiaceae) herb from two different localities in Serbia were evaluated [176].
Antioxidant activity was assessed in four different model systems. Free radical scavenging capacity (RSC) was examined by measuring the scavenging activity of extracts on 2,2-diphenyl-1pycrylhydrazil (DPPH) and hydroxyl radical (OH), as well as on hydrogen peroxide. In addition, the protective effects of lipid peroxidation (LP) in corn oil were evaluated by the TBA-assay using the Fe2+/ascorbate system of induction. The amount of dried extract, the content of total phenolics, flavonoids and chlorophylls was also determined. Extracts from both locations expressed very strong scavenger activity, reducing the DPPH (IC50=3.10 g/ml and 8.04 g/ml) and OH radical formation (IC50= 0.05 g/ml and 0.54 g/ml) and neutralising H2O2 (IC50= 4.98 g/ml and 3.80 g/ml), in a dose dependant manner. Also, examined extracts showed notable
3943
inhibition of LP (IC50= 11.69 g/ml and 19.47 g/ml) [176]. The ethanolic extract of Symphyopappus casarettoi syn., Eupatorium casarettoi containing coumarins, was partitioned in hexane, chloroform and methanolic fractions [177]. Extract and fractions were tested for their antioxidant activity in vitro and ex vivo assays. The methanolic fraction showed a higher antioxidant potential compared to the others fractions, which was correlated with its total phenol content. In addition, the ethanolic extract and the methanolic fraction attenuated ex vivo iron-induced cell death, quantified by lactate dehydrogenase leakage, and effectively protected against lipid damage induced by iron. These findings suggest that the ethanolic extract of S. casarettoi inflorescence and its methanolic fraction have in vitro and ex vivo antioxidant properties. Moussonia deppeana (Schldl. & Cham) Hanst is a species of Mexican Medicinal Flora used in Veracruz state. EtOAc extract was the most active in free radical scavenging test DPPH (CI50 18.33.4 g/mL). The phytochemical screening revealed the presence of phenolic compounds (flavonoids and coumarins) in EtOAc and EtOH extracts [178]. Anti-inflammatory activity was evaluated by topical application of the extracts (doses 2 mg/ear) giving a greater inhibition in hexane and EtOAc extracts. The model of paw edema was evaluated in EtOAc extract, observing a similar inhibition to indomethacin. These results support the biological effect attributed in their traditional use. Antioxidant activity assay-guided chemical analysis, using a rat pancreas homogenate model, of aerial parts from Eysenhardtia subcoriacea, led to the isolation of the new compound subcoriacin [3-(2-hydroxy-4,5-methylendioxyphenyl)6-(3-hydroxymethyl-4 -hydroxybut-2-enyl)-7-hydroxycoumarin] (69) together with the known substances: (+)-catechin, ()epicatechin, (+)-afzelechin (70), eriodictyol (71), (+)-catechin--O -d-galactopyranoside and quercetin 3-O --d-galactopyranoside as bioactive constituents [179]. The bioactive compounds showed moderate to strong radical scavenging properties against diphenylpicrylhydrazyl radical (DPPH). In addition, subcoriacin, (+)catechin, ( )-epicatechin and (+)-afzelechin improved the reduced glutathione levels in rat pancreatic homogenate. Grapefruit juice has been shown to increase the oral bioavailability of several clinically important drugs by inhibiting first pass metabolism [180]. Several compounds in grapefruit juice have shown different biological activities. Unique among them are furocoumarins with potent inhibitory activity against cytochrome P450 enzymes. Two bioactive compounds were isolated from grapefruit juice and grapefruit peel oil [180]. Structures of the compounds were elucidated and identified as bergaptol (72) and geranylcoumarin (73). The isolated compounds were tested for their radical scavenging activity
HO O O HO
using 2,2-azobis (3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazil (DPPH) methods at different concentrations. Bergaptol showed very good radical scavenging activity at all the tested concentrations. Furthermore, these compounds were evaluated for their inhibitory activity against CYP3A4 enzyme. Bergaptol and geranylcoumarin were found to be potent inhibitors of debenzylation activity of CYP3A4 enzyme with an IC50 value of 24.92 and 42.93 M, respectively. The isocoumarins, paepalantine (9,10-dihydroxy-5,7-dimethoxy-1H-naptho(2,3c)pyran-1-one) (74), 8,8-paepalantine dimer, and vioxanthin (75) isolated from Paepalanthus bromelioides, were assessed for antioxidant activity using isolated rat liver mitochondria and non-mitochondrial systems, and compared with the flavonoid quercetin [181]. The paepalantine and paepalantine dimers, but not vioxanthin, were effective at scavenging both 1,1-diphenyl-2picrylhydrazyl (DPPH) and superoxide radicals in nonmitochondrial systems, and protected mitochondria from tertbutylhydroperoxide-induced H2O2 accumulation and Fe2+-citratemediated mitochondrial membrane lipid peroxidation, with almost the same potency as quercetin. These results point towards paepalantine, followed by paepalantine dimer, as being a powerful agent affording protection, apparently via superoxide radicals scavenging, from oxidative stress conditions imposed on mitochondria, the main intracellular source and target of those reactive oxygen species. This strong antioxidant action of paepalantine was reproduced in HepG2 cells exposed to oxidative stress condition induced by H2O2 [181]. Acacia confusa Merr. (Leguminosae) is traditionally used as a medicinal plant in Taiwan [182]. The XOD-inhibitory activity of ethanolic extracts from A. confusa was investigated for the first time. Results demonstrated that the ethanolic extract of A. confusa heartwood had a strong XOD-inhibitory activity. Okanin and melanoxetin showed excellent inhibition on XOD in noncompetitive and competitive mode, respectively, and their inhibitory activity is better than that of allopurinol. This is the first study that demonstrates the XOD-inhibitory performance of okanin and melanoxetin [182]. Cucurbita maxima Duch. ex Lam.( Cucurbitaceae) known as Dadhiphala in Sanskrit, contains triterpenoids, flavonoids, coumarins, saponins, cucurbitacins, carotenoids, vitamins, minerals and amino acids. Attarde et al. [183] evaluated in vitro antioxidant activities of petroleum ether, chloroform and methanolic extract of pericarp of C.maxima. All extracts were tested for DPPH radical scavenging, nitric oxide radical scavenging and hydrogen peroxide scavenging activities. Cortex fraxini was extracted with 95 % ethanol to obtain a crude antioxidant extract [184]. The antioxidant activity was evaluated
OH O O HO O
O OH 67
O O HO 68 OH OH 69 O O OH
OH OH 70
HO
O OH O OH 71 O O 72 O O 73 O O
Kostova et al.
using the linoleic acid peroxidation method and the free radical scavenging assays, namely 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals. Cortex fraxini extract (CFE) showed high inhibition of peroxidation of linoleic acid when compared with butylated hydroxytoluene (BHT). CFE also exhibited excellent scavenging activity on DPPH and hydroxyl radicals. Total antioxidant activity was measured by the reduction of Mo(VI) to Mo(V) by the extract, and subsequent formation of a green phosphate/Mo(V) complex at acidic pH. CFE had significant total antioxidant activity and the effects were increased with increasing reaction time. The suitability of CFE as an antioxidant was determined in peanut oil, and the decrease of lipid oxidation was monitored using thiobarbituric acid-reactive substances (TBARS) assay. CFE treatment significantly (P < 0.05) reduced lipid oxidation in peanut oil compared to the control. No significant differences (P = 0.05) in lipid oxidation were detected between CFE antioxidant and BHT antioxidant samples [184]. Stingless bee honey samples from west Amazonian Ecuador were studied for their physiochemical, chemical and functional properties [185]. Coumarins and flavonoids were determined by densitometric HPTLC: fraxin and bergamotin (76) among coumarins & luteolin, quercitrin and isoramnetin among flavonoids. Among the vitamin E isomers, evaluated by HPLC, the occurrence of only -tocopherol was noted. All these results were compared with those acquired for two multifloral Apis mellifera honeys. DPPH and -carotene bleaching tests were performed, showing interesting values for Ecuadorian honey samples, higher than those shown by multifloral A. mellifera honeys. Ecuadorian Meliponinae honey samples also showed anti-mutagenic activity assayed with Saccharomyces cerevisiae D7 strain, inhibiting back mutation over the entire range of concentrations. The acetone extract of the aerial parts of the plant Salvia cedronella Boiss. was screened for its total phenolic content and flavonoid content [186]. The antioxidant potential was evaluated, in vitro by using three different assays; -carotenelinoleic acid test system for total antioxidant activity, DPPH for free radical scavenging activity, Fe2+ ferrozine test system for metal chelation. A high content of phenolics, potent radical scavenging ability and significant iron chelating effect were observed. However, the inhibition of lipid peroxidation was not significant in -carotenelinoleic acid test system. A phytochemical analysis yielded a new coumarin, 3-methoxy-4hydroxymethylcoumarin, together with p-hydroxyphenylethyl docosanoate, and two triterpenoids, namely oleanolic acid and betulinic acid. Mansonones (mansorin A (77) and mansorin B (78)) isolated from the heartwood of Mansonia gagei were tested for their antifungal activities against Cladosporium cucumerinum and Candida albicans, as well as for their larvicidal activities against Aedes aegypti and radical scavenging properties in a DPPH assay [187].
A variety of bisbenzyl coumarins isolated from the Chinese herbs were tested for antioxidant activity as reflected in the ability to inhibit lipid peroxidation in rat brain and kidney homogenates and rat erythrocyte hemolysis [188]. The pro-oxidant activities of the compounds were assessed by their effects on bleomycininduced DNA damage. The coumarin xanthotoxol (79) exhibited potent antioxidative activity in both lipid peroxidation and hemolysis assays. The coumarins bergapten (80) and angelicin (81) slightly inhibited lipid peroxidation in brain and kidney homogenates. It is worth stressing that the compounds with antioxidant effects in this assay have at least one free aromatic hydroxyl group in their structure. Obviously, the aromatic hydroxyl group is very important for antioxidative effects of the compounds. Many new compounds were isolated from different plants and tested for their antioxidative activity [189-191]. The structureactivity relationships among the identified coumarin analogs suggest that hydroxyl groups at the C-6 and C-7 positions of the coumarin skeleton played an important role in the expression of tyrosinase inhibitory activity. Phytochemical studies on the aerial parts of Prangos uloptera, an endemic Iranian species of the genus Prangos, yielded five coumarins xanthotoxin (82), prangenin (83), scopoletin, deltoin (84) and prangolarin (85) [192]. The structures of these coumarins were elucidated by spectroscopic means, and their antioxidant potential was evaluated by the DPPH assay. Their chemotaxonomic significance was also discussed. In the quantitative DPPH assay, scopoletin was the most active among all compounds, and displayed a significant antioxidant activity. Scopoletin and cleomiscosins A (86), C (87), and D (88), have been isolated from the root bark of Hibiscus syriacus [193]. Scopoletin inhibited monoamine oxidase with moderate IC50 values. Cleomiscosin C showed lipid peroxidation inhibitory activity comparable to vitamin E. The quantification of coumarin derivatives such as scopoletin, 7-hydroxycoumarin and 4-hydroxycoumarin in Noni (Morinda citrifolia) was described by Ikeda et al. [194]. Furthermore, the quenching effects of Noni products and coumarin derivatives on reactive oxygen species were evaluated by a luminol chemiluminescent assay. Both Noni samples and coumarin derivatives dose-dependently quenched ROS such as superoxide (O2-), singlet oxygen (1O2), hydroxyl radical ( OH) and peroxynitrite (ONOO). The EC50 of scopoletin for O2-, 1O2, OH and ONOO were 1.27 0.22 mg/ml, 0.68 0.04 mg/ml, >4.00 mg/ml, and 0.0420.002 mg/ml, respectively. The contribution ratio of scopoletin for ROS in Noni juices was also evaluated. Nahata et al. [195] investigated the effects of Evolvulus alsinoides (EA) on learning and memory in rodents. The ethanol extract of EA and its ethyl acetate and aqueous fractions were evaluated for their memory enhancing properties. The chromatographic analysis of the ethanol extract of Evolvulus alsinoides led to the isolation of a marker
OH
OH
O MeO O O O OH OH MeO 75 O O
OMe OH
OH
O O CH3
MeO OMe 74
O 76
O OMe
OH
77
78
3945
compound, i.e. scopoletin. The presence of scopoletin is reported for the first time in this plant [195]. The presence of this furanocoumarin in EA further strongly support the view of involvement of antioxidant mode of action and the memory potentiating and cognition enhancing activity as reflected by the extracts. The occurrence of scopoletin has been reported in Convulvulus microphyllus and to have memory enhancing properties [196]. Hornick et al. [196] evaluated the effects of scopoletin on learning and memory, on the release of acetylcholine from brain synaptosomes and on long term potentiation in the hippocampus. Scopoletin has also been reported to possess sufficient anticholinergic potential [197]. Compounds, such as scopoletin and rutin are considered as key compounds of noni fruits [198,199]. In in vitro and in vivo (animal) experiments, noni fruit extracts or juice scavenges free radicals, inhibits oxidation of lowdensity lipoproteins, and shows anticancer and anti-inflammatory activity, and stimulates the immune system [194, 200]. Total phenolics, ascorbic acid, and antioxidant capacity of noni (Morinda citrifolia L.) juice and powder and the effects of light on its antioxidant capacity during storage under various conditions were recently determined [201]. The structure-activity relationships of the antioxidant activity of natural coumarins isolated from four Korean medicinal plants ( F. rhynchophylla, A. dahuria, E. daniellii and P. japonicum) and four other coumarins has been recently studied [202]. The free radical scavenging and lipid peroxidation assays revealed that five phenolic coumarins, scopoletin, esculetin, fraxetin, umbelliferone and daphnetin, possessed considerable antioxidant activities. The coumarins having a catechol group showed significant free radical scavenging activity and inhibitory effects on
lipid peroxidation, indicating that the catechol group significantly contributed to the antioxidant activities of coumarins. In contrast, the sugar moiety markedly reduced the activities of coumarin glycosides. The results also demonstrate that the -pyrone ring of coumarins significantly enhanced the capacity of inhibiting oxidative reactions of coumarins [202]. Many other reports on naturally occurring coumarins and their biological role appear in the literature [203,204]. Tumor-modulating effects of coumarin antioxidants also have been studied using carcinogens [205,206]. Nishiyama et al. [205] compared the antioxidative activities of several hydrocoumarins with those of alpha-tocopherol for the oxidation of tetralin and linoleic acid in a homogeneous solution. Hydrocoumarins exhibited a higher induction period than that of alpha-Toc in both systems. 6,7Ddihydroxy-4,4-dimethylhydrocoumarin [(89), refer. Table 1] showed less cytotoxicity toward human fibroblasts than did 2,6-dit-butyl-4-methylphenol. An antioxidant auraptene (7-geranyloxycoumarin) [(90), refer Table 1] isolated from the peel of citrus fruit (Citrus natsudaidai Hayata) has been reported to have chemopreventive effects on chemically induced carcinogenesis [206]. The findings suggested that auraptene may exert a part of its cancer chemopreventive activity through enhancement of immune function. Further, auraptene isolated from the citrus fruit has demonstrated its anti-tumor promoting effect in mouse skin and anticarcinogenesis activities in the rat tongue, esophagus and colon [207]. The first report on the occurrence of auraptene, imperatorin (91) and 7-prenyloxycoumarin (92) in the genus Zosima appeared recently [208]. Zosima absinthifolia belongs to the Apiaceae family and is found in Iran, Turkey, Iraq and different countries of the
Me O
O O 79 Me
O O 80 O O O 81 O O
O OMe 82
O O 83
O O O 84 O O
H3CO O HOH2C O O CH3 O 85 O O 86 OH 87 O O O O O O O HO
OMe OH OMe
OH MeO OMe
O O O O
OH
OMe OMe 88
Kostova et al.
Table 1.
Structures of Coumarins Used as Antioxidants

Compound R3 H H H H H H H H H H H H OH NH2 acetylamino COOH OH OH OH H 2H H R4 H H H H H Me Me Me H Me H Me H H H H H H H OH 2Me H R5 H H H H H H H H H H H H H H H H H H H H H H R6 H H OH OGl H H H OH OMe H OMe H H H H H OMe OH H H OH H R7 H OH OH OH OH OH OH OH OH H OH acetoxy H H H H OH OMe OH H OH OGer R8 H H H H OH OH H H OH H H acetoxy H H H H H H H H H H
1 2 3 4 5 6 10 12 13 16 17 18 23 24 25 26 27 28 29 31 89 90
Coumarin 7-hydroxycoumarin (Umbelliferone) 6,7-dihydroxycoumarin (Esculetin) Esculin 7,8-Dihydroxycoumarin 7,8-dihydroxy-4-methylcoumarin 4-methyl-7-hydroxycoumarin (Mendiaxon) 4-methyl-6,7-dihydroxycoumarin 7,8-dihydroxy-6-methoxycoumarin (Fraxetin) 4-methylcoumarin Scopoletin 7,8-diacetoxy-4-methylcoumarin 3-hydroxycoumarin 3-aminocoumarin 3-acetylaminocoumarin Coumarin-3-carboxylic acid 3-hydroxyscopoletin 3-hydroxyisoscopoletin 3,7-dihydroxycoumarin (3-hydroxyumbelliferone) 4-hydroxycoumarin 6,7-dihydroxy-4,4-dimethylhydrocoumarin Auraptene
Caucasus, Middle East and Central Asia. The fruits are used as food flavoring and as a food spice in Iran. The results [208] indicated that auraptene, imperatorin and 7-prenyloxycoumarin, especially imperatorin exhibited fungi toxic activity against Sclerotinia sclerotiorum, a common plant pathogen. Naturally occurring coumarins possess anti-carcinogenic activities in part by inducing carcinogen-detoxifying enzymes, viz glutathione S-transferase (GST) and/or NAD(P)H quinone oxidoreductase (NQO1). Prince et al. [209] examined a broader range of naturally occurring citrus coumarins for their abilities to activate the antioxidant response element (ARE) and to induce GST and NQO1. Oltipraz, imperatorin, isopimpinellin (93), and auraptene all significantly increased liver cytosolic GST activities in Nrf2 heterozygous mice. Of these compounds, only isopimpinellin significantly increased liver cytosolic NQO1 activities, and this effect was not attenuated in Nrf2( /) mice. These results strongly suggested that imperatorin and auraptene induce murine liver cytosolic GST activities via the Nrf2/ARE mechanism. Structurally diverse compounds can confer resistance to aflatoxin B1 hepatocarcinogenesis. It has been reported that feeding
with a diet containing coumarin can prevent the initiation of Aflatoxin-B1 (AFB1) hepatocarcinogenesis in association with the induction of AFB1-aldehyde reductase (AFAR) and m-class glutathione transferase GSTA5, p-class GSTP1 and NAD(P)H quinine oxido-reductase in rat liver [210,211]. The study showed that coumarin is highly effective at inducing not only AFAR and GSTA5, but also certain other drug-metabolizing enzymes. On the basis of this information, the hypothesis that enzyme induction by coumarin would confer resistance to aflatoxin B1 tumorigenesis was tested in the rat. The results from dietary intervention showed that coumarin consumption does indeed provide protection against initiation of aflatoxin B1 hepatocarcinogenesis. The data presented [210] also reveal the ability of different phytochemicals and synthetic drugs to induce different enzymes in the liver in zone- and sex-specific fashions. Therefore, one of the effective methods to overcome the toxic and carcinogenic effects of AFB1 is to enhance AFB1 metabolism toward its detoxification in humans or animals. There have been some trials of the intervention of chemo-protective agents against AFB1-induced DNA damage and carcinogenesis by inducing class I and II enzymes [212]. Recently, to clarify whether enzymes involved in AFB1 metabolism in pigs respond to
O O O O O
O O
O O 91 O 92 93 O
3947
antioxidant agents, the effect of feeding piglets with diets containing green tea extracts (sunphenon) or coumarin on in vitro AFB1 metabolism by their liver and intestinal tissues was studied [213]. It was concluded that coumarin may affect AFB 1 metabolism towards the enhancement of detoxification through the suppression of P450 enzymes in the liver and intestine, and through the enhancement of GST toward AFB1 in the intestine. The effect of the green tea extracts (sunphenon) was not as prominent as that of coumarins. CONCLUSION Coumarins occupy an important place in the realm of natural products and synthetic organic chemistry. As substitutions can occur at any of the six available sites of their basic molecular moiety, these compounds are extremely variable in structure and activity. This structural diversity leads to coumarins displaying multiple biological properties that promote human health and help reducing the risk of diseases. Of the many actions of coumarins, antioxidant and antiproliferative effects stand out. A large number of structurally novel coumarin derivatives have been reported to show substantial antioxidant and cytotoxic activity in vitro and in vivo. Moreover, the inhibitory action on inflammatory cells appears to surpass any other clinically available compounds. A number of coumarins were found to affect the formation and scavenging of reactive oxygen species, and reactive nitrogen species, exhibiting tissue-protective antioxidant properties, which may include numerous different molecular mechanisms and are probably related to their structural analogy with flavonoids and benzophenones. Such studies are of importance in view of the presence in the human diet of many coumarins and other plant polyphenolics, some of which are attracting interest on account of their antioxidant properties and possible roles in therapy and for food preservation. Given that certain substituents are known to be required or increase their actions, the therapeutic potential of select coumarins is fairly obvious. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. Although some coumarins have already been characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity and define their mechanism of action to achieve new therapeutic drugs. The present review highligts the current progress in the development of coumarin scaffolds for drug discovery as novel antioxidant agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the medical treatment. ABBREVIATIONS RS OS DPPH ODC TBHQ = = = = = reactive species oxidative stress 1,1-diphenyl-2-picryl-hydrazyl ornithine decarboxylase tert-butylhydroquinone 3-(p-(6-phenyl)-1,3,5-hexatrienyl)phenylpropionic acid t-butyl hydroperoxide lactate dehydrogenase alanine transaminase malondialdehyde total antioxidant capacity peripheral blood lymphocytes
LDL AAPH BP DSBP TOH SECCA KHB NK GST AFAR
= = = = = = = = = =
low-density lipoprotein 2,2'-azobis(2-amidinopropane hydrochloride) benzophenone 3,3'-disulfobenzophenonate alpha-tocopherol the succinimidyl ester of coumarin-3-carboxylic acid Krebs-Henseleit bicarbonate natural killer cells glutathione S-transferase Aflatoxin B1 aldehyde reductase
REFERENCES
[1] L J-M, Lin PH, Yao Q, Chen C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med 2010; 14: 840-60. Traykova M, Kostova I. Coumarin Derivatives and Oxidative Streess. Int J Pharm 2005; 1: 29-32. Kostova I. Synthetic and Natural Coumarins as Antioxidants. Mini-Rev Med Chem 2006; 6: 365-74. Giles GI, Jacob C. Reactive sulfur species: an emerging concept in oxidative stress. Biol Chem 2002; 383: 37588. Ames BN, Shigenaga MK, Gold LS. DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 1993; 101: 35-44. Liu RH, Hotchkiss JH. Potential genotoxicity of chronically elevated nitric oxide: a review. Mutat Res 1995; 339: 73-89. Geier DA, Kern JK, Garver CR, et al. A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res 2009; 34: 38693. Geier DA, Kern JK, Garver CR, et al. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci 2009; 280: 101-8. Kostova I. Synthetic and natural coumarins as cytotoxic agents. Curr Med Chem - Anti-Cancer Agents 2005; 5: 29-46. Kostova I. Studying plant derived coumarins for their pharmacological and therapeutic properties as potential anticancer drugs. Expert Opin Drug Discov 2007; 2: 1605-18. Kostova I. Coumarins as Inhibitors of HIV Reverse Transcriptase. Curr HIV Res 2006; 4: 347-63. Kostova I, Mojzis J. Biologically active coumarins as inhibitors of HIV-1 (RT, IN and PR). Fut HIV Ther 2007; 1: 315-29. Rietjens IM, Martena MJ, Boersma MG, Spiegelenberg W, Alink GM. Molecular mechanisms of toxicity of important food-borne phytotoxins. Mol Nutr Food Res 2005; 49: 131-58. Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, Nicolaides DN. Natural and synthetic coumarin derivatives with anti-inflammatory/ antioxidant activities. Curr Pharm Des 2004; 10: 3813-33. Galvano F, Piva A, Ritieni A, Galvano G. Dietary strategies to counteract the effects of mycotoxins: A review. J Food Prot 2001; 64: 120-31. Hayes JD, Pulford DJ, Ellis EM, McLeod R, James RF, Seidegard J, Mosialou E, Jernstrom B, Neal GE. Regulation of rat glutathione S-transferase A5 by cancer chemopreventive agents: mechanisms of inducible resistance to aflatoxin B1. Chem Biol Inter 1998; 111-112: 51-67. Riveiro ME, De Kimpe N, Moglioni A, Vazquez R, Monczor F, Shayo C, Davio C. Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives. Curr Med Chem 2010; 17; 1325-38. Foti M, Piattelli M, Baratta MT, Ruberto G. Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure-Activity Relationship. J Agric Food Chem 1996; 44: 497-501. Yu W, Zai ZQ, Liu ZL. Antioxidant effect of coumarin derivatives on free radical initiated and photosensitized peroxidation of linoleic acid in micelles. J Chem Soc Perkin Trans 1999; 2: 969-74. Zhang H-Y, Wang L-F. Theoretical elucidation of structureactivity relationship for coumarins to scavenge peroxyl radical. J Mol Str THEOCHEM 2004; 673: 199-202. Chang WS, Chiang HC. Structureactivity relationship of coumarins in xanthine oxidase inhibition. Anticancer Res 1995; 15: 1969-73. Ferrari AM, Sgobba M, Gamberini MC, Rastelli G. Relationship between quantum-chemical descriptors of proton dissociation and experimental acidity constants of various hydroxylated coumarins. Identification of the biologically active species for xanthine oxidase inhibition. Eur J Med Chem 2007; 42: 1028-31. Lin H-C, Tsai S-H, Chen C-S, Chang Y-C, Lee C-M, Lai Z-Y, Lin C-M. Structureactivity relationship of coumarin derivatives on xanthine oxidaseinhibiting and free radical-scavenging activities. Biochem Pharm 2008; 75: 1416-25.
[2] [3] [4] [5]
[6] [7] [8] [9] [10]
[11] [12] [13]
[14]
[15] [16]
[17]
[18]
[19]
[20]
DPH-PA = t-BHP LDH ALT MDA TAC PBL = = = = = =
[21] [22]
[23]
3948 Current Medicinal Chemistry, 2011 Vol. 18, No. 25 [24] Ramesh B, Viswanathan P, Pugalendi KV. Protective effect of Umbelliferone on membranous fatty acid composition in streptozotocin-induced diabetic rats. Eur J Pharm 2007; 566: 231-9. Ramesh B, Pugalendi KV. Antihyperglycaemic effect of Umbelliferone in STZ-diabetic rats. J Med Food 2006; 9: 562-6. Ramesh B, Pugalendi KV. Antihyperlipidemic and antidiabetic effects of Umbelliferone in streptozotocin diabetic rats. Yale J Biol Med 2005; 78: 189-96. Ramesh B, Pugalendi KV. Impact of Umbelliferone on erythrocyte redox status in STZ-diabetic rats. Yale J Biol Med 2005; 78: 133-38. Ramesh B, Pugalendi KV. Effect of Umbelliferone on cellular redox status in STZ-diabetic rats. W W W J Biol 2005; 9: 1. Ramesh B, Pugalendi KV. Antioxidant role of Umbelliferone in STZdiabetic rats. Life Sci 2006; 79: 306-10. Yuce B, Danis O, Ogan A, Sener G, Bulut M, Yarat A. Antioxidative and lipid lowering effects of 7,8-dihydroxy-3- (4-methylphenyl) coumarin in hyperlipidemic rats. Arzneim-Forsch Drug Res 2009; 59: 129-34. Madhavan GR, Balraju V, Mallesham B, Chakrabarti R, Lohray VB. Novel coumarin derivatives of heterocyclic compounds as lipid-lowering agents. Bioorg Med Chem Lett 2003; 13: 2547-51. enol FS, Yilmaz G, ener B, Koyuncu M, Orhan I. Preliminary screening of acetylcholinesterase inhibitory and antioxidant activities of Anatolian Heptaptera species. Pharm Biol 2010; 48: 337-41. Orhan I, Tosun F, ener B. Coumarin, anthroquinone, and stilbene derivatives with anticholinesterase activity. Z Naturforsch 2008; 63c: 366-70. Kontogiorgis CA, Hadjipavlou-Litina D. Biological evaluation of several coumarin derivatives designed as possible anti-inflammatory/antioxidants agents. J. Enzyme Inhib Med Chem 2003; 18: 63-69. Khan N, Sharma S, Sultana S. Attenuation of potassium bromate-induced nephrotoxicity by coumarin (1,2-benzopyrone) in Wistar rats: chemoprevention against free radical-mediated renal oxidative stress and tumor promotion response. Redox Rep 2004; 9: 19-28. Arora A, Nair MG, Strasburg GM. Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system. Free Radic Biol Med 1998; 24: 1355-63. Baccard N, Mechiche H, Nazeyrollas P, Manot L, Lamiable D, Devillier P, Millart H. Effects of 7-hydroxycoumarin (umbelliferone) on isolated perfused and ischemic-reperfused rat heart. Arzneim Forsch 2000; 50: 890-6. Cooke D, O'Kennedy R. Comparison of the tetrazolium salt assay for succinate dehydrogenase with the cytosensor microphysiometer in the assessment of compound toxicities. Anal Biochem 1999; 274: 188-94. Yousef JM, Saddiq AA. Some Microbiological, Biochemical and Histological Investigations on Pendant Coumarin Thiocarbohydrazone and its Cobalt (II) Complex in Rats. Int J Microbiol Res 2010; 1: 1-13. Lin WL, Wang CJ, Tsai YY, Liu CL, Hwang JM, Tseng TH. Inhibitory effect of esculetin on oxidative damage induced by t-butyl hydroperoxide in rat liver. Arch Toxicol 2000; 74; 467-72. Pay M, Halliwell B, Hoult JRS. Interactions of a series of coumarins with reactive oxygen species. Scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochem Pharmacol 1992; 44: 205-14. Kaneko T, Tahara S, Takabayashi F. Suppression of lipid hydroperoxideinduced oxidative damage to cellular DNA by esculetin. Biol Pharm Bull 2003; 26: 840-4. Leung KN, Leung PY, Kong LP, Leung PK. Immunomodulatory effects of esculetin (6,7-dihydroxycoumarin) on murine lymphocytes and peritoneal macrophages. Mol Immunol 2005; 2: 181-8. Kuo HC, Lee HJ, Hu CC, Shun HI, Tseng TH. Enhancement of esculetin on taxol-induced apoptosis inhumanhepatomaHepG2cells. Toxicol Appl Pharm 2006; 210: 55-62. Kok SH, Yeh CC, Chen ML, Kuo MYP. Esculetin enhances TRAIL-induced apoptosis through DR5 upregulation in human oral cancer SAS cells. Oral Oncol 2009; 45: 1067-72. Mabalirajan U, Dinda AK, Sharma SK, Ghosh B. Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model. J Immunol 2009; 183: 2059-67. Hoult JRS, Forder RA, Heras B, Lobo I, Pay M. Inhibitory activity of a series of coumarins on leukocyte eicosanoid generation. Agents Actions 1994; 42: 44-9. Okada Y, Miyauchi N, Suzuki K, Kobayashi T, Tsutsui C, Mayuzumi K, Nishibe S, Okuyama T. Inhibitory effect of coumarin and flavonoids derivates on bovine reductase and rabbit platelet aggregation. Chem Pharm Bull 1995; 43: 1385-7. Yamada H, Watanabe K, Saito T, Hayashi H, Niitani Y, KiKuchi T, Ito A, Fujikawa K, Lohmander LS. Esculetin (dihydroxycoumarin) inhibits the production of matrix metalloproteinases in cartilage explants, and oral administration of its prodrug, CPA-926, suppresses cartilage destruction in rabbit experimental osteoarthritis. J Rheumatol 1999; 26: 654-62. Watanabe K, Ito A, Sato T, Hayashi H, Niitani Y. Esculetin suppresses proteoglycan metabolism by inhibiting the production of matriz metalloproteinases in rabbit chondrocytes. Eur J Pharmacol 1999; 16: 297305. Wang CJ, Hsieh YJ, Chu CY, Lin YL, Tseng TH. Inhibition of cell cycle progression in human leukemia HL-60 cells by esculetin. Cancer Lett 2002; 183: 163-8. [52]
Kostova et al. Hu Y, Chen X, Duan H, Hu Y, Mu X. Chinese herbal medicinal ingredients inhibit secretion of IL-6, IL-8, E-selectin and TXB2 in LPS-induced rat intestinal microvascular endothelial cells. Immunopharmacol Immunotoxicol 2009; 31: 550-5. Bettini V, Cal L, Cantaro S, Martino R, Munari L, Salvatico E, Ton P, Liberation of prostaglandin-like substances from the isolated coronary artery in presence of angiotensin and of 4-methylesculetin. Acta Vitaminol Enzymol 1985; 7: 25767. Hajime M, Shuichi Y, Makoto N, Masanori Y, Ikuko K, Atsushi K, Mutsuo S, Keiichi T. Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. Int J Cancer 2007; 120: 2704-9. Witaicenis A, Seito LN, Di Stasi LC. Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chem Biol Inter 2010; 186: 211-8. Neichi T, Koshihara Y, Mutora SI. Inhibitory effects of esculetin on lipoxygenase and leukotriene biosynthesis. Biochim Biophys Acta 1983; 753: 130-2. Loggia RD, Ragazzi E, Tubaro A, Fassina G, Vertua R. Anti-inflammatory activity of benzopyrone that are inhibitors of cyclo- and lipoxygenase. Pharmacol Res Commun 1988; 20: 91-4. Sharma SD, Rajor HK, Chopra S, Sharma RK. Studies on structure activity relationship of some dihydroxy-4-methylcoumarin antioxidants based on their interaction with Fe(III) and ADP. BioMetals 2005; 18: 143-54. Luchini AC, Rodrigues-Orsi P, Cestari SH, Seito LN, Witaicenis A, Pellizzon CH, Di Stasi LC. Intestinal anti-inflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzenosulphonic acid model of rat colitis. Biol Pharm Bull 2008; 37: 1343-50. Sekiya K, Okuda H, Arichi S. Selective inhibition of platelet lipoxygenase by esculetin. Biochim Biophys Acta 1982; 713: 68-72. Zhao J, Liu X J, Ma JW, Zheng RL. DNA damage in healthy term neonate. Early Hum Dev 2004; 77: 89-98. Liu GA, Zheng RL. Protection against damaged DNA in the single cell by polyphenols. Pharmazie 2002; 57: 852-4. Kaneko T, Baba N, Matsuo M. Protection of coumarins against linoleic acid hydroperoxide-induced cytotoxicity. Chem Biol Inter 2003; 142: 239-54. von Kruedener S, Schneider W, Elstner EF. Effects of extracts from Populus tremula L., solidago virgaurea L. and Fraxinus excelsior L. on various myeloperoxidase systems. Arzn Forsch 1996; 46: 809-14. Liu R, Sun Q, Sun A, Cui J. Isolation and purification of coumarin compounds from Cortex fraxinus by high-speed countercurrent chromatography. J Chromat A 2005; 1072: 195-9. Wu C-R, Huang M-Y, Lin Y-T, Ju H-Y, Ching H. Antioxidant properties of Cortex Fraxini and its simple coumarins. Food Chem 2007; 104: 1464-71. Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structureactivity relationships. J Nutr Biochem 2002; 13: 572-84. Liu ZQ, Yu W, Liu ZL. Antioxidative and prooxidative effects of coumarin derivatives on free radical initiated and photosensitized peroxidation of human low-density lipoprotein. Chem Phys Lipids 1999; 103: 125-35. Pemysl M, Mackov K, Zatloukalov L, ehkov Z, Singh BK, Prasad AK, Parmar VS, Jahod L, Hrdina R, Saso L. In vitro interactions of coumarins with iron. Biochimie 2010; Article in Press. Fort DJ, Stover EL, Propst T, Hull MA, Bantle JA. Evaluation of the developmental toxicities of coumarin, 4-hydroxycoumarin, and 7hydroxycoumarin using FETAX. Drug Chem Toxicol 1998; 21: 15-26. Pedersen JZ, Oliveira C, Incerpi S, et al. Antioxidant activity of 4methylcoumarins. J Pharm Pharmacol 2007; 59: 1721-8. Kimura Y, Okuda H, Arichi S, Bada K, Kozawa M. Inhibition of the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid from arachidonic acid in polymorphonuclear leukocytes by various coumarins. Biochem Biophys Acta 1985; 834: 224-9. Raj HG, Sharma SK, Garg BS, Parmar VS, Jain SC, Goel S, Tyagi YK, Singh A, Olsen CE, Wengel J. Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part 3: A novel mechanism for the inhibition of biological membrane lipid peroxidation by dioxygenated 4-methylcoumarins mediated by the formation of a stable ADP-Fe-inhibitor mixed ligand complex. Bioorg Med Chem 1998; 6: 2205-12. Morel I, Lescoat G, Cogrel P, et al. Antioxidant and ironchelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 1993; 45: 13-9. Porter JB, Huehns ER, Hider RC. In: Hershko C; Ed. Baillieres Clinical haematology London: Bailliere Tindall 1989; Vol 2: pp. 257-92. Raj HG, Parmar VS, Jain SC, Goel S, Poonam H, Malhotra S, Singh A, Olsen CE, Wengel J. Mechanism of biochemical action of substituted 4methylbenzopyran-2-ones. Part I: Dioxygenated 4-methyl coumarins as superb antioxidant and radical scavenging agents. Bioorg Med Chem 1998; 6: 833-9. Raj HG, Parmar VS, Jain SC, Priyadarsini KI, Mittal JP, Goel S, Das SK, Sharma SK, Olsen CE, Wengel J. Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part 5: Pulse radiolysis studies on the antioxidant action of 7,8-diacetoxy-4-methylcoumarin. Bioorg Med Chem 1999; 7: 2091-4.
avar S, Kova F, Maksimovi M. Synthesis and antioxidant activity of selected 4-methylcoumarins. Food Chem 2009; 117: 135-42.
[25] [26]
[53]
[27] [28] [29] [30]
[54]
[55]
[56]
[31]
[57]
[32]
[58]
[33] [34]
[59]
[35]
[60] [61] [62] [63] [64]
[36]
[37]
[38]
[65]
[39]
[66] [67]
[40]
[41]
[68]
[42]
[69]
[43]
[70]
[44]
[71] [72]
[45]
[46]
[73]
[47]
[48]
[74]
[75] [76]
[49]
[50]
[77]
[51]
[78]
Coumarins as Antioxidants [79] Kumar A, Singh BK, Tyagi R, et al., Mechanism of biochemical action of substituted 4-methylcoumarins. Part 11: comparison of the specificities of acetoxy derivatives of 4-methylcoumarin and 4-phenylcoumarin to acetoxy coumarins: protein transacetalase. Bioorg Med Chem 2005; 13: 4300-5. Vassallo JD, Hicks SM, Born SL, Daston GP. Roles for epoxidation and detoxification of coumarin in determining species differences in clara cell toxicity. Toxicol Sci 2004; 82: 26-33. Morabito G, Trombetta D, Brajendra KS, Prasad AK, Parmar SV, Naccari C, Mancari F, Saija A, Cristani M, Firuzi O, Saso L. Antioxidant properties of 4-methylcoumarins in in vitro cell-free systems. Biochimie 2010; Article in Press. Kancheva VD, Saso L, Boranova PV, Khan A, Saroj MK, Pandey MK, Malhotra S, Nechev JZ, Sharma SK, Prasad AK, Georgieva MB, Joseph C, DePass AL, Rastogi RC, Parmar VS. Structure-activity relationship of dihydroxy-4-methylcoumarins as powerful antioxidants: Correlation between experimental & theoretical data and synergistic effect. Biochimie 2010; Article in Press. Kancheva V. Phenolic antioxidants: antiradical and antioxidant activity: comparable study. Eur J Lipid Sci Technol 2009; 111: 1072-89. Petrucci R, Saso L, Kumar V, Prasad AK, Malhotra SV, Parmar VS, Marrosu G. A spectroelectrochemical and chemical study on oxidation of 7,8dihydroxy-4-methylcoumarin (DHMC) and some related compounds in aprotic medium. Biochimie 2010; Article in Press. Lake BG. Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food Chem Toxicol 1999; 37: 423-53. Rehakova Z, Koleckar V, Cervenka F, Jahodar L, Saso L, Opleatal L, et al. DPPH radical scavenging activity of several naturally occurring coumarins and their synthesized analogs measured by the SIA method. Toxicol Mech Meth 2008; 18: 413-8. Natella F, Lorrain B, Prasad AK, Parmar VS, Saso L, Scaccini C. 4Methylcoumarins as antioxidants: Scavenging of peroxyl radicals and inhibition of human low-density lipoprotein oxidation. Biochimie, 2010; Article in Press. Beillerot A, Domnguez J-CR, Kirsch G, Bagrel D. Synthesis and protective effects of coumarin derivatives against oxidative stress induced by doxorubicin. Bioorg Med Chem Lett 2008; 18: 1102-5. Takemura G, Fujiwara H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 2007; 49: 33052. Goel A, Prasad AK, Parmar VS, Ghosh B, Saini N. Apoptogenic effect of 7,8-diacetoxy-4-methylcoumarin and 7,8-diacetoxy-4-methylthiocoumarin in human lung adenocarcinoma cell line: Role of NF-B, Akt, ROS and MAP kinase pathway. Chem Biol Inter 2009; 179: 363-74. Goel A, Prasad AK, Parmar VS, Ghosh B, Saini N. 7,8,Dihydroxy-4methylcoumarin induces apoptosis of human lung adenocarcinoma by ROSindependent mitochondrial pathway through inhibition of ERK/MAPK signaling, FEBS Lett 2007; 581: 2447-54. Liang S-C, Ge G-B, Liu H-X, Zhang Y-Y, Wang L-M, Zhang J-W, Yin L, Li W, Fang Z-Z, Wu J-J, Li G-H, Yang L. Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Daphnetin. Drug Metab Dispos 2010; 38: 973-80. Finn GJ, Creaven BS, Egan DA. Daphnetin induced differentiation of human renal carcinoma cells and its mediation by p38 mitogen-activated protein kinase. Biochem Pharmacol 2004; 67: 1779-88. Huang HC, LaiMW,Wang HR, Chung YL, Hsieh LM, et al. Antiproliferative effect of esculetin on vascular smooth-muscle cells-possible roles of signaltransduction pathways. Eur J Pharmacol 1993; 237: 39-44. Huang W-Y; Cai Y-Z; Zhang Y. Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants: Potential Use for Cancer Prevention. Nutr Cancer 2010; 62: 1-20. Cai Y, Luo Q, Sun M, Corke H. Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer. Life Sci 2004; 74: 2157-84. Fernandez-Puntero B, Barroso I, Iglesias I, Benedi J, Villar A. Antioxidant activity of Fraxetin: in vivo and ex vivo parameters in normal situation versus induced stress. Biol Pharm Bull 2001; 24: 777-84. Frimer AA, Marks V, Gilinsky-Sharon P. On the reactions of superoxide with keto enols, aci-reductones and ascorbic acid derivatives. Free Radic Res Commun 1991; 12: 93-8. Vladimirov IA, Parfenov EA, Epanchintseva OM, Smirnov LD. Antiradical activity of 3-substituted coumarins and their effect on iron-dependent chemiluminescence. Biull Eksp Biol Med 1991; 112: 358-60. Aihara K, Higuchi T, Hirobe M. 3-Hydroxycoumarins: first direct preparation from coumarins using a Cu2(+)-ascorbic acid-O2 system, and their potent bioactivities. Biochem Biophys Res Commun 1990; 168: 169-75. Nicolaides DN, Gautam DR, Litinas KE, Hadjipavlou-Litina DJ, Fylaktakidou KC. Synthesis and evaluation of the antioxidant and antiinflammatory activities of some benzo[1]khellactone derivatives and analogues. Eur J Med Chem 2004; 39: 323-32. Fylaktakidou KC, Gautam DR, Hadjipavlou-Litina DJ, Kontogiorgis CA, Litinas KE, Nicolaides DN. Reactions of 4-methylchromene-2,7,8-trione with phosphonium ylides. Synthesis and evaluation of fused 1,3dioxolaneocoumarins as antioxidants and anti-inflammatories. J Chem Soc Perkin Trans 2001; 1: 3073-9. [103]
3949
[104]
[80]
[105]
[81]
[106]
[82]
[107]
[108]
[83] [84]
[109]
[110]
[85] [86]
[111]
[87]
[112]
[113]
[88]
[114] [115]
[89]
[90]
[116]
[91]
[117]
[92]
[118]
[93]
[119]
[94]
[120]
[95]
[121]
[96]
[122]
[97]
[123]
[98]
[124]
[99]
[125]
[100]
[126]
[101]
[127]
[102]
[128]
Chakrabarti S, Makrigiorgos GM, O'Brien K, Bump E, Kassis AI. Measurement of hydroxyl radicals catalyzed in the immediate vicinity of DNA by metal-bleomycin complexes. Free Radic Biol Med 1996; 20: 777-83. Roussaki M, Kontogiorgis CA, Hadjipavlou-Litina D, Hamilakis S, Detsi A. A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant and lipoxygenase inhibitory activity. Bioorg Med Chem Lett 2010; 20: 3889-92. Kabeya LM, de Marchi AA, Kanashiro A, Lopes NP, da Silva CHTP, Pupo MT, Lucisano-Valima YM. Inhibition of horseradish peroxidase catalytic activity by new 3-phenylcoumarin derivatives: synthesis and structureactivity relationships. Bioorg Med Chem 2007; 15: 1516-24. Singh OM, Devi NS, Thokchom DS, Sharma GJ. Novel 3alkanoyl/aroyl/heteroaroyl-2H-chromene-2-thiones: Synthesis and evaluation of their antioxidant activities. Eur J Med Chem 2010; 45: 2250-7. Nazemiyeh H, Kazemi EM, Zare K, Jodari M, Nahar L, Sarker SD. Free radical scavengers from the aerial parts of Euphorbia petiolata . J Nat Med 2010; 64: 187-90. Kennedy SH, Manevich Y, Biaglow J. Benzoyl peroxide acts as a promoter of radiation induced malignant transformation in vitro. Biochem Biophys Res Commun 1995; 212: 118-25. Andrievsky GV, Bruskov VI, Tykhomyrov AA, Gudkov SV. Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vitro and in vivo. Free Rad Biol Med 2009; 47: 786-93. Gudkov SV, Shtarkman IN, Smirnova VS, Chernikov AV, Bruskov VI. Guanosine and inosine display antioxidant activity, protect DNA in vitro from oxidative damage induced by reactive oxygen species, and serve as radioprotectors in mice. Radiat Res 2006; 165: 53845. Sato M, Maulik G, Ray PS, Bagchi D, Das DK. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury. J Mol Cell Cardiol 1999; 31: 1289-97. Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. Bioorg Med Chem Lett 2004; 14: 611-4. Kontogiorgis CA, Savvoglou K, Hadjipavlou-Litina DJ. Antiinflammatory and antioxidant evaluation of novel coumarin derivatives. J Enz Inhib Med Chem 2006; 21: 21-9. Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and Antiinflammatory Activity of Coumarin Derivatives. J Med Chem 2005; 48: 6400-8. Detsi A, Bouloumbasi D, Prousis KC, Koufaki M, Athanasellis G, Melagraki G, Afantitis A, Igglessi-Markopoulou O, Kontogiorgis C, Hadjipavlou-Litina DJ. Design and synthesis of novel quinolinone-3-aminoamides and their lipoic acid adducts as antioxidant and anti-inflammatory agents. J Med Chem 2007; 50: 2450-8. Melagraki G, Afantitis A, Igglessi-Markopoulou O, Detsi A, Koufaki M, Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adducts. Eur J Med Chem 2009; 44: 3020-6. Hamdi N, Puerta MC, Valerga P. Synthesis, structure, antimicrobial and antioxidant investigations of dicoumarol and related compounds. Eur J Med Chem 2008; 43: 2541-8. Hamdi N, Saoud M, Romerosa A. Synthesis, spectroscopic and antibacterial investigations of new hydroxy ethers and heterocyclic coumarin derivatives. J Het Chem 2008; 45: 1835-42. Hamdi N, Bouabdallah F, Romerosa A, Benhassen R. Expedious synthesis for , -unsaturated coumarin derivatives using boran chelates: A novel class of potential antibacterial and antioxidant agents. Compt Rend Chim, 2010; Article in Press. Kancheva VD, Boranova PV, Nechev JT, Manolov I. Structureactivity relationships of new 4-hydroxy- bis-coumarins as radical scavengers and chain-breaking antioxidants. Biochimie, 2010; Article in Press. Stanchev S, Hadjimitova V, Traykov T, Boyanov T, Manolov I. Investigation of the antioxidant properties of some new 4-hydroxycoumarin derivatives. Eur J Med Chem 2009; 44: 3077-82. Kirkiachiarian S, Bakhchinian R, Chidiak H, Mazmanian M, Planche C. [Free radical scavenging activity of 4-hydroxycoumarin derivatives]. Ann Pharm Fr 1999; 57: 251-4. Kaneko T, Baba N, Matsuo M. Structure-activity relationship of antioxidants for inhibitors of linoleic acid hydroperoxide-induced toxicity in cultured human umbilical vein endothelial cells. Cytotechnology 2001; 35: 4355. Vukovic N, Sukdolak S, Solujic S, Niciforovic N. Substituted imino and amino derivatives of 4-hydroxycoumarins as novel antioxidant, antibacterial and antifungal agents: Synthesis and in vitro assessments. Food Chem 2010; 120: 1011-8. Vukovic N, Sukdolak S, Solujic S, Niciforovic N.. An efficient synthesis and antioxidant properties of novel imino and amino derivatives of 4-hydroxy coumarins. Arch Pharm Res 2010; 33: 5-15. Panteleon V, Kostakis IK, Marakos P, Pouli N, Andreadou I. Synthesis and free radical scavenging activity of some new spiropyranocoumarins. Bioorg Med Chem Lett 2008; 18: 5781-4. Sashidhara KV, Rosaiah JN, Kumar A, Bhatia G, Khanna AK. Synthesis of novel benzocoumarin derivatives as lipid lowering agents. Bioorg Med Chem Lett 2010; 20: 3065-9. Sashidhara KV, Kumar A, Kumar M, Sonkar R, Bhatia G, Khanna AK. Novel coumarin derivatives as potential antidyslipidemic agents. Bioorg Med Chem Lett 2010; 20: 4248-51.
3950 Current Medicinal Chemistry, 2011 Vol. 18, No. 25 [129] Tyagi YK, Kumar A, Raj HG, Vohra P, Gupta G, Kumari R, Kumar P, Gupta RK. Synthesis of novel amino and acetyl amino-4-methylcoumarins and evaluation of their antioxidant activity. Eur J Med Chem 2005; 40: 41320. Parmar VS, Kumar A, Prasad AK, Singh SK, Kumar N, Raj HG, et al. Synthesis of E- and Z-pyrazolylacrylonitriles and their evaluation as novel antioxidants. Bioorg Med Chem 1999; 7: 1425-36. Sashidhara KV, Rosaiah JN, Bhatia G, Saxena JK. Novel keto-enamine Schiffs bases from 7-hydroxy-4-methyl-2-oxo-2H-benzo[h] chromene-8,10dicarbaldehyde as potential antidyslipidemic and antioxidant agents. Eur J Med Chem 2008; 43: 2592-6. Sashidhara KV, Rosaiah JN, Narender T. Highly efficient and regioselective synthesis of keto-enamine Schiff bases from 7-hydroxy-4-methyl-2-oxo-2H benzo[h] chromene-8,10-dicarbaldehyde and 1-hydroxynaphthalene-2,4dicarbaldehyde. Tetrahedron Lett 2007; 48: 1699702. Sashidhara KV, Rosaiah JN, Kumar A. Unusual Reaction of 6-Formyl-2oxo-2H-benzo[h]chromene-3-carboxylic Acid Ethyl Ester with Aliphatic Amines. Synth Commun 2010; 40: 21-8. Sashidhara KV, Rosaiah JN. Vicarious nucleophilic substitution in enamine derivatives of 1-hydroxylnaphthalene-2,4-dicarbaldehyde. Tetrahedron Lett 2007; 48: 3285-7. Gacche RN, Gond DS, Dhole NA, Dawane BS. Coumarin Schiff-bases: As Antioxidant and Possibly Anti-inflammatory Agents. J Enz Inhib Med Chem 2006; 21: 157-61. Nicolaides DN, Fylaktakidou KC, Litinas KE, Hadjipavlou-Litina DJ. Synthesis and Biological Evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin -4-yl)-1,2,4-oxadiazole Derivatives. Eur J Med Chem 1998; 33: 715-24. Jeong T-S, Kim KS, Kim J-R, Cho K-H, Lee S, Lee WS. Novel 3,5-diaryl pyrazolines and pyrazole as low-density lipoprotein (LDL) oxidation inhibitor. Bioorg Med Chem Lett 2004; 14: 2719-23. Manojkumar P, Ravi TK, Gopalakrishnan S. Antioxidant and antibacterial studies of arylazopyrazoles and arylhydrazonopyrazolones containing coumarin moiety. Eur J Med Chem 2009; 44: 4690-4. Symeonidis T, Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE. Synthesis and anti-inflammatory evaluation of novel angularly or linearly fused coumarins. Eur J Med Chem 2009; 44: 5012-7. Belluti F, Fontana G, Bo LD, Carenini N, Giommarelli C, Zunino F. Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg Med Chem 2010; 18: 3543-50. Kostova I, Traykova M. Cerium(III) and neodymium(III) complexes as scavengers of X/XO-derived superoxide radical. Med Chem 2006; 2: 463-70. Vladimirov IA, Parfenov EA, Epanchintseva OM, Sharov VS, Dremina ES, Smirnov LD. [Antiradical activity of complex copper compounds (II) on coumarin ligand base]. Biull Eksp Biol Med 1992; 113: 479-81. Datta P, Mukhopadhyay AP, Manna P, Tiekink ERT, Sil PC, Sinha C. Structure, Photophysics, Electrochemistry, DFT Calculation, In-Vitro Antioxidant Activity of Coumarin Schiff Base Complexes of Group 6 Metal Carbonyls. J Inorg Biochem 2010; Article in Press. Hoult JR, Paya M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacol 1996; 27: 713-22. Fresco P, Borges F, Diniz C, Marques MPM. New insights on the anticancer properties of dietary polyphenols. Med Res Rev 2006; 26: 74766. Cai YZ, Sun M, Xing J, Luo Q, Corke H. Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci 2006; 78: 287288. Surveswaran S, Cai YZ, Corke H, Sun M: Systematic evaluation of natural phenolic antioxidants from 133 Indian medicinal plants. Food Chem 2007; 102: 93853. Cai YZ, Sun M, Corke H. Antioxidant activity of betalains from plants of the Amaranthaceae. J Agric Food Chem 2003; 51: 228894. Sonnenberg H, Kaloga M, Eisenbach N, Fromming KK. Isolation and characterization of an angular-type dihydropyranocoumaringlycoside from the fruits of Ammi visnaga (L) Lam (Apiaceae). Zeitschrift Natur C-A J BioSci 1995; 50: 72931. Shan B, Cai YZ, Sun M, Corke H. Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem 2005; 53: 774959. Oh H, Ko E-K, Jun J-Y, Oh M-H, Park S-U, Kang K-H, Lee H-S, Kim Y-C. Hepatoprotective and Free Radical Scavenging Activities of Prenylflavonoids, Coumarin, and Stilbene from Morus alba. Planta Med 2002; 68: 932-4. Akak CM, Djama CM, Nkengfack AE, Tu P-F, Lei L-D. New coumarin glycosides from the leaves of Diospyros crassiflora (Hiern). Fitoterapia 2010; Article in Press. Koleckar V, Opletal L, Brojerova E, Rehakova Z, Cervenka F, Kubikova K, Kuca K, Jun D, Polasek M, Kunes J, Jahodar L. Evaluation of natural antioxidants of Leuzea carthamoides as a result of a screening study of 88 plant extracts from the European Asteraceae and Cichoriaceae. J Enzyme Inhib Med Chem 2008; 23: 218-24. David JP, Meira M, David JM, Brando HN, Branco A, de Ftima Agra M, Barbosa MRV, de Queiroz LP, Giulietti AM. Radical scavenging, antioxidant and cytotoxic activity of Brazilian Caatinga plants. Fitoterapia 2007; 78: 215-18. [155]
Kostova et al. Kong Y, Fu Y-J, Zu Y-G, Chang F-R, Chen Y-H, Liu X-L, Stelten J, Schiebel H-M. Cajanuslactone, a new coumarin with anti-bacterial activity from pigeon pea [Cajanus cajan (L.) Millsp.] leaves. Food Chem 2010; 121: 11505. Fu Y, Zu Y, Liu W, Efferth T, Zhang N, Liu X, et al. Optimization of luteolin separation from pigeonpea [Cajanus cajan (L.) Millsp.] leaves by macroporous resins. J Chromat A 2006; 1137: 14552. Fu Y, Zu Y, Liu W, Zhang L, Tong M, Efferth T, et al. Determination of vitexin and isovitexin in pigeonpea using ultrasonic extraction followed by LCMS. J Sep Sci 2008; 31: 26875. Wu N, Fu K, Fu YJ, Zu YG, Chang FR, Chen YH, et al. Antioxidant activities of extracts and main components of pigeonpea [Cajanus cajan (L.) Millsp.] leaves. Molecules 2009; 14: 103243. Mohammadi M, Yousefi M, Habibi Z, Shafiee A. Two New Coumarins from the Chloroform Extract of Angelica Urumiensis from Iran. Chem Pharm Bull 2010; 58: 546. Lee S, Kang SS, Shin KS. Coumarins and pyrimidine from Angelica gigas roots. Nat Product Sci 2002; 8: 58-61. Ahn M-J, Lee MK, Kim YC, Sung SH. The simultaneous determination of coumarins in Angelica gigas root by high performance liquid chromatography-diode array detector coupled with electrospray ionization/mass spectrometry. J Pharm Biomed Anal 2008; 46: 258-66. Kang SY, Lee KY, Sung SH, Kim YC. Four new neuroprotective dihydropyranocoumarins from Angelica gigas. J Nat Prod 2005; 68: 56-9. Lee S, Shin DS, Kim JS, Oh KB, Kang SS. Antibacterial coumarins from Angelica gigas roots. Arch Pharm Res 2003; 26: 449-52. Jung MH, Lee SH, Ahn E-M, Lee YM. Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2signaling pathway. Carcinogenesis 2009; 30: 65561. Ahn KS, Sim WS, Kim IH. Decursin: a cytotoxic agent and protein kinase C activator from the root of Angelica gigas. Planta Med 1996; 62: 79. Ahn KS, Sim WS, Lee IK, Seu YB, Kim IH. Decursinol angelate: a cytotoxic and protein kinase C activating agent from the root of Angelica gigas. Planta Med 1997; 63: 3601. Lee S, Lee YS, Jung SH, Shin KH, Kim BK, Kang SS. Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res 2003; 26: 72730. Jiang C, Guo J, Wang Z, Xiao B, Lee H-J, Lee E-O, Kim S-H, Lu J. Decursin and decursinol angelate inhibit estrogenstimulated and estrogenindependent growth and survival of breast cancer cells. Breast Cancer Res 2007; 9: R77. Kim K-Y, Lee S, Cha C-J. Biotransformation of Plant Secondary Metabolite Decursin by Mycobacterium sp. PYR1001. J Agric Food Chem 2010; 58: 29314. Torres R, Faini F, Modak B, Urbina F, Labb C, Guerrero J. Antioxidant activity of coumarins and flavonols from the resinous exudate of Haplopappus multifolius. Phytochem 2006; 67: 984-7. Yang H , Protiva P, Gil RR, Jiang B, Baggett S, Basile MJ, Reynertson KA, Weinstein IB, Kennelly EJ. Antioxidant and Cytotoxic Isoprenylated Coumarins from Mammea Americana. Planta Med 2005; 71: 852-60. Prasad KN, Xie H, Hao J, Yang B, Qiu S, Wei X, Chen F, Jiang Y. Antioxidant and anticancer activities of 8-hydroxypsoralen isolated from wampee [Clausena lansium (Lour.) Skeels] peel. Food Chem 2010; 118: 62-6. Srividya AR, Dhanabal SP, Misra VK, Suja G. Antioxidant and antimicrobial activity of Alpinia officinarum. Ind J Pharmac Sci 2010; 72: 145-8. Zhu Y, Zhang L-X, Zhao Y, Huang G-D. Unusual sesquiterpene lactones with a new carbon skeleton and new acetylenes from Ajania przewalskii. Food Chem 2010; 118: 228-38. Ryu YB, Kim JH, Park S-J, Chang JS, Rho M-C, Bae K-H, Park KH, Lee WS. Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis. Bioorg Med Chem Lett 2010; 20: 971-4. Laki NS, Mimica-Duki NM, Isak JM, Boin BN. Antioxidant properties of Galium verum L. (Rubiaceae) extracts. Centr Eur J Biol 2010; 5: 331-7. Benetti MRN, Rudnicki M, Zanotto-Filho A, de Oliveira MR, Kurek AG, Coitinho A, Schwartsmann G, Moreira JCF. Evaluation of antioxidant effect of extracts of Symphyopappus casarettoi. Fitoterap 2007; 78: 3232-4. Domnguez-Ortiz MA, Muoz-Muiz O, Garca-Rodrguez RV, VzquezHernndez M, Gallegos-Estudillo J, Cruz-Snchez JS. Antioxidant and antiinflammatory activity of Moussonia deppeana. Bol Latinoamer Caribe Plant Med Aromat 2009; 9: 13-9. Narvez-Mastache JM, Novillo F, Delgado G. Antioxidant arylprenylcoumarin, flavan-3-ols and flavonoids from Eysenhardtia subcoriacea. Phytochem 2008; 69: 451-6. Girennavar B, Jayaprakasha GK, Jadegoud Y, Gowda GAN, Patil BS. Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit. Bioorg Med Chem 2007; 15: 3684-91. Devienne KF, Clgaro-Helena AF, Dorta DJ, Prado IMR, Raddi MSG, Vilegas W, Uyemura SA, Santos AC, Curti C. Antioxidant activity of isocoumarins isolated from Paepalanthus bromelioides on mitochondria. Phytochemistry 2007; 68: 1075-80. Tung Y-T, Chang S-T. Inhibition of Xanthine Oxidase by Acacia confusa Extracts and Their Phytochemicals. J Agric Food Chem 2010; 58: 7816.
[130]
[156]
[131]
[157]
[158]
[132]
[159]
[133]
[160] [161]
[134]
[135]
[162] [163] [164]
[136]
[137]
[165] [166]
[138]
[139]
[167]
[140]
[168]
[141] [142]
[169]
[170]
[143]
[171]
[144]
[172]
[145] [146]
[173] [174]
[147]
[175]
[148] [149]
[176] [177]
[150]
[178]
[151]
[179]
[152]
[180]
[153]
[181]
[154]
[182]
Coumarins as Antioxidants [183] Attarde D L, Kadu S S, Chaudhari B J, Kale S S, Bhamber R S. In vitro Antioxidant activity of Pericarp of Cucurbita maxima Duch. ex Lam. Intern J Pharm Tech Res 2010; 2: 1533-8. Pan Y, Zhu J, Wang H, Zhang X, Zhang Y, He C, Ji X, Li H. Antioxidant activity of ethanolic extract of Cortex fraxini and use in peanut oil. Food Chem 2007; 103: 913-8. Guerrini A, Bruni R, Maietti S, Poli F, Rossi D, Paganetto G, Muzzoli M, Scalvenzi L, Sacchetti G. Ecuadorian stingless bee (Meliponinae) honey: A chemical and functional profile of an ancient health product . Food Chem 2009; 114: 1413-20. Ye ilyurt V, Halfon B, ztrk M, Topu G. Antioxidant potential and phenolic constituents of Salvia cedronella. Food Chem 2008; 108: 31-9. Tiew P, Ioset JR, Kokpol U, Chavasiri W, Hostettmann K. Antifungal, Antioxidant and Larvicidal Activities of Compounds Isolated from the Heartwood of Mansonia gagei. Phytother Res 2003; 17: 190-3. Ng TB, Liu F, Wang ZT. Antioxidative activity of natural products from plants. Life Sci 2000; 66: 709-23. Leu YL, Shi LS, Damu AG. Chemical constituents of Taraxacum formosanum. Chem Pharm Bull (Tokyo) 2003; 51: 599-601. Masamoto Y, Ando H, Murata Y, Shimoishi Y, Tada M, Takahata K. Mushroom tyrosinase inhibitory activity of esculetin isolated from seeds of Euphorbia lathyris L. Biosci Biotechnol Biochem 2003; 67: 631-4. Reilly K, Gomez-Vasquez R, Buschmann H, Tohme J, Beeching JR. Oxidative stress responses during cassava post-harvest physiological deterioration. Plant Mol Biol 2003; 53: 669-85. Razavi SM, Nazemiyeh H, Hajiboland R, Kumarasamy Y, Delazar A, Nahar L, Sarker SD. Coumarins from the aerial parts of Prangos uloptera (Apiaceae). Rev Brasil Farm 2008; 18: 1-5. Yun BS, Lee IK, Ryoo IJ, Yoo ID. Coumarins with monoamine oxidase inhibitory activity and antioxidative coumarino-lignans from Hibiscus syriacus. J Nat Prod 2001; 64: 1238-40. Ikeda R, Wada M, Nishigaki T, Nakashima K. Quantification of coumarin derivatives in Noni (Morinda citrifolia) and their contribution of quenching effect on reactive oxygen species. Food Chem 2009; 113: 41169-72. Nahata A, Patil UK, Dixit VK. Effect of Evolvulus alsinoides Linn. on learning behavior and memory enhancement activity in rodents. Phytother Res 2010; 24: 486-93. Hornick A, Lieb A, Vo PN, Rollinger J, Stuppner H, Prast H. Effects of the coumarin scopoletin on learning and memory, on release of acetylcholine from brain synaptosomes and on long-term potentiation in hippocampus. BMC Pharmacol 2008; 8: A36. Rollinger JM, Hornick A, Langer T, Stuppner H, Prast H. Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products. J Med Chem 2004; 47: 6248-54. Pawlus AD, Kinghorn DA. Review of the ethnobotany, chemistry, biological activity and safety of the botanical dietary supplement Morinda citrifolia (noni). J Pharm Pharmacol 2007; 59: 1587-609. Potterat O. Morinda citrifolia (noni) fruit phytochemistry, pharmacology, safety. Planta Medica 2007; 73: 191-9.
Revised: July 19, 2011 Accepted: July 21, 2011
Current Medicinal Chemistry, 2011 Vol. 18, No. 25 [200]
3951
[184]
[201]
[185]
[202]
[186] [187]
[203] [204]
[188] [189] [190]
[205]
[206]
[191]
[207]
[192]
[208] [209]
[193]
[194]
[210]
[195]
[196]
[211]
[197]
[212]
[198]
[213]
Palu AK, Kim AH, West BJ, Deng S, Jensen J, White L. The effects of Morinda citrifolia L. (noni) on the immune system: its molecular mechanisms of action. J Ethnopharm 2008; 115: 502-6. Yang J, Gadi R, Paulino R, Thomson T. Total phenolics, ascorbic acid, and antioxidant capacity of noni (Morinda citrifolia L.) juice and powder as affected by illumination during storage. Food Chem 2010; 122: 627-32. Thuong PT, Hung TM, Ngoc TM, Ha DT, Min BS, Kwack SJ, Kang TS, Choi JS, Bae KH. Antioxidant activities of coumarins from Korean medicinal plants and their structure-activity relationships. Phytother Res 2010; 24: 101-6. Lee C-J, Chen L-G, Liang W-L, Wang C-C. Anti-inflammatory effects of Punica granatum Linne in vitro and in vivo. Food Chem 2010; 118: 315-22. Pan Y, Zhang X, Wang H, Liang Y, Zhu J, Li H, Zhang Z, Wu Q. Antioxidant potential of ethanolic extract of Polygonum cuspidatum and application in peanut oil. Food Chem 2007; 105: 1518-24. Nishiyama T, Ohnishi J, Hashiguchi Y. Fused heterocyclic antioxidants: antioxidative activities of hydrocoumarins in a homogeneous solution. Biosci Biotechnol Biochem 2001; 65: 1127-33. Tanaka T, Sugiura H, Inaba R, Nishikawa A, Murakami A, Koshimizu K, Ohigashi H. Immunomodulatory action of citrus auraptene on macrophage functions and cytokine production of lymphocytes in female BALB/c mice. Carcinogenesis 1999; 20: 1471-6. Murakami A, Nakamura Y, Tanaka T, Kawabata K, Takahashi D, Koshimizu K, Ohigashi H. Suppression by citrus auraptene of phorbol ester-and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation. Carcinogenesis 2000; 21: 1843-50. Razavi SM, Imanzadeh G, Davari M. Coumarins from Zosima absinthifolia seeds, with allelopatic effects. EurAsia J BioSci 2010; 4: 17-22. Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE. Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice. Toxicol Lett 2009; 185: 180-6. Kelly VP, Ellis EM, Manson MM, Chanas SA, Moffat GJ, McLeod R, Judah DJ, Neal GE, Hayes JD. Chemoprevention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione Stransferase A5 and P1 subunits, and NAD(P)H: quinine oxidoreductase in rat liver. Cancer Res 2000; 60: 957-69. Kelly VP, Ireland LS, Ellis EM, Hayes JD. Purification from rat liver of a novel constitutively expressed member of the aldo-keto reductase 7 family that is widely distributed in extrahelatic tissues. Biochem J 2000; 348: 389400. Manson MM, Ball HW, Barrett MC, Clark HL, Judah DJ, Williamson G, Neal GE. Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1metabolism. Carcinogenesis 1997; 18: 1729-38. Tulayakul P, Dong KS, Li JY, Manabe N, Kumagai S. The effect of feeding piglets with the diet containing green tea extracts or coumarin on in vitro metabolism of aflatoxin B1 by their tissues. Toxicon 2007; 50: 339-48.
[199]
Received: April 26, 2011

Coumarins As Antioxidants

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Coumarins As Antioxidants

Загружено:

Авторское право:

Доступные форматы

Current Medicinal Chemistry, 2011, 18, 3929-3951

3930 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3932 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

OH OH OH OH O HO OH OH O 7 CH3 OH C H H2 C H C O OH 8 CH3 OH OH O O-rutinose 9 HO O OH OH

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3934 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3936 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3938 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3940 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3942 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

3944 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

H3CO O HOH2C O O CH3 O 85 O O 86 OH 87 O O O O O O O HO

3946 Current Medicinal Chemistry, 2011 Vol. 18, No. 25

Structures of Coumarins Used as Antioxidants

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

LDL AAPH BP DSBP TOH SECCA KHB NK GST AFAR

[2] [3] [4] [5]

[6] [7] [8] [9] [10]

[11] [12] [13]

DPH-PA = t-BHP LDH ALT MDA TAC PBL = = = = = =

[27] [28] [29] [30]

[60] [61] [62] [63] [64]

Current Medicinal Chemistry, 2011 Vol. 18, No. 25

[162] [163] [164]

Current Medicinal Chemistry, 2011 Vol. 18, No. 25 [200]

[188] [189] [190]

Received: April 26, 2011

Вам также может понравиться