Antioxidative and antiradical properties of plant phenolics

The plant phenolic compounds such as flavonoids, tannins and phenolic acids appeared to be strong antiradical and antioxidant compounds. The number of hydroxy groups and the presence of a 2,3-double bond and orthodiphenolic structure enhance antiradical and antioxidative activity of flavonoids. The glycosylation, blocking the 3-OH group in C-ring, lack of a hydroxy group or the presence of only a methoxy group in B-ring have a decreasing effect on antiradical or antioxidative activity of these compounds. Tannins show strong antioxidative properties. Some tannins in red wine or gallate esters were proved to have antioxidative effect in vivo. The number of hydroxy groups connected with the aromatic ring, in ortho or para position relative to each other, enhance antioxidative and antiradical activity of phenolic acids. The substitution of a methoxy group in ortho position to the OH in monophenols seems to favour the antioxidative activity of the former.     

Design,synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC₅₀ values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC₅₀ values of 0.37, 0.16 and 0.17?μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC₅₀: 18?μM). This derivative also displayed cytotoxic properties (IC₅₀ values ～1?μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G₂-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.     

Indole and its alkyl‐substituted derivatives protect erythrocyte and DNA against radical‐induced oxidation

The antioxidant properties of 1,2,3,4‐tetra‐hydrocarbazole, 6‐methoxy‐1,2,3,4‐tetrahydrocar‐bazole (MTC), 2,3‐dimethylindole, 5‐methoxy‐2,3‐dimethylindole, and indole were investigated in the case of hemolysis of human erythrocytes and oxidative damage of DNA induced by 2,2′‐azobis(2‐amidinopropane hydrochloride) (AAPH), respectively. The aim of this work was to explore the influence of methoxy, methyl, and cyclohexyl substituents on the antioxidant activities of indole derivatives. These indole derivatives were able to protect erythrocytes and DNA in a concentration‐dependent manner. The alkyl‐substituted indole can protect erythrocytes and DNA against AAPH‐induced oxidation. Especially, the structural features of cyclohexyl and methoxy substituents made MTC the best antioxidant among the indole derivatives used herein. Finally, the interaction between these indole derivatives and 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonate) radical cation and 2,2′‐diphenyl‐1‐picrylhydrazyl, respectively, provided direct evidence for these indole derivatives to scavenge radicals and emphasized the importance of electron‐donating groups for the free radical–scavenging activity of indole derivatives. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:273–279, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20289     

Bicyclic melatonin receptor agonists containing a ring-junction nitrogen: Synthesis, biological evaluation, and molecular modeling of the putative bioactive conformation

Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT1 and MT2 receptors. Shifting the methoxy group from position 5 to 2 of the 7a-azaindole ring led to a substantial reduction of MT1 binding when MT2 recognition was maintained. We theoretically investigated the hypothesis whether the 2-methoxy function of the azamelatonin analogue 27 is able to mimic the 5-methoxy group of the neurohormone by directing its 2-methoxy function toward the methoxy binding site. DFT calculations and experimental binding differences of analogue compounds indicate that the energy gained by forming the methoxy-specific hydrogen-bond interaction should exceed the energy required for adopting an alternative conformation.     

A review of the molecular conformations of melatonin ligands at the melatonin receptor

This review examines the 1992-2000 literature on studies of the molecular conformations of melatonin ligands at the melatonin receptor. In order to investigate quantitative structure-affinity relationships between different chemical classes of melatonergic ligands binding to the melatonin GPCR, CoMFA has been applied to extended sets of compounds, to obtain 3D-QSAR agonist/antagonist models. The results of several authors have suggested that the active conformation of the C-3 aminoethyl side chain of melatonin and related compounds is in a folded form, orthogonal to the aromatic ring. Positive steric potentials were found in the C-2 region, surrounding the C-5 methoxy group and near the N -acyl group of the side chain, while substituents in positions C-6 and C-7 cause a decrease in affinity. Negative steric regions were found between indole N-1 and C-2. Receptor binding affinities have been predicted for a range of structurally diverse compounds for the sheep brain melatonin receptor considering steric, electrostatic and lipophilic fields.     

Significant enhancement in radical-scavenging activity of curcuminoids conferred by acetoxy substituent at the central methylene carbon

For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl group as well as β-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from β-diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical-scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC(50)=23.2-30.3 μM) with the exception of the acetoxy-substituted derivative (EC(50)=8.7 μM) which showed more potent activity than curcumin (EC(50)=22.6 μM). When substituted to the non-phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl相似文献   

Effect of phenolic acids on manganese peroxidase-dependent peroxidation of linoleic acid and degradation of a non-phenolic lignin model compound

The influence of aromatic phenolic and non-phenolic acids on manganese peroxidase (MnP)-dependent peroxidation of linoleic acid, and oxidation of a non-phenolic lignin model compound (LMC) was studied. Phenolic compounds inhibited both the MnP-dependent lipid peroxidation (LPO) and non-phenolic LMC degradation in the system. The antioxidant activity of the aromatic compounds in the enzymatic system with MnP-dependent LPO depends on the presence of the phenolic hydroxyl groups attached to the aromatic ring structure, the methoxylation of the hydroxyl group in the ortho position in diphenolics, and number of carbon atoms in the side chain. Natural phenolic compounds inhibit the oxidation of non-phenolic lignin in the system based on MnP-mediated LPO, but do not prevent it. This result indicates that MnP-mediated LPO may play an important role in lignin degradation even in the presence of the phenolic antioxidant compounds, and supports the possibility of the involvement of LPO in the degradation of lignin in wood.     

Estrogen A-ring structure and antioxidative effect on lipoproteins

The oxidative modification of lipoprotein particles is an important step in atherogenesis. Estrogens are known to be powerful antioxidants independently of their binding to the estrogen receptors and the hormonal functions. We explored the structural determinants for the antioxidant activity of a large number of estrogen derivatives (n=43) in an aqueous lipoprotein solution in vitro by monitoring formation of conjugated dienes. Our results indicate that estrogen derivatives with an unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups provide strongest antioxidant protection of low density lipoprotein (LDL) and high density lipoprotein (HDL). The electron donating methoxy groups may enhance the antioxidant effect by weakening the phenolic OH bond and providing stability to the formed phenoxyl radical. With some exceptions, compounds completely lacking unsubstituted hydroxyl groups in the A-ring exhibited no antioxidant effect, e.g. the most hydrophilic "tetrol" compound with three unsubstituted A-ring hydroxyl groups had no antioxidant effect. Moreover, additional hydroxyl groups in the B-, C- or D-ring seemed to weaken the antioxidant effect. Accordingly, both the presence of unsubstituted hydroxyl groups and adjacent substituents, as well as the lipophilicity of the derivatives determine the antioxidant activity of estrogen derivatives in aqueous lipoprotein solutions.     

Auxin and Sodium Nitroprusside Effects on Wheat Antioxidants in Salinity

The effect of indole butyric acid (IBA) as auxin hormone and sodium nitroprusside (SNP) on total antioxidant, carotenoid, total phenolic compounds, catalase activity and shoot dry weight in wheat (Triticum aestivum L. cv. Chamran) under 50 and 100 mM NaCl as salt stress were studied. These two experiments were done separately and in a completely randomized design, in three replications. Indole butyric acid in three levels and sodium nitroprusside in one level were used as spray on the plant to compare their effects. According to the results, the amount of carotenoid, total phenolic compounds, antioxidants and catalase activity have increased but shoot dry weight have decreased by either salinity alone and/or combined with IBA and SNP in our experiments, comparison to the control but with different level. None of the carotenoid, total phenolic compounds, antioxidants, catalase activity and shoot dry weight showed significant changes when indole butyric acid or sodium nitroprusside treatment were induced alone that shows their nontoxicity for seedlings. In connection with indole butyric acid or sodium nitroprusside treatment, these compounds appears to alleviate the stress conditions by showing significant decreasing of carotenoid, total phenolic compounds, antioxidants and catalase activity and significant increasing of shoot dry weight. Our results showed that IBA and SNP had the same effects in salt stress, so in salt stress conditions it is recommended to use IBA for crop and non-crop plants and SNP for only not edible plants.     

Effect of structural modulation of polyphenolic compounds on the inhibition of Escherichia coli ATP synthase

In this paper we present the inhibitory effect of a variety of structurally modulated/modified polyphenolic compounds on purified F(1) or membrane bound F(1)F(o)Escherichia coli ATP synthase. Structural modulation of polyphenols with two phenolic rings inhibited ATP synthase essentially completely; one or three ringed polyphenols individually or fused together inhibited partially. We found that the position of hydroxyl and nitro groups plays critical role in the degree of binding and inhibition of ATPase activity. The extended positioning of hydroxyl groups on imino diphenolic compounds diminished the inhibition and abridged position enhanced the inhibition potency. This was contrary to the effect by simple single ringed phenolic compounds where extended positioning of hydroxyl group was found to be effective for inhibition. Also, introduction of nitro group augmented the inhibition on molar scale in comparison to the inhibition by resveratrol but addition of phosphate group did not. Similarly, aromatic diol or triol with rigid or planar ring structure and no free rotation poorly inhibited the ATPase activity. The inhibition was identical in both F(1)F(o) membrane preparations as well as in isolated purified F(1) and was reversible in all cases. Growth assays suggested that modulated compounds used in this study inhibited F(1)-ATPase as well as ATP synthesis nearly equally.     

Indole melatonin agonists and antagonists derived by shifting the melatonin side chain from the C-3 to the N-1 or to the C-2 indole position

This article reviews our efforts in the development of indole melatonin (MLT) agonist and antagonist compounds. Evidence is presented which indicates that high-affinity melatonergic agonists were obtained by shifting the MLT amido side chain from the C-3 to the N-1 indole position. Conversely, by moving the side chain from the C-3 to the C-2 indole position it is possible to produce MLT antagonist compounds.     

Endogenous and dietary indoles: a class of antioxidants and radical scavengers in the ABTS assay

Indoles are very common in the body and diet and participate in many biochemical processes. A total of twenty-nine indoles and analogs were examined for their properties as antioxidants and radical scavengers against 2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) ABTS*+ radical cation. With only a few exceptions, indoles reacted nonspecifically and quenched this radical at physiological pH affording ABTS. Indoleamines like tryptamine, serotonin and methoxytryptamine, neurohormones (melatonin), phytohormones (indoleacetic acid and indolepropionic acid), indoleamino acids like L-tryptophan and derivatives (N-acetyltryptophan, L-abrine, tryptophan ethyl ester), indolealcohols (tryptophol and indole-3-carbinol), short peptides containing tryptophan, and tetrahydro-beta-carboline (pyridoindole) alkaloids like the pineal gland compound pinoline, acted as radical scavengers and antioxidants in an ABTS assay-measuring total antioxidant activity. Their trolox equivalent antioxidant capacity (TEAC) values ranged from 0.66 to 3.9 mM, usually higher than that for Trolox and ascorbic acid (1 mM). The highest antioxidant values were determined for melatonin, 5-hydroxytryptophan, trp-trp and 5-methoxytryptamine. Active indole compounds were consumed during the reaction with ABTS*+ and some tetrahydropyrido indoles (e.g. harmaline and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid ethyl ester) afforded the corresponding fully aromatic beta-carbolines (pyridoindoles), that did not scavenge ABTS*+. Radical scavenger activity of indoles against ABTS*+ was higher at physiological pH than at low pH. These results point out to structural compounds with an indole moiety as a class of radical scavengers and antioxidants. This activity could be of biological significance given the physiological concentrations and body distribution of some indoles.     

Comparative effects of melatonin and vitamin E in restoring aortic relaxation in pancreatectomized rats

In a previous study we reported the efficacy of melatonin to restore the decreased relaxation response to acetylcholine (ACh) or to sodium nitroprusside (SNP) in aortic rings of rats turned hyperglycemic by subtotal pancreatectomy. The effect was amplified by pre-incubation in a high (44 mmol/l) glucose solution, a situation that resulted in oxidative stress. We hereby compare the effect of another antioxidant, vitamin E, with that of melatonin on ACh response in intact aortic rings or on SNP response in endothelium-denuded aortic rings obtained from pancreatectomized or sham-operated rats. Dose-response curves to ACh or SNP were performed in the presence or absence of melatonin or vitamin E (10-5 mol/1) in 10 or 44 mmol/1 glucose medium. Melatonin was more effective than vitamin E in restoring ACh- or SNP-induced relaxation of aortic rings in a high glucose medium. The differences between the two antioxidants may rely on the ability of melatonin to diffuse readily into intracellular compartments.     

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the head-group, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC). Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the head-group. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phase-transition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.     

Synthesis and evaluation of the anti-proliferative activity of diaryl-3-pyrrolin-2-ones and fused analogs

Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity. This work provides a framework to better understand structure-activity relationships for inducing anti-proliferative activity in diaryl heterocyclic scaffolds.     

Synthesis and Antioxidant Evaluation of O-Methylated Emodacidamides: Starting from Parietin,a Secondary Metabolite of Lichen Xanthoria parietina

Polyhydroxy-anthraquinones bearing amino acids are found rather seldom in nature. Emodacidamides, isolated from a marine-derived fungus, Penicillium sp. SCSIO sof101 by Luo et al. (2017) are the first natural example of amino acid conjugated anthraquinone. In this study, O-methylated emodacidamides and emodinic acid-anilides were synthesized starting from parietin, extracted from the lichen Xanthoria parietina (L.) Th. Fr. The structural elucidations of prepared compounds were confirmed by 1D and 2D NMR analyses including HSQC and HMBC techniques. In addition, all newly synthesized compounds were evaluated for the antioxidant activities with free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging. The synthesized compounds showed low to moderate antioxidant and DPPH scavenging activities. The antioxidant activities were supported within quantum chemical calculations using the DFT−B3LYP/6-311++G(d,p) level of theory. It is observed that the antioxidant activity of emodacidamides mostly depends on the phenolic groups on anthraquinone ring. The phenolic groups on other substituents help to improve antioxidant activity and also the position of hydroxy group is a decisive factor for antioxidant ability.     

Effect of different rootstocks on PAL activity and phenolic compounds in flowers, leaves, hulls and kernels of three pistachio (Pistacia vera L.) cultivars

Phenylalanine ammonia-lyase (PAL) is a biochemical marker of environmental stress and plays a pivotal role in phenolic synthesis. Lower ROS levels and oxidative damage were observed in grafted plants; moreover, the rootstocks have a profound influence on the biochemical composition, especially of phenolic compounds. Regarding the importance of the effect rootstocks have on scion in pistachio trees, this study was carried out to assess and compare three pistachio cultivars (Ahmadaghaii, Ohadi and Kallehghuchi) on four rootstocks (Mutica, Ahli, Sarakhs and Atlantica). PAL activity, phenolic compounds, and flavonoid and anthocyanin contents in leaves, flowers and fruits were measured for the selection of the most suitable and compatible rootstock/scion resistant to environmental stresses. The results showed that PAL activity was different among the cultivars and organs. A positive correlation was observed between PAL activity and phenolic compounds in the leaves and flowers of Mutica-Ahmadaghaii, suggesting that it was more resistant than the others to environmental stresses. PAL activity and total phenolics in pistachio fruits suffered a decrease when the maturation processes began. The hulls of the pistachio fruits contained high levels of phenolic compounds, especially in Mutica-Ahmadaghaii, suggesting its function as a protective layer and a defense chemical against ultraviolet radiation and pathogens. Our results indicated the presence of a number of bioactive compounds in kernels with the highest amount belonging to Mutica-Ahmadaghaii. Therefore, we concluded that pistachio rootstocks mighy affect the antioxidant compounds in kernels.     

Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant,photoprotective and antiproliferative activity of indole hydrazones

Two series of indole derivatives 4–17, 20–22 were easily prepared and assayed for their radical-scavenging ability. Arylidene-1H-indole-2-carbohydrazones showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety as well as to the presence of methoxy or 4-(diethylamino) group. On the contrary low antioxidant activity is showed by the isomeric 1H-indol-2-yl(methylene)-benzohydrazides. Furthermore, hydrazones 4–17 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The indole 16 and 17, showing the best antioxidant and photoprotective profile, were included in different formulation and their topical release was evaluated. Varying the formulation composition, it was possible to optimize skin adsorption and solubility of the active indole in the formulation. The antiproliferative effect of the hydrazones 4–17 was tested on human erythroleukemia K562 and melanoma Colo-38 cells. Hydrazones 11, 16 and 17 showed growth inhibition at sub micromolar concentrations on both cell lines. These results indicate indole hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 16 and 17 correlated to their high antiproliferative activity.