Inhibition of horseradish peroxidase catalytic activity by new 3-phenylcoumarin derivatives: synthesis and structure-activity relationships

Twenty hydroxylated and acetoxylated 3-phenylcoumarins were synthesized, and the structure-activity relationships were investigated by evaluating the ability of these compounds to modulate horseradish peroxidase (HRP) catalytic activity and comparing the results to four flavonoids (quercetin, myricetin, kaempferol and galangin), previously reported as HRP inhibitors. It was observed that 3-phenylcoumarins bearing a catechol group were as active as quercetin and myricetin, which also show this substituent in the B-ring. The presence of 6,2'-dihydroxy group or 6,7,3',4'-tetraacetoxy group in the 3-phenylcoumarin structure also contributed to a significant inhibitory effect on the HRP activity. The catechol-containing 3-phenylcoumarin derivatives also showed free radical scavenger activity. Molecular modeling studies by docking suggested that interactions between the heme group in the HRP active site and the catechol group linked to the flavonoid B-ring or to the 3-phenyl coumarin ring are important to inhibit enzyme catalytic activity.     

Structure–Activity Relationships for Antioxidant Activities of a Series of Flavonoids in a Liposomal System

Structurally diverse plant phenolics were examined for their abilities 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. The antioxidant abilities of flavonoids were compared with those of coumarin and tert-butylhydroquinone (TBHQ). The antioxidant efficacies of these compounds were evaluated on the basis of their abilities 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 flavonoids tested exhibited higher antioxidant efficacies against metal-ion-induced peroxidations than peroxyl-radical-induced peroxidation, suggesting that metal chelation may play a larger role in determining the antioxidant activities of these compounds than has previously been believed. Distinct structure–activity relationships were also revealed for the antioxidant abilities of the flavonoids. Presence of hydroxyl substituents on the flavonoid nucleus enhanced activity, whereas substitution by methoxy groups diminished antioxidant activity. Substitution patterns on the B-ring especially affected antioxidant potencies of the flavonoids. In cases where the B-ring could not contribute to the antioxidant activities of flavonoids, hydroxyl substituents in an catechol structure on the A-ring were able to compensate and become a larger determinant of flavonoid antioxidant activity.     

Metal complexes with superoxide dismutase-like activity as candidates for anti-prion drug

Various compounds were evaluated for ability to inhibit the formation of the abnormal protease-resistant form of prion protein (PrP-res) in two cell lines infected with different prion strains. Examination of the structure-activity relationships indicated that compounds with copper-selective chelating ability and whose copper complexes have high SOD-like activity are candidates for anti-prion drug.     

Modification of flavonoid biosynthesis in crop plants

Flavonoids comprise the most common group of polyphenolic plant secondary metabolites. In plants, flavonoids play an important role in biological processes. Beside their function as pigments in flowers and fruits, to attract pollinators and seed dispersers, flavonoids are involved in UV-scavenging, fertility and disease resistance. Since they are present in a wide range of fruits and vegetables, flavonoids form an integral part of the human diet. Currently there is broad interest in the effects of dietary polyphenols on human health. In addition to the potent antioxidant activity of many of these compounds in vitro, an inverse correlation between the intake of certain polyphenols and the risk of cardiovascular disease, cancer and other age related diseases has been observed in epidemiological studies. The potential nutritional effects of these molecules make them an attractive target for genetic engineering strategies aimed at producing plants with increased nutritional value. This review describes the current knowledge of the molecular regulation of the flavonoid pathway and the state of the art with respect to metabolic engineering of this pathway in crop plants.     

Selective in vitro antioxidant properties of bisphosphonates

The aim of this study was to investigate the in vitro antioxidant profile of different bisphosphonates. Bisphosphonates were tested for their xanthine oxidase and microsomal lipid peroxidation inhibiting capacity. Furthermore, the effect of these different compounds on DPPH, a stable radical, was investigated. Clodronate, risedronate, and pyrophosphate were further tested for their hydroxyl radical scavenging activity. None of the tested compounds showed xanthine oxidase inhibiting activity or DPPH scavenging activity. All the tested bisphosphonates exhibited inhibiting capacities on the microsomal lipid peroxidation. The hydroxyl radical scavenging activity was dependent on the order of adding the different reagents and was highest for risedronate. Bisphosphonates possess an inhibiting activity on the microsomal lipid peroxidation and the Fenton reaction. In these reactions iron plays an important role suggesting that the selective in vitro antioxidant properties of the bisphosphonates are due to their iron chelating characteristics.     

Free radical scavengers, antioxidants and aldose reductase inhibitors from Camptosorus sibiricus Rupr

Flavonoids and organic acids were recommended in the literature as the main active constituents of Camptosorus sibiricus Rupr. Assay-guided fractionation led to the isolation of 9 flavonoids and 8 phenolic acids. All compounds were tested for DPPH scavenging activity, SOD-like and aldose reductase inhibition. Among them, compounds 1, 2, 3, 5, 6, 7, 8, 9, 11, 15 showed activities. The most active free radical scavenger and antioxidant was compound 8, while compound 1 exhibited strong inhibiting activity of aldose reductase. The structure-activity relation was dicussed briefly.     

Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties

Flavonoids, including isoflavones, are natural components in our diet and, with the burgeoning interest in alternative medicine, are increasingly being ingested by the general population. Plant phenolics, which form moieties on flavonoid rings, such as gallic acid, are also widely consumed. Several beneficial properties have been attributed to these dietary compounds, including antioxidant, anti-inflammatory, and anticarcinogenic effects. Flavonoid preparations are marketed as herbal medicines or dietary supplements for a variety of alleged nontoxic therapeutic effects. However, they have yet to pass controlled clinical trials for efficacy, and their potential for toxicity is an understudied field of research. This review summarizes the current knowledge regarding potential dietary flavonoid/phenolic-induced toxicity concerns, including their pro-oxidant activity, mitochondrial toxicity (potential apoptosis-inducing properties), and interactions with drug-metabolizing enzymes. Their chemopreventive activity in animal in vivo experiments may result from their ability to inhibit phase I and induce phase II carcinogen metabolizing enzymes that initiate carcinogenesis. They also inhibit the promotion stage of carcinogenesis by inhibiting oxygen radical-forming enzymes or enzymes that contribute to DNA synthesis or act as ATP mimics and inhibit protein kinases that contribute to proliferative signal transduction. Finally, they may prevent tumor development by inducing tumor cell apoptosis by inhibiting DNA topoisomerase II and p53 downregulation or by causing mitochondrial toxicity, which initiates mitochondrial apoptosis. While most flavonoids/phenolics are considered safe, flavonoid/phenolic therapy or chemopreventive use needs to be assessed as there have been reports of toxic flavonoid-drug interactions, liver failure, contact dermatitis, hemolytic anemia, and estrogenic-related concerns such as male reproductive health and breast cancer associated with dietary flavonoid/phenolic consumption or exposures.     

MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization

The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas aeruginosa is described. Synthesis and in vitro structure-activity relationships (SARs) are outlined. Early leads lacked activity in animal models, and efforts to improve solubility and reduce serum protein binding by the introduction of polar groups are discussed.     

Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants

Traditional Chinese medicinal plants associated with anticancer contain a wide variety of natural phenolic compounds with various structural features and possessing widely differing antioxidant activity. The structure-radical scavenging activity relationships of a large number of representative phenolic compounds (e.g., flavanols, flavonols, chalcones, flavones, flavanones, isoflavones, tannins, stilbenes, curcuminoids, phenolic acids, coumarins, lignans, and quinones) identified in the traditional Chinese medicinal plants were evaluated using the improved ABTS*+ and DPPH methods. Different categories of tested phenolics showed significant mean differences in radical scavenging activity. Tannins demonstrated the strongest activity, while most quinones, isoflavones, and lignans tested showed the weakest activity. This study confirmed that the number and position of hydroxyl groups and the related glycosylation and other substitutions largely determined radical scavenging activity of the tested phenolic compounds. The differences in radical scavenging activity were attributed to structural differences in hydroxylation, glycosylation and methoxylation. The ortho-dihydroxy groups were the most important structural feature of high activity for all tested phenolic compounds. Other structural features played a modified role in enhancing or reducing the activity. Within each class of phenolic compounds, the structure-activity relationship was elucidated and discussed. This study reveals the structure-activity relationships of a large series of representative natural phenolic compounds more systematically and fully than previous work. Structure-radical scavenging activity relationships of some natural phenolics identified in the medicinal plants were evaluated for the first time.     

Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin

Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases. This has led to considerable interest in the antioxidant activity of dietary compounds. Flavonoids have received the most attention and much is known about the structural requirements for antioxidant activity. However, little is known about the antioxidant activity of other plant derived phenolic compounds such as the xanthones. We have previously shown that the prenylated xanthone, mangostin, can inhibit the oxidation of low density lipoprotein. In order to examine the effects of structure modification on antioxidant activity of this class of compound we have prepared a number of derivatives of mangostin and tested antioxidant activity in an isolated LDL and plasma assay. The results of this study show that structural modification of mangostin can have a profound effect on antioxidant activity. Derivatisation of the C-3 and C-6 hydroxyl groups with either methyl, acetate, propane diol or nitrile substantially reduces antioxidant activity. In contrast, derivatisation of C-3 and C-6 with aminoethyl derivatives enhanced antioxidant activity, which may be related to changes in solubility. Cyclisation of the prenyl chains had little influence on antioxidant activity.     

Flavonoids and auxin transport: modulators or regulators?

Flavonoids are polyphenolic compounds found in all vascular and non-vascular plants. Although nonessential for plant growth and development, flavonoids have species-specific roles in nodulation, fertility, defense and UV protection. Flavonoids have been shown to modulate transport of the phytohormone auxin in addition to auxin-dependent tropic responses. However, flavonoids are not essential regulators of these processes because transport and tropic responses occur in their absence. Flavonoids modulate the activity of auxin-transporting P-glycoproteins and seem to modulate the activity of regulatory proteins such as phosphatases and kinases. Phylogenetic analysis suggests that auxin transport mechanisms evolved in the presence of flavonoid compounds produced for the scavenging of reactive oxygen species and defense from herbivores and pathogens.     

Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin

Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases. This has led to considerable interest in the antioxidant activity of dietary compounds. Flavonoids have received the most attention and much is known about the structural requirements for antioxidant activity. However, little is known about the antioxidant activity of other plant derived phenolic compounds such as the xanthones. We have previously shown that the prenylated xanthone, mangostin, can inhibit the oxidation of low density lipoprotein. In order to examine the effects of structure modification on antioxidant activity of this class of compound we have prepared a number of derivatives of mangostin and tested antioxidant activity in an isolated LDL and plasma assay. The results of this study show that structural modification of mangostin can have a profound effect on antioxidant activity. Derivatisation of the C-3 and C-6 hydroxyl groups with either methyl, acetate, propane diol or nitrile substantially reduces antioxidant activity. In contrast, derivatisation of C-3 and C-6 with aminoethyl derivatives enhanced antioxidant activity, which may be related to changes in solubility. Cyclisation of the prenyl chains had little influence on antioxidant activity.     

药用真菌灵芝液体培养过程中的抗氧化活性研究

灵芝Ganoderma lingzhi是一种重要的药用真菌,已被《中国药典》正式收录。本研究主要以菌丝体干重、多糖含量、多酚含量、黄酮含量、抗坏血酸（ascorbic acid,AA）含量、总抗氧化能力（total antioxidant capacity,T-AOC）、超氧化物歧化酶（superoxide dismutase,SOD）活性、羟自由基清除能力、超氧阴离子清除能力、1,1-二苯基-2-三硝基苯肼（1,1-diphenyl-2-picrylhydrazyl,DPPH）自由基清除能力、2,2′-连氮-双(3-乙基苯并噻唑-6-磺酸)[2,2′-azino-bis(3- ethylbenzthiazoline-6-sulphonic acid),ABTS]自由基清除能力、铁离子还原能力（ferric reducing antioxidant power,FRAP）和亚铁离子螯合能力为测定指标,对灵芝液体培养过程中的抗氧化活性进行了评价。结果显示,该菌具有较高的抗氧化活性,体现在液体培养过程中生长代谢旺盛,可分泌大量多糖、多酚、黄酮、AA等物质和SOD等酶类,对羟自由基、超氧阴离子、DPPH自由基及ABTS自由基等的清除效果显著,且具有较强的铁离子还原能力和亚铁离子螯合作用,这也说明该菌的抗氧化活性与其自身的生长状况、次级代谢产物分泌及还原能力等密切相关。此外,一定的环境胁迫压力也可以激发该菌启动自身的抗氧化系统以保护机体免受氧化损伤。     

The basic antioxidant structure for flavonoid derivatives

An antioxidant structure-activity study is carried out in this work with ten flavonoid compounds using quantum chemistry calculations with the functional of density theory method. According to the geometry obtained by using the B3LYP/6-31G(d) method, the HOMO, ionization potential, stabilization energies, and spin density distribution showed that the flavonol is the more antioxidant nucleus. The spin density contribution is determinant for the stability of the free radical. The number of resonance structures is related to the π-type electron system. 3-hydroxyflavone is the basic antioxidant structure for the simplified flavonoids studied here. The electron abstraction is more favored in the molecules where ether group and 3-hydroxyl are present, nonetheless 2,3-double bond and carbonyl moiety are facultative.     

Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin

Oxidative stress has been implicated in the development of many neurodegenerative diseases and also responsible from aging and some cancer types. Indolic compounds are a broad family of substances present in microorganisms, plants and animals. They are mainly related to tryptophan metabolism, and present particular properties that depend on their respective chemical structures. Due to free radical scavenger and antioxidant properties of indolic derivatives such as indolinic nitroxides and melatonin, a series of 2-phenyl indole derivatives were prepared and their in vitro effects on rat liver lipid peroxidation levels, superoxide formation and DPPH stable radical scavenging activities were determined against melatonin, BHT and alpha-tocopherol. The compounds significantly inhibited (72-98%) lipid peroxidation at 10(-3) M. These values were similar to that observed with BHT (88%). Possible structure-activity relationships of the compounds were discussed.     

Flavones are inhibitors of HIV-1 proteinase.

Substituted gamma-chromones were found to weakly inhibit HIV-1 proteinase, an important enzyme in the replication and processing of the AIDS virus. Chromones bearing hydroxyl substituents and a phenolic group at the 2-position (flavones) were the most active compounds and structure-activity relationships for a limited series of flavone inhibitors are presented. Dixon plots are reported and a possible mechanism for flavone-induced inhibition is proposed. The results are also compared with those for some structurally related non-peptidic inhibitors of HIV-1 proteinase. Since some flavonoid compounds have already been shown to have antiviral activity against AIDS, the present observations of anti-HIV-1 proteinase activity may be particularly significant.     

Antioxidant properties of gingerol related compounds from ginger

Ginger (Zingiber officinale Roscoe) shows an antioxidant activity, and we have been engaging to determine the structures of more than 50 antioxidants isolated from the rhizomes of ginger. The isolated antioxidants are divided into two groups; gingerol related compounds and diarylheptanoids. In this study, structure-activity relationship of gingerol related compounds was evaluated. Gingerol related compounds substituted with an alkyl group bearing 10-, 12- or 14-carbon chain length were isolated from the dichloromethane extract of rhizomes using repeated chromatographic techniques. The antioxidant activities of these compounds were evaluated by the following measurements; 1) 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, 2) inhibitory effect on oxidation of methyl linoleate under aeration and heating by the Oil Stability Index (OSI) method, and 3) inhibitory effect on oxidation of liposome induced by 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH). These results suggested that the substituents on the alkyl chain might contribute to both radical scavenging effect and inhibitory effect of autoxidation of oils, while inhibitory effects against the AAPH-induced peroxidation of liposome was somewhat influenced by the alkyl chain length; the antioxidant activity might be due to not only radical scavenging activity of antioxidants but also their affinity of the antioxidants to the substrates.     

Evaluation of antioxidant properties of medical plants using microbial test systems

The antioxidant activities of extracts from leaves of the medicinal plants growing in Siberia were examined. Total antioxidant activity was determined using in vitro methods including DPPH (2,2-diphenyl-1-picrylhydrazyl radical) free radical scavenging assay, chelating capacity assay with ferrozine, evaluation of capacity to protect plasmid DNA against oxidative damage, measurement of H₂O₂ production, and measurement of total flavonoid and tannin content as well. Using in vivo experiments, we also evaluated capacities of the plant extracts to protect bacteria Escherichia coli against bacteriostatic and bactericidal effects of H₂O₂, and influence of the plant extracts on expression of antioxidant gene katG, encoding catalase. The extracts from Chamerion angustifolium, Filipendula vulgaris and Pyrola rotundifolia indicated the highest levels of antioxidant activity both in vivo and in vitro. Our data suggest that the extracts of the tested plants may provide antioxidant effects on bacteria simultaneously through different pathways, including direct radical scavenging, iron chelation and induction of genes encoding antioxidant enzymes.     

Modulation of flavonoid and tannin production of Carpobrotus rossii by environmental conditions

Dietary supplementation with plant-derived polyphenolic compounds such as the flavonoids epigallocatechin-3-gallate (EGCG), quercetin and resveratrol can result in a beneficial effect on degenerative disease processes through both radical scavenging and activation of cellular ion channels. Preliminary investigations have shown that extracts from the halophyte species Carpobrotus rossii have high in vitro antioxidant and in vivo low-density-lipoprotein-lowering activities. In this study, we have investigated the environmental conditions responsible for inducing flavonoid production in C. rossii in an attempt to maximise production of these compounds. Both field surveys and controlled glasshouse experiments were conducted. Flavonoid production appears to be related to conditions known to cause oxidative stress in plants such as exposure to excessive light, reduced water availability, and low soil potassium levels. Flavonoid production was minimal under salinity levels optimal for C. rossi growth (around 50 mM NaCl) and increased dramatically at sub- and supra-optimal salinities. Flavonoids were clearly concentrated in metabolically active palisade mesophyll tissue rather than the spongy parenchyma. Non-optimal (outside 50–100 mM range) NaCl levels significantly increased flavonoid concentration on a per leaf basis. However, the reduction in biomass production at sub and supra optimal salinities diminished absolute flavonoid production per plant. As a result, saline conditions favouring optimal plant growth appear to be most suitable for maximising production of flavonoids in C. rossii.