Antileishmanial and antifungal activities of xanthanolides isolated from Xanthium macrocarpum

ArticleinFitoterapia 76(3-4):363-6 · July 2005with 143 Reads
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Abstract
Seven xanthanolides, xanthinosin, xanthatin, 4-hydroxyxanthinosin, xanthinin, 4-epiisoxanthanol, 4-epixanthanol, 2-hydroxyxanthinosin and 4-oxobedfordia acid, were isolated from the fruits of Xanthium macrocarpum. A valuation of the antifungal activity of these xanthanolides against Candida albicans, Candida glabrata and Aspergillus fumigatus and of their antileishmanial activity against Leishmania infantum and Leishmania mexicana is presented.

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    Plants and their extracts have been used traditionally against different pathologies, and in some poor regions they are the only therapeutic source for treatments and the presence of specific active secondary metabolites can be account for amelioration of clinical status of suffering individual. A series of ethnopharmacological surveys conducted in Brazil recorded the traditional use of plants against different pathologies and interestingly, some of them presented antileishmanial activity in vitro and in vivo, possibly due to their immunostimulatory, healing and microbicidal properties. Of note, Leishmania parasites can alter patient's immunological status, leading to the development of extensive skin and/or visceral alterations. Therefore, the extracts or secondary metabolites presented in plants that might be capable of modifying these pathological conditions can be attractive candidates in the development of new chemotherapeuticals against leishmaniosis.
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    As part of our ongoing search for natural sources of therapeutic and preventive agents for diabetic complications, we evaluated the inhibitory effects of components of the fruit of Xanthium strumarium (X. strumarium) on aldose reductase (AR) and galactitol formation in rat lenses with high levels of glucose. To identify the bioactive components of X. strumarium, 7 caffeoylquinic acids and 3 phenolic compounds were isolated and their chemical structures were elucidated on the basis of spectroscopic evidence and comparison with published data. The abilities of 10 X. strumarium-derived components to counteract diabetic complications were investigated by means of inhibitory assays with rat lens AR (rAR) and recombinant human AR (rhAR). From the 10 isolated compounds, methyl-3,5-di-O-caffeoylquinate showed the most potent inhibition, with IC50 values of 0.30 and 0.67 μM for rAR and rhAR, respectively. In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate, methyl-3,5-di-O-caffeoylquinate showed competitive inhibition of rhAR. Furthermore, methyl-3,5-di-O-caffeoylquinate inhibited galactitol formation in the rat lens and in erythrocytes incubated with a high concentration of glucose, indicating that this compound may be effective in preventing diabetic complications.
  • Article
    Anti-cancer investigations on Xanthatin mainly focus on in vitro experiments. We herein reported the anti-tumor effects of Xanthatin both in vitro and in vivo. MTS assay results showed that Xanthatin had a remarkable anti-proliferative effect on B16-F10 cells. Moreover, the expression of β-catenin was up-regulated both in vitro and in vivo. Animal studies further revealed that Xanthatin killed the tumor cells around the blood vessels which contributes to reduce microvascular density extremely. All these results indicate that Xanthatin inhibited murine melanoma B16-F10 cell proliferation possibly associated with activation of Wnt/β-catenin pathway and its activity against melanoma tumor might also be relevant to inhibition of angiogenesis.
  • Article
    Full-text available
    The medicinal plant Xanthium strumarium L. (X. strumarium) is covered with glandular trichomes, which are the sites for synthesizing pharmacologically active terpenoids such as xanthatin. MicroRNAs (miRNAs) are a class of 21-24 nucleotide (nt) non-coding RNAs, most of which are identified as regulators of plant growth development. Identification of miRNAs involved in the biosynthesis of plant secondary metabolites remains limited. In this study, high-throughput Illumina sequencing, combined with target gene prediction, was performed to discover novel and conserved miRNAs with potential roles in regulating terpenoid biosynthesis in X. strumarium glandular trichomes. Two small RNA libraries from leaves and glandular trichomes of X. strumarium were established. In total, 1,185 conserved miRNAs and 37 novel miRNAs were identified, with 494 conserved miRNAs and 18 novel miRNAs being differentially expressed between the two tissue sources. Based on the X. strumarium transcriptome data that we recently constructed, 3,307 annotated mRNA transcripts were identified as putative targets of the differentially expressed miRNAs. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis suggested that some of the differentially expressed miRNAs, including miR6435, miR5021 and miR1134, might be involved in terpenoid biosynthesis in the X. strumarium glandular trichomes. This study provides the first comprehensive analysis of miRNAs in X. strumarium, which forms the basis for further understanding of miRNA-based regulation on terpenoid biosynthesis.
  • Article
    A sensitive, specific and rapid ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been established to study pharmacokinetic properties of xanthatin. Xanthatin, a compound which belongs to sesquiterpene lactone group, was determined in rat plasma with psoralen as internal standard. Chromatographic separation was performed on an Agilent Zorbax Eclipse plus C18 column (50mm×2.1mm, 3.5μm) with gradient elution system at a flow rate of 0.3mL/min. The mobile phase was composed of methanol and 0.1% formic acid water solution. Analysis was performed under a triple-quadruple tandem mass-spectrometer with an electrospray ionization (ESI) source via the multiple reaction monitoring (MRM) mode to determine xanthatin at [M+H](+)m/z 247.3→m/z 205.2 and that of IS at [M+H](+)m/z 187.1→m/z 143.0 within 5min. The assay method exhibited good separation of xanthatin from the interference of endogenous substances. The lower limit of quantification (LLOQ) was 1ng/mL, with a good linearity within the concentration range of 1-5000ng/mL (r=0.9990). Intra-day and inter-day precision RSD was less than 9.27%; intra-day and inter-day accuracy was 88.48% and 102.25% respectively. The extraction recoveries of xanthatin range from 82.12% to 89.55%, and the extraction RSD was less than 9.01%. The established LC-ESI-MS/MS method is rapid and sensitive, which has been successfully applied to quantify xanthatin in rat plasma for the first time.
  • Article
    Full-text available
    The purpose of this review is to survey the antiparasitic plants of the Asteraceae family and their applicability in the treatment of parasites. This review is divided into three major parts: (a) literature on traditional uses of Asteraceae plants for the treatment of parasites; (b) description of the major classes of chemical compounds from Asteraceae and their antiparasitic effects; and (c) antiparasitic activity with special reference to flavonoids and terpenoids. This review provides detailed information on the reported Asteraceae plant extracts found throughout the world and on isolated secondary metabolites that can inhibit protozoan parasites such as Plasmodium, Trypanosoma, Leishmania, and intestinal worms. Additionally, special attention is given to the Asteraceae plants of Odisha, used by the tribes of the area as antiparasitics. These plants are compared to the same plants used traditionally in other regions. Finally, we provide information on which plants identified in Odisha, India and related compounds show promise for the development of new drugs against parasitic diseases. For most of the plants discussed in this review, the active compounds still need to be isolated and tested further.
  • Article
    Full-text available
    The aim of this work was to evaluate the antimicrobial activity of Xanthium strumarium L. leaf extracts against Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Clostridium perfringens, as well as to investigate the presence of the toxic compound carboxyatractyloside in different plant parts. S. aureus and C. perfringens were more sensitive to non-polar than to polar fractions, and there was no difference between extracts for the remaining bacteria. All extracts had strong antimicrobial activity against the evaluated microorganisms. Carboxyatractyloside was found in cotyledons and seeds but not in adult leaves and burrs. Thus, only Xanthium strumarium leaves in adult stage can be used for medicinal purposes.
  • Article
    Xanthium sibiricum, an annual weed, unexpectedly and dramatically occupied the exposed drawdown area after water had been impounded for the first time in the newly created Three Gorges Reservoir in China. In order to explain this phenomenon and establish an appropriate management strategy, the effects of constant submersion on seed viability and germination of X. sibiricum were investigated at two constant temperature regimes (25°C and 30°C) under artificial laboratory conditions. The results indicated that the seeds of X. sibiricum exhibited a high level of tolerance of submersion and up to 99% of seeds were viable in each treatment regime. The effect of submersion on germination was not obvious at 25°C until the submersion was prolonged for 180 days, while at 30°C the eventual germination rate of X. sibiricum, even after submergence for only one day, was significantly improved. The speed of germination was also consistently accelerated by prolonged periods of submersion. The proportion of seeds that germinated in all treatments combined was less that 56% due to seed dimorphism, thereby providing a seed bank. We conclude that the interaction between long-term winter flooding and high temperature in summer is the major reason that X. sibiricum was able to occupy the newly exposed drawdown area in the absence of competition. These findings provided further insight into how germination strategy and reservoir water-management regime contributed to this dramatic species outbreak.
  • Article
    Full-text available
    Two phytotoxic xanthanolides, xanthinin and xanthatin, were isolated from the leaves and fruits of invasive weed, Xanthium italicum Morretti, commonly known as Italian cocklebur. They slightly inhibited the seedling growth of Italian cocklebur, but were very inhibitory to lettuce, ryegrass and two indigenous species (African rue and redroot pigweed). Xanthinin significantly decreased the growth of lettuce (Lectuca sativa L.), ryegrass (Lolium multiforum Lam.), Syrian me (Peganum harmala L.) and redroot pigweed (Amaranthus retroflexus L.) even at low concentration (10 mu g/mL). In contrast, the root length of Italian cocklebur slightly inhibited (2%) compared to control at 50 mu g/mL xanthinin treatment. The application of xanthatin also inhibited the growth of receiver plants. Ryegrass and Syrian rue were most sensitive species, whose root growth was inhibited by 78% and 96%, respectively, at 50 mu g/mL dose of xanthatin, while the root length of Italian cocklebur was only inhibited by 23%. In fact, Italian cocklebur was the only receiver species that survived at 1 mg/mL xanthatin and xanthinin treatment. Our results suggested that the selective phytotoxicity of Italian cocklebur and other species facilitated its successful invasion. This is the first report on the phytotoxic activity of xanthatin.
  • Article
    The aqueous extraction of the sesquiterpene lactone xanthatin from Xanthium spinosum L. favours the conversion of xanthinin (1) to xanthatin (2) via the loss of acetic acid. The cytotoxic (Hep-G2 and L1210 human cell lines) and antiviral activities of isolated xanthatin are established. This natural compound shows significant cytotoxicity against the Hep-G2 cell line and our experimental results reveal its strong anti-angiogenesis capacity in vitro. The structure of xanthatin is determined by spectroscopic methods and for the first time confirmed by X-ray diffraction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
  • Chapter
    Full-text available
    The epidemiological data suggest that the incidence and prevalence of serious mycoses continues to be a public health problem. The increased use of antifungal agents has resulted in the development of resistance to these drugs. The spread of multidrug-resistant strains of fungus and the reduced number of drugs available make it necessary to discover new classes of antifungals from natural products including medicinal plants. Historically, herbs and spices have enjoyed a rich tradition of use for their medicinal properties and provide unlimited opportunities for new drug leads because of the huge chemical diversity. Assays of bioactive compounds have been reported with good antifungal properties in vitro or in vivo. It is almost impossible to discuss the various characteristics of these plants such as mode of action and extraction of active compounds in a single review. Therefore, we have focussed here mainly on the antifungal plant extracts, their use against pathogeinc and drug resistant fungi. The various classes of compounds such as phenolics, terpenoids, saponins, and alkaloids, etc., are discussed in detail. The new emerging classes of antifungal proteins and peptides are also reviewed briefly. In this chapter, we also describe the technical aspects related to the methodology for screening and identification of antifungal compounds. The technical aspects regarding the use of reliable methodology of extraction, screening, bioautography, and identification of pure compounds from crude extracts and fractions are also discussed here.
  • Article
    The enantioselective synthesis of cytostatic and antibiotic xanthatin (1 a) is reported. As a key intermediate, a bicyclic compound 2 was identified, which can be readily synthesized from methyl-2-furoic acid in diastereo- and enantiomerically pure form. Compound 2 can be functionalized regio- and stereoselectively at C-6 and C-7, allowing the facile introduction of the functionalities found in xanthatin, as well as the synthesis of derivatives thereof. Moreover, a robust strategy for the introduction of the exo-methylene group at C-3, commonly found in many sesquiterpenes, was developed that makes use of masking the alkene in the α,β-unsaturated carbonyl system by O-pivaoyl, which is stable under acidic and mild basic conditions but eliminated upon treatment with strong bases.
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  • Article
    An investigation of Inula helenium, I. royleana, I. salicina and I. bifrons afforded in addition to known sesquiterpene lactones 20 new lactones, the eudesmanolides 3, 6 and 8–12, the germacranolides 14–18 and 20–22, the guaianolides 23 and 25, the pseudoguaianolide 26, the xanthanolides 28 and 32 and the cyclopropane analogue 30. Structures and configurations of these new compounds were established by extensive PMR studies and by some chemical transformations. Some of the investigated species contain besides the widely distributed pentaynene 33 several known thymol derivatives together with a new one (40).
  • Article
    The investigation of Pulicaria crispa afforded, in addition to known xanthanolides, three new ones, a new pseudoguaianolide epoxide and a new type of seco-sesquiterpene lactone. The structures were elucidated by spectroscopic methods.
  • Article
    The re-investigation of the aerial parts of Telekia speciosa afforded five new sesquiterpene lactones, two eudesmanolides and three xanthanolides, all closely related to those isolated before from this species or from related genera. The structures were elucidated by 1H NMR spectroscopy.
  • Article
    The therapeutic armentarium against leishmaniasis is very restricted, using mainly up to now drugs showing several side effects and resistance. Consequently, there is a real need to find new compounds as alternatives for the treatment of leishmaniasis. However, most of the classic antileishmanial primary screening assays are not suitable for measuring the cytotoxicity of large number of drug candidates because of the manipulations required. We have established a new assay that incorporate a fluorometric growth indicator based on the detection of a metabolic activity in culture medium after the chemical reduction of alamar Blue® by cells. This antileishmanial test was evaluated on amphotericin B, meglumine antimoniate, allopurinol, ketoconazole and edelfosine. The results reported show the advantages of this fluorochrome on the tetrazolium salt 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) for Leishmania cytotoxicity measurement. Moreover, this study is the first report of the use of alamar Blue® fluorogenic assay for activity assessment of potential antileishmanial drugs against promastigotes.
  • Article
    Three new xanthanolides have been isolated from Xanthium spinosum and X. strumarium subsp. italicum, together with other known compounds. The absolute configurations of xanthanol, isoxanthanol and their C-4 epimers have been established.
  • Article
    Dichloromethane extracts from Xanthium spinosum L. were fractionated and the fractions tested for their bactericidal and fungicidal activity. From the active fraction, a compound was isolated and identified as xanthatin (I). Xanthatin was active against Colletotrichum gloesporoides, Trichothecium roseum, Bacillus cereus and Staphylococcus aureus.
  • Article
    Seven xanthanolides were identified in the extract of X. italicum leaves. Antibacterial and cytotoxic activities were found for the total extract and its major constituents xanthinin and xanthatin.
  • Article
    Antitrypanosomal activity of crude 50% ethanolic extract of Xanthium strumarium leaves was studied in vitro and in vivo. The extract exhibited trypanocidal activity at all four concentrations tested i.e. 5, 50, 500 and 1000 micrograms/ml, in vitro. In vivo trial revealed that the extract exerted antitrypanosomal effect at dosage of 100, 300 and 1000 mg/kg, intraperitoneally. At 100 and 300 mg/kg doses the survival period of the Trypanosoma evansi infected mice was significantly prolonged. However, the extract was found to be toxic to the animals at 1000 mg/kg dose.
  • Article
    The lipophilic flavonoids in leaf and flower of Tanacetum parthenium and T. vulgaris have been compared. While those of T. parthenium are methyl ethers of the flavonols 6-hydroxykaempferol and quercetagetin, the surface flavonoids of T. vulgare are methyl ethers of the flavones scutellarein and 6-hydroxyluteolin. Apigenin and two flavone glucuronides are surprisingly present in glandular trichomes on the lower epidermis of the ray florets of T. parthenium. The opportunity has been taken to revise the structures of the four 6-hydroxyflavonol methyl ethers of T. parthenium based on NMR measurements. These are now shown to be uniformly 6- rather than 7-O-methylated. Tanetin, previously thought to be a new structure, is now formulated as the known 6-hydroxykaempferol 3,6,4'-trimethyl ether. The vacuolar flavonoids of both plants are dominated by the presence of apigenin and luteolin 7-glucuronides; nine other glycosides were present, including the uncommon 6-hydroxyluteolin 7-glucoside in T. vulgare. When the major flavonol and flavone methyl ethers of the two plants were tested pharmacologically, they variously inhibited the major pathways of arachidonate metabolism in leukocytes. There were significant differences in potency, with the tansy 6-hydroxyflavones less active than the feverfew 6-hydroxyflavonols as inhibitors of cyclo-oxygenase and 5-lipoxygenase.
  • Article
    Fungicidal activity of 36 natural and synthetic sesquiterpene lactones with guaianolide, trans, trans-germacranolide, cis, cis-germacranolide, melampolide, and eudesmanolide carbon skeletons was evaluated against the phytopathogenic fungi Colletotrichum acutatum, C. fragariae, C. gloeosporioides, Fusarium oxysporum, Botrytis cinerea, and Phomopsis sp. Dose-response data for the active compounds dehydrozaluzanin C, dehydrocostuslactone, 5alpha-hydroxydehydrocostuslacone, costunolide, and zaluzanin C are presented. A new 96-well microbioassay procedure for fast and easy evaluation of antifungal activity was used to compare these compounds with commercial fungicide standards. Some structure-activity conclusions are also presented.
  • Article
    In the search for new sources of sesquiterpene lactones, six Centaurea species have been analyzed. The activity against the fungus Cunninghamella echinulata of (+)-cnicin (1) and (+)-salonitenolide (2), isolated from the Centaurea plants, as well as that of (+)-costunolide (3), (-)-dehydrocostuslactone (4), (-)-lychnopholide (5) and (-)-eremantholide C (6), has been evaluated. Compounds 3 and 4 showed noticeable EC50 values, whilst more polar lactones were inactive. These results suggest that a relatively low polarity is one of the molecular requirements for the antifungal activity of sesquiterpene lactones.
  • Article
    The leishmanicidal compounds isolated from whole plants of Elephantopus mollis H.B.K. were identified as follows. Three new sesquiterpenoid lactones, 2,5-epoxy-2beta-hydroxy-8alpha-(2-methylpropenoyloxy)-4(15),10(14),11(13)-germacratrien-12,6alpha-olide, (4betaH)-8alpha-(2-methylpropenoyloxy)-2-oxo-1(5),10(14), 11(13)-guaiatrien-12,6alpha-olide and (4betaH)-5alpha-hydroxy-8alpha-(2-methylpropenoyloxy)-1(10),11(13)-guaiadiene-12,6alpha-olide, were isolated from Peruvian and Brazilian collections together with four known sesquiterpenoids, molephantin, elephantopin, isoelephantopin and 2-deethoxy-2beta-methoxyphantomolin. They exhibited potent in vitro leishmanicidal activities against Leishmania major. The alpha-methylene-gamma-butyrolactone moiety was found to be essential to the potent leishmanicidal effect observed.
  • Article
    From the aerial parts of Xanthium strumarium, three new xanthanolide and xanthane-type sesquiterpenoids, 11alpha,13-dihydroxanthatin, 4beta,5beta-epoxyxanthatin-1alpha,4alpha-endoperoxide, and 1beta,4beta,4alpha,5alpha-diepoxyxanth-11(13)-en-12-oic acid have been isolated, together with seven known compounds. The structures were determined by spectroscopic methods, particularly high resolution 1D, 2D NMR spectroscopy and NOE experiments.