Furofuran Lignans Research Articles

Anxiolytic activity and active principles of Piper amalago (Piperaceae), a medicinal plant used by the Q’eqchi’ Maya to treat susto, a culture-bound illness

Ethnopharmacological relevanceThe medicinal plant, Piper amalago L. (Piperaceae), is used traditionally by Q’eqchi’ Maya healers for the treatment of “susto” a culture-bound syndrome. Previous research suggests that susto symptoms may be a manifestation of anxiety. The objectives were to characterize the effect of ethanolic extract of P. amalago in behavioral assays of anxiety at doses representative of traditional use and to isolate active principles. Materials and methodsRats treated orally with low dose ethanolic extracts of P. amalago leaves (8–75mg/kg) were tested in several behavioral paradigms including the elevated plus maze (EPM), social interaction (SI), and conditioned emotional response (CER) tests, and compared to diazepam, a positive control. The active anxiolytic principle was isolated by bioassay guided isolation using an in vitro GABAA competitive binding assay. ResultsExtracts had significant anxiolytic activity in all behavioral tests, with the strongest activity in the SI and the CER paradigms. In an in vitro GABAA competitive binding assay, a 66.5µg/mL concentration of P. amalago ethanol extract displaced 50% of the GABAA–BZD receptor ligand [3H]-Flunitrazepam. Bioassay-guided fractionation identified a furofuran lignan, a molecule with structural similarity to yangambin, with high affinity for the GABAA-BZD receptor as the principle bioactive. ConclusionThe results suggest that the ethnobotanical use of this plant may have a pharmacological basis in its anxiolytic activity, as demonstrated in animal behaviour tests

Isolation and characterization of wound-induced compounds from the leaves of Citrus hassaku

Citrus plants are world widely cultivated as horticultural tree crops, and nowadays their pharmacological activities have been well studied. Since research of defense responses in citrus plants have been mainly focused on the post-harvested fruits because of their commercial importance, defense mechanisms during their developmental stages have not been well understood. In the present study, two wound-induced compounds were isolated from leaves of Citrus hassaku, and their structures were elucidated by high-resolution electron spray ionization mass spectra (HRESIMS) and nuclear magnetic resonance (NMR) analyses. One of these compounds was identified as a known flavanone, hesperetin. The other was characterized as a novel furofuran lignan, and was named 'biscitrusnin-A'. Their antimicrobial activities were also evaluated.

Generation of Triple-Transgenic Forsythia Cell Cultures as a Platform for the Efficient, Stable, and Sustainable Production of Lignans

Sesamin is a furofuran lignan biosynthesized from the precursor lignan pinoresinol specifically in sesame seeds. This lignan is shown to exhibit anti-hypertensive activity, protect the liver from damages by ethanol and lipid oxidation, and reduce lung tumor growth. Despite rapidly elevating demand, plant sources of lignans are frequently limited because of the high cost of locating and collecting plants. Indeed, the acquisition of sesamin exclusively depends on the conventional extraction of particular Sesamum seeds. In this study, we have created the efficient, stable and sustainable sesamin production system using triple-transgenic Forsythia koreana cell suspension cultures, U18i-CPi-Fk. These transgenic cell cultures were generated by stably introducing an RNAi sequence against the pinoresinol-glucosylating enzyme, UGT71A18, into existing CPi-Fk cells, which had been created by introducing Sesamum indicum sesamin synthase (CYP81Q1) and an RNA interference (RNAi) sequence against pinoresinol/lariciresinol reductase (PLR) into F. koreanna cells. Compared to its transgenic prototype, U18i-CPi-Fk displayed 5-fold higher production of pinoresinol aglycone and 1.4-fold higher production of sesamin, respectively, while the wildtype cannot produce sesamin due to a lack of any intrinsic sesamin synthase. Moreover, red LED irradiation of U18i-CPi-Fk specifically resulted in 3.0-fold greater production in both pinoresinol aglycone and sesamin than production of these lignans under the dark condition, whereas pinoresinol production was decreased in the wildtype under red LED. Moreover, we developed a procedure for sodium alginate-based long-term storage of U18i-CPi-Fk in liquid nitrogen. Production of sesamin in U18i-CPi-Fk re-thawed after six-month cryopreservation was equivalent to that of non-cryopreserved U18i-CPi-Fk. These data warrant on-demand production of sesamin anytime and anywhere. Collectively, the present study provides evidence that U18i-CP-Fk is an unprecedented platform for efficient, stable, and sustainable production of sesamin, and shows that a transgenic and specific light-regulated Forsythia cell-based metabolic engineering is a promising strategy for the acquisition of rare and beneficial lignans.

Stereocontrolled Total Syntheses of Optically Active Furofuran Lignans

Plant products (+)-sesamin, (+)-sesaminol, (+)-methylpiperitol, (+)-aschantin, and (+)-5'-hydroxymethylpiperitol were synthesized in a highly stereocontrolled manner through l -proline-catalyzed bifunctional-urea-accelerated cross-aldol reaction, followed by biomimetic construction of the furofuran lignan skeleton through a quinomethide intermediate.

A new furofuran lignan diglycoside and other secondary metabolites from the antidepressant extract of Castilleja tenuiflora Benth.

Castilleja tenuiflora has been used for the treatment of several Central Nervous System (CNS) diseases. Herein we report the antidepressant activity of the methanol extract from the leaves of this medicinal plant. The oral administration of MeOH extract (500 mg/kg) induced a significant (p < 0.05) decrement of the immobility parameter on Forced Swimming Test (FST) and an increment in the latency and duration of the hypnosis, induced by administration of sodium pentobarbital (Pbi, 40 mg/kg, i.p.). Chemical analysis of this antidepressant extract allowed the isolation of (+)-piperitol-4-O-xylopyranosyl-(1→6)-O-glucopyranoside. This new furofuran lignan diglycoside was named tenuifloroside (1) and its complete chemical structure elucidation on the basis of 1D and 2D NMR spectra analysis of the natural compound 1 and its peracetylated derivative 1a is described. This compound was found together with two flavones—apigenin and luteolin 5-methyl ether—a phenylethanoid—verbascoside—and three iridoids—geniposide, caryoptoside and aucubin. All these compounds were purified by successive normal and reverse phase column chromatography. Tenuifloroside, caryoptoside and luteolin 5-methyl ether were isolated from Castilleja genus for the first time. These findings demonstrate that C. tenuiflora methanol extract has beneficial effect on depressive behaviors, and the knowledge of its chemical constitution allows us to propose a new standardized treatment for future investigations of this species in depressive illness.

Evaluation of plant growth regulatory activity of furofuran lignan bearing a 7,9':7',9-diepoxy structure using optically pure (+)- and (-)-enantiomers.

The plant growth regulatory activity of furofuran lignan (7,9':7',9-diepoxylignan) was evaluated by employing optically pure synthesized (+)- and (-)-enantiomers. (+)-Sesamin possessing a 3,4-methylenedioxy group on the aromatic rings and 7-aryl structure showed growth promotion activity against lettuce roots (EC50 = 0.50 mM); on the other hand, growth inhibitory activity was observed against lettuce shoots (EC50 = 0.38 mM). Against ryegrass shoots, (-)-sesamolin, which has 3,4-methylenedioxy groups on the aromatic rings and a 7-acetal structure, was effective in showing growth inhibitory activity (EC50 = 0.23 mM). Different activity levels were observed between (+)- and (-)-enantiomers. It was assumed that the 3,4-methylenedioxy group on the aromatic ring was more potent for the plant growth regulatory activity.

Ethyl acetate-soluble chemical constituents from branch of Hypericum petiolulatum

The stems and branches of Hypericum petiolulatum were extracted by alcohol and liquid-liquid extraction. Seven furofuran lignans were isolated from the ethyl acetate fraction of ethanol extract of H. petiolulatum by using silica gelchromatography, Sephadex LH-20 chromatography, medium-pressure liquid chromatography and preparative HPLC. Their structures were identified by the spectroscopic methods as pinoresinol (1), medioresinol (2), 8-acetoxypinoresinol (3), epipinoresinol (4), (+)-syringaresinol (5), (+)-1-hydroxysyringaresinol (6) and erythro-buddlenolE (7). All the isolates were firstly found in H. petiolulatum. In the bioassay, compound 7 showed remarkable antioxidative activity inhibiting Fe(+2)-cystine induced rat liver microsomal lipid peroxidation with inhibitory rate 38% at a concentration of 1 x 10(-6) mol · L(-1) (positive control Vit E with the inhibitory rate of 35% at the same concentration).

Furofuran lignans display schistosomicidal and trypanocidal activities

Parasitic diseases continue to be a major worldwide health problem, and there is an urgent need for development of therapeutic drugs. This paper describes synthesis of dehydrodiferulic acid dilactone 1 and dehydrodisinapic acid dilactone 2 furofuran lignans by oxidative coupling of ferulic and sinapic acids, respectively. Their schistosomicidal, trypanocidal, and leishmanicidal activities were evaluated in vitro against Schistosoma mansoni adult worms, trypomastigote and amastigotes forms of Trypanosoma cruzi, and promastigote forms of Leishmania amazonensis. Compound 1 did not display significant schistosomicidal activity, but it presented potent trypanocidal activity, since it induced death of trypomastigotes and amastigotes with IC50/24h of 9.3μM and 7.3μM, respectively. Compound 2 had slight trypanocidal and schistosomicidal activities. None of the compounds were active against L. amazonensis. These results demonstrated that furofuran lignans are potentially useful for anti-parasitic drugs development and should be further investigated.

Total Syntheses of (+)-Sesamin and (+)-Sesaminol

Abstract Total syntheses of (+)-sesamin (1a) and (+)-sesaminol (1b), which are major components of sesame lignans derived from Sesamum indicum, were accomplished in a highly stereocontrolled manner. Key steps include an l-proline-catalyzed cross-aldol reaction, which was accelerated with the aid of bifunctional urea 7, and the construction of a furofuran lignan skeleton through a quinomethide intermediate.

Antimycobacterial furofuran lignans from the roots of Anemopsis californica.

Topical preparations of Anemopsis californica have been used by Native American tribes in the southwestern United States and northern Mexico to treat inflammation and infections. We report results of bioassay-guided isolation conducted on a sample of A.californica roots. The furofuran lignans sesamin (1) and asarinin (2) were isolated and shown to have MIC values ranging from 23 to 395 µM against five different species of environmental nontuberculous mycobacteria. These findings are significant given that these bacteria can cause skin, pulmonary, and lymphatic infections. Crude A.californica extracts were analyzed by liquid chromatography-mass spectrometry, and it was determined that sesamin and asarinin were extracted at relatively high levels from the roots (1.7-3.1 g/kg and 1.1-1.7 g/kg, respectively), but at lower levels from the leaves (0.13 g/kg for both compounds). Our findings suggest that the majority of activity of crude A.californica root extracts against nontuberculous mycobacteria can be attributed to the presence of sesamin and asarinin. This paper is the first to report the isolation of these compounds from a member of the Saururaceae family, and the first to describe their activity against nontuberculous mycobacteria.

Stereocontrolled Total Synthesis of Hedyotol A

The total synthesis of hedyotol A (1), a natural product isolated from Hedyotis lawsoniae (DC.) Wight et Arn. (Rubiaceae), was accomplished in a highly stereocontrolled manner. Key steps include an L-proline-catalyzed cross-aldol reaction and the biomimetic construction of a furofuran lignan skeleton through a quinomethide intermediate.

Quantitative and structural analysis of amides and lignans in Zanthoxylum armatum by UPLC-DAD-ESI-QTOF–MS/MS

A rapid and simple ultra performance liquid chromatography-diode array detection (UPLC-DAD) method has been developed for the simultaneous quantification of four biologically important furofuran lignans, asarinin, sesamin, fargesin and kobusin, and an amide, armatamide in Zanthoxylum armatum within 7min. The separation was carried out on a BEH C18 column (2.1mm×100mm, 1.7μm particle size) with 0.05% formic acid aqueous solution and acetonitrile as mobile phase under gradient conditions at 25°C. The method was validated and found to be linear (R2≥0.9997), precise in terms of peak areas (intra-day RSDs≤0.62% and inter-day RSDs≤2.95%) and accurate (95.6–104.0%). The developed method was applied to the quality assessment of different parts (leaves, bark and seeds) of Z. armatum including locational variation of leaves samples. Significant variation in the amount of amides and furofuran lignans was observed. Tandem electrospray ionization–mass spectrometry (UPLC-DAD-ESI–MS/MS) of samples led to the identification of sixteen compounds in the category of amides and furofuran lignans.

Simultaneous Determination of Asaranin and Sesamin in Piper chaba Fruit by using HPTLC-MS Method: Effect of Different Extraction Methods on the Yield of Marker Compounds

A simple, rapid and accurate HPTLC-MS method was developed for the simultaneous quantification of asaranin (AS) and sesamin (SM), the two epimeric furofuran lignans in Piper chaba (Piperaceae) fruit extracts obtained by cold percolation (PER), Soxhlet extraction (SOX), ultrasound assisted extraction (USAE), accelerated solvent extractor (ASE) and microwave assisted extraction (MAE). Separation of AS and SM was achieved on 20×10 cm pre-coated silica gel 60 F254S HPTLC plates with ethyl acetate: hexane (30:70) as mobile phase. Detection and quantification were performed densitometrically at λmax 295 nm. The peak identity was confirmed by electron spray ionization (ESI) mass spectra, which showed the [M + Na]+ ions for both AS and SM at m/z 377. The method was validated according to the ICH guidelines in terms of limit of detection (LOD) and limit of quantification (LOQ), selectivity, linearity, precision, accuracy, and robustness. The results indicate that AS (2.108%) and SM (0.103%) found to present maximum in ASE extract and minimum in PER extract (AS 0.848%; SM 0.048%). By considering the validation results, the method was found to be reproducible and convenient for quantitative analysis of AS and SM in different P. chaba fruit extracts.

ChemInform Abstract: Two New Furofuran Lignans from Kandelia obovata.

AbstractThe two new furofuran lignans kandelisesquilignan A (Ia) and B (Ib) are isolated from the aerial part of Kandelia obovata.

Simultaneous Determination of Two Epimeric Furofuran Lignans (Sesamin and Asarinin) of Asarum heterotropoides Extract in Rat Plasma by LC/MS/MS: Application to Pharmacokinetic Study

A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry was developed to determine two epimeric furofuran lignans (sesamin and asarinin) simultaneously from Asarum heterotropoides extract in rat plasma. Simple protein precipitation with acetonitrile was performed to extract analytes by using alantolactone as an internal standard. Chromatographic separation was achieved using a DIKMA Diamonsil C18 analytical column (4.6 mm × 150 mm, i.d., 5 µm) by isocratically eluting with a mobile phase consisting of methanol/5 mM ammonium acetate/formic acid (75:25:0.1, v/v/v) at a flow rate of 0.8 mL/min. Tandem mass spectrometric detection with an electrospray ionization interface was performed by multiple reaction monitoring in positive ionization mode. This method was validated according to specificity, sensitivity, linearity, intra- and inter-day precision (<10.7%) and accuracy (<2.3%) and recovery and stability in a concentration range of 25.0-15 000 ng/mL for sesamin and 5.00-3 000 ng/mL for asarinin. This method has been successfully applied in a pharmacokinetic study of A. heterotropoides extract containing sesamin and asarinin after this extract was orally administrated in rats.

New Lignans from the Aerial Parts of Rudbeckia laciniata

AbstractThree new furofuran lignans, (+)‐4,4′‐O‐diangeloylpinoresinol (1), (+)‐4,4′‐O‐diangeloylmedioresinol (2), and (+)‐4,4′‐O‐diangeloylsyringaresinol (3), together with the known compound (+)‐syringaresinol, were isolated from the MeOH extract of Rudbeckia laciniata. The structure elucidation of these compounds were based on 1D‐ and 2D‐NMR, and HR‐ESI‐MS data. The additional structural evidence was obtained from alkaline hydrolysis of the compounds.

Root tubers of Lactuca tuberosa as a source of antioxidant phenolic compounds and new furofuran lignans

From the root tubers of Lactuca tuberosa, a wild edible plant species, nine phenolic compounds were isolated, including two new furofuran lignan glucosides, named lactuberin A and lactuberin B. Their structures were elucidated by spectroscopic methods, especially HRESIMS and 2D NMR techniques. This is the first time that compounds belonging to the epi series of 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane type furofuran lignans have been found in Lactuca species. The total phenolic content of the root tuber extract was evaluated and its major phenolic constituents, caffeic acid, chlorogenic acid and 3,5 dicaffeoylquinic acid, known to possess antioxidant activity, were quantified. Additionally, the root tuber extract showed DPPH radical scavenging activity implying its potential as functional food.

Synthesis and trypanocidal activity of a furofuran lignan against trypomastigote and amastigote forms of Trypanosoma Cruzi

Chagas disease, which affects approximately 8 million people in Latin American and more than 25 million people are at risk of this infection, is a neglected tropical disease caused by the protozoan Trypanosoma cruzi. Drugs currently used to treat it, such as benznidazole, do not completely eliminate the trypomastigote forms (present in the blood), are ineffective against the intracellular stage of the parasite and cause some side effects. In this work, a furofuran lignan was obtained by oxidative coupling of ferulic acid with FeCl3 in presence of O2, according to Ahmed, 1973. Then, it was evaluated in vitro against trypomastigote and amastigote forms of T. cruzi. The results showed that this lignan presents potent tripanocidal activity since it induces trypomastigote and amastigote lysis with IC50 values of 9.3 and 7.3µmol/L, respectively. On the other hand, the direct effect of benznidazole, the positive control, was also evaluated and it showed an IC50 value of 1.9µmol/L on trypomastigotes and an IC50 of 69.2µmol/L against the other form tested. These results indicate that this lignan is promising compound that could be used for the development of a new trypanocidal agent, therefore further studies are in progress to elucidate it mechanism of action. The authors thank FAPESP and CNPq for their fellowships. Ahmed, R., Lehner, M., Stevenson, R. Tetrahedron, 29, 3753–3759, 1973.

Antioxidant furofuran lignans from Premna integrifolia

Two new furofuran lignans premnadimer (1) and 4β-hydroxyasarinin-1-O-β-glucopyranoside (2) along with 9 known compounds have been isolated from the stem bark of Premna integrifolia. Their chemical structures were elucidated using detailed spectroscopic studies. Their relative configurations were established using analysis of NOESY correlations and coupling constants observed in 1H NMR. Compounds 1 and 2 together with four known iridoid glycosides (3–6) were evaluated for radical scavenging and ferric reducing antioxidant power. Radical scavenging activity was found maximum in 4″-hdroxy-E-globularinin (4) followed by 10-O-trans-p-coumaroylcatalpol (3) and new dimer (1). In FRAP assay, premnosidic acid (5), 10-O-trans-p-coumaroyl-6-O-α-l-rhamnopyranosyl catalpol (6) showed maximum ferric reducing ability supported by high reducing power.

(+)-Medioresinol leads to intracellular ROS accumulation and mitochondria-mediated apoptotic cell death in Candida albicans

The phytochemical (+)-Medioresinol, a furofuran type lignan identification and isolation on the stem bark of Sambucus williamsii, which is a folk medicinal plant used in traditional medicine. (+)-Medioresinol is known to possess a lesishmanicidal activity and cardiovascular disease risk reduction but its antifungal effects have not yet been identified. In this study, to confirm (+)-Medioresinol's antifungal properties and mode of action, we observed morphological and physiological change in Candida albicans. In cells exposed to (+)-Medioresinol, arrested the cell cycle and intracellular reactive oxygen species (ROS) which is a major cause of apoptosis were increased. The increase of ROS induced oxidative stress and the mitochondria dysfunction which causes release of pro-apoptotic factors. We investigated a series of characteristic cellular changes of apoptosis by using various apoptosis detection methods. We report here for the first time that (+)-Medioresinol has effects on mitochondria and induced the accumulation of ROS in C.albicans cells. We demonstrated that one of the important features of apoptosis, mitochondrial membrane depolarization is caused by ROS. Substantially, we investigated the release of cytochrome c, which is one of the factors of metacaspase activity. We also show that the effects of (+)-Medioresinol are mediated at an early stage in apoptosis acting on the plasma membrane phosphatidylserine externalization. In addition, (+)-Medioresinol induced apoptotic morphological changes, showing the reduced cell size (low FSC) and enhanced intracellular density (high SSC). In late stage of confirmation of diagnostic markers in yeast apoptosis include the effects of nucleus morphological change, DNA fragmentation and condensation by influence of oxidative stress. These apoptotic phenomena represent that oxidative stress and mitochondria dysfunctions by inducing the phytochemical (+)-Medioresinol must be an important factors of the apoptotic process in C.albicans. These results support the elucidation of the underlying antifungal mechanisms of (+)-Medioresinol.