benzofurans and phthalide

Phthalides, an important class of bioactive natural products, are widely distributed in plants, fungi, lichens, and liverworts. Amon them, n-butylphthalide, a phthalide monomer, has been approved to cure ischemic stroke. Owing to their good bioactivities in anti-microbial, anti-inflammatory, anti-tumor, anti-diabetic, and other aspects, a large number of researches have been conducted on phthalides from nature materials. In recent years, hundreds of novel natural phthalides were obtained. This review provides profiles of the advances in the distribution, chemistry, and biological activities of natural phthalides in 2016-2022.

Topics: Anti-Inflammatory Agents; Benzofurans; Fungi; Molecular Structure; Plants

The study aims at the derivatization of "Phthalides" and synthesizes 3- arylaminophthalides & 3-indolyl-phthalides compounds, and evaluates their anti-tubercular and antioxidant activities. The study has also intended to employ the in silico methods for the identification of possible drug targets in Mycobacterium and evaluate the binding affinities of synthesized compounds.. This report briefly explains the synthesis of phthalide derivatives using ammonium chloride. The synthesized compounds were characterized using spectral analysis. Resazurin Microtiter Assay (REMA) plate method was used to demonstrate the anti-mycobacterial activity of the synthesized compounds. An in-silico pharmacophore probing approach was used for target identification in Mycobacterium. The structural level interaction between the identified putative drug target and synthesized phthalides was studied using Lamarckian genetic algorithm-based software.. In the present study, we report an effective, environmentally benign scheme for the synthesis of phthalide derivatives. Compounds 5c and 5d from the current series appear to possess good anti-mycobacterial activity. dCTP: deaminasedUTPase was identified as a putative drug target in Mycobacterium. The docking results clearly showed the interactive involvement of conserved residues of dCTP with the synthesized phthalide compounds.. On the eve of evolving anti-TB drug resistance, the data on anti-tubercular and allied activities of the compounds in the present study demonstrates the enormous significance of these newly synthesized derivatives as possible candidate leads in the development of novel anti-tubercular agents. The docking results from the current report provide a structural rationale for the promising anti-tubercular activity demonstrated by 3-arylaminophthalides and 3-indolyl-phthalides compounds.

Topics: Algorithms; Ammonium Chloride; Antioxidants; Antitubercular Agents; Benzofurans; Drug Design; Humans; Hydroxyl Radical; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Nucleotide Deaminases; Structure-Activity Relationship; Tuberculosis

Phthalides and α,β-butenolides are two related classes of oxygenated heterocycles with a wide range of biological activities. An innovative strategy to prepare these compounds is based on C-H bond functionalization reactions, in which two simple, unfunctionalized molecules are coupled together with cleavage of a C-H bond and formation of a C-X bond (X=C or heteroatom). This paper reviews the methods for the synthesis of phthalides and α,β-butenolides by C-H bond functionalization from non-halogenated starting materials. Over 30 methods are reported, mostly developed during the past ten years.

Topics: 4-Butyrolactone; Benzofurans; Catalysis; Coordination Complexes; Cycloaddition Reaction; Molecular Structure; Oxidation-Reduction; Transition Elements

Apiaceae plants exhibit a broad spectrum of activities, for instance, antithrombotic, hypotensive, antioxidant, and insecticidal. They also provide a source of phthalides, which display antimicrobial activity. Considering the fact of rising resistance of both bacteria and fungi against commonly used antibiotics, developing of new naturally derived compounds is undeniably attractive approach. To our best knowledge, there are no other reviews concerning this subject in the literature. In view of above, an attempt to summarize an antimicrobial potential of isolated compounds and extracts from Apiaceae plants has been made, by specifying techniques of activity determination and methods of extraction. Techniques of antimicrobial activity evaluation are mainly based on bioautography, diffusion, and dilution methods. Therefore, we focused on in vitro data described in literature so far.

Topics: Anti-Infective Agents; Apiaceae; Bacteria; Benzofurans; Fungi; Microbial Sensitivity Tests; Plant Extracts

Essential oil is the low polar and volatile components distilled or extracted from Ligusticum chuanxiong, the dry root of perennial herb L. chuanxiong, which has proven to be one of the main biological active ingredients of L. chuanxiong. Studies suggested that essential oil of L. chuanxiong mainly contains phthalide, terpene alcohols and fatty acids compounds. Different regions or varied extraction technology had influences on the type and contents of compound in essential oil of L. chuanxiong and the total yield efficiency of essential oil, while the differences among the distribution of compounds leads to the variant pharmacological function of essential oil of L. chuanxiong. Researches confirmed that essential oil of L. chuanxiong has kinds of pharmacological activities such as sedation, analgesia, improve function of blood vessels, protected nerve cells and fever-reducing, all these benefits were verified by experiment studies in vivo and some of which were used as therapies in treating migraine, the underlining mechanisms include anti-inflammation, apoptosis pathway and studies found that essential oil of L. chuanxiong possessed very low acute and chronic toxicity at the same time, revealed its great value of development and utilization in clinical applications. Recent studies light some problems such as lack of quality standards and the research of relationship between efficacy and material. The key to apply the usage of essential oil of L. chuanxiong locate in its substantial basis research, the establishment of the quality standards and the joint research institute, more study should work on these fields.

Topics: Animals; Benzofurans; Drugs, Chinese Herbal; Fatty Acids; Humans; Ligusticum; Oils, Volatile; Terpenes

Topics: Anti-Bacterial Agents; Bacteria; Benzoates; Benzofurans; Biological Products; Cyclization; Lactones; Oxidation-Reduction; Phthalimides

Phthalides, and their corresponding dihydro and tetrahydro analogues, are components of several genera of the plant family Apiaceae. These taxa have been reported as exhibiting a wide range of bioactivities against experimental models of several illnesses and physiological conditions, including microbial and viral infections, stroke, tuberculosis, and vasoconstriction. Many of these genera are purported to possess medicinal values, and of these several are considered to be traditional herbal medicines. This review provides an overview of the methods of investigation, the structural diversity, and the bioactivity of phthalides, dihydrophthalides, tetrahydrophthalides, and dimers from plants in the Apiaceae.

Topics: Apiaceae; Benzofurans; Molecular Structure; Plants, Medicinal

Herein, we report direct electrochemical C(sp

Topics: Benzofurans; Lactones

There are six new phthalide derivatives Verbalide A ~ F (1-6) together with another known derivative (7) isolated from the endophytic fungus Preussia sp. CPCC 400972. Their structures were established by comprehensive spectroscopic analyses, including NMR and HRESIMS. In addition, compounds 1-7 exhibited excellent inhibitory effect against influenza A virus.

Topics: Ascomycota; Benzofurans; Magnetic Resonance Spectroscopy; Molecular Structure

An electrochemical cascade sulfonylation and lactonization process of alkenes and a most widely used arylsulfonylation reagent─sulfonyl hydrazines─was developed for the first time. This electrochemical sulfonyl lactonization avoided the use of toxic metal catalysts or stoichiometric oxidants and was carried out under mild conditions. The target product γ-sulfonylated phthalides with broad and excellent substrate tolerance were achieved.

Topics: Alkenes; Benzofurans; Catalysis; Molecular Structure

Two new phthalide derivatives (1-2) and four known phthalide compounds (3-6) were purified from the culture of a mangrove endophytic fungus Pestalotiopsis sp. SAS4. Their chemical structures were established by analyses of 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-MS) spectroscopic data. All of these compounds were evaluated in vitro for antibacterial, cytotoxicity, and resistance to hypoxic-ischemic injury activities.

Topics: Benzofurans; Fungi; Molecular Structure; Pestalotiopsis

Herein, we report the asymmetric Ru/cinchonine dual catalysis that provides straightforward access to enantioselective synthesis of C-3 substituted phthalides via tandem C-H activation/Michael addition cascade. The use of readily accessible and less expensive [RuCl

Topics: Acrylates; Benzoates; Benzofurans; Catalysis; Cinchona Alkaloids; Molecular Structure; Stereoisomerism

Three undescribed isoindoline alkaloids, (+)-(R)-3-butyl-3-ethoxyisoindolin-1-one, (+)-(3S,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, and (-)-(3R,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, along with nine known phthalides were isolated from a water decoction of the rhizomes of Ligusticum chuanxiong using chromatographic methods. Their structures and absolute configurations were determined by extensive spectroscopic analyses and ECD data calculations. The relaxant effects of the isolated compounds on uterine contractions induced by oxytocin were investigated using a rat uterine smooth muscle contraction model. Furthermore, the effects of riligustilide on extracellular Ca

Topics: Animals; Benzofurans; Ligusticum; Muscle, Smooth; Oxytocin; Rats; Rhizome

Two pairs of unprecedented enantiomeric phthalide dimers, spiroligustolides A (1a/1b) and B (2a/2b), featuring a unique spiroorthoster linkage between two monomeric units to form a 5/6/5/6/6-fused ring system, were isolated from the roots of Ligusticum chuanxiong. The structures and relative configurations of 1 and 2 were determined by HR-ESI-MS, IR, and NMR spectroscopic data, coupled with single-crystal X-ray diffraction analysis, and the absolute configurations of 1a, 1b, 2a, and 2b were established by comparing the experimental and calculated electronic circular dichroism (ECD) data. Plausible biosynthetic pathway for 1 and 2 was proposed. Moreover, compounds 1, 1b, and 2b showed remarkable inhibitory activities on Ca

Topics: Benzofurans; Calcium Channels; Ligusticum; Molecular Structure; Stereoisomerism

An annulation of phthalide-derived activated alkenes is initially disclosed in this work. Specifically, we have developed an unprecedented [5 + 2] cycloaddition/ring-contraction tandem process of activated tetrasubstituted alkenes derived from phthalides or butyrolactone with vinylethylene carbonates under Pd(0) catalysis. Differing from the traditional spirolactonization strategy, this method renders an efficient and mechanistically distinct approach to benzo-[5,5]-spiroketal lactones and [5,5]-spiroketal lactones bearing two vicinal tetrasubstituted centers with high diastereoselectivity.

Topics: Alkenes; Benzofurans; Carbonates; Catalysis; Cycloaddition Reaction; Furans; Lactones; Palladium; Spiro Compounds

A new family of stabilized benzylic nucleophiles for the palladium-catalyzed decarboxylative allylic alkylation reaction has been developed. Allyl esters derived from 3-carboxyphthalides were found to undergo palladium-catalyzed deallylation and decarboxylation under mild reaction conditions, a process facilitated by the formation of a stabilized aromatic anion. The regioselective allylic coupling of this intermediate afforded a variety of functionalized phthalides in 73-96% yields.

Topics: Alkylation; Allyl Compounds; Benzofurans; Catalysis; Molecular Structure; Palladium

Six pairs of enantiomeric phthalide dimers (1-6) were isolated from the rhizomes of Ligusticum chuanxiong. Their structures and absolute configurations were elucidated by NMR spectroscopy, X-ray diffraction analyses, and electronic circular dichroism calculations. Compounds (+)-1 and (-)-1 are new phthalide dimers, featuring two classes of monomeric units (a phthalide and an unusual 2,3-seco-phthalide) with an uncommon linkage (3,6'/8,3'a). Compounds (+)-2 and (-)-3 are also novel phthalide dimers that had not been reported previously. Although (-)-2 and (+)-3 have been successfully isolated in previous studies, their absolute configurations were not unambiguously determined. As for compound 4, it was reported as a racemate in one study, and one of its enantiomers was identified in a subsequent study. Herein, all enantiomeric phthalide dimers were successfully separated, and their absolute configurations were determined. The inhibitory effects of all isolates against lipopolysaccharide-induced nitric oxide production were tested using RAW264.7 cells. The results show that compounds (+)-2, (-)-2, (+)-3, (-)-3, (+)-4, (-)-4, (+)-5, (+)-6, and (-)-6 have inhibitory activities, with compound (+)-5 being the most active (IC

Topics: Anti-Inflammatory Agents; Benzofurans; Ligusticum; Molecular Structure; Rhizome

A series of novel pathalide-1,2,4-oxadiazole analogs were synthesized for discovering novel anti-inflammatory agents. After the assessment of their cytotoxicity in vitro, all compounds had been screened for their anti-inflammatory activity by evaluating their inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages. SARs had been concluded, and finally compound E13 was found to be the most potent compound. This compound could also significantly decrease the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound E13 could inhibit the TLR4/NF-κB and ERK/p38 signaling pathways. These findings indicate that E13 holds great potential to be a lead compound for discovering novel anti-inflammatory drugs.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxadiazoles; RAW 264.7 Cells

The Rh-catalyzed ortho-C(sp

Topics: Acylation; Benzamides; Benzofurans; Carboxylic Acids; Catalysis; Rhodium

Two new phthalide derivatives, rhytidhylides A (

Topics: Ascomycota; Benzofurans; Cell Line, Tumor; Endophytes; Escherichia coli; Humans; Leptospermum; Molecular Structure

The extract from

Topics: Animals; Benzofurans; Cnidium; Glycosides; Hair Cells, Auditory; Neomycin; Rhizome; Silicon Dioxide; Zebrafish

Two new phthalide dimers (1 and 2) were obtained from the rhizomes of Ligusticum sinense Oliv., along with three known dimeric phthalides (3-5). Their structures were determined with the aid of the spectroscopic data, and their absolute configurations were elucidated based on the comparison of calculated and experimental electronic circular dichroism (ECD) spectra. All the compounds were evaluated in vitro for their inhibitory activities against NO production in LPS-treated RAW264.7 macrophages. Among them, compounds 1 and 3 showed potent NO prohibitive activity with IC

Topics: Animals; Benzofurans; China; Ligusticum; Mice; Molecular Structure; Nitric Oxide; Phytochemicals; Plants, Medicinal; RAW 264.7 Cells; Rhizome

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzofurans; Benzylidene Compounds; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Electrophorus; Female; Humans; Male; Mannich Bases; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

This study aims to establish a method for the determination of the concentration of five main components of phthalide target areas of Chaxiong(CPTA) and its inclusion of β-CD in the plasma of rats, and determine the pharmacokinetic parameters, absolute bioavailability and relative bioavailability of CPTA/β-CD inclusion compound in vivo. The plasma concentrations of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide were determined with UPLC-MS/MS. The content determination was conducted at the chromatographic conditions as follows: Shim-pack GIST C_(18)-AQ HP column(2.1 mm×100 mm, 3 μm), mobile phase of 0.1% formic acid solution(A)-acetonitrile(B), gradient elution, flow rate of 0.3 mL·min~(-1), column temperature of 35 ℃ and injection volume of 2 μL. The mass spectra were obtained with electrospray ion source(ESI), positive ion mode and multi reaction monitoring. CPTA/β-CD inclusion compound was prepared by grinding method, DAS 2.0 software was used to model the data, and the absolute bioavailability of CPTA and relative bioavailability of inclusion compound were calculated. Finally, the methods for the determination of five components of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide in CPTA, were successfully established. The linear relationship among the five components was good within their respective ranges, r>0.99. The absolute bioavailability of the five components in rats was 22.30%, 16.32%, 21.90%, 10.16% and 12.43%, respectively. After CPTA/β-CD inclusion was prepared, the relative bioavailability of the five components was 138.69%, 198.39%, 218.01%, 224.54% and 363.55%, respectively, significantly improved. This method is rapid, accurate and sensitive, so it is suitable for the pharmacokinetic study of extracts in traditional Chinese medicine and their preparations.

Topics: Animals; Benzofurans; Chromatography, High Pressure Liquid; Chromatography, Liquid; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry

The dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated.. At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC.. The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC.. SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.

Topics: Administration, Oral; Animals; Benzofurans; Infusions, Intravenous; Ligusticum; Male; Molecular Structure; Phytotherapy; Plant Oils; Rats; Rats, Sprague-Dawley; Rhizome

Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Isoquinolines; Noscapine; Papaver; Protein Binding; Small Molecule Libraries; Tubulin

As part of our continuing efforts to discover structurally interesting bioactive phthalide derivatives, 23 of them with a structure incorporating thiophen or halogens were designed and synthesized, 17 of which are previously unreported.

Topics: Animals; Antioxidants; Benzofurans; Hydrogen Peroxide; Molecular Structure; Platelet Aggregation Inhibitors; Rats

Phtalides are secondary metabolites found in several fungi with a wide range of biological activities. A novel phthalide analog was synthesized by Diels-Alder reaction between cyclopentadiene and 3,4-dichlorofuran-2(5H)-one. Quantum mechanical calculations were used in conjunction with the spectrometric methods to determine the structure of the title compound. The calculated NMR chemical shifts for eight candidate pairs of enantiomers were compared with the experimental NMR chemical shifts applying the DP4 probability and mean absolute errors methodology. DP4 analysis using

Topics: Benzofurans; Carbon Isotopes; Density Functional Theory; Magnetic Resonance Spectroscopy; Protons

Topics: Acetylcholinesterase; Animals; Benzofurans; Cholinesterase Inhibitors; Drosophila melanogaster; Pesticides

The activation of NLRP3 inflammasome is closely related to ischemic brain injury and inhibition of NLRP3 inflammasome activation may be a new therapeutic strategy for ischemic stroke. Our previous studies showed that ligustilide (LIG) had a dose-dependent neuroprotective effect on various models of cerebral ischemia and dementia in vivo and in vitro. CD21, a kind of phthalide derivative, was modified from LIG. In this study, we established a global cerebral ischemia-reperfusion model in mice by bilateral common carotid artery ligation (2VO), and explored the neuroprotective effect of CD21 and its anti-inflammatory mechanism on cerebral ischemia mice. CD21 significantly improved weight loss, neurobehavioral deficits and neurons loss in hippocampal CA1 and caudate putamen (CPu) subregions, which were induced by 2VO in mice. CD21 significantly inhibited the overactivation of astrocyte and microglia, and decreased the mRNA level of IL-6, TNF-α and IL-1β. Moreover, CD21 significantly inhibited the activation of TLR4/NF-κB signaling pathway mediated by HMGB1 and NLRP3/ASC/Caspase-1 signaling pathway mediated by Cathepsin B, thus inhibiting the activation of NLRP3 inflammasome. Our results demonstrated that CD21 may exert a neuroprotection by inhibiting NLRP3 inflammasome activation after cerebral ischemia. These findings provide a new strategy for the treatment of ischemic stroke.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Benzofurans; Body Weight; Brain Injuries; Brain Ischemia; CARD Signaling Adaptor Proteins; Caspase 1; Cathepsins; Cytokines; Disease Models, Animal; HMGB1 Protein; Inflammasomes; Male; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; NF-kappa B p50 Subunit; NLR Family, Pyrin Domain-Containing 3 Protein; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4

The isobenzofuran-1(3H)-ones (phthalides) exhibit various biological activities, including antioxidant activity on reactive oxygen species (ROS). An excess of ROS that cannot be naturally contained by cellular enzymatic systems is called redox imbalance, which damage cell membranes, proteins, and DNA, thereby possibly triggering neuronal death in several neurodegenerative diseases. Considering our ongoing efforts to find useful compounds to control redox imbalance, herein we evaluated the antioxidant activity of two phtalides (compounds 3 and 4), using primary cultures of hippocampal neurons. Spectrophotometric assays showed that compound 3 significantly reduced (p ≤ 0.05) ROS levels and lipid peroxidation compared to the control treatment, while compound 4 was unable at any of the tested concentrations. Despite their structural similarity, these compounds behave differently in the intracellular environment, which was reliably corroborated by the determination of oxidation potentials via cyclic voltammetry. It was demonstrated that compound 3 presents a lower oxidation potential. The combination of the mentioned methods allowed us to find a strong correlation between the chemical structure of compounds and their biological effects. Taking together, the results indicate that compound 3 presents desirable characteristics to act as a candidate pharmacological agent for use in the prevention and treatment of neurodegenerative diseases.

Topics: Animals; Antioxidants; Benzofurans; Cell Survival; Cells, Cultured; Female; Hippocampus; Lipid Peroxidation; Male; Mice, Inbred C57BL; Neurons; Reactive Oxygen Species; Spectrophotometry

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Chemistry Techniques, Synthetic; Inhibitory Concentration 50; MAP Kinase Signaling System; Mice; NF-E2-Related Factor 2; NF-kappa B; RAW 264.7 Cells; Reactive Oxygen Species

A novel route for the production of the versatile chemical building block phthalide from biorenewable furfuryl alcohol and acrylate esters is presented. Two challenges that limit sustainable aromatics production via Diels-Alder (DA) aromatisation-an unfavourable equilibrium position and undesired regioselectivity when using asymmetric addends-were addressed using a dynamic kinetic trapping strategy. Activated acrylates were used to speed up the forward and reverse DA reactions, allowing for one of the four DA adducts to undergo a selective intramolecular lactonisation reaction in the presence of a weak base. The adduct is removed from the equilibrium pool, pulling the system completely to the product with a fixed, desired regiochemistry. A single 1,2-regioisomeric lactone product was formed in up to 86 % yield and the acrylate activating agent liberated for reuse. The lactone was aromatised to give phthalide in almost quantitative yield in the presence of Ac

Topics: Benzofurans; Biomass; Cycloaddition Reaction; Furans

Microglia can be activated to become the classic phenotype (M1) or alternative phenotype (M2), which play an important role in regulating neuroinflammatory response and tissue repair after ischemic stroke. CD21, a novel phthalide derivative, is a potential neuroprotectant against ischemic brain injury. The present study further investigated the effects of CD21 on post-ischemic microglial polarization and the underlying mechanisms. Transient middle cerebral artery occlusion (tMCAO) was used as a mouse model of ischemic stroke, while BV2 cells stimulated with conditioned medium collected from oxygen-glucose deprivation-treated HT22 cells were used in in vitro ischemic studies. The current results showed that CD21 dose-dependently and significantly improved neurological outcomes in tMCAO mice. Biochemical analyses revealed that CD21 decreased the expression of M1 phenotype markers (CD86, interleukin-1β and inducible nitric oxide synthase) and increased the expression of M2 phenotype markers (CD206, interleukin-10 and YM1/2) in both ischemic brain tissues and BV2 cells. Meanwhile, CD21 decreased the production of proinflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α), promoted the release of the antiinflammatory cytokine (interleukin-10), and enhanced the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) in ischemic brain tissue and BV2 cells. Furthermore, the AMPK inhibitor (compound C) reversed these effects of CD21 in BV2 cells. These findings indicate that CD21 alleviates post-ischemic neuroinflammation through induction of microglial M2 polarization that is at least in part medicated by AMPK activation, suggesting that CD21 may be a promising candidate for protecting against ischemic brain injury.

Topics: 4-Butyrolactone; AMP-Activated Protein Kinases; Animals; Behavior, Animal; Benzofurans; Brain Ischemia; Cell Line; Cell Polarity; Cytokines; Dose-Response Relationship, Drug; Encephalitis; Enzyme Activation; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Phenotype; Psychomotor Performance

A pair of novel lipopeptide epimers, sinulariapeptides A (

Topics: A549 Cells; Acetylcholinesterase; Antineoplastic Agents; Benzofurans; Cholinesterase Inhibitors; Curvularia; Glyceryl Ethers; GPI-Linked Proteins; HeLa Cells; Humans; K562 Cells; Lipopeptides; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

The genus Angelica encompasses 80 species worldwide. Among them, only Angelica sinensis is widely used in China and Japan. To explore the quality and geographical distribution of A. sinensis, we collected 1,530 plants from Gansu Province and analyzed them for their contents of chlorogenic acid (CA), ferulic acid (FA), senkyunolide I(SI), senkyunolide A(SA), senkyunolide H (SH), coniferyl ferulate (CF), ligustilide (LI), and butenyl phthalide (BP) using UPLC. We also assessed the relationship between the ecological environment and quality of A. sinensis through maximum entropy modeling and a geographical information system. The habitat suitability distribution demonstrated that the most influential ecological factors for the growth of A. sinensis were altitude, precipitation during March, May, and December, precipitation during the wettest month, and the soil pH. The most suitable areas for cultivation are concentrated to the south of Gansu Province, including Linxia Hui Autonomous Prefecture, Dingxi City, Tianshui City, south of Wuwei City, east of Gannan Tibetan Autonomous Prefecture, north of Longnan City, and northwest of Pingliang City. The quality suitability regionalization analysis divulged that the most influential ecological factors for the index components of A. sinensis were the altitude, sunshine, rainfall, temperature, and soil pH. The highest quality A. sinensis grow in Dingxi City, Tangchang, Lixian, and Wen counties in Longnan City, Wushan County in Tianshui City, Lintan, Zhouqu, and Zhuoni counties in Gannan Tibetan Autonomous Prefecture, Kangle and Linxia counties in Linxia Hui Autonomous Prefecture. The experiment yielded highly accurate results (accuracy of 0.955), suggesting that the results were consistent with the actual distribution of A. sinensis in Gansu. The inferences of this research will naturally draw the attention of the authorities in the fields of natural resources and agriculture departments and provide a scientific basis for the rational selection of A. sinensis cultivation areas.

Topics: 4-Butyrolactone; Angelica sinensis; Benzofurans; China; Chlorogenic Acid; Chromatography, High Pressure Liquid; Coumaric Acids; Plant Extracts

Three new ophiobolin sesterterpenoids, (6

Topics: Aspergillus; Benzofurans; Cold Temperature; Oceans and Seas; Prenylation; Sesterterpenes; Spectrum Analysis

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Bacillus cereus; Benzofurans; Cell Line, Tumor; Chlorocebus aethiops; Humans; Molecular Structure; Plasmodium falciparum; Polycyclic Sesquiterpenes; Sesquiterpenes; Thailand; Vero Cells; Xylariales

Phthalides and their precursors have demonstrated a large variety of biological activities. Eighteen phthalides were synthesized and tested on the stored grain pest Rhyzopertha dominica. In the screening bioassay, compounds rac-(2R,2aS,4R,4aS,6aR,6bS,7R)-7-bromohexahydro-2,4-methano-1,6-dioxacyclopenta[cd]pentalen-5(2H)-one (15) and rac-(3R,3aR,4R,7S,7aS)-3-(propan-2-yloxy)hexahydro-4,7-methano-2-benzofuran-1(3H)-one (17) showed mortality similar to the commercial insecticide, Bifenthrin® (≥90 %). The time (LT

Topics: Animals; Benzofurans; Coleoptera; Dose-Response Relationship, Drug; Insecticides; Molecular Structure; Structure-Activity Relationship

Fu-Ke-Zai-Zao pills, the famous traditional Chinese medicine formula, composed of 42 medicinal herbs, have been widely used to treat various gynecological diseases. However, the chemical constituents and metabolic profiling of Fu-Ke-Zai-Zao pills remain largely unknown, which hampers improvement of the quality control and pharmacological elucidation of this formula. In the present study, a sensitive and selective ultra high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry method was developed to separate and identify the comprehensive chemical constituents of Fu-Ke-Zai-Zao pills. According to the results, a total of 83 compounds were identified, including phenylpropionic acids, flavonoids, terpenoids, triterpene saponins, and phthalides, and 81 compounds were first reported in Fu-Ke-Zai-Zao pills. Moreover, the absorbed components and metabolites in rat plasma after intragastric administration of Fu-Ke-Zai-Zao pills were also detected by the same analytical method. A total of 36 compounds were identified, including 21 prototypes and 15 metabolites. The latter were generated through the metabolic pathways of methylation and glucuronidation, and glucuronidated metabolites were the main constituents in the plasma. This is the first systematic study on the chemical constituents and metabolic profiling of Fu-Ke-Zai-Zao pills, and the results provide valuable chemical information for further elucidating pharmacological effects and mechanism of action of Fu-Ke-Zai-Zao pills.

Topics: Animals; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Female; Flavonoids; Methylation; Monoterpenes; Plasma; Propionates; Quality Control; Rats; Rats, Sprague-Dawley; Saponins; Tandem Mass Spectrometry; Triterpenes

Triangeliphthalides A-D (1-4), four novel phthalide trimers with two new linkage styles, were isolated from Angelica sinensis, together with two related phthalide dimers (5-6). Their structures including absolute configurations were determined. The production mechanism of phthalide polymers was proposed, and their bioactivities were also evaluated.

Topics: Angelica sinensis; Benzofurans; Biopolymers; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure

Five new phthalide dimers, chaxiongnolides C-G (1-5), the two enantiomers of riligustilide (6a and 6b) and tokinolide B (7) were isolated from the aerial parts of Ligusticum sinense Oliv cv. Chaxiong. The structures of 1-5 were elucidated through extensive spectroscopic analysis, and the relative configurations of compounds 2 and 3 were further confirmed by an X-ray diffraction experiment. The absolute configurations of 1-3 were assigned by comparing calculated and experimental ECD spectra. The ECD exciton chirality method was used to confirm the absolute configurations of compounds 4, 5, 6a and 6b. Compounds 1-3 are the first dimeric phthalides to be reported that are comprising a sedanolide unit. The compounds were evaluated in vitro for their cytotoxic activity against select human cell lines.

Topics: Benzofurans; Cell Line; China; Humans; Ligusticum; Molecular Structure; Phytochemicals; Plant Components, Aerial; Stereoisomerism; X-Ray Diffraction

Cnidium officinale Makino is an important medicinal plant of oriental clinics and is considered as the main source of phthalides, polyphenols, and flavonoids. However, there is no available report regarding the effect of different light colors on the secondary metabolites composition of C. officinale. In this study different light (dark, white, blue, red and red: blue) conditions were arranged to raise callus on MS medium containing 0.5 mg·L

Topics: Antioxidants; Ascorbate Peroxidases; Benzofurans; Chromatography, High Pressure Liquid; Cnidium; Flavonoids; Light; Phenols; Plant Cells; Plants, Medicinal; Superoxide Dismutase

Five new phthalide derivatives, biscogniphthalides A-D (1, 2, 3a/3b, and 4), were isolated from Biscogniauxia sp. (No. 69-8-7-1), along with one related known phthalide (5). Their structures were determined by comprehensive spectroscopic analyses, chemical derivatization, and quantum chemical ECD calculations. In addition, the anti-acetyl cholinesterase, antimicrobial, and anti-α-glucosidase activities of 1-5 were evaluated.

Topics: Anti-Infective Agents; Benzofurans; China; Cholinesterase Inhibitors; Molecular Structure; Xylariales

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Benzofurans; HEK293 Cells; Humans; Immunologic Factors; Inflammation Mediators; Lipids; Male; Mice, Inbred C57BL; NF-kappa B; Proto-Oncogene Proteins c-akt; Transcription Factor AP-1; Tumor Necrosis Factor Receptor Superfamily, Member 9

Ten batches of Angelica sinensis from three producing areas( Tuoxiang,Minxian and Weiyuan of Gansu province) were selected as the research objects,and processed into raw A. sinensis,A. sinensis with alcohol,and A. sinensis with soil respectively through the standard processing methods. Ultra-high performance liquid chromatography( UPLC) was used to establish fingerprint for three processed products of A. sinensis,and determine the contents of 9 phenolic acids and phthalide compounds. The similarity was analyzed with Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine,which showed that the chromatographic peaks of the same processed samples of A. sinensis were basically similar,with all similarities greater than 0. 950. The difference between different processed products and their control spectra was not obvious,with all similarities also higher than 0. 950.On the basis of using principal component analysis( PCA) and OPLS-DA to seek the difference components between groups,the improved distance coefficient method can be used to effectively distinguish the three processed products of A. sinensis by fingerprint similarity. At the same time,the determination method of nine phenolic acids and phthalide in A. sinensis was established by UPLC,and the comparison between different processed products was carried out. The results showed that the content of various components was changed as compared with the raw A. sinensis. The contents of coniferyl ferulate and ligustilide in the A. sinensis with alcohol were increased significantly,and the content of coniferyl ferulate was obviously increased in A. sinensis with soil. The method established in this paper can effectively distinguish different processed products of A. sinensis and determine the content of the main components in them.

Topics: 4-Butyrolactone; Angelica sinensis; Benzofurans; Chromatography, High Pressure Liquid; Coumaric Acids; Drugs, Chinese Herbal; Hydroxybenzoates; Medicine, Chinese Traditional; Principal Component Analysis

Synthetically derived (

Topics: 4-Butyrolactone; Benzofurans; Catalysis; Crystallography, X-Ray; Cycloaddition Reaction; Dimerization; Metals; Molecular Structure; Photochemistry

In this study, the insecticide potential of eight phthalides derived from furan-2(5H)-one was evaluated against Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) larvae. The potency of the most active phthalides and the susceptibility of six different T. absoluta populations to these compounds were determined. The toxicity of these molecules to two non-target species (Solenopsis saevissima Smith and Tetragonisca angustula Latreille) was also evaluated. Two phthalides (3 and 4) presented insecticide potential against T. absoluta. Phthalide 4 was as toxic as piperine (positive control) and both phthalides exhibited rapid action (LT

Topics: Animals; Ants; Bees; Benzofurans; Drug Evaluation, Preclinical; Insecticides; Larva; Lepidoptera

An inside job: Enantioselective phthalide synthesis was achieved through internal redox allylation of o-phthalaldehydes. Oxidative esterification is balanced by reductive carbonyl addition to achieve an overall redox-neutral process. This method enabled formal syntheses of ent-spirolaxine methyl ether and CJ-12,954.

Topics: Benzofurans; Catalysis; Esterification; Hydrogenation; Iridium; o-Phthalaldehyde; Oxidation-Reduction; Stereoisomerism

Topics: Adolescent; Adult; Angelica sinensis; Animals; Benzofurans; Drugs, Chinese Herbal; Female; Glucuronosyltransferase; Humans; Injections; Male; Rats; Rats, Sprague-Dawley; Sepsis; Young Adult

High-resolution mass spectrometry (HRMS) provides a powerful tool for the rapid analysis and identification of compounds in herbs. However, the diversity and large differences in the content of the chemical constituents in herbal medicines, especially isomerisms, are a great challenge for mass spectrometry-based structural identification. In the current study, a new strategy for the structural characterization of potential new phthalide compounds was proposed by isomer structure predictions combined with a quantitative structure-retention relationship (QSRR) analysis using phthalide compounds in Chuanxiong as an example. This strategy consists of three steps. First, the structures of phthalide compounds were reasonably predicted on the basis of the structure features and MS/MS fragmentation patterns: (1) the collected raw HRMS data were preliminarily screened by an in-house database; (2) the MS/MS fragmentation patterns of the analogous compounds were summarized; (3) the reported phthalide compounds were identified, and the structures of the isomers were reasonably predicted. Second, the QSRR model was established and verified using representative phthalide compound standards. Finally, the retention times of the predicted isomers were calculated by the QSRR model, and the structures of these peaks were rationally characterized by matching retention times of the detected chromatographic peaks and the predicted isomers. A multiple linear regression QSRR model in which 6 physicochemical variables were screened was built using 23 phthalide standards. The retention times of the phthalide isomers in Chuanxiong were well predicted by the QSRR model combined with reasonable structure predictions (R

Topics: Benzofurans; Chromatography, High Pressure Liquid; Dimerization; Drugs, Chinese Herbal; Isomerism; Linear Models; Quantitative Structure-Activity Relationship; Reproducibility of Results; Tandem Mass Spectrometry

A chemical investigation of the ascomycetes of Daldinia concentrica was performed using silica gel column chromatography, ODS column chromatography, and preparative HPLC. Two new isoindolinone compounds, daldinans B (1) and C (2), two new phthalide compounds, daldinolides A (3) and B (4), and a new naphthoquinone, daldiquinone (5), were isolated together with two known compounds (6 and 7). The structures of 1, 2, and 5 were established using NMR, MS, and IR methods, and the structures of 3 and 4 were determined by derivatization from known compounds (6 and 7). 5 exhibited antiangiogenesis activity against HUVECs (IC

Topics: Ascomycota; Benzofurans; Cell Line; Chromatography, High Pressure Liquid; Human Umbilical Vein Endothelial Cells; Humans; Magnetic Resonance Spectroscopy; Naphthoquinones; Phthalimides

Four new dimeric phthalides, angesinenolides C-F (1-4), along with three known ones, were isolated from the roots of Angelica sinensis. Their structures were determined by means of HRMS and NMR experiments. The structures of compounds 1 and 3 were confirmed using X-ray crystallographic data. All isolated compounds were tested for activities on the inhibition of COX-2 enzyme in vitro. Compounds 1-6 exhibited inhibitory activity against COX-2 with IC

Topics: Angelica sinensis; Benzofurans; Crystallography, X-Ray; Cyclooxygenase 2 Inhibitors; Molecular Structure; Plant Roots

This study reports the effect of explant type and plant growth regulators (PGRs) on callus induction in Cnidium officinale. Compared to stem, root explant showed maximum percent callus formation of 75% on Murashige and Skoog (MS) medium containing 2.3 µM 2,4-dichlorophenoxyacetic acid (2,4-D) and 2.2 µM benzyladenine (BA). At 30th day of callus culture on the said medium, callus fresh weight was sevenfold higher than other tested PGRs treatments. It was noted that MS medium supplemented with 27.1 µM 2,4-D showed the highest 0.30 mg g

Topics: Antioxidants; Benzofurans; Cell Culture Techniques; Chromatography, High Pressure Liquid; Cnidium; Flavonoids; Phenols; Plant Growth Regulators; Plant Roots; Plant Shoots

Enantiomerically enriched phthalans were synthesized efficiently via an enantioselective copper-catalyzed alkene carboetherification reaction. In this reaction, 2-vinylbenzyl alcohols enantioselectively cyclize then couple with vinylarenes. The utility of the method was demonstrated by the enantioselective synthesis of ( R)-fluspidine, a σ

Topics: Alkenes; Benzofurans; Benzyl Alcohols; Catalysis; Copper; Cyclization; Stereoisomerism; Vinyl Compounds

The characterization of unknown compounds is still a great challenge currently. A strategy for deduction of potential new phthalides through the characterization of isomers based on ultra-performance liquid chromatography coupled with quadrupole time of flight tandem mass spectrometry was proposed here to characterize the unknown compounds of Ligusticum chuanxiong Hort. (Chuanxiong). This proposed strategy consisted of four steps: (1) the high resolution MS data was collected, and the peaks were screened preliminarily by UNIFI

Topics: Benzofurans; Chromatography, Liquid; Drugs, Chinese Herbal; Ligusticum; Tandem Mass Spectrometry

Chemometrics-enhanced one-dimensional/comprehensive two-dimensional gas chromatographic (GC/GC×GC) technologies, were used to explore the compositions of Chaihu Shugan San essential oils, that were extracted from the herbal formulae by different schemes. We have shown that chemometric resolution using gas chromatographic- mass spectrometry (GC-MS) could be used for the qualitative and quantitative analysis of the majority of Terpenoids or Phthalides from herb formulae and single herbs. A GC×GC system was further optimized to achieve the increased peak capacity and the enhanced signal of the hydro-distillation sample (CSSh). When hardware bottleneck resulted from very complex sample, chemometric tools were once again applied to recover the stained information in the second dimension (

Topics: Benzofurans; Gas Chromatography-Mass Spectrometry; Oils, Volatile; Plant Extracts; Terpenes

One new phthalide (1) was isolated from aerial parts of Peperomia nivalis, along with known compounds (2 and 3), reported in this species for the first time. The structure of the new compound was characterised on the basis of 1D (

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Benzofurans; Helicobacter pylori; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Peperomia; Peru; Plasmodium falciparum; Spectrophotometry, Ultraviolet

A simple and efficient palladium-catalyzed intramolecular carbonylative synthesis of isocoumarins and phthalides from the easily available starting materials by employing phenyl formate as a CO surrogate has been achieved. The approach affords target compounds in good to excellent yields with the advantages of lower toxicity, milder conditions, easy operation and wide functional group tolerance.

Topics: Benzofurans; Carbon Monoxide; Catalysis; Formates; Isocoumarins; Molecular Structure; Palladium

Two pairs of diastereoisomers, namely (3'Z)-(3S,8S,3a'S,6'R)-4,5-dehydro-3.3a',8.6'-diligustilide (1) and (3'Z)-(3S,8R,3a'S,6'R)-4,5-dehydro-3.3a',8.6'-diligustilide (3), chuanxiongdiolide R3 (2), and chuanxiongdiolide R1 (4), were isolated from the 95% ethanolic aqueous extract of the rhizomes of Ligusticum chuanxiong. Among these Phthalide dimers, compounds 1 and 2 were new ones. The structures of the new isolates were elucidated based on spectroscopic data analyses, and their absolute configurations were determined by comparison of experimental and calculated electronic circular dichroism spectra.

Topics: Benzofurans; Circular Dichroism; Drugs, Chinese Herbal; Ligusticum; Molecular Structure; Rhizome; Stereoisomerism

In order to clarify the chemical constituents in Yangxue Qingnao granule, we established a rapid ultra-performance liquid chromatography/orthogonal acceleration time-of-flight mass spectrometry (UPLC-Q-TOF/MS(E)) method. According to the high resolution MS spectra data, fragmentation ion information and retention time,142 peaks were identified or tentatively presumed by comparison with reference standards data and literature reports. The herbal sources of these peaks were assigned. The results implied that phenolic acids, alkaloids, anthraquinones, phthalides, monoterpene glycosides were included in the main components of Yangxue Qingnao granule. The method is rapid for systematically elucidation of the constituents of Yangxue Qingnao granule and the results would facilitate the quality control of Yangxue Qingnao granule for safe and efficacious use.

Topics: Alkaloids; Anthraquinones; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Glycosides; Hydroxybenzoates; Monoterpenes; Quality Control; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

In this study, we reported the analysis of the medium polarity fraction obtained from an accession of Helichrysum microphyllum subsp. tyrrhenicum from La Maddalena Island. Besides several compounds already evidenced in this species and related genera, i.e. micropyrone (1), arzanol (2), helipyrone (3), acetyl-bitalin derivatives (4, 5), gnaphaliol (6), caffeic acid (7), ursolic acid (8), 7-O-β-(D-glucopyranosyl)-5-methoxy-1(3H)-isobenzofuranone (9), gnaphaliol-9-O-β-D-glucopyranoside (11) and gnaphaliol-3-O-β-D-glucopyranoside (12), the presence of a new glycosidic phthalide, 6-O-β-(D-glucopyranosyl)-4-methoxy-1(3H)-benzofuranone (10), was evidenced for the first time, which resulted in a structural isomer of compound (9). The occurrence of this new benzofuranone derivative is an additional evidence of the deep intraspecific variability expressed by this species, which was also stated for the non-volatile components, and may be a distinctive trait of the population growing on La Maddalena Island.

Topics: Benzofurans; Caffeic Acids; Glucosides; Helichrysum; Italy; Molecular Structure; Monosaccharides; Phloroglucinol; Pyrones; Triterpenes; Ursolic Acid

Three new phthalide derivatives, emefuranones A1, A2 and B (1-3); six new phthalane derivatives, emefuran A, B1, B2, C1, C2 and D (4-9); three new farnesylated phthalide derivatives, farnesylemefuranones A-C (10-12); xylarinol C (13); and emericelloxide (14), along with four known compounds (dustanin, sorbicillin, aspergillodiol and xylarinol A), were isolated from the culture extracts of Emericella sp. IFM57991. Structures of 1-14 were elucidated on the basis of spectroscopic analysis and chemical evidence. Compounds 4-7 and 13 showed moderate antibacterial activities against Bacillus subtilis.

Topics: Anti-Infective Agents; Bacillus subtilis; Benzofurans; Culture Media; Disk Diffusion Antimicrobial Tests; Emericella; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Phthalimides

Despite being of great importance to crop protection, the disadvantages of intensive and inappropriate use of pesticides have stimulated the search for more selective and less harmful agrochemicals. Thus, we have evaluated the effectiveness of 16 synthetic molecules (phthalides and precursors) to control the melonworm Diaphania hyalinata, a key pest in cucurbit crops of economic importance in Brazil. The selectivity to beneficial organisms Solenopsis saevissima and Tetragonisca angustula and the phytotoxicity to Cucumis sativus of the promising insecticides were also assessed.. In the screening assay, compounds 1 and 6 provided 91 and 88% mortality of the melonworm. Compound 1 presented higher toxicity (median lethal dose LD50 = 15.99 µmol g(-1) ) and higher speed on pest control (median survival time LT50 = 420 min) than compound 6 (LD50 = 44.51 µmol g(-1) and LT50 = 840 min). Both compounds inhibited less than 11% of host-plant growth and caused ≤36 and ≥93% mortality of predator and pollinator respectively.. Among the tested compounds, only compounds 1 and 6 were effective in melonworm control. Both compounds presented no considerable phytotoxicity and were selective to predator but non-selective to pollinator, which enables their application for pest control if the exposure of the bees is minimised. © 2015 Society of Chemical Industry.

Topics: Animals; Ants; Bees; Benzofurans; Cucumis sativus; Food Chain; Furans; Insecticides; Larva; Moths

A fast, sensitive, and reliable ultra-high performance liquid chromatography with tandem mass spectrometry method has been developed and validated for the simultaneous quantitation and pharmacokinetic study of five phthalides (senkyunolide A, ligustilide, butylidenephthalide, 3-butylphthalide, and levistilide A) in rat plasma after oral administration of Huo Luo Xiao Ling Dan (HLXLD) or Angelica sinensis--Ligusticum chuanxiong herb pair (DG-CX) between normal and arthritis rats. After extraction from blood, the analytes and internal standard were subjected to ultra-high performance liquid chromatography with a Shim-pack XR-ODS column (75 × 3.0 mm(2) , 2.2 μm particles) and mobile phase was composed of methanol and water (containing 0.05% formic acid) under gradient elution conditions, with an electrospray ionization source in the positive ionization and multiple reaction monitoring mode. The lower limits of quantification were 0.192-0.800 ng/mL for all the analytes. Satisfactory linearity, precision, accuracy, mean extraction recovery, and acceptable matrix effect have been achieved. The validated method was successfully applied to a comparative pharmacokinetic study of five bioactive components in rat plasma after oral administration of HLXLD or DG-CX alone, respectively, between normal and arthritic rats. The results showed that there were unlike characters of pharmacokinetics among different groups.

Topics: Administration, Oral; Animals; Arthritis; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Freund's Adjuvant; Male; Medicine, Chinese Traditional; Molecular Structure; Plant Extracts; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma) in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships) study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γ agonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-γ activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Benzofurans; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Hep G2 Cells; Humans; Ligands; Liver; Mice; Phthalimides; PPAR gamma; Rats

Two new phthalide derivatives, angesinenolides A and B (1 and 2), were isolated from the roots of Angelica sinensis. Their structures were elucidated using HRMS, NMR, and X-ray crystallographic data. Compound 1 is the first example of a phthalide trimer presumably formed through two [2+2] cycloaddition reactions. Compound 2 is a unique dimeric phthalide with a peroxy bridge between C-3a and C-6. Both phthalides were evaluated for in vitro anticoagulation activities. Compound 1 reduced the level of fibrinogen (FIB). Compound 2 significantly extended thrombin time and activated partial thromboplastin time, as well as markedly reduced the content of FIB.

Topics: Angelica sinensis; Anticoagulants; Benzofurans; Crystallography, X-Ray; Drugs, Chinese Herbal; Fibrinogen; Molecular Structure; Plant Roots; Thrombin

The photo-isomerization of o-acetylbenzaldehyde (oABA) in acetonitrile was studied by femto- and nanosecond transient absorption spectroscopy. Spectroscopic signatures are assigned with the aid of TD-DFT, TD-CAM-DFT and DFT-MRCI computations. The isomerization yields a lactone, 3-methylphthalide (3MP), with a quantum yield of 0.3 (30%). As evidenced by femtosecond stimulated Raman spectroscopy (FSRS), the isomerization proceeds via a ketene intermediate. It is formed within ∼2-3 ps after photo-excitation. Intersystem crossing (ISC) populating the triplet state of oABA seems to compete with the ketene formation. Experiments on the non-reactive meta- and para-derivatives, which undergo efficient ISC with time constants of 5 ps, support this statement. The triplet state of oABA also contributes to the ketene formation, presumably involving a biradical intermediate. The ketene exhibits a lifetime of 1.4 μs and generates an additional intermediate in the cascade towards the lactone.

Topics: Benzaldehydes; Benzofurans; Ethylenes; Isomerism; Ketones; Lactones; Light; Quantum Theory; Spectrum Analysis, Raman

One new ergostane-type steroid, (12β,15β,22R,23S,24S)-22,25-epoxy-12,15,23-trihydroxyergost-4,6,8(14)-trien-3-one (1), three new phthalide derivatives, 5-(2',3'-epoxy-3',3'-dimethylpropoxy)-7-methoxy-6-methylphthalide (2), (2')-(Z)-5-(3'-hydroxymethyl-3'-methylallyloxy)-7-methoxy-6-methylphthalide (3), and 5-(3',3'-dimethylallyloxy)-7-hydroxy-6-methylphthalide (4), along with one known phthalide derivative, 5-(3',3'-dimethylallyloxy)-7-methoxy-6-methylphthalide (5), were isolated from cultures of the basidiomycete Albatrellus confluens. The structures of the new compounds were established on the basis of extensive spectroscopic data (IR, MS, 1D, and 2D NMR) analyses. All compounds were evaluated for their cytotoxic activities on five tumor cell lines.

Topics: Antineoplastic Agents; Basidiomycota; Benzofurans; China; Drug Screening Assays, Antitumor; Ergosterol; HL-60 Cells; Humans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism

Supported ruthenium catalysts promote coupling of various kinds of aromatic carboxylic acids with internal alkynes, giving the corresponding multi-substituted phthalide derivatives in high yields. The supported Ru catalyst can be recycled at least five times with no loss of activity.

Topics: Alkynes; Benzofurans; Carboxylic Acids; Catalysis; Molecular Structure; Ruthenium

This study evaluated the potential anti-inflammatory effects of natural phthalides, isolated from Ligusticum porteri, and of semi-synthetic phthalides. Anti-inflammatory activity was investigated in two mouse models; one with ear edema, induced with 12-O-tetradecanoylphorbol-13-acetate, and the other with paw edema, induced with carrageenan. The effect on the RAW 264.7 stimulated with lipopolysaccharide cells was evaluated and after application of 12-O-tetradecanoylphorbol-13-acetate, the activity of myeloperoxidase was assessed to serve as an index of leukocytes infiltration together with the histological evaluations. We also assessed the inhibition of cyclooxygenases 1 and 2 in vitro. Our results demonstrated that administration of semi-synthetic phthalides significantly inhibited the ear edema induced by 12-O-tetradecanoylphorbol-13-acetate, and reduced the paw edema caused by carrageenan. The anti-inflammatory activity of phthalides could, in part, be explained by the reduction in myeloperoxidase activity and the infiltration of leukocytes. The semi-synthetic phthalides also inhibited the production of oxide nitric in RAW cells.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Biological Products; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Inflammation; Male; Mice; Nitric Oxide Synthase; Nitrites; Peroxidase; RAW 264.7 Cells; Skin; Tetradecanoylphorbol Acetate

A novel asymmetric synthetic approach for the construction of enantioenriched functionalized dihydroquinones incorporating adjacent quaternary and tertiary stereocenters has been reported, in which enantioenriched 3-allylic phthalides engaged in an unprecedented sulfa-Michael addition-triggered stereoselective ring-expansion reaction, and furnished the desired sulfur-incoporated dihydronaphthoquinones with high stereoselectivity.

Topics: Allyl Compounds; Benzofurans; Molecular Structure; Naphthoquinones; Stereoisomerism

An N-heterocyclic carbene (NHC) catalyzed domino reaction triggered by a δ-LUMO activation of α,β-γ,δ-diunsaturated enal has been developed for the formal [4 + 2] construction of multisubstituted arenes and 3-ylidenephthalide. These two products, formed in a highly chemo- and regioselective manner, were obtained via different catalytic pathways due to a simple change of the substrate. The activation of the remote δ-carbon of unsaturated aldehydes expands the synthetic potentials of NHC organocatalysis.

Topics: Aldehydes; Benzene Derivatives; Benzofurans; Carbon; Catalysis; Cyclization; Heterocyclic Compounds; Methane; Molecular Structure; Stereoisomerism

A study of the palladium-catalyzed hydroarylation/hydrovinylation reaction of γ-(2-methoxycarbonylphenyl)propargylic alcohols with aryl iodides/vinyl triflates and of the rhodium-catalyzed one with organoboron derivatives is described. The opposite regiochemical outcome of the two processes allows an easy selective approach to 5- or 4-substituted benzoxepin-1(3H)-ones by combining the hydroarylative/hydrovinylative step with cyclocondensation between -OH and -COOMe groups in the intermediate γ,γ-disubstituted or β,γ-disubstituted allylic alcohols. A one-flask procedure to give benzo[c]oxepin-1(3H)-ones directly from the starting alkyne has been also developed. Treatment of crude γ,γ-disubstituted allylic alcohols with NaOH, followed by acidification, affords 3,3-disubstituted phthalides.

Topics: Alkynes; Benzofurans; Catalysis; Lactones; Molecular Structure; Palladium; Propanols; Rhodium

Qi-Fu-Yin (QFY), a classical traditional Chinese medicine formula, is proven to have significant neuroprotective effects by modern pharmacological studies. However, the chemical constituents of QFY have not been fully explored. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF MS) was developed for comprehensive analysis of chemical constituents in QFY. By using characteristic ions and fragmentation rules, a reliable identification of 156 compounds was described here, including 69 triterpene saponins, 23 oligosaccharide esters, 22 flavanoids, 9 alkaloids, 9 phenolic acids, 8 phthalides, 7 phenylethanoid glycosides, 3 xanthones, 3 sesquiterpene lactones, 2 ionones and 1 iridoid glycoside. Twenty-six major compounds were then determined in a single run by UHPLC coupled with triple quadrupole tandem mass spectrometry (QQQ MS) with fast positive/negative polarity switching. It allows for the acquisition of MS data in both ionization modes from a single run. The proposed method was then validated in terms of linearity, accuracy, precision and recovery. The overall recoveries for 26 analytes ranged from 91.35% to 109.58%, with RSDs ranging from 0.82% to 4.83%. In addition, the content of 26 analytes in QFY prepared by five batches of herbal materials was also analyzed. These results demonstrated that our present method was effective and reliable for comprehensive quality evaluation of QFY. Meanwhile, the study might provide the chemical evidence for revealing the material basis of its therapeutic effects.

Topics: Alkaloids; Benzofurans; Calibration; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Drugs, Chinese Herbal; Esters; Flavonoids; Ginsenosides; Glycosides; Lactones; Limit of Detection; Magnetic Resonance Spectroscopy; Medicine, Chinese Traditional; Reference Values; Reproducibility of Results; Saponins; Tandem Mass Spectrometry; Temperature; Triterpenes

A new α-pyrone xylaripyrone A (1) and a new phthalide xylariphthalide A (2) were isolated from the Xylariaceae fungus (no. 63-19-7-3), along with four related known phthalides (3-6): 4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H)-isobenzofuranone (3), convolvulol (4), 7-methoxy-4,6-dimethyl-3H-isobenzofuran-1-one (5), and convolvulanic acid B (6). Their structures were determined on the basis of IR, MS, and NMR spectroscopic analyses.

Topics: Benzofurans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrones; Xylariales

Chuanxiong Rhizoma (CR), a well-known traditional Chinese medicine originated from the rhizome of Ligusticum chuanxiong Hort., was effective for treating various vascular diseases. To identify the metabolites of CR in vivo, the drug-containing urine samples of WZS-miniature pigs after orally administrated CR decoction were collected, after sequential column chromatography 17 metabolites (M1-M17) were isolated from the methanol extract of the urine samples. Their structures, including nine phthalides (M1-M9) and eight phenolic acids (M10-M17), were identified by spectroscopic means. Among them, 8 were new ones (M1-M6, M11-M12). On the basis of the structures of identified metabolites, seven original constituents, including 2 phthalides (senkyunolideI/H) and 5 phenolic acids (ferulic acid, isoferulic acid, caffeic acid, 3-hydroxycinnamoyl acid and 4-hydroxybenzonic acid) were deduced to be the major absorbed original constituents of CR in vivo. This is the first study on the metabolites of CR decoction in non-rodent animal (WZS-miniature pig), the results will give an insight into the metabolism profiles of phthalides and phenolic acids in CR decoction in vivo.

Topics: Administration, Oral; Animals; Benzofurans; Drugs, Chinese Herbal; Hydroxybenzoates; Ligusticum; Male; Molecular Structure; Rhizome; Swine; Swine, Miniature; Urinalysis

Furomollugin was synthesized in three steps from commercially available starting materials using phthalide annulation chemistry.

Topics: Anions; Benzofurans; Chemistry Techniques, Synthetic; Molecular Structure; Naphthols; Pyrones

New versatile and selective methods for the syntheses of substituted amino- and methoxyphenolic anthraquinones (I-IV) based on fusion of cyanophthalides (V) and semiquinone aminals (VI, VII) under basic conditions are described.

Topics: Amination; Amines; Anthraquinones; Benzofurans; Phenols

The green Chinese onion (Allium fistulosum L.), which is widely cultivated and has been naturalized in many places, is an important spice and vegetable in East and Southeast Asia. It is used to treat the common cold in China. In the ongoing search for antibacterial activity in fungi derived from natural, pungently scented vegetables, the secondary metabolites of Talaromyces pinophilus AF-02, which was isolated from the stem of the green Chinese onion, were investigated. The genus Talaromyces (Trichocomaceae) is an important fungal genus because of its ubiquity and the role of many of its species in food and agriculture production. Three new phthalide derivatives, talaromycolides A-C, 1-3; a new long-chain dicarboxylic acid, 11; and 12 known compounds were isolated from methanolic extracts of this fungus. Their structures were determined via extensive NMR, HR-ESI-MS, and CD spectroscopic analyses. Compounds 1-3 are rare phthalide derivatives with a novel linkage position between the phenyl and phthalide moieties. The biological properties of 1-16 were evaluated using six different bacteria, and 1-3, 5, and 11 exhibited significant antibacterial activity in response to some of the tested strains.

Topics: Allium; Anti-Bacterial Agents; Bacteria; Benzofurans; Molecular Structure; Talaromyces

A quantitative analysis method of multi-components with a single marker (QAMS) for simultaneous determination of six marker compounds (one from phenolic acids and five from phthalides) in Chuanxiong Rhizoma was established by applying HPLC and using butylidenephthalide as the internal reference substance. And also the feasibility and accuracy of the established method for quality evaluation and application of Chuanxiong Rhizoma were investigated and validated. The analysis was performed with the mobile phase consisting of acetonitrile - 0.2% aqueous formic acid. The flow rate was 1.0 mL . min-1 and the column temperature was maintained at 30 °C. The detection wavelengths were set at 252 nm (for ferulic acid, Z-ligustilide, and butylidenephthalide) and 266 nm (for senkyunolide I, senkyunolide A, and coniferyl ferulate), separately, and 20 µL was injected for analysis with gradient elution. The results showed that there were no significant differences observed between the HPLC-QAMS method and the external standard method (RSD <5%). The relative correction factors were credible (RSD < 5%) in changed chromatographic conditions. The established HPLC-QAMS method can be accurately used for simultaneously evaluating and controlling the quality of Chuanxiong Rhizoma with multi-components.

Topics: 4-Butyrolactone; Acetonitriles; Benzofurans; Chromatography, High Pressure Liquid; Coumaric Acids; Drugs, Chinese Herbal; Hydroxybenzoates; Quality Control; Rhizome

The study concentrates on an important natural product, phthalide isoquinoline alkaloid Corlumine (COR) [(6R)-6-[(1S)-1,2,3,4-Tetrahydro-6,7-dimethoxy-2-methylisoquinolin-1-yl] furo [3,4-e]-1,3-benzodioxol-8(6H)-one] well known to exhibit spasmolytic and GABA antagonist activity. It was fully characterized by a variety of experimental methods including vibrational spectroscopy (IR and Raman), thermal analysis (DSC), UV and SEM. For a better interpretation and analysis of the results quantum chemical calculations employing DFT were also performed. TD-DFT was employed to elucidate electronic properties for both gaseous and solvent environment using IEF-PCM model. Graphical representation of HOMO and LUMO would provide a valuable insight into the nature of reactivity and some of the structural and physical properties of the title molecule. The structure-activity relationship have been interpreted by mapping electrostatic potential surface (MEP), which is valuable information for the quality control of medicines and drug-receptor interactions. Stability of the molecule arising from hyper conjugative interactions, charge delocalisation has been analyzed using natural bond orbital (NBO) analysis. Computation of thermodynamical properties would help to have a deep insight into the molecule for further applications.

Topics: Alkaloids; Benzofurans; Biological Products; GABA Antagonists; Isoquinolines; Models, Molecular; Molecular Conformation; Quantum Theory; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Static Electricity; Thermodynamics

In the present study, the effect of drying methods on the quality of Angelicae Sinensis Radix (DG), was evaluated by newly developed high performance liquid chromatography photodiode array detector (HPLC-DAD) and ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS). Ten major bioactive components including two phenolic acids, two hydroxyl phthalides, four alkyl phthalides and two phthalide dimers were selected as evaluation chemical markers and the newly-established method was qualitatively and quantitatively validated. DG slices and whole roots dried in shade, sun light, hot air, vacuum, microwave, far infrared ray and combination of microwave and far infrared ray as well as the fresh DG samples were determined by the established methods. DG slices dried in hot air kept the similar chemical composition to that of fresh DG, while DG whole roots dried in vacuum retained highest contents of the major components. Coniferyl ferulate and ligustilide degraded significantly in DG slices dried by microwave, far infrared ray and their combination. The influence of such chemical changes induced by different drying methods on the bioactivities of DG warrants further investigation, so that the optimal drying method can be obtained for the standardization of DG herb.

Topics: Angelica sinensis; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hydroxybenzoates; Plant Roots; Tandem Mass Spectrometry

An efficient NHC-catalyzed domino oxidation/oxa-Michael addition reaction of 2-alkenylbenzaldehydes has been developed to afford 3-substituted phthalides bearing a C3-stereogenic center with a broad substrate scope and wide functional group tolerance. The preliminary results of the asymmetric process have been provided as well.

Topics: Benzofurans; Catalysis; Cyclization; Heterocyclic Compounds; Methane; Oxidation-Reduction

A new dimeric phthalide, chaxiongnolide A (1), and a new natural product, chaxiongnolide B (2), together with a known compound Z-ligustilide (3), were isolated from the rhizome of Ligusticum sinense Oliv cv. Chaxiong. Their structures were elucidated by various spectroscopic methods and confirmed by X-ray crystallographic analysis.

Topics: 4-Butyrolactone; Benzofurans; Crystallography, X-Ray; Drugs, Chinese Herbal; Ligusticum; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Rhizome

The diastereomeric aziridine carbinols are applied, respectively, as efficient chiral ligand in the catalysis of asymmetric arylation and sequential arylation-lactonization cascade. The two diastereomers, which are facilely synthesized from the same chiral source, function as pseudo enantiomers in arylation of aromatic aldehydes providing the different enantiomers of the diarylmethanols with almost the same excellent enantioselectivities. The arylation method is also carried out in tandem with lactonization process to afford a concise synthetic approach to both enantiomers of optically active 3-aryl phthalide.

Topics: Aldehydes; Aziridines; Benzofurans; Catalysis; Molecular Structure; Stereoisomerism

Fo-Shou-San (FSS) is an ancient and classic formula comprised of Angelicae Sinensis Radix (Danggui, DG) and Chuanxiong Rhizoma (Chuanxiong, CX) in a weight ratio of 3:2 with nourishing blood and dissipating blood stasis activities for the treatment of blood deficiency and blood stasis. In this study, a ultra-high-performance liquid chromatography coupled with a triple quadrupole electrospray tandem mass spectrometry (UHPLC-TQ-MS/MS) method was developed for simultaneous quantification of three aromatic acids (chlorogenic acid, caffeic acid, ferulic acid) and six phthalides (senkyunolide I, senkyunolide H, senkyunolide A, butylphthalide, ligustilide and butylidenephthalide) in DG, CX and FSS. The nine components were simultaneously determined within 10min. The proposed method was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery. The results showed that there were significant differences in their contents of DG and CX, and there were remarkable differences between the theorized content and observed content in FSS. The content of each component in formulae was not just the simple addition among its content in the single herbs. These research results might be helpful to illustrate the drug interactions during decocting process of herb pair according to the quantity changes of these marker compounds, which would lay foundation to further reveal the compatibility rule of the herb pair and other related formulae.

Topics: Angelica sinensis; Benzofurans; Caffeic Acids; Chlorogenic Acid; Chromatography, High Pressure Liquid; Coumaric Acids; Drugs, Chinese Herbal; Ligusticum; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

The hexadehydro-Diels-Alder (HDDA) cascade enables the synthesis of complex benzenoid products with various substitution patterns through aryne intermediates. The first stage of this cascade involves the generation of a highly reactive ortho-benzyne intermediate by a net [4+2] cycloisomerization of a triyne substrate. The benzyne can be rapidly 'trapped' either intramolecularly or intermolecularly with myriad nucleophilic or π-bond-donating reactants. As a representative example of a general procedure for synthesizing highly substituted benzenoids, this protocol describes the synthesis of a typical triyne substrate and its use as the reactant in an HDDA cascade to form a phthalide. The synthetic procedure detailed herein (four chemical reactions) takes 16-20 h of active effort over a period of several days for the preparation of the triyne precursor and ∼2 h of active effort over a 3-d period for the generation and trapping of the benzyne and isolation of the phthalide product.

Topics: Benzene Derivatives; Benzofurans; Cycloaddition Reaction; Molecular Structure

The phthalide compounds of Chuanxiong rhizoma including senkyunolide A, levistolide A, Z-ligustilide and 3-butylidenephthalide, have been reported as the biologically active compounds because of their therapeutic effects. In this work, online high-speed counter-current chromatography coupled with semi-preparative liquid chromatography instrument was set up, and online separation of the four compounds has been simultaneously achieved using this instrument. In this study, using all the selected solvent system, Z-ligustilide and 3-butylidenephthalide were eluted in one peak by high-speed counter-current chromatography. Using high-speed counter-current chromatography with a solvent system of n-hexane-ethyl acetate-methanol-water-acetonitrile (8:2:5:5:5, v/v), 3.6 mg of senkyunolide A (94.4%) and 3.0mg of levistolide A (95.3%) were obtained from 100mg of the crude extract. Coeluted Z-ligustilide and 3-butylidenephthalide peak fraction (8 mL) from high-speed counter-current chromatography was directly transferred and injected to the semi-preparative liquid chromatography for further separation. Finally, 5.6 mg of Z-ligustilide (97.5%) and 4.8 mg of 3-butylidenephthalide (99.3%) were obtained. The identification of these four compounds was performed by quadrupole time-of-flight mass spectrometer, (1)H and (13)C nuclear magnetic resonance spectrometer.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Countercurrent Distribution; Drugs, Chinese Herbal; Nuclear Magnetic Resonance, Biomolecular

The first asymmetric Michael addition of 3-substituted phthalides to nitroolefins promoted by amino acid-incorporating multifunctional catalysts has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in high yields, and in a highly diastereoselective and enantioselective manner. Facile synthesis of a chiral bicyclic lactam has also been demonstrated.

Topics: Alkenes; Amino Acids; Benzofurans; Catalysis; Crystallography, X-Ray; Lactams; Molecular Conformation; Stereoisomerism

MP [4-(3',3'-dimethylallyloxy)-5-methyl-6-methoxyphthalide] was obtained from liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. MP significantly inhibited the proliferation of HeLa tumor cell lines. After treatment with MP, characteristic apoptotic features such as DNA fragmentation and chromatin condensation were observed in DAPI-stained HeLa cells. Flow cytometry showed that MP induced G1 cell cycle arrest and apoptosis in a dose-dependent manner. Western blotting and real-time reverse transcription-polymerase chain reaction were used to investigate protein and mRNA expression. MP caused significant cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27(KIP1) protein and p21(CIP1) mRNA levels in HeLa cells. The expression of p73 protein was increased after treatment with various MP concentrations. mRNA expression of the cell cycle-related genes, p21(CIP1), p16(INK4a) and Gadd45α, was significantly upregulated and mRNA levels demonstrated significantly increased translation of p73, JunB, FKHR, and Bim. The results indicate that MP may be a potential treatment for cervical cancer.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Benzofurans; Cell Cycle Proteins; Cell Proliferation; Cycadopsida; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins; Endophytes; Flow Cytometry; Forkhead Box Protein O1; Forkhead Transcription Factors; G1 Phase Cell Cycle Checkpoints; Genes, p16; HeLa Cells; Humans; Nuclear Proteins; Real-Time Polymerase Chain Reaction; Transcription Factors; Transcription, Genetic; Tumor Protein p73; Tumor Suppressor Proteins; Xylariales

Following the recent identification of the naturally occurring 3-ylidene-4,5-dihydrophthalide ligustilide and its oxidation product dehydroligustilide as novel TRPA1 modulators, a series of seventeen 3-ylidenephthalides was synthesized and tested on TRPA1 and TRPM8 channels. Most of these compounds acted as strong modulators of the two channel types with EC50 and/or IC50 values distinctly lower than those of the reference compounds.

Topics: 4-Butyrolactone; Animals; Benzofurans; HEK293 Cells; Humans; Oxidation-Reduction; Protein Binding; Rats; TRPA1 Cation Channel; TRPC Cation Channels; TRPM Cation Channels

Sporotrichum laxum ATCC 15155 is the producing strain of the potent anti-Helicobacter pylori natural product spirolaxine (1). Investigation of the secondary metabolites in this fungus led to the isolation of five phthalides (1, 2, 3, 6 and 9) and five resorcylic acid derivatives (4, 5, 7, 8 and 10), among which 5, 7 and 8 are new compounds. The structures were elucidated by spectroscopic analyses, and the absolute configurations of 7 and 8 were determined by Mosher's method. Addition of soy flour into the potato dextrose agar has led to the increased production of 4-10. A biosynthetic pathway consisting of a highly reducing polyketide synthase (PKS), a nonreducing PKS and a series of tailoring enzymes was proposed to produce these fungal natural products. The resorcylic acid derivatives are proposed to result from early hydrolysis of the polyketide chain or incorporation of a longer fatty acyl starter unit.

Topics: Benzofurans; Biological Products; Biosynthetic Pathways; Hydroxybenzoates; Polyketide Synthases; Resorcinols; Sporothrix

A novel oxidative coupling of aldehydes to form C3-substituted phthalides facilitated by co-operative dual catalysis of a Rh(III) complex and an aryl amine is reported. The reaction involves a cascade ortho C-H activation-insertion-annulation sequence. This methodology is efficient and applicable for the homo- and heterocoupling of various functionalized aldehydes generating the corresponding phthalides in moderate to high yields.

Topics: Aldehydes; Amines; Benzofurans; Catalysis; Molecular Structure; Organometallic Compounds; Oxidation-Reduction; Rhodium

Topics: Acylation; Benzoates; Benzofurans; Carbon; Catalysis; Coordination Complexes; Hydrogen; Rhodium

Two new phthalides, chuanxiongdiolides A and B, were isolated from the roots of Ligusticum chuanxiong Hort. Their structures were established by UV, IR, 1D (¹H, ¹³C) and 2D (HSQC, ¹H-¹H COSY, HMBC, NOESY) NMR, and HR-ESI-MS methods, and their absolute configurations were assigned via circular dichroism exciton chirality. The two compounds showed different degrees of inhibitory effects against butyrylcholine esterase.

Topics: Benzofurans; Butyrylcholinesterase; Cholinesterase Inhibitors; Drugs, Chinese Herbal; Ligusticum; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Roots

Based on recent reports that the small molecules, isatin and phthalimide, are suitable scaffolds for the design of high potency monoamine oxidase (MAO) inhibitors, the present study examines the MAO inhibitory properties of a series of phthalide [2-benzofuran-1(3H)-one] analogues. Phthalide is structurally related to isatin and phthalimide and it is demonstrated here that substitution at C6 of the phthalide moiety yields compounds endowed with high binding affinities to both human MAO isoforms. Among the nineteen homologues evaluated, the lowest IC(50) values recorded for the inhibition of MAO-A and -B were 0.096 and 0.0014 μM, respectively. In most instances, C6-substituted phthalides exhibit MAO-B specific inhibition. Among a series of 6-benzyloxyphthalides bearing substituents on the para position of the phenyl ring the general order of potency was CF(3) > I > Br > Cl > F > CH(3) > H. The results also show that the binding modes of representative phthalides are reversible and competitive at both MAO isoforms. Based on these data, C6-substituted phthalides may serve as leads for the development of therapies for neurodegenerative disorders such as Parkinson's disease.

Topics: Benzofurans; Binding Sites; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Structure-Activity Relationship

The phytochemical investigation of extracts from the radix of Angelica sinensis yielded a new phthalide dimer, 3,3'Z-6.7',7.6'-diligustilide, along with a known dimer, levistolide A. Their structures were established on the basis of spectral data, particularly using 1D-NMR and several 2D shift-correlated NMR pulse sequences (¹H-¹H COSY, HSQC, HMBC and NOESY).

Topics: Angelica sinensis; Benzofurans; Dimerization; Magnetic Resonance Spectroscopy; Molecular Structure; Plants, Medicinal

The synthesis of stilbenoids and styryl carboxylic acids is accomplished with high E-stereoselectivity by olefination of aldehydes with thiophthalides under basic conditions. The olefination is highly atom-efficient as it only loses elemental sulfur during the reaction. This olefination, in conjunction with retro Kolbe-Schmitt reaction, allows facile synthesis of E-hydroxystilbenoids with minimal employment of protecting groups. This study also discloses two important findings: formation of i) 4-methylsulfanyl isocoumarins and ii) an 2-arylindenone.

Topics: Aldehydes; Alkenes; Benzofurans; Hydroxylation; Models, Molecular; Molecular Structure; Stereoisomerism; Stilbenes; Styrenes; Sulfhydryl Compounds

A straightforward synthesis of (S)-3-methylphthalides has been developed, with the key asymmetric step being the bioreduction of 2-acetylbenzonitriles. Enzymatic processes have been found to be highly dependent on the pH value, with acidic conditions being required to avoid undesired side reactions. Baker's yeast was found to be the best biocatalyst acting in a highly stereoselective fashion. The simple treatment of the reaction crudes with aqueous HCl has provided access to enantiopure (S)-3-methylphthalides in moderate to excellent yields.

Topics: Benzofurans; Catalysis; Molecular Structure; Stereoisomerism

The first Mannich reaction employing phthalides using a quinidine-based multifunctional catalyst has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in excellent yields, with good diastereo- and enantioselectivities. Convenient synthesis of chiral isoquinolinones and isoquinolines has also been demonstrated.

Topics: Benzofurans; Catalysis; Isoquinolines; Molecular Structure; Quinolones; Stereoisomerism

The asymmetric dihydroxylation (AD) of o-cyano cinnamates and styrene derivatives leads to efficient construction of chiral phthalide frameworks in high optical purities. This unique reaction is characterized by unusual synergism between CN and osmate groups resulting in rate enhancement of the AD process. The method is amply demonstrated by the synthesis and the structural/stereochemical assignment of the natural products.

Topics: Benzofurans; Cinnamates; Cyclization; Molecular Structure; Nitriles; Oxidation-Reduction; Styrenes

The surprisingly facile conversion (isomerization) of 2-formyl-arylketones into 3-substituted phthalides, as observed for the marine natural product pestalone and its per-O-methylated derivative, was investigated using a series of simple 2-acylbenzaldehydes as substrates. The transformation generally proceeds smoothly in DMSO, either in a Cannizarro-Tishchenko-type reaction under nucleophile catalysis (NaCN) or under photochemical conditions (DMSO, 350 nm).

Topics: Benzofurans; Benzophenones; Biological Products; Catalysis; Dimethyl Sulfoxide; Ketones; Light; Molecular Structure

Nine new fungal metabolites, one phthalide derivative, acremonide (1), and eight isocoumarin derivatives, acremonones A-H (2-9), were isolated from the mangrove-derived fungus Acremonium sp. PSU-MA70 together with 10 known compounds. Their structures were determined by NMR analysis. The known 8-deoxytrichothecin and trichodermol exhibited moderate antifungal activity against Candida albicans and Cryptococcus neoformanns, respectively.

Topics: Acremonium; Antifungal Agents; Benzofurans; Candida albicans; Cryptococcus neoformans; Isocoumarins; Microbial Sensitivity Tests; Molecular Structure; Rhizophoraceae; Thailand

Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of chiral 3,3-disubstituted phthalides. Highly enantioselective regiodivergent synthesis of γ-selective or β-selective allylic alkylation products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine-thioureas as the catalyst, respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an S(N)2'-S(N)2' pathway and an addition-elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomerically pure form.

Topics: Alkylation; Allyl Compounds; Benzofurans; Carbonates; Stereoisomerism

A one-pot synthesis of chiral C(3)-substituted phthalides via an indium-mediated allylation/transesterification reaction is described. The development of this reaction was facilitated through the applied use of DFT calculations to rationalize the stereoselection of a chiral In-mediated process. It was discovered that the enantiomeric excess of this reaction depended upon the steric size, chain length, and substitution of the aldehyde employed.

Topics: Aldehydes; Benzofurans; Catalysis; Esterification; Indium; Molecular Structure; Quantum Theory

Absolute configurations (ACs) of 3-alkylphthalides including natural products (-)-3-n-butylphthalide ((-)-1) and fuscinarin have been studied using chiroptical properties and quantum chemical calculation. Electronic circular dichroism and optical rotatory dispersion spectra of (S)-1 predicted adopting time-dependent density functional theory and hybrid functionals coincide very well with the experimental and literature data of (-)-1, leading unambiguously to AC assignment as S for levorotatory isomer. The relationship between structures and chiroptical properties of 3-alkylphthalides were also studied using theoretical calculation. It is found that when the alkyl group is adjacent to the single chiral center in the molecule, both the length of the alkyl side chain and the polarity of solvent may exert significant effect on electronic circular dichroism spectra. On the basis of these observations, it is recommended that the long-chain alkyl group may be replaced by at least propyl instead of methyl group in such compounds. The present work shows that combination of chiroptical properties and ab initio calculations can provide a feasible and reliable way to the AC establishment of novel 3-alkylphthalide derivatives with a high degree of confidence.

Topics: Benzofurans; Biological Products; Models, Molecular; Molecular Conformation; Optical Phenomena; Quantum Theory; Rotation; Spectrum Analysis; Stereoisomerism

On the basis of a marine fungal phthalide (paecilocin A) skeleton, we synthesized 20 analogs and evaluated them for peroxisome proliferator-activated receptor gamma (PPAR-γ) binding and activation. Among these analogs, 6 and 7 had significant PPAR-γ binding activity, and 7 showed further PPAR-γ activation in rat liver Ac2F cells. In docking simulation, 7 formed H bonds with key amino acid residues of the PPAR-γ binding domain, and the overall positioning was similar to rosiglitazone. This new phthalide derivative is considered an interesting new molecular class of PPAR-γ ligands.

Topics: Animals; Benzofurans; Binding, Competitive; Cell Line; Drug Design; Liver; Models, Molecular; Molecular Structure; PPAR gamma; Rats

A highly convergent total synthesis of 7',8'-dihydroaigialospirol is described. Key steps of the synthesis include a Nozaki-Hiyama-Kishi (NHK) coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid-mediated global deprotection/spiroacetalization.

Topics: Aldehydes; Alkenes; Alkynes; Benzofurans; Molecular Structure; Spiro Compounds

A novel and highly efficient strategy for the synthesis of isocoumarins and phthalides through a palladium(0)-catalyzed reaction incorporating tert-butyl isocyanide has been developed. This process, providing one of the simplest methods for the synthesis of this class of valuable lactones, involves two steps including cyclization reaction and simple acid hydrolysis. The methodology is tolerant of a wide range of substrates and applicable to library synthesis.

Topics: Benzofurans; Catalysis; Cyclization; Hydrolysis; Isocoumarins; Lactones; Molecular Structure; Nitriles; Palladium

A sensitive LC/MS method was established to investigate the in vivo metabolism of GuanXin II prescription, a five-component Chinese herbal medicine formulation. Rat plasma, bile, urine, and feces were collected and analyzed following oral administration of the water decoction. A total of 50 compounds were identified, including 17 prototypes and 33 metabolites underwent methylation, oxidation, hydrolysis, sulfate conjugation, glucuronide conjugation, and glutathion conjugation. In addition, the component herb of the formulation from which the metabolites were derived was also identified. Among the five component herbs, Rhizoma Chuanxiong, Flos Carthami, and Lignum Dalbergiae Odoriferae were actively metabolized, contributing 26 metabolites and 2 prototypes, while Radix Salviae Miltiorrhizae and Radix Paeoniae Rubra underwent less biotransformation, yielding 7 metabolites and 15 prototypes. This is the first study on the metabolic profile of GuanXin II prescription. The results could be valuable to elucidate the material basis of this formulated Chinese medicine.

Topics: Animals; Benzofurans; Bicyclic Monoterpenes; Bile; Biotransformation; Chromatography, High Pressure Liquid; Coronary Artery Disease; Drugs, Chinese Herbal; Feces; Flavonoids; Male; Molecular Structure; Phenols; Polyphenols; Rats; Rats, Sprague-Dawley; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Technology, Pharmaceutical; Terpenes

Five known isocoumarins, monocerin (1), derivative 2, and fusarentin derivatives 3-5, and a new phthalide (6) were isolated from the endophytic fungus Colletotrichum sp. 2 selectively exhibited cytotoxic activity toward the HepG2 cell line. Compounds 2 and 4 scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals (IC(50) values of 23.4 and 16.4 μM, respectively) and inhibited superoxide anion radical formation (IC(50) values of 52.6 and 4.3 μM, respectively). The C-7 hydroxyl group in 2 and 4 might be important for radical scavenging activities. Isocoumarins 1-3 and phthalide 6 showed potent antioxidant activity.

Topics: Antineoplastic Agents; Antioxidants; Aromatase Inhibitors; Benzofurans; Biphenyl Compounds; Colletotrichum; Drug Screening Assays, Antitumor; Free Radical Scavengers; Hep G2 Cells; HL-60 Cells; Humans; Isocoumarins; Lactones; Molecular Structure; Picrates; Piper; Structure-Activity Relationship; Thailand

In this work, the metabolite profiles of Danggui Buxue Tang (DBT) in rat bile and plasma were qualitatively described, and the possible metabolic pathways of DBT were subsequently proposed. Emphasis was put on correlative analysis of metabolite profiling in different biological fluids. After oral administration of DBT, bile and plasma samples were collected and pretreated by solid phase extraction. Rapid resolution liquid chromatography coupled to time-of-flight mass spectrometry (RRLC-TOFMS) was used for characterization of DBT-related compounds (parent compounds and metabolites) in biological matrices. A total of 142 metabolites were detected and tentatively identified from the drug-containing bile and plasma samples. Metabolite profiling shows that rat bile contained relatively more glutathione-derived conjugates, more saponins compounds and more diverse forms of metabolites than urine. The metabolite profile in plasma revealed that glucuronide conjugates of isoflavonoids, dimmers, acetylcysteine conjugates and parent form of phthalides, as well as saponin aglycones were the major circulating forms of DBT. Collectively, the metabolite profile analysis of DBT in different biological matrices provided a comprehensive understanding of the in vivo metabolic fates of constituents in DBT.

Topics: Acetylcysteine; Animals; Benzofurans; Bile; Biotransformation; Chromatography, High Pressure Liquid; Dietary Supplements; Drugs, Chinese Herbal; Glucuronides; Glutathione; Isoflavones; Male; Metabolome; Rats; Rats, Sprague-Dawley; Saponins; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization

The annulation of phthalides with α-alkyl/arylacrylates in the presence of LDA/LHMDS is shown to directly give alkyl/aryl-1-naphthols. The method involving a novel dealkoxycarbonylation obviates the regiochemical issues in the synthesis of polysubstituted naphthalenes, and it forms the key step in a three-step total synthesis of arnottin I, a naphthobenzopyranone natural product.

Topics: Acrylates; Benzofurans; Coumarins; Naphthols; Stereoisomerism; Substrate Specificity

The residual contact toxicity of three benzofuranoids (Z)-butylidenephthalide (1), (3S)-butylphthalide (2), and (Z)-ligustilide (3) identified in the rhizome of Cnidium officinale (Apiaceae) to B- and Q-biotype females of Bemisia tabaci was evaluated using a leaf-dip bioassay. Results were compared with those of eight conventional insecticides. Based on 24 h LC(50) values, (Z)-butylidenephthalide (254 ppm) and (Z)-ligustilide (268 ppm) were more toxic than (3S)-butylphthalide (339 ppm) against B-biotype females, whereas (Z)-ligustilide (254 ppm) and (3S)-butylphthalide (338 ppm) were more toxic than (Z)-butylidenephthalide (586 ppm) against Q-biotype females. Thiamethoxam, imidacloprid, and acetamiprid differ significantly in toxicity between the B- and Q-biotype females (LC(50), 1.7 to 11.6 vs 364.5 to >3000 ppm). This original finding indicates that the phthalides and the neonicotinoids do not share a common mode of action or elicit cross-resistance. Structure-activity relationship indicates that the presence of conjugation rather than aromaticity appeared to play an important role for phthalide toxicities to the B-biotype females. Global efforts to reduce the level of highly toxic synthetic insecticides in the agricultural environment justify further studies on C. officinale rhizome-derived materials as potential insecticides for the control of B. tabaci populations.

Topics: Animals; Benzofurans; Cnidium; Female; Hemiptera; Insecticides; Male; Plant Extracts; Rhizome; Structure-Activity Relationship

The chemical constituents of the organic extracts from the rhizomes of Ligusticum porteri were isolated, characterised and identified as Z-ligustilide, Z-butylidenephthalide, diligustilide, tokinolide B, riligustilide, senkyunolides F and I, ferulic acid, among other known compounds. The preparation of 4,5-dehydrotokinolide B from tokinolide B is reported, and its structure confirmed by X-ray analysis. The sedative and spasmolytic activities of some of these natural products and derivatives were evaluated by applying them to in vivo and in vitro models. Several of these dimeric phthalides displayed sedative and spasmolytic properties that may correlate with some popular uses of L. porteri.

Topics: Benzofurans; Biological Products; Hypnotics and Sedatives; Ligusticum; Models, Molecular; Parasympatholytics; X-Ray Diffraction

A cobalt-catalyzed addition of aryl- and alkenylboronic acids to aldehydes and phthalaldehyde to give the corresponding biarylketones and 3-aryl phthalides in good to excellent yields in one pot is described.

Topics: Aldehydes; Benzofurans; Boronic Acids; Catalysis; Cobalt; Ketones; Organometallic Compounds

Three new phthalide derivatives (1-3) named 5-(3'-methyl-2'-butenyl)-2-hydroxy-3-methoxy-4-methylbenzoic acid (1), 5-(3'-carboxyl-3'-methyl-2E-allyloxy)-3-methoxy-4-methylphthalide (2) and 5-(3',3'-dimethylallyloxy)-2-methoxycarbonyl-3-methoxy-4-methylbenzoic acid (3) together with six known phthalide derivatives named 5-(3',3'-dimethylallyloxy)-3-methoxy-4-methylphthalide (4), zinnimidine (5), 5-(3',3'-dimethylallyloxy)-3-methoxy-4-methylphthalide (6), 5-(3',3'-dimethylallyloxy)-3-methoxy-4-methylphthalic acid (7), zinniol anhydride (8) and porriolide (9) were isolated from the liquid culture of the plant endophytic fungus Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. Their structures were elucidated by extensive spectroscopic analysis. Compounds 1-9 displayed significant antifungal activities against three plant pathogens.

Topics: Antifungal Agents; Benzofurans; Culture Media; Models, Molecular; Molecular Structure; Spectrum Analysis; Tracheophyta; Xylariales

Two new compounds, 7-hydroxy-5-methoxy-4,6-dimethyl-7-O-α-L-rhamnosyl-phthalide and 7-hydroxy-5-methoxy-4,6-dimethyl-7-O-β-D-glucopyranosyl-phthalide, along with one known and related metabolite 7-hydroxy-5-methoxy-4,6-dimethylphthalide were isolated from the EtOAc extract of fermentation broth of an endophytic fungus Pestalotiopsis heterocornis. The structures of these compounds were elucidated on the basis of spectroscopic methods (UV, IR, HR-ESI-MS, 1D NMR, and 2D NMR).

Topics: Benzofurans; Glycosides; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Xylariales

The development of efficient methods for the facile construction of important molecular frameworks is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in a large collection of natural products with broad, potent, and potentially path-pointing biological activities. In this investigation, we have uncovered an unprecedented organocatalytic asymmetric aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient construction of the enantioenriched "privileged" scaffold. As a result of the sensitive nature of substrate structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interestingly, it is found that in this reaction, addition of an acid additive PhCO(2)H can significantly enhance reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the sensitivity of reaction conditions toward a sequential aldol-lactonization process without affecting enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile lactonization reaction in the presence of K(2)CO(3). The aldol-lactonization processes serve as a powerful approach to the preparation of synthetically and biologically important 3-substituted phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the natural product of 3-butylphthalide is reported.

Topics: Aldehydes; Benzofurans; Catalysis; Cyclization; Ketones; Magnetic Resonance Spectroscopy; Molecular Structure; Stereoisomerism; Structure-Activity Relationship

Phthalides are important bio-active constituents in Si-Wu-Tang and Fo-Shou-San, two commonly used Traditional Chinese Medicine (TCM) combined prescriptions mainly derived from Radix Angelica and Rhizoma Chuanxiong. In this paper, the contents of eight phthalides, including Z-ligustilide, E-ligustilide, Z-butylenephthalide, E-butylene-phthalide, 3-butylphthalide, neocnidilide and senkyunolide A were determined or estimated by gas chromatography-mass spectrometry (GC-MS). The results showed GC-MS was a simple, rapid, and high sensitive method for analyzing phthalides in Si-Wu-Tang, Fo-Shou-San, Radix Angelica and Rhizoma Chuanxiong, and the extractable contents of each phthalides including Z-ligustilide, E-ligustilide, Z-butylenephthalide, etc. varied after Radix Angelica, Rhizoma Chuanxiong were combined into a formulation, such as Si-Wu-Tang and Fo-Shou-San. Furthermore, inhibition activity of essential oils from Si-Wu-Tang, Fo-Shou-San, Radix Angelica and Rhizoma Chuanxiong on uterine contraction was tested in an in vitro assay, and the results showed that the activity of the essential oil is higher as the content of the phthalides increase, which demonstrated that phthalides are possibly main active components inhibiting mice uterine contraction in vitro. All of the results suggested that comparative analysis of chemical components and pharmacological activities of each herb and formula is possibly helpful to elucidate the active components in traditional Chinese medicine, and to reveal the compatibility mechanism of TCM formulae.

Topics: Angelica sinensis; Animals; Benzofurans; Drugs, Chinese Herbal; Female; Gas Chromatography-Mass Spectrometry; Mice; Oils, Volatile; Uterine Contraction

Transition metal-catalyzed addition of arylboronic acids to 2-formylbenzoates afforded 3-substituted phthalides. By using SPINOL-based phosphites as ligands, a Rh(I)-catalyzed asymmetric version of such an addition reaction was achieved.

Topics: Benzoates; Benzofurans; Boronic Acids; Catalysis; Organometallic Compounds; Stereoisomerism; Transition Elements

Topics: Benzofurans; Boron; Catalysis; Esters; Heterocyclic Compounds; Molecular Structure; Rhodium

An expeditious synthesis of 5,7-dihydroxy-6-methylphthalide from open-chain precursors is described. The key intermediates, synthons 3 and 4, were readily obtained from accessible materials and were further transformed to a common precursor, a five-membered lactone derivative, via an intramolecular Michael addition. Lactone 2 was aromatised to the phthalide system under basic conditions. The process thus constitutes a formal synthesis of the phthalide framework.

Topics: Benzofurans; Lactones; Molecular Structure; Phthalic Anhydrides; Spectrophotometry, Infrared

Sparassis crispa (SC), known as Hanabiratake in Japanese, is an edible mushroom with various medicinal properties. We isolated 3 novel phthalides, designated hanabiratakelide A (1), B (2), and C (3), from the SC fruit body. In this investigation, 3 known phthalides (4-6), ubiquinone-9, and 2 known unsaturated fatty acids were also isolated. Their structures were elucidated primarily through extensive NMR experiments. The isolated compounds 1-6 were tested for their anti-oxidant activity. The in vitro superoxide dismutase-like activity of the 3 hanabiratakelides was stronger than that of vitamin C. The compounds also exerted inhibitory effects on lipopolysaccharide-stimulated nitric oxide and prostaglandin E2 production by a murine macrophage cell line, RAW264. In addition, the growth of the colon cancer cell lines Caco-2 and colon-26 was significantly inhibited by treatment with the 3 hanabiratakelides. In vivo, the frequency of azoxymethane-induced aberrant crypt foci was reduced in SC-fed F344/N rats compared to rats fed a standard diet. In conclusion, 3 novel phthalides, hanabiratakelides, derived from SC were shown to possess anti-oxidant, anti-inflammatory, and anti-tumor activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Azoxymethane; Benzofurans; Caco-2 Cells; Cell Proliferation; Colonic Neoplasms; Dinoprostone; Dose-Response Relationship, Drug; Female; Humans; Macrophages; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Nitric Oxide; Polyporales; Rats; Rats, Inbred F344; Superoxide Dismutase

A palladium-catalyzed addition of arylboronic acids to phthalaldehyde, followed by an intramolecular lactonization to access 3-substituted phthalides, is described. The procedure tolerates a series of functional groups, such as methoxyl, fluoro, chloro, and trifluoromethyl groups. It represents a procedure for the synthesis of 3-substituted phthalides.

Topics: Benzofurans; Boronic Acids; Catalysis; Cyclization; Lactones; Molecular Structure; o-Phthalaldehyde; Palladium; Stereoisomerism

Five new compounds (1-5), were isolated from the rhizomes of Matteuccia orientalis (HOOK.) TREV. The structures of new compounds were elucidated on the basis of their 1D-, 2D-NMR, MS, IR and circular dichroism (CD) data.

Topics: Benzofurans; Circular Dichroism; Dryopteridaceae; Isocoumarins; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Conformation; Rhizome; Spectrophotometry, Infrared

Two new prenylated phthalide glycosides 1 and 2 were isolated from the whole plant of Helichrysum arenarium, and their structures were elucidated on the basis of spectral data.

Topics: Benzofurans; Drugs, Chinese Herbal; Glycosides; Helichrysum; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular

Studies towards the biomimetic synthesis of cardinalin 3 are described. Despite the successful enantioselective synthesis of the monomeric pyranonaphthoquinone ventiloquinone L, it subsequently failed to undergo a proposed biomimetic homodimerisation to cardinalin 3 using a range of oxidants. However, treatment of a related naphthopyran with cerium ammonium nitrate (CAN) facilitated a tandem biaryl bond formation-oxidative demethylation sequence furnishing a dimeric pyranonaphthoquinone that had exclusively dimerised at C6. The nature of this unusual sequence is discussed and the product subsequently converted to the C6 regioisomer of cardinalin 3.

Topics: Benzofurans; Benzoquinones; Biological Products; Biomimetics; Dimerization; Naphthoquinones; Plant Roots; Pyrans; Rhamnaceae; Stereoisomerism

Chemical investigation of the onion pathogenic fungus Alternaria porri resulted in the isolation of two new phthalides named zinnimide (2) and deprenylzinnimide (8), along with a new bianthraquinone, alterporriol F (10). The structures of the new metabolites were characterised by spectroscopic analysis and chemical degradation. Of the new compounds isolated, alterporriol F was highly cytotoxic towards HeLa and KB cells, with IC(50) values of 6.5 and 7.0 microg mL(-1).

Topics: Alternaria; Anthraquinones; Antineoplastic Agents; Benzofurans; Colorimetry; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Inhibitory Concentration 50; KB Cells; Lactones; Magnetic Resonance Spectroscopy; Molecular Structure; Phthalic Acids

A new diamine ligand for asymmetric transfer hydrogenation (ATH) was discovered. The reductive cyclization of 2-acylarylcarboxylates was found to proceed highly stereoselectively by the new Ru complex-catalyzed ATH and subsequent in situ lactonization under aqueous conditions. It enables efficient access to a wide variety of 3-substituted phthalides in enantiomerically pure form.

Topics: Benzofurans; Carboxylic Acids; Catalysis; Cyclization; Diamines; Hydrogenation; Ligands; Oxidation-Reduction; Ruthenium; Stereoisomerism; Substrate Specificity; Water

The synthesis of 3-arylphthalides via palladium-catalyzed arylation of aldehydes with organoboronic acids was achieved using the thioether-imidazolinium carbene ligand in good to excellent yields and was carried out using 1.0 mol % of the catalyst with high substrate tolerance.

Topics: Aldehydes; Benzofurans; Boronic Acids; Catalysis; Hydrocarbons, Aromatic; Palladium

Two new compounds, named ligusticoside A (1), a novel phthalide derivative with a lactone ring, and 4-pentylcyclohex-3-ene-1alpha,2beta-diol (2), were isolated from the rhizomes of Ligusticum chuanxiong. Their structures were determined by spectral methods (MS, IR, UV, 1D and 2D NMR). An X-ray diffraction experiment was performed to confirm the structure of compound 1.

Topics: Benzofurans; Crystallography, X-Ray; Cyclohexanones; Drugs, Chinese Herbal; Glycosides; Ligusticum; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Rhizome

To analyze the constituents of the essential oil extracted from the rhizomes of Ligusticum chuanxiong. cultivated in "GAP base for Chinese medicinal materials of China" (GAP demonstrative base of L. chuanxiong in Dujiangyan City of China), and to provide scientific foundation for the quality control and standard establishment of ones.. The essential oil was extracted by water-steam distillation and separated by GC capillary column chromatography. The components were determined with normalization method, and identified by GC-MS and co-artificial searches.. One hundred forty-two chromatographic peaks were isolated, among them sixty-two components were identified, which was composed of 87.36% of the total essential oil. The mass fragmentation rules of phthalides and its derivatives in the essential oil were summarized, which primarily underwent two electron impact fragmentation pathways: side-chain cleavage with losses of alkenes/alkanes and ring-opening with elimination of H2O followed by losses of CO. On the basis of these rules, the plane structure of 4, 5-dihydro-3, 1 '-dihydroxy-3-pentylphthalide as a new compound was determined.. The main components of the essential oil extracted from the rhizomes of L. chuanxiong cultivated in "GAP Demonstrative Base of L. chuanxiong in Dujiangyan City of China" were phthalides and its derivatives. 4,5-Dihydro-3,1'-dihydroxy-3-pentylphthalide was a new compound.

Topics: Benzofurans; Gas Chromatography-Mass Spectrometry; Ligusticum; Molecular Structure; Oils, Volatile; Rhizome

A novel rapid resolution liquid chromatography (RRLC) method coupled with diode-array detection (DAD) and time-of-flight mass spectrometry (TOFMS) in both positive and negative modes has been developed for quick and sensitive identification of the major compounds in Danggui Buxue Tang (DBT) preparation. Significant advantages of the use of RRLC with 1.8-microm porous particles include the much higher speed of chromatographic separation and great enhancement in sensitivity, compared with the conventional high-performance liquid chromatography (HPLC). With dynamic adjustment of the key role as fragmentor voltage in TOFMS, an efficient transmission of the ions was achieved to obtain the best sensitivity for providing the molecular formula for each analyte, and abundant fragment ions for structural information. The structural characterization of the major compounds in DBT was elucidated with authentic standards by DAD-TOF/MS, including phenolic acids, phthalides, saponins and isoflavonoids. The targets were rapidly screened from the complicated DBT matrix using a narrow mass window of 0.01 Da to restructure extracted ion chromatograms. By accurate mass measurements within 3 ppm error for each molecular ion and subsequent fragment ions, ten phenolic acids and phthalides including three groups of isomers, thirteen major saponins with a 20,24-epoxy-9,19-cyclolanostane-3,6,16,25-tetrol skeleton, sixteen isoflavonoids, corresponding glycosides, malonylglycosides, and acetylglycosides were identified in DBT preparation. The appropriate fragmentation pathways for them were also proposed based on definite elemental composition of the fragment ions.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hydroxybenzoates; Isoflavones; Plant Extracts; Reproducibility of Results; Saponins; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Angelica sinensis is a Chinese medicinal herb for treating gynecological and gastrointestinal disorders, and also in conjunction with cancer chemotherapy.. In the present study, the cytotoxic and anti-proliferative effects of three main Angelica sinensis phthalides, namely n-butylidenephthalide (BLP), senkyunolide A (SKA) and z-ligustilide (LGT), and their synergy on colon cancer HT-29 cells were investigated. Moreover, the results obtained in both human colon cancer HT-29 and normal colon CCD-18Co cells were compared for the investigation of selectivity.. MTT and [3H] thymidine incorporation assays were used for the evaluation of cytotoxic and anti-proliferative effects, respectively. Interactions among phthalides were determined by median-effect analysis.. All three phthalides dose-dependently decreased cell viability more potently in HT-29 than in CCD-18Co cells. The IC50 values for inhibition of cell proliferation for SKA, LGT and BLP were 54.17+/-5.10, 60.63+/-6.79 and 236.90+/-18.22microM, respectively, in HT-29 cells. Angelica sinensis extract demonstrated significant synergy in inhibiting cell proliferation.. The three phthalides might have anti-cancer potential, yet the phthalides, in combination with other ingredients in Angelica sinensis extract, display significant synergy leading to a stronger anti-tumor effect.

Topics: Adenocarcinoma; Angelica; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Drugs, Chinese Herbal; HT29 Cells; Humans; Inhibitory Concentration 50; Plant Extracts

Celery-based products were investigated for chemical composition, skin irritation, and mosquito repellency in comparison to commercial repellents and the standard chemical, N,N-diethyl-3-methylbenzamide (DEET), with a goal to develop a natural alternative to synthetic repellents for protection against mosquitoes. Chemical identification by gas chromatography coupled with mass spectrometry discovered that the major constituents of Apium graveolens hexane extract (AHE) were 3-n-butyl-tetrahydrophthalide (92.48%), followed by 5.10% beta-selinene and 0.68% gamma-selinene. Evaluation of skin irritation in 27 human volunteers revealed no irritant potential from 25% ethanolic AHE solution. Laboratory investigated repellent against female Aedes aegypti mosquitoes demonstrated that G10 formula, the best AHE-developed product, provided remarkable repellency with a median protection time of 4.5 h (4.5-5 h), which was greater than that of ethanolic DEET solution (25% DEET, 3.5 h) and comparable to that of the best commercial repellent, Insect Block 28 (28.5% DEET, 4.5 h). According to significantly promising results, including highly effective repellency and no potential skin irritation or other side effects, the G10 formula is a worthwhile product that has the promise of being developed for commercialized registration. This developed AHE product could be an acceptable and affordable alternative to conventional synthetic chemicals in preventing mosquito bites, and in turn, helping to interrupt mosquito-borne disease transmission.

Topics: Administration, Topical; Adult; Aedes; Animals; Apium; Benzofurans; DEET; Female; Humans; Insect Bites and Stings; Insect Repellents; Male; Middle Aged; Plant Extracts; Sesquiterpenes; Sesquiterpenes, Eudesmane; Skin; Tetrahydronaphthalenes; Young Adult

Six new phthalides, (S)-3-ethyl-7-hydroxy-6-methoxyphthalide (1), (S)-3-ethyl-7-hydroxy-5,6-dimethoxyphthalide (2), (S)-3-ethyl-5,6,7-trimethoxyphthalide (3), (R)-3-ethyl-7-hydroxy-6-methoxyphthalide (4), (Z)-3-ethylidene-7-hydroxy-6-methoxyphthalide (5), and (Z)-3-ethylidene-6,7-dimethoxyphthalide (6), have been isolated from the root of Pittosporum illicioides var. illicioides, together with seven known compounds. The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 1-4 exhibited inhibition (IC50

Topics: Benzofurans; Cytochalasin B; Humans; Inhibitory Concentration 50; Molecular Structure; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nuclear Magnetic Resonance, Biomolecular; Pancreatic Elastase; Plant Roots; Plants, Medicinal; Rosales; Rotenone; Superoxides; Taiwan

To analyze and identify the principal composition of ethyl acetate part of Huangqi Danggui decoction by high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS).. The analysis conditions are as follows: Zorbax SB C18 (4.6 mm x 250 mm, 5 microm) column; mobile phase (A) water mobile phase (B) acetonitrile, gradient elution; UV detection wavelength 254 nm; ESI source and data acquisition in positive and negative mode.. The accurate molecular weights of 20 compounds were measured and identified in ethyl acetate part of Huangqi Danggui decoction. Furthermore, the types of them are as below: flavonoids and flavonoid glycosides, saponins, oligosaccharides, amino acids and phthalides.. It is a rapid and accurate method that the compositions of compound prescription of traditional Chinese medicine can be identified in terms of the separation of high performance liquid chromatography, the accurate molecular weights measured by MS and other information, which can clarify the potential effective compounds of Huangqi Danggui decoction.

Topics: Acetates; Amino Acids; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Flavonoids; Glycosides; Molecular Weight; Oligosaccharides; Saponins; Spectrometry, Mass, Electrospray Ionization

The flavor-enhancing effects of the volatile constituents in celery were investigated. The test samples were prepared by adding celery fractions to chicken broth at a concentration that distinct odors of them were not detected, and the samples were sensorially evaluated for the perceived intensities of 8 terms such as "thick," "impactful," "mild," "lasting," "satisfied," "complex," "refined," and "clarified," which are considered to be the elements of the complex flavor and for 3 terms such as "sweet," "salty," and "umami" taste. A comparison of effects between the volatile and nonvolatile fractions of celery revealed that the volatile compounds in celery enhanced the complex flavor of chicken broth more than the nonvolatile compounds. Among the characteristic odorants of celery, three phthalides, namely, sedanenolide, 3- n-butylphthalide, and sedanolide, were shown to contribute to the complex flavor of chicken broth, and sedanenolide was most effective. The three phthalides enhanced perceived intensities of "umami" and "sweet" despite their no taste properties in addition to the complex flavor.

Topics: Animals; Apium; Benzofurans; Chickens; Hot Temperature; Humans; Meat; Odorants; Solutions; Taste; Volatilization

Five metabolites, ( Z)-6-benzylidene-3-hydroxymethyl-1,4-dimethyl-3-methylsulfanylpiperazine-2,5-dione ( 1), (3S,3'R)-3-(3'-hydroxybutyl)-7-methoxyphthalide ( 2), ( S)-3-butyl-7-methoxyphthalide ( 3), (3R,6R)-bisdethiodi(methylthio)hyalodendrin ( 4), and bis- N-norgliovictin ( 5), were isolated from the culture broth of the marine derived fungus of the order Pleosporales strain CRIF2. Compounds 1 and 2 are new fungal metabolites, while 3 was isolated for the first time as a natural product. Compounds 1, 3, and 4 exhibited only weak cytotoxic activity, while 5 was inactive at 50 microg/mL.

Topics: Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line, Tumor; Diketopiperazines; Fungi; Humans; Phytotherapy; Seawater

The naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.

Topics: Anti-Bacterial Agents; Benzofurans; Helicobacter pylori; Heterocyclic Compounds; Microbial Sensitivity Tests; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

[structure: see text]. We have developed a cationic rhodium(I)/Solphos complex-catalyzed asymmetric one-pot transesterification and [2 + 2 + 2] cycloaddition of 1,6-diyne esters with tertiary propargylic alcohols leading to enantioenriched tricyclic 3,3-disubstituted phthalides. The present method represents a versatile new route to the synthesis of enantioenriched tricyclic 3,3-disubstituted phthalides in view of the easy access to both coupling partners.

Topics: Alkynes; Benzofurans; Catalysis; Models, Molecular; Molecular Structure; Polycyclic Compounds; Propanols; Rhodium; Stereoisomerism

3-Phenylsulfanylphthalides (e.g. 8a) readily react with p-benzoquinones in the presence of LiOtBu in THF to furnish 1,4-dihydroxyanthraquinones in good yields and one-pot operations.

Topics: Anthracyclines; Anthraquinones; Benzofurans; Benzoquinones; Hydroxylation; Molecular Structure; Naphthacenes

Suppression of hepatic stellate cell (HSC) growth and activation, and induction of apoptosis, have been proposed as therapeutic strategies for the treatment and prevention of liver fibrosis. Our previous study showed that the Chinese herb Ligusticum chuanxiong (LC) inhibits platelet-derived growth factor (PDGF-BB)-induced HSC proliferation. The present study was designed to investigate the active principles and their action mechanisms. With a bioactivity-directed fractionation approach, DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of active principles of LC. Two phthalides, Z,Z'-6,8',7,3'-diligustilide (1) and levistolide A (2), from LC significantly abrogated PDGF-BB-induced proliferation in both rat and human HSC lines. These inhibitory effects of compounds 1 and 2 were associated with reduction of alpha-smooth muscle actin and collagen expressions. The cell cycle promoting proteins, cyclins D1, D2, E, A and B1, were downregulated while the inhibitory proteins p21 and 27 were up-regulated. JNK phosphorylation was up-regulated by compounds 1 and 2. In HSC-T6, the two compounds induced apoptosis through the activation of caspases 9 and 3, increase in cytosolic cytochrome c release, and downregulation of Bcl-2 and Akt phosphorylation. Moreover, neither phthalides caused direct cytotoxicity to either HSCs or rat primary hepatocytes under experimental concentrations. These results indicate that two phthalides from LC inhibited PDGF-BB-activated HSC proliferation possibly through cell cycle inhibition and apoptosis mechanisms. They might be potential anti-fibrotic drugs for the treatment and prevention of hepatic fibrosis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Flow Cytometry; Hepatocytes; Humans; In Situ Nick-End Labeling; Ligusticum; Liver Cirrhosis; Phytotherapy; Plant Extracts; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Rhizome

Topics: Alkynes; Benzofurans; Biological Products; Catalysis; Furans; Molecular Structure; Phenol; Spiro Compounds; Stereoisomerism

The reductive dechlorinating abilities for chloroethenes of seven enrichment cultures from polychlorinated-dioxin-dechlorinating microcosm were investigated using culture-independent and -dependent methods. These cultures were constructed and maintained with 1,2,3-trichlorobenzene (1,2,3-TCB) or fthalide as an electron acceptor and hydrogen as an electron donor. Denaturing gradient gel electrophoresis (DGGE) analysis of the amplified fragments targeting the 16S rRNA gene showed one or two major bands, whose nucleotide sequences were then analyzed and were found to suggest that Dehalococcoides was one of the dominant bacteria in all enrichment cultures. The nucleotide sequence data revealed that the identity of the major band was 100% identical to the 16S rRNA gene sequence of the Pinellas subgroup of the Dehalococcoides clusters, that is, strains CBDB1 and FL2. Genetic diagnosis targeting the pceA, tceA, bvcA, vcrA and reductive dehalogenase homologous (rdh) gene was performed to investigate the potential for reductive chloroethene dechlorination of cultures. The required length of PCR-amplified fragments was not observed, suggesting that these cultures are not capable of reductively dechlorinating chloroethenes. However, a culture-dependent test indicated that two cultures, TUT1903 and TUT1952, reductively dechlorinated tetrachloroethene (PCE) to trichloroethene (TCE), although not completely. While, TUT2260 and TUT2264 completely converted PCE to TCE and dichloroethenes, but not further. These results suggest that these TUT cultures might include a novel type of bacteria belonging to the Dehalococcoides group and that currently available information on both the 16S rRNA gene and rdh gene sequences is insufficient to definitively evaluate the potential abilities for reductive dechlorination.

Topics: Bacterial Proteins; Benzofurans; Chlorine; Chlorobenzenes; Chloroflexi; Dioxins; DNA Fingerprinting; DNA, Bacterial; DNA, Ribosomal; Electrophoresis, Polyacrylamide Gel; Fresh Water; Hydrogen; Molecular Sequence Data; Nucleic Acid Denaturation; Oxidation-Reduction; Polymerase Chain Reaction; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Vinyl Chloride; Water Pollutants

The raw and boiled odors of celery leaves and stalks were investigated. Among 12 compounds identified as potent odorants, 3-n-butylphthalide 1, sedanenolide 2, and trans- and cis-sedanolides 3, 4 were assessed to be most contributive to the overall odor of celery. These three phthalides, (3E,5Z)-1,3,5-undecatriene, myrcene, and (E)-2-nonenal were common to both raw and boiled materials. Two compounds, ((Z)-3-hexenal and (Z)-3-hexenol), were dominant in raw materials and four compounds, (2-methylbutanoic acid, sotolon, beta-damascenone, and beta-ionone), were dominant in boiled materials. Sensory evaluations were performed on natural celery odor and a series of reconstructed model aromas by assigning each intensity ratings for a set of seven odor qualities which aptly describe the odors of raw and boiled celery. According to the evaluation results, six common components contributed to the moderate odor of raw celery, two components dominant in raw materials enhanced the raw celery character, and four components dominant in boiled materials reduced the raw celery character and enhanced the boiled celery character. It was clarified that boiling-induced changes in celery odor were not affected by the amounts of phthalides, but by thermally generated compounds such as sotolon, beta-damascenone, and beta-ionone, which reduce the "green spicy" note.

Topics: Adult; Apium; Benzofurans; Female; Hot Temperature; Humans; Male; Models, Biological; Molecular Structure; Plant Extracts; Plant Leaves; Plant Stems; Smell; Water

In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.

Topics: Benzofurans; Cell Line, Tumor; Cell Proliferation; Humans; Magnetic Resonance Spectroscopy; Spectrophotometry, Infrared; Structure-Activity Relationship

Two new phthalide dimers, namely chuanxiongnolide A (1) and chuanxiongnolide B (2), along with eleven known phthalides and derivatives ( 3 - 13), were isolated from the roots of Ligusticum chuanxiong Hort. (Umbelliferae). The chemical structures of the new compounds were established by HR-ESI-MS, 1D- and 2D-NMR spectroscopic analysis, whilst the relative stereochemistry of 1 was confirmed by X-ray crystallographic data.

Topics: Benzofurans; Crystallography, X-Ray; Ligusticum; Spectrum Analysis

Topics: Agriculture; Benzofurans; Fresh Water; Fungicides, Industrial; Gas Chromatography-Mass Spectrometry; Japan; Oryza; Water Pollutants, Chemical

To study the protective effect of ligusticum chuanxiong phthalides on cerebral ischemia in rats and its related mechanism of action.. Middle cerebral artery occlusion (MCAO) model, thrombosis formation, platelet aggregation and hemorrheological parameters were measured to evaluate the protective effect of ligusticum chuanxiong phthalides.. Ligusticum chuanxiong phthalides could markedly decrease the infarct size and behavior deficits score, inhibit the thrombus formation and platelet aggregation, ameliorate hemorrheological parameters with a dose-dependent manner in rats.. Ligusticum chuanxiong phthalides has protective effects on focal cerebral ischemia in rats, and its mechanism may be relevant to its inhibition of platelet-dependent thrombosis and amelioration of hemorrheological parameters.

Topics: Animals; Benzofurans; Blood Viscosity; Brain Ischemia; Dose-Response Relationship, Drug; Hematocrit; Infarction, Middle Cerebral Artery; Ligusticum; Male; Neuroprotective Agents; Plants, Medicinal; Platelet Aggregation; Rats; Rats, Wistar; Venous Thrombosis

Enantiopure phthalides 2 and 5-8 were synthesized via enantioresolution of the corresponding alcohols with a chiral auxiliary of camphorsultam dichlorophthalic acid, (1S,2R,4R)-(-)-CSDP acid 3, followed by solvolysis with KOH in MeOH and the catalytic oxidation of chiral glycols with iridium complex 28. The absolute configurations of phthalides 2 and 5-8 were determined by applying the (1)H-NMR anisotropy method of MalphaNP acid (4), 2-methoxy-2-(1-naphthyl)propionic acid, to the chiral synthetic precursory alcohols. In the case of 3-phenylphthalide (R)-(-)-7, the absolute configuration determined by the (1)H-NMR anisotropy method using MalphaNP acid 4 agreed with that by the X-ray crystallographic method. By applying these methods, 3-butylphthalide (S)-(-)-2, a fragrance component of essential oil of celery, has been synthesized in an enantiopure form, and its absolute configuration was unambiguously determined.

Topics: Alcohols; Apium; Benzofurans; Chromatography, High Pressure Liquid; Esters; Molecular Structure; Oils, Volatile; Perfume; Plant Oils; Silica Gel; Silicon Dioxide; Spectrum Analysis; Stereoisomerism

Anxiolytic effects induced by benzalphthalides on mice have been evaluated. The evaluation was based on the spent time and the number of entries of animals into the open arms in the elevated plus maze test. Single administration of benzalphthalides 1 and 11 induced significant increments in both parameters, thus revealing their potentiality as new leads for the development of non-benzodiazepinic and non-nitrogenated antianxiety agents.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Benzamides; Benzodiazepines; Benzofurans; Brain; Dose-Response Relationship, Drug; Maze Learning; Mice

The insecticidal activity of the chloroform extract of Cnidium officinale rhizomes and its constituents was investigated against larvae and adults of Drosophila melanogaster and compared with that of rotenone. Bioassay-guided isolation of the chloroform extract of C. officinale resulted in the isolation and characterization of four alkylphthalides, cnidilide (1), (Z)-ligustilide (2), (3S)-butylphthalide (3), and neocnidilide (4). The structures of these compounds were established by spectroscopic analysis. The isolated compounds 2, 3, and 4 exhibited LC50 values of 2.54, 4.99, and 9.90 micromol/mL of diet concentration against larvae of D. melanogaster, respectively. Against both sexes (males/females, 1:1) of adults (5-7 days old), compound 3 showed the most potent activity of the compounds isolated with the LD50 value of 5.93 microg/adult, comparable to that of rotenone (LD50 = 3.68 microg/adult). Structure-activity relationships of phthalides isolated suggest that the presence of conjugation with the carbonyl group in the lactone ring appeared to play an important role in the larvicidal activity. Acetylcholinesterase (prepared from the adult heads of D. melanogaster) inhibitory activity was also investigated in vitro to determine the insecticide mode of action for the acute adulticidal activity.

Topics: Alkylation; Animals; Benzofurans; Chloroform; Cholinesterase Inhibitors; Cnidium; Drosophila melanogaster; Insecticides; Larva; Plant Extracts; Rhizome

The dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae) is a traditional Chinese medicine (TCM) herb for the prevention and treatment of inflammatory and cardiovascular diseases. However, the role of phthalide lactones from Ligusticum chuanxiong in the therapeutic actions is not yet fully understood. In the present study, two phthalide lactones from the herb, Z-ligustilide and senkyunolide A, were identified and characterized as inhibitors of lipopolysaccharide (LPS)-induced TNF-alpha production in monocytes. The results of gene expression studies showed that the observed TNF-alpha suppression was related to their inhibitory activity on TNF-alpha mRNA transcription. Furthermore, the two phthalides exhibited significant suppressive effects on TNF-alpha-mediated nuclear factor-kappaB (NF-kappaB) activation in reporter gene assays. Taken together, the results suggest that Z-ligustilide and senkyunolide A may have potential applications in the treatment of inflammation and related diseases based on their inhibitory activity on TNF-alpha production and TNF-alpha bioactivity. New insights into the therapeutic basis of the TCM herb, Ligusticum chuanxiong, are presented.

Topics: Benzofurans; Humans; Lactones; Ligusticum; Lipopolysaccharides; Monocytes; NF-kappa B; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Rhizome; Tumor Necrosis Factor-alpha

The studies presented here deal with the convenient and efficient one-step conversion of o-alkylbenzoic acids into their corresponding isobenzofuran-1 (3H)-ones (phthalides) using NaBrO3/NaHSO3 in a two-phase system. A range of o-alkylbenzoic acids was used with the object of getting a variety of phthalide derivatives as multipurpose biologically active compounds. Seventeen phthalides have been synthesized and tested for cytotoxicity, antibacterial and antifungal activities. Some of these compounds showed promising cytotoxic effects against Artemia salina. Compounds 4j-4p were highly active against Gram-negative and Gram-positive bacteria among all tested compounds. In the fungicidal assay, the compounds showed a broad spectrum of activity against six fungi. All compounds were characterized via elemental analysis, UV, IR, mass and-NMR spectroscopy.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Artemia; Bacteria; Benzofurans; Fungi; Indicators and Reagents; Lethal Dose 50; Microbial Sensitivity Tests; Structure-Activity Relationship

Insecticidal activity of Angelica acutiloba extract and its constituents was investigated and compared with that of rotenone. Bioassay-guided isolation of the chloroform extract of A. acutiloba against larvae of Drosophila melanogaster afforded two phthalides, (Z)-butylidenephthalide (1) and (Z)-ligustilide (2), and two furanocoumarins, xanthotoxin (3) and isopimpinellin (4). The structures of these compounds were established by spectroscopic analysis. The isolated compounds 1, 2, 3, and 4 exhibited LC(50) values of 0.94, 2.54, 3.35, and 0.82 micromol/mL of diet concentration against larvae of D. melanogaster, respectively. Against both sexes (males/females, 1:1) of adults (5-7 days old), compound 1 showed the most potent activity with a LD(50) value of 0.84 microg/adult. Compound 1 is a more active insecticide than rotenone (LD(50) = 3.68 microg/adult) and has potential as a novel insect control agent. However, compound 2 was inactive against adults. The structure-activity relationship of phthalides isolated indicated that the aromaticity appeared to play an important role in the activity of both larvae and adults. To determine the insecticide mode of action for acute adulticidal activity, acetylcholinesterase (AChE) inhibitory activity was also investigated in vitro, and the result indicated that the acute adulticidal activity of compounds 3 and 4 was due to the inhibition of AChE.

Topics: Angelica; Animals; Benzofurans; Cholinesterase Inhibitors; Drosophila melanogaster; Female; Furocoumarins; Insecticides; Larva; Male; Structure-Activity Relationship

A screening campaign was implemented utilizing capillary electrophoresis as a primary assay to discover binders to the cancer target Akt1 from a crude natural extract library. Fungal extracts with binding activities were characterized for biochemical inhibition of Akt1 to phosphorylate the downstream substrate protein Bad. One of the crude extracts with bioactivity selected for isolation and structure elucidation from fermentation of the fungal culture Oidiodendron sp. F01895 yielded a new trihydroxy phthalide (1). The structure of 1 was determined by a combination of 1D and 2D NMR spectroscopic data along with high-resolution mass spectrometric data. Compound 1 displays inhibition of Akt1 biochemical activity in vitro and confers growth inhibition on some cancer-derived cell lines in culture.

Topics: Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fungi; Humans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured

[reaction: see text] Condensation of a benzopyranonphthalide with Michael acceptors provides an efficient, general method for regiospecific preparation of xanthones as well as linear and angular polycyclic aromatic systems containing a xanthone fragment.

Topics: Benzofurans; Benzopyrans; Stereoisomerism; Xanthones

High-performance liquid chromatography (HPLC) with diode-array detection interfaced to atmospheric pressure chemical ionization (APCI)-mass spectrometry (MS) is applied to analyze phthalides from Chuanxiong (the rhizome of Ligusticum chuanxiong). This herb material, containing plenty of phthalide compositions, is selected as the analytical target in this paper for its hematological activity. Some of the phthalides are not stable and are difficult to analyze by gas chromatography-MS. Under optimized LC-MS-MS conditions, six phthalides in the methanol extract of Chuanxiong are unambiguously identified, and characteristic fragments are obtained using homemade reference standards. Ten other phthalides in the extract are confirmed by means of LC-APCI-MS with positive-negative ion mode and collision-induced dissociation in combination with UV spectrophotometry. The results show that LC-MS-MS is a method of choice for fast detection and detailed structural analysis of such mixtures in the crude extract of Chuanxiong.

Topics: Atmospheric Pressure; Benzofurans; Chromatography, High Pressure Liquid; Dimerization; Drugs, Chinese Herbal; Ligusticum; Mass Spectrometry

From the water-soluble portion of the methanol extract of celery seed (fruit of Apium graveolens L.) five sesquiterpenoid glucosides (celerioside A-E) and three phthalide glycosides (celephtalide A-C) were isolated together with six aromatic compound glucosides, two norcarotenoid glucosides and a lignan glucoside. Their structures were determined by spectral investigations.

Topics: Apium; Benzofurans; Carotenoids; Glucosides; Glycosides; Lignans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Extracts; Plants, Medicinal; Seeds; Sesquiterpenes

Both the enantiomers as well as the racemate of 3-butyl-7-hydroxyphthalide (1) were synthesized, and the absolute configuration of the naturally occurring (-)-1 (a weakly cytotoxic metabolite of Penicillium vulpinum) was identified as S.

Topics: Benzofurans; Cytotoxins; Hydroxylation; Magnetic Resonance Spectroscopy; Penicillium; Stereoisomerism

[reaction: see text] Condensation of the phthalide sulfide with an ortho-quinone monoketal was employed as a key step in the first total synthesis of a derivative of (+/-)-PD 116740.

Topics: Benz(a)Anthracenes; Benzofurans; Hydroxylation; Quinones; Stereoisomerism; Sulfides

An alternative versatile synthesis of 5-cyanophthalide, a key synthetic intermediate in the preparation of the antidepressant drug Citalopram, is presented. The synthesis reported here allows the preparation of this important intermediate in three steps, avoiding the manipulation of environmentally detrimental cyanides.

Topics: Antidepressive Agents, Second-Generation; Benzofurans; Citalopram

Seven new phthalide compounds with anti-Helicobacter pylori activities were isolated from the basidiomycete Phanerochaete velutina CL6387. The two most potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The structure-activity relationship shows that the presence of a spiroketal part in addition to the phthalide part, greatly enhances the activity. The phthalide compounds appear to be specific for H. pylori, since they did not show antibacterial activities when tested against a panel of other microorganisms.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Basidiomycota; Benzofurans; Fermentation; Helicobacter pylori; Microbial Sensitivity Tests; Molecular Structure; Spiro Compounds; Structure-Activity Relationship

In the structure of the phthalide form of 2-acetylbenzoic acid, C9H8O3, there is a single type of hydrogen bond. Each molecule donates one and accepts one hydrogen bond. The hydrogen-bonded molecules form sets of puckered ribbons running along the c direction which are not crosslinked to each other. The dihedral angle between the planes of adjacent molecules along a hydrogen-bonded ribbon is 77.4(1) degrees.

Topics: Benzofurans; Crystallography, X-Ray; Hydrogen Bonding; Molecular Structure

Topics: Alkaloids; Benzofurans; Chemistry, Pharmaceutical; Lactones; Phthalic Acids; Pyrroles; Pyrrolidines; Research

Topics: Anhydrides; Benzofurans; Indans; Phthalic Acids