ABSTRACT
Chuanxiongdiolides R4-R6 (1-3), three novel phthalide dimers featuring two classes of unreported monomeric units (ligustilide/senkyunolide A and ligustilide/neocnidilide) with an unprecedented linkage style (3a,7'/7a,7'a), were isolated from the aerial parts of Ligusticum chuanxiong, together with three pairs of enantiomeric phthalide dimers [(-)/(+)-4a/4b, 5a/5b, and 6a/6b]. The bioassays revealed that compounds 1, 3, 4, 5, and 6 showed significant vasodilation effects, and the mechanism may be attributed to Cav1.2 activation blockade. Based on the established compounds library, the structure activity relationship of the phthalides was proposed. Our findings afford possible leads for developing new vasodilator against cardiovascular and cerebrovascular diseases such as hypertension and ischemic stroke.
Subject(s)
Benzofurans/pharmacology , Heterocyclic Compounds, Bridged-Ring/pharmacology , Ligusticum/chemistry , Vasodilator Agents/pharmacology , Animals , Benzofurans/chemistry , Benzofurans/isolation & purification , Benzofurans/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/isolation & purification , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/metabolism , HEK293 Cells , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Plant Components, Aerial/chemistry , Protein Binding , Rabbits , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Vasodilator Agents/chemistry , Vasodilator Agents/isolation & purification , Vasodilator Agents/metabolismABSTRACT
Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5µM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic.
Subject(s)
Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, Bridged-Ring/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Xanthones/pharmacology , A549 Cells , Amino Acids/chemical synthesis , Amino Acids/pharmacology , Amino Acids/toxicity , Ampicillin/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Bacterial Adhesion/drug effects , Garcinia , HEK293 Cells , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/isolation & purification , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/toxicity , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/toxicity , Humans , Methicillin-Resistant Staphylococcus aureus/physiology , Microbial Sensitivity Tests , Oxacillin/pharmacology , Xanthones/chemical synthesis , Xanthones/chemistry , Xanthones/isolation & purification , Xanthones/toxicityABSTRACT
Five new polyketides, trichocladinols D-H (1-5) with dioxatricyclic (1-3) and oxabicyclic (4 and 5) skeletons, and the known massarilactone C (6) were isolated from the solid-substrate fermentation cultures of the ascomycete fungus Trichocladium opacum. The structures of 1-5 were determined mainly by NMR experiments, and 1, 3, and 4 were confirmed by X-ray crystallography. The absolute configurations of 1 and 3 were assigned by X-ray crystallography using Cu Kα radiation, whereas that of C-5 in 2 and 4 was deduced via the circular dichroism (CD) data. Compounds 2-4 showed weak cytotoxicity against the human tumor cell lines A549, HCT116, and SW480.
Subject(s)
Antineoplastic Agents/isolation & purification , Ascomycota/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Polyketides/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Circular Dichroism , Crystallography, X-Ray , Drug Screening Assays, Antitumor , HCT116 Cells , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Humans , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Polyketides/chemistry , Polyketides/pharmacology , TibetABSTRACT
The novel natural product acremostrictin was isolated from the culture broth of Acremonium strictum, a marine fungus collected from a Choristida sponge off the coast of Korea. Structurally, acremostrictin is a tricyclic lactone of an unprecedented skeletal class based on combined spectroscopic and X-ray crystallographic analyses. The new compound exhibited weak antibacterial and moderate antioxidant activities.
Subject(s)
Acremonium/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Animals , Antioxidants/metabolism , Biphenyl Compounds/pharmacology , Crystallography, X-Ray , Heterocyclic Compounds, Bridged-Ring/chemistry , Korea , Marine Biology , Molecular Conformation , Molecular Structure , Picrates/pharmacology , Porifera/microbiologyABSTRACT
The skin of the Ecuadorian poison frog Epipedobates anthonyi contains the potent nicotinic agonists epibatidine (1) and N-methylepibatidine (3). In addition, a condensed tetracyclic epibatidine congener has been identified with activity at nicotinic acetylcholine receptors, but different selectivity than epibatidine. This rigid tetracycle has been named phantasmidine (4). Phantasmidine has a molecular formula of C(11)H(11)N(2)OCl, shares a chloropyridine moiety with 1, and also contains furan, pyrrolidine, and cyclobutane rings. A combination of GC-MS and GC-FTIR analysis with on-column derivatization, 1D NMR spectroscopy with selective irradiation, and spectral simulation, along with 2D NMR, were used to elucidate the structure from a total sample of approximately 20 microg of HPLC-purified 4 and its corresponding acetamide (5). After synthesis, this novel rigid agonist may serve as a selective probe for beta4-containing nicotinic receptors and potentially lead to useful pharmaceuticals.
Subject(s)
Alkaloids/isolation & purification , Amphibian Venoms/isolation & purification , Bridged Bicyclo Compounds, Heterocyclic/isolation & purification , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Pyridines/isolation & purification , Ranidae , Alkaloids/chemistry , Alkaloids/pharmacology , Amphibian Venoms/chemistry , Amphibian Venoms/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Ecuador , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pyridines/chemistry , Pyridines/pharmacology , StereoisomerismABSTRACT
New spirocyclic and bicyclic hemiacetals, isariotins E (1) and F (2), together with TK-57-164A (3) were isolated from the entomopathogenic fungus Isaria tenuipes BCC 12625. The absolute configuration of 3 was addressed by application of the modified Mosher's method. Isariotin F (2) exhibited activity against the malaria parasite Plasmodium falciparum K1 with an IC(50) value of 5.1 microM and cytotoxic activities against cancer cell lines (KB, BC, and NCI-H187) and nonmalignant (Vero) cells with respective IC(50) values of 15.8, 2.4, 1.6, and 2.9 microM.
Subject(s)
Antimalarials/isolation & purification , Antitubercular Agents/isolation & purification , Bridged Bicyclo Compounds, Heterocyclic/isolation & purification , Epoxy Compounds/isolation & purification , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Hypocreales/chemistry , Plasmodium falciparum/drug effects , Spiro Compounds/isolation & purification , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Candida albicans/drug effects , Chlorocebus aethiops , Drug Screening Assays, Antitumor , Epoxy Compounds/chemistry , Heterocyclic Compounds, Bridged-Ring/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Mycobacterium tuberculosis/drug effects , Parasitic Sensitivity Tests , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Thailand , Vero CellsABSTRACT
Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynthetic pathways for 1-3 were proposed on the basis of the coexisting alkaloid monomers as the precursors. Compound 2 exhibited significant activity in promoting neuronal differentiation of Neuro-2a cells.
Subject(s)
Azepines/pharmacology , Euphorbiaceae/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Lactones/pharmacology , Piperidines/pharmacology , Animals , Azepines/chemistry , Azepines/isolation & purification , Cell Differentiation/drug effects , Cell Line, Tumor , Dimerization , Dose-Response Relationship, Drug , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Lactones/chemistry , Lactones/isolation & purification , Mice , Molecular Conformation , Piperidines/chemistry , Piperidines/isolation & purification , Structure-Activity RelationshipABSTRACT
Two new Lycopodium alkaloids, 4ß-hydroxynankakurine B (1) and Δ(13,N),N(α)-methylphlegmarine-N(ß)-oxide (2), together with three known analogues, lycoposerramine E (3), nankakurine B (4) and lobscurinol (5), were isolated from Phlegmariurus phlegmaria. Their structures were established by mass spectrometry and 1D and 2D NMR techniques.
Subject(s)
Alkaloids/chemistry , Huperzia/chemistry , Alkaloids/isolation & purification , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Lycopodium/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Spectrometry, Mass, Electrospray IonizationABSTRACT
[structure: see text] A novel trispiropentacyclic diterpene, intricarene (1), was isolated from the hexane extract of the Caribbean gorgonian octocoral Pseudopterogorgia kallos. Its highly entangled structure was established by interpretation of NMR, IR, UV, and HREIMS data and subsequently confirmed by X-ray diffraction analysis. The unprecedented carbon skeleton of 1 constitutes a new addition to the already impressive architectural diversity of the diterpene class of marine secondary metabolites.
Subject(s)
Anthozoa/chemistry , Diterpenes , Heterocyclic Compounds, Bridged-Ring , Animals , Crystallography, X-Ray , Diterpenes/chemistry , Diterpenes/isolation & purification , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Molecular Conformation , TriterpenesABSTRACT
AIM: To study the chemical constituents of the stems and leaves of Aconitum coreanum (Lèvl.) Rapaics. METHODS: The constituents of Aconitum coreanum were isolated by using various kinds of modern chromatographic methods. The new alkaloid was identified on the basis of spectral analysis. RESULTS: Two compounds were isolated and identified as: 13-dehydro-1beta-acetyl-2alpha,6beta-dihydroxyhetisine (I) and Guanfu base G (II). CONCLUSION: Compound I is a new alkaloid.
Subject(s)
Aconitum/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Plants, Medicinal/chemistry , Diterpene Alkaloids , Diterpenes , Heterocyclic Compounds, Bridged-Ring/chemistry , Molecular Conformation , Molecular Structure , Plant Leaves/chemistry , Plant Stems/chemistryABSTRACT
[sstructure: see text] A novel, fused-tetracyclic Lycopodium alkaloid, nankakurine A (1), consisting of a cyclohexane ring and a 3-aza-bicyclo[3.3.1]nonane ring connected to a piperidine ring through a spiro carbon, was isolated from the club moss Lycopodium hamiltonii. The structure and relative stereochemistry were elucidated on the basis of spectroscopic data.
Subject(s)
Alkaloids/chemistry , Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Lycopodium/chemistry , Plants, Medicinal/chemistry , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Drug Screening Assays, Antitumor , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Tumor Cells, CulturedABSTRACT
Three quassinoids, iandonosides A and B and iandonone, were isolated from the root of Eurycoma harmandiana, along with five known quassinoids, casteloside B, 13 beta, 21-dihydroeurycomanone, chaparrinone, glaucarubolone and ailanquassin B as well as the coumarin, scopoletin. The structural elucidations were based on analyses of spectroscopic data.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/isolation & purification , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Plants/chemistry , Chromatography, High Pressure Liquid , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, Bridged-Ring/chemistry , Magnetic Resonance Spectroscopy , Plant Roots/chemistry , Scopoletin/isolation & purification , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
Five oleanane-type pentacyclic triterpenoids were isolated by chromatographic separation of a chloroform extract of the stem bark of Embelia schimperi. Three of these compounds have a methyleneoxy bridge. Two compounds, embelinone and schimperinone, are reported here for the first time from a natural source (they have been synthesized previously during chemical transformations). Their structures were determined by spectroscopic techniques, among which 2-D NMR was useful for complete characterization. Three of the triterpenoids exhibited mild antibacterial properties against the gram-positive bacterial strain Rhodococcus sp.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Embelia/chemistry , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Rhodococcus/drug effects , Triterpenes/isolation & purification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/pharmacology , Kenya , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Bark/chemistry , Plants, Medicinal/chemistry , Triterpenes/chemistry , Triterpenes/pharmacologyABSTRACT
(-)-Securinine (SE) is a major alkaloid found in plant Securinega suffruticosa, which has a wide range of pharmacological activities including anticancer, anti-parasitic and central nervous system stimulating effects, etc. To aid the pharmacological study of SE, we developed an LC-MS/MS method for quantitative determination of SE in mouse plasma. In this method, plasma samples were first prepared with salting-out assisted liquid-liquid extraction using cold acetonitrile (-20°C) and 2.00 M ammonium acetate. Separation of SE and the internal standard (IS) from sample matrix was achieved on a Gemini Nx C18 column using 40% acetonitrile and 60% 10.0mM ammonium acetate at a flow rate of 0.200 mL min(-1). Quantification of SE was accomplished with positive electrospray ionization tandem mass spectrometry using mass transitions m/z 218.1â84.1 for SE, and m/z 204.1â70.2 for the IS. This method has a lower limit of quantitation (LLOQ) of 0.600 ng mL(-1) and a linear calibration range up to 600 ng mL(-1) in mouse plasma. The intra- and inter-run accuracy (%RE) and precision (%CV) were ≤ ± 6% and 6%, respectively. The IS normalized matrix factors from six lots of plasma matrices ranged 0.92-1.07, and the recoveries of plasma SE were 99-109%. The validated method has been applied to the measurement of SE in plasma samples of a mouse study.
Subject(s)
Azepines/blood , Chromatography, Reverse-Phase/methods , Heterocyclic Compounds, Bridged-Ring/blood , Lactones/blood , Piperidines/blood , Tandem Mass Spectrometry/methods , Animals , Azepines/chemistry , Azepines/isolation & purification , Azepines/pharmacokinetics , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/pharmacokinetics , Lactones/chemistry , Lactones/isolation & purification , Lactones/pharmacokinetics , Linear Models , Liquid-Liquid Extraction , Mice , Mice, Inbred BALB C , Piperidines/chemistry , Piperidines/isolation & purification , Piperidines/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Solubility , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Fragment-based screening is commonly used to identify compounds with relatively weak but efficient localized binding to protein surfaces. We used mass spectrometry to study fragment-sized three-dimensional natural products. We identified seven securinine-related compounds binding to Plasmodium falciparum 2'-deoxyuridine 5'-triphosphate nucleotidohydrolase (PfdUTPase). Securinine bound allosterically to PfdUTPase, enhancing enzyme activity and inhibiting viability of both P. falciparum gametocyte (sexual) and blood (asexual) stage parasites. Our results provide a new insight into mechanisms that may be applicable to transmission-blocking agents.
Subject(s)
Antimalarials/pharmacology , Biological Products/chemistry , Life Cycle Stages/drug effects , Plasmodium falciparum/drug effects , Protozoan Proteins/antagonists & inhibitors , Small Molecule Libraries/chemistry , Alkaloids/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Antimalarials/chemistry , Antimalarials/isolation & purification , Azepines/chemistry , Azepines/isolation & purification , Azepines/pharmacology , Deoxyuracil Nucleotides/antagonists & inhibitors , Deoxyuracil Nucleotides/chemistry , Deoxyuracil Nucleotides/metabolism , Dose-Response Relationship, Drug , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/pharmacology , Kinetics , Lactones/chemistry , Lactones/isolation & purification , Lactones/pharmacology , Life Cycle Stages/physiology , Piperidines/chemistry , Piperidines/isolation & purification , Piperidines/pharmacology , Plasmodium falciparum/enzymology , Plasmodium falciparum/growth & development , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Coccidiosis is one of the more common and costly diseases in poultry that is caused by various Eimeria species. In our quest to discover coccidiostats from natural products, we discovered a microbial fermentation extract that exhibited in vivo anticoccidial activity. Fractionation of this extract led to the discovery of two potent antiprotozoals, emecorrugatin A (1) and coccidiostatin A (2). The former compound exhibited only in vitro activity, whereas the latter new compound exhibited in vivo activity against Eimeria species in chickens at 150 ppm dosed in chicken feed. The isolation, structure elucidation, relative configuration, and activity of coccidiostatin A (2) are described.
Subject(s)
Coccidiostats , Eimeria/drug effects , Heterocyclic Compounds, Bridged-Ring , Penicillium/chemistry , Animals , Coccidiosis/etiology , Coccidiostats/chemistry , Coccidiostats/isolation & purification , Coccidiostats/pharmacology , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/pharmacology , Molecular StructureABSTRACT
Three new Securinega alkaloids, secu'amamines B-D ( 1- 3), were isolated from the wood of the Japanese medicinal plant Securinega suffruticosa var. amamiensis, together with five known analogues ( 4, 6- 9). The structures 1- 3 were elucidated by spectroscopic methods including 2D NMR, and all eight compounds were evaluated for cytotoxicity against two cancer cell lines.
Subject(s)
Alkaloids/isolation & purification , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Euphorbiaceae/chemistry , Heterocyclic Compounds, Bridged-Ring/isolation & purification , Heterocyclic Compounds, Bridged-Ring/pharmacology , Plants, Medicinal/chemistry , Alkaloids/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Heterocyclic Compounds, Bridged-Ring/chemistry , Humans , Japan , Mice , Molecular Conformation , Nuclear Magnetic Resonance, Biomolecular , Wood/chemistryABSTRACT
A ureido Diels-Alder adduct of sorbicillinol 3 has been isolated from an intertidal marine Paecilomyces marquandii strain, in a screening for new natural products. The structure was determined by spectroscopic methods, and the relative stereochemistry was confirmed by molecular modeling. The absolute stereochemistry was deduced by comparison of the CD curves with those of known members of the bisorbicillinol family. This is the first report of the isolation of a ureido sorbicillinol derivative.