ABSTRACT
Six new nostocyclophanes and four known compounds have been isolated from Nostoc linckia (Nostocaceae) cyanobacterial strain UTEX B1932. The new compounds, nostocyclophanes E-J (1-6), were characterized by NMR and MS techniques. The known compounds were nostocyclophanes B-D, previously isolated from this strain, and dedichloronostocyclophane D. Structural modifications on the new [7.7]paracyclophane analogs 1-5, isolated from the 80% methanol fraction, range from simple changes such as the lack of methylation or halogenation to more unusual modifications such as those seen in nostocyclophane H (4), in which the exocyclic alkyl chains are of different length; this is the first time this modification has been observed in this family of natural products. In addition, nostocyclophane J (6) is a linear analog in which C-20 is chlorinated in preparation for the presumed enzymatic Friedel-Craft cyclization needed to form the final ring structure, analogous to the biosynthesis of the related cylindrocyclophanes. Nostocyclophane D, dedichloronostocyclophane D, and nostocyclophanes E-J demonstrated moderate to weak growth inhibition against MDA-MB-231 breast cancer cells.
Subject(s)
Nostoc , Nostoc/chemistry , Magnetic Resonance SpectroscopyABSTRACT
As part of a study examining polar metabolites produced by cyanobacterial strains, we examined media extracts of a Calothrix sp. (strain R-3-1) and a Scytonema sp. (strain U-3-3). The cell mass of each was separated from the media, and HP20 resin was added for adsorption of secreted metabolites, a relatively unexplored area of cyanobacterial chemistry. HPLC-UV-LCMS-guided isolation led to the discovery of seven sesquiterpenoid compounds with five new, one known, and one previously isolated as the methyl ester. Through a complement of 1D and 2D NMR spectroscopic techniques, the planar structures and relative configurations of the seven compounds were elucidated. Spironostoic acid (1), 11,12-didehydrospironostoic acid (2), and 12-hydroxy-2-oxo-11-epi-hinesol (4) are spirovetivane-type compounds from R-3-1, while stigolone (5), 11R,12-dihydroxystigolone (6), and 11S,12-dihydroxystigolone (7) are three eudesmane-type compounds from U-3-3. Circular dichroism was utilized to decipher the absolute configurations of new compounds 1, 2, 4, 5, 6, and 7. Due to the structural variety observed among the spirovetivane- and eudesmane-type compounds in the literature and often a lack of clarity in how determinations were made, computational spectra and model compounds were used to support the interpretation of ECD and NMR spectra. A straightforward process to determine the configuration of these systems is presented.
Subject(s)
Sesquiterpenes, Eudesmane , Sesquiterpenes , Culture Media , Molecular Structure , Sesquiterpenes/chemistry , Sesquiterpenes, Eudesmane/chemistryABSTRACT
A new benzo[g]isochromene possessing a conformationally mobile moiety was identified from Rubia philippinensis. The 2D structure was established utilizing spectrometric and spectroscopic techniques with variable temperatures. The configurational investigation of the flexible moiety was investigated utilizing contemporary NMR-combined computational tools such as DP4, direct J-DP4, and DP4 Plus. The probabilities computed from DP4 Plus analysis, featuring inclusion of an additional geometry optimization process, demonstrated more conclusive probability scores among the analyses used. The configurational assignment was also supported by compositional and molecular orbital analyses. Compound 1 inhibited soluble epoxide hydrolase (IC50 = 0.6 ± 0.01 µM), an enzyme associated with cardiovascular disorders.
Subject(s)
Benzopyrans/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Rubia/chemistry , Benzopyrans/chemistry , Molecular Structure , Resins, Plant/chemistry , VietnamABSTRACT
Exposure of 10π-electron benzazaphosphole 1 to HCl, followed by nucleophilic substitution with the Grignard reagent BrMgCCPh afforded alkynyl functionalized 3 featuring an exocyclic -C[triple bond, length as m-dash]C-Ph group with an elongated P-C bond (1.7932(19) Å). Stoichiometric experiments revealed that treatment of trans-Pd(PEt3)2(Ar)(i) (Ar = p-Me (C) or p-F (D)) with 3 generated trans-Pd(PEt3)2(Ar)(CCPh) (Ar = p-Me (E) or p-F (F)), 5, which is the result of ligand exchange between P-I byproduct 4 and C/D, and the reductively eliminated product (Ar-C[triple bond, length as m-dash]C-Ph). Cyclic voltammetry studies showed and independent investigations confirmed 4 is also susceptible to redox processes including bimetallic oxidative addition to Pd(0) to give Pd(i) dimer 6-Pd2-(P(t-Bu)3)2 and reduction to diphosphine 7. During catalysis, we hypothesized that this unwanted reactivity could be circumvented by employing a source of fluoride as an additive. This was demonstrated by conducting a Sonogashira-type reaction between 1-iodotoluene and 3 in the presence of 10 mol% Na2PdCl4, 20 mol% P(t-Bu)Cy2, and 5 equiv. of tetramethylammonium fluoride (TMAF), resulting in turnover and the isolation of Ph-C[triple bond, length as m-dash]C-(o-Tol) as the major product.
Subject(s)
Alkynes/chemistry , Organophosphorus Compounds/chemistry , Palladium/chemistry , Oxidation-ReductionABSTRACT
In order to stabilize a 10-P-3 species with C 2v symmetry and two lone pairs on the central phosphorus atom, a specialized ligand is required. Using an NCN pincer, previous efforts to enforce this planarized geometry at P resulted in the formation of a C s-symmetric, 10π-electron benzazaphosphole that existed as a dynamic "bell-clapper" in solution. Here, OCO pincers 1 and 2 were synthesized, operating under the hypothesis that the more electron-withdrawing oxygen donors would better stabilize the 3-center, 4-electron O-P-O bond of the 10-P-3 target and the sp3-hybridized benzylic carbon atoms would prevent the formation of aromatic P-heterocycles. However, subjecting 1 to a metalation/phosphination/reduction sequence afforded cyclotriphosphane 3, resulting from trimerization of the P(i) center unbound by its oxygen donors. Pincer 2 featuring four benzylic CF3 groups was expected to strengthen the O-P-O bond of the target, but after metal-halogen exchange and quenching with PCl3, unexpected cyclization with loss of CH3Cl was observed to give monochlorinated 5. Treatment of 5 with (p-CH3)C6H4MgBr generated crystalline P-(p-Tol) derivative 6, which was characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography. The complex 19F NMR spectra of 5 and 6 observed experimentally, were reproduced by simulations with MestreNova.
ABSTRACT
Alarming rate of resistance to the existing antibiotics exhibits the importance of developing new antibiotic molecules from relatively under explored sources as well as implementing alternative approaches like antibiotic adjuvants. Six previously undescribed fungal polyketides, kaneoheoic acids A-F (1-6) were isolated from a fungal strain Fusarium sp. FM701 which was collected from a muddy sample of Hawaiian beach. The structures of these six compounds were elucidated by spectroscopic interpretation, including HRESIMS and NMR, and electronic circular dichroism (ECD) analysis. All six compounds that were inactive when tested alone showed significant antibacterial activity against Staphylococcus aureus and Bacillus subtilis, in the range of 10-80 µg/mL when assayed in combination with either chloramphenicol (half of the MIC, 1 µg/mL), an FDA approved antibiotic or disulfiram (6 µg/mL), an established antibiotic adjuvant that augmented the activity of antibiotics.
Subject(s)
Fusarium , Polyketides , Anti-Bacterial Agents/pharmacology , Fungi , Hawaii , Microbial Sensitivity Tests , Polyketides/pharmacologyABSTRACT
Chemical investigation of cyanobacterial strain HT-58-2, which most closely aligns with the genus Brasilomena, has led to the isolation of two compounds related to tolypodiol. The structures and absolute configuration of 6-deoxytolypodiol (1) and 11-hydroxytolypodiol (2) were elucidated by spectroscopic and spectrometric analysis. While tolypodiol previously showed anti-inflammatory activity in a mouse ear edema assay, only 2 reduced in vitro thromboxane B2 and superoxide anion (O2-) generation from Escherichia coli lipopolysaccharide-activated rat neonatal microglia to any appreciable degree.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cyanobacteria/chemistry , Diterpenes/chemistry , Ear Diseases/drug therapy , Escherichia coli/chemistry , Lipopolysaccharides/chemistry , Superoxides/chemistry , Thromboxane B2/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Edema , Mice , RatsABSTRACT
Cubozoan nematocyst venoms contain known cytolytic and hemolytic proteins, but small molecule components have not been previously reported from cubozoan venom. We screened nematocyst extracts of Alatina alata and Chironex yamaguchii by LC-MS for the presence of small molecule metabolites. Three isomeric compounds, cnidarins 4A (1), 4B (2), and 4C (3), were isolated from venom extracts and characterized by NMR and MS, which revealed their planar structure as cyclic γ-linked tetraglutamic acids. The full configurational assignments were established by syntheses of all six possible stereoisomers, comparison of spectral data and optical rotations, and stereochemical analysis of derivatized degradation products. Compounds 1-3 were subsequently detected by LC-MS in tissues of eight other cnidarian species. The most abundant of these compounds, cnidarin 4A (1), showed no mammalian cell toxicity or hemolytic activity, which may suggest a role for these cyclic tetraglutamates in nematocyst discharge.
Subject(s)
Cubozoa/chemistry , Glutamic Acid/biosynthesis , Glutamic Acid/isolation & purification , Animals , Aquatic Organisms/chemistry , Cell Death/drug effects , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Cnidarian Venoms/chemistry , Cnidarian Venoms/toxicity , Glutamic Acid/chemistry , HEK293 Cells , Hemolysis/drug effects , Humans , Proton Magnetic Resonance Spectroscopy , Tissue DistributionABSTRACT
Tolyporphins L-R (2-8) have been isolated from a mixed cyanobacterium-microbial culture. The structures of tolyporphins L and M have been revised to four constitutional isomers, isolated as two mixtures of dioxobacteriochlorins (2/3 and 4/5). In contrast, tolyporphin P (6) is a fully oxidized tetrapyrrole, while tolyporphins Q and R (7 and 8) are oxochlorins. X-ray structures are reported for the first time for tolyporphins A (1), R (8), and E (9), revealing unexpected stereochemical variation within the series.
Subject(s)
Cyanobacteria/chemistry , Porphyrins/chemistry , Tetrapyrroles/chemistry , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Molecular Structure , Porphyrins/isolation & purification , Spectrum Analysis/methods , Tetrapyrroles/isolation & purificationABSTRACT
The bioactivity-guided examination of a Leptolyngbya sp. led to the isolation of leptazolines A-D (1-4), from the culture media, along with two degradation products (5 and 6). Density functional theory nuclear magnetic resonance calculations established the relative configurations of 1 and 2 and revealed that the calculated shifts depended on the operating system when using the "Willoughby-Hoye" Python scripts to streamline the processing of the output files, a previously unrecognized flaw that could lead to incorrect conclusions.
Subject(s)
Cyanobacteria/chemistry , Oxazoles/chemical synthesis , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Oxazoles/chemistry , Reference Standards , StereoisomerismABSTRACT
Several known sesquiterpenoid quinones and quinols (1-9), and kauamide (10), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge Dactylospongia elegans. The planar structure of 10 was determined from spectroscopic analyses, and its relative and absolute configurations were established from density functional theory (DFT) calculations of the GIAO NMR shielding tensors, and advanced Marfey's analysis of the N-MeLeu residue, respectively. Compounds 1 and 3 showed moderate inhibition of ß-secretase 1 (BACE1), whereas 1-9 exhibited moderate to potent inhibition of growth of human glioma (U251) cells. Compounds 1-2 and 4-7 were also active against human pancreatic carcinoma (Panc-1) cells.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Porifera/chemistry , Sesquiterpenes/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Aspartic Acid Endopeptidases/antagonists & inhibitors , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Glioma/drug therapy , Glioma/pathology , Hawaii , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/isolation & purification , Heterocyclic Compounds/pharmacology , Humans , Hydroquinones/chemistry , Hydroquinones/isolation & purification , Hydroquinones/pharmacology , Molecular Structure , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Quinones/chemistry , Quinones/isolation & purification , Quinones/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Pancreatic NeoplasmsABSTRACT
Pyridine-phosphaalkene (PN) ligands 2a-e were prepared in an E-selective fashion using phospha-Wittig methodology. Treatment of these five ligands, varying only in their 6-substituent with RuCl2(PPh3)3, produced four distinct types of coordination complexes: pyridine-phosphaalkene-derived 3b,d, cyclized 4e, and six-coordinate 5a and 6c. Prolonged heating of 3b,d in THF resulted in C-H activation of the Mes* group and cyclization to give 4b,d featuring a bidentate pyridine-phospholane ligand bound to the metal center. Complex 5a, also possessing a newly formed phospholane ring, contained a different spatial arrangement of donors to Ru(II) with an agostic Ru-H-C interaction serving as the sixth donor to the transition metal center. Ligands 2b,d,e and Ru(II) complexes 3b, 4b,e and 5a were all characterized by X-ray crystallography. Six-coordinate 6c featured a structure similar to 4b,d,e, but with the CF3 substituent acting as a weakly bound sixth ligand to the Ru(II) center, as observed by 31P{1H} and19F NMR spectroscopy. The calculated structure of 6c established that the closest Ru- - -F contact was at 2.978 Å.
ABSTRACT
Three new ulapualides (3-5) were isolated from egg masses of the nudibranch Hexabranchus sanguineus. The structures of 3-5 were deduced by analyses of physical and spectroscopic data in comparisons with ulapualides A (1) and B (2). Ulapualide C demonstrated submicromolar cytotoxicity against select NCI cell lines (768-0, DU-145, MDA-MB-231, and A549) with the most potent activity against MDA-MB-231 cells (IC50 0.58 µM). Ulapualides A (1) and B (2) were 2- to 4-fold more potent than 3.
Subject(s)
Gastropoda/chemistry , Ovum/chemistry , Oxazoles/isolation & purification , Animals , Drug Screening Assays, Antitumor , Hawaii , Humans , Marine Biology , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacologyABSTRACT
The trapping of a phosphinidene (R-P) in an NCN pincer is presented. Stabilized phosphinidene 1 was characterized by 31 P{1 H}, 1 H, and 13 C{1 H} NMR spectroscopy, exhibiting an averaged C2v symmetry in solution between -60 and 60 °C. In the solid state, the phosphinidene is coordinated by one adjacent N atom featuring a formal P-N bond (1.757(2)â Å) to give a five-membered ring with some aromatic character, confirmed by DFT calculations (B3LYP-D3/6-311G**++) to be the ground-state structure. Equilibration of the two N ligands occurs rapidly in solution via a "bell-clapper"-type process through an associative symmetric transition state calculated to lie 4.0â kcal mol-1 above the ground state.
ABSTRACT
Four new pregnanes, 3ß,4ß-dihydroxy-17-methyl-17α-pregna-5,13-diene-10,2-carbolactone (1), 6ß-chloro-3ß-hydroxy-17-methyl-17α-pregna-4,13-diene-10,2-carbolactone (2), 3ß-hydroxy-6ß-methoxy-17-methyl-17α-pregna-4,13-diene-10,2-carbolactone (3), and 3ß,6ß-dihydroxy-17-methyl-17α-pregna-4,13-diene-10,2-carbolactone (4), were isolated from an undescribed species of Myrmekioderma Ehlers along with the known pregnane carbolactone (5). The structures of the new compounds were determined by spectroscopic methods and comparison with previously described compounds. Compound 5 showed almost 4-fold activation of pregnane X receptor, while 2 inhibited BACE1 with an IC50 value of 82 µM.
Subject(s)
Lactones/isolation & purification , Porifera/chemistry , Pregnanes/isolation & purification , Animals , Hawaii , Lactones/chemistry , Lactones/pharmacology , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Porifera/genetics , Pregnanes/chemistry , Pregnanes/pharmacologyABSTRACT
Seven new bromotyrosine-derived metabolites, purpuramine M-N (1-2), araplysillin VII-XI (3-7) and six known compounds (8-13) were isolated from an Indonesian sponge belonging to the family Aplysinellidae (Order Verongiida). The structures of the new compounds were determined by extensive NMR experiments and mass spectrometric measurements. These compounds were screened against BACE1 and five cancer cell lines.
Subject(s)
Antineoplastic Agents/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Porifera/chemistry , Protease Inhibitors/pharmacology , Tyrosine/analogs & derivatives , Tyrosine/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Isoxazoles/chemistry , Isoxazoles/isolation & purification , Isoxazoles/pharmacology , Mice , NIH 3T3 Cells , Oximes/chemistry , Oximes/isolation & purification , Oximes/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/isolation & purification , Tyrosine/chemistry , Tyrosine/isolation & purificationABSTRACT
Two new polycyclic alkaloids, neopetrocyclamines A and B (1 and 2), along with the known metabolites papuamine (3) and haliclonadiamine (4), were isolated from the Indonesian sponge Neopetrosia cf exigua. Neopetrocyclamine A contains a formamidinium moiety, a rare functional group. While these compounds share the same basic biosynthetic building blocks, the size of the ring system differs in 1 and 2 because of the formamidinium moiety. Biological evaluations of 1-4 revealed that papuamine is cytotoxic against glioblastoma SF-295 cells (GI50 = 0.8 µM).
Subject(s)
Alkaloids/isolation & purification , Antineoplastic Agents/isolation & purification , Diamines/isolation & purification , Polycyclic Compounds/isolation & purification , Porifera/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Diamines/chemistry , Diamines/pharmacology , Drug Screening Assays, Antitumor , Humans , Indonesia , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Polycyclic Compounds/chemistry , Polycyclic Compounds/pharmacologyABSTRACT
New compounds 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one (1), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (2), and spongiapyridine (3) and the known compound 17-hydroxy-4-epi-spongialactone A (4) were isolated from an Indonesian sponge of the genus Spongia. The structures of 1-3 were deduced by analyses of physical and spectroscopic data. Diterpene 3 is unusual, as the D-ring is a pyridyl ring system rather than the standard δ-lactone. The structure elucidation of this compound was complicated by facile exchange of the axial proton at the C-11 methylene with deuterium from methanol-d4. The isolated compounds were tested for biological activity in a battery of in vitro assays (TNF-α-induced NFκB, LPS-induced iNOS, RXR stimulation, quinone reductase 1 induction, aromatase inhibition, TRPM7 ion channels, and aspartic protease BACE1 inhibition). Norditerpene 2 modestly inhibited aromatase with an IC50 of 34 µM and induced quinone reductase 1 activity with a CD (the concentration needed to double the enzymatic response) of 11.2 µM. The remaining isolates were inactive.
Subject(s)
Diterpenes/isolation & purification , Porifera/chemistry , Animals , Diterpenes/chemistry , Diterpenes/pharmacology , Lactones/chemistry , Lipopolysaccharides/pharmacology , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/drug effects , NF-kappa B/antagonists & inhibitors , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Examination of an active extract of the fruit of Ficus benjamina var. nuda (Miq.) Barrett has led to the isolation of six new isoflavones and two coumarano-chroman-4-ones, along with fifteen known compounds. The structures of the eight new compounds were elucidated on the basis of extensive NMR experiments and mass spectrometric measurements. The inhibitory activity of the compounds on the proteolytic cleavage of amyloid precursor protein by the aspartic protease BACE1 was evaluated. Both coumarano-chroma-4-ones and some isoflavones showed moderate activity in this assay.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Ficus/chemistry , Flavonoids/isolation & purification , Flavonoids/pharmacology , Fruit/chemistry , Molecular StructureABSTRACT
Bioassay-guided fractionation of an extract prepared from the fruiting bodies of a Daedalea sp. has led to the isolation of daedalols A-C (1-3). The structures of these new triterpenes were elucidated based on extensive NMR spectroscopic and mass spectrometric measurements. Assignment of the relative configuration of 3 required the preparation of a suitable derivative via a Payne rearrangement. The aspartic protease BACE1, an Alzheimer's drug target, was inhibited by 3 with an IC(50) value of 14.2 µM.