Structure determination of a 4-pyrone from the liverwort <i>Plagiochila bifaria</i> (Sw.) Lindenb. (Plagiochilaceae)

The centenary of the presentation in 1907 of the "polyketide" hypothesis by Collie, along with his use of a 4-pyrone as an example, is marked by reporting the discovery and isolation of 2-(3,4-dimethoxyphenethyl)-6-methyl-4-pyrone from &lt;i&gt;Plagiochila bifaria&lt;/i&gt;. This compound dominates the phytochemical profile of the deuteriochloroform extract of a Venezuelan specimen of &lt;i&gt;P. bifaria&lt;/i&gt; and the structure was determined using spectroscopic techniques, especially 2D NMR. This natural product is novel because it contains what appears to be the first example of a monocyclic 4-pyrone that has a polyketide origin. The hypothetical pathway for cyclization of a triketocarboxylic acid to a 4-pyrone was known to be applicable to model systems but no examples of natural products from this route were known. This compound is the same as one of a series of compounds observed previously in an extract of a Brazilian specimen of &lt;i&gt;P. bifaria&lt;/i&gt;; the working structures that were proposed earlier require revision. The mass spectral characteristics are the same as those reported (parent and base peak) in 1987 for the major component observed in the GC-MS profile of an extract of a specimen of &lt;i&gt;P. bifaria&lt;/i&gt; from Peru. The roles played by Birch and Robinson in the renaissance of the polyketide hypothesis almost fifty years after its initial launch are considered. Based on evidence from their publications, they worked independently of each other. It appears Robinson always had knowledge of Collie's hypothesis when developing ideas about structural relations of natural products whereas Birch initially was unaware of both Collie's and Robinson's ideas on the subject

Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster

BACKGROUND: Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol. RESULTS: The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed (3)H-labeled cholesteryl oleate along with inhibitor 1, 0–200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED(50 )of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups. CONCLUSIONS: Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption

Enantiomeric oxidation of organic sulfides by the filamentous fungi Botrytis cinerea, Eutypa lata and Trichoderma viride

The biotransformations of a series of substituted sulfides were carried out with the filamentous fungi Botrytis cinerea, Eutypa lata and Trichoderma viride. Several products underwent microbial oxidation of sulfide to sulfoxide with medium to high enantiomeric purity. With regard to sulfoxide enantioselectivity, the (R)-enantiomer was favoured in biotransformations by T. viride and E. lata while the (S)-enantiomer was favoured in those by B. cinerea. A minor amount of sulfone product was also obtained

Degradation of Chloroaromatics: Purification and Characterization of a Novel Type of Chlorocatechol 2,3-Dioxygenase of Pseudomonas putida GJ31

A purification procedure for a new kind of extradiol dioxygenase, termed chlorocatechol 2,3-dioxygenase, that converts 3-chlorocatechol productively was developed. Structural and kinetic properties of the enzyme, which is part of the degradative pathway used for growth of Pseudomonas putida GJ31 with chlorobenzene, were investigated. The enzyme has a subunit molecular mass of 33.4 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Estimation of the native Mr value under nondenaturating conditions by gel filtration gave a molecular mass of 135 ± 10 kDa, indicating a homotetrameric enzyme structure (4 × 33.4 kDa). The pI of the enzyme was estimated to be 7.1 ± 0.1. The N-terminal amino acid sequence (43 residues) of the enzyme was determined and exhibits 70 to 42% identity with other extradiol dioxygenases. Fe(II) seems to be a cofactor of the enzyme, as it is for other catechol 2,3-dioxygenases. In contrast to other extradiol dioxygenases, the enzyme exhibited great sensitivity to temperatures above 40°C. The reactivity of this enzyme toward various substituted catechols, especially 3-chlorocatechol, was different from that observed for other catechol 2,3-dioxygenases. Stoichiometric displacement of chloride occurred from 3-chlorocatechol, leading to the production of 2-hydroxymuconate.

Novel, male-produced aggregation pheromone of the cerambycid beetle Rosalia alpina, a priority species of European conservation concern.

Several recent studies have demonstrated the great potential for exploiting semiochemicals in ecology and conservation studies. The cerambycid beetle Rosalia alpina represents one of the flagship species of saproxylic insect biodiversity in Europe. In recent years its populations appear to have declined substantially, and its range has shrunk considerably as a result of forest management and urbanization. Here, we collected volatile chemicals released by males and females of R. alpina. Analyses of the resulting extracts revealed the presence of a single male-specific compound, identified as a novel alkylated pyrone structure. In field bioassays in Slovenia, traps baited with the synthesized pyrone captured both sexes of R. alpina, indicating that the pyrone functions as an aggregation pheromone. Our results represent the first example of a new structural class of pheromones within the Cerambycidae, and demonstrate that pheromone-baited traps can provide a useful tool for sampling R. alpina. This tool could be particularly useful in the ongoing development of conservation strategies for the iconic but endangered Alpine longicorn

Total synthesis of aurofusarin: studies on the atropisomeric stability of bis-naphthoquinones

An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ-naphthopyrone monomeric precursor to the bis-naphthoquinone natural product aurofusarin. Dimerization was achieved through PdII -catalyzed dehydrogenative coupling. Further studies employing asymmetric nucleophilic epoxidation indicate that the atropisomers of aurofusarin and derivatives are not configurationally stable at ambient temperature.R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HH

Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors.

Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand

Benzo-pyrones for reducing and controlling lymphoedema of the limbs.

Background Lymphoedema is the accumulation of excess fluid in the body caused by obstruction of the lymphatic drainage mechanisms. Treatment with Benzo-pyrones is thought to reduce fluid forming in the subcutaneous tissues and reduce pain and discomfort of the affected area. Objectives To assess the effectiveness of benzo-pyrones compared to placebo in the management of lymphoedema. Search strategy We searched the Cochrane Breast Cancer Group register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4,2003), MEDLINE, EMBASE, CINAHL, UnCover, PASCAL, SIGLE, reference lists produced by The British Lymphology Society, the National Research Register (NRR) and The International Society of Lymphology congress proceedings. Selection criteria Randomised controlled trials comparing Benzo-pyrones with placebo. Data collection and analysis Trials were selected for eligibility and tested for quality by two blinded reviewers who independently extracted data. Meta-analysis was not performed due to the poor quality of the trials. Main results Fifteen trials were included. Three oxerutin trials tested the same dose over 6 months against placebo and included a total of 127 participants (data were available for 81). There were insufficient data from these to calculate the per cent reduction or increase in baseline excess limb volume. One trial testing Cyclo 3 Fort (approved name) was found (57 participants) but insufficient data was provided to allow a proper analysis of its findings. A single trial of Daflon (approved name) was found (104 participants) but this also provided insufficient information to reach a conclusion about the effectiveness of the drug. Three trials of coumarin combined with troxerutin were found which tested two different doses of the drug against each other with no placebo, however participant numbers and baseline data were not provided. Eight trials of coumarin were identified. Two of these reported the same trial and the other potentially also referred to the same trial but this could not be confirmed. A further two papers also appeared to refer to the same trial but again this was unconfirmed. Five studies added anti-filarial drugs to the interventions tested. Participant data could not be extracted and the reporting of outcome measures in most was unclear. Loprinzi's 1999 trial was reported in more detail but its conclusions were very much at odds with other findings. Authors' conclusions It is not possible to draw conclusions about the effectiveness of Benzopyrones in the management of lymphoedema from the current available trials