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PubMed2003

Aromatic and pyrone polyketides synthesized by a stilbene synthase from Rheum tataricum.

A cDNA encoding a stilbene synthase, RtSTS, was isolated from the rhizomes of Tatar rhubarb, Rheum tataricum L. (Polygonaceae), a medicinal plant containing stilbenes and other polyketides. Recombinant RtSTS was expressed in E. coli and assayed with acetyl-coenzyme A (CoA), n-butyryl-CoA, isovaleryl-CoA, n-hexanoyl-CoA, cinnamoyl-CoA and p-coumaroyl-CoA as primers of polyketide synthesis. RtSTS synthesized resveratrol and a trace amount of naringenin chalcone from p-coumaroyl-CoA, supporting the enzyme's identification as a resveratrol-type stilbene synthase (EC 2.3.1.95). Bis-noryangonin and p-coumaroyl triacetic acid lactone (CTAL)-type pyrones were observed in minor amounts in the reaction with p-coumaroyl-CoA and as major products with cinnamoyl CoA. As well, such pyrones, and not aromatic polyketides, were identified as the only products in assays with aliphatic and benzoyl CoA esters. Acetonyl-4-hydroxy-2-pyrone, a pyrone synthesized from acetyl-CoA, was identified as a new product of a stilbene synthase. Using Northern blot analysis, RtSTS transcript was found to be highly expressed in R. tataricum rhizomes, with low transcript levels also present in young leaves. This expression pattern correlated with the occurrence of resveratrol, which was detected in higher amounts in R. tataricum rhizomes compared with leaves and petioles using HPLC. Few stilbene synthases have been found in plants, and the identification of RtSTS provides additional sequence and catalytic information with which to study the evolution of plant polyketide synthases.

Acyl Coenzyme A↗

PubMed2001

Kava pyrones exert effects on neuronal transmission and transmembraneous cation currents similar to established mood stabilizers--a review.

1. Antiepileptic drugs that are successful as mood stabilizers, e.g. carbamazepine, valproate and lamotrigine, exhibit a characteristic pattern of action on ion fluxes. As a common target, they all affect Na+- and Ca2+ inward and K+ outward currents. 2. Furthermore, they have a variety of interactions with the metabolism and receptor occupation of biogenic amines and excitatory and inhibitory amino acids, and, by this, also influence long- term potentiation (LTP) to different degrees. 3. The kava pyrones (+/-)-kavain and dihydromethysticin are constituents of Piper methysticum. Anticonvulsant, analgesic and anxiolytic properties have been described in small open trials. 4. In the studies summarized in this article the effects mainly of (+/-)-kavain were tested on neurotransmission and especially on voltage gated ion channels. It is assumed that effects on ion channels may significantly contribute to clinical efficacy. 5. Experimental paradigms included current and voltage clamp recordings from rat hippocampal CA 1 pyramidal cells and dorsal root ganglia as well as field potential recordings in guinea pig hippocampal slices. 6. The findings suggest that (i) kava pyrones have a weak Na+ antagonistic effect that may contribute to their antiepileptic properties (ii) that they have pronounced L- type Ca2+ channel antagonistic properties and act as an positive modulator of the early K+ outward current. These two actions may be of importance for mood stabilization. (iii) Furthermore, kava pyrones have additive effects with the serotonin-1A agonist ipsapirone probably contributing to their anxiolytic and sleep- inducing effects. (iv) Finally, they show a distinct pattern of action on glutamatergic and GABAergic transmission without affecting LTP. The latter, however, seems not to be true for the spissum extract of Kava where suppression of LTP was observed. 7. In summary, kava pyrones exhibit a profile of cellular actions that shows a large overlap with several mood stabilizers, especially lamotrigine.

Animals↗

PubMed2002

Bioactive 4-substituted-6-methyl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines.

Bioactive synthetic 4-substituted-6-methyl-2-pyrones are reported. Various 4-substitutents have been incorporated using Pd-catalysed carbon-carbon bond coupling procedures. Preliminary screening of the 2-pyrones against human ovarian carcinoma (A2780) and human chronic myelogenous leukaemia (K562) cell lines show that 4-alkynyl-6-methyl-2-pyrones have excellent potential as anticancer agents. The pyrones demonstrate broad spectrum antimicrobial activities.

Anti-Bacterial Agents↗

PubMed1985

Inactivation of chymotrypsin by 5-benzyl-6-chloro-2-pyrone: 13C NMR and X-ray diffraction analyses of the inactivator-enzyme complex.

The inactivation of chymotrypsin by 5-benzyl-6-chloro-2-pyrone has been studied. Chloride analysis of the inactivated enzyme suggests that chlorine is no longer present in the complex. 13C NMR spectroscopy of chymotrypsin inactivated with 5-benzyl-6-chloro-2-pyrone-2,6-13 C2 shows the presence of two new resonances from the protein-bound inactivator. The chemical shift values of these resonances are consistent with an intact pyrone ring on the enzyme as well as the replacement of the C-6 chlorine by a different heteroatom. X-ray diffraction analysis at 1.5-A resolution of the inactivator-enzyme complex demonstrates that the gamma-oxygen of the active site serine residue (serine 195) is covalently attached to C-6 of the inactivator and that the pyrone ring is intact. The 5-benzyl group of the inactivator is bound to the enzyme in the hydrophobic specificity pocket. The conformational changes that occur in the protein as a result of complexation with the inactivator are discussed.

Binding Sites↗

PubMed1987

Inhibition of human sputum elastase by substituted 2-pyrones.

Nineteen 4-hydroxy- and 4-methoxy-2-pyrones related to elasnin (I) have been assayed for in vitro inhibition of human sputum elastase (HSE), porcine pancreatic elastase, alpha-chymotrypsin, and trypsin. Inhibition is reported as Ki and Ki'; percentage inhibition was dependent on [S] in a number of cases, making it unsuitable as a measure of relative inhibition. The 3-(1-oxoalkyl)-4-hydroxy-6-alkyl-2-pyrones were found to be most effective, the octyl homologue 11 being the most potent inhibitor (Ki = 4.6 microM, 30 times better than the lead compound). A further reduction in inhibition was observed when the hitherto hydrophobic 6-substituent was substituted by a branched functionality of hydrophilic nature. Conversely, methylation of the 4-hydroxy group of the 6-alkyl-2-pyrones increased inhibitory activity. The mechanism of inhibition varied from pure noncompetitive to mixed type to uncompetitive and was found to be dependent on the pattern of substitution. We believe that the 4-hydroxy-2-pyrone binds to the S4 subsite, with the 6-substituent extending across the S4-S1 subsites and the 3-substituent occupying the S5 subsite. The length of the inhibitor binding region was calculated to be approximately 24 A. None of the hydrophobic compounds were found to have any appreciable inhibition (less than 10%) with porcine pancreatic elastase, bovine alpha-chymotrypsin, and bovine trypsin when tested at the limit of their solubility. The hydrophilic compounds were nonspecific, inhibiting all four enzymes. Dialysis was used to show that the interaction is fully reversible.

Humans↗

PubMed1999

3-Alkyl-6-chloro-2-pyrones: selective inhibitors of pancreatic cholesterol esterase.

A series of 3-alkyl-6-chloro-2-pyrones with cyclohexane rings tethered to the 3-position was synthesized. The tether ranged from 0 to 4 methylene units. Inhibition of pancreatic cholesterol esterase by this series of pyrones was markedly dependent upon the length of the tether. Dissociation constants as low as 25 nM were observed for 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyranone. This class of cholesterol esterase inhibitors functioned as simple competitive inhibitors of substrate binding rather than as suicide substrates or active site inactivators. Trypsin and chymotrypsin were not strongly inhibited by this class of pyrones. Selectivities for cholesterol esterase were greater than 10(3). This is in contrast to 3-aryl-6-chloro-2-pyrones which are nonselective, irreversible inactivators of serine hydrolases. Thus, replacement of the 3-aryl group by an appropriately tethered 3-alkyl ring can produce highly selective inhibitors of cholesterol esterase. A second series of halogen-containing esters was prepared in which cholesterol was esterified with alpha-haloacyl halides. These haloesters were simple substrates of cholesterol esterase with no evidence of irreversible inactivation.

Cholesterol↗

PubMed1997

[3H]-monoamine uptake inhibition properties of kava pyrones.

Three kava pyrones, the natural compounds (+)-methysticine and (+)-kavain, and the synthetic racemate (+/-)-kavain, were tested concerning their action on in vitro uptake of monoamines in synaptosomes prepared from the cerebral cortex and hippocampus of rats. (+/-)-Kavain and (+)-kavain were found to potently inhibit the uptake of [3H]-noradrenaline. Uptake of [3H]-noradrenaline was inhibited in the following order of potency: (+/-)-kavain = (+)-kavain > (+)-methysticine, whereas none of the kava pyrones efficiently blocked the uptake of [3H]-serotonin. The results indicate a pyrone-specific non-stereo-selective inhibition of the [3H]-noradrenaline uptake which might be responsible for or, at least, contribute to the psychotropic properties of kava pyrones.

Animals↗

PubMed2000

Detailed reaction mechanism of macrophomate synthase. Extraordinary enzyme catalyzing five-step transformation from 2-pyrones to benzoates.

Macrophomate synthase from the fungus Macrophoma commelinae IFO 9570 is a Mg(II)-dependent dimeric enzyme that catalyzes an extraordinary, complex five-step chemical transformation from 2-pyrone and oxalacetate to benzoate involving decarboxylation, C-C bond formation, and dehydration. The catalytic mechanism of the whole pathway was investigated in three separate chemical steps. In the first decarboxylation step, the enzyme loses oxalacetate decarboxylation activity upon incubation with EDTA. Activity is fully restored by addition of Mg(II) and is not restored with other divalent metal cations. The dissociation constant of 0.93 x 10(-)(7) for Mg(II) and atomic absorption analysis established a 1:1 stoichiometric complex. Inhibition of pyruvate formation with 2-pyrone revealed that the actual product in the first step is a pyruvate enolate, which undergoes C-C bond formation in the presence of 2-pyrone. Incubation of substrate analogs provided aberrant adducts that were produced via C-C bond formation and rearrangement. This strongly indicates that the second step is two C-C bond formations, affording a bicyclic intermediate. Based on the stereospecificity, involvement of a Diels-Alder reaction at the second step is proposed. Incubation of the stereospecifically deuterium-labeled malate with 2-pyrones in the presence of malate dehydrogenase provided information for the stereochemical course of the reaction catalyzed by macrophomate synthase, indicating that the first decarboxylation provides pyruvate (Z)-[3-(2)H]enolate and that dehydration at the final step occurs with anti-elimination accompanied by concomitant decarboxylation. Examination of kinetic parameters in the individual steps suggests that the third step is the rate-determining step of the overall transformation.

Benzoates↗

PubMed1997

gamma-Pyrones from Gonystylus keithii, as new inhibitors of parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria.

New gamma-pyrones, 9'-oxopodopyrone (3) and 8-methyl-9'-oxopodopyrone (4) were isolated from the leaves of Gonystylus keithii, along with known gamma-pyrones, 10'-oxopodopyrone (1) and 8-methyl-10'-oxopodopyrone (2). These gamma-pyrones markedly inhibited the bovine parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria in vitro. It is the first time that gamma-pyrones showed inhibitory effects on bone resorption, and these compounds may be seed compounds of new drugs for osteoporosis.

Animals↗

PubMed1988

Similar binding sites for unsaturated fatty acids and alkyl 2-pyrone inhibitors of human sputum elastase.

Evidence is presented to support the hypothesis that oleic acid and 3-(1'-oxo-7'-carboxyheptyl)-4-hydroxy-6-octyl-2-pyrone (and other 3,6-dialkyl-2-pyrones) occupy the same binding region on human sputum elastase. The mechanism of inhibition is strongly dependent on the substitution pattern of the 2-pyrone, and these mechanisms correlate with those of oleic acid and 11-undecenoic acid ("half oleic acid"). Based on the assumption that the 2-pyrone moiety and the double bond of the fatty acids bind to the same region of elastase (subsite S3), we believe that the alkyl chain points towards the S1 subsite, with the carboxylate anion fragment pointing away and probably associated with positively charged Arg217. (subsite S4 or S5).

Binding Sites↗

PubMed1999

Synthesis of Isocoumarins and alpha-Pyrones via Palladium-Catalyzed Annulation of Internal Alkynes.

A number of 3,4-disubstituted isocoumarins and polysubstituted alpha-pyrones have been prepared in good yields by treating halogen- or triflate-containing aromatic and alpha,beta-unsaturated esters, respectively, with internal alkynes in the presence of a palladium catalyst. Synthetically, the methodology provides an especially simple and convenient, regioselective route to isocoumarins and alpha-pyrones containing aryl, silyl, ester, tert-alkyl, and other hindered groups. The reaction is believed to proceed through a seven-membered palladacyclic complex in which the regiochemistry of the reaction is controlled by steric factors. A number of 3,4-disubstituted isocoumarins and polysubstituted alpha-pyrones have been prepared in good yields by treating halogen- or triflate-containing aromatic and alpha,beta-unsaturated esters, respectively, with internal alkynes in the presence of a palladium catalyst. Synthetically, the methodology provides an especially simple and convenient regioselective route to isocoumarins and alpha-pyrones containing aryl, silyl, ester, tert-alkyl, and other hindered groups. The reaction is believed to proceed through a seven-membered palladacyclic complex in which the regiochemistry of the reaction is controlled by steric factors.

Journal Article↗

PubMed1999

Benzo-pyrones in the treatment of lymphoedema.

Fifty clinical trials of 4 benzo-pyrones in the treatment of lymphoedema, by over 37 authors in 8 countries, are reviewed: 38 oral and 12 topical (11 and 6 of these, added to other therapies). Oral benzo-pyrones reduced oedema, symptoms (in almost all) and inflammation (SAI). These were significant and clinically important. There were no significant differences between arms and Grades 1 and 2 legs. Combining these 20 trials gave mean annual reductions of 55% of oedema (SE: 7.8%; 95% Confidence Interval: 40% to 71%) (p<0.001). Four trials of elephantitic legs gave 17% (4.8%; 7.6% to 27%), significantly less (p<0.01). Meta-analyses, tested by omitting non-double-blind or non-peer-reviewed trials, were robust. The greater the oedema, the greater the rate of reduction-lessening as time passed and the oedema reduced: annual reduction=37%x(79%) Period (p=0.01). Reductions varied with the molar dose (p=10(-8)): =0.10% (SE 0.013%) Dose (mg of coumarin or molar equivalent of other drugs). Topical coumarin also reduced oedema and symptoms. The results of some other therapies were improved by oral or topical benzo-pyrones 15% to 22% over a month and 0% to 78% over a year. These drugs are slow, but effective, cheap and convenient. Because of their slowness, compression garments are unnecessary. They were seldom used in trials. Side-effects are minimal. Only oral coumarin may cause idiosyncratic hepatitis (3 per 1,000). Topical coumarin does not, nor other benzo-pyrones.

Administration, Oral↗

PubMedDate not supplied

Determination of the absolute configuration of 6-alkylated alpha-pyrones from Ravensara crassifolia by LC-NMR.

The absolute configuration of asymmetric centres of two alpha-pyrones isolated from Ravensara crassifolia was determined using the Mosher method. The conventional analysis of the purified ester derivatives by 1H-NMR was replaced by a rapid and sensitive method in which the alpha-pyrones were analysed under isocratic reversed-phase LC-NMR conditions prior to and after derivatisation reactions. Comparison of the LC-1H-NMR spectra of the actual alpha-pyrones with those of the corresponding Mosher's esters recorded in the acetonitrile:deuterated water solvent system exhibited shifts comparable with those obtained using conventional deuterated solvents. Based on the shifts recorded, determination of the absolute configuration was possible by application of Mosher rules. The use of LC-NMR has permitted a direct analysis of crude reaction mixtures containing less than 50 microg of the starting material. Completion of the reaction was checked by LC-MS and the crude reaction mixture was analysed by stop-flow LC-NMR. This methodology seems very promising for the determination at the micro-scale level of the absolute configuration of natural products which are available only in very small amounts.

Alkylation↗

PubMed2002

Computer-assisted optimization in the development of a high-performance liquid chromatographic method for the analysis of kava pyrones in Piper methysticum preparations.

A computer simulation program was used to optimize the separation for six kava pyrones and two unidentified components obtaining the best resolution and the shortest run time. With DryLab it was possible to find the best separation conditions without running a large number of possible combination of variables in the laboratory. Additionally, due to the systematic progress in method development a new eluent was found with excellent properties, namely 2-propanol. With 2-propanol, the largest number of components could be revealed in the shortest analysis time. Starting with four initial experiments, the software allowed to optimize gradient time tG and temperature T simultaneously. Changing other variables such as type of organic modifier, the eluent pH, the gradient form, and the flow-rate, the optimization resulted in resolution Rs > 1.5 for all kava pyrones and the two additional new bands. The HPLC method is used to analyze kava pyrones in Piper methysticum preparations.

2-Propanol↗

PubMed2000

Styryl- and dihydrostyryl-2-pyrones derivatives from Polygala sabulosa.

Two dihydrostyrylpyrones and a styrylpyrone were isolated from Polygala sabulosa, together with five known styrylpyrones. Their structures were established on the basis of spectral evidence as 4-methoxy-6-(11,12-methylenedioxy-14-methoxydihydrostyryl)-2-pyrone, 4-methoxy-6-(11,12-methylenedioxy-10,14-dimethoxydihydrostyryl)-2-pyrone, and 4-methoxy-6-(11,12-methylenedioxy-14-methoxystyryl)-2-pyrone.

Molecular Structure↗

PubMed2002

Structure of a geranyl-alpha-pyrone from Mimulus aurantiacus leaf resin.

A previously reported but misidentified geranyl-alpha-pyrone, in addition to six known compounds, was isolated from the leaf resin of Mimulus aurantiacus. HMBC NMR analyses of the geranyl-alpha-pyrone resolved uncertainties in the site of attachment of the two side chains and necessitated a revision of the previously reported structure. This compound is shown to be 3-geranyl-4-hydroxy-6-(2-hydroxypropyl)-2-pyrone.

Magnetic Resonance Spectroscopy↗

PubMed1999

Long-chain gamma-pyrones in epicuticular wax of two vanilla bean species: V. fragrans and V. tahitensis.

Analyses of the neutral lipids from Vanilla species before saponification resulted in the identification of a new product family in this genus: long-chain gamma-pyrone compounds with an aliphatic chain containing a cis double bond at the n-9 position. These compounds represent 7-8% of the neutral lipids in mature beans. Using NMR and gas chromatography/mass spectrometry, three gamma-pyrones have been identified, including 2-(10-nonadecenyl)-2, 3-dihydro-6-methyl-4H-pyran-4-one, 2-(12-heneicosenyl)-2, 3-dihydro-6-methyl-4H-pyran-4-one, and 2-(14-tricosenyl)-2, 3-dihydro-6-methyl-4H-pyran-4-one. The major constituent was 2-(14-tricosenyl)-2,3-dihydro-6-methyl-4H-pyran-4-one, which represented 70.3% of the gamma-pyrone fraction. The variability of this compound family has been studied in relation to bean maturity in V. fragrans and V. tahitensis beans. This compound family has not been found either in leaves or in stems or in V. madagascariensis beans.

Flavoring Agents↗

PubMed2002

Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone: a new ambident diene.

D-A cycloadditions of 3,5-dibromo-2-pyrone were investigated with a series of electronically and sterically distinct dienophiles. Our results showed that it is a highly potent ambident diene, being more reactive and stereoselective than monobromo-2-pyrones, and thus capable of generating a variety of bicycloadducts in much higher chemical yields and endo/exo ratios than monobromo-2-pyrones. Another interesting feature of this study is that the two bromine groups on the cycloadducts could be independently manipulated to produce other synthetically useful bicyclolactones.

Alkadienes↗