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PubMed1997

Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety.

Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.

Enzyme Inhibitors↗

PubMed1997

Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety

Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.

Journal Article↗

PubMed1999

High performance liquid chromatography for the analysis of fusapyrone and deoxyfusapyrone, two antifungal alpha-pyrones from Fusarium semitectum.

A simple, very sensitive and rapid HPLC method was developed for the simultaneous quantitative analysis of both fusapyrone (FP) and deoxyfusapyrone (DFP), the two antifungal 3-substituted-4-hydroxy-6-alkyl-2-pyrones isolated from rice culture of Fusarium semitectum, in crude extracts. Such method was optimized on C-18 reverse phase column, using the isolated metabolites as standards, with a sequence of linear elution steps with a MeOH-H(2)O mixture and using an ultraviolet detector fixed at 285 nm, where both alpha-pyrones showed a characteristic absorption maximum. This method was used to quantify the bioactive metabolites in crude organic extracts from two F. semitectum strains. The recovery of FP and DFP was measured in a crude extract from a poor metabolite producer F. semitectum strain. The recovery values ranged from 84% to 99% for FP and from 99% to 101% for DFP, indicating that the method was close to quantitative recovery. Furthermore, an efficient medium pressure column chromatography and TLC combined method was developed for the isolation and purification of FP and DFP from fungal culture extracts.

Antifungal Agents↗

PubMed2000

Study on the production of 6-pentyl-alpha-pyrone using two methods of fermentation.

The lactone 6-pentyl-alpha-pyrone has a characteristic coconut aroma and is produced by Trichoderma species. A study on the fermentative production of 6-pentyl-alpha-pyrone in both surface and submerged conditions by Trichoderma harzianum was carried out. Maximum concentrations of 455 mg/l and 167 mg/l after 96 h and 48 h of fermentation in surface and submerged conditions, respectively, were obtained without using any additional recovery operations. The resultant yields are higher than those previously reported in the literature, which may be attributable to strain characteristics in combination with the choice of fermentation conditions employed in the present study. Enough scope exists for further improvement in the yields by optimizing the cultural and nutritional parameters.

Biomass↗

PubMed2001

Pyrone and pyridone compounds in the liquid culture of Physisporinus sanguinolentus.

Chromatographic separation of the liquid culture filtrate of the basidiomycete fungus Physisporinus sanguinolentus has yielded three new compounds viz., 2-methyl-4-pyrone, 2-methyl-5,6-dihydro-4-pyrone and the pyridone form of 4-hydroxy-2-methylpyridine, together with the known triacetic acid lactone, the sesquiterpene dialdehyde merulidial and a derivative of merulidial. Their structures were elucidated by spectroscopic analysis and by comparison to literature data and a synthetic sample. One of the compounds, merulidial, was shown to inhibit the germination of spores and the hyphal growth of the wood-rotting basidiomycete Heterobasidion annosum and the saprophytic mould Cladosporium cucumerinum.

Chromatography, High Pressure Liquid↗

PubMed1994

An antifungal gamma-pyrone and xanthones with monoamine oxidase inhibitory activity from Hypericum brasiliense.

A new gamma-pyrone (hyperbrasilone), three known xanthones (1,5-dihydroxyxanthone, 5-hydroxy-1-methoxyxanthone and 6-deoxyjacareubin) and betulinic acid have been isolated from a dichloromethane extract of stems and roots of Hypericum brasiliense. Their structures were established by spectroscopic methods (UV, EI-MS, 1H and 13C NMR) and that of the gamma-pyrone was confirmed by X-ray crystallography. Hyperbrasilone and the xanthones were all antifungal against Cladosporium cucumerinum, while the three xanthones showed differing degrees of inhibition of monoamine oxidase A and B.

Animals↗

PubMed2001

Isolation, characterization, and systematic significance of 2-pyrone-4,6-dicarboxylic acid in Rosaceae.

2-Pyrone-4,6-dicarboxylic acid was isolated from Potentilla anserina. Until now this substance was only found in bacteria and not in higher plants. By sterile cultivation it was verified that this compound is genuine also in plants. In addition the systematic relevance of 2-pyrone-4,6-dicarboxylic acid within the Rosaceae was tested. The compound seems to be a chemotaxonomic marker for the Rosoideae sensu stricto proposed by Morgan et al. (Morgan, D.R., Soltis, D.E., Robertson, K.R., 1994. Systematic and evolutionary implications of rbcL sequence variation in Rosaceae. American Journal of Botany 81, 890-903).

Chromatography, High Pressure Liquid↗

PubMed2002

Coumarins and gamma-pyrone derivatives from Prangos pabularia: antibacterial activity and inhibition of cytokine release.

The n-hexane and ethyl acetate extracts of the stems and the ethyl acetate extracts of roots from Prangos pabularia afforded an gamma-pyrone derivative and furanocoumarin derivatives with three glucose and gamma-pyrone (pabularin A, B and C), along with 26 previously known compounds (18 coumarins, six terpenoids and two glycosides). Their structures were established on the basis of spectroscopic studies. Of these, 16 coumarin derivatives isolated from P. pabularia were tested for antibacterial activity and inhibition of cytokine release.

Anti-Bacterial Agents↗

PubMed1998

4-Hydroxy-2-pyrone formation by chalcone and stilbene synthase with nonphysiological substrates.

Valerophenone synthase (VPS) is a polyketide synthase that catalyzes the formation of the phloroglucinol derivatives in the synthesis of the bitter acids in hop (Humulus lupulus). The reaction uses isovaleryl-CoA or isobutyryl-CoA, but otherwise it is identical to that of the chalcone synthase in flavonoid biosynthesis. Our study showed that chalcone synthase can perform the function of VPS, but not perfectly, because the majority of the reactions terminated after two condensation reactions (products: 4-hydroxy-2-pyrone derivatives). The same experiments with stilbene synthase yielded exclusively the 4-hydroxy-2-pyrone derivatives, not the products expected from three condensation reactions. The results are discussed in the context of the functional diversity and evolution in the family of CHS-related polyketide synthases.

Acyltransferases↗

PubMed1984

Mechanism of inactivation of chymotrypsin by 3-benzyl-6-chloro-2-pyrone.

The mechanism of inactivation of chymotrypsin by 3-benzyl-6-chloro-2-pyrone has been studied. Chloride analysis of the inactivated enzyme suggests that the complex does not contain intact chloropyrone or an acid chloride. 13C NMR studies of the enzyme inactivated with 13C-enriched chloropyrones show that (1) the pyrone ring is no longer intact, (2) C-6 becomes a carboxylate group and C-2 becomes esterified to the enzyme, probably to serine-195, and (3) a double bond is present adjacent to the serine ester. The inactivated enzyme slowly regains catalytic activity with the concomitant release of (E)-4-benzyl-2-pentenedioic acid. It is concluded that double bond migration occurs during reactivation since the position of the double bond in the released diacid product is different than in the inactivator-enzyme complex. When the reactivation is carried out in [18O]H2O-enriched water, a single oxygen-18 is incorporated into the released product and is further evidence that the inactivator is bound to the enzyme only through a single ester linkage. A deuterium isotope effect on reactivation is observed when a chloropyrone deuterated at C-5 is used. This result demonstrates that removal of a proton from C-5 is required for reactivation and that isomerization of the double bond and not hydrolysis of the acyl-enzyme is rate determining. A variety of amines accelerate the rate of reactivation by functioning as general bases and not as nucleophiles. A reaction scheme is presented that accounts for the formation of the stable inactivator-enzyme complex as well as the production of two products derived from enzymatic hydrolysis of the chloropyrone.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗

PubMed1985

Inhibition of human leukocyte elastase, porcine pancreatic elastase, and chymotrypsin by elasnin and other 4-hydroxy-2-pyrones.

Elasnin and 15 related 4-hydroxy-2-pyrones have been assayed for in vitro inhibition of human leukocyte elastase, porcine pancreatic elastase, and bovine chymotrypsin. Inhibition constants for HL elastase range from 0.1 to 10 mM. The principal determinant of potency against the elastases is probably the substituent at position 3, which may account for the observed strong homology between the elastases in their inhibition by these compounds. Acetylation of the 4-hydroxy group has no effect on inhibition. The inhibition is noncovalent; there is no evidence of enzyme acylation by these pyrones.

Animals↗

PubMed1988

(Acyloxy)benzophenones and (acyloxy)-4-pyrones. A new class of inhibitors of human neutrophil elastase.

A series of 4-(acyloxy)- and 4,4'-bis(acyloxy)benzophenones were synthesized. Some of them, pivalates (trimethylacetates) and isobutyrates in particular, were found to be potent and selective inhibitors of human neutrophil (leukocyte) elastase. A series of 2-[(acyloxy)methyl]-5-(acyloxy)-4-pyrones were synthesized regioselectively from kojic acid. The 4-pyrones bearing a long chain acyl group at the 2-position and either pivaloyloxy or isobutyryloxy at the 5-position were potent and selective inhibitors of the human elastase. A number of analogues and derivatives in both series were synthesized in order to study the structure-activity relationship as summarized in Tables I-VI and in Tables IX and X. The inhibition was selective to human neutrophil elastase. No inhibition of porcine pancreatic elastase or bovine pancreatic chymotrypsin (Tables VII and XI) was observed. The most likely mechanism of inhibition is discussed. The implication of these findings for the treatment of rheumatoid arthritis and emphysema is outlined.

Benzophenones↗

PubMed1996

Structure-based design of novel HIV protease inhibitors: sulfonamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent non-peptidic inhibitors.

The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover non-peptidic HIV protease inhibitors previously identified compound I (phenprocoumon, Ki = 1 microM) as a lead template. Structure-based design of potent non-peptidic inhibitors, utilizing crystal structures of HIV protease/inhibitor complexes, provided a rational basis for the previously reported carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones. The amino acid containing compound V (Ki = 4 nM) provided an example of a promising new series of HIV protease inhibitors with significantly improved enzymatic binding affinity. In this report, further structure-activity relationship studies, in which the carboxamide is replaced by a sulfonamide functionality, led to the identification of another series of nonamino acid containing promising inhibitors with significantly enhanced enzyme binding affinity and in vitro antiviral activity. The most active diastereomer of the sulfonamide-containing pyrone XVIII (Ki = 0.5 nM) shows improved antiviral activity (IC50 = 0.6 nM) and represents an example of a new design direction for the discovery of more potent non-peptidic HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.

4-Hydroxycoumarins↗

PubMed1989

New antihepatotoxic naphtho-pyrone glycosides from the seeds of Cassia tora.

Two new naphtho-pyrone glycosides, 9-[(beta-D-glucopyranosyl-(1----6)-O-beta-D-glucopyranosyl)oxy]-10- hydroxy-7-methoxy-3-methyl-1H-naphtho[2,3-c]pyran-1 -one (5) and 6-[(alpha-apiofuranosyl-(1----6)-O-beta-D-glucopyranosyl)oxy]- rubrofusarin (6), together with cassiaside (3) and rubrofusarin-6-beta-gentiobioside (4) were isolated from the seeds of Cassia tora L. Their structures were elucidated on the basis of chemical and spectral data. The naphtho-gamma-pyrone glycosides (3, 4, and 6) were found to have significant hepato-protective effects against galactosamine damage, which were higher than that of silybin from Silybum marianum.

Cassia↗

PubMed2000

Macrophomate synthase: characterization, sequence, and expression in Escherichia coli of the novel enzyme catalyzing unusual multistep transformation of 2-pyrones to benzoates.

Macrophoma commelinae isolated from spots on leaves of Commelina communis has the ability to transform 5-acetyl-4-methoxy-6-methyl-2-pyrone (1) to 4-acetyl-3-methoxy-5-methylbenzoic acid (macrophomic acid, 2). This biotransformation includes the condensation of the 2-pyrone ring with a C3-unit precursor to form a substituted benzoic acid. We optimized conditions for induction of enzyme activity in M. commelinae, identified oxalacetate as a C3-unit precursor with cell extract, and purified the novel enzyme, macrophomate synthase. Oxalacetate inhibited the enzyme activity at a concentration higher than 5 mM, and magnesium chloride stimulated the enzyme activity. Kinetic analyses gave K(m) of 1.7 mM for 1 at 5 mM oxalacetate, K(m) of 1.2 mM for oxalacetate at 5 mM 1, and k(cat) of 0.46 s(-1) per subunit. Pyruvate was a weak substrate, with K(m) of 35.2 mM and k(cat) of 0.027 s(-1) at 5 mM 1. We cloned and sequenced a cDNA encoding the macrophomate synthase. The cDNA of 1,225 bp contained an open reading frame that encoded a polypeptide of 339 amino acid residues and 36,244 Da, the sequence of which showed no significant similarity with known proteins in a homology search with BLAST programs. Transformed E. coli cells carrying the cDNA encoding the mature protein of macrophomate synthase overproduced macrophomate synthase under the control of the T7 phage promoter induced by IPTG. The purified enzyme showed the same values of K(m) and optimum pH as the native macrophomate synthase.

Amino Acid Sequence↗

PubMed1993

Gamma-pyrone compounds as potential anti-cancer drugs.

The gamma-pyrones, artomunoxanthotrione epoxide, cyclocommunol, cyclomulberrin, and cyclocommunin exhibited potent inhibition of human PLC/PRF/5 and KB cells in-vitro. Dihydroisocycloartomunin showed significant and potent inhibition of human PLC/PRF/5 and KB cells in-vitro, respectively. Cyclomorusin, dihydrocycloartomunin and artomunoxanthone showed significant inhibition of KB cells in-vitro. Based on the above finding and the reported antileukaemic activity of xanthone psorospermin, a series of natural gamma-pyrones was prepared and the inhibition of human PLC/PRF/5 and KB cells in-vitro was measured. Structure-activity analysis indicated the epoxide group substituted at 3-hydroxyl and 2,6-; 3,6-; and 3,5-dihydroxyl xanthone enhanced the anti-tumour activity. The epoxide group substituted at the 6-hydroxyl group of 1,6-dihydroxyxanthone did not show anti-tumour activity.

Antineoplastic Agents↗

PubMed2000

Substrate diversity of macrophomate synthase catalyzing an unusual multistep transformation from 2-pyrones to benzoates.

Macrophomate synthase, which we have recently purified, catalyzes an unusual multistep transformation from 5-acetyl-4-methoxy-6-methyl-2-pyrone to 4-acetyl-3-methoxy-5-methyl-benzoic acid (macrophomic acid). To investigate the substrate diversity of the enzyme, 40 analogs of 2-pyrone were prepared and their relative efficiency was examined in the enzymatic conversions. The experimental results reveal the structural requirements of the substrates and the rough size of the enzyme active site, and eliminate the ambiguity caused by contamination by other enzymes in the whole-cell experiments.

Benzoates↗

PubMed1999

A novel (6S)-4,6-dimethyldodeca-2E,4E-dienoyl ester of phomalactone and related alpha-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity.

A series of novel 6-substituted 5,6-dihydro-5-hydroxy-alpha-pyrone esters, 1 approximately 3, isolated from fermentations of a Phomopsis sp. (Xenova culture collection no. X22502) have been identified as inhibitors of lipopolysaccharide (LPS)-induced cytokine production. These include the (6S)-4,6-dimethyldodecadien-2E,4E-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2E-enoic acid moiety at the 6-position of the alpha-pyrone ring. (6S)-4,6-Dimethyl-2E,4E-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited LPS-induced tumour necrosis factor alpha (TNFalpha) production by U937 cells and LPS-induced interleukin 1beta (IL-1beta) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selective for IL-1beta relative to TNFalpha. The inhibition of IL-1beta production by 1 involved a post-translational mechanism of action at the level of IL-1beta secretion as demonstrated by the lack of an effect on cell-associated IL-1beta production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.

Dose-Response Relationship, Drug↗