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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↗

PubMed2000

Quantitative determination of secoiridoid and gamma-pyrone compounds in Gentiana lutea cultured in vitro.

The production of secondary metabolites was studied in shoots, roots, and hairy roots of Gentiana lutea obtained in vitro. In shoots, both secoiridoid and gamma-pyrone compounds were detected in amounts similar to those found in aerial parts of plants collected from nature. The most abundant secoiridoid was gentiopicrin while mangiferin was the main compound among the gamma-pyrones. The adventitious roots obtained in vitro showed a poor biosynthetic capacity. Upon infection with Agrobacterium rhizogenes, nine hairy root clones were established which differed in the amount of secondary metabolites.

Chromatography, High Pressure Liquid↗

PubMed2002

A cartilage derived novel compound DDP (2,6-dimethyldifuro-8-pyrone): isolation, purification, and identification.

OBJECTIVE: Fluorescent biomolecules within cartilage matrix can be used as specific markers of cartilage metabolism. While establishing the protocol to evaluate mature collagen crosslinks in articular cartilage (AC) associated with maturation, aging, and osteoarthritis, chromatographic analysis of the crosslinks also revealed an apparently novel fluorescent peak. Preliminary investigation of this compound (now abbreviated DDP) in various tissues from rabbits, calves, chickens, and humans showed that this compound is AC-specific. We aimed to isolate, purify, and identify this fluorescent compound. METHODS: Fully encapsulated, bovine metacarpophalangeal joints (n = 350, age < 2 years) were used as the source for AC. DDP was isolated and purified by reverse phase high pressure liquid chromatography, and its elution was monitored using a fluorescence detector at excitation lambda = 306 nm, and emission lambda = 395 nm. The liquid phase of DDP was characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. DDP solution (5.7 microg/microl) was crystallized in 100% deuterated methanol and the DDP crystal was characterized by single crystal x-ray diffraction. RESULTS: From bulk preparations, 12 pg (58 nmol) per gram dried AC of the novel compound was isolated and purified. Analytical techniques to identify this AC-specific compound, 2,6-dimethyldifuro-8-pyrone, corroborate and confirm its molecular structure and atomic connectivity in both liquid and solid phase. DDP is a symmetrical aromatic compound with molecular weight 204, molecular forrmula C11H8O4, and a molar extinction coefficient 4,700 M(-1) at maximal UV absorption (lambda = 306 nm). CONCLUSION: 2,6-dimethyldifuro-8-pyrone (DDP) is a novel cartilage-specific compound that could have potential application as a unique biochemical marker in joint diseases involving articular cartilage degradation.

Animals↗

PubMed1984

Chronic active hepatitis in mice induced by 3-hydroxy-4-pyrone.

Chronic active hepatitis was selectively induced in mice by the feeding of a diet containing 3-hydroxy-4-pyrone (0.5% by weight) for periods of 6 weeks and longer. This model should be of particular value in elucidating the pathogenesis of drug-induced forms of chronic active hepatitis. Maltol (3-hydroxy-2-methyl-4-pyrone) did not produce any liver lesion.

Animals↗

PubMed1979

Antithyroid and antiperoxidase activity of tropolone and 3-hydroxy-4-pyrone.

Tropolone (TR) and 3-hydroxy-4-pyrone were investigated for antithyroid activity following the finding that the 2-hydroxy-oxo pyridine, 3-hydroxy-4(1H)-pyridone (DHP, I), is goitrogenic. Both compounds inhibited the thyroidal uptake of radioiodine in rats and resembled the thioamide drugs in inhibiting the organic binding of iodine by the thyroid gland rather than the trapping of iodide, but were weaker binding inhibitors than 6-methyl-2-thiouracil (MeTU). Both compounds also inhibited the iodination of bovine serum albumin and thyroglobulin, catalyzed by thyroidperoxidase (TPO), lactoperoxidase (LPO), chloroperoxidase (CPO) and horseradish peroxidase (HPO) in vitro. The inhibitory effect of TR but not that of 3-hydroxy-4-pyrone was antagonized by ferrous ions. When fed to mice at levels of intake expected to produce goitre both compounds were toxic and caused severe liver damage. Thyroid enlargement was not observed in any of these feeiding experiments, but the thyroids of mice fed 0.1% TR showed moderate hyperplasia. It was concluded that both compounds are weakly goitrogenic. Hyperactivity was observed in the mice fed TR which may be associated with inhibition of catechol methyl transferase (COMT).

Animals↗

PubMed1990

Molecular mechanics and dynamics of DNA-furocoumarin complexes: effect of the aromatization of the pyrone ring on the intercalation geometry.

Results of molecular mechanics and dynamics calculations on intercalation complexes of DNA with various furocoumarins (psoralen, angelicin, 7-methylpyrido[3,4-c]psoralen and 7-methylpyrido[4,3-c]psoralen) and their corresponding aromatized derivatives are presented. These calculations were undertaken with the aim to elucidate the roles of the pyrone and pyridine moieties in the interactions which tend to orient the furocoumarins and pyridopsoralens between DNA base pairs. It appears that the intercalation geometries are very similar for the furocoumarins and related aromatized compounds. Therefore the oxygen and nitrogen atoms of the pyrone and pyridine moieties are not important in the orientation of the drug within the oligonucleotide.

Base Composition↗

PubMed1995

Photoreaction of 5-methoxypsoralen with thymidine. Isolation and characterization of a pyrone-side monoadduct involving the pyrimidine methyl group.

The UVA-mediated photoreaction of 5-methoxypsoralen (5-MOP) with thymidine has been investigated in the dry state. Under these conditions, the main products are 5-MOP pyrone-side monoadducts to thymidine. We report the isolation and characterization of an unusual 5-MOP-thymidine photoproduct. The assignment of the photoadduct was achieved on the basis of extensive spectroscopic measurements (UV, mass spectrometry (MS), 1H and 13C nuclear magnetic resonance (NMR), nuclear Overhauser effect (NOE) experiments). The formation of the photoadduct, which is rationalized in terms of a radical mechanism, appears to involve, in a covalent bond, the C-4 pyrone moiety of 5-MOP and the methyl group of thymidine.

5-Methoxypsoralen↗

PubMed2001

The potential application of aqueous two-phase systems for in situ recovery of 6-pentyl-infinity-pyrone produced by Trichoderma harzianum.

Commercial production of aroma compounds by de novo microbial biosynthesis has been principally limited by the low productivity so far achieved. Production of 6-pentyl-alpha-pyrone (6PP), a coconut-like aroma compound, by Trichoderma harzianum has been limited by the toxic effect that occurs even at low concentration (<100 ppm). This work evaluated the feasibility of the use of aqueous-two phase systems (ATPS), as in situ extraction systems, in order to overcome the toxic effects of 6PP and to improve culture productivity. The partition behaviour of 6-pentyl-alpha-pyrone and Trichoderma harzianum mycelium in polyethylene glycol (PEG)-salt and PEG-dextran two-phase systems was investigated and it is reported for the first time. The evaluation of system parameters such as PEG molecular mass, concentration of PEG as well as salt, volume ratio (Vr) and dextran molecular mass, was carried out to determine under which conditions the 6PP partitions to the opposite phase that mycelium does. PEG-dextran systems proved to be unsuitable for the in situ recovery of 6PP because either 6PP and biomass partitioned to the same phase or a large extraction phase was required for the process. ATPS extraction comprising Vr = 0.26, PEG 1450 (7.2% w/w) and sulphate (16.6% w/w) provided the best conditions for the maximum accumulation of the biomass into the bottom phase and concentrated the 6PP in the opposite phase (i.e. 86% of biomass and 56% of 6PP of the total amount loaded from the fermentation extract into the ATPS) for ex situ bioseparation. However, this system caused complete inhibition of the growth of the microorganism during the in situ bioseparation, probably as a consequence of the high ionic strength resulting from the salt concentration. Consequently, two ATPS PEG 8000-sulphate (12%/7% and 6%/14%) were evaluated and proved to be more suitable in the potential application for the in situ recovery of 6PP.

Journal Article↗

PubMed2002

Oxidative degradation of a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone in aqueous/organic cosolvent mixtures.

PURPOSE: To predict the oxidative stability of a sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone in lipid-based delivery systems, N-(3-(1[(3alpha,6R)-4-hydroxy-2-oxo-6-phenyl-6-propyltetrahydro-2H-pyran-3-yl]propyl)phenyl)-5-(trifluoromethyl)-2-pyridinylsulfonamide (DHP) was oxidized by peroxides and peroxyl radicals in binary mixtures of water and organic cosolvents. METHODS: DHP was oxidized by hydrogen peroxide, t-butylhydroperoxide, or peroxyl radicals derived from the thermal decomposition of 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) in 40% (v/v) organic cosolvent and 5 mM buffer at or near 40 degrees C. Interactions between DHP and ]propane sulfonic acid and imidazole) and DH- were assessed by 1H-NMR spectroscopy. The formation of CO likely involves a free radical mechanism. RESULTS: The reaction of DHP with peroxides in 40% (v/v) acetonitrile yields epimeric monohydroxylation products, R-OH and S-OH, at C-3 of the pyrone ring, and a keto-derivative (CO). Hydroxylation rates depend on the protonation state of DHP, and the nature of buffer and the organic cosolvent. Organonitriles accelerate the oxidation through formation of peroxycarboximidic acid. Peroxyl radicals do not yield significant amounts of R/S-OH or CO. CONCLUSIONS. The hydrogen peroxide-induced degradation of DHP in the presence of acetonitrile involves two reactions, hydroxylation and carbonyl formatin. Hydroxylation proceeds via nucleophilic attack by the monodeprotonated form of DHP (DH-) on peroxycarboximidic acid. The oxidation rate is slowed by ion pairing between nitrogen-containing buffers ([3-N-morpholino]propane sulfonic acid and imidazole) and DH-. The formation of CO likely involves a free radical mechanism.

Organic Chemicals↗

PubMed1993

Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone.

BACKGROUND: Benzopyrones can reduce the volume of high-protein edema fluid by stimulating proteolysis. These compounds provide a method for removing excess protein and its consequent edema and reduce its clinical sequelae, such as chronic inflammation and secondary infections. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover trial of 5,6-benzo-[alpha]-pyrone in 31 patients with postmastectomy lymphedema of the arm and 21 patients with lymphedema of the leg of various causes (this agent, also known as 56 BaP, 1,2-benzopyrone, or coumarin, is not an anticoagulant). The patients received 400 mg of the active drug or placebo, each for six months. RESULTS: During the placebo period, lymphedema often worsened, especially in the arms. Measurements of limb volume showed that the active drug reduced the mean amount of edema fluid in the arms from 46 percent above normal to 26 percent above normal (P < 0.001) and the amount in the legs from 25 percent to 17 percent above normal (P < 0.001). The circumference of the arms was reduced from 17 percent to 13 percent above normal, and the circumference of the legs from 11 percent to 7 percent above normal (P < 0.001). The softness of the limb tissue was increased (P < 0.001), and elevated skin temperatures were reduced (P < 0.001). There were fewer attacks of secondary acute inflammation (P = 0.01). Bursting pains and feelings of hardness were decreased, as were feelings of tightness, tension, swelling, and heaviness; limb mobility also improved. The active drug was preferred to the placebo by 93 percent of the patients (P < 0.001). Side effects--mild nausea or diarrhea--occurred in seven patients taking the active drug. None withdrew from the trial, and the side effects disappeared after the first month of therapy. CONCLUSIONS: 5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.

Arm↗

PubMed1993

Reduction of filaritic lymphoedema and elephantiasis by 5,6 benzo-alpha-pyrone (coumarin), and the effects of diethylcarbamazine (DEC).

Chronic filaritic lymphoedema and elephantiasis, in India, were treated orally with 5,6 benzo-alpha-pyrone (56 BaP; 1,2 benzo-alpha-pyrone; coumarin) in a double-blind, randomized, matched-group trial. Each group finally contained 40-55 patients. Patients were observed for about 2 years (ranging from 6 to 45 months, with 75% completing the 2 years). The 56 BaP slowly, but very significantly (P < 0.0001), reduced all grades of lymphoedema and elephantiasis. Two thirds of the oedema was lost by grade 2 over 2 years. Grades 3 to 5 were reduced by a fifty over that time. The greater the initial oedema, the greater was its rate of resolution. A slowly worsening condition thus became a slowly improving one. Slowness has its advantages: compression stockings, that are impractical in hot, wet or dirty conditions, are not necessary. The slowly remodelling fibrous tissue, while lessening in amount, is still able to hold the tissues together. The 56 BaP considerably improved many symptoms and complications, particularly bursting-pains, inflammation and ulcers. It is cheap and of very low toxicity. Diethylcarbamazine (DEC) was studied with and without 56 BaP. DEC alone gave some reduction of the oedema, but this was much smaller than that with 56 BaP. It considerably worsened the reductions by 56 BaP, while 56 Bap slightly improved those by DEC and reduced the fever caused by DEC. Together, they reduced feelings of swelling and bursting-pain, fungal infections, lymphangitis and lymphadenitis more than when used alone.

Adult↗