Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pyrones”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMed2003

Stilbenecarboxylate biosynthesis: a new function in the family of chalcone synthase-related proteins.

Chalcone (CHS), stilbene (STS) synthases, and related proteins are key enzymes in the biosynthesis of many secondary plant products. Precursor feeding studies and mechanistic rationalization suggest that stilbenecarboxylates might also be synthesized by plant type III polyketide synthases; however, the enzyme activity leading to retention of the carboxyl moiety in a stilbene backbone has not yet been demonstrated. Hydrangea macrophylla L. (Garden Hortensia) contains stilbenecarboxylates (hydrangeic acid and lunularic acid) that are derived from 4-coumaroyl and dihydro-4-coumaroyl starter residues, respectively. We used homology-based techniques to clone CHS-related sequences, and the enzyme functions were investigated with recombinant proteins. Sequences for two proteins were obtained. One was identified as CHS. The other shared 65-70% identity with CHSs and other family members. The purified recombinant protein had stilbenecarboxylate synthase (STCS) activity with dihydro-4-coumaroyl-CoA, but not with 4-coumaroyl-CoA or other substrates. We propose that the enzyme is involved in the biosynthesis of lunularic acid. It is the first example of a STS-type reaction that does not lose the terminal carboxyl group during the ring folding to the end product. Comparisons with CHS, STS, and a pyrone synthase showed that it is the only enzyme exerting a tight control over decarboxylation reactions. The protein contains unusual residues in positions highly conserved in other CHS-related proteins, and mutagenesis studies suggest that they are important for the structure or/and the catalytic activity. The formation of the natural products in vivo requires a reducing step, and we discuss the possibility that the absence of a reductase in the in vitro reactions may be responsible for the failure to obtain stilbenecarboxylates from substrates like 4-coumaroyl-CoA.

Acyltransferases↗
PubMed2003

Covalent binding of chloroacetamide herbicides to the active site cysteine of plant type III polyketide synthases.

Chloroacetamide herbicides inhibit very-long-chain fatty acid elongase, and it has been suggested that covalent binding to the active site cysteine of the condensing enzyme is responsible [Pest Manage Sci 56 (2000), 497], but direct evidence was not available. The proposal implied that other condensing enzymes might also be targets, and therefore we have investigated four purified recombinant type III plant polyketide synthases. Chalcone synthase (CHS) revealed a high sensitivity to the chloroacetamide metazachlor, with 50% inhibition after a 10 min pre-incubation with 1-2 molecules per enzyme subunit, and the inactivation was irreversible. Stilbene synthase (STS) inactivation required 20-fold higher amounts, and 4-coumaroyltriacetic acid synthase and pyrone synthase revealed no response at the highest metazachlor concentrations tested. A similar spectrum of differential responses was detected with other herbicides that also inhibit fatty acid elongase (metolachlor and cafenstrole). The data indicate that type III polyketide synthases are potential targets of these herbicides, but each combination has to be investigated individually. The interaction of metazachlor with CHS was investigated by mass spectrometric peptide mapping, after incubation of the enzymes with the herbicides followed by tryptic digestion. A characteristic mass shift and MS/MS sequencing of the respective peptide showed that metazachlor was covalently bound to the cysteine of the active site, and the same was found with STS. This is the first direct evidence that the active site cysteine in condensing enzymes is the primary common target of these herbicides.

Acetamides↗
PubMed1998

The role of proteolysis during differentiation of Trypanosoma brucei from the bloodstream to the procyclic form.

The in vitro differentiation of Trypanosoma brucei from bloodstream to procyclic (insect) forms is accompanied by diminishing variant surface glycoprotein (VSG) and increasing levels of procyclin and phosphoenolpyruvate carboxykinase (PEPCK). In this study, we examined the fate of several glycolytic enzymes of T. brucei during differentiation. We observed a down-regulation of glycosomal phosphoglycerate kinase (gPGK) during differentiation. In contrast, intracellular levels of glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH), aldolase (ALD), and phosphoglucoisomerase (PGI) remained unchanged during differentiation and apparently continued to be synthesized in the procyclic form. To determine the potential role of proteasomes and other proteases during the differentiation process, we tested the effect of lactacystin, a specific inhibitor of proteasome activity, and morpholinourea-Phe-homoPhe-benz-alpha-pyrone (P27), a selective inhibitor of cysteine proteases, on the in vitro differentiation of T. brucei. Cells differentiated normally in the presence of 1 microM lactacystin, which confirmed our previous observation that this differentiation does not require crossing any phase boundaries in the cell cycle (Mutomba and Wang, Mol Biochem Parasitol 1996;80:89-102). But the cells thus differentiated did not increase in number and retained gPGK. Cells differentiated under 2 microM P27 also proceeded at a normal rate but failed to multiply and retained gPGK. However, most of the differentiated cells under 2 microM P27 also retained VSG on the cell membrane surface and expressed higher levels of procyclin suggesting that a cysteine protease(s) may be involved in releasing VSG and partially reducing procyclin during differentiation. This cysteine protease(s) has been tentatively identified in the procyclic cells as a 48 kDa protein through labeling of cysteine protease(s) with a biotinylated P27 homolog K02 (morpholinourea-Phe-homoPhe-vinylsulfone).

Acetylcysteine↗
PubMed2002

New analgesic and antiinflammatory agents 4(1H)-pyridinone derivatives.

A series of 1,2,5-trisubstituted 4(1H)-pyridinone derivatives (7-14) were synthesised by using 4-pyrone derivatives with primary amines in ethanol. The structures of the synthesised compounds were confirmed by analytical and spectral data (UV, IR and 1H-NMR and microanalysis). Analgesic and antiinflammatory activities of the synthesised compounds were investigated by acetic acid-induced writhing syndrome and carrageenan rat paw edema tests. All of the test compounds exhibited higher analgesic activities than acetyl salicylic acid and showed higher antiinflammatory activities than indomethacin. The anti-inflammatory activity and gastric ulceration potential of the compounds were tested using indomethacin as reference drug.

Analgesics, Non-Narcotic↗
PubMed2000

Aroma compounds recovery from mycelial cultures in aqueous two-phase processes.

This paper presents the evaluation of the potential use of aqueous two-phase systems (ATPS) for the recovery of 6-pentyl-alpha-pyrone (6PP) produced by Trichoderma harzianum. The partition behaviour of 6PP and Trichoderma harzianum mycelium (biomass) in polyethylene glycol (PEG)-salt (phosphate and sulphate) and PEG-dextran ATPS was investigated. The influence of defined system parameters (e.g. molecular mass of PEG and dextran, volume ratio, etc.) on the partition behaviour of 6PP and Trichoderma harzianum mycelium was evaluated to select under which conditions 6PP and mycelium partition to opposite phases. In PEG-dextran systems either large extraction phases were required or mycelium and 6PP partitioned to the same phase. ATPS comprising V(r)=0.23, PEG 8000 6.6% w/w and sulphate 14.0% w/w provided the best conditions to satisfy the process requirement of biomass accumulation into the bottom phase and 6PP concentration in the top phase.

Dextrans↗
PubMed2002

New developments in anti-HIV chemotherapy.

Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP64222, which were initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors, the latter through blockade of CXCR4.

Anti-HIV Agents↗
PubMed2000

Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor.

Natural product acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by gamma-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC50 7.9 microM) and no ACAT inhibitory activity IC50 = >1000 microM.

Cholinesterase Inhibitors↗
PubMed2001

Anti-MRSA cephems. Part 1: C-3 substituted thiopyridinium derivatives.

Sixteen novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds were synthesized using substituted thiopyridones, generated either by cyclization of functionalized precursors, or by direct alkylation of the enolate of 2-methyl substituted pyrones. The most active compound in vitro against a strain of MRSA (A27223) displayed an MIC of 0.5 microg/mL. The most efficacious compound in vivo had a PD50 of 2.1 mg/kg.

Cephalosporins↗
PubMed2002

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.

Glucagon↗
PubMed2002

2,2-Disubstituted analogues of the natural hormone 1 alpha,25-dihydroxyvitamin D(3): chemistry and biology.

Six new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues. Analogues 7a and are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue is considerably less calcemic than calcitriol. Dimethylated analogue strongly suppresses parathyroid hormone (PTH) secretion.

Animals↗
PubMed1997

Activity of 3-carbethoxyangelicin photolysis products.

3-Carbethoxyangelicin (3-CA), carrying an electron-withdrawing group at the pyrone side, has been prepared to have a fully monofunctional angelicin derivative. 3-CA does not photoreact with DNA and induces a moderate antiproliferative activity. 3-CA proved to be extremely sensitive to ultraviolet A (UVA) light, undergoing rapid photolysis. Only one photolysis product has been isolated and identified. By means of alkaline elution, we observed that 3-CA and its photolysis products are able to induce a large amount of single-strand breaks in DNA in vivo. The results obtained from studying the capacity to produce singlet oxygen suggest that the photodynamic mechanism of action of 3-CA very likely results from its capacity--as well as that of its photolysis products--to produce singlet oxygen.

Animals↗
PubMed1986

Wavelength dependence for the photoreversal of a psoralen-DNA cross-link.

We report an action spectrum for the photoreversal of a psoralen cross-link joining two self-complementary DNA oligonucleotides. The cross-link was formed between two thymines (T) on opposite strands of the DNA oligomers and 4'-(hydroxymethyl)-4,5',8-trimethylpsoralen (HMT). For comparison, we also present an action spectrum for the photoreversal of the isolated diadduct T-HMT-T. The wavelength dependence for the diadduct photoreversal parallels its absorption spectrum. Both the diadduct and the cross-linked DNA can be photoreversed by exposure to light with wavelengths between 240 and 313 nm. We did not observe photoreversal at 334 nm or above. At least two distinct absorption bands appear to contribute to photoreversal. We measured a quantum yield of 0.16 for photoreversal of the isolated diadduct at wavelengths between 240 and 266 nm. For wavelengths above 280 nm, the quantum yield is 0.30. We also observed a preferential photoreversal at the furan end of the psoralen in the T-HMT-T diadduct. In contrast, the cross-linked DNA oligonucleotides preferentially photoreversed at the pyrone end of the psoralen adduct. The rate constant for photoreversal of the cross-linked DNA is larger than that for the isolated diadduct at wavelengths below 300 nm.

Base Sequence↗
PubMed1988

Interaction of psoralen-derivatized oligodeoxyribonucleoside methylphosphonates with single-stranded DNA.

Oligodeoxyribonucleoside methylphosphonates derivatized at the 5' end with 4'-(amino-alkyl)-4,5',8-trimethylpsoralen were prepared. The interaction of these psoralen-derivatized methylphosphonate oligomers with synthetic single-stranded DNAs 35 nucleotides in length was studied. Irradiation of a solution containing the 35-mer and its complementary methylphosphonate oligomer at 365 nm gave a cross-linked duplex produced by cycloaddition between the psoralen pyrone ring of the derivatized methylphosphonate oligomer and a thymine base of the DNA. Photoadduct formation could be reversed by irradiation at 254 nm. The rate and extent of cross-linking were dependent upon the length of the aminoalkyl linker between the trimethylpsoralen group and the 5' end of the methylphosphonate oligomer. Methylphosphonate oligomers derivatized with 4'-[[N-(2-aminoethyl)amino]methyl]- 4,5',8-trimethylpsoralen gave between 70% and 85% cross-linked product when irradiated for 20 min at 4 degrees C. Further irradiation did not increase cross-linking, and preirradiation of the psoralen-derivatized methylphosphonate oligomer at 365 nm reduced or prevented cross-linking. These results suggest that the methylphosphonate oligomers undergo both cross-linking and deactivation reactions when irradiated at 365 nm. The extent of cross-linking increased up to 10 microM oligomer concentration and dramatically decreased at temperatures above the estimated Tm of the methylphosphonate oligomer-DNA duplex. The cross-linking reaction was dependent upon the fidelity of base-pairing interactions between the methylphosphonate oligomers and the single-stranded DNA. Noncomplementary oligomers did not cross-link, and the extent of cross-linking of oligomers containing varying numbers of noncomplementary bases was greatly diminished or eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1988

Alkali reversal of psoralen cross-link for the targeted delivery of psoralen monoadduct lesion.

Psoralen intercalates into double-stranded DNA and photoreacts mainly with thymines to form monoadducts and interstrand cross-links. We used an oligonucleotide model to demonstrate a novel mechanism: the reversal of psoralen cross-links by base-catalyzed rearrangement at 90 degrees C (BCR). The BCR reaction is more efficient than the photoreversal reaction. We show that the BCR occurs predominantly on the furan side of a psoralen cross-link. The cleavage does not result in the breaking of the DNA backbone, and the thymine base freed from the cross-link by the cleavage reaction appears to be unmodified. Similarly, BCR of the furan-side monoadduct of psoralen removed the psoralen molecule and regenerated the unaltered native oligonucleotide. The pyrone-side psoralen monoadduct is relatively resistant to BCR. One can use BCR to perform efficient oligonucleotide-directed, site-specific delivery of a psoralen monoadduct. As a demonstration of this approach, we have hybridized a 19 base long oligonucleotide vehicle containing a furan-side psoralen monoadduct to a 56 base long complementary oligonucleotide target strand and formed a specific cross-link at the target site with 365-nm UV. Subsequent BCR released the oligonucleotide vehicle and deposited the psoralen at the target site.

Base Sequence↗
PubMed1998

Plant polyketide synthases: a chalcone synthase-type enzyme which performs a condensation reaction with methylmalonyl-CoA in the biosynthesis of C-methylated chalcones.

Heterologous screening of a cDNA library from Pinusstrobus seedlings identified clones for two chalcone synthase (CHS) related proteins (PStrCHS1 and PStrCHS2, 87.6% identity). Heterologous expression in Escherichia coli showed that PStrCHS1 performed the typical CHS reaction, that it used starter CoA-esters from the phenylpropanoid pathway, and that it performed three condensation reactions with malonyl-CoA, followed by the ring closure to the chalcone. PstrCHS2 was completely inactive with these starters and also with linear CoA-esters. Activity was detected only with a diketide derivative (N-acetylcysteamine thioester of 3-oxo-5-phenylpent-4-enoic acid) that corresponded to the CHS reaction intermediate postulated after the first condensation reaction. PstrCHS2 performed only one condensation, with 6-styryl-4-hydroxy-2-pyrone derivatives as release products. The enzyme preferred methylmalonyl-CoA against malonyl-CoA, if only methylmalonyl-CoA was available. These properties and a comparison with the CHS from Pinus sylvestris suggested for PstrCHS2 a special function in the biosynthesis of secondary products. In contrast to P. sylvestris, P. strobus contains C-methylated chalcone derivatives, and the methyl group is at the position predicted from a chain extension with methylmalonyl-CoA in the second condensation of the biosynthetic reaction sequence. We propose that PstrCHS2 specifically contributes the condensing reaction with methylmalonyl-CoA to yield a methylated triketide intermediate. We discuss a model that the biosynthesis of C-methylated chalcones represents the simplest example of a modular polyketide synthase.

Acyl Coenzyme A↗
PubMed2003

Examination of novel zinc-binding groups for use in matrix metalloproteinase inhibitors.

The tetrahedral zinc complex [(Tp(Ph,Me))ZnOH] (Tp(Ph,Me) = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined with 1-hydroxy-2(1H)-pyridinone, 3-hydroxy-2(1H)-pyridinone, 3-hydroxy-1-methyl-2(1H)-pyridinone, 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone, 1-hydroxy-2(1H)-pyridinethione, and 3-hydroxy-2-methyl-4-pyrone to generate the complexes [(Tp(Ph,Me))Zn(ZBG)] (ZBG = zinc-binding group). These complexes were synthesized to explore the coordination geometry of potential novel zinc-binding groups for use in matrix metalloproteinase (MMP) inhibitors. The solid-state structures of all six metal complexes were determined by X-ray crystallography. These structures combined with IR and (1)H NMR data demonstrate that these ZBGs bind in a strong, bidentate fashion to the zinc(II) ion. Modeling studies indicate that these ZBGs can easily fit into the MMP active site. In an effort to develop more effective inhibitors of MMPs, this work has revealed molecular-level interactions for six potential new ZBGs.

Binding Sites↗
PubMed2005

Group 13 and lanthanide complexes with mixed O,S anionic ligands derived from maltol.

Four mixed O,S binding ligand precursors derived from maltol (3-hydroxy-2-methyl-4-pyrone) have been chelated to gallium(III), indium(III), and lanthanide(III) ions to yield a series of metal complexes. The four ligand precursors include two pyranthiones, 3-hydroxy-2-methyl-4-pyranthione, commonly known as thiomaltol (Htma), and 2-ethyl-3-hydroxy-4-pyranthione, commonly known as ethylthiomaltol (Hetma), and two pyridinethiones, 3-hydroxy-2-methyl-4(H)-pyridinethione (Hmppt) and 3-hydroxy-1,2-dimethyl-4-pyridinethione (Hdppt). Dimeric forms of the pyridinethiones, Hmppt dimer and Hdppt dimer, were also isolated and characterized. Complete characterization of the monomeric organic compounds is reported including acidity constants and crystal structures of Htma, Hetma, and Hdppt dimer. Reacting the four monomeric ligand precursors with Ga(3+) and In(3+) ions yielded new tris(bidentate ligand) complexes. X-ray-quality crystals of the fac isomer of Ga(tma)(3) were also obtained. New complexes with a range of lanthanides (Ln(3+)) were also synthesized with the two pyranthiones, Htma and Hetma. The synthesis reactions yielded complexes of the type LnL(3).xH(2)O and LnL(2)(OH).xH(2)O, as indicated by elemental analysis and spectroscopic evidence such as mass spectral data and IR and NMR spectra.

Journal Article↗
PubMed2006

Model complexes of cobalt-substituted matrix metalloproteinases: tools for inhibitor design.

The tetrahedral cobalt(II) complex [(Tp(Ph,Me))CoCl] (Tp(Ph,Me) = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined with several hydroxypyridinone, hydroxypyridinethione, pyrone, and thiopyrone ligands to form the corresponding [(Tp(Ph,Me))Co(L)] complexes. X-ray crystal structures of these complexes were obtained to determine the mode of binding for each ligand L. The structures show that the [(Tp(Ph,Me))Co(L)] complexes are pentacoordinate complexes, with a general tendency toward square pyramidal geometry. The electronic, EPR, and paramagnetic NMR spectroscopy of the [(Tp(Ph,Me))Co(L)] complexes have been examined. The frozen-solution EPR spectra are indicative of pentacoordination in frozen solution, while the NMR indicates some dynamics in ligand binding. The findings presented here suggest that [(Tp(Ph,Me))Co(L)] complexes can be used as spectroscopic references for investigating the mode of inhibitor binding in metalloproteinases of medicinal interest. Potential limitations when using cobalt(II) model complexes are also discussed.

Binding Sites↗