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PubMedDate not supplied

Antitumoral activity of new pyrimidine derivatives of sesquiterpene lactones.

Sesquiterpene lactones display a wide variety of biological effects such as antiviral, anti-inflammatory and cytotoxic activity. In previous studies some derivatives of sesquiterpene lactones were prepared to be tested as antiviral and/or cytoxic agents. In the present report we describe the effects of seven modified sesquiterpene lactones on the proliferation of several cancer cell lines. We demonstrated antitumoral activity of two of them: III (JLNZ-106) and IV (EDAG-IV-Sme) in HeLa, C-33, CALO, INBL, VIPA, SW480, SW620, MCF-7 and CHO cancer cell lines. Compounds III (JLNZ-106) and IV (EDAG-IV-Sme-IV) presented cytotoxic activity (IC50) by inhibiting the incorporation of (14)C-thymidine to DNA. These experiments suggest that derivatives III and IV should inhibit DNA replication in cancer cell lines.

Animals↗
PubMed1975

Increase in dissociation rate constants of cardiotonic steroid-brain (Na+ + K+)-ATPase complexes by reduction of the unsaturated lactone.

Several cardiotonic steroids have been modified by reduction of the unsaturated lactone and their interactions with the sodium- and potassium-activated ATPase ((Na+ + K+)-ATPase) have been investigated. Reduction of the unsaturated lactone results in a decrease in binding affinity due primarily to an increase in the dissociation rate constant concomitant with a decrease in the activation free energy of dissociation. This decrease in activation free energy is about 2 to 4 kcal, which is approximately equal to the energy of one hydrogen bond. It is suggested that the increase in dissociation rate due to reduction of the unsaturated lactone may make possible the use of these compounds as affinity ligands for purification of the (Na+ + K+)-ATPase or an ouabain-binding fragment.

Adenosine Triphosphatases↗
PubMedDate not supplied

[Kinetics of the lactone-carboxylate transition of hybrid camptothecin-netropsin molecules].

The kinetics of the hydrolysis of the lactone ring of a hybrid molecule containing the molecules of the antitumor drug camptothecin and a derivative of the antibiotic netropsines, which is highly affine and specific to the DNA A-T sequences was investigated. It was shown that intramolecular interaction significantly slows down the rate of hydrolysis but does not change the equilibrium ratio of concentrations of the lactone and carboxylate forms of the camptothecin fragment of the hybrid molecule, which corresponds to the pH value. The use of intramolecular interaction for controlling the kinetics of the lactone/carboxylate transition makes it possible to create the drugs of the camptothecin family, which preserve the biologically active lactone form under the physiological conditions for a longer time and, therefore, are more effective as anticancer agents.

Camptothecin↗
PubMed2005

[Determination of lactone components in chuanxiong by reversed-phase high performance liquid chromatography].

A reversed-phase high performance liquid chromatographic method was developed for the simultaneous determination of four main lactone components including senkyunolide-H, senkyunolide-I, sedanenolide and Z-ligustilide in Chuanxiong, a Chinese herbal medicine. The samples were pretreated using ultrasonic extraction, and 80% ethanol was used as extractant in the experiment. The chromatographic analysis was carried out using an XDB-C8 column and the mobile phase consisted of methanol-1% (volume fraction) acetic acid water (55:45-->100:0, v/v, in 15 min). The flow rate was 0. 8 mL/min. A diode array detector was used to detect the compositions and 280 nm was chosen as the detection wavelength. The whole process could be performed within 15 min. The operating curves were found to be linear over the ranges of 0.4 - 2.2 mg/L (r=0. 9992), 0.4 -2.2 mg/L (r=0.9979), 2.6 -7.8 mg/L (r=0. 9992) and 4.8 14.3 mg/L (r = 0.9998) and the detection limits (S/N = 3) were 0.024, 0.027, 0.018 and 0.011 microg for senkyunolide-H, senkyunolide-I, sedanenolide and Z-ligustilide, respectively. The recoveries of the four lactone components were found in the range of 96% - 108%. The rapid and accurate method has been successfully applied to the simultaneous determination of the four lactone components in Chuanxiong.

4-Butyrolactone↗
PubMed1980

Toxicity of sesquiterpene lactones.

The intraperitoneal LD50 of 7 sesquiterpene lactones were determined (in mg/kg): mexicanin-E (3, 3.08 +/- .10), helenalin (1, 9.86 +/- .08), hymenoxon (2, 16.24 +/- .10), psilotropin (4, 112.25 +/- .17), hymenoxon dimethyl ether (5, 141.42 +/- 0), tenulin (6, 184.65 +/- .06), and hymenolane (7, above 200). The toxicity of a sesquiterpene lactone depends on the number of alkylating centers such as cyclopentenone, alpha-methylene-gamma-lactone, or hemiacetal moieties in the molecules.

Animals↗
PubMed2004

Total assignment of 1H and 13C NMR data for the sesquiterpene lactone 15-deoxygoyazensolide.

We describe a complete analysis of the 1H and 13C spectra of the anti-inflamatory, schistossomicidal and trypanosomicidal sesquiterpene lactone 15-deoxygoyazensolide. This lactone, with a structure similar to other important ones, was studied by NMR techniques such as COSY, HMQC, HMBC, Jres and NOE experiments. The comparison of the data with some computational results led to an unequivocal assignment of all hydrogen and carbon chemical shifts, even eliminating some previous ambiguities. We were able to determine all hydrogen coupling constants (J) and signal multiplicities and to confirm the stereochemistry. A new method for the determination of the relative position of the lactonization and the position of the ester group on a medium-sized ring by NMR was developed.

Heterocyclic Compounds, 3-Ring↗
PubMed2000

Antagonistic action of novel 1alpha,25-dihydroxyvitamin D(3)-26, 23-lactone analogs on 25-hydroxyvitamin-D(3)-24-hydroxylase gene expression induced by 1alpha,25-dihydroxy-vitamin D(3) in human promyelocytic leukemia (HL-60) cells.

We have demonstrated that 1alpha,25-dihydroxyvitamin D(3)-26, 23-lactone analogs, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647, TEI-9648, respectively), inhibit HL-60 cell differentiation induced by 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], but not differentiation caused by all-trans retinoic acid (D. Miura et al., 1999, J. Biol. Chem. 274, 16392). To assess whether the antagonistic actions of TEI-9647 and TEI-9648 in HL-60 cells are related to 1alpha,25(OH)(2)D(3) breakdown, we investigated their effects on catabolism of 1alpha,25(OH)(2)D(3). In HL-60 cells, the C-24 but not the C-23 side-chain oxidation pathway of 1alpha,25(OH)(2)D(3) has been reported. Here we demonstrate that 1alpha,25(OH)(2)D(3) was metabolized both to 24,25,26,27-tetranor-1alpha,23-(OH)(2)D(3) and 1alpha,25(OH)(2)D(3)-26,23-lactone; thus HL-60 cells constitutively possess both the 24- and the 23-hydroxylases. Metabolism of 1alpha, 25(OH)(2)D(3) was strongly suppressed by 10(-7) M TEI-9647 or 10(-6) M TEI-9648. 1alpha,25(OH)(2)D(3) alone slightly induced 24-hydroxylase gene expression by 8 h with full enhancement by 24-48 h; this induction was inhibited by 10(-6) M TEI-9647 and 10(-6) M TEI-9648 (86.2 and 31.9%, respectively) 24 h after treatment. However, analogs of TEI-9647 and TEI-9648 without the 25-dehydro functionality induced 24-hydroxylase gene expression. These results indicate that TEI-9647 and TEI-9648 clearly mediate their stereoselective antagonistic actions independent of their actions to block the catabolism of 1alpha,25(OH)(2)D(3). Therefore, TEI-9647 and TEI-9648 appear to be the first antagonists specific for the nuclear 1alpha,25(OH)(2)D(3) receptor-mediated genomic actions of 1alpha,25(OH)(2)D(3) in HL-60 cells.

Calcitriol↗
PubMed1996

Transgenic expression of L-gulono-gamma-lactone oxidase in medaka (Oryzias latipes), a teleost fish that lacks this enzyme necessary for L-ascorbic acid biosynthesis.

Transfer of the gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis in scurvy-prone animals, into medaka (Oryzias latipes) was successfully done. The expression plasmid pSVL-GLO, carrying rat liver L-gulono-gamma-lactone oxidase cDNA, was microinjected into the cytoplasm of fertilized eggs during the one-cell stage. Four male F0 fish having the transgene in their germ cells came to maturity, and F1 progeny derived from one of the F0 fish possessed L-gulono-gamma-lactone oxidase activity, indicating that the transgene was functionally expressed in the fish. Genomic Southern blot analysis demonstrated that the transgene existed in both chromosome-integrated and extrachromosomal forms.

Animals↗
PubMed1992

Anti-GM3-lactam monoclonal antibodies of the IgG type recognize natural GM3-ganglioside lactone but not GM3-ganglioside.

Immunization of mice with a synthetic GM3-lactam-BSA (bovine serum albumin) conjugate (designed to emulate the corresponding natural GM3-lactone conjugate), followed by fusion of splenocytes with myeloma cells, gave rise to more than 300 monoclonal hybridomas producing antibodies to GM3-lactam-BSA, which did not react with Glc-BSA and BSA. Eight antibody clones were randomly chosen from the positive 300 hybridomas. The eight clones, all belonging to the IgG class, were unreactive against GM3-ganglioside, whereas two antibodies (P5-1 and P5-3, both IgG1, kappa) reacted with GM3-ganglioside lactone. Binding of these two antibodies to the GM3-lactam-BSA conjugate was inhibited by soluble glycosides of GM2-, GM3-, and GM4-lactam and by GM3- and GM4-lactam, respectively, but not by Gb3 or asialo-GM1 and GM2-saccharides. A third antibody (P3; IgG2b, kappa) was inhibited by GM2-, GM3-, and GM4-lactam, but did not recognize GM3-ganglioside lactone.

Animals↗
PubMed2005

Use of solid-phase extraction to enable enhanced detection of acyl homoserine lactones (AHLs) in environmental samples.

A challenge for understanding the role of bacterial cell-cell signalling in the environment is the detection of those signals, which are often present in low (nmol L(-1)) concentrations. We describe here a simple purification method, solid-phase extraction (SPE), for increasing the sensitivity of detection for one such group of signals, acyl homoserine lactones (AHLs), in environmental samples. Spiking of dried marine sponge tissue (Stylinos sp.) with AHLs resulted in detection down to 0.01 ppm for 3-oxo-hexanoyl homoserine lactone (3-oxo C6-HSL) and 1 ppm for hexanoyl homoserine lactone (C6-HSL). Compared with liquid extraction methods use of SPE resulted in twofold and tenfold improvements in sensitivity, respectively.

4-Butyrolactone↗
PubMed1994

Analysis of the active lactone form of 9-aminocamptothecin in plasma using solid-phase extraction and high-performance liquid chromatography.

We have developed a sensitive HPLC assay to quantitate the active lactone form of 9-aminocamptothecin (9AC) in human plasma over the concentration range 10-0.25 nM (0.091 ng/ml). Solid-phase extraction separated 9AC lactone from its less active metabolite, 9AC carboxylate, allowing samples to be stored for up to two months prior to reversed-phase HPLC analysis. An acidic (pH 2.55) isocratic HPLC mobile phase was used to enhance 9AC fluorescence resulting in an over 50-fold increase in assay sensitivity compared to previous methods. This assay was able to measure steady-state 9AC lactone concentrations even at the lowest dose level of 9AC used in our Phase I clinical trial.

Antineoplastic Agents↗
PubMed2004

PA-I lectin from Pseudomonas aeruginosa binds acyl homoserine lactones.

The study analyses the binding affinities of Pseudomonas aeruginosa PA-I lectin (PA-IL) to three N-acyl homoserine lactones (AHSL), quorum sensing signal molecules responsible for cell-cell communication in bacteria. It shows that like some plant lectins, PA-IL has a dual function and, besides its carbohydrate-binding capacity, can accommodate AHLS. Formation of complexes between PA-IL and AHSL with acyl side chains composed of 4, 6 or 12 methyl groups is characterized by changes in the emissions of two incorporated fluorescent markers, TNS and IAEDANS, both derivatives of naphthalene sulfonic acid. PA-IL shows increasing affinities to lactones with longer aliphatic side chains. The values of the apparent dissociation constants (K(d)), which are similar to the previously determined K(d) for the adenine high affinity binding, and the similar effects of lactones and adenine on the TNS emission indicate one identical binding site for these ligands, which is suggested to represent the central cavity of the oligomeric molecule formed after the association of the four identical subunits of PA-IL. Intramolecular distances between the fluorescent markers and protein Trp residues are determined by fluorescence resonance energy transfer (FRET).

Adhesins, Bacterial↗
PubMed2006

Synthesis and biological evaluation of homoserine lactone derived ureas as antagonists of bacterial quorum sensing.

A series of 15 racemic alkyl- and aryl-N-substituted ureas, derived from homoserine lactone, were synthesized and tested for their ability to competitively inhibit the action of 3-oxohexanoyl-l-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri. N-alkyl ureas with an alkyl chain of at least 4 carbon atoms, as well as certain ureas bearing a phenyl group at the extremity of the alkyl chain, were found to be significant antagonists. In the case of N-butyl urea, it has been shown that the antagonist activity was related to the inhibition of the dimerisation of the N-terminal domain of ExpR, a protein of the receptor LuxR family. Molecular modelling suggested that this would result from the formation of an additional hydrogen bond in the protein acylhomoserine lactone binding cavity.

4-Butyrolactone↗
PubMed2005

Determination of kava lactones in food supplements by liquid chromatography-atmospheric pressure chemical ionisation tandem mass spectrometry.

Reversed-phase liquid chromatography and detection with atmospheric pressure chemical ionisation tandem mass spectrometry was used for the determination of kava extracts in herbal mixtures. One percent of kava extract can be detected, corresponding to approximately 0.05-0.2 mg/g of the individual kava lactones kavain, dihydrokavain, yangonin, desmethoxyyangonin, methysticin and dihydromethysticin. Reliable quantification is obtained from concentrations of 0.25-1 mg/g, depending on the compound. At these concentration levels, the relative standard deviations were 10-14%. Validation showed good linearity and recoveries for all the kava lactones with the exception of yangonin. During method development, degradation of yangonin was observed. The degradation product was identified by nuclear magnetic resonance (NMR) as cis-yangonin. The method was applied to the analysis of commercial herbal products available in the Dutch market before and after market restrictions of kava-containing preparations. The results showed that even though 'old' products contained kava extract, the new formulations were negative on kava lactones. cis-Yangonin was also present in the herbal products.

Atmospheric Pressure↗
PubMed2004

The Aeromonas hydrophila LuxR homologue AhyR regulates the N-acyl homoserine lactone synthase, AhyI positively and negatively in a growth phase-dependent manner.

Aeromonas hydrophila is a pathogen of fish, amphibians and humans which produces N-acylhomoserine lactone quorum sensing signal molecules and possesses homologues of the Vibrio fischeri luxI and luxR quorum sensing genes termed ahyI and ahyR, respectively. The ahyI and ahyR genes of A. hydrophila comprise a divergon with a 62 bp intergenic region and control biofilm maturation and extracellular protease production. Stationary phase culture supernatants from an ahyR but not an ahyI mutant contain N-butanoylhomoserine lactone (C4-HSL) which is shown to be required for maximal ahyI expression. To determine whether AhyR regulates ahyI, the expression of AhyI was followed throughout growth by Western blot analysis. This revealed that AhyI can be detected in the exponential phase but appears to be degraded in stationary phase in the parent A. hydrophila strain. In an ahyR mutant however, the AhyI protein is only produced in stationary phase but production is sustained suggesting that AhyR controls the timing of AhyI production and turnover. By using RT-PCR, we mapped the transcriptional start site of ahyI which revealed that the 12 bp symmetrical lux-box like sequence present in the 62 bp ahyRI intergenic region overlaps with the -10 region of the ahyI promoter. To determine whether AhyR could bind to the ahyRI intergenic region, the ahyR gene was expressed and purified as a maltose binding protein (MalE) fusion. Electrophoretic mobility shift assays demonstrated that MalE-AhyR specifically bound to this sequence in both the presence and absence of N-butanoylhomoserine lactone (C4-HSL). Taken together, these data suggest that AhyR acts as both a negative and a positive regulator of ahyI and hence C4-HSL production in a growth phase dependent manner.

4-Butyrolactone↗
PubMed2005

Inter-kingdom signaling: deciphering the language of acyl homoserine lactones.

Bacteria use small secreted chemicals or peptides as auto-inducers to coordinately regulate gene expression within a population in a process called quorum sensing. Quorum sensing controls several important functions in different bacterial species, including the production of virulence factors and biofilm formation in Pseudomonas aeruginosa and bioluminescence in Vibrio fischeri. Many gram-negative bacterial species use acyl homoserine lactones as auto-inducers that function as ligands for transcriptional regulatory proteins. Several recent reports indicate that bacterial acyl homoserine lactones can also affect gene expression in host cells. Direct signaling also appears to function in the opposite direction as some eukaryotic cell types produce mimics that interact with quorum sensing systems in bacteria. Here, we will describe the evidence to support the existence of bi-directional inter-kingdom signaling via acyl homoserine lactones and eukaryotic mimics and discuss the potential molecular mechanisms that mediate these responses. The functional consequences of inter-kingdom signaling will be discussed in relation to both pathogenic and non-pathogenic bacterial-host interactions.

4-Butyrolactone↗
PubMed1999

Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus.

Two morphologically marked strains of Haemonchus contortus, CAVRS (smooth-macrocyclic lactone resistant) and McMaster (linguiform-macrocyclic lactone susceptible), were used to investigate the selection for anthelmintic resistance following exposure to ivermectin (IVM), a non-persistent anthelmintic. and a more persistent anthelmintic, oral moxidectin (MOX). Three types of selection were investigated: (1) selection of resident worms at the time of treatment (Head selection); (2) selection of incoming-larvae post-treatment (Tail selection); and (3) selection of both resident population and incoming larvae (Head + Tail selection). The experimental animals were adult sheep and lambs. In the controls where there was no anthelmintic selection, the proportion of CAVRS in the adult worm population was the same as the proportion in larvae given to both adults and lambs indicating that CAVRS and McMaster H. contortus were equally infective. There was a significant effect of anthelmintic on total worm numbers in adult sheep with MOX treated adults having less worms, but selection type was non-significant. Anthelmintic type had a significant effect on numbers of resistant worms in adult sheep with less resistant worms in the MOX treated groups, but selection type had no effect. Analysis of variance of arcsine-transformed proportions of resistant worms found that the type of anthelmintic had a highly significant effect, with MOX treated adults having a higher proportion of resistant worms, while type of selection was not significant. In the lambs, nil treated controls and IVM Head + Tail and Tail selected groups had similar geometric mean total worm burdens while Head selected had less total worms. In the MOX treated lamb groups the worm burdens were similar within selection type but less than the IVM treated groups. In the lambs, the types of selection that resulted in more resistant worms were IVM Tail, MOX Head + Tail and MOX Tail. Resistant worm numbers were similar in both adult and lamb groups with Head selection by either MOX or IVM. Moxidectin selected out higher proportions of resistant worms than did IVM in the lambs, with Tail and Head + Tail being stronger selectors than Head. Computer simulations were used to estimate the rate at which resistance developed in the field using the information generated in the present study. The anthelmintic treatments used in the simulation followed a strategic parasite control program for H. contortus in which all sheep receive three Closantel (CLS) treatments in summer. all sheep receive a broad-spectrum (BS) drench or capsule at weaning and lambs receive an additional two BS drenches insummer or no further treatment in the case of the capsule. Moxidectin, IVM-capsule and IVM were the broad spectrum anthelmintics simulated. All simulations were run four times assuming high or low efficacy against resident resistant worms and in the presence or absence of CLS resistance. The simulations indicated that the presence of CLS resistance hastened selection for macrocyclic lactone (ML) resistance. While the IVM-capsule will select most rapidly for ML resistance, IVM oral is expected to be least selective. Moxidectin treatment is intermediate, except in simulations with no CLS resistance and when MOX is assumed to be highly effective against resident ML-resistant worms, in which case MOX can be expected to select more slowly than IVM oral treatments.

Animals↗
PubMed2000

Degradation pathway of homoserine lactone bacterial signal molecules by halogen antimicrobials identified by liquid chromatography with photodiode array and mass spectrometric detection.

The degradation pathway of acylated homoserine lactone bacterial signaling molecules by oxidizing hypochlorite and stabilized hypobromite antimicrobials has been characterized. A reversed-phase HPLC separation using a cyano column was developed to detect the parent lactones, lactone-hydrolysis products, and halogenation products. Elucidation of the structures of the reaction products was done with the aid of online photodiode array UV spectroscopy and atmospheric pressure chemical ionization mass spectrometry. Quantitative output of the HPLC method was also used to estimate the kinetics of the degradation pathway. The results of this work found that only beta-keto-amide signal molecules are halogenated, where normal amide signals are not, and may represent one possible mechanism for control of industrial biofilms.

4-Butyrolactone↗