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PubMed2004

Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells.

PURPOSE: HDAC inhibitors (HDACIs) have been shown to inhibit cancer cell proliferation, stimulate apoptosis, and induce cell cycle arrest. Our purpose was to investigate the antiproliferative effects of the HDACIs [suberoyl anilide bishydroxamine, valproic acid (VPA), trichostatin A, and sodium butyrate] against six endometrial cancer cell lines. EXPERIMENTAL DESIGN: Endometrial cancer cells were treated with a variety of HDACIs, and the effect on cell growth, cell cycle, and apoptosis was measured. The ability of VPA to inhibit the growth of endometrial tumors growing in immunodeficient mice was also assessed. RESULTS: Clonogenic assays showed that all cancer cell lines were sensitive to the growth inhibitory effect of HDACIs. Cell cycle analysis indicated that treatment with HDACIs decreased the proportion of cells in S phase and increased the proportion of cells in the G(0)-G(1) and/or G(2)-M phases of the cell cycle. Terminal deoxynucleotidyl transferase-mediated nick end labeling assays showed that HDACIs induced apoptosis. This was concomitant with altered expression of genes related to malignant phenotype, including an increase in p21(Waf1), p27(Kip7), and E-cadherin and a decrease in Bcl-2 and cyclin-D1 and -D2. Chromatin immunoprecipitation analysis revealed a remarkable increase in levels of acetylated histones associated with the p21 promoter after suberoyl anilide bishydroxamine treatment. In nude mice experiments, VPA inhibited significantly human uterine tumor growth without toxic side effects. CONCLUSIONS: These results suggest that HDACIs are effective in inhibiting growth of endometrial cancer cells in vitro and in nude mice, without toxic side effects. The findings raise the possibility that HDACIs may prove particularly effective in treatment of endometrial cancers.

Agar↗
PubMed2005

Correlation analyses for bimolecular nucleophilic substitution reactions of chloroacetanilide herbicides and their structural analogs with environmentally relevant nucleophiles.

Second-order rate constants (kNuc) for aqueous-phase bimolecular nucleophilic substitution (SN2) reactions of a range of anionic nucleophiles with alachlor, propachlor, and two analogs of propachlor (a thioacetanilide and a beta-anilide) were fit to the Swain-Scott and Edwards models. Correlations of literature kNuc values for analogous reactions of methyl chloride and methyl benzenesulfonate were included for comparison. The Swain-Scott correlation yielded poor to fair results for chloroacetanilides and their analogs, with adjusted (adj) r2 values ranging from 0.67 to 0.89, which are comparable to correlations for CH3Cl and CH3OSO2Ph (r2 (adj) = 0.80 and 0.85, respectively). Both the one- and two-parameter Edwards models yielded improved correlations for the majority of substrates. A pronounced dependence on the substrate polarizability (alpha) factor generally was observed for the Edwards model, with a negligible dependence on the substrate basicity (beta) factor. Substrate polarizability factors for the one-parameter Edwards model were significantly larger for alachlor, propachlor, and the beta-anilide analog of propachlor than for methyl chloride and methyl benzenesulfonate. This indicates that the chloroacetanilides are activated toward SN2 reactions with highly reactive nucleophiles (e.g., HS-, PhS-, and Sn(2-)) relative to other saturated carbon substrates. At best, the Swain-Scott and Edwards models only furnish order-of-magnitude predictions of kNuc for the substrates investigated.

Acetamides↗
PubMed1992

Synthesis of condensed heterocycles from 3-aryl-2,4-dicarbethoxy-5-methylcyclohexanones and their testing for antimicrobial activity.

Condensation of the title compounds (1) with hydroxylamine hydrochloride, hydrazines and/or aromatic amines resulted in the formation of the benzisoxazoles 2, oximes 3, indazolines 4 and beta-keto anilides 6. The oxime derivatives and anilides underwent cyclization to compounds 2. The interaction between 1 and thiourea gave the benzothiazines 7 and thiouracils 8. Compounds 8 on treatment with monochloroacetic acid gave the dioxo compounds 9, while their reaction with hydrazine hydrate afforded the hydrazino derivatives 10, which upon treatment with nitrous acid gave the azido or tetrazolo derivatives 11 and 12. Treatment of 1 with 2,3-diaminopyridine and/or 2-amino-3-hydroxy-pyridine gave the pyrimidoquinazolines 13 or 14. Some of the synthesized compounds were screened to test their antimicrobial properties.

Anti-Bacterial Agents↗
PubMed1983

NADPH-diaphorase used to estimate alterations in the toxic rapeseed oil syndrome.

The evaluation of NADPH-diaphorase in the post-mitochondrial fraction of rat liver has been shown a sensitive method to estimate alterations of microsomal oxidase systems in acute and chronic intoxications. It is also useful to demonstrate the interaction of drugs with barbiturates, which normally induce this enzyme. To study the biochemical liver damage which may occur in the toxic rapeseed oil syndrome, we measured NADPH-diaphorase in the post-mitochondrial fraction of rats given oral doses of toxic rapeseed oil (1 ml/day for 6 days), or oleil or linoleil anilide (10 mg/kg for 6 days). One-half the rats were sacrificed at the end of the dosing period and the other half were killed 4 weeks later. In both circumstances one-half the rats were treated with 2 doses of 80 mg phenobarbital/kg. NADPH-diaphorase was strongly inhibited by toxic oil and fatty acid anilides (72-93%). Phenobarbital induction was completely depressed. Enzyme activity remained depressed after a 4-week latency period.

Animals↗
PubMed1993

[Features of interaction of Escherichia coli DNA polymerase I and its Klenow fragment with dTTP gamma-p-azidoanilide].

gamma-p-Azidoanilidate of dTTP was used to study the photoaffinity modification of DNA polymerase I and Klenow fragment. The analog was found to be a mixed-type inhibitor with respect to dTTP of the polymerization reaction catalyzed by DNA polymerase I and Klenow fragment. In the absence of the reagent both UV-irradiated enzymes were rapidly inactivated. Substrates (dNTP and template-primer) protected the enzymes from inactivation by UV-light with different efficiency. In the presence of the template-primer UV-irradiation induced activation of DNA polymerase I. The effect of the analog on both enzyme forms under irradiation is different. At concentration of 10(-5)M gamma-p-anilidate of dTTP accelerated the activation of DNA polymerase I initiated by UV-irradiation and at 10(-4)M concentration it inactivated the enzyme by 20-25%. Under such conditions one enzyme molecule covalently bound two molecules of the analog. While the template-complementary substrate (dTTP) protected DNA polymerase I both from inactivation and modification, the non-complementary one (dCTP) worked only against modification. In contrast to DNA polymerase I Klenow fragment was not inactivated when exposed to UV-irradiation and gamma-p-anilidate of dTTP neither modified the protein nor exerted any significant effect on its polymerization activity. The data accumulated suggest the presence on the DNA polymerase I molecule of a regulatory region providing additional dNTP binding sites.

Azides↗
PubMed1997

Synthesis and evaluation of antitumor activity of arylamides and cyclohexylamides of isomeric 3-chloro-4-(2-chloroethylthio)butanoic- and 4-chloro-3-(2-chloroethylthio)butanoic acids.

In the hope to find antitumor candidates among di-(2-chloroethyl)sulfides it was found that only 3-chloro-4-(2-chloroethylthio)butanoic (3-chloro) and 4-chloro-3-(2-chloroethylthio)butanoic (4-chloro) acids possess definite alkylating ability which is suggested to be a reason of their high antitumor activity. However, the clinical use of these agents is hampered by their high toxicity. A number of arylamides and cyclohexylamides of 3-chloro and 4-chloro acids were synthesized. A study of the toxicity and antitumor activity of synthesized derivatives in comparison with known 4-chloro-3-(2-chloroethylthio)butanoic acids shows that both 3-chloro and 4-chloro isomers possess high antitumor activity. Substitution of 3-chloro and 4-chloro butanoic acids by arylamides and cyclohexylamides residues R did not appear to increase the antitumor activity of the compounds. The presence of an anilide and cyclohexylamides carboxylic or alkylenecarboxylic substituent reduced the toxicity of the compounds 3-5 times in comparison with 3-chloro and 4-chloro anilides and cyclohexylamides. All synthesized compounds possess a broad spectrum of antitumor activity and are less toxic than the parent compound 4-chloro-3-(2-chloroethylthio)butanoic acid.

Amides↗
PubMed1976

[Isolation and characterization of a microsomal arylaminopeptidase from rat kidney].

The isolation and characterization of a microsomal arylaminopeptidase from rat kidney is reported. By treatment of a microsomal arylaminopeptidase-phosphatase-complex with trypsin and subsequent gel filtration of the solubilized proteins on Sepharose 6B a electrophoretic homogeneous arylaminopeptidase was obtained (yield, 3%; enrichment, 900 times). The following properties of the purified enzyme were determined: 1. Molecular weight: 182000 (gel filtration on Sepharose 6B) to 192000 (SDS-polyacrylamide gel electrophoresis). 2. Subunit structure: In the presence of 6 M guanidine - HC1 + 1% BETA-mercaptoethanol the enzyme dissociates into subunits (MW 46700, ESTIMATED BY SDS gel electrophoresis method). 3. Isoelectric point: 4,71 (agarose gel electrophoresis method). 4. UV characteristics: E 280nm/E260NM=1.3. 5. Substrate specifity: optimal substrates L-alanyl derivatives (anilide, beta-naphthyl amide, p-nitroanilide, 4-(phenylazo)-phenylamide and hydrazide). Among these compounds the anilide derivative was hydrolyzed most rapidly. Furthermore, di- and tripeptides, especially L-methionyl-L-leucine, were also split. No hydrolysis was observed with hemoglobin (pH 4.5 and 7.5) and amino acid- or peptide-ester substrates. 6. Optimal pH: 7.5 +/- 0,1; optimal temperature: 45 to 50 degrees C. 7. The enzyme has no transamidation activity with L-alanyl amide both as aminoacyl donator and -acceptor. 8. Influence of effectors: Heavy metal ions (Ni2+, Cd2+, Cu2+, Zn2+), chelating agents (EDTA, o-phenanthroline) and puromycin inhibit the enzyme significantly. SH-group reagents are without any influence. 9. L-alanyl-L-alanyl-4 (phenylazo)-phenylamide, a dipeptide aryl aminopeptidase substrate, is hydrolyzed by the purified enzyme preparation according to a consecutive or step by step mechanism.

Aminopeptidases↗
PubMed1999

Involvement of nuclear factor-kappaB in a murine model for the acute form of autoimmune-like toxic oil syndrome.

The toxic oil syndrome (TOS) represents an exogenously induced autoimmune disease with acute or chronic symptoms similar to systemic lupus erythematosus or scleroderma. When genetically different mouse strains were exposed to oleic acid anilide (OAA), it was possible to mimic the different syndrome manifestations. The aim of the present study was to examine the role of NF-kappaB/Rel transcription factors in the development of the severe acute wasting disease observed in A/J mice. Within a week of OAA exposure, the A/J, but not B10.S strain, displayed weight loss, cachexia, apathy, reduced activity, and breathing difficulties. In affected A/J mice we observed a marked increase in NF-kappaB activation (p50/p65 dimers) both in splenic T cells and peritoneal macrophages as well as in tissue from aorta and gut. Incubation of splenocytes with OAA in vitro induced a dose-dependent removal of IkappaB-alpha, accompanied by NF-kappaB activation, whereas Sp-1 binding was not affected. Furthermore, we demonstrated the increased expression of the two NF-kappaB target genes IL-6 and IL-1beta in OAA-exposed mice and a transient OAA-induced accumulation of TNFalpha in vitro. This is the first report which implicates NF-kappaB/Rel in acute forms of chemically induced autoimmune-like disease and may serve as a paradigm for the involvement of this transcriptional system in acute processes associated with autoimmunity, suggesting possible avenues of therapeutic intervention.

Acute Disease↗
PubMed1993

Cyclooxygenase and lipoxygenase arachidonate metabolites synthesized by mouse peritoneal macrophages: in vitro effect of N-phenyllinoleamide from toxic oil samples.

N-phenyllinoleamide (NPLA) has been detected as extraneous compound in adulterated cooking oils associated with a unique epidemic disease known as the Toxic Oil Syndrome (TOS). In this communication we report on the action of NPLA on the endogenous cyclooxygenase and lipoxygenase arachidonate metabolism. Results show that mouse peritoneal macrophages (MPM) exposed to 1 mM NPLA for 2 h undergo significant increases of 6-keto prostaglandin F1a, prostaglandin E2, leukotriene B4, 12- and 15-hydroxyeicosatetraenoic acids. MPM prelabelled with 3H-AA showed an enhanced release when exposed to NPLA. Thus, it is concluded that NPLA potentiates AA release from cell membrane phospholipids and the subsequent cyclooxygenase and lipoxygenase oxidative metabolism of this precursor to various eicosanoids. This is in agreement with the implication of peroxidative process mediated by fatty acids anilides in TOS.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

Inhibition of acylcoenzyme A: cholesterol acyltransferase activity by PD128O42: effect on cholesterol metabolism and secretion in CaCo-2 cells.

The regulation of cholesterol uptake and secretion by acylcoenzyme A:cholesterol acyltransferase (ACAT) was investigated in the human intestinal cell line, CaCo-2. A new ACAT inhibitor, PD128042 (CI-976), was first characterized. The addition of the fatty acid anilide to membranes prepared from CaCo-2 cells inhibited ACAT activity without altering the activities of HMG-CoA reductase, fatty acid Co-A hydrolase, or triglyceride synthetase. PD128042 was a competitive inhibitor of ACAT with 50% inhibition occurring at a concentration of 0.2 micrograms/mL. When added to the medium of CaCo-2 cells at a concentration of 5 micrograms/mL, PD128042 inhibited oleate incorporation into cholesteryl oleate by 92% and increased oleate incorporation into triglycerides and phospholipids by 51% and 38%, respectively. After incubating CaCo-2 cells with the ACAT inhibitor, the rate of newly synthesized cholesterol decreased by 75% and membranes prepared from these cells contained significantly less HMG-CoA reductase activity. PD128042 significantly decreased the basolateral secretion of newly synthesized cholesteryl esters without affecting the secretion of newly synthesized triglycerides or phospholipids. The inhibitor decreased the esterification of labeled exogenous cholesterol which was taken up by the cell from bile salt micelles. Moreover, after 16 hr of ACAT inhibition, less labeled unesterified micellar cholesterol was associated with the cell. The esterification of cholesterol in CaCo-2 cells plays an integral role in the uptake of cholesterol through the apical membrane and its eventual secretion at the basolateral membrane.

Acyl Coenzyme A↗
PubMed2004

Flutolanil and carboxin resistance in Coprinus cinereus conferred by a mutation in the cytochrome b560 subunit of succinate dehydrogenase complex (Complex II).

A gene that confers resistance to the systemic fungicide flutolanil was isolated from a mutant strain of the basidiomycete Coprinus cinereus. The flutolanil resistance gene was mapped to a chromosome of approximately 3.2 Mb, and a chromosome-specific cosmid library was constructed. Two cosmid clones that were able to transform a wild-type, flutolanil-sensitive, strain of C. cinereus to resistance were isolated from the library. Analysis of a subclone containing the resistance gene revealed the presence of the sdhC gene, which encodes the cytochrome b560 subunit of the succinate dehydrogenase (SDH) complex (Complex II) in the mitochondrial membrane. Comparison between the sdhC gene of a wild-type strain and that of a mutant strain revealed a single point mutation, which results in the replacement of Asn by Lys at position 80. Measurements of succinate-cytochrome c reductase activity in the transformants with mutant sdhC gene(s) suggest that flutolanil resistance of the fungus is caused by a decrease in the affinity of the SDH complex for flutolanil. This sdhC mutation also conferred cross-resistance against another systemic fungicide, carboxin, an anilide that is structurally related to flutolanil. In other organisms carboxin resistance mutations have been found in the genes sdhB and sdhD, but this is the first demonstration that a mutation in sdhC can also confer resistance. The mutant gene cloned in this work can be utilized as a dominant selectable marker in gene manipulation experiments in C. cinereus.

Amino Acid Sequence↗
PubMed1992

Oxidative metabolism of N-phenyllinoleamide by human nasal polyps.

N-phenyllinoleamide (NPLA), the anilide of linoleic acid, has been associated with the epidemiology of Toxic Oil Syndrome, but no data are available on its metabolism. On account of the similarity in chemical structure between the linoleic acid and NPLA, the aim of this study has been to investigate the oxidative metabolism of this xenobiotic by the human nasal polyp, a tissue with elevated 15-lipoxygenase activity. For this purpose, tissue homogenates have been incubated for 2 h with NPLA (0.1 mM) spiked with either N-(ring G-3H)PLA (0.2 microCi/ml) or N-P(1-14C)LA (0.05 microCi/ml). Gas chromatographic/mass spectrometric analysis of the high performance liquid radiochromatographic fractions shows that the 9,12,13-trihydroxy, 12,13-epoxy-11-hydroxy and 13-hydroxy NPLA derivatives are the major metabolites. These results revealed that NPLA metabolites are chemical structures related to the linoleic acid derivatives, some of which may show biological activity.

Anilides↗
PubMed1988

1-Phenyl-5-vinyl-2-imidazolidinethione, a proposed causative agent of Spanish toxic oil syndrome: synthesis, and identification in one of a group of case-associated oil samples.

A method is described for the synthesis and characterization of N-(2-hydroxy-3-butenyl)-N'-phenylthiourea, and its cyclization product, 1-phenyl-5-vinyl-2-imidazolidinethione (PVIZT). Fourteen coded oil samples associated with toxic oil syndrome cases in Spain were examined by gas chromatography-electron impact mass spectrometry for the presence of PVIZT. Although these samples were obtained from households where cases of toxic oil syndrome had been recorded, they differed extremely with regard to their anilide and sulphur contents. In one sample PVIZT was detected at an estimated concentration of 1 mg/kg.

Anilides↗
PubMed1991

Evaluation of a peripherally selective antiandrogen (Casodex) as a tool for studying the relationship between testosterone and spermatogenesis in the rat.

The endocrine profile and the effects on spermatogenesis of the new antiandrogen, Casodex [2RS)-4-cyano-3-(4-fluorophenylsulphonyl)-2-anilide, CAS) were evaluated in the adult rat. In the first experiment rats were administered CAS at daily doses of 10, 20 and 40 mg/kg for 14 days. For comparison groups receiving flutamide (FL, 10 mg/kg) and ethane dimethane sulphonate (EDS) were included. Unlike FL, administration of CAS (10 and 20 mg/kg) did not significantly raise serum concentrations of gonadotropic hormones and testosterone. With 40 mg/kg CAS gonadotropin secretion, but not testosterone levels, were elevated on day 15. Administration of CAS lowered the weight of the seminal vesicles and coagulating glands comparable to the administration of the Leydig cell toxin EDS. In contrast to FL a significant loss of germ cells in stage VII of spermatogenesis was observed with CAS. In a second experiment the ability of FL and CAS to block testicular androgen action was compared in rats with reduced testicular androgen production induced by a gonadotropin-releasing hormone antagonist. Both antiandrogens markedly enhanced spermatogenic involution as revealed by quantitative flow cytometric analysis of germ cell numbers. The study demonstrates that (a) CAS is a peripherally selective antiandrogen and (b) CAS might provide a feasible approach to study androgen dependence of spermatogenesis in the presence of normal FSH levels.

Androgen Antagonists↗
PubMed1976

Thin-layer chromatography for detection of peptide cleavage or integrity during reactions of the Z-alanylglycines with aniline or phenylhydrazine under papain catalysis.

Z-l-Ala-gly and Z-dl-ala-gly can yield anilides and phenylhydrazides through peptide cleavage or peptide integrity during papain-catalyzed reactions with aniline (NH2Ph) or phenylhydrazine (NH2NHPh). Since Z-d-ala-gly yielded only uncleaved Z-d-ala-gly-NHPh or Z-d-ala-gly-NHNHPh, these were used as standards in thinlayer chromatography (TLC) for detecting integrity. Known Z-l-ala-NHPh and Z-l-ala-NHNHPh were the standards for cleavage. Depending on the time of incubation, cleaved or unsplit products, or both, were readily detected. The solvent systems that were used for TLC were also effectively employed for separations of reasonable amounts of mixtures of cleaved and uncleaved products through thick-layer chromatography on Chrom AR. This was followed by isolation of the separated components.

Alanine↗
PubMed1997

Voltammetric detection of nitric oxide (NO) in the rat brain: its variations throughout the sleep-wake cycle.

A sensor allowing the specific detection of nitric oxide (NO) is reported. Together with differential pulsed voltammetry, it allows the detection of a 650 mV signal either in NO solutions or in the rat frontal cortex. The intraperitoneal (i.p.) administration of a NO donor (S-nitrosoglutathione, 20 mg/kg i.p.) increases the signal height (+30%) while that of a nitric oxide synthase (NOS) inhibitor like L-nitro-arginine-p-nitro-anilide (100 mg/kg i.p.), produces its complete disappearance in the cortex of anesthetized rats. These results suggest that the 650 mV signal might be NO-dependent. Some other NOS inhibitors have been found either inefficient (L-nitro-arginine-methyl-ester) or partially efficient (7-nitro-indazole) on the signal height. In freely moving rats, also equipped with polygraphic electrodes, the signal measured in the frontal cortex exhibits the highest height during waking. It decreases during slow-wave sleep (-6%) and paradoxical sleep (-9%).

Activity Cycles↗
PubMed1976

Mechanism of action of serine proteases: tetrahedral intermediate and concerted proton transfer.

Stopped-flow spectrophotometry and proton inventory experiments have been used to define the reaction pathway for hydrolysis of a specific peptide substrate, Ac-L-Ala-L-Pro-L-Ala p-nitroanilide, by the serine proteases elastase and alpha-lytic protease. The stopped-flow studies reveal the existence and buildup of a tetrahedral adduct between the active site serine hydroxyl group and the sensitive carbonyl group of the substrate. The decomposition of this tetrahedral intermediate to the acyl enzyme and p-nitroaniline is the rate-limiting step for the hydrolytic reaction. The proton inventory data suggest the simultaneous transfer of two protons (presumably from the catalytic carboxyl of Asp-102 to N pi of the catalytic imidazole of His-57 and from N pi of the imidazole to the anilide NH) in the transition state leading to breakdown of the tetrahedral complex. That these proton transfers occur in a concerted, rather than stepwise, process attests to the ability of enzymes to lower the enthalpy of activation most effectively when the precise alignment of a highly specific substrate and catalytic groups minimizes the entropy of activation.

Anilides↗