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PubMed1999

Cloning and molecular analyses of a gibberellin 20-oxidase gene expressed specifically in developing seeds of watermelon.

To understand the biosynthesis and functional role of gibberellins (GAs) in developing seeds, we isolated Cv20ox, a cDNA clone from watermelon (Citrullus lanatus) that shows significant amino acid homology with GA 20-oxidases. The complementary DNA clone was expressed in Escherichia coli as a fusion protein, which oxidized GA(12) at C-20 to the C(19) compound GA(9), a precursor of bioactive GAs. RNA-blot analysis showed that the Cv20ox gene was expressed specifically in developing seeds. The gene was strongly expressed in the integument tissues, and it was also expressed weakly in inner seed tissues. In parthenocarpic fruits induced by 1-(2-chloro-4-pyridyl)-3-phenylurea treatment, the expression pattern of Cv20ox did not change, indicating that the GA 20-oxidase gene is expressed primarily in the maternal cells of developing seeds. The promoter of Cv20ox was isolated and fused to the beta-glucuronidase (GUS) gene. In a transient expression system, beta-glucuronidase staining was detectable only in the integument tissues of developing watermelon seeds.

5' Untranslated Regions↗

PubMed1989

Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.

The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism-dependent toxicity of the latter is potentiated by pre-treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase.

Animals↗

PubMed2006

Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: a toxicogenomics approach.

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and beta-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic end-points at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

Alanine Transaminase↗

PubMed2003

Role of cysteine S-conjugate beta-lyase in the metabolism of cisplatin.

Cisplatin is nephrotoxic, but the mechanism by which cisplatin kills renal proximal tubule cells is not well defined. Inhibition of gamma-glutamyl transpeptidase or pyridoxal 5'-phosphate (PLP)-dependent enzymes blocks the nephrotoxicity. Our hypothesis is that cisplatin is metabolized to a renal toxin through a platinum-glutathione conjugate to a reactive sulfur-containing compound. The final step in this bioactivation is the conversion of a platinum-cysteine S-conjugate to a reactive thiol by a PLP-dependent cysteine S-conjugate beta-lyase. LLC-PK1 cells, a proximal tubule cell line with low cysteine S-conjugate beta-lyase activity, are used to study cisplatin nephrotoxicity. We proposed that the beta-elimination reaction catalyzed by cysteine S-conjugate beta-lyase is the rate-limiting step in the metabolism of cisplatin to a toxin in these cells. In this study, LLC-PK1 cells were transfected with human glutamine transaminase K, which catalyzes the beta-elimination reaction. Cisplatin was significantly more toxic in confluent monolayers of cells with increased cysteine S-conjugate beta-lyase activity. In contrast, carboplatin, a non-nephrotoxic derivative of cisplatin, was 20-fold less toxic than cisplatin in confluent cells, and its toxicity was not altered by overexpression of cysteine S-conjugate beta-lyase. We propose that carboplatin is not nephrotoxic because it is not metabolized through this pathway. Dividing cells were more sensitive to both cisplatin and carboplatin toxicity. Overexpression of cysteine S-conjugate beta-lyase activity had no effect on the toxicity of either drug. These data demonstrate that cisplatin kills quiescent renal cells by a mechanism that is distinct from the mechanism by which it kills dividing cells and that the renal toxicity of cisplatin is dependent on cysteine S-conjugate beta-lyase activity.

Animals↗

PubMed2003

The 4-arylaminocoumarin derivatives log P values calculated according to Rekker's method.

In the QSAR (quantitative structure-activity relationship) and QSPR (quantitative structure-property-activity relationship) study physico-chemical property, lipophilicity is used, to predict bioactivity of the newly synthesized coumarin compounds. Lipophilicity is a property of a molecule which depends on and can be changed by modifications in molecular structure. The parameter of the lipophilicity, partition coefficient (log P), is commonly used in drug designing and it is a numeric characteristic of lipophilicity of the examined substance, potential drug. The synthesis of 4-arylaminocoumarins derivatives from 4-hydroxycoumarin, has been carried out. In this work we described the fragmental method of calculation of partition coefficient according to the Rekker's method, because the best correlation between calculated and experimental values log P was determined according to the Rekker model. 4-Arylaminocoumarin has negative value of log P, but substitution with alkyl or allyl groups on the position 3 increases lipofilicity. Introduction of methyl or ethyl group into position 3 increases lipofilicity, suggesting that by increasing the chain length the values of log P become higher. The influence of allyl substituent in position three increases lipophilicity similar to methyl group. The aryl supstitent decreases lipoflicity, but a general relationship among them could not be established. The results obtained in this study enable further synthesis of new coumarin derivatives and predict their biological activity and properties.

Journal Article↗

PubMed2000

Trans-resveratrol modulates the catalytic activity and mRNA expression of the procarcinogen-activating human cytochrome P450 1B1.

The present study was performed to determine if trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) modulates the catalytic activity and gene expression of cytochrome P450 1B1 (CYP1B1). In vitro, trans-resveratrol decreased human recombinant CYP1B1-catalyzed 7-ethoxyresorufin O-dealkylation activity, with an IC50 value of 1.4 +/- 0.2 microM (mean +/- SEM). Enzyme kinetic analysis indicated that trans-resveratrol inhibited CYP1B1 enzyme activity by a mixed-type inhibition and the apparent Ki was 0.75 +/- 0.06 microM. To determine if trans-resveratrol modulates constitutive CYP1B1 gene expression, cultured MCF-7 human breast carcinoma cells were treated with trans-resveratrol. As indicated by RT-PCR analysis, treatment of MCF-7 cells with 10 microM trans-resveratrol decreased relative CYP1B1 mRNA levels after 5 h, but not after 1.5 or 3 h, of exposure. trans-Resveratrol treatment at 5, 7.5, 10, or 20 microM for 5 h produced a concentration-dependent decrease in CYP1B1 mRNA levels. The extent of suppression was approximately 50% at 20 microM concentration. The suppressive effect was not a consequence of a toxic response to the compound as assessed by a cell proliferation assay. Overall, our novel finding that trans-resveratrol inhibits the catalytic activity and suppresses the constitutive gene expression of CYP1B1 leads to the possibility that this nutraceutical confers protection against toxicity and carcinogenicity induced by compounds that undergo CYP1B1-catalyzed bioactivation.

Anticarcinogenic Agents↗

PubMed2003

[Identification of four new ceramides from Anthopleura pacifica].

AIM: To study the bioactive constituents from Anthopleura pacifica. METHODS: Compounds were separated by Pyricularia oryzae bioassay-guided fractionation method with a combination of multi-chromatography. Their chemical structures were determined on the basis of spectral analysis and chemical evidence. RESULTS: A portion showing activity against P. oryzae was obtained and from the portion four compounds were identified as N-hydroxyethyl-N-tetradecanoyl-(2S,3R)-octadecasphinga-4(E), 8(E)-dienine (a), N-hydroxyethyl-N-(9Z-hexadecenoyl)-(2S,3R)-octadecasphinga-4 (E), 8 (E)-dienine (b), N-hydroxyethyl-N-hexadecanoyl-(2S,3R)-octadecasphinga-4(E), 8 (E)-dienine (c) and N-hydroxyethyl-N-(13Z-docosenoyl-(2S,3R)-octadecasphinga-4(E), 8(E)-dienine(d). CONCLUSION: All the four compounds are new ceramides.

Animals↗

PubMed2004

[Structure identification of two new cerebrosides from Helicia nilagirica Beed].

AIM: To study the bioactive components from Helicia nilagirica. METHODS: Compounds were separated with a combination of multi-chromatography. Their chemical structures were determined on the basis of spectral analysis and chemical evidence. RESULTS: Two compounds were isolated from the leaves of Helicia nilagirica. Compound 1 was elucidated as 1-O-3-D-glucopyranosyl-(2S,3S,4R,8Z)-2-[(2'R)-2'-hyd roxylignocenoyl-amino]-8-octadecene-1, 3, 4-triol. Compound 2 was an analogue of 1. CONCLUSION: The two compounds are new cerebrosides.

Cerebrosides↗

PubMed2006

Membrane association of N-oleoyl-dopamine in rat brain.

N-oleoyl-dopamine (OLDA) belongs to a novel class of bioactive amides of fatty acids. The compound, a lipid derivative of dopamine, holds promise as a potential prodrug or carrier of dopamine into the brain. In this context, a key issue concerning OLDA is the integrity of the compound once it enters the brain. We addressed this issue in the current study by assessing the propensity of OLDA for hydrolysis in rat brain tissue in vitro. The brains were dissected from surgically anesthetized rats after they had been sacrificed by perfusion with physiological saline through the heart. Membrane fractions of brain tissue were isolated and incubated with 1 mmol/l OLDA. Stability of the OLDA molecule was assessed from the spectrophotometric recordings of OLDA spectra in membrane fractions at hourly time points for up to 24 hours. The methodological assumption was that any major change in the shape of the OLDA spectrum would point to a structural, and thus also possibly functional, alteration of the molecule. We found that the OLDA spectrum remained unchanged in the assays for up to 17 h of incubation. We conclude that OLDA strongly resists hydrolysis in brain membrane fractions. The results suggest that dopamine-like biological effects of OLDA might have to do with the interaction of the integral OLDA compound, rather than a dissociated-off dopamine moiety, with the dopaminergic system.

Animals↗

PubMed2007

Pentacyclic triterpenes with selective bioactivity from Sebastiania adenophora leaves, Euphorbiaceae.

Six known pentacyclic triterpenes possessing oleanane, lupane, or taraxerane-type skeletons were isolated from the leaves of Sebastiania adenophora (Euphorbiaceae) and are reported for the first time in this species. These compounds include 3-epi-beta-amyrin, beta-amyrinone, 3-epi-lupeol, lupenone, taraxerol, and taraxerone. Structures were elucidated by comparison with literature data. The bioactivities of these compounds were tested on the root growth of Amaranthus hypochondriacus, amaranth (Amaranthaceae), Lycopersicon esculentum, tomato (Solanaceae), and Echinochloa crus-galli, barnyard grass (Poaceae). All six triterpenes were selectively bioactive. An important stimulatory effect was observed on amaranth root growth (23% to 56%) for almost all tested triterpenes (250 microg/ml). These triterpenes significantly inhibited the root growth of barnyard grass (28% to 78%) and tomato (23% to 49%). Aqueous leachate and organic extracts of S. adenophora leaves significantly inhibited the root growth of all test species. The possible ecological role of the allelochemicals isolated is discussed.

Euphorbiaceae↗

PubMed1995

2-Aminofluorene bioactivation by human term placental peroxidase.

Earlier investigations from our laboratory demonstrated that human term placental peroxidase (HTPP) is capable of metabolism of xenobiotics and endogenous compounds. In this study, purified HTPP was found to bioactivate 2-aminofluorene (2-AF) in the presence of H2O2. 2-AF oxidation was studied spectrophotometrically while radiometry was employed to assess the bioactivation. The rate of oxidation and covalent binding to protein and DNA was dependent upon the pH of the reaction medium and the concentration of 2-AF, the enzyme, and H2O2. To observe maximal enzyme velocity of oxidation, the presence of 16.5 microM H2O2, 100 microM 2-AF, 37 micrograms of the enzyme protein/ml, and pH 7.2 was required. Under optimal assay conditions, the range of specific activity between 130 and 165 nmol of 2-AF oxidized/min/mg HTPP was observed. Using similar assay conditions, the magnitude of covalent binding of [3H]-2-AF to protein (BSA) and calf thymus DNA was found to be about 508 pmol bound/min/mg HTPP/mg BSA and 84 pmol bound/min/mg HTPP/mg DNA, respectively. Potassium cyanide and sodium azide, the known inhibitors of different peroxidases, significantly blocked both the oxidation and covalent binding of 2-AF in a dose dependent manner. These results strongly suggest that peroxidase may be one of the important pathways responsible for the bioactivation of arylamines in human term placenta.

Azides↗

PubMed2001

Design, synthesis, and bioactivity of the first nonsteroidal mimetics of brassinolide.

Ten novel compounds, each consisting of two subunits and a linker, were designed with the aid of molecular modeling to resemble the natural steroidal phytohormone brassinolide. The mimetics were synthesized and subjected to the rice leaf lamina inclination bioassay to test for brassinosteroid activity. Most of the mimetics displayed very weak or no bioactivity, but two were strongly active when coapplied with the auxin indole-3-acetic acid (IAA), which synergizes the activity of brassinosteroids. Thus, 1-(4,6 alpha,7 alpha-trihydroxy-5,6,7,8-tetrahydronaphthyl)-2-(6 alpha',7 alpha'-dihydroxy-5',6',7',8'-tetrahydronaphthyl)ethyne (4) and (E)-1,2-bis[trans-(4a alpha,8a beta)-4-oxo-6 alpha,7 alpha-dihydroxy-4a,5,6,7,8,8a-hexahydro-(3H)-naphthyl]ethylene (11) showed exceptional activity at doses as low as 0.01 ng and 0.001 ng/plant, respectively. These compounds are the first biologically active nonsteroidal brassinolide mimetics.

Brassinosteroids↗

PubMed1996

Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.

A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.

Acetamides↗

PubMed1982

Arylhydroxamic acid bioactivation via acyl group transfer. Structural requirements for transacylating and electrophile-generating activity of N-(2-fluorenyl)hydroxamic acids and related compounds.

The synthesis of a series of 12 N-(2-fluorenyl)hydroxamic acids, N-(2-fluorenyl)-N-hydroxyureas, and N-(2-fluorenyl)-N-hydroxycarbamates is reported. The compounds were evaluated for their ability to serve as substrates for a partially purified hamster hepatic arylhydroxamic acid N,O-acyltransferase preparation. Transacylating activity was measured spectrophotometrically with 4-aminoazobenzene as the acyl group acceptor, and electrophile-generating activity was quantified by the N-acetylmethionine trapping assay. Only the N-acetyl, N-propionyl, and N-methoxyacetyl derivatives exhibited relatively high levels of activity as measured by either of the assay methods. These results are generally consistent with previously reported conclusions regarding the steric and electronic characteristics of acyl groups that are required for activation by this enzyme system. N,O-Acyltransferase inactivation by N-hydroxy-2-acetamidofluorene depressed the bioactivation of the N-acetyl compound to a greater extent than either the N-propionyl or N-methyloxyacetyl derivative.

Acetyltransferases↗

PubMed1996

Cell-cycle specific cytotoxicity mediated by rearranged ent-kaurene diterpenoids isolated from Parinari curatellifolia.

Two structurally novel cytotoxic ent-kaurene diterpenoids, 13-methoxy-15-oxozoapatlin and 13-hydroxy-15-oxozoapatlin, were isolated from the root bark of Parinari curatellifolia, together with the known compound, 15-oxozoapatlin, on the basis of bioactivity-guided chromatographic fractionation and found to demonstrate broad-spectrum cytotoxic activity against a panel of cultured human cancer cell lines. The structures of these compounds were determined by analysis of their spectroscopic data. The presence of an alpha, beta-unsaturated carbonyl group in 13-methoxy-15-oxozoapatlin suggested that the cytotoxic potential of this compound could be mediated through reaction with cellular nucleophiles by means of a Michael-type addition. The compound 13-methoxy-15-oxozoapatlin reacted with the nucleophiles L-cysteine and beta-mercaptoethanol. The adduct with beta-mercaptoethanol was isolated, structurally characterized and found to be approximately 5-fold less cytotoxic than 13-methoxy-15-oxozoapatlin itself. The compound 13-methoxy-15-oxozoapatlin did not interact with DNA nor guanosine, and it was not mutagenic for Salmonella typhimurium strain TM677. The effects of 13-methoxy-15-oxozoapatlin on the growth of human cancer cells were analyzed utilizing cultured ZR-75-1 breast cancer cells. Biosynthesis of DNA, RNA and protein was reduced in treated cells, and accumulation at the G2/M phase of the cell cycle was observed. The compound 13-methoxy-15-oxozoapatlin did not mediate antimitotic activity with dibutyryl cAMP-treated cultured astrocytoma cells, suggesting that the cell cycle effect is G2 specific. No antitumor activity was observed when athymic mice carrying KB cells were treated with 13-methoxy-15-oxozoapatlin. These data indicate that the cytotoxic activity of 13-methoxy-15-oxozoapatlin is mediated in part by covalent reaction with a cellular component (such as sulfhydryl-containing protein) by means of a Michael-type addition, and this results in the blockage of cell-cycle progression.

Africa↗

PubMed2005

Microwave-assisted synthesis of N-alkylated benzotriazole derivatives: antimicrobial studies.

Synthesis and characterization of N-alkylated benzotriazole derivatives 2(a-g) bearing pharmaceutically important bioactive substituents and their antimicrobial studies in vitro are described. The syntheses of the compounds were achieved by N-alkylation of the benzotriazole with different bioactive alkyl halides in presence of powdered K2CO3 in DMF solution and by microwave irradiation method with good yield compared to conventional method. The crystal structure analysis shows that compound 4'-benzotriazol-1-yl-methyl-biphenyl-2-carbonitrile 2a crystallizes in the space group P1 with cell parameters a = 8.526 (3) A, b = 12.706 (3) A, c = 7.966 (2) A, alpha = 100.89 (2) degrees , beta = 101.63 (3) degrees , gamma = 102.20(2) degrees, Volume = 801.7(4) A degrees , Z = 2 and the final R factor is 0.0559 for 6130 reflections with 218 parameters and zero restraint. This structure exhibits intermolecular hydrogen bonding. Compounds 2e, 2a showed significant antimicrobial activity.

Anti-Bacterial Agents↗

PubMed1988

Interferon induction inhibition and mutagenic activity of nitrosated coal dust extract.

Specified cytotoxicity and mutagenicity of coal dust extract (mixture of solvent extractions of bituminous coal nitrosated by NaNO2) were investigated because of the association of an excess risk of gastric cancer in coal miners. The effect of nitrosated coal dust on a cellular defense component of the interferon system, the induction of interferon (alpha/beta) in mammalian cell cultures by influenza virus, and mutagenicity, using the Salmonella/microsome assay, were determined. Nitrosated coal dust extract contained both bioactivation-independent and -dependent (microsome enzymatic activation) compounds that significantly inhibited the viral induction of interferon by greater than 50%. Nitrosated extract was mutagenic but exhibited no increase in mutagenic activity in the presence of microsomal enzymes. With further extraction of nitrosated coal dust extract by horse serum and fractionation thereof, the soluble chemical complexes formed with fractions of high molecular weight without bioactivation were dominant in both mutagenicity and inhibition of interferon induction. Low-molecular-weight fractions, with or without a metal chelator, and with or without bioactivation, all inhibited interferon induction comparably and significantly. There was no mutagenic activity manifested by these serum fractions. Metal-serum complexes were either not formed, or, if present, were ineffectual according to the biologic criteria employed. The findings of this study are discussed in terms of the association between nitrosated coal dust and gastric carcinogenesis.

Animals↗

PubMed2005

A robust homogeneous binding assay for alpha4beta2 nicotinic acetylcholine receptor.

AIM: To develop a homogeneous high-throughput screening (HTS) assay based on scintillation proximity assay (SPA) technology for identification of novel alpha4beta2 nicotinic acetylcholine receptor (nAChR) modulators. METHODS: Membrane preparation of HEK293 cells expressing alpha4beta2 nAChR, [(3)H]cytisine and wheat germ agglutinin (WGA)-coupled microbeads were used to develop an HTS assay based on SPA technology. This method was validated against a conventional filter binding approach and applied to large-scale screening of a library containing 32 000 synthetic compounds. Intracellular calcium measurement was carried out to verify the bioactivities of the hits found by the SPA assay. RESULTS: IC(50) values of 2 reference compounds (epibatidine and RJR 2403) determined by SPA and filter binding methods were comparable and consistent with those reported elsewhere. A total of 54 compounds, showing more than 60% competitive inhibition on [(3)H]cytisine binding to alpha4beta2 nAChR, were identified initially following an HTS campaign. Secondary screening confirmed that 17 compounds with novel chemical structures possessed relatively high binding affinity to alpha4beta2 nAChR (K(i)<2 micromol/L). Eight compounds displayed antagonistic effects with >50% inhibition on ABT-594-induced calcium mobilization while none showed any agonist activity. CONCLUSIONS: This homogeneous binding assay is a highly efficient, amenable to automation and robust tool to screen potential alpha4beta2 nAChR modulators in an HTS setting. Its application may be expanded to other membrane receptors and ion channels.

Alkaloids↗