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At least 325 records · Page 18Linked to original sources
PubMed1994

Chemical mutagenesis testing in Drosophila. IX. Results of 50 coded compounds tested for the National Toxicology Program.

Fifty chemicals were tested for mutagenic activity in post-meiotic and meiotic germ cells of male Drosophila melanogaster using the sex-linked recessive lethal (SLRL) assay. As in the previous studies in this series, feeding was chosen as the first route of administration. If the compound failed to induce mutations by this route, injection exposure was used. One gaseous chemical (1,3-butadiene) was tested only by inhalation. Those chemicals that were mutagenic in the sex-linked recessive lethal assay were further tested for the ability to induce reciprocal translocations. Eleven of the 50 chemicals tested were mutagenic in the SLRL assay. These included bis(2-chloroethyl) ether, 1,4-butanediol diglycidyl ether, 1-chloro-2-propanol, dimethyl methylphosphonate, dimethyl morpholinophosphoramidate, dimethyloldihydroxyethylene urea, 2,2-dimethyl vinyl chloride, hexamethylphosphoramide, isatin-5-sulfonic acid (Na salt), isopropyl glycidyl ether, and urethane. Five of these, including 1,4-butanediol diglycidyl ether, 2,2-dimethyl vinyl chloride, hexamethylphosphoramide, isopropyl glycidyl ether, and urethane, also induced reciprocal translocations.

Animals↗
PubMed1993

Synthesis of propargylic alcohols and biological effects on Echinococcus multilocularis metacestodes.

This study describes the synthesis of propargylic alcohols derived from isatin and their biochemical and morphological effects on Echinococcus multilocularis metacestodes in Meriones unguiculatus. Propargylic alcohols decreased the alkaline phosphatase and the lactate dehydrogenase activities of the metacestode selectively. The most effective compound, 1b, decreased the lactate dehydrogenase enzymatic activity, and the glucose concentration in the parasite increased, whereas the glycogen content was partially decreased. Furthermore, the ultrastructure study revealed several damages. The host-parasite relationships are very important in the intrahepatic cestodes as shown by the biochemical side effects observed in the host's liver during the treatment. An in vitro enzymatic study was performed with alcohols 1b and 1c.

Alkaline Phosphatase↗
PubMed1993

Temperature-sensitive mutants in the vaccinia virus A18R gene increase double-stranded RNA synthesis as a result of aberrant viral transcription.

Mutations in the vaccinia gene A18R cause activation of the cellular ribonucleolytic 2-5A pathway. To determine the mechanism of 2-5A pathway activation, mutant infections were analyzed for synthesis of double-stranded RNA and for transcription of individual virus genes. At late times postinfection, A18R mutant-infected cells contained an increased amount of complementary RNA and a higher steady state level of RNA from regions of the genome transcribed normally only early in the infection. The phenotype of A18R ts mutants is indistinguishable from that of wild-type infections done in the presence of isatin-beta-thiosemicarbazone (IBT). Actinomycin D is a potent inhibitor of activation of the 2-5A pathway in IBT-treated wt infections. Based on these observations, we conclude that the phenotype induced by A18R mutants or by IBT treatment of wt infections is caused by a loss of control of late viral transcription.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Monoamine oxidase A-inhibiting components of urinary tribulin: purification and identification.

The endogenous monoamine oxidase (MAO) inhibitory activity, termed tribulin, contains several components. We have previously identified one of them, isatin, which is a selective inhibitor of MAO B. In the present study we have purified several further components of human urinary tribulin which act as selective inhibitors of MAO A. They have been identified by gas chromatography-mass spectrometry (GC-MS) as ethyl indole-3-acetate (and/or methyl indole-3-propionate), methyl indole-3-acetate and ethyl 4-hydroxyphenylacetate. IC50 values for MAO A were found to be 44 microM (105 microM for methyl indole-3-propionate), 88 microM and 120 microM, respectively, whilst those for MAO B were each greater than 1 mM. The artificial formation of these esters was excluded by carrying the parent acids, from which they are presumably synthesized, through the purification procedure. As tribulin output is increased during stress or anxiety, these results point to a possible role for tryptamine and tyramine pathways in such disorders.

Blood Platelets↗
PubMed2004

Low-molecular-weight, biologically active compounds from marine Pseudoalteromonas species.

We have examined the ability of marine Proteobacteria from the Pseudoalteromonas genus and Alteromonas macleodii to produce low-molecular-weight, biologically active compounds with antimicrobial and surface-active properties. A new marine bacterium, Pseudoalteromonas issachenkonii, exhibited a high level of biological activity and produced antifungal and hemolytic compounds. A detailed spectroscopic investigation based on UV, IR, high-resolution mass spectrometry, and 2D 1H and 13C nuclear magnetic resonance revealed that the former was indole-2,3-dione (isatin). The chemical structure of red-brown pigment (C9H7N3OS3) responsible for hemolytic activity remained unclear. Four of the 15 strains studied (P. luteoviolacea, P. rubra, P. undina, and P. issachenkonii) produced cell-bound, two (P. elaykovii and P. carrageenovora) produced extracellular, and one strain (P. citrea) produced cell-bound and extracellular fatty acids and phospholipids with surface activity. Neither peptides nor glycolipids with surface activity were detected.

Alteromonas↗
PubMed1991

Assay of HIV-1 proteinase: a colorimetric method using small peptide substrates.

A colorimetric assay for HIV proteinase using small protected peptide substrates is described. Substrates are cleaved to release N-terminal prolyl peptides which react with isatin to form a blue product which is measured spectrophotometrically. The assay is suitable for use with pure enzyme or crude extracts derived from genetically engineered Escherichia coli.

Amino Acid Sequence↗
PubMed1992

Increase of brain endogenous monoamine oxidase inhibitory activity (tribulin) in experimental audiogenic seizures in rats: evidence for a monoamine oxidase A inhibiting component of tribulin.

Brain tribulin activity in rats with an inherited predisposition to audiogenic epilepsy was studied after seizures of different intensity were induced by an electric bell. Weak seizures (from 0 to 2 arbitrary units) did not produce any changes in endogenous inhibitory activity towards either monoamine oxidase (MAO) A or B. Moderate seizures were characterized by increases in both MAO A and MAO B inhibitory activity (up to 1.9-fold). Complete tonic epileptiform seizures with total areflexia (4 arbitrary units) induced further augmentation (up to 2.5-fold) of MAO A but not of MAO B inhibitory activity. This dissociation between the two inhibitory activities points to the existence of a separate MAO A-inhibiting component of brain tribulin which is different from isatin.

Animals↗
PubMed1991

Alkaline phosphatase from Echinococcus multilocularis: purification and characterization.

1. Kinetic and physical parameters of purified alkaline phosphatase from Echinococcus multilocularis metacestodes, livers of infected gerbils and control animals were determined. 2. Km value for p-nitrophenyl phosphate was about 0.05 +/- 0.02 mM for the three enzymes. 3. Vmax values were 357 +/- 67 nmol/min/mg proteins for metacestode enzyme, and 6.7 +/- 1.1 and 6.7 +/- 0.8 nmol/min/mg proteins for liver enzyme of infected and control animals, respectively. 4. Mr and pI were different for the parasite and hepatic enzyme. 5. The parasite enzyme was less sensitive to the elevation of temperature than hepatic enzyme. 6. The isatin inhibition was a competitive inhibition type for parasite and uncompetitive type for host liver enzyme.

Alkaline Phosphatase↗
PubMed2005

Synthesis and in-vitro cytotoxicity evaluation of gatifloxacin Mannich bases.

Mannich bases of gatifloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. The compounds were tested in-vitro against a panel of 58 human tumour cell lines derived from nine neoplastic diseases. Among them compound 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-(3'-sulphadoximino)-1'-(5-bromoisatinyl) methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (6) emerged as a potent anticancer agent being more active than standard DNA topoisomerase II inhibitor, etoposide against 30 cancer cell lines.

Antineoplastic Agents↗
PubMed2004

Atrial natriuretic peptide modulates the hyperpolarization-activated current (If) in human atrial myocytes.

OBJECTIVES: The relationship between atrial stretching and changes in cell excitability is well documented. Once stretched, human atrial myocytes (HuAM) release atrial natriuretic peptide (hANP). Receptors for hANP (NPR) are coupled to a guanylyl cyclase (GC) activity, and are present on HuAM, but the electrophysiological effects of hANP are largely unknown. We investigated the effect of hANP on If, the hyperpolarization-activated current present in HuAM, and the underlying intracellular pathway. METHODS: HuAM were isolated from atrial appendages and utilized for patch-clamp recording. RESULTS: hANP caused a significant and concentration dependent shift of the midpoint activation potential (DeltaVh) toward less negative potentials of 6.9 +/- 1.0 mV at 0.1 nM; 13.0 +/- 2.6 mV at 1 nM and 15.3 +/- 2.2 mV at 10 nM (p < 0.001 for all); a parallel increase of If rate of activation occurred. The effect of hANP was completely blocked by isatin, a potent antagonist of NPR (p < 0.01 vs. hANP). In the presence of the inhibitors of guanylyl cyclase (ODQ and LY83583), hANP caused a significantly smaller DeltaVh (p < 0.01 vs. hANP for both). 8Br-cGMP mimicked the effect of hANP, both in the presence and absence of KT5823, a selective inhibitor of Protein kinase G. Pretreatment with pertussis toxin (PTX) did not change the effect of hANP, thus excluding a major role for the coupling of NPR with the Gi-Proteins system. Pretreating cells with cyclopentyladenosine (CPA), an A1-adenosine receptor agonist, completely blocked hANP effect. Adding hANP to maximal serotonin concentration produced an additive response. CONCLUSIONS: Our data demonstrate for the first time that ANP is able to increase If, likely through a modulation of intracellular cGMP and cAMP levels. This effect could have implications in the relationship between stretch and arrhythmogenesis in the human atrium.

Adenosine↗
PubMed2006

Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinase inhibitors, anticancer and antiangiogenic agents.

Several analogues of the 3-substituted-2-oxoindole chemotype were synthesized by condensing isatin or the appropriate haloisatin with some amino acids or histamine under neutral conditions. All the imino derivatives produced were tested for kinase inhibitory properties against three serine/threonine kinases, namely CDK1/cyclin B, CDK5/p25 and GSK3alpha/beta. Most of the histidine derivatives showed inhibitory properties to the three kinases in the low micromolar range. The histamine derivatives were less potent against CDK1/cyclin B and CDK5/p25 and totally inactive against GSK3alpha/beta. So, the management of the carboxyl function may be a tool to impart selectivity in such family of kinases. Docking of 2-[[-5-bromo-2-oxoindolin-3-ylidene]amino]-3-(1H-imidazol2-yl)propanoic acid 14 to CDK5/p25 indicates that this compound can interact with the enzyme through four hydrogen bonds; for GSK/3beta, the ligand poses itself in another orientation, also four hydrogen bonds can be formed between the ligand and the receptor, otherwise hydrophobic interactions seem to predominate. Also, all the final compounds were tested for their in vitro antitumor properties against MCF7 (breast), NCI-H460 (lung) and SF268 (CNS) cancer cell lines. None of the synthesized compounds was cytotoxic at 10(-4) molar concentration. Moreover, compounds 13 and 14 were tested for potential antiangiogenic properties by testing their ability to inhibit the proliferation of human umbilical vein endothelial cells (HUVECs), cord formation and migration in response to chemoattractant. Only compound 14 showed moderate inhibitory properties to HUVECs proliferation and cord formation while its non-brominated derivative 13 did not. Thus, the antiangiogenesis properties are not apparently caused by inhibition of any of the tested kinases.

Angiogenesis Inhibitors↗
PubMed2004

Tribulin and endogenous MAO-inhibitory regulation in vivo.

Tribulin is the name given to a family of endogenous nonpeptide substances which inhibit monoamine oxidase (MAO) and benzodiazepine binding. It is widely distributed in mammalian tissues and body fluids, and exhibit some species and tissue variations. Several components selectively inhibiting MAO A, MAO B, central and peripheral benzodiazepine binding (tribulins A, B, BZc and BZp, respectively) have been recognised. Tribulin A represents some tissue-specific metabolites of trace amines, whereas isatin is the major component of tribulin B. Tribulin content increases in brain under conditions of stress and anxiety and is reduced under sedation. Changes in tribulin content in the brain are accompanied by corresponding changes in the content of monoamines and their acidic metabolites, and also by altered susceptibility of MAO to specific mechanism-based inhibitors. This suggests that tribulin is involved in MAO inhibitory regulation in vivo.

Animals↗
PubMed2001

Indigo degradation with purified laccases from Trametes hirsuta and Sclerotium rolfsii.

The degradation of the textile dye indigo with purified laccases from the fungi Trametes hirsuta (THL1 and THL2) and Sclerotium rolfsii (SRL1) was studied. All laccases were able to oxidize indigo yielding isatin (indole-2,3-dione), which was further decomposed to anthranilic acid (2-aminobenzoic acid). Based on the oxygen consumption rate of the laccases during indigo degradation, a potential mechanism for the oxidation of indigo involving the step-wise abstraction of four electrons from indigo by the enzyme was suggested. Comparing the effect of the known redox-mediators acetosyringone, 1-hydroxybenzotriazole (HOBT) and 4-hydroxybenzenesulfonic acid (PHBS) on laccase-catalyzed degradation of indigo, we found a maximum of about 30% increase in the oxidation rate of indigo with SRL1 and acetosyringone. The particle size of indigo agglomerates after laccase treatment was influenced by the origin of the laccase preparation and by the incubation time. Diameter distributions were found to have one maximum and compared to the indigo particle size distribution of the control, for all laccases, the indigo agglomerates seemed to have shifted to smaller diameters. Bleaching of fabrics by the laccases (based on K/S values) correlated with the release of indigo degradation products.

Basidiomycota↗
PubMed2001

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, (1)H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.

Anti-HIV Agents↗
PubMed2001

An efficient conversion of 5-nitroisatin into 5-nitroindole derivative.

Our process research on OPC-35564 revealed that a mixed borohydride reducing agent (ZrCl4/NaBH4) in DME (Itsuno system) afforded a rapid and direct conversion of N-alkyl-nitroisatin into nitroindole nucleus. Comparison with other reducing agents indicated the superiority of the present system and the key function of ZrCl4. For the manipulation of base-labile isatin, a useful procedure for its N-alkylation using Cu2CO3 is also presented.

Alkylation↗
PubMed2000

Oxidation of indole by cytochrome P450 enzymes.

Indole is a product of tryptophan catabolism by gut bacteria and is absorbed into the body in substantial amounts. The compound is known to be oxidized to indoxyl and excreted in urine as indoxyl (3-hydroxyindole) sulfate. Further oxidation and dimerization of indoxyl leads to the formation of indigoid pigments. We report the definitive identification of the pigments indigo and indirubin as products of human cytochrome P450 (P450)-catalyzed metabolism of indole by visible, (1)H NMR, and mass spectrometry. P450 2A6 was most active in the formation of these two pigments, followed by P450s 2C19 and 2E1. Additional products of indole metabolism were characterized by HPLC/UV and mass spectrometry. Indoxyl (3-hydroxyindole) was observed as a transient product of P450 2A6-mediated metabolism; isatin, 6-hydroxyindole, and dioxindole accumulated at low levels. Oxindole was the predominant product formed by P450s 2A6, 2E1, and 2C19 and was not transformed further. A stable end product was assigned the structure 6H-oxazolo[3,2-a:4, 5-b']diindole by UV, (1)H NMR, and mass spectrometry, and we conclude that P450s can catalyze the oxidative coupling of indoles to form this dimeric conjugate. On the basis of these results, we propose that the P450/NADPH-P450 reductase system can catalyze oxidation of indole to a variety of products.

Animals↗
PubMedDate not supplied

Trityl isothiocyanate support for solid-phase synthesis.

Trityl isothiocyanate resin [1], prepared from commercially available trityl chloride resin, is a useful precursor of the trityl thiosemicarbazide resin [2]. This resin can be employed in the solid-phase synthesis of a variety of supported isatin beta-thiosemicarbazones [4] and their Mannich derivatives [6]. A variety of thioureas [7] can be easily prepared by the reaction of [1] with amines. The supported thioureas are directly and efficiently converted to 2-aminothiazole-5-carboxylates [8] by reaction with methyl 2-chloroacetoacetate.

Combinatorial Chemistry Techniques↗
PubMed2005

N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: synthesis, in vitro activity, and molecular modeling studies.

A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, caspase-3 and caspase-7, were identified. These compounds were also observed to have a low potency for inhibiting the initiator caspases, caspase-1 and caspase-8, and caspase-6. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The results of the current study revealed a number of non-peptide-based caspase inhibitors that may be useful in assessing the role of inhibiting the executioner caspases in minimizing tissue damage in disease conditions characterized by unregulated apoptosis.

Apoptosis↗