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Cytotoxic Compounds (cytotoxic + compound)
Selected AbstractsSynthesis and Antiproliferative Activity of Substituted Benzopyranoisoindoles: A New Class of Cytotoxic Compounds.CHEMINFORM, Issue 49 2006Christiana Hadjipavlou Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Chronic hypothyroidism only marginally affects adult-type Leydig cell regeneration after EDS administrationINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2010Eddy Rijntjes Summary Chronic prenatally induced dietary hypothyroidism delays adult-type Leydig cell development, but does not block this process. Using a chemical model to induce hypothyroidism, it was suggested that development of a new population of Leydig cells was completely inhibited following the addition of the cytotoxic compound ethane-1,2-dimethyl sulphonate (EDS). In this study, we used a dietary approach to induce hypothyroidism and reinvestigated the regeneration of the Leydig cell population following EDS administration. Eighty-four day old euthyroid and chronically hypothyroid rats received an injection of EDS and were killed directly before or at regular intervals up to 77 days after EDS. In some control and hypothyroid animals, the first progenitor-type Leydig cells were observed at day 12 after EDS. At day 16, Leydig cell progenitors were present in all rats. The percentage of proliferating Leydig cells peaked in the euthyroid animals at day 21 after EDS. In the hypothyroid testis such a peak was not observed, although the percentage of proliferating regenerating Leydig cells was significantly higher from days 35 to 56 compared with the controls. This suggested that the wave of Leydig cell proliferation was delayed in the hypothyroid animals as compared with the euthyroid controls. On the day of EDS injection, the Leydig/Sertoli cell ratio was 37% lower in the hypothyroid rats compared with the controls. The Leydig/Sertoli cell ratio remained lower in the EDS-treated hypothyroid animals compared with the controls at all time points investigated. At day 77 after EDS, the Leydig cell population had returned to its pre-treatment size in both groups. Plasma testosterone production was reduced to below detectable levels immediately after EDS injection, and started to increase again on day 16, reaching pre-treatment values on day 21 in both groups. Taken together, severely reduced thyroid hormone levels did not block the regeneration of the adult-type Leydig cell population following EDS, as has been suggested previously. [source] Isolation and immunomodulatory properties of a flavonoid, casticin from Vitex agnus-castusPHYTOTHERAPY RESEARCH, Issue 11 2009M. Ahmed Mesaik Abstract Casticin (1), a flavonoid isolated from the aerial parts of Vitex agnus-castus, was found to be a potent immunomodulatory and cytotoxic compound. The activity was tested in vitro for chemiluminescence, chemotaxis, T-cell proliferation and cytotoxicity. Casticin (1) exhibited a significant inhibitory effect on monocyte oxidative burst in a dose dependent manner. It was found to have a significant suppressive effect on the chemotaxic action at higher concentrations on fMLP (10,8m) stimulated neutrophils. It also showed a potent suppressive effect on PHA stimulated T-cell (PMBC). Copyright © 2009 John Wiley & Sons, Ltd. [source] Hydroxycinnamic Acids as DNA-Cleaving Agents in the Presence of CuII Ions: Mechanism, Structure,Activity Relationship, and Biological ImplicationsCHEMISTRY - A EUROPEAN JOURNAL, Issue 46 2009Gui-Juan Fan Abstract The effectiveness of hydroxycinnamic acids (HCAs), that is, caffeic acid (CaA), chlorogenic acid (ChA), sinapic acid (SA), ferulic acid (FA), 3-hydroxycinnamic acid (3-HCA), and 4-hydroxycinnamic acid (4-HCA), as pBR322 plasmid DNA-cleaving agents in the presence of CuII ions was investigated. Compounds bearing o -hydroxy or 3,5-dimethoxy groups on phenolic rings (CaA, SA, and ChA) were remarkably more effective at causing DNA damage than the compounds bearing no such groups; furthermore, CaA was the most active among the HCAs examined. The involvement of reactive oxygen species (ROS) and CuI ions in the DNA damage was affirmed by the inhibition of the DNA breakage by using specific scavengers of ROS and a CuI chelator. The interaction between CaA and CuII ions and the influence of ethylenediaminetetraacetic acid (EDTA), the solvent, and pH value on the interaction were also studied to help elucidate the detailed prooxidant mechanism by using UV/Vis spectroscopic analysis. On the basis of these observations, it is proposed that it is the CaA phenolate anion, instead of the parent molecule, that chelates with the CuII ion as a bidentate ligand, hence facilitating the intramolecular electron transfer to form the corresponding CaA semiquinone radical intermediate. The latter undergoes a second electron transfer with oxygen to form the corresponding o -quinone and a superoxide, which play a pivotal role in the DNA damage. The intermediacy of the semiquinone radical was supported by isolation of its dimer from the CuII -mediated oxidation products. Intriguingly, CaA was also the most cytotoxic compound among the HCAs toward human promyelocytic leukemia (HL-60) cell proliferation. Addition of exogenous CuII ions resulted in an effect dichotomy on cell viability depending on the concentration of CaA; that is, low concentrations of CaA enhanced the cell viability and, conversely, high concentrations of CaA almost completely inhibited the cell proliferation. On the other hand, when superoxide dismutase was added before, the two stimulation effects of exogenous CuII ions were significantly ameliorated, thus clearly indicating that the oxidative-stress level regulates cell proliferation and death. These findings provide direct evidence for the antioxidant/prooxidant mechanism of cancer chemoprevention. [source] Identification of genes involved in the biosynthesis of the cytotoxic compound glidobactin from a soil bacteriumENVIRONMENTAL MICROBIOLOGY, Issue 7 2007Barbara Schellenberg Summary Glidobactins (syn. cepafungins) are a family of structurally related cytotoxic compounds that were isolated from the soil bacterial strain K481-B101 (ATCC 53080; DSM 7029) originally assigned to Polyangium brachysporum and, independently, from an undefined species related to Burkholderia cepacia. Glidobactins are acylated tripeptide derivatives that contain a 12-membered ring structure consisting of the two unique non-proteinogenic amino acids erythro -4-hydroxy- l -lysine and 4(S)-amino-2(E)-pentenoic acid. Here we report the cloning and functional analysis of a gene cluster (glbA,glbH) involved in glidobactin synthesis from K481-B101, which according to its 16S rRNA sequence belongs to the Burkholderiales. The putative encoded proteins include a mixed non-ribosomal peptide/polyketide synthetase whose structure and architecture allowed to build a biosynthetic pathway model explaining the biosynthesis of the unique peptide part of glidobactins. Intriguingly, among the more than 600 bacterial strains whose genome sequence is currently available, homologous gene clusters were found in Burkholderia pseudomallei, the causing agent of melioidosis, and in the insect pathogen Photorhabdus luminescens, strongly suggesting that these organisms are capable to synthesize compounds similar to glidobactins. In addition, a glb gene cluster that was inactivated by transposon-mediated rearrangements was also present in Burkholderia mallei, a very close relative of B. pseudomallei and the causing agent of glanders in horse-like animals. [source] Upregulation of Brain Expression of P-Glycoprotein in MRP2-deficient TR - Rats Resembles Seizure-induced Up-regulation of This Drug Efflux Transporter in Normal RatsEPILEPSIA, Issue 4 2007Katrin Hoffmann Summary:,Purpose: The multidrug resistance protein 2 (MRP2) is a drug efflux transporter that is expressed predominantly at the apical domain of hepatocytes but seems also to be expressed at the apical membrane of brain capillary endothelial cells that form the blood,brain barrier (BBB). MRP2 is absent in the transport-deficient (TR,) Wistar rat mutant, so that this rat strain was very helpful in defining substrates of MRP2 by comparing tissue concentrations or functional activities of compounds in MRP2-deficient rats with those in transport-competent Wistar rats. By using this strategy to study the involvement of MRP2 in brain access of antiepileptic drugs (AEDs), we recently reported that phenytoin is a substrate for MRP2 in the BBB. However, one drawback of such studies in genetically deficient rats is the fact that compensatory changes with upregulation of other transporters can occur. This prompted us to study the brain expression of P-glycoprotein (Pgp), a major drug efflux transporter in many tissues, including the BBB, in TR, rats compared with nonmutant (wild-type) Wistar rats. Methods: The expression of MRP2 and Pgp in brain and liver sections of TR, rats and normal Wistar rats was determined with immunohistochemistry, by using a novel, highly selective monoclonal MRP2 antibody and the monoclonal Pgp antibody C219, respectively. Results: Immunofluorescence staining with the MRP2 antibody was found to label a high number of microvessels throughout the brain in normal Wistar rats, whereas such labeling was absent in TR, rats. TR, rats exhibited a significant up-regulation of Pgp in brain capillary endothelial cells compared with wild-type controls. No such obvious upregulation of Pgp was observed in liver sections. A comparable overexpression of Pgp in the BBB was obtained after pilocarpine-induced seizures in wild-type Wistar rats. Experiments with systemic administration of the Pgp substrate phenobarbital and the selective Pgp inhibitor tariquidar in TR, rats substantiated that Pgp is functional and compensates for the lack of MRP2 in the BBB. Conclusions: The data on TR, rats indicate that Pgp plays an important role in the compensation of MRP2 deficiency in the BBB. Because such a compensatory mechanism most likely occurs to reduce injury to the brain from cytotoxic compounds, the present data substantiate the concept that MRP2 performs a protective role in the BBB. Furthermore, our data suggest that TR, rats are an interesting tool to study consequences of overexpression of Pgp in the BBB on access of drugs in the brain, without the need of inducing seizures or other Pgp-enhancing events for this purpose. [source] Therapy-induced antitumor vaccination by targeting tumor necrosis factor-, to tumor vessels in combination with melphalanEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Lorenzo Mortara Abstract Treatment of tumor-bearing mice with mouse (m)TNF-,, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6,days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-, and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response. [source] The transporters Pdr5p and Snq2p mediate diazaborine resistance and are under the control of the gain-of-function allele PDR1-12FEBS JOURNAL, Issue 6 2004Eva Wehrschütz-Sigl The spontaneous acquisition of resistance to a variety of unrelated cytotoxic compounds has important implications in medical treatment of infectious diseases and anticancer therapy. In the yeast Saccharomyces cerevisiae this phenomenon is caused by overexpression of membrane efflux pumps and is called pleiotropic drug resistance. We have found that allelic forms of the genes for the transcription activators Pdr1p and Pdr3p, designated PDR1-12 and PDR3-33, respectively, mediate resistance to diazaborine. Here we demonstrate that the transporters Pdr5p and Snq2p are involved in diazaborine detoxification. We report that in the PDR3-33 mutant diazaborine resistance is exerted mainly via overexpression of the PDR5 and SNQ2 genes, while in the PDR1-12 mutant, additional genes, i.e. the Yap1p target genes FLR1 and YCF1, are also involved in diazaborine detoxification. In addition, we show that in the presence of cycloheximide or diazaborine PDR5 can be activated by additional transcription factors beside Pdr1p and Pdr3p. [source] CYTOTOXICITY ASSESSMENT OF BACILLUS STRAINS ISOLATED FROM STREET-VENDED FOODS IN JOHANNESBURG, SOUTH AFRICAJOURNAL OF FOOD SAFETY, Issue 2 2002F.M. MOSUPYE ABSTRACT Twenty-one isolates each of Bacillus (B.) cereus, B. licheniformis and B. subtilis from street foods, collected in central Johannesburg, were randomly selected to test for cytotoxicity against McCoy 5A Mouse cells using a 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide assay, and observation by confocal scanning laser microscopy (CSLM) and scanning electron microscopy (SEM). Forty-eight percent of B. cereus, 33% of B. licheniformis and 19% of B. subtilis strains produced cytotoxic compounds. For B. cereus strains, all supernatants exhibiting cytotoxic effects were inactivated by heat treatment at 121C for 15 min. By contrast, 24% of B. licheniformis and 10% of B. subtilis supernatants exhibited cytotoxic effects following heat treatment. CSLM and SEM showed that McCoy cells treated with cytotoxic supernatants exhibited leakage and necrosis. Presence of B. cereus, B. licheniformis and B. subtilis in street foods in high numbers may pose potetnial safety risks due to production of cytotoxic compounds. [source] The QSAR Modeling of Cytotoxicity on AnthraquinonesMOLECULAR INFORMATICS, Issue 8 2009Kalev Takkis Abstract A QSAR analysis was carried out on a dataset of 126 anthraquinone-based cytotoxic compounds. A PCA of the molecular descriptors was used to cluster the dataset into smaller subsets according to their structural features and QSAR models were derived for the selected sets. During the modeling, protonated states of molecules and nonlinear transformations of the descriptors were considered. The developed models have been interpreted in the context of cytotoxicity and validated with leave-one-out, and leave-many-out cross-validation. The descriptors in the resulting models describe the size and charge distribution of molecules although in different clusters their proportions vary. [source] Synthesis, in-vitro Cytotoxicity, and a Preliminary Structure-Activity Relationship Investigation of Pyrimido[4,5- c]quinolin-1(2H)-onesARCHIV DER PHARMAZIE, Issue 8 2010Kamel Metwally Abstract As part of our ongoing research effort to develop new antimitotic agents based on the recently reported pyrimido[4,5- c]quinoline-1(2H)-one ring skeleton, we were interested in identifying structural elements that contribute to the cytotoxicity of this class of compounds. The effect of several quinoline-ring substituents was examined and the new compounds were evaluated in vitro for cytotoxicity against three human cancer cell lines namely, lung fibrosarcoma HT-1080, colon adenocarcinoma HT-29, and breast carcinoma MDA-MB-231. Most of the compounds showed cytotoxic activity in the low micromolar and sub-micromolar range. Structure-activity relationship information revealed that a combination of electronic and steric factors may be involved. Flow cytometric cell cycle analysis performed on HT-1080 cells revealed that the most cytotoxic compounds 48, 50, 54, 59, and 63 inhibit the S-phase and arrest the cells in the G2/M phase of the cell cycle suggesting an antimitotic action of these compounds. [source] Conformational change of the AcrR regulator reveals a possible mechanism of inductionACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2008Ruoyu Gu The Escherichia coli AcrR multidrug-binding protein represses transcription of acrAB and is induced by many structurally unrelated cytotoxic compounds. The crystal structure of AcrR in space group P2221 has been reported previously. This P2221 structure has provided direct information about the multidrug-binding site and important residues for drug recognition. Here, a crystal structure of this regulator in space group P31 is presented. Comparison of the two AcrR structures reveals possible mechanisms of ligand binding and AcrR regulation. [source] | |||||||||||||