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Sample records for 3-aminopyridine-2-carboxaldehyde thiosemicarbazone 3-ap

  1. Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia

    PubMed Central

    Kunos, Charles A; Radivoyevitch, Tomas; Ingalls, Stephen T; Hoppel, Charles L

    2012-01-01

    The anticancer agent 3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase's small subunits, M2 and M2b (p53R2). Unfortunately, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe2+) in hemoglobin. This creates Fe3+ methemoglobin that does not deliver oxygen. Fe2+ in hemoglobin normally auto-oxidizes to inactive Fe3+ methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen, ascorbate and, most importantly, intravenously administered methylene blue as a therapeutic antidote. PMID:22335579

  2. Modulating Radiation Resistance by Inhibiting Ribonucleotide Reductase in Cancers with Virally or Mutationally Silenced p53 Protein

    PubMed Central

    Kunos, Charles A.; Chiu, Song-mao; Pink, John; Kinsella, Timothy J.

    2009-01-01

    Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine® NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G1/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes that rely on deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of human cancers. PMID:19929413

  3. Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates

    SciTech Connect

    Kunos, Charles A.; Colussi, Valdir C.; Pink, John; Radivoyevitch, Tomas; Oleinick, Nancy L.

    2011-07-15

    Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: The cells were exposed to low-dose-rate radiation (11, 23, 37, 67 cGy/h) using a custom-fabricated cell irradiator or to high-dose-rate radiation (330 cGy/min) using a conventional cell irradiator. The radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated using a clonogenic survival and an RNR activity assay. Alteration in the cell cycle distribution was monitored using flow cytometry. Results: Increasing radiation sensitivity of both CaSki and C33-a cells was observed with the incremental increase in radiation dose rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity from the radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and extended G{sub 1}-phase cell cycle arrest. Conclusions: We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation.

  4. Triapine and a more potent dimethyl derivative induce endoplasmic reticulum stress in cancer cells.

    PubMed

    Trondl, Robert; Flocke, Lea S; Kowol, Christian R; Heffeter, Petra; Jungwirth, Ute; Mair, Georg E; Steinborn, Ralf; Enyedy, Éva A; Jakupec, Michael A; Berger, Walter; Keppler, Bernhard K

    2014-03-01

    Triapine (3-AP; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of endoplasmic reticulum (ER) stress in the anticancer activity of 3-AP and the derivative N(4),N(4)-dimethyl-triapine (3-AP-Me), differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a, ATF6) by phosphorylation of eIF2α and upregulation of gene expression of activating transcription factors ATF4 and ATF6. In particular, 3-AP-Me led to an upregulation of the alternatively spliced mRNA variant XBP1 (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response, a significant upregulation of proapoptotic proteins was detected, including the transcription factor CHOP and Bim, an essential factor for ER stress-related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the antiproliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal dimethylation leads to an even more pronounced manifestation of this effect.

  5. Methemoglobin formation by triapine, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and other anticancer thiosemicarbazones: identification of novel thiosemicarbazones and therapeutics that prevent this effect.

    PubMed

    Quach, Patricia; Gutierrez, Elaine; Basha, Maram Talal; Kalinowski, Danuta S; Sharpe, Philip C; Lovejoy, David B; Bernhardt, Paul V; Jansson, Patric J; Richardson, Des R

    2012-07-01

    Thiosemicarbazones are a group of compounds that have received comprehensive investigation as anticancer agents. The antitumor activity of the thiosemicarbazone, 3-amino-2-pyridinecarboxaldehyde thiosemicarbazone (3-AP; triapine), has been extensively assessed in more than 20 phase I and II clinical trials. These studies have demonstrated that 3-AP induces methemoglobin (metHb) formation and hypoxia in patients, limiting its usefulness. Considering this problem, we assessed the mechanism of metHb formation by 3-AP compared with that of more recently developed thiosemicarbazones, including di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). This was investigated using intact red blood cells (RBCs), RBC lysates, purified oxyhemoglobin, and a mouse model. The chelation of cellular labile iron with the formation of a redox-active thiosemicarbazone-iron complex was found to be crucial for oxyhemoglobin oxidation. This observation was substantiated using a thiosemicarbazone that cannot ligate iron and also by using the chelator, desferrioxamine, that forms a redox-inactive iron complex. Of significance, cellular copper chelation was not important for metHb generation in contrast to its role in preventing tumor cell proliferation. Administration of Dp44mT to mice catalyzed metHb and cardiac metmyoglobin formation. However, ascorbic acid administered together with the drug in vivo significantly decreased metHb levels, providing a potential therapeutic intervention. Moreover, we demonstrated that the structure of the thiosemicarbazone is of importance in terms of metHb generation, because the DpT analog, di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), does not induce metHb generation in vivo. Hence, DpC represents a next-generation thiosemicarbazone that possesses markedly superior properties. This investigation is important for developing more effective thiosemicarbazone treatment regimens. PMID:22508546

  6. Functional interaction between the glucocorticoid receptor and GANP/MCM3AP

    SciTech Connect

    Osman, Waffa; Laine, Sanna; Zilliacus, Johanna . E-mail: johanna.zilliacus@mednut.ki.se

    2006-10-06

    Glucocorticoids are widely used to treat inflammatory diseases but have a number of side effects that partly are connected to inhibition of cell proliferation. Glucocorticoids mediated their action by binding to the glucocorticoid receptor. In the present study, we have identified by two-hybrid screens the germinal center-associated protein (GANP) and MCM3-associated protein (MCM3AP), a splicing variant of GANP, as glucocorticoid receptor interacting proteins. GANP and MCM3AP can bind to the MCM3 protein involved in initiation of DNA replication. Glutathione-S-transferase-pull-down and co-immunoprecipitation assays showed that the C-terminal domain of GANP, encompassing MCM3AP, interacts with the ligand-binding domain of the glucocorticoid receptor. Characterization of the intracellular localization of GANP revealed that GANP is shuttling between the nucleus and the cytoplasm. Furthermore, we show that glucocorticoids are unable to inhibit DNA replication in HeLa cells overexpressing MCM3AP suggesting a role for both glucocorticoid receptor and GANP/MCM3AP in regulating cell proliferation.

  7. PAN-811 inhibits oxidative stress-induced cell death of human Alzheimer's disease-derived and age-matched olfactory neuroepithelial cells via suppression of intracellular reactive oxygen species.

    PubMed

    Nelson, Valery M; Dancik, Chantée M; Pan, Weiying; Jiang, Zhi-Gang; Lebowitz, Michael S; Ghanbari, Hossein A

    2009-01-01

    Oxidative stress plays a significant role in neurotoxicity associated with a variety of neurodegenerative diseases including Alzheimer's disease (AD). Increased oxidative stress has been shown to be a prominent and early feature of vulnerable neurons in AD. Olfactory neuroepithelial cells are affected at an early stage. Exposure to oxidative stress induces the accumulation of intracellular reactive oxygen species (ROS), which in turn causes cell damage in the form of protein, lipid, and DNA oxidations. Elevated ROS levels are also associated with increased deposition of amyloid-beta and formation of senile plaques, a hallmark of the AD brain. If enhanced ROS exceeds the basal level of cellular protective mechanisms, oxidative damage and cell death will result. Therefore, substances that can reduce oxidative stress are sought as potential drug candidates for treatment or preventative therapy of neurodegenerative diseases such as AD. PAN-811, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or Triapine, is a small lipophilic compound that is currently being investigated in several Phase II clinical trials for cancer therapy due to its inhibition of ribonucleotide reductase activity. Here we show PAN-811 to be effective in preventing or reducing ROS accumulation and the resulting oxidative damages in both AD-derived and age-matched olfactory neuroepithelial cells.

  8. Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L.

    PubMed

    Parker, Erica N; Song, Jiangli; Kishore Kumar, G D; Odutola, Samuel O; Chavarria, Gustavo E; Charlton-Sevcik, Amanda K; Strecker, Tracy E; Barnes, Ashleigh L; Sudhan, Dhivya R; Wittenborn, Thomas R; Siemann, Dietmar W; Horsman, Michael R; Chaplin, David J; Trawick, Mary Lynn; Pinney, Kevin G

    2015-11-01

    Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 μM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 μM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre

  9. Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores.

    PubMed

    Akladios, Fady N; Andrew, Scott D; Parkinson, Christopher J

    2016-02-01

    Zinc is the second most abundant transition metal in the human body, between 3 and 10% of human genes encoding for zinc binding proteins. We have investigated the interplay of reactive oxygen species and zinc homeostasis on the cytotoxicity of the thiosemicarbazone chelators against the MCF-7 cell line. The cytotoxicity of thiosemicarbazone chelators against MCF-7 can be improved through supplementation of ionic zinc provided the zinc ion is at a level exceeding the thiosemicarbazone concentration. Elimination of the entire cell population can be accomplished with this regime, unlike the plateau of cytotoxicity observed on thiosemicarbazone monotherapy. The cytotoxic effects of copper complexes of the thiosemicarbazone are not enhanced by zinc supplementation, displacement of copper from the complex being disfavoured. Treatment of MCF-7 with uncomplexed thiosemicarbazone initiates post G1 blockade alongside the induction of apoptosis, cell death being abrogated through subsequent supplementation with zinc ion after drug removal. This would implicate a metal depletion mechanism in the cytotoxic effect of the un-coordinated thiosemicarbazone. The metal complexes of the species, however, fail to initiate similar G1 blockade and apparently exert their cytotoxic effect through generation of reactive oxygen species, suggesting that multiple mechanisms of cytotoxicity can be associated with the thiosemicarbazones dependant on the level of metal ion association. PMID:26683314

  10. Synthesis, characterization and biological evaluation of paeonol thiosemicarbazone analogues as mushroom tyrosinase inhibitors.

    PubMed

    Zhu, Tian-Hua; Cao, Shu-Wen; Yu, Yan-Ying

    2013-11-01

    A series of hydroxy- and methoxy-substituted paeonol thiosemicarbazone analogues were synthesized as potential tyrosinase inhibitors and their inhibitory effects on mushroom tyrosinase and inhibitory mechanism were evaluated. Paeonol thiosemicarbazone analogues have been found exhibiting more remarkable inhibition than their indexcompounds on mushroom tyrosinase. Among them, compound 2,4-dihydroxy acetophenone-4-phenyl-3-thiosemicarbazone (d1) had the most potent inhibition activity with the IC50 value of 0.006 ± 0.001 mM, displayed as a reversible competitive inhibitor. The inhibitory ability of o- or p-substituted acetophenone thiosemicarbazones was: di-substituted acetophenone thiosemicarbazones>mono-substituted acetophenone thiosemicarbazones>non-substituted acetophenone thiosemicarbazones. Copper ions chelation assay explained that compound d1 exhibited competitive inhibition by forming a chelate with the copper ions at the catalytic domain of tyrosinase as well as indicate a 1.5:1 binding ratio of compound d1 with copper ions. In the fluorescence spectrum study, compound d1 behaved stronger fluorescence quenching on tyrosinase towards d1-Cu(2+) complex, inhibiting tyrosinase mainly by means of chelating the two copper ions in the active site. The newly synthesized compounds may serve as structural templates for designing and developing novel tyrosinase inhibitors.

  11. Synthesis, characterization and biological evaluation of paeonol thiosemicarbazone analogues as mushroom tyrosinase inhibitors.

    PubMed

    Zhu, Tian-Hua; Cao, Shu-Wen; Yu, Yan-Ying

    2013-11-01

    A series of hydroxy- and methoxy-substituted paeonol thiosemicarbazone analogues were synthesized as potential tyrosinase inhibitors and their inhibitory effects on mushroom tyrosinase and inhibitory mechanism were evaluated. Paeonol thiosemicarbazone analogues have been found exhibiting more remarkable inhibition than their indexcompounds on mushroom tyrosinase. Among them, compound 2,4-dihydroxy acetophenone-4-phenyl-3-thiosemicarbazone (d1) had the most potent inhibition activity with the IC50 value of 0.006 ± 0.001 mM, displayed as a reversible competitive inhibitor. The inhibitory ability of o- or p-substituted acetophenone thiosemicarbazones was: di-substituted acetophenone thiosemicarbazones>mono-substituted acetophenone thiosemicarbazones>non-substituted acetophenone thiosemicarbazones. Copper ions chelation assay explained that compound d1 exhibited competitive inhibition by forming a chelate with the copper ions at the catalytic domain of tyrosinase as well as indicate a 1.5:1 binding ratio of compound d1 with copper ions. In the fluorescence spectrum study, compound d1 behaved stronger fluorescence quenching on tyrosinase towards d1-Cu(2+) complex, inhibiting tyrosinase mainly by means of chelating the two copper ions in the active site. The newly synthesized compounds may serve as structural templates for designing and developing novel tyrosinase inhibitors. PMID:24120880

  12. Isatin based thiosemicarbazone derivatives as potential bioactive agents: Anti-oxidant and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Haribabu, J.; Subhashree, G. R.; Saranya, S.; Gomathi, K.; Karvembu, R.; Gayathri, D.

    2016-04-01

    A new series of isatin based thiosemicarbazones has been synthesized from benzylisatin and unsubstituted/substituted thiosemicarbazides (1-5). The synthesized compounds were characterized by elemental analyses, and UV-Visible, FT-IR, 1H &13C NMR and mass spectroscopic techniques. Three dimensional molecular structure of three compounds (1, 3 and 4) was determined by single crystal X-ray crystallography. Anti-oxidant activity of the thiosemicarbazone derivatives showed their excellent scavenging effect against free radicals. In addition, all the compounds showed good anti-haemolytic activity. In silico molecular docking studies were performed to screen the anti-inflammatory and anti-tuberculosis properties of thiosemicarbazone derivatives.

  13. An API LC/MS/MS quantitation method for ansamitocin P-3 (AP3) and its preclinical pharmacokinetics.

    PubMed

    Liu, Zhongfa; Floss, Heinz G; Cassady, John M; Xiao, Jim; Chan, Kenneth K

    2004-11-19

    Ansamitocin P-3 (AP3) is a potent maytansinoid antitumor agent isolated from microorganisms and mosses. In this study, a highly sensitive and specific electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for quantitation of AP3 was developed and validated. AP3 was extracted from rat plasma along with the internal standard, depsipeptide FK228 (NSC-630176, FR) with ethyl acetate. Components in the extract were separated on a 50mm x 2.1mm Betabasic C 85 microm stainless steel column by isocratic elution with 70% acetonitrile/0.9% formic acid. The liquid flow was passed through a pre-source splitter and 5% of the eluent was introduced into the API source. The components were analyzed in the multiple-reaction-monitoring (MRM) mode as the precursor/product ion pair of m/z 635.2/547.2 for AP3 and of m/z 541.5/424.0 for the internal standard FR. Linear calibration curves were obtained in the range 1-500 ng/mL using 0.2 mL rat plasma. The within-day coefficients of variation (CVs) were 12.9, 6.7, and 5.5% and the between-day CVs were 10.4, 6.5, and 6.4% (all n = 5) at 1, 10, and 200 ng/mL, respectively. A formulation based on normal saline and PEG300 was then developed and Sprague-Dawley male rats were given this formulated drug by i.v. bolus. Plasma drug concentrations were measured by this method and the pharmacokinetics were analyzed by standard techniques. Plasma concentration-time profiles were found to follow a triexponential decline and the terminal phase was nearly flat, suggesting that the drug distributed in deep tissue compartments or organs and then equilibrates slowly with the blood stream. PMID:15533675

  14. Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: structure-activity relationship studies on their anti-proliferative and iron chelation efficacy.

    PubMed

    Lukmantara, Adeline Y; Kalinowski, Danuta S; Kumar, Naresh; Richardson, Des R

    2014-12-01

    Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2'-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

  15. Influence of anthraquinone scaffold on E/Z isomer distribution of two thiosemicarbazone derivatives. 2D NMR and DFT studies

    NASA Astrophysics Data System (ADS)

    Marković, Violeta; Joksović, Milan D.; Marković, Svetlana; Jakovljević, Ivan

    2014-01-01

    A distribution of possible isomeric and tautomeric forms of two tautomerizable anthraquinone-thiosemicarbazones with pronounced cytotoxic potential was investigated using 2D NMR and DFT studies. Conformational analysis of the E and Z isomers of both thiosemicarbazones was performed to find out the most stable conformation for each molecule. It was found that superior stability of E-isomers results from ten-membered intramolecular hydrogen bond between thiosemicarbazone N2H and anthraquinone carbonyl group. This hydrogen bond is stronger than that between thiosemicarbazone N2H and ester oxygen, owing to the large partial negative charge on the anthraquinone oxygen.

  16. Impact of terminal dimethylation on the resistance profile of α-N-heterocyclic thiosemicarbazones

    PubMed Central

    Heffeter, Petra; Pirker, Christine; Kowol, Christian R.; Herrman, Gerrit; Dornetshuber, Rita; Miklos, Walter; Jungwirth, Ute; Koellensperger, Gunda; Keppler, Bernhard K.; Berger, Walter

    2012-01-01

    Triapine is an α-N-heterocyclic thiosemicarbazone with promising anticancer activity against hematologic malignancies but widely ineffective against solid tumor types in clinical trials. The anticancer activity of thiosemicarbazones can be dramatically increased by terminal dimethylation. KP1089 is a gallium compound containing two terminal dimethylated thiosemicarbazone ligands. To gain insights on the vulnerability of this highly active terminal dimethylated thiosemicarbazone to drug resistance mechanisms, a new cell model with acquired resistance against the lead compound KP1089 was established. Subsequent genomic analyses (arrayCGH and FISH) revealed amplification of the ABCC1 gene on double minute chromosomal DNA in KP1089-resistant cells as well as overexpression of ABCC1 and ABCG2 on the protein level. KP1089 was further confirmed as a substrate of ABCC1 and ABCG2 but not of ABCB1 using a panel of ABC transporter-overexpressing cell models as well as ABC transporter inhibitors. Moreover, glutathione depletion strongly enhanced KP1089 activity, although no glutathione conjugate formation by glutathione-S-transferase was observed. Thus, a co-transport of KP1089 together with glutathione is suggested. Finally, a panel of thiosemicarbazone derivatives was tested on the new KP1089-resistant cell line. Notably, KP1089-resistant cells were not cross-resistant against thiosemicarbazones lacking terminal dimethylation (e.g. Triapine) which are less active than KP1089. This suggests that terminal dimethylation of thiosemicarbazones – linked with distinctly enhanced anticancer activity – leads to altered resistance profiles compared to classical thiosemicarbazones making this compound class of interest for further (pre)clinical evaluation. PMID:22426010

  17. Transition metal quinone-thiosemicarbazone complexes 3: Spectroscopic characterizations of spin-mixed iron (III) of naphthoquinone-thiosemicarbazones.

    PubMed

    Chikate, Rajeev C; Padhye, Subhash B

    2007-04-01

    An interesting series of iron (III) complexes with naphthoquinone-thiosemicarbazones are synthesized and physico-chemically characterized by elemental analysis, UV-vis, IR, EPR and magnetic susceptibility measurements. They possess a cationic octahedral [FeL2]+ species and a tetrahedral [FeCl4]- anion and exhibit unusual spin-mixed states involving high-spin and low-spin ferric centers as revealed from magnetic behavior with significant amount of exchange interactions mediated by intermolecular associations. The magnetic susceptibility data is fitted with S1=5/2 and S2=1/2 Heisengberg's exchange coupled model; H=-2JS1S2 and the magnetic exchange interactions are found to be of the order of -13.6 cm-1 indicating the moderate coupling between two paramagnetic centers present in different chemical and structural environment. The presence of spin-paired iron (III) cation having dxz2dxz2dxz1 ground state is revealed from the EPR spectra with three prominent peaks while the high-spin tetrahedral iron (III) anion exhibits characteristics g=4 signal whose intensity increases with lowering the temperature suggesting its influence on the magnetic properties of the complex molecule. FTIR measurements indicate tridentate ONS donor systems involving quinone/hydroxyl oxygen, imine/hydrazinic nitrogen and thione/thiol sulfur atoms as binding sites for naphthoquinone-thiosemicarbazones. PMID:16876470

  18. Spectral studies of copper(II) complexes of 6-(3-thienyl) pyridine-2-thiosemicarbazone

    SciTech Connect

    Mahjoub, Omima Abdalla; Farina, Yang

    2014-09-03

    Two novel copper(II) complexes [Cu(HL)Cl]Cl.H{sub 2}O (1) and [Cu(L)NO{sub 3}]Ðœ‡H{sub 2}O (2) of the three NNS donor thiosemicarbazone ligand 6-(3-thienyl) pyridine-2-thiosemicarbazone have been synthesized. The ligand and its copper(II) complexes were characterized by elemental analysis (C, H, N, and S), FT-IR, UV-visible, magnetic susceptibility and molar conductance. The thiosemicarbazone is present either as the thione form in complex 1 or as thiol form in complex 2 and is coordinated to copper(II) atom via the pyridine nitrogen atom, the azomethine nitrogen atom and the sulfur atom. The physicochemical and spectral data suggest square planar geometry for copper(II) atoms.

  19. Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: cellular iron chelation mediating cytotoxic activity.

    PubMed

    Opletalová, Veronika; Kalinowski, Danuta S; Vejsová, Marcela; Kunes, Jirí; Pour, Milan; Jampílek, Josef; Buchta, Vladimír; Richardson, Des R

    2008-09-01

    Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. The most effective compound identified in terms of both antifungal and antitumor activity was N, N-dimethyl-2-(1-pyrazin-2-ylethylidene)hydrazinecarbothioamide (5a). The mechanism of action of this and its related thiosemicarbazones was due, at least in part, to its ability to act as a tridentate ligand that binds metal ions. This was deduced from preparation of the related thiosemicarbazones [acetophenone thiosemicarbazone (6) and acetophenone N, N-dimethylthiosemicarbazone (7)] that do not possess a coordinating ring-N, which plays a vital role in metal ion chelation. Furthermore, 5a and several other thiosemicarbazones that showed high antiproliferative activity were demonstrated to have marked iron (Fe) chelation efficacy. In fact, these agents were highly effective at mobilizing (59)Fe from prelabeled SK-N-MC cells and preventing (59)Fe uptake from the serum Fe transport protein, transferrin. In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands. PMID:18698850

  20. EPR, mass, IR, electronic, and magnetic studies on copper(II) complexes of semicarbazones and thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Gupta, Lokesh Kumar

    2005-01-01

    Copper(II) complexes having the general composition Cu(L) 2X 2 [where L = isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC), and 4-aminoacetophenone thiosemicarbazone (LLD) and X = Cl -, 1/2SO 42-] have been synthesized. All the Cu(II) complexes reported here have been characterized by elemental analyses, molar conductance, magnetic moment susceptibility, EI mass, 1H NMR, IR, EPR, and electronic spectral studies. All the complexes were found to have magnetic moments corresponding to one unpaired electrons. The possible geometries of the complexes were assigned on the basis of EPR, electronic, and infrared spectral studies.

  1. Spectroscopic evaluation of manganese(II) complexes derived from semicarbazones and thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Gupta, Lokesh Kumar

    2005-09-01

    Manganese(II) complexes having the general composition Mn(L) 2X 2 [where L = isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC) and 4-aminoacetophenone thiosemicarbazone (LLD) and X = Cl -, 1/2SO 42-] have been synthesized. All the complexes were characterized by elemental analyses, molar conductance, magnetic moment susceptibility, EI-mass, 1H NMR, IR, EPR and electronic spectral studies. All the complexes show magnetic moments corresponding to five unpaired electrons. The possible geometries of the complexes were assigned on the basis of EPR, electronic and infrared spectral studies.

  2. Intermolecular interaction of thiosemicarbazone derivatives to solvents and a potential Aedes aegypti target

    NASA Astrophysics Data System (ADS)

    da Silva, João Bosco P.; Hallwass, Fernando; da Silva, Aluizio G.; Moreira, Diogo Rodrigo; Ramos, Mozart N.; Espíndola, José Wanderlan P.; de Oliveira, Ana Daura T.; Brondani, Dalci José; Leite, Ana Cristina L.; Merz, Kenneth M.

    2015-08-01

    DFT calculations were used to access information about structure, energy and electronic properties of series of phenyl- and phenoxymethyl-(thio)semicarbazone derivatives with demonstrated activity against the larvae of Aedes aegypti in stage L4. The way as the thiosemicarbazone derivatives can interact with solvents like DMSO and water were analyzed from the comparison between calculated and experimental 1H NMR chemical shifts. The evidences of thiosemicarbazone derivatives making H-bond interaction to solvent have provide us insights on how they can interact with a potential A. aegypti's biological target, the Sterol Carrier Protein-2.

  3. metal ion interactions of picoline-2-aldehyde thiosemicarbazone.

    PubMed

    Leggett, D J; McBryde, W A

    The reactions of picoline-2-aldehyde thiosemicarbazone (PATS) with silver, mercury, iron(II) and cobalt have been investigated in various environments. The compositions of the complexes have been investigated by continuous variation and molar ratio methods. Stability constants have been evaluated by means of SCOGS and a new program SQUAD. The formation constants, measured at 25 degrees and 0.10M ionic strength were as follows: Ag(PATS), logbeta(101) = 13.40; HgH(PATS), log beta(1110) = 23.6; HgH(2)(PATS)(2), log beta(1220) = 42.1; HgH(2)(PATS)(EDTA), log beta = 44.0; FeH(3)(PATS)(3), log beta(133) = 44.9; FeH(2)(PATS)(3), log beta(123) = 41.7; FeH(PATS)(3), log beta(113) = 38.4; Fe(PATS)(3), log beta(103) = 34.2. A tentative value for a cobalt complex is also suggested. A computer program, suitable for calculation of optimum conditions for a chemical analysis is also introduced and its use is illustrated for the silver-PATS-EDTA system.

  4. A novel series of thiosemicarbazone drugs: From synthesis to structure

    NASA Astrophysics Data System (ADS)

    Ebrahimi, Hossein Pasha; Hadi, Jabbar S.; Alsalim, Tahseen A.; Ghali, Thaer S.; Bolandnazar, Zeinab

    2015-02-01

    A new series of thiosemicarbazones (TSCs) and their 1,3,4-thiadiazolines (TDZs) containing acetamide group have been synthesized from thiosemicarbazide compounds by the reaction of TSCs with cyclic ketones as well as aromatic aldehydes. The structures of newly synthesized 1,3,4-thiadiazole derivatives obtained by heterocyclization of the TSCs with acetic anhydride were experimentally characterized by spectral methods using IR, 1H NMR, 13C NMR and mass spectroscopic methods. Furthermore, the structural, thermodynamic, and electronic properties of the studied compounds were also studied theoretically by performing Density Functional Theory (DFT) to access reliable results to the experimental values. The molecular geometry, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and Mulliken atomic charges of the studied compounds have been calculated at the B3LYP method and standard 6-31+G(d,p) basis set starting from optimized geometry. The theoretical 13C chemical shift results were also calculated using the gauge independent atomic orbital (GIAO) approach and their respective linear correlations were obtained.

  5. Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators.

    PubMed

    Akam, Eman A; Tomat, Elisa

    2016-08-17

    The implication of iron in the pathophysiology of colorectal cancer is documented at both the biochemical and epidemiological levels. Iron chelators are therefore useful molecular tools for the study and potential treatment of this type of cancer characterized by high incidence and mortality rates. We report a novel prochelation strategy that utilizes a disulfide redox switch to connect a thiosemicarbazone iron-binding unit with carbohydrate moieties targeting the increased expression of glucose transporters in colorectal cancer cells. We synthesized three glycoconjugates (GA2TC4, G6TC4, and M6TC4) with different connectivity and/or carbohydrate moieties, as well as an aglycone analog (ATC4). The sugar conjugates present increased solubility in neutral aqueous solutions, and the ester-linked conjugates M6TC4 and G6TC4 compete as effectively as d-glucose for transporter-mediated cellular uptake. The glycoconjugates show improved selectivity compared to the aglycone analog and are 6-11 times more toxic in Caco-2 colorectal adenocarcinoma cells than in normal CCD18-co colon fibroblasts. PMID:27471913

  6. Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.

    PubMed

    Espíndola, José Wanderlan Pontes; Cardoso, Marcos Veríssimo de Oliveira; Filho, Gevanio Bezerra de Oliveira; Oliveira E Silva, Dayane Albuquerque; Moreira, Diogo Rodrigo Magalhaes; Bastos, Tanira Matutino; Simone, Carlos Alberto de; Soares, Milena Botelho Pereira; Villela, Filipe Silva; Ferreira, Rafaela Salgado; Castro, Maria Carolina Accioly Brelaz de; Pereira, Valéria Rego Alves; Murta, Silvane Maria Fonseca; Sales Junior, Policarpo Ademar; Romanha, Alvaro José; Leite, Ana Cristina Lima

    2015-08-28

    The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones. PMID:26231082

  7. Thiosemicarbazone modification of 3-acetyl coumarin inhibits Aβ peptide aggregation and protect against Aβ-induced cytotoxicity.

    PubMed

    Ranade, Dnyanesh S; Bapat, Archika M; Ramteke, Shefali N; Joshi, Bimba N; Roussel, Pascal; Tomas, Alain; Deschamps, Patrick; Kulkarni, Prasad P

    2016-10-01

    Aggregation of amyloid β peptide (Aβ) is an important event in the progression of Alzheimer's disease. Therefore, among the available therapeutic approaches to fight with disease, inhibition of Aβ aggregation is widely studied and one of the promising approach for the development of treatments for Alzheimer's disease. Thiosemicarbazone compounds are known for their variety of biological activities. However, the potential of thiosemicarbazone compounds towards inhibition of Aβ peptide aggregation and the subsequent toxicity is little explored. Herein, we report synthesis and x-ray crystal structure of novel compound 3-acetyl coumarin thiosemicarbazone and its efficacy toward inhibition of Aβ(1-42) peptide aggregation. Our results indicate that 3-acetyl coumarin thiosemicarbazone inhibits Aβ(1-42) peptide aggregation up to 80% compared to the parent 3-acetyl coumarin which inhibits 52%. Further, 3-acetyl coumarin thiosemicarbazone provides neuroprotection against Aβ-induced cytotoxicity in SH-SY5Y cell line. These findings indicate that thiosemicarbazone modification renders 3-acetyl coumarin neuroprotective properties.

  8. The synthesis and antiparasitic activity of aryl- and ferrocenyl-derived thiosemicarbazone ruthenium(II)-arene complexes.

    PubMed

    Adams, Muneebah; Li, Yiqun; Khot, Heena; De Kock, Carmen; Smith, Peter J; Land, Kirkwood; Chibale, Kelly; Smith, Gregory S

    2013-04-01

    A series of aryl-functionalized and ferrocenyl monothiosemicarbazone compounds (L1-L4) were synthesized in moderate yields via a general Schiff-base condensation reaction. The thiosemicarbazone (TSC) ligands were reacted with the ruthenium dimer [Ru(Ar)(μ-Cl)Cl](2) (Ar = benzene; p-cymene) to yield a series of cationic mononuclear ruthenium(II)-arene thiosemicarbazone complexes of the general type [Ru(Cl)(TSC)(Ar)]Cl (1-8). The thiosemicarbazone ligands act as bidentate chelating ligands that coordinate to the ruthenium(ii) ion via the imine nitrogen and the thione sulfur atoms. The thiosemicarbazone ligands, as well as their metal complexes, were characterized by NMR, IR spectroscopy and ESI(+)-mass spectrometry. The molecular structure of the mononuclear ruthenium(II)-arene thiosemicarbazone complex (6) was determined by single-crystal X-ray diffraction analysis. The ruthenium(II)-arene thiosemicarbazone complexes were further evaluated for their in vitro antiparasitic activities against the Plasmodium falciparum chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains, as well as the G3 strain of Trichomonas vaginalis.

  9. Thiosemicarbazone modification of 3-acetyl coumarin inhibits Aβ peptide aggregation and protect against Aβ-induced cytotoxicity.

    PubMed

    Ranade, Dnyanesh S; Bapat, Archika M; Ramteke, Shefali N; Joshi, Bimba N; Roussel, Pascal; Tomas, Alain; Deschamps, Patrick; Kulkarni, Prasad P

    2016-10-01

    Aggregation of amyloid β peptide (Aβ) is an important event in the progression of Alzheimer's disease. Therefore, among the available therapeutic approaches to fight with disease, inhibition of Aβ aggregation is widely studied and one of the promising approach for the development of treatments for Alzheimer's disease. Thiosemicarbazone compounds are known for their variety of biological activities. However, the potential of thiosemicarbazone compounds towards inhibition of Aβ peptide aggregation and the subsequent toxicity is little explored. Herein, we report synthesis and x-ray crystal structure of novel compound 3-acetyl coumarin thiosemicarbazone and its efficacy toward inhibition of Aβ(1-42) peptide aggregation. Our results indicate that 3-acetyl coumarin thiosemicarbazone inhibits Aβ(1-42) peptide aggregation up to 80% compared to the parent 3-acetyl coumarin which inhibits 52%. Further, 3-acetyl coumarin thiosemicarbazone provides neuroprotection against Aβ-induced cytotoxicity in SH-SY5Y cell line. These findings indicate that thiosemicarbazone modification renders 3-acetyl coumarin neuroprotective properties. PMID:26232353

  10. Microwave-assisted synthesis of new N₁,N₄-substituted thiosemicarbazones.

    PubMed

    Reis, Camilla Moretto dos; Pereira, Danilo Sousa; Paiva, Rojane de Oliveira; Kneipp, Lucimar Ferreira; Echevarria, Aurea

    2011-01-01

    We present an efficient procedure for the synthesis of thirty-six N₁,N₄-substituted thiosemicarbazones, including twenty-five ones that are reported for the first time, using a microwave-assisted methodology for the reaction of thiosemicarbazide intermediates with aldehydes in the presence of glacial acetic acid in ethanol and under solvent free conditions. Overall reaction times (20-40 min when ethanol as solvent, and 3 min under solvent free conditions) were much shorter than with the traditional procedure (480 min); satisfactory yields and high-purity compounds were obtained. The thiosemicarbazide intermediates were obtained from alkyl or aryl isothiocyanates and hydrazine hydrate or phenyl hydrazine by stirring at room temperature for 60 min or by microwave irradiation for 30 min, with lower yields for the latter. The preliminary in vitro antifungal activity of thiosemicarbazones was evaluated against Aspergillus parasiticus and Candida albicans. PMID:22186954

  11. Spectroscopic and biological studies on newly synthesized nickel(II) complexes of semicarbazones and thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Gupta, Lokesh Kumar

    2005-12-01

    Nickel(II) complexes, having the general composition Ni(L) 2X 2, have been synthesized [where L: isopropyl methyl ketone semicarbazone (LLA), isopropyl methyl ketone thiosemicarbazone (LLB), 4-aminoacetophenone semicarbazone (LLC) and 4-aminoacetophenone thiosemicarbazone (LLD) and X = Cl -, 1/2SO 42-]. All the Ni(II) complexes reported here have been characterized by elemental analyses, magnetic moments, IR, electronic and mass spectral studies. All the complexes were found to have magnetic moments corresponding to two unpaired electrons. The possible geometries of the complexes were assigned on the basis of electronic and infrared spectral studies. Newly synthesized ligand and its nickel(II) complexes have been screened against different bacterial and fungal growth.

  12. Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents.

    PubMed

    Taşdemir, Demet; Karaküçük-İyidoğan, Ayşegül; Ulaşli, Mustafa; Taşkin-Tok, Tuğba; Oruç-Emre, Emİne Elçİn; Bayram, Hasan

    2015-02-01

    A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound exhibited the most potent activity (IC50 4.6 μM) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. PMID:25399965

  13. Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents.

    PubMed

    Taşdemir, Demet; Karaküçük-İyidoğan, Ayşegül; Ulaşli, Mustafa; Taşkin-Tok, Tuğba; Oruç-Emre, Emİne Elçİn; Bayram, Hasan

    2015-02-01

    A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound exhibited the most potent activity (IC50 4.6 μM) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents.

  14. Structural studies on acetophenone- and benzophenone-derived thiosemicarbazones and their zinc(II) complexes

    NASA Astrophysics Data System (ADS)

    Ferraz, Karina S. O.; Silva, Nayane F.; Da Silva, Jeferson G.; Speziali, Nivaldo L.; Mendes, Isolda C.; Beraldo, Heloisa

    2012-01-01

    In the present work N(3)- meta-chlorophenyl-(HAc3 mCl, 1) and N(3)- meta-fluorphenyl-(HAc3 mF, 2) acetophenone thiosemicarbazone, and N(3)- meta-chlorophenyl-(HBz3 mCl, 3) and N(3)- meta-fluorphenyl-(HBz3 mF, 4) benzophenone thiosemicarbazone were obtained, as well as their zinc(II) complexes [Zn(Ac3 mCl) 2] ( 5), [Zn(Ac3 mF) 2] ( 6), [Zn(Bz3 mCl) 2] ( 7) and [Zn(Bz3 mF) 2] ( 8). Upon re-crystallization in DMSO:acetone conversion of 8 into [Zn(Bz3 mF) 2]·(DMSO) ( 8a) occurred. The crystal structures of 2, 5 and 8a were determined.

  15. Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors.

    PubMed

    Hameed, Abdul; Khan, Khalid Mohammed; Zehra, Syeda Tazeen; Ahmed, Ramasa; Shafiq, Zahid; Bakht, Syeda Mahwish; Yaqub, Muhammad; Hussain, Mazhar; de la Vega de León, Antonio; Furtmann, Norbert; Bajorath, Jürgen; Shad, Hazoor Ahmad; Tahir, Muhammad Nawaz; Iqbal, Jamshed

    2015-08-01

    Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N-phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 ± 0.001 and 24.04 ± 0.14 μM compared to standard inhibitor, thiourea (IC50 = 21 ± 0.11 μM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones. PMID:26119990

  16. Synthesis and Antiproliferative Activity of Steroidal Thiosemicarbazone Platinum (Pt(II)) Complexes

    PubMed Central

    Huang, Yanmin; Kong, Erbin; Gan, Chunfang; Liu, Zhiping; Lin, Qifu; Cui, Jianguo

    2015-01-01

    Steroidal compounds exhibit particular physiological activities. In this paper, some steroidal thiosemicarbazones platinum (Pt(II)) complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide using estrone, chenodeoxycholic acid, and 7-deoxycholic acid as starting materials and complexation of steroidal thiosesemicarbazones with Pt(II). The complexes were characterized by IR, NMR, and MS, and their antiproliferative activities were evaluated. The results showed that some steroidal thiosemicarbazones platinum (Pt(II)) complexes displayed moderate cytotoxicity to HeLa and Bel-7404 cells. Thereinto, complex 6 showed an excellent inhibited selectivity to HeLa cells with an IC50 value of 9.2 μM and SI value of 21.7. At the same time, all compounds were almost inactive to HEK293T (normal kidney epithelial cells). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs. PMID:26635511

  17. Bis(thiosemicarbazones) as bifunctional chelators for the room temperature 64-copper labeling of peptides.

    PubMed

    Hueting, Rebekka; Christlieb, Martin; Dilworth, Jonathan R; García Garayoa, Elisa; Gouverneur, Véronique; Jones, Michael W; Maes, Veronique; Schibli, Roger; Sun, Xin; Tourwé, Dirk A

    2010-04-21

    A range of new carboxylate functionalised bis(thiosemicarbazone) ligands and their Cu(II) complexes have been prepared, fully characterised and radiolabeled in high yield with both (64)Cu and (99m)Tc. Conjugation to a bombesin derivative was achieved using standard solid phase synthetic methodologies and the (64)Cu-labeled conjugate was shown to have good tumour uptake in mice with xenografted PC-3 tumours.

  18. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease.

    PubMed

    Rogolino, Dominga; Bacchi, Alessia; De Luca, Laura; Rispoli, Gabriele; Sechi, Mario; Stevaert, Annelies; Naesens, Lieve; Carcelli, Mauro

    2015-10-01

    The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg²⁺ or Mn²⁺) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1-6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure-activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg²⁺, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors.

  19. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease.

    PubMed

    Rogolino, Dominga; Bacchi, Alessia; De Luca, Laura; Rispoli, Gabriele; Sechi, Mario; Stevaert, Annelies; Naesens, Lieve; Carcelli, Mauro

    2015-10-01

    The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg²⁺ or Mn²⁺) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1-6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure-activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg²⁺, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors. PMID:26323352

  20. Zinc(II)-Thiosemicarbazone Complexes Are Localized to the Lysosomal Compartment Where They Transmetallate with Copper Ions to Induce Cytotoxicity.

    PubMed

    Stacy, Alexandra E; Palanimuthu, Duraippandi; Bernhardt, Paul V; Kalinowski, Danuta S; Jansson, Patric J; Richardson, Des R

    2016-05-26

    As the di-2-pyridylketone thiosemicarbazone (DpT) and 2-acetylpyridine thiosemicarbazone (ApT) series show potent antitumor activity in vitro and in vivo, we synthesized their fluorescent zinc(II) complexes to assess their intracellular distribution. The Zn(II) complexes generally showed significantly greater cytotoxicity than the thiosemicarbazones alone in several tumor cell-types. Notably, specific structure-activity relationships demonstrated the importance of the di-2-pyridyl pharmacophore in their activity. Confocal fluorescence imaging and live cell microscopy showed that the Zn(II) complex of our lead compound, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which is scheduled to enter clinical trials, was localized to lysosomes. Under lysosomal conditions, the Zn(II) complexes were shown to transmetallate with copper ions, leading to redox-active copper complexes that induced lysosomal membrane permeabilization (LMP) and cytotoxicity. This is the first study to demonstrate direct lysosomal targeting of our novel Zn(II)-thiosemicarbazone complexes that mediate their activity via transmetalation with copper ions and LMP. PMID:27023111

  1. Synthesis, characterization and binding affinities of rhenium(I) thiosemicarbazone complexes for the estrogen receptor (α/β).

    PubMed

    Núñez-Montenegro, Ara; Carballo, Rosa; Vázquez-López, Ezequiel M

    2014-11-01

    The binding affinities towards estrogen receptors (ERs) α and β of a set of thiosemicarbazone ligands (HL(n)) and their rhenium(I) carbonyl complexes [ReX(HL(n))(CO)3] (X=Cl, Br) were determined by a competitive standard radiometric assay with [(3)H]-estradiol. The ability of the coordinated thiosemicarbazone ligands to undergo deprotonation and the lability of the ReX bond were used as a synthetic strategy to obtain [Re(hpy)(L(n))(CO)3] (hpy=3- or 4-hydroxypyridine). The inclusion of the additional hpy ligand endows the new thiosemicarbazonate complexes with an improved affinity towards the estrogen receptors and, consequently, the values of the inhibition constant (Ki) could be determined for some of them. In general, the values of Ki for both ER subtypes suggest an appreciable selectivity towards ERα.

  2. Strong effect of copper(II) coordination on antiproliferative activity of thiosemicarbazone-piperazine and thiosemicarbazone-morpholine hybrids.

    PubMed

    Bacher, Felix; Dömötör, Orsolya; Chugunova, Anastasia; Nagy, Nóra V; Filipović, Lana; Radulović, Siniša; Enyedy, Éva A; Arion, Vladimir B

    2015-05-21

    In this study, 2-formylpyridine thiosemicarbazones and three different heterocyclic pharmacophores were combined to prepare thiosemicarbazone–piperazine mPip-FTSC (HL1) and mPip-dm-FTSC (HL2), thiosemicarbazone–morpholine Morph-FTSC (HL3) and Morph-dm-FTSC (HL4), thiosemicarbazone–methylpyrrole-2-carboxylate hybrids mPyrr-FTSC (HL5) and mPyrr-dm-FTSC (HL6) as well as their copper(II) complexes [CuCl(mPipH-FTSC-H)]Cl (1 + H)Cl, [CuCl(mPipH-dm-FTSC-H)]Cl (2 + H)Cl, [CuCl(Morph-FTSC-H)] (3), [CuCl(Morph-dm-FTSC-H)] (4), [CuCl(mPyrr-FTSC-H)(H2O)] (5) and [CuCl(mPyrr-dm-FTSC-H)(H2O)] (6). The substances were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy (HL1–HL6), ESI mass spectrometry, IR and UV–vis spectroscopy and single crystal X-ray diffraction (1–5). All compounds were prepared in an effort to generate potential antitumor agents with an improved therapeutic index. In addition, the effect of structural alterations with organic hybrids on aqueous solubility and copper(II) coordination ability was investigated. Complexation of ligands HL2 and HL4 with copper(II) was studied in aqueous solution by pH-potentiometry, UV–vis spectrophotometry and EPR spectroscopy. Proton dissociation processes of HL2 and HL4 were also characterized in detail and microscopic constants for the Z/E isomers were determined. While the hybrids HL5, HL6 and their copper(II) complexes 5 and 6 proved to be insoluble in aqueous solution, precluding antiproliferative activity studies, the thiosemicarbazone–piperazine and thiosemicarbazone–morpholine hybrids HL1–HL4, as well as copper(II) complexes 1–4 were soluble in water enabling cytotoxicity assays. Interestingly, the metal-free hybrids showed very low or even a lack of cytotoxicity (IC50 values > 300 μM) in two human cancer cell lines HeLa (cervical carcinoma) and A549 (alveolar basal adenocarcinoma), whereas their copper(II) complexes were cytotoxic showing IC50 values from 25.5 to 65.1

  3. Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity.

    PubMed

    Dilović, Ivica; Rubcić, Mirta; Vrdoljak, Visnja; Kraljević Pavelić, Sandra; Kralj, Marijeta; Piantanida, Ivo; Cindrić, Marina

    2008-05-01

    The paper describes synthesis of several novel thiosemicarbazone derivatives. Furthermore, crystal and molecular structure of 4-diethylamino-salicylaldehyde 4-phenylthiosemicarbazone revealed planarity of conjugated aromatic system, which suggested the possibility of DNA binding by intercalation, especially for here studied naphthalene derivatives. However, here presented DNA binding studies excluded this mode of action. Physicochemical and structural properties of novel derivatives were compared with previously studied analogues, taken as reference compounds, revealing distinctive differences. In addition, novel thiosemicarbazone derivatives (1, 2 and 5-8) clearly display stronger antiproliferative activity on five tumor cell lines than the reference compounds 3 and 4, which supports their further investigation as potential antitumor agents.

  4. Synthesis, experimental and theoretical studies on its crystal structure and FT-IR spectrum of new thiosemicarbazone compound E-2-(4-isopropylbenzylidene)thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Khalaji, Aliakbar Dehno; Mehrani, Sepideh; Eigner, Vaclav; Dusek, Michal

    2013-09-01

    The title compound E-2-(4-isopropylbenzylidene)thiosemicarbazone (1) derived from the reaction of 4-isopropylbenzaldehyde and thiosemicarbazide in ethanol solution has been synthesized and characterized by elemental analyses, FT-IR and 1H NMR spectroscopy and single-crystal X-ray diffraction. Its optimized geometry together with the theoretical assignment of the vibrational frequencies of the title compound has been computed by using density functional theory (DFT) method. In the gas phase the four conformers of the title compound were found and it was found that the conformer Sn1 is the most stable one. The title compound crystallizes in the monoclinic space group P21/c with unit cell parameters: a = 14.4054(4), b = 5.6832(10), c = 14.4337(3) Å, β = 93.306(2)°, V = 1179.70(5) Å3 and Z = 4.

  5. Synthesis of 1H-indole-2,3-dione-3-thiosemicarbazone ribonucleosides as antibacterial agents.

    PubMed

    Kassab, Shaymaa E; Hegazy, Gehan H; Eid, Nahed M; Amin, Kamelia M; El-Gendy, Adel A

    2010-01-01

    A new isatin ribonucleoside (3) was synthesized in a good yield by trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed coupling reaction between the silylated nitrogenated base of 1H-Indole-2,3-dione (1) and 1,2,3,5-tetra-O-acetyl-beta-D-ribfuranose (2). Thiosemicarbazides 4a-e were utilized by the prepared ribonucleoside (3) to give new series of 1H-indole-2,3-dione-3-thiosemicarbazone ribonucleosides 5a-e. All compounds tested as antibacterial agents showed slight inhibitory activity against the selected bacterial strains.

  6. Novel heterocyclic thiosemicarbazones derivatives as colorimetric and “turn on” fluorescent sensors for fluoride anion sensing employing hydrogen bonding

    NASA Astrophysics Data System (ADS)

    Ashok Kumar, S. L.; Saravana Kumar, M.; Sreeja, P. B.; Sreekanth, A.

    2013-09-01

    Two novel heterocyclic thiosemicarbazone derivatives have been synthesized, and characterized, by means of spectroscopic and single crystal X-ray diffraction methods. Their chromophoric-fluorogenic response towards anions in competing solvent dimethyl sulfoxide (DMSO) was studied. The receptor shows selective recognition towards fluoride anion. The binding affinity of the receptors with fluoride anion was calculated using UV-visible and fluorescence spectroscopic techniques.

  7. Synthesis and Characterization of New Palladium(II) Thiosemicarbazone Complexes and Their Cytotoxic Activity against Various Human Tumor Cell Lines

    PubMed Central

    Hernández, Wilfredo; Paz, Juan; Carrasco, Fernando; Spodine, Evgenia; Manzur, Jorge; Sieler, Joachim; Blaurock, Steffen; Beyer, Lothar

    2013-01-01

    The palladium(II) bis-chelate complexes of the type [Pd(TSC1-5)2] (6–10), with their corresponding ligands 4-phenyl-1-(acetone)-thiosemicarbazone, HTSC1 (1), 4-phenyl-1-(2′-chloro-benzaldehyde)-thiosemicarbazone, HTSC2 (2), 4-phenyl-1-(3′-hydroxy-benzaldehyde)-thiosemicarbazone, HTSC3 (3), 4-phenyl-1-(2′-naphthaldehyde)-thiosemicarbazone, HTSC4 (4), and 4-phenyl-1-(1′-nitro-2′-naphthaldehyde)-thiosemicarbazone, HTSC5 (5), were synthesized and characterized by elemental analysis and spectroscopic techniques (IR and 1H- and 13C-NMR). The molecular structure of HTSC3, HTSC4, and [Pd(TSC1)2] (6) have been determined by single crystal X-ray crystallography. Complex 6 shows a square planar geometry with two deprotonated ligands coordinated to PdII through the azomethine nitrogen and thione sulfur atoms in a cis arrangement. The in vitro cytotoxic activity measurements indicate that the palladium(II) complexes (IC50 = 0.01–9.87 μM) exhibited higher antiproliferative activity than their free ligands (IC50 = 23.48–70.86 and >250 μM) against different types of human tumor cell lines. Among all the studied palladium(II) complexes, the [Pd(TSC3)2] (8) complex exhibited high antitumor activity on the DU145 prostate carcinoma and K562 chronic myelogenous leukemia cells, with low values of the inhibitory concentration (0.01 and 0.02 μM, resp.). PMID:24391528

  8. Generating nanoparticles containing a new 4-nitrobenzaldehyde thiosemicarbazone compound with antileishmanial activity.

    PubMed

    Britta, Elizandra Aparecida; da Silva, Cleuza Conceição; Rubira, Adley Forti; Nakamura, Celso Vataru; Borsali, Redouane

    2016-12-01

    Thiosemicarbazones are an important class of compounds that have been extensively studied in recent years, mainly because of their broad profile of pharmacological activity. A new 4-nitrobenzaldehyde thiosemicarbazone compound (BZTS) that was derived from S-limonene has been demonstrated to have significant antiprotozoan activity. However, the hydrophobic characteristic of BZTS limits its administration and results in low oral bioavailability. In the present study, we proposed the synthesis of nanoparticle-based block copolymers that can encapsulate BZTS, with morphological evaluation of the nanoparticle suspensions being performed by transmission and cryo-transmission electronic microscopy. The mean particle sizes of the nanoparticle suspensions were determined by static light and dynamic light scattering (SLS/DLS), and the hydrodynamic radius (Rh) was determined using the Stokes-Einstein equation. The zeta potential (ζ) and polydispersity index (PDI) were also determined. The entrapment encapsulation efficiency of the BZTS nanoparticles was measured by ultraviolet spectrophotometry. In vitro activity of BZTS nanoparticle suspensions against intracellular amastigotes of Leishmania amazonensis and cytotoxic activity were also evaluated. The results showed the production of spherical nanoparticles with varied sizes depending on the hydrophobic portion of the amphiphilic diblock copolymers used. Significant concentration-dependent inhibitory activity against intracellular amastigotes was observed, and low cytotoxic activity was demonstrated against macrophages. PMID:27612813

  9. Generating nanoparticles containing a new 4-nitrobenzaldehyde thiosemicarbazone compound with antileishmanial activity.

    PubMed

    Britta, Elizandra Aparecida; da Silva, Cleuza Conceição; Rubira, Adley Forti; Nakamura, Celso Vataru; Borsali, Redouane

    2016-12-01

    Thiosemicarbazones are an important class of compounds that have been extensively studied in recent years, mainly because of their broad profile of pharmacological activity. A new 4-nitrobenzaldehyde thiosemicarbazone compound (BZTS) that was derived from S-limonene has been demonstrated to have significant antiprotozoan activity. However, the hydrophobic characteristic of BZTS limits its administration and results in low oral bioavailability. In the present study, we proposed the synthesis of nanoparticle-based block copolymers that can encapsulate BZTS, with morphological evaluation of the nanoparticle suspensions being performed by transmission and cryo-transmission electronic microscopy. The mean particle sizes of the nanoparticle suspensions were determined by static light and dynamic light scattering (SLS/DLS), and the hydrodynamic radius (Rh) was determined using the Stokes-Einstein equation. The zeta potential (ζ) and polydispersity index (PDI) were also determined. The entrapment encapsulation efficiency of the BZTS nanoparticles was measured by ultraviolet spectrophotometry. In vitro activity of BZTS nanoparticle suspensions against intracellular amastigotes of Leishmania amazonensis and cytotoxic activity were also evaluated. The results showed the production of spherical nanoparticles with varied sizes depending on the hydrophobic portion of the amphiphilic diblock copolymers used. Significant concentration-dependent inhibitory activity against intracellular amastigotes was observed, and low cytotoxic activity was demonstrated against macrophages.

  10. Lanthanum(III) and praseodymium(III) complexes with isatin thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Rai, Anita; Sengupta, Soumitra K.; Pandey, Om P.

    2005-09-01

    Ten new lanthanum(III) and praseodymium(III) complexes of the general formula Na[La(L) 2H 2O] (Ln = La(III) or Pr(III); LH 2 = thiosemicarbazones) derived from the condensation of isatin with 4-phenyl thiosemicarbazide, 4-(4-chlorophenyl) thiosemicarbazide, 4-(2-nitrophenyl) thiosemicarbazide, 4-(2-bromophenyl) thiosemicarbazide and 4-(2-methylphenyl) thiosemicarbazide, have been synthesized in methanol in presence of sodium hydroxide. The XRD spectra of the complexes were monitored to verify complex formation. The complexes have also been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H and 13C NMR spectral studies. Thermal studies of these complexes have been carried out in the temperature range 25-800 °C using TG, DTG and DTA techniques. All these complexes decompose gradually with the formation of Ln 2O 3 as the end product. The Judd-ofelt intensity parameter, oscillator strength, transition probability, stimulated emission cross section for different transitions of Pr 3+ for 4-phenyl thiosemicarbazones have been calculated.

  11. Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules

    NASA Astrophysics Data System (ADS)

    Beckford, Floyd A.; Brock, Alyssa; Gonzalez-Sarrías, Antonio; Seeram, Navindra P.

    2016-10-01

    We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 to 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 × 104 M-1 to 3.25 × 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104-105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA.

  12. Lanthanum(III) and praseodymium(III) complexes with isatin thiosemicarbazones.

    PubMed

    Rai, Anita; Sengupta, Soumitra K; Pandey, Om P

    2005-09-01

    Ten new lanthanum(III) and praseodymium(III) complexes of the general formula Na[La(L)2H2O] (Ln=La(III) or Pr(III); LH2=thiosemicarbazones) derived from the condensation of isatin with 4-phenyl thiosemicarbazide, 4-(4-chlorophenyl) thiosemicarbazide, 4-(2-nitrophenyl) thiosemicarbazide, 4-(2-bromophenyl) thiosemicarbazide and 4-(2-methylphenyl) thiosemicarbazide, have been synthesized in methanol in presence of sodium hydroxide. The XRD spectra of the complexes were monitored to verify complex formation. The complexes have also been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H and 13C NMR spectral studies. Thermal studies of these complexes have been carried out in the temperature range 25-800 degrees C using TG, DTG and DTA techniques. All these complexes decompose gradually with the formation of Ln2O3 as the end product. The Judd-ofelt intensity parameter, oscillator strength, transition probability, stimulated emission cross section for different transitions of Pr3+ for 4-phenyl thiosemicarbazones have been calculated.

  13. Vanadium(IV/V) complexes of Triapine and related thiosemicarbazones: Synthesis, solution equilibrium and bioactivity.

    PubMed

    Kowol, Christian R; Nagy, Nóra V; Jakusch, Tamás; Roller, Alexander; Heffeter, Petra; Keppler, Bernhard K; Enyedy, Éva A

    2015-11-01

    The stoichiometry and thermodynamic stability of vanadium(IV/V) complexes of Triapine and two related α(N)-heterocyclic thiosemicarbazones (TSCs) with potential antitumor activity have been determined by pH-potentiometry, EPR and (51)V NMR spectroscopy in 30% (w/w) dimethyl sulfoxide/water solvent mixtures. In all cases, mono-ligand complexes in different protonation states were identified. Dimethylation of the terminal amino group resulted in the formation of vanadium(IV/V) complexes with considerably higher stability. Three of the most stable complexes were also synthesized in solid state and comprehensively characterized. The biological evaluation of the synthesized vanadium complexes in comparison to the metal-free ligands in different human cancer cell lines revealed only minimal influence of the metal ion. Thus, in addition the coordination ability of salicylaldehyde thiosemicarbazone (STSC) to vanadium(IV/V) ions was investigated. The exchange of the pyridine nitrogen of the α(N)-heterocyclic TSCs to a phenolate oxygen in STSC significantly increased the stability of the complexes in solution. Finally, this also resulted in increased cytotoxicity activity of a vanadium(V) complex of STSC compared to the metal-free ligand.

  14. Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules

    NASA Astrophysics Data System (ADS)

    Beckford, Floyd A.; Brock, Alyssa; Gonzalez-Sarrías, Antonio; Seeram, Navindra P.

    2016-10-01

    We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 to 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 × 104 M-1 to 3.25 × 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104-105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA.

  15. Identification of differential anti-neoplastic activity of copper bis(thiosemicarbazones) that is mediated by intracellular reactive oxygen species generation and lysosomal membrane permeabilization.

    PubMed

    Stefani, Christian; Al-Eisawi, Zaynab; Jansson, Patric J; Kalinowski, Danuta S; Richardson, Des R

    2015-11-01

    Bis(thiosemicarbazones) and their copper (Cu) complexes possess unique anti-neoplastic properties. However, their mechanism of action remains unclear. We examined the structure-activity relationships of twelve bis(thiosemicarbazones) to elucidate factors regarding their anti-cancer efficacy. Importantly, the alkyl substitutions at the diimine position of the ligand backbone resulted in two distinct groups, namely, unsubstituted/monosubstituted and disubstituted bis(thiosemicarbazones). This alkyl substitution pattern governed their: (1) Cu(II/I) redox potentials; (2) ability to induce cellular (64)Cu release; (3) lipophilicity; and (4) anti-proliferative activity. The potent anti-cancer Cu complex of the unsubstituted bis(thiosemicarbazone) analog, glyoxal bis(4-methyl-3-thiosemicarbazone) (GTSM), generated intracellular reactive oxygen species (ROS), which was attenuated by Cu sequestration by a non-toxic Cu chelator, tetrathiomolybdate, and the anti-oxidant, N-acetyl-l-cysteine. Fluorescence microscopy suggested that the anti-cancer activity of Cu(GTSM) was due, in part, to lysosomal membrane permeabilization (LMP). For the first time, this investigation highlights the role of ROS and LMP in the anti-cancer activity of bis(thiosemicarbazones).

  16. Nickel(II) complexes containing thiosemicarbazone and triphenylphosphine: Synthesis, spectroscopy, crystallography and catalytic activity

    NASA Astrophysics Data System (ADS)

    Priyarega, S.; Kalaivani, P.; Prabhakaran, R.; Hashimoto, T.; Endo, A.; Natarajan, K.

    2011-09-01

    Four new Ni(II) complexes of the general formula [Ni(PPh 3)(L)] (L = dibasic tridentate ligand derived from 4-diethylamino-salicylaldehyde and thiosemicarbazide or 4-N-substituted thiosemicarbazide) have been reported. The new complexes have been synthesized and characterized by analytical and spectroscopic (IR, electronic, 1H NMR and 31P NMR) techniques. Molecular structure of one of the complexes has been determined by X-ray crystallography. The complex, [Ni(PPh 3)(L4)] (H 2L4 = thiosemicarbazone prepared from 4-diethylamino-salicylaldehyde and 4-phenylthiosemicarbazide) crystallized in monoclinic space group with two molecules per unit cell and has the dimensions of a = 13.232(6) Å, b = 10.181(5) Å, c = 13.574(7) Å, α = 90°, β = 98.483(2)° and γ = 90°. Catalytic activity of the complexes has been explored for aryl-aryl coupling reaction.

  17. Synthesis of isatin thiosemicarbazones derivatives: In vitro anti-cancer, DNA binding and cleavage activities

    NASA Astrophysics Data System (ADS)

    Ali, Amna Qasem; Teoh, Siang Guan; Salhin, Abdussalam; Eltayeb, Naser Eltaher; Khadeer Ahamed, Mohamed B.; Majid, A. M. S. Abdul

    New derivatives of thiosemicarbazone Schiff base with isatin moiety were synthesized L1-L6. The structures of these compounds were characterized based on the spectroscopic techniques. Compound L6 was further characterized by XRD single crystal. The interaction of these compounds with calf thymus (CT-DNA) exhibited high intrinsic binding constant (kb = 5.03-33.00 × 105 M-1) for L1-L3 and L5 and (6.14-9.47 × 104 M-1) for L4 and L6 which reflect intercalative activity of these compounds toward CT-DNA. This result was also confirmed by the viscosity data. The electrophoresis studies reveal the higher cleavage activity of L1-L3 than L4-L6. The in vitro anti-proliferative activity of these compounds against human colon cancer cell line (HCT 116) revealed that the synthesized compounds (L3, L6 and L2) exhibited good anticancer potency.

  18. Novel aldehyde and thiosemicarbazone derivatives: Synthesis, spectroscopic characterization, structural studies and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Karakurt, Tuncay; Tahtaci, Hakan; Subasi, Nuriye Tuna; Er, Mustafa; Ağar, Erbil

    2016-12-01

    In this study our purpose is that, synthesis and characterization of compounds containing the aldehyde and thiosemicarbazone groups and comparison of the theoretical results with the experimental results. The structures of all synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, elemental analyses techniques. The structure of compound (4) (C9H8N4O2S) was also elucidated by X-ray diffraction analysis. In addition, the theoretical IR spectrum, 1H NMR and 13C NMR chemical shift values, frontier molecular orbital values (FMO) of these molecules were analyzed by using Becke-3- Lee-Yang-Parr (B3LYP) method with LanL2DZ basis set. Finally, molecular docking studies were performed on synthesized compounds using the 4DKI beta-lactam protein structure to determine the potential binding mode of inhibitors.

  19. Copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals.

    PubMed

    Paterson, Brett M; Donnelly, Paul S

    2011-05-01

    The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating biological activity. This critical review presents an historical perspective of their progression from potential chemotherapeutics through to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references).

  20. Vibrational spectroscopic studies and computational study of ethyl methyl ketone thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Anoop, M. R.; Binil, P. S.; Suma, S.; Sudarsanakumar, M. R.; Y, Sheena Mary.; Varghese, Hema Tresa; Panicker, C. Yohannan

    2010-04-01

    FT-IR and FT-Raman spectra of ethyl methyl ketone thiosemicarbazone were recorded and analyzed. The crystal structure is also described. The vibrational wavenumbers were computed using HF/6-31G(d) and B3LYP/6-31G(d) basis sets and are assigned with the aid of MOLEKEL program. The first hyperpolarizability, infrared intensities and Raman activities are also reported. The calculated first hyperpolarizability is comparable with the reported values of similar derivatives and is an attractive molecule for future applications in non-linear optics. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated values. The red shift of the NH stretching wavenumber in the infrared spectrum compared to the computed wavenumber indicates the weakening of the N-H bond resulting in proton transfer to the neighbouring sulfur atom.

  1. Copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals.

    PubMed

    Paterson, Brett M; Donnelly, Paul S

    2011-05-01

    The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating biological activity. This critical review presents an historical perspective of their progression from potential chemotherapeutics through to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references). PMID:21409228

  2. Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites.

    PubMed

    Fernández, Mariana; Arce, Esteban Rodríguez; Sarniguet, Cynthia; Morais, Tânia S; Tomaz, Ana Isabel; Azar, Claudio Olea; Figueroa, Roberto; Diego Maya, J; Medeiros, Andrea; Comini, Marcelo; Helena Garcia, M; Otero, Lucía; Gambino, Dinorah

    2015-12-01

    Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule.

  3. Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs.

    PubMed

    Rettondin, Andressa R; Carneiro, Zumira A; Gonçalves, Ana C R; Ferreira, Vanessa F; Oliveira, Carolina G; Lima, Angélica N; Oliveira, Ronaldo J; de Albuquerque, Sérgio; Deflon, Victor M; Maia, Pedro I S

    2016-09-14

    Tridentate thiosemicarbazone ligands with an ONS donor set, H2L(R) (R = Me and Et) were prepared by reactions of 1-phenyl-1,3-butanedione with 4-R-3-thiosemicarbazides. H2L(R) reacts with Na[AuCl4]·2H2O in MeOH in a 1:1 M ratio under formation of green gold(III) complexes of composition [AuCl(L(R))]. These compounds represent the first examples of gold(III) complexes with ONS chelate-bonded thiosemicarbazones. The in vitro anti-Trypanosoma cruzi activity against both trypomastigote and amastigote forms (IC50try/ama) of CL Brener strains as well as the cytotoxicity against LLC-MK2 cells of the free ligands and complexes was evaluated. The complex [AuCl(L(Me))] was found to be more active and more selective than its precursor ligand and the standard drug benznidazole with a SItry/ama value higher than 200, being considered as a lead candidate for Chagas disease treatment. Moreover the in vitro activity against the replicative amastigote form (IC50ama) of T. cruzi was additionally investigated revealing that [AuCl(L(Me))] was also more potent than benznidazole still with a similar selectivity index. Finally, docking studies showed that free ligands and complexes interact with the same residues of the parasite protease cruzain but with different intensities, suggesting that this protease could be a possible target for the trypanocidal action of the obtained compounds. PMID:27191616

  4. Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics.

    PubMed

    Park, Kyung Chan; Fouani, Leyla; Jansson, Patric J; Wooi, Danson; Sahni, Sumit; Lane, Darius J R; Palanimuthu, Duraippandi; Lok, Hiu Chuen; Kovačević, Zaklina; Huang, Michael L H; Kalinowski, Danuta S; Richardson, Des R

    2016-09-01

    Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.

  5. Copper and conquer: copper complexes of di-2-pyridylketone thiosemicarbazones as novel anti-cancer therapeutics.

    PubMed

    Park, Kyung Chan; Fouani, Leyla; Jansson, Patric J; Wooi, Danson; Sahni, Sumit; Lane, Darius J R; Palanimuthu, Duraippandi; Lok, Hiu Chuen; Kovačević, Zaklina; Huang, Michael L H; Kalinowski, Danuta S; Richardson, Des R

    2016-09-01

    Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed. PMID:27334916

  6. Novel heterocyclic thiosemicarbazones derivatives as colorimetric and "turn on" fluorescent sensors for fluoride anion sensing employing hydrogen bonding.

    PubMed

    Ashok Kumar, S L; Saravana Kumar, M; Sreeja, P B; Sreekanth, A

    2013-09-01

    Two novel heterocyclic thiosemicarbazone derivatives have been synthesized, and characterized, by means of spectroscopic and single crystal X-ray diffraction methods. Their chromophoric-fluorogenic response towards anions in competing solvent dimethyl sulfoxide (DMSO) was studied. The receptor shows selective recognition towards fluoride anion. The binding affinity of the receptors with fluoride anion was calculated using UV-visible and fluorescence spectroscopic techniques. PMID:23714188

  7. Preparation and Biodistribution Studies of a Radiogallium-Acetylacetonate Bis (Thiosemicarbazone) Complex in Tumor-Bearing Rodents

    PubMed Central

    Jalilian, Amir Reza; Yousefnia, Hassan; Shafaii, Kamaleddin; Novinrouz, Aytak; Rajamand, Amir Abbas

    2012-01-01

    Various radiometal complexes have been developed for tumor imaging, especially Ga-68 tracer. In the present study, the development of a radiogallium bis-thiosemicarbazone complex has been reported. [67Ga] acetylacetonate bis(thiosemicarbazone) complex ([67Ga] AATS) was prepared starting [67Ga]Gallium acetate and freshly prepared acetylacetonate bis (thiosemicarbazone) (AATS) in 30 min at 90°C. The partition co-efficient and the stability of the tracer were determined in final solution (25°C) and the presence of human serum (37°C) up to 24 h. The biodistribution of the labeled compound in wild-type and fibrosarcoma-bearing rodents were determined up to 72 h. The radiolabled Ga complex was prepared in high radiochemical purity (> 97%, HPLC) followed by initial biodistribution data with the significant tumor accumulation of the tracer in 2 h which is far higher than free Ga-67 cation while the compound wash-out is significantly faster. Above-mentioned pharmacokinetic properties suggest an interesting radiogallium complex while prepared by the PET Ga radioisotope, 68Ga, in accordance with the physical half life, for use in fibrosarcoma tumors, and possibly other malignancies. PMID:24250475

  8. Copper(II) complexes with 2-pyridineformamide-derived thiosemicarbazones: Spectral studies and toxicity against Artemia salina

    NASA Astrophysics Data System (ADS)

    Ferraz, Karina O.; Wardell, Solange M. S. V.; Wardell, James L.; Louro, Sonia R. W.; Beraldo, Heloisa

    2009-07-01

    The copper(II) complexes [Cu(H2Am4DH)Cl 2] ( 1), [Cu(H2Am4Me)Cl 2] ( 2), [Cu(H2Am4Et)Cl 2] ( 3) and [Cu(2Am4Ph)Cl] ( 4) with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives were studied by means of infrared and EPR spectral techniques. The crystal structure of 4 was determined. The studied compounds proved to be toxic to Artemia salina, suggesting that they could present cytotoxic activity against solid tumors. Among the free thiosemicarbazones H2Am4Ph presented higher toxicity than all other compounds, which showed comparable effects. In the case of complexes 2 and 3 toxicity is probably attributable to the complex as an entity or to a synergistic effect involving the thiosemicarbazone and copper. H2Am4Ph and complexes 2 and 3 revealed to be the most promising compounds as potential antineoplasic agents.

  9. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

    PubMed Central

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4’-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  10. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound.

    PubMed

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4'-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  11. Synthesis and biological evaluation of substituted 2-benzoylpyridine thiosemicarbazones: novel structure-activity relationships underpinning their anti-proliferative and chelation efficacy.

    PubMed

    Lukmantara, Adeline Y; Kalinowski, Danuta S; Kumar, Naresh; Richardson, Des R

    2013-02-15

    The 2-benzoylpyridine thiosemicarbazone (BpT) chelators demonstrate potent anti-proliferative effects against tumor cells. To understand their structure-activity relationships, BpT analogues incorporating electron-donating substituents on the pyridine and phenyl rings of the BpT scaffold were designed and represent the first attempts to modify the pyridine ring of these thiosemicarbazones. Eight analogues showed significantly (p <0.001) greater anti-proliferative activity than the 'gold-standard' chelator, desferrioxamine. Structure-activity analysis revealed that mono- or di-methoxy substitution at the phenyl ring resulted in lower anti-proliferative activity, while methoxy substitutions at the phenyl ring enhanced iron chelation efficacy. These important findings facilitate the design of thiosemicarbazones with greater anti-tumor activity.

  12. Structural and biological evaluation of some metal complexes of vanillin-4N-(2-pyridyl) thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Yousef, T. A.; Abu El-Reash, G. M.; Al-Jahdali, M.; El-Rakhawy, El-Bastawesy R.

    2013-12-01

    The synthesis and characterization of Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II) and U(VI)O2 complexes of vanillin-4N-(2-pyridyl) thiosemicarbazone (H2PVT) are reported. Theoretical calculations have been performed to obtain IR spectra of ligand and its complexes using AM1, Zindo/1, MM+ and PM3, methods. The Schiff base and its metal complexes have been screened for antibacterial Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis and Staphylococcus saprophyticus. H2VPT shows no apparent digestion effect on the egg albumin while Mn(II), Hg(II) and Cu(II) complexes exhibited a considerable digestion effect following the order Cu(II) > Mn(II) > Hg(II). Moreover, Ni(II) and Co(II) complexes revealed strong digestion effect. Fe(II), Mn(II), Cu(II), Zn(II) and Ni(II) acted as metal co- SOD enzyme factors, which are located in different compartments of the cell.

  13. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents.

    PubMed

    Altıntop, Mehlika Dilek; Atlı, Özlem; Ilgın, Sinem; Demirel, Rasime; Özdemir, Ahmet; Kaplancıklı, Zafer Asım

    2016-01-27

    New thiosemicarbazone derivatives (1-10) were obtained via the reaction of 4-(naphthalen-1-yl)thiosemicarbazide with fluoro-substituted aromatic aldehydes. The synthesized compounds were evaluated for their in vitro antifungal effects against pathogenic yeasts and molds using broth microdilution assay. Ames and umuC assays were carried out to determine the genotoxicity of the most effective antifungal derivatives. Furthermore, all compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using XTT test. Among these derivatives, 4-(naphthalen-1-yl)-1-(2,3-difluorobenzylidene)thiosemicarbazide (1) and 4-(naphthalen-1-yl)-1-(2,5-difluorobenzylidene)thiosemicarbazide (3) can be identified as the most promising antifungal derivatives due to their notable inhibitory effects on Candida species and no cytotoxicity against NIH/3T3 mouse embryonic fibroblast cell line. According to Ames and umuC assays, compounds 1 and 3 were classified as non-mutagenic compounds. On the other hand, 4-(naphthalen-1-yl)-1-(2,4-difluorobenzylidene)thiosemicarbazide (2) can be considered as the most promising anticancer agent against A549 cell line owing to its notable inhibitory effect on A549 cells with an IC50 value of 31.25 μg/mL when compared with cisplatin (IC50 = 16.28 μg/mL) and no cytotoxicity against NIH/3T3 cells.

  14. Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators

    PubMed Central

    Akam, Eman A.; Chang, Tsuhen M.; Astashkin, Andrei V.

    2014-01-01

    Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is activated for iron coordination following reduction to the thiolate chelator. In glutathione redox buffer, this reduction event occurs at physiological concentrations and half-cell potentials. Consistent with concurrent reduction and activation, higher intracellular thiol concentrations increase cell susceptibility to prochelator toxicity in cultured cancer cells. The reduction of the disulfide switch and intracellular iron chelation are confirmed in cell-based assays using calcein as a fluorescent probe for paramagnetic ions. The resulting low-spin Fe(III) complex is identified in intact Jurkat cells by EPR spectroscopy measurements, which also document a decreased concentration of active ribonucleotide reductase following exposure to the prochelator. Cell viability and fluorescence-based assays show that the iron complex presents low cytotoxicity and does not participate in intracellular redox chemistry, indicating that this antiproliferative chelation strategy does not rely on the generation of reactive oxygen species. PMID:25100578

  15. Spectroscopic analysis, AIM, NLO and VCD investigations of acetaldehyde thiosemicarbazone using quantum mechanical simulations

    NASA Astrophysics Data System (ADS)

    Moorthy, N.; Prabakar, P. C. Jobe; Ramalingam, S.; Govindarajan, M.; Gnanamuthu, S. Joshua; Pandian, G. V.

    2016-08-01

    The prepared Acetaldehyde thiosemicarbazone (ATSC) have been investigated by both the experimental and theoretical methods; through this work, the essentiality of elucidation of molecular fragments source linear and non-linear optical properties was explored. The stability of the structure and entire calculations have been performed on HF and B3LYP methods with 6-311++G(d,p) level of basis set. The Mulliken charge profile, electronic, optical and hyper polarizability analyses have been carried out in order to evaluate nonlinear optical (NLO) performance of the present compound. The exact optical location of the ATSC was determined by executing UV-Visible calculations on TDSCF method. The existence of the molecular group for the inducement and tuning of NLO properties were thoroughly investigated by performing fundamental vibrational investigation. The optical energy transformation among frontier molecular levels has been described in UV-Visible region. The Gibbs energy coefficient of thermodynamic functions was monitored in different temperature and it was found constant irrespective of temperatures. The appearance of different chemical environment of H and C was monitored from the 1H and 13C NMR spectra. The vibrational optical polarization characteristics with respect to molecular composition in the compound have been studied by VCD spectrum. The bond critical point, Laplacian of electron density, electron kinetic energy density and total electron energy density have calculated and analysed using AIM study.

  16. Benzaldehyde Thiosemicarbazone Derived from Limonene Complexed with Copper Induced Mitochondrial Dysfunction in Leishmania amazonensis

    PubMed Central

    Britta, Elizandra Aparecida; Barbosa Silva, Ana Paula; Ueda-Nakamura, Tânia; Dias-Filho, Benedito Prado; Silva, Cleuza Conceição; Sernaglia, Rosana Lázara; Nakamura, Celso Vataru

    2012-01-01

    Background Leishmaniasis is a major health problem that affects more than 12 million people. Treatment presents several problems, including high toxicity and many adverse effects, leading to the discontinuation of treatment and emergence of resistant strains. Methodology/Principal Findings We evaluated the in vitro antileishmanial activity of benzaldehyde thiosemicarbazone derived from limonene complexed with copper, termed BenzCo, against Leishmania amazonensis. BenzCo inhibited the growth of the promastigote and axenic amastigote forms, with IC50 concentrations of 3.8 and 9.5 µM, respectively, with 72 h of incubation. Intracellular amastigotes were inhibited by the compound, with an IC50 of 10.7 µM. BenzCo altered the shape, size, and ultrastructure of the parasites. Mitochondrial membrane depolarization was observed in protozoa treated with BenzCo but caused no alterations in the plasma membrane. Additionally, BenzCo induced lipoperoxidation and the production of mitochondrial superoxide anion radicals in promastigotes and axenic amastigotes of Leishmania amazonensis. Conclusion/Significance Our studies indicated that the antileishmania activity of BenzCo might be associated with mitochondrial dysfunction and oxidative damage, leading to parasite death. PMID:22870222

  17. Study on the Interaction between Isatin-β-Thiosemicarbazone and Calf Thymus DNA by Spectroscopic Techniques

    PubMed Central

    Pakravan, Parvaneh; Masoudian, Shahla

    2015-01-01

    The interaction between isatin-β-thiosemicarbazone (IBT) and calf thymus DNA (CT-DNA) was investigated in physiological buffer (pH 7.4) using Neutral Red (NR) dye as a spectral probe by UV–Vis absorption and fluorescence spectroscopy, as well as viscosity measurements. The IBT is stabilized by intercalation in the DNA (K [IBT –DNA] = 1.03×105 M−1), and displaces the NR dye from the NR–DNA complex. The binding constants Kf and number of binding sites (n≈1) of IBT with DNA were obtained by fluorescence quenching method at different temperatures. Furthermore, the enthalpy and entropy of the reaction between IBT and CT-DNA showed that the reaction is enthalpy-favored and entropy-disfavored. The changes in the base stacking of CT-DNA upon the binding of IBT are reflected in the circular dichroic (CD) spectral studies. The viscosity increase of CT-DNA solution is another evidence to indicate that, IBT is able to be intercalated in the DNA base pairs. PMID:25561917

  18. The binding of β-d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors.

    PubMed

    Alexacou, Kyra-Melinda; Tenchiu Deleanu, Alia-Cristina; Chrysina, Evangelia D; Charavgi, Maria-Despoina; Kostas, Ioannis D; Zographos, Spyros E; Oikonomakos, Nikos G; Leonidas, Demetres D

    2010-11-15

    Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(β-d-glucopyranosyl)thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to α-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3μM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23Å resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as α-d-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the β-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the β-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.

  19. Synthesis and cytotoxic activity of N-substituted thiosemicarbazones of 3-(3,4-methylenedioxy)phenylpropanal.

    PubMed

    Joselice e Silva, M; Alves, A J; Do Nascimento, S C

    1998-03-01

    Five new N-substituted thiosemicarbazones of 3-(3,4-methylenedioxy)phenylpropanal were synthesized. Safrole, a natural product obtained from sassafras oil (Ocotea pretiosa), was oxidized to alcohol using BH3-THF and H2O2, followed by oxidation to aldehyde using pyridinium dichromate (PDC) and condensation with five N-substituted derivatives of thiosemicarbazide. Tests were performed to evaluate the cytotoxic activity with continuous chain KB cells (epidermoide carcinoma of the floor of the mouth). Compounds 5 and 6 showed IC50 values of 1.5 and 4.6 micrograms/ml, respectively.

  20. Inhibitory effect of synthetic aromatic heterocycle thiosemicarbazone derivatives on mushroom tyrosinase: Insights from fluorescence, (1)H NMR titration and molecular docking studies.

    PubMed

    Xie, Juan; Dong, Huanhuan; Yu, Yanying; Cao, Shuwen

    2016-01-01

    Three structurally similar aromatic heterocyclic compounds 2-thiophenecarboxaldehyde (a), 2-furaldehyde (b), 2-pyrrolecarboxaldehyde (c) were chosen and a series of their thiosemicarbazone derivatives(1a-3a, 1b-3b and 1c-3c) were synthesized to evaluate their biological activities as mushroom tyrosinase inhibitors. The inhibitory effects of these compounds on tyrosinase were investigated by using spectrofluorimetry, (1)H NMR titration and molecular docking techniques. From the results of fluorescence spectrum and (1)H NMR titration, it was found that forming complexes between the sulfur atom from thiourea and copper ion of enzyme center may play a key role for inhibition activity. Moreover, investigation of (1)H NMR spectra further revealed that formation of hydrogen bond between inhibitor and enzyme may be helpful to above complexes formation. The results were well coincident with the suggestion of molecular docking and obviously showed that 2-thiophone N(4)-thiosemicarbazone (1a), 2-furfuran N(4)-thiosemicarbazone (1b) and 2-pyrrole N(4)-thiosemicarbazone (1c) are potential inhibitors which deserves further investigation. PMID:26213029

  1. Inhibitory effect of synthetic aromatic heterocycle thiosemicarbazone derivatives on mushroom tyrosinase: Insights from fluorescence, (1)H NMR titration and molecular docking studies.

    PubMed

    Xie, Juan; Dong, Huanhuan; Yu, Yanying; Cao, Shuwen

    2016-01-01

    Three structurally similar aromatic heterocyclic compounds 2-thiophenecarboxaldehyde (a), 2-furaldehyde (b), 2-pyrrolecarboxaldehyde (c) were chosen and a series of their thiosemicarbazone derivatives(1a-3a, 1b-3b and 1c-3c) were synthesized to evaluate their biological activities as mushroom tyrosinase inhibitors. The inhibitory effects of these compounds on tyrosinase were investigated by using spectrofluorimetry, (1)H NMR titration and molecular docking techniques. From the results of fluorescence spectrum and (1)H NMR titration, it was found that forming complexes between the sulfur atom from thiourea and copper ion of enzyme center may play a key role for inhibition activity. Moreover, investigation of (1)H NMR spectra further revealed that formation of hydrogen bond between inhibitor and enzyme may be helpful to above complexes formation. The results were well coincident with the suggestion of molecular docking and obviously showed that 2-thiophone N(4)-thiosemicarbazone (1a), 2-furfuran N(4)-thiosemicarbazone (1b) and 2-pyrrole N(4)-thiosemicarbazone (1c) are potential inhibitors which deserves further investigation.

  2. Effects of terminal dimethylation and metal coordination of proline-2-formylpyridine thiosemicarbazone hybrids on lipophilicity, antiproliferative activity, and hR2 RNR inhibition.

    PubMed

    Bacher, Felix; Dömötör, Orsolya; Kaltenbrunner, Maria; Mojović, Miloš; Popović-Bijelić, Ana; Gräslund, Astrid; Ozarowski, Andrew; Filipovic, Lana; Radulović, Sinisa; Enyedy, Éva A; Arion, Vladimir B

    2014-12-01

    The nickel(II), copper(II), and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H2L(1)) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (D-Pro-FTSC or (R)-H2L(1)), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine 4,4-dimethyl-thiosemicarbazone (dm-L-Pro-FTSC or (S)-H2L(2)), namely, [Ni(L-Pro-FTSC-2H)]2 (1), [Ni(D-Pro-FTSC-2H)]2 (2), [Ni(dm-L-Pro-FTSC-2H)]2 (3), [Cu(dm-L-Pro-FTSC-2H)] (6), [Zn(L-Pro-FTSC-2H)] (7), and [Zn(D-Pro-FTSC-2H)] (8), in addition to two previously reported, [Cu(L-Pro-FTSC-2H)] (4), [Cu(D-Pro-FTSC-2H)] (5), were synthesized and characterized by elemental analysis, one- and two-dimensional (1)H and (13)C NMR spectroscopy, circular dichroism, UV-vis, and electrospray ionization mass spectrometry. Compounds 1-3, 6, and 7 were also studied by single-crystal X-ray diffraction. Magnetic properties and solid-state high-field electron paramagnetic resonance spectra of 2 over the range of 50-420 GHz were investigated. The complex formation processes of L-Pro-FTSC with nickel(II) and zinc(II) were studied in aqueous solution due to the excellent water solubility of the complexes via pH potentiometry, UV-vis, and (1)H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore, introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds. PMID:25391085

  3. Synthesis, spectroscopic characterization, structural studies and antibacterial and antitumor activities of diorganotin complexes with 3-methoxysalicylaldehyde thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Khandani, Marzieh; Sedaghat, Tahereh; Erfani, Nasrollah; Haghshenas, Mohammad Reza; Khavasi, Hamid Reza

    2013-04-01

    Three organotin(IV) complexes, Ph2Sn(mstsc) (1), Me2Sn(mstsc) (2) and Bu2Sn(mstsc) (3), have been synthesized from reaction of R2SnCl2 (R = Ph, Me and Bu) with 3-methoxysalicylaldehyde thiosemicarbazone (H2mstsc). The synthesized complexes have been characterized by elemental analysis and FT-IR, 1H, 13C and 119Sn NMR spectroscopy. The structures of 2 and 3 have been also confirmed by X-ray crystallography. On the basis of spectral and structural data thiosemicarbazone acts as a tridentate dianionic ligand and coordinates to tin through phenolic oxygen, the azomethine nitrogen and thiolate sulfur atoms. The metal coordination geometry for 2 and 3 is described as distorted square pyramid and the crystal lattices are stabilized by intermolecular hydrogen bands. On the basis of 119Sn NMR data, coordination number of tin retains five in solution. The in vitro antibacterial activity of ligand and its complexes has been evaluated against one Gram-positive and three Gram-negative bacteria. Complex 2 exhibited good activity along with the standard antibacterial drugs. The in vitro cytotoxicities of the synthesized compounds against Jurkat cells were evaluated by the standard WST-1 assay. The activity decreases in the order 3 > 1 > 2 = H2mstsc.

  4. Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells.

    PubMed

    Dos Santos, Thiago André R; da Silva, Aline Caroline; Silva, Elany Barbosa; Gomes, Paulo André Teixeira de Moraes; Espíndola, José Wanderlan Pontes; Cardoso, Marcos Veríssimo de Oliveira; Moreira, Diogo Rodrigo Magalhaes; Leite, Ana Cristina Lima; Pereira, Valéria R A

    2016-08-01

    Cancer remains a high incidence and mortality disease, causing around 8.2 million of deaths in the last year. Current chemotherapy needs to be expanded, making research for new drugs a necessary task. Immune system modulation is an emerging concept in cancer cell proliferation control. In fact, there are a number of mechanisms underlying the role immune system plays in tumor cells. In this work, we describe the structural design, synthesis, antitumor and immunomodulatory potential of 31 new 1,3-thiazole and thiosemicarbazone compounds. Cisplatin was used as anticancer drug control. Cytotoxicity against J774A.1 macrophages and antitumor activity against HT-29 and Jurkat cells was determined. These 1,3-thiazole and thiosemicarbazone compounds not only exhibited cytotoxicity in cancer cells, but were able to cause irreversible cancer cell damage by inducing necrosis and apoptosis. In addition, these compounds, especially pyridyl-thiazoles compounds, regulated immune factors such as interleukin 10 and tumor necrosis factor, possible by directing immune system in favor of modulating cancer cell proliferation. By examining their pharmacological activity, we were able to identify new potent and selective anticancer compounds.

  5. Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.

    PubMed

    de Oliveira, Jamerson Ferreira; da Silva, Anekécia Lauro; Vendramini-Costa, Débora Barbosa; da Cruz Amorim, Cezar Augusto; Campos, Júlia Furtado; Ribeiro, Amélia Galdino; Olímpio de Moura, Ricardo; Neves, Jorge Luiz; Ruiz, Ana Lúcia Tasca Gois; Ernesto de Carvalho, João; Alves de Lima, Maria do Carmo

    2015-11-01

    A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 μM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 μM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.

  6. Vibrational, NMR and UV-Visible spectroscopic investigation, VCD and NLO studies on Benzophenone thiosemicarbazone using computational calculations

    NASA Astrophysics Data System (ADS)

    Moorthy, N.; Jobe Prabakar, P. C.; Ramalingam, S.; Periandy, S.; Parasuraman, K.

    2016-04-01

    In order to explore the unbelievable NLO property of prepared Benzophenone thiosemicarbazone (BPTSC), the experimental and theoretical investigation has been made. The theoretical calculations were made using RHF and CAM-B3LYP methods at 6-311++G(d,p) basis set. The title compound contains Cdbnd S ligand which helps to improve the second harmonic generation (SHG) efficiency. The molecule has been examined in terms of the vibrational, electronic and optical properties. The entire molecular behavior was studied by their fundamental IR and Raman wavenumbers and was compared with the theoretical aspect. The molecular chirality has been studied by performing vibrational circular dichroism (circularly polarized infrared radiation). The Mulliken charge levels of the compound ensure the perturbation of atomic charges according to the ligand. The molecular interaction of frontier orbitals emphasizes the modification of chemical properties of the compound through the reaction path. The enormous amount of NLO activity was induced by the Benzophenone in thiosemicarbazone. The Gibbs free energy was evaluated at different temperature and from which the enhancement of chemical stability was stressed. The VCD spectrum was simulated and the optical dichroism of the compound has been analyzed.

  7. Structural studies and investigation on the activity of imidazole-derived thiosemicarbazones and hydrazones against crop-related fungi.

    PubMed

    Reis, Débora C; Despaigne, Angel A Recio; Da Silva, Jeferson G; Silva, Nayane F; Vilela, Camila F; Mendes, Isolda C; Takahashi, Jacqueline A; Beraldo, Heloisa

    2013-10-14

    New imidazole derived thiosemicarbazones and hydrazones were prepared by condensation of 4(5)-imidazole carboxaldehyde, 4-(1H-imidazole-1-yl)benzaldehyde and 4-(1H-imidazole-1-yl)acetophenone with a thiosemicarbazide or hydrazide. All compounds were characterized by quantitative elemental analysis, IR and NMR techniques. Eight structures were determined by single crystal X-ray diffraction. The antifungal activities of the compounds were evaluated. None of the compounds exhibited significant activity against Aspergillus flavus and Candida albicans, while 4(5)-imidazolecarboxaldehyde thiosemicarbazone (ImT) and 4-(1H-imidazole-1-yl)benzaldehyde thiosemicabazone (4ImBzT) were highly and selectively active against Cladosporium cladosporioides. 4(5)-Imidazolecarboxaldehyde benzoyl hydrazone (4(5)ImPh), 4(5)-imidazolecarboxaldehyde-para-chlorobenzoyl hydrazone (4(5)ImpClPh), 4(5)-imidazolecarboxaldehyde-para-nitrobenzoyl hydrazone (4(5)ImpNO2Ph), 4-(imidazole-1-yl)acetophenone-para-chloro-benzoyl hydrazone (4ImAcpClPh) and 4-(imidazole-1-yl)acetophenone-para-nitro-benzoylhydrazone (4ImAcpNO2Ph) were highly active against Candida glabrata. 4(5)ImpClPh and 4(5)ImpNO2Ph were very effective against C. cladosporioides. In many cases, activity was superior to that of the reference compound nystatin.

  8. Vibrational, NMR and UV-visible spectroscopic investigation and NLO studies on benzaldehyde thiosemicarbazone using computational calculations

    NASA Astrophysics Data System (ADS)

    Moorthy, N.; Prabakar, P. C. Jobe; Ramalingam, S.; Pandian, G. V.; Anbusrinivasan, P.

    2016-04-01

    In order to investigate the vibrational, electronic and NLO characteristics of the compound; benzaldehyde thiosemicarbazone (BTSC), the XRD, FT-IR, FT-Raman, NMR and UV-visible spectra were recorded and were analysed with the calculated spectra by using HF and B3LYP methods with 6-311++G(d,p) basis set. The XRD results revealed that the stabilized molecular systems were confined in orthorhombic unit cell system. The cause for the change of chemical and physical properties behind the compound has been discussed makes use of Mulliken charge levels and NBO in detail. The shift of molecular vibrational pattern by the fusing of ligand; thiosemicarbazone group with benzaldehyde has been keenly observed. The occurrence of in phase and out of phase molecular interaction over the frontier molecular orbitals was determined to evaluate the degeneracy of the electronic energy levels. The thermodynamical studies of the temperature region 100-1000 K to detect the thermal stabilization of the crystal phase of the compound were investigated. The NLO properties were evaluated by the determination of the polarizability and hyperpolarizability of the compound in crystal phase. The physical stabilization of the geometry of the compound has been explained by geometry deformation analysis.

  9. Comparative evaluation of Bis(thiosemicarbazone)- Biotin and Met-ac-TE3A for tumor imaging

    NASA Astrophysics Data System (ADS)

    Singh, Sweta; Tiwari, Anjani K.; Varshney, Raunak; Mathur, R.; Shukla, Gauri; Bag, N.; Singh, B.; Mishra, Anil K.

    2016-01-01

    2,2‧,2″-(11-(2-((4-mercapto-1-methoxy-1-oxobutan-2-yl)amino)-2-oxoethyl)-1,4,8,11-tetraaza cyclotetradecane-1,4,8-triyl)triacetic acid, Met-ac-TE3A and (E)-N-methyl-2-((E)-3-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)hydrazinecarbono-thioyl)hydrazonobutan-2-ylidene)hydrazinecarbothioamide, Bis(thiosemicarbazone)- Biotin were synthesized and evaluated for imaging application. The pharmacokinetics of these ligands were determined by tracer methods. In vitro human serum stability of 99mTc Met-ac-TE3A/99mTc Bis(thiosemicarbazone)-Biotin after 24 h was found to be 96.5% and 97.0% respectively. Blood kinetics of both ligands in normal rabbits showed biphasic clearance pattern. Ex vivo biodistribution study revealed significant initial tumor uptake and high tumor/muscles ratio which is a pre-requisite condition for a ligand to work as SPECT-radiopharmaceutical for tumor imaging.

  10. Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.

    PubMed

    de Oliveira, Jamerson Ferreira; da Silva, Anekécia Lauro; Vendramini-Costa, Débora Barbosa; da Cruz Amorim, Cezar Augusto; Campos, Júlia Furtado; Ribeiro, Amélia Galdino; Olímpio de Moura, Ricardo; Neves, Jorge Luiz; Ruiz, Ana Lúcia Tasca Gois; Ernesto de Carvalho, João; Alves de Lima, Maria do Carmo

    2015-11-01

    A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 μM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 μM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies. PMID:26454648

  11. Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis.

    PubMed

    de Melos, Jorge Luiz R; Torres-Santos, Eduardo Caio; Faiões, Viviane dos S; Del Cistia, Catarina de Nigris; Sant'Anna, Carlos Maurício R; Rodrigues-Santos, Cláudio Eduardo; Echevarria, Aurea

    2015-10-20

    A series of eleven 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones (16-27) was synthesised as part of a study to search for potential new drugs with a leishmanicidal effect. The thiosemicarbazones, ten of which are new compounds, were prepared in good yields (85-98%) by the reaction of 3,4-methylenedioxyde-6-benzaldehydes (6-X-piperonal), previously synthesised for this work by several methodologies, and thiosemicarbazide in ethanol with a few drops of H2SO4. These compounds were evaluated against Leishmania amazonensis promastigotes, and derivatives where X = I (22) and X = CN (23) moieties showed impressive results, having IC₅₀ = 20.74 μM and 16.40 μM, respectively. The intracellular amastigotes assays showed IC₅₀ = 22.00 μM (22) and 17.00 μM (23), and selectivity index >5.7 and >7.4, respectively, with a lower toxicity compared to pentamidine (positive control, SI = 4.5). The results obtained from the preliminary QSAR study indicated the hydrophobicity (log P) as a fundamental parameter for the 2D-QSAR linear model. A molecular docking study demonstrated that both compounds interact with flavin mononucleotide (FMN), important binding site of NO synthase. PMID:26375353

  12. Comparative evaluation of Bis(thiosemicarbazone)- Biotin and Met-ac-TE3A for tumor imaging.

    PubMed

    Singh, Sweta; Tiwari, Anjani K; Varshney, Raunak; Mathur, R; Shukla, Gauri; Bag, N; Singh, B; Mishra, Anil K

    2016-01-15

    2,2',2″-(11-(2-((4-mercapto-1-methoxy-1-oxobutan-2-yl)amino)-2-oxoethyl)-1,4,8,11-tetraaza cyclotetradecane-1,4,8-triyl)triacetic acid, Met-ac-TE3A and (E)-N-methyl-2-((E)-3-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)hydrazinecarbono-thioyl)hydrazonobutan-2-ylidene)hydrazinecarbothioamide, Bis(thiosemicarbazone)- Biotin were synthesized and evaluated for imaging application. The pharmacokinetics of these ligands were determined by tracer methods. In vitro human serum stability of (99m)Tc Met-ac-TE3A/(99m)Tc Bis(thiosemicarbazone)-Biotin after 24h was found to be 96.5% and 97.0% respectively. Blood kinetics of both ligands in normal rabbits showed biphasic clearance pattern. Ex vivo biodistribution study revealed significant initial tumor uptake and high tumor/muscles ratio which is a pre-requisite condition for a ligand to work as SPECT-radiopharmaceutical for tumor imaging. PMID:26436844

  13. Antibacterial, antifungal and in vitro antileukaemia activity of metal complexes with thiosemicarbazones

    PubMed Central

    Pahontu, Elena; Julea, Felicia; Rosu, Tudor; Purcarea, Victor; Chumakov, Yurie; Petrenco, Petru; Gulea, Aurelian

    2015-01-01

    1-phenyl-3-methyl-4-benzoyl-5-pyrazolone 4-ethyl-thiosemicarbazone (HL) and its copper(II), vanadium(V) and nickel(II) complexes: [Cu(L)(Cl)]·C2H5OH·(1), [Cu(L)2]·H2O (2), [Cu(L)(Br)]·H2O·CH3OH (3), [Cu(L)(NO3)]·2C2H5OH (4), [VO2(L)]·2H2O (5), [Ni(L)2]·H2O (6), were synthesized and characterized. The ligand has been characterized by elemental analyses, IR, 1H NMR and 13C NMR spectroscopy. The tridentate nature of the ligand is evident from the IR spectra. The copper(II), vanadium(V) and nickel(II) complexes have been characterized by different physico-chemical techniques such as molar conductivity, magnetic susceptibility measurements and electronic, infrared and electron paramagnetic resonance spectral studies. The structures of the ligand and its copper(II) (2, 4), and vanadium(V) (5) complexes have been determined by single-crystal X-ray diffraction. The composition of the coordination polyhedron of the central atom in 2, 4 and 5 is different. The tetrahedral coordination geometry of Cu was found in complex 2 while in complex 4, it is square planar, in complex 5 the coordination polyhedron of the central ion is distorted square pyramid. The in vitro antibacterial activity of the complexes against Escherichia coli, Salmonella abony, Staphylococcus aureus, Bacillus cereus and the antifungal activity against Candida albicans strains was higher for the metal complexes than for free ligand. The effect of the free ligand and its metal complexes on the proliferation of HL-60 cells was tested. PMID:25708540

  14. Nickel(ii) radical complexes of thiosemicarbazone ligands appended by salicylidene, aminophenol and aminothiophenol moieties.

    PubMed

    Kochem, Amélie; Gellon, Gisèle; Jarjayes, Olivier; Philouze, Christian; du Moulinet d'Hardemare, Amaury; van Gastel, Maurice; Thomas, Fabrice

    2015-07-28

    The nickel(ii) complexes of three unsymmetrical thiosemicarbazone-based ligands featuring a sterically hindered salicylidene (1), aminophenol (2) or thiophenol (3) moiety were synthesized and structurally characterized. The metal ion lies in an almost square planar geometry in all the complexes. The cyclic voltammetry (CV) curve of 1 shows an irreversible oxidation wave at E = 0.49 V, which is assigned to the phenoxyl/phenolate redox couple. The CV curves of 2 and 3 display a reversible one-electron oxidation wave (E1/2 = 0.26 and 0.22 V vs. Fc(+)/Fc, respectively) and an one-electron reduction wave (E1/2 = -1.55 and -1.46 V, respectively). The cations 2(+) and 3(+) as well as the anions 2(-) and 3(-) were generated. The EPR spectra of the cations in THF show a rhombic signal at g1 = 2.034, g2 = 2.010 and g3 = 1.992 (2(+)) and g1 = 2.069, g2 = 2.018, g3 = 1.986 (3(+)) that is consistent with a main radical character of the complexes. The difference in anisotropy is assigned to the different nature of the radical, iminosemiquinonate vs. iminothiosemiquinonate. The anions display an isotropic EPR signal at giso = 2.003 (2(+)) and 2.006 (3(+)), which is indicative of a main α-diimine radical character of the compounds. Both the anions and cations exhibit charge transfer transitions of low to moderate intensity in their visible spectrum. Quantum chemical calculations (B3LYP) reproduce both the g-values and Vis-NIR spectra of the complexes. The radical anions readily react with dioxygen to give the radical cations. 2(+) catalyzes the aerobic oxidation of benzyl alcohol into benzaldehyde. PMID:26086684

  15. Cytotoxic and Antitumour Studies of Acetoacetanilide N(4)-methyl(phenyl)thiosemicarbazone and its Transition Metal Complexes

    PubMed Central

    Priya, N. P.; Firdous, A. P.; Jeevana, R.; Aravindakshan, K. K.

    2015-01-01

    Cytotoxic activities of acetoacetanilide N(4)-methyl(phenyl)thiosemicarbazone (L2H) and its seven different metal complexes were studied. Of these, IC50 value of the copper complex was found to be 46 μg/ml. Antitumour studies of this copper complex was carried out using Daltons Lymphoma Ascites cell-induced solid tumour model and Ehrlich's Ascites Carcinoma cell-induced ascites tumour model. Administration of the copper complex at different concentrations (10, 5 and 1 mg/kg b. wt) inhibited the solid tumour development in mice and increased the mean survival rate and the life span of Ascites tumour bearing mice in a concentration dependent manner. PMID:26997691

  16. Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia.

    PubMed

    Alam, Israt S; Arrowsmith, Rory L; Cortezon-Tamarit, Fernando; Twyman, Frazer; Kociok-Köhn, Gabriele; Botchway, Stanley W; Dilworth, Jonathan R; Carroll, Laurence; Aboagye, Eric O; Pascu, Sofia I

    2016-01-01

    We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under 'cold' and 'hot' biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. (68)Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration.

  17. Eco-Friendly Synthesis of Some Thiosemicarbazones and Their Applications as Intermediates for 5-Arylazothiazole Disperse Dyes.

    PubMed

    Gaffer, Hatem E; Khalifa, Mohamed E

    2015-01-01

    The solid-solid reactions of thiosemicarbazide with 4-formylantipyrine, 2-acetylpyrrole and camphor were performed to afford the thiosemicarbazones 1-3 which underwent hetero-cyclization with phenacyl bromide to furnish the corresponding thiazole derivatives 4-6. The yields of the reactions are quantitative in all cases and the products do not require further purification. A series of 5-arylazo-2-(substituted ylidene-hydrazinyl)-thiazole dyes 7-9 was then prepared by diazo coupling of thiazole derivatives 4-6 with several diazonium chlorides. The synthesized dyes were applied as disperse dyes for dyeing polyester fabric. The dyed fabrics exhibit good washing, perspiration, sublimation and light fastness properties, with little variation in their moderate to good rubbing fastness. PMID:26690111

  18. Two thiosemicarbazones derived from salicylaldehyde: very specific hydrogen-bonding interactions of the N-H...S=C type.

    PubMed

    Rubcić, Mirta; Dilović, Ivica; Cindrić, Marina; Matković-Calogović, Dubravka

    2008-10-01

    The molecular structures of two salicylaldehyde thiosemicarbazone derivatives, namely salicylaldehyde 4-phenylthiosemicarbazone, C(14)H(13)N(3)OS, (I), and 4-methoxysalicylaldehyde 4-phenylthiosemicarbazone, C(15)H(15)N(3)O(2)S, (II), both of potential pharmacological interest, are found in the keto (thione) tautomeric form. The first compound represents a second triclinic polymorph of composition beta-C(14)H(13)N(3)OS. Although both polymorphs crystallize in the same space group (P1), the alpha-polymorph [Seena, Kurup & Suresh (2008). J. Chem. Crystallogr. 38, 93-96] differs from the beta form in its unit-cell volume at 293 K. The molecules in the crystal structures of (I) and (II) are linked into centrosymmetric R(2)(2)(8) dimers by hydrogen bonds of the N-H...S=C type. These dimers are connected through pi-pi stacking and T-shaped C-H...pi interactions into three-dimensional networks.

  19. Spectroscopic evaluation of Co(II), Ni(II) and Cu(II) complexes derived from thiosemicarbazone and semicarbazone

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Kumar, Anil

    2007-12-01

    Co(II), Ni(II) and Cu(II) complexes were synthesized with thiosemicarbazone (L 1) and semicarbazone (L 2) derived from 2-acetyl furan. These complexes were characterized by elemental analysis, molar conductance, magnetic moment, mass, IR, electronic and EPR spectral studies. The molar conductance measurement of the complexes in DMSO corresponds to non-electrolytic nature. All the complexes are of high-spin type. On the basis of different spectral studies six coordinated geometry may be assigned for all the complexes except Co(L) 2(SO 4) and Cu(L) 2(SO 4) [where L = L 1 and L 2] which are of five coordinated square pyramidal geometry.

  20. The Investigation of Electronic Properties and Microscopic Second-Order Nonlinear Optical Behavior of 1-SALICYLIDENE-3-THIO-SEMICARBAZONE

    NASA Astrophysics Data System (ADS)

    Karakas, Asli; Unver, Huseyin; Elmali, Ayhan

    To investigate the microscopic second-order nonlinear optical (NLO) behavior of the 1-salicylidene-3-thio-semicarbazone Schiff base compound, the electric dipole moments (μ), linear static polarizabilities (α) and first static hyperpolarizabilites (β) have been calculated using finite field second-order Møller-Plesset perturbation (FF MP2) theory. The ab-initio results on (hyper)polarizabilities show that the investigated molecule might have microscopic NLO properties with non-zero values. To understand the NLO behavior in the context of molecular orbital structure, we have also examined the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and the HOMO-LUMO gap in the same theoretical framework as the (hyper)polarizability calculations. In addition to the NLO properties, the electronic transition spectra have been computed using a semi-empirical method (ZINDO). ZINDO calculation results show that the electronic transition wavelengths have been estimated to be shorter than 400 nm.

  1. Spectrophotometric determination of Cu(II) in soil and vegetable samples collected from Abraha Atsbeha, Tigray, Ethiopia using heterocyclic thiosemicarbazone.

    PubMed

    Admasu, Daniel; Reddy, Desam Nagarjuna; Mekonnen, Kebede Nigussie

    2016-01-01

    Two selective and sensitive reagents, 2-acetylpyridine thiosemicarbazone (2-APT) and 3-acetylpyridine thiosemicarbazone (3-APT) were used for the spectrophotometric determination of Cu(II). Both reagents gave yellowish Cu(II) complex at a pH range of 8.0-10.0. Beer's law was obeyed for Cu(II)-2-APT and Cu(II)-3-APT in the concentration range of 0.16-1.3 and 0.44-1.05 µg/mL, respectively. The molar absorptivity and of Cu(II)-2-APT and Cu(II)-3-APT were 2.14 × 10(4) at 370 nm, and 6.7 × 10(3) L/mol cm at 350 nm, respectively, while the Sandell's sensitivity were 0.009 and 0.029 µg/cm(2) in that order. The correlation coefficient of the standard curves of Cu(II)-2-APT and Cu(II)-3-APT were 0.999 and 0.998, respectively. The detection limit of the Cu(II)-2-APT and Cu(II)-3-APT methods were 0.053 and 0.147 µg/mL, respectively. The results demonstrated that the procedure is precise (relative standard deviation <2 %, n = 10). The method was tested for Cu(II) determination in soil and vegetable samples. Comparisons of the results with those obtained using a flame atomic absorption spectrophotometer for Cu(II) determination also tested the validity of the method using paired sample t test at the 0.05 level showing a good agreement between them.

  2. Spectrophotometric determination of Cu(II) in soil and vegetable samples collected from Abraha Atsbeha, Tigray, Ethiopia using heterocyclic thiosemicarbazone.

    PubMed

    Admasu, Daniel; Reddy, Desam Nagarjuna; Mekonnen, Kebede Nigussie

    2016-01-01

    Two selective and sensitive reagents, 2-acetylpyridine thiosemicarbazone (2-APT) and 3-acetylpyridine thiosemicarbazone (3-APT) were used for the spectrophotometric determination of Cu(II). Both reagents gave yellowish Cu(II) complex at a pH range of 8.0-10.0. Beer's law was obeyed for Cu(II)-2-APT and Cu(II)-3-APT in the concentration range of 0.16-1.3 and 0.44-1.05 µg/mL, respectively. The molar absorptivity and of Cu(II)-2-APT and Cu(II)-3-APT were 2.14 × 10(4) at 370 nm, and 6.7 × 10(3) L/mol cm at 350 nm, respectively, while the Sandell's sensitivity were 0.009 and 0.029 µg/cm(2) in that order. The correlation coefficient of the standard curves of Cu(II)-2-APT and Cu(II)-3-APT were 0.999 and 0.998, respectively. The detection limit of the Cu(II)-2-APT and Cu(II)-3-APT methods were 0.053 and 0.147 µg/mL, respectively. The results demonstrated that the procedure is precise (relative standard deviation <2 %, n = 10). The method was tested for Cu(II) determination in soil and vegetable samples. Comparisons of the results with those obtained using a flame atomic absorption spectrophotometer for Cu(II) determination also tested the validity of the method using paired sample t test at the 0.05 level showing a good agreement between them. PMID:27512628

  3. Synthesis, X-ray structure and in vitro cytotoxicity studies of Cu(I/II) complexes of thiosemicarbazone: special emphasis on their interactions with DNA.

    PubMed

    Saswati; Chakraborty, Ayon; Dash, Subhashree P; Panda, Alok K; Acharyya, Rama; Biswas, Ashis; Mukhopadhyay, Subhadip; Bhutia, Sujit K; Crochet, Aurélien; Patil, Yogesh P; Nethaji, M; Dinda, Rupam

    2015-04-01

    4-(p-X-phenyl)thiosemicarbazone of napthaldehyde {where X = Cl (HL¹) and X = Br (HL²)}, thiosemicarbazone of quinoline-2-carbaldehyde (HL³) and 4-(p-fluorophenyl)thiosemicarbazone of salicylaldehyde (H₂L⁴) and their copper(I) {[Cu(HL¹)(PPh₃)₂Br]·CH₃CN (1) and [Cu(HL²)(PPh₃)₂Cl]·DMSO (2)} and copper(II) {[(Cu₂L³₂Cl)₂(μ-Cl)₂]·2H₂O (3) and [Cu(L⁴)(Py)] (4)} complexes are reported herein. The synthesized ligands and their copper complexes were successfully characterized by elemental analysis, cyclic voltammetry, NMR, ESI-MS, IR and UV-Vis spectroscopy. Molecular structures of all the Cu(I) and Cu(II) complexes have been determined by X-ray crystallography. All the complexes (1-4) were tested for their ability to exhibit DNA-binding and -cleavage activity. The complexes effectively interact with CT-DNA possibly by groove binding mode, with binding constants ranging from 10⁴ to 10⁵ M⁻¹. Among the complexes, 3 shows the highest chemical (60%) as well as photo-induced (80%) DNA cleavage activity against pUC19 DNA. Finally, the in vitro antiproliferative activity of all the complexes was assayed against the HeLa cell line. Some of the complexes have proved to be as active as the clinical referred drugs, and the greater potency of 3 may be correlated with its aqueous solubility and the presence of the quinonoidal group in the thiosemicarbazone ligand coordinated to the metal.

  4. Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

    PubMed

    Kumar, Kewal; Schniper, Sarah; González-Sarrías, Antonio; Holder, Alvin A; Sanders, Natalie; Sullivan, David; Jarrett, William L; Davis, Krystyn; Bai, Fengwei; Seeram, Navindra P; Kumar, Vipan

    2014-10-30

    A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.

  5. Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

    PubMed

    Kumar, Kewal; Schniper, Sarah; González-Sarrías, Antonio; Holder, Alvin A; Sanders, Natalie; Sullivan, David; Jarrett, William L; Davis, Krystyn; Bai, Fengwei; Seeram, Navindra P; Kumar, Vipan

    2014-10-30

    A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine. PMID:25147149

  6. Synthesis of a Sugar-Based Thiosemicarbazone Series and Structure-Activity Relationship versus the Parasite Cysteine Proteases Rhodesain, Cruzain, and Schistosoma mansoni Cathepsin B1

    PubMed Central

    Fonseca, Nayara Cristina; da Cruz, Luana Faria; da Silva Villela, Filipe; do Nascimento Pereira, Glaécia Aparecida; de Siqueira-Neto, Jair Lage; Kellar, Danielle; Suzuki, Brian M.; Ray, Debalina; de Souza, Thiago Belarmino; Alves, Ricardo José; Júnior, Policarpo Ademar Sales; Romanha, Alvaro José; Murta, Silvane Maria Fonseca; McKerrow, James H.; Caffrey, Conor R.; de Oliveira, Renata Barbosa

    2015-01-01

    The pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC50s) of ≤10 μM. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC50 = 1.2 ± 1.0 μM). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. PMID:25712353

  7. Novel thiosemicarbazones of the ApT and DpT series and their copper complexes: identification of pronounced redox activity and characterization of their antitumor activity.

    PubMed

    Jansson, Patric J; Sharpe, Philip C; Bernhardt, Paul V; Richardson, Des R

    2010-08-12

    The novel chelators 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone (HAp44mT) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (HDp44mT) have been examined to elucidate the structure-activity relationships necessary to form copper (Cu) complexes with pronounced antitumor activity. Electrochemical studies demonstrated that the Cu complexes of these ligands had lower redox potentials than their iron complexes. Moreover, the Cu complexes where the ligand/metal ratio was 1:1 rather than 2:1 had significantly higher intracellular oxidative properties and antitumor efficacy. Interestingly, the 2:1 complex was shown to dissociate to give significant amounts of the 1:1 complex that could be the major cytotoxic effector. Both types of Cu complex showed significantly more antiproliferative activity than the ligand alone. We also demonstrate the importance of the inductive effects of substituents on the carbonyl group of the parent ketone, which influence the Cu(II/I) redox potentials because of their proximity to the metal center. The structure-activity relationships described are important for the design of potent thiosemicarbazone Cu complexes.

  8. Tricarbonyl (99m)Tc(i) and Re(i)-thiosemicarbazone complexes: synthesis, characterization and biological evaluation for targeting bacterial infection.

    PubMed

    Nayak, Dipak Kumar; Baishya, Rinku; Natarajan, Ramalingam; Sen, Tuhinadri; Debnath, Mita Chatterjee

    2015-09-28

    Methyl, ethyl and phenyl nitrofuryl thiosemicarbazone ligands (, and respectively) were radiolabeled with freshly prepared aqueous solution of a fac[(99m)Tc(CO)3(H2O)3](+) precursor. The radiochemical yield was around 98% as determined by thin layer chromatography and HPLC. The complexes exhibited substantial stability. The corresponding Re(i) complexes were prepared from a Re(CO)5Br precursor to understand the coordination behavior of the ligands against a tricarbonyl rhenium(i) precursor. The rhenium(i) complexes were characterized by means of IR, NMR and mass spectroscopic studies as well as by X-ray crystallography, and correlated with the technetium complexes by means of HPLC studies. Electrochemical reduction of monomeric Re(CO)3-complexes of nitrofuryl ethyl thiosemicarbazone was also studied using cyclic voltammetry. Biodistribution studies of (99m)Tc(CO)3-labeled thiosemicarbazones in rats intramuscularly infected with S. aureus exhibited substantial in vivo stability of the complex and moderate accumulation at the site of focal infection. PMID:26289802

  9. Copper(II) complexes with highly water-soluble L- and D-proline-thiosemicarbazone conjugates as potential inhibitors of Topoisomerase IIα.

    PubMed

    Bacher, Felix; Enyedy, Éva A; Nagy, Nóra V; Rockenbauer, Antal; Bognár, Gabriella M; Trondl, Robert; Novak, Maria S; Klapproth, Erik; Kiss, Tamás; Arion, Vladimir B

    2013-08-01

    Two proline-thiosemicarbazone bioconjugates with excellent aqueous solubility, namely, 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [L-Pro-FTSC or (S)-H2L] and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [D-Pro-FTSC or (R)-H2L], have been synthesized and characterized by elemental analysis, one- and two-dimensional (1)H and (13)C NMR spectroscopy, and electrospray ionization mass spectrometry. The complexation behavior of L-Pro-FTSC with copper(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance, (1)H NMR spectroscopy, and spectrofluorimetry. By the reaction of copper(II) acetate with (S)-H2L and (R)-H2L in water, the complexes [Cu(S,R)-L] and [Cu(R,S)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu(S,R)-L] showed the formation of a square-pyramidal complex, with the bioconjugate acting as a pentadentate ligand. Both copper(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited Topoisomerase IIα activity in a DNA plasmid relaxation assay. PMID:23829568

  10. Quinoline-2-carboxaldehyde thiosemicarbazones and their Cu(II) and Ni(II) complexes as topoisomerase IIa inhibitors.

    PubMed

    Bisceglie, Franco; Musiari, Anastasia; Pinelli, Silvana; Alinovi, Rossella; Menozzi, Ilaria; Polverini, Eugenia; Tarasconi, Pieralberto; Tavone, Matteo; Pelosi, Giorgio

    2015-11-01

    A series of quinoline-2-carboxaldehyde thiosemicarbazones and their copper(II) and nickel(II) complexes were synthesized and characterized. In all complexes the ligands are in the E configuration with respect to the imino bond and behave as terdentate. The copper(II) complexes form square planar derivatives with one molecule of terdentate ligand and chloride ion. A further non-coordinated chloride ion compensates the overall charge. Nickel(II) ions form instead octahedral complexes with two ligands for each metal ion, independently from the stoichiometric metal:ligand ratio used in the synthesis. Ligands and complexes were tested for their antiproliferative properties on histiocytic lymphoma cell line U937. Copper(II) derivatives are systematically more active than the ligands and the nickel complexes. All copper derivatives result in inhibiting topoisomerase IIa in vitro. Computational methods were used to propose a model to explain the different extent of inhibition presented by these compounds. The positive charge of the dissociated form of the copper complexes may play a key role in their action. PMID:26335598

  11. Synthesis and evaluation of simple naked-eye colorimetric chemosensors for anions based on azo dye-thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Radchatawedchakoon, Widchaya; Sangsuwan, Withsakorn; Kruanetr, Senee; Sakee, Uthai

    2014-03-01

    A series of novel, highly selective azo dye-thiosemicarbazones based anion sensors (3e-f) have been synthesized from the condensation reaction between thiosemicarbazide and six different azo salicylaldehydes. The structure of the sensors was confirmed by spectroscopic methods. The selectivity and sensitivity in the recognition for acetate anion over other anions such as fluoride, chloride, iodide and dihydrogenphosphate anions were determined by naked-eyes and UV-vis spectra. The color of the solution containing sensor had an obvious change from light yellow to orange only after the addition of acetate anion in aqueous solution (water/dimethylsulfoxide, 7:3, v/v) while other anions did not cause obvious color change. The anion recognition property of the receptor via proton-transfer is monitored by UV-vis titration and 1H NMR spectroscopy. Under condition in aqueous solution of sensor 3e (water/dimethylsulfoxide, 7:3, v/v), linearity range for the quantification of acetate anion was 1-22 μM and limit of detection (LOD) of acetate anion was 0.71 μM.

  12. Transition metal complexes of Vanillin- 4N-(2-pyridyl) thiosemicarbazone (H 2VPT); thermal, structural and spectroscopic studies

    NASA Astrophysics Data System (ADS)

    El-Reash, Gaber Abu; El-Ayaan, Usama; Gabr, I. M.; El-Rachawy, El-Bastawesy

    2010-04-01

    The present work carried out a study on the ligational behavior of the new ligand, Vanillin- 4N-(2-pyridyl) thiosemicarbazone (H 2VPT) 1 towards some transition metal ions namely, Mn 2+, Co 2+, Ni 2+, Cu 2+, Zn 2+,Cd 2+, Hg 2+ and U 6+. These complexes namely [Mn(HVPT)Cl] 2, [Co(VPT)(H 2O)] 2H 2O 3, [Ni(HVPT)Cl(H 2O)] 4, [Cu(HVPT)Cl(H 2O)] 5, [Zn(VPT)(H 2O)]H 2O 6, [Cd(HVPT)Cl(H 2O)] 7, [Hg(VPT)(H 2O)]H 2O 8 and [UO 2(H 2VPT)(OAc) 2]H 2O 9, were characterized by elemental analysis, spectral (IR, 1H NMR and UV-vis) and magnetic moment measurements. The suggested structures were confirmed by applying geometry optimization and conformational analysis. Thermal properties and decomposition kinetics of all compounds are investigated. The interpretation, mathematical analysis and evaluation of kinetic parameters ( E, A, Δ H, Δ S and Δ G) of all thermal decomposition stages have been evaluated using Coats-Redfern equation. ESR spectra of [Cu(HVPT)Cl]H 2O at room temperature show broad signal, indicating spin-exchange interactions between copper(II) ions.

  13. Synthesis, spectroscopic, anticancer and antibacterial studies of Ni(II) and Cu(II) complexes with 2-carboxybenzaldehyde thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Vandana

    2014-08-01

    Ni(II) and Cu(II) complexes of 2-carboxybenzaldehyde thiosemicarbazone (L) were synthesized and investigated by their spectral and analytical data. These newly synthesized complexes have a composition of M(L)X(H2O)2 (where M = Ni(II), Cu(II) and X = Cl-, NO3-, CH3COO-) and (L) is the tridentate Schiff base ligand. The ligand and its complexes have been characterized on the basis of analytical, molar conductivity, magnetic susceptibility measurements, FT-IR, ESR, 1H NMR and electronic spectral analysis. All the compounds were non-electrolytic in nature. On the basis of spectral studies an octahedral geometry has been assigned for Ni(II) and a tetragonal geometry for Cu(II) complexes. The ligand and its metal complexes were screened for their anticancer studies against human breast cancer cell lines MCF-7 and calculated minimum inhibitory concentration and also for antibacterial activity using Kirby-Bauer single disk susceptibility test.

  14. SAR of Cu (II) thiosemicarbazone complexes as hypoxic imaging agents: MM3 analysis and prediction of biologic properties.

    PubMed

    Singh, Sweta; Tiwari, Anjani K; Ojha, Himanshu; Kumar, Nitin; Singh, Bachcha; Mishra, Anil K

    2010-02-01

    Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r(2) = 0.95 and q(2) = 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: Log P = {3.01698 (+/-0.0590)} - LUMO {0.1248 (+/-0.068)} + MR {0.3219 (+/-0.086)} n = 21 |r| = 0.972 s = 0.188 F = 98.102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds.

  15. Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species.

    PubMed

    Zhang, Xu-Meng; Guo, Hui; Li, Zai-Shun; Song, Fu-Hang; Wang, Wei-Min; Dai, Huan-Qin; Zhang, Li-Xin; Wang, Jian-Guo

    2015-08-28

    Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-β-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the "familiar" IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure-activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance.

  16. Copper(II) and nickel(II) complexes of benzyloxybenzaldehyde-4-phenyl-3-thiosemicarbazone: Synthesis, characterization and biological activity

    NASA Astrophysics Data System (ADS)

    Prathima, B.; Subba Rao, Y.; Adinarayana Reddy, S.; Reddy, Y. P.; Varada Reddy, A.

    2010-09-01

    Benzyloxybenzaldehyde-4-phenyl-3-thiosemicarbazone ligand (L) has been synthesized from benzyloxybenzaldehyde and 4-phenyl-3-thiosemicarbazide. Complexes of this ligand with chlorides of Cu(II) and Ni(II) have been prepared. The structure of the ligand (L) is proposed based on elemental analysis, IR and 1H NMR spectra. Its complexes with Cu(II) and Ni(II) ions are characterized from the studies of electronic as well as EPR spectra. On the basis of electronic and EPR studies, rhombically distorted octahedral structure has been proposed for Cu(II) complex while the Ni(II) complex has been found to acquire an octahedral structure. The ligand and their metal complexes have been tested in vitro for their biological effects. Their antibacterial activities against Gram-negative bacteria ( Escherichia coli and Klebsiella pneumoniae) and Gram-positive bacteria ( Staphylococcus aureus and Bacillus subtilis) have been investigated. The prepared metal complexes exhibit higher antibacterial activities than the parent ligand. The in vitro antioxidant activity of free ligand and its metal(II) complexes have also been investigated and the results however reveal that the ligand exhibits greater antioxidant activity than its complexes.

  17. Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species.

    PubMed

    Zhang, Xu-Meng; Guo, Hui; Li, Zai-Shun; Song, Fu-Hang; Wang, Wei-Min; Dai, Huan-Qin; Zhang, Li-Xin; Wang, Jian-Guo

    2015-08-28

    Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-β-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the "familiar" IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure-activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance. PMID:26185006

  18. A 119Sn Mössbauer Study of Tin(IV) Complexes of 2- and 4-Benzoylpyridine Thiosemicarbazone and 4-Benzoylpyridine Semicarbazone

    NASA Astrophysics Data System (ADS)

    Pérez-Rebolledo, Anayive; Ardisson, José D.; de Lima, Geraldo M.; Macedo, Waldemar A. A.; Beraldo, Heloisa

    2005-06-01

    A 119Sn Mössbauer study was carried out of tin(IV) complexes with 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4)-phenyl (H2Bz4Ph) derivatives: [Sn(2Bz4DH)Cl3] (1), [Sn(2Bz4DH)PhCl2] (2), [Sn(2Bz4M)Cl3] (3), [H22Bz4M]2[Ph2SnCl4] (4), [Sn(2Bz4Ph)PhCl2] (5), [Sn(2Bz4Ph)Ph2Cl] (6), in which H2Bz4R stands for the neutral ligand and 2Bz4R stands for the anionic thiosemicarbazone. In addition, 119Sn Mössbauer studies of the tin(IV) complexes [Sn(H4Bz4DH)2Cl4H2O] (7), [Sn(H4BzPS)2Cl4H2O] (8) with 4-benzoylpyridine thiosemicarbazone (H4Bz4DH) and the correspondent semicarbazone (H4BzPS) were performed. The isomer shifts decrease upon coordination due to the variation in the percentage of s character as tin changes from approximately sp3 hybridization in the tin salts to sp3d2 in the octahedral or sp3d3 in the heptahedral complexes. The Mössbauer parameters of compound (4) showed the existence of two tin(IV) sites, which have been attributed to the presence of the cis and trans isomers.

  19. Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents

    PubMed Central

    Sestak, Vit; Stariat, Jan; Cermanova, Jolana; Potuckova, Eliska; Chladek, Jaroslav; Roh, Jaroslav; Bures, Jan; Jansova, Hana; Prusa, Petr; Sterba, Martin; Micuda, Stanislav; Simunek, Tomas; Kalinowski, Danuta S.; Richardson, Des R.; Kovarikova, Petra

    2015-01-01

    Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment. PMID:26623727

  20. L- and D-proline thiosemicarbazone conjugates: coordination behavior in solution and the effect of copper(II) coordination on their antiproliferative activity.

    PubMed

    Milunovic, Miljan N M; Enyedy, Éva A; Nagy, Nóra V; Kiss, Tamás; Trondl, Robert; Jakupec, Michael A; Keppler, Bernhard K; Krachler, Regina; Novitchi, Ghenadie; Arion, Vladimir B

    2012-09-01

    Two enantiomerically pure thiosemicarbazone-proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(S)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [L-Pro-STSC or (S)-H(2)L] and 2-hydroxy-3-methyl-(R)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [D-Pro-STSC or (R)-H(2)L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV-vis and (1)H and (13)C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of L-Pro-STSC, stoichiometry, and thermodynamic stability of iron(II), iron(III), copper(II), and zinc(II) complexes in 30% (w/w) dimethyl sulfoxide/H(2)O solvent mixture have been studied by pH-potentiometric, UV-vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, (1)H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl(2)·2H(2)O with (S)-H(2)L and (R)-H(2)L, respectively, the complexes [Cu[(S)-H(2)L]Cl]Cl and [Cu[(R)-H(2)L]Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu[(R)-H(2)L]Cl]Cl showed the formation of a square-planar copper(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone-proline conjugates L- and D-Pro-STSC show only moderate cytotoxic potency with IC(50) values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC(50) values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, L-Pro-STSC as well as its copper(II) complex show slightly stronger antiproliferative activity than the

  1. L- and D-proline thiosemicarbazone conjugates: coordination behavior in solution and the effect of copper(II) coordination on their antiproliferative activity.

    PubMed

    Milunovic, Miljan N M; Enyedy, Éva A; Nagy, Nóra V; Kiss, Tamás; Trondl, Robert; Jakupec, Michael A; Keppler, Bernhard K; Krachler, Regina; Novitchi, Ghenadie; Arion, Vladimir B

    2012-09-01

    Two enantiomerically pure thiosemicarbazone-proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(S)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [L-Pro-STSC or (S)-H(2)L] and 2-hydroxy-3-methyl-(R)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [D-Pro-STSC or (R)-H(2)L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV-vis and (1)H and (13)C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of L-Pro-STSC, stoichiometry, and thermodynamic stability of iron(II), iron(III), copper(II), and zinc(II) complexes in 30% (w/w) dimethyl sulfoxide/H(2)O solvent mixture have been studied by pH-potentiometric, UV-vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, (1)H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl(2)·2H(2)O with (S)-H(2)L and (R)-H(2)L, respectively, the complexes [Cu[(S)-H(2)L]Cl]Cl and [Cu[(R)-H(2)L]Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu[(R)-H(2)L]Cl]Cl showed the formation of a square-planar copper(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone-proline conjugates L- and D-Pro-STSC show only moderate cytotoxic potency with IC(50) values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC(50) values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, L-Pro-STSC as well as its copper(II) complex show slightly stronger antiproliferative activity than the

  2. Synthesis and spectral characterization of mono- and binuclear copper(II) complexes derived from 2-benzoylpyridine-N4-methyl-3-thiosemicarbazone: Crystal structure of a novel sulfur bridged copper(II) box-dimer

    NASA Astrophysics Data System (ADS)

    Jayakumar, K.; Sithambaresan, M.; Aiswarya, N.; Kurup, M. R. Prathapachandra

    2015-03-01

    Mononuclear and binuclear copper(II) complexes of 2-benzoylpyridine-N4-methyl thiosemicarbazone (HL) were prepared and characterized by a variety of spectroscopic techniques. Structural evidence for the novel sulfur bridged copper(II) iodo binuclear complex is obtained by single crystal X-ray diffraction analysis. The complex [Cu2L2I2], a non-centrosymmetric box dimer, crystallizes in monoclinic C2/c space group and it was found to have distorted square pyramidal geometry (Addison parameter, τ = 0.238) with the square basal plane occupied by the thiosemicarbazone moiety and iodine atom whereas the sulfur atom from the other coordinated thiosemicarbazone moiety occupies the apical position. This is the first crystallographically studied system having non-centrosymmetrical entities bridged via thiolate S atoms with Cu(II)sbnd I bond. The tridentate thiosemicarbazone coordinates in mono deprotonated thionic tautomeric form in all complexes except in sulfato complex, [Cu(HL)(SO4)]·H2O (1) where it binds to the metal centre in neutral form. The magnetic moment values and the EPR spectral studies reflect the binuclearity of some of the complexes. The spin Hamiltonian and bonding parameters are calculated based on EPR studies. In all the complexes g|| > g⊥ > 2.0023 and the g values in frozen DMF are consistent with the dx2-y2 ground state. The thermal stabilities of some of the complexes were also determined.

  3. Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2-Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling.

    PubMed

    Wangpu, Xiongzhi; Lu, Jiaoyang; Xi, Ruxing; Yue, Fei; Sahni, Sumit; Park, Kyung Chan; Menezes, Sharleen; Huang, Michael L H; Zheng, Minhua; Kovacevic, Zaklina; Richardson, Des R

    2016-05-01

    Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway. In the present study, NDRG1 overexpression and silencing models of HT29 colon cancer and DU145 prostate cancer cells were used to examine the activation of FAK/paxillin signaling and the formation of focal adhesions. The expression of NDRG1 resulted in a marked and significant decrease in the activating phosphorylation of FAK and paxillin, whereas silencing of NDRG1 resulted in an opposite effect. The expression of NDRG1 also inhibited the formation of focal adhesions as well as cell migration and cell-collagen adhesion. Incubation of cells with novel thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, that upregulate NDRG1 also resulted in decreased phosphorylation of FAK and paxillin. The ability of these thiosemicarbazones to inhibit cell migration and metastasis could be mediated, at least in part, through the FAK/paxillin pathway. PMID:26895766

  4. Redox activation of Fe(III)-thiosemicarbazones and Fe(III)-bleomycin by thioredoxin reductase: specificity of enzymatic redox centers and analysis of reactive species formation by ESR spin trapping

    PubMed Central

    Myers, Judith M.; Cheng, Qing; Antholine, William E.; Kalyanaraman, Balaraman; Filipovska, Aleksandra; Arnér, ArnerElias S.J.; Myers, Charles R.

    2013-01-01

    Thiosemicarbazones such as triapine (Tp) and Dp44mT are tridentate iron (Fe) chelators that have well-documented anti-neoplastic activity. While Fe-thiosemicarbazones can undergo redox-cycling to generate reactive species that may have important roles in their cytotoxicity, there is only limited insight into specific cellular agents that can rapidly reduce Fe(III)-thiosemicarbazones and thereby promote their redox activity. Here we report that thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) have this activity, and that there is considerable specificity to the interactions between specific redox centers in these enzymes and different Fe(III) complexes. Site-directed variants of TrxR1 demonstrate that the selenocysteine (Sec) of the enzyme is not required, whereas the C59 residue and the flavin have important roles. While TrxR1 and GR have analogous C59/flavin motifs, TrxR is considerably faster than GR. For both enzymes, Fe(III)(Tp)2 is reduced faster than Fe(III)(Dp44mT)2. This reduction promotes redox cycling and the generation of hydroxyl radical (HO•) in a peroxide-dependent manner, even with low μM levels of Fe(Tp)2. TrxR also reduces Fe(III)-bleomycin and this activity is Sec-dependent. TrxR cannot reduce Fe(III)-EDTA at significant rates. Our findings are the first to demonstrate pro-oxidant reductive activation of Fe(III)-based antitumor thiosemicarbazones by interactions with specific enzyme species. The marked elevation of TrxR in many tumors could contribute to the selective tumor toxicity of these drugs by enhancing the redox activation of Fe(III)-thiosemicarbazones and the generation of reactive oxygen species such as HO• PMID:23485585

  5. Indole-7-carbaldehyde thiosemicarbazone as a flexidentate ligand toward ZnII, CdII, PdII and PtII ions: cytotoxic and apoptosis-inducing properties of the PtII complex.

    PubMed

    Ibrahim, Abeer A; Khaledi, Hamid; Hassandarvish, Pouya; Mohd Ali, Hapipah; Karimian, Hamed

    2014-03-14

    A new thiosemicarbazone (LH2) derived from indole-7-carbaldehyde was synthesized and reacted with Zn(II), Cd(II), Pd(II) and Pt(II) salts. The reactions with zinc and cadmium salts in 2 : 1 (ligand-metal) molar ratio afforded complexes of the type MX2(LH2)2, (X = Cl, Br or OAc), in which the thiosemicarbazone acts as a neutral S-monodentate ligand. In the presence of potassium hydroxide, the reaction of LH2 with ZnBr2 resulted in deprotonation of the thiosemicarbazone at the hydrazine and indole nitrogens to form Zn(L)(CH3OH). The reaction of LH2 with K2PdCl4 in the presence of triethylamine, afforded Pd(L)(LH2) which contains two thiosemicarbazone ligands: one being dianionic N,N,S-tridentate while the other one is neutral S-monodentate. When PdCl2(PPh3)2 was used as the Pd(II) ion source, Pd(L)(PPh3) was obtained. In a similar manner, the analogous platinum complex, Pt(L)(PPh3), was synthesized. The thiosemicarbazone in the latter two complexes behaves in a dianionic N,N,S-tridentate fashion. The platinum complex was found to have significant cytotoxicity toward four cancer cells lines, namely MDA-MB-231, MCF-7, HT-29, and HCT-116 but not toward the normal liver WRL-68 cell line. The apoptosis-inducing properties of the Pt complex was explored through fluorescence microscopy visualization, DNA fragmentation analysis and propidium iodide flow cytometry.

  6. Cinnamaldehyde and cuminaldehyde thiosemicarbazones and their copper(II) and nickel(II) complexes: a study to understand their biological activity.

    PubMed

    Bisceglie, Franco; Pinelli, Silvana; Alinovi, Rossella; Goldoni, Matteo; Mutti, Antonio; Camerini, Alessandro; Piola, Lorenzo; Tarasconi, Pieralberto; Pelosi, Giorgio

    2014-11-01

    This paper reports the synthesis and characterization of trans-cinnamaldehyde thiosemicarbazone (Htcin), cuminaldehyde thiosemicarbazone (Htcum) and their copper and nickel complexes. All the compounds, which on healthy cells (human fibroblasts) show a neglectable cytotoxicity, were screened in vitro in cell line U937 for their antileukemic activity. These compounds, in spite of their molecular similarity, present variegated behaviors. Htcin shows no inhibition activity in U935 cells, while both its metal complexes inhibit proliferation with IC50 at μM concentrations. The other ligand, Htcum, and its metal complexes, besides inhibiting proliferation, induce apoptosis. The cell cycle analysis highlights a G2/M checkpoint stop suggesting a possible direct action on DNA or on topoisomerase IIa. From CD and UV spectroscopy experiments, the DNA results to be not the main target of all these molecules, while both copper complexes are effective topoisomerase IIa inhibitors. All of these molecules activate caspase-9 and caspase-3, while caspase-8 activity is significantly induced by both cinnamaldehyde metal complexes. Tests on PgP and intracellular metal concentrations (determined by mean of atomic absorption spectrometry) show that the compounds tend to accumulate in the cytoplasm and that the cells do not manage to pump out copper and nickel ions.

  7. A dual radiolabelling approach for tracking metal complexes: investigating the speciation of copper bis(thiosemicarbazonates) in vitro and in vivo.

    PubMed

    Hueting, Rebekka; Kersemans, Veerle; Tredwell, Matthew; Cornelissen, Bart; Christlieb, Martin; Gee, Antony D; Passchier, Jan; Smart, Sean C; Gouverneur, Véronique; Muschel, Ruth J; Dilworth, Jonathan R

    2015-05-01

    Copper(II)bis(thiosemicarbazonato) complexes such as [(64)Cu]Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the copper metal and the ligand, we designed a pair of (123)I/(64)Cu-copper bis(thiosemicarbazonates), radiolabelled at either the metal or at the ligand. In vitro cellular retention studies of the orthogonal pair demonstrate for the first time that retention under hypoxia involves dissociation of the copper bis(thiosemicarbazone) complex, consistent with the previously suggested mechanism of reductive trapping of copper. In contrast, in vivo biodistribution and dynamic PET/SPECT imaging of the orthogonally labelled complexes underline our previous findings for [(64)Cu]Cu-ATSM and [(64)Cu]Cu-acetate, providing further support for the important contribution of copper metabolism in the in vivo hypoxia selectivity of Cu-ATSM. This dual radiolabelling approach may find applications for determining the speciation of other metal complexes in vitro and in vivo.

  8. The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the "Triad of Death" in cancer by Di-2-pyridylketone thiosemicarbazones.

    PubMed

    Jansson, Patric J; Kalinowski, Danuta S; Lane, Darius J R; Kovacevic, Zaklina; Seebacher, Nicole A; Fouani, Leyla; Sahni, Sumit; Merlot, Angelica M; Richardson, Des R

    2015-10-01

    Cancer is a disease that is a "moving target", since as the condition progresses, the molecular targets change and evolve. Moreover, due to clonal selection, a specific anti-cancer drug with one molecular target may only be effective for a limited time period before drug resistance results and the agent becomes ineffective. Hence, the concept of an anti-tumor therapeutic exhibiting polypharmacology can be highly advantageous, rather than a therapeutic obstacle. A novel class of agents possessing these desirable properties are the di-2-pyridylketone thiosemicarbazones, which bind iron and copper to affect a variety of critical molecular targets in tumors. In fact, these compounds possess multiple properties that enable them to overcome the "triad of death" in cancer, namely: primary tumor growth, drug resistance and metastasis. In fact, at the molecular level, their potent anti-oncogenic activity includes: up-regulation of the metastasis suppressor, N-myc downstream regulated gene 1; up-regulation of the tumor suppressor, PTEN; down-regulation of the proto-oncogene, cyclin D1; inhibition of the rate-limiting step in DNA synthesis catalyzed by ribonucleotide reductase; and the inhibition of multiple oncogenic signaling pathways, e.g., Ras/MAPK signaling, protein kinase B (AKT)/phosphatidylinositol-3-kinase, ROCK/pMLC2, etc. This Perspective article discusses the advantages of incorporating polypharmacology into anti-cancer drug design using the di-2-pyridylketone thiosemicarbazones as a pertinent example. PMID:26318762

  9. Evaluation of anti-inflammatory effect of derivative (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone.

    PubMed

    de Oliveira, Jamerson Ferreira; Nonato, Fabiana Regina; Zafred, Rafael Rosolen Teixeira; Leite, Nayara Maria Siqueira; Ruiz, Ana Lúcia Tasca Gois; de Carvalho, João Ernesto; da Silva, Anekécia Lauro; de Moura, Ricardo Olímpio; Alves de Lima, Maria do Carmo

    2016-05-01

    The present study aimed to further investigate the anti-inflammatory activity of (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone (BTTSC) as well as its antinociceptive effects. The anti-inflammatory activity was assessed using the model of ear edema induced by croton oil-induced and also evaluated in models of paw edema carrageenan-induced and by compound 48/80. Evaluation of the antinociceptive effect was performed through formalin test. In the nociception test induced by formalin the BTTSC showed activity in both phases of the pain, highlighting inflammatory pain, where it was able to reduce the time to paw lick 62.3, 84.30 and 100% at doses of 30, 100 and 300mgkg(-1). The anti-inflammatory activity was performed ear edema induced by croton oil, where none of the doses tested was capable of significantly regress edema. The paw edema carrageenan-induced showed activity compound, where the edema was reduced by 81.9 and 83.2% in the first two times of the experiment at the highest dose used. The paw edema assay induced by compound 48/80, showed that BTTSC after 15min of the inoculum phlogistic agent showed significant reduction of edema with values of 56.53% at a dose of 30mgkg(-1). Our results suggesting this compound exerts its antinociception effects connected with peripheral mechanisms. Furthermore, the compound was able to act in two phases of inflammation carrageenan-induced, highlighting the initial phase. This suggests an action on the early mediators of inflammation. The paw edema assay induced by compound 48/80 confirmed our hypothesis indicating action of the compound via histamine.

  10. Pterostilbene carboxaldehyde thiosemicarbazone, a resveratrol derivative inhibits 17β-Estradiol induced cell migration and proliferation in HUVECs.

    PubMed

    Nikhil, Kumar; Sharan, Shruti; Wishard, Rohan; Palla, Srinivasa Rao; Krishna Peddinti, Rama; Roy, Partha

    2016-04-01

    Angiogenesis plays important roles in tumor growth and metastasis, thus development of a novel angiogenesis inhibitor is essential for the improvement of therapeutics against cancer. Thrombospondins-1 (TSP-1) is a potent endogenous inhibitor of angiogenesis that acts through direct effects on endothelial cell migration, proliferation, survival, and activating apoptotic pathways. TSP-1 has been shown to disrupt estrogen-induced endothelial cell proliferation and migration. Here we investigated the potential of pterostilbene carboxaldehyde thiosemicarbazone (PTERC-T), a novel resveratrol (RESV) derivative, to inhibit angiogenesis induced by female sex steroids, particularly 17β-Estradiol (E2), on Human umbilical vein endothelial cells (HUVECs) and to elucidate the involvement of TSP-1 in PTERC-T action. Our results showed that PTERC-T significantly inhibited 17β-E2-stimulated proliferation of HUVECs and induced apoptosis as determined by annexin V/propidium iodide staining and cleaved caspase-3 expression. Furthermore, PTERC-T also inhibited endothelial cell migration, and invasion in chick chorioallantoic membrane (CAM) assay. In contrast, RESV failed to inhibit 17β-E2 induced HUVECs proliferation and invasion at similar dose. PTERC-T was also found to increase TSP-1 protein expression levels in a dose-dependent manner which, however, was counteracted by co-incubation with p38MAPK or JNK inhibitors, suggesting involvement of these pathways in PTERC-T action. These results suggest that the inhibitory effect of PTERC-T on 17β-E2 induced angiogenesis is associated, at least in part, with its induction of endothelial cell apoptosis and inhibition of cell migration through targeting TSP-1. Thus, PTERC-T could be considered as a potential lead compound for developing a class of new drugs targeting angiogenesis-related diseases.

  11. Evaluation of anti-inflammatory effect of derivative (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone.

    PubMed

    de Oliveira, Jamerson Ferreira; Nonato, Fabiana Regina; Zafred, Rafael Rosolen Teixeira; Leite, Nayara Maria Siqueira; Ruiz, Ana Lúcia Tasca Gois; de Carvalho, João Ernesto; da Silva, Anekécia Lauro; de Moura, Ricardo Olímpio; Alves de Lima, Maria do Carmo

    2016-05-01

    The present study aimed to further investigate the anti-inflammatory activity of (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone (BTTSC) as well as its antinociceptive effects. The anti-inflammatory activity was assessed using the model of ear edema induced by croton oil-induced and also evaluated in models of paw edema carrageenan-induced and by compound 48/80. Evaluation of the antinociceptive effect was performed through formalin test. In the nociception test induced by formalin the BTTSC showed activity in both phases of the pain, highlighting inflammatory pain, where it was able to reduce the time to paw lick 62.3, 84.30 and 100% at doses of 30, 100 and 300mgkg(-1). The anti-inflammatory activity was performed ear edema induced by croton oil, where none of the doses tested was capable of significantly regress edema. The paw edema carrageenan-induced showed activity compound, where the edema was reduced by 81.9 and 83.2% in the first two times of the experiment at the highest dose used. The paw edema assay induced by compound 48/80, showed that BTTSC after 15min of the inoculum phlogistic agent showed significant reduction of edema with values of 56.53% at a dose of 30mgkg(-1). Our results suggesting this compound exerts its antinociception effects connected with peripheral mechanisms. Furthermore, the compound was able to act in two phases of inflammation carrageenan-induced, highlighting the initial phase. This suggests an action on the early mediators of inflammation. The paw edema assay induced by compound 48/80 confirmed our hypothesis indicating action of the compound via histamine. PMID:27133079

  12. Effects of butane-2,3-dione thiosemicarbazone oxime on testicular damage induced by cadmium in mice.

    PubMed

    de Freitas, Mayara Lutchemeyer; Dalmolin, Laíza; Oliveira, Lia Pavelacki; da Rosa Moreira, Laís; Roman, Silvane Souza; Soares, Félix Alexandre Antunes; Bresolin, Leandro; Duarte, Marta Maria Medeiros Frescura; Brandão, Ricardo

    2012-01-01

    Our group of studies investigated the action of butane-2,3-dione thiosemicarbazone oxime against the testicular damage caused by cadmium chloride (CdCl(2)) in mice. Mice received a single injection of CdCl(2 )(5 mg/kg, intraperitoneally) and, after thirty minutes, the oxime (10 mg/kg, subcutaneously) was administered. Twenty four hours after the last administration, the animals were killed by cervical dislocation and the testes and serum were removed for analysis. The parameters determined were δ-aminolevulinate dehydratase (δ-ALA-D), myeloperoxidase (MPO), glutathione-S-transferase (GST) and glutathione peroxidase (GPx) activities. The levels of thiobarbituric acid-reactive substances (TBARS), nonprotein thiols (NPSH), ascorbic acid, cadmium and testosterone were also determined. In addition, histological analysis and cytokines quantification (IL-1, IL-6, IL-10, TNF-α and IFN-γ) were performed. Our results demonstrated that the oxime was effective in restoring the inhibition in δ-ALA-D activity induced by CdCl(2). The activation of MPO and increase in IL-1, IL-6, TNF-α and IFN-γ levels induced by CdCl(2) were also reduced by oxime. IL-10, which was reduced by cadmium, was restored by oxime administration. In addition, the oxime was effective in restoring the increase in TBARS levels and the reduction on NPSH levels induced by CdCl(2). Our results demonstrated that oxime was effective in containing the histological alterations induced by CdCl(2). In addition, oxime was able to increase the testosterone levels, reduced by cadmium exposure. In conclusion, the oxime tested was effective in reducing the testicular damage induced by CdCl(2) in mice. The beneficial effects of this oxime are related to its antioxidant and anti-inflammatory action. PMID:23038000

  13. Characterization of the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound, in vitro and in vivo

    PubMed Central

    Liu, Min-yu; Xiao, Lin; Dong, Yu-qiong; Liu, Ying; Cai, Li; Xiong, Wei-xia; Yao, Yu-long; Yin, Ming; Liu, Quan-hai

    2014-01-01

    Aim: To investigate the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound in vitro and in vivo. Methods: The anti-proliferative action of S115 was analyzed in 12 human and mouse cancer cell lines using MTT assay. Autograft and xenograft cancer models were made by subcutaneous inoculation of cancer cells into mice or nude mice. The mice were orally treated with S115 (2, 8, 32 mg·kg−1·d−1) for 7 d, and the tumor size was measured every 3 d. Cell apoptosis and cell cycle distribution were examined using flow cytometry, gene expression profile analyses, Western blots and RT-PCR. Results: The IC50 values of S115 against 12 human and mouse cancer cell lines ranged from 0.3 to 6.6 μmol/L. The tumor growth inhibition rate caused by oral administration of S115 (32 mg·kg−1·d−1) were 89.7%, 81.7%, 78.4% and 77.8%, respectively, in mouse model of B16 melanoma, mouse model of Colon26 colon cancer, nude mouse model of A549 lung cancer and nude mouse model of SK-OV-3 ovarian cancer. Furthermore, oral administration of S115 (7.5 mg·kg−1·d−1) synergistically enhanced the anticancer effects of cyclophosphamide, cisplatin, or 5-fluorouracil in mouse model of S180 sarcoma. Treatment of A549 human lung cancer cells with S115 (1.5 μmol/L) induced G0/G1 cell cycle arrest, and increased apoptosis. Furthermore, S115 downregulated the level of ubiquitin, and upregulated the level of Tob2 in A549 cells. Conclusion: S115 exerts anticancer effects against a variety of cancer cells in vitro and in grafted cancer models by inducing apoptosis, downregulating ubiquitin and upregulating Tob2. PMID:25220642

  14. Nickel(II) Complex of Polyhydroxybenzaldehyde N4-Thiosemicarbazone Exhibits Anti-Inflammatory Activity by Inhibiting NF-κB Transactivation

    PubMed Central

    Loh, Sheng Wei; Looi, Chung Yeng; Hassandarvish, Pouya; Phan, Alicia Yi Ling; Wong, Won Fen; Wang, Hao; Paterson, Ian C.; Ea, Chee Kwee; Mustafa, Mohd Rais; Maah, Mohd Jamil

    2014-01-01

    Background The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity. Methodology/Principal Findings Four ligands (1–4) and their respective nickel-containing complexes (5–8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis. Conclusions/Significance Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects. PMID:24977407

  15. Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates.

    PubMed

    Belicchi-Ferrari, Marisa; Bisceglie, Franco; Buschini, Annamaria; Franzoni, Susanna; Pelosi, Giorgio; Pinelli, Silvana; Tarasconi, Pieralberto; Tavone, Matteo

    2010-02-01

    This paper reports the syntheses and characterization of ethylmorpholine substituted citronellal thiosemicarbazone copper(II) and nickel(II) metal complexes. The compounds were characterized through elemental analyses and spectroscopic (IR, UV-Vis, NMR, MS) methods. The X-ray analysis of the two complexes shows that both Ni and Cu derivatives present a square planar coordination, where the coordinating homologous donor atoms bind in trans to each other. The compounds were tested for their biological activity after determination of their octanol-saline partition coefficients, followed by their radical scavenging properties. Eventually the complexes were tested for their proliferation inhibition on human histiocytic lymphoma U937 cell line. The GI(50) values resulted to be 2.3microM for the copper derivative and 12.3microM for the nickel derivative.

  16. Spectral studies on Co(II), Ni(II) and Cu(II) complexes with thiosemicarbazone (L 1) and semicarbazone (L 2) derived from 2-acetyl furan

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Kumar, Anil

    2007-04-01

    Co(II), Ni(II) and Cu(II) complexes are synthesized with thiosemicarbazone (L 1) and semicarbazone (L 2) derived from 2-acetyl furan. These complexes are characterized by elemental analysis, molar conductance, magnetic susceptibility measurements, mass, IR, electronic and EPR spectral studies. The molar conductance measurements of the complexes in DMSO correspond to non-electrolytic nature except Ni(L) 2(NO 3) 2, which is 1:2 electrolyte. All the complexes are of high-spin type. On the basis of spectral studies an octahedral geometry may be assigned for Co(II) and Ni(II) complexes except nitrato complexes of Ni(II) which is of tetrahedral geometry, whereas tetragonal geometry for Cu(II) complexes.

  17. Cu(II) Bis(thiosemicarbazone) Radiopharmaceutical Binding to Serum Albumin: Further Definition of Species-Dependence and Associated Substituent Effects

    PubMed Central

    Basken, Nathan E.; Green, Mark A.

    2009-01-01

    Introduction The Cu-PTSM (pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II)) and Cu-ATSM (diacetyl bis(N4-methylthiosemicarbazonato)copper(II)) radiopharmaceuticals exhibit strong, species-dependent binding to the IIA site of human serum albumin (HSA), while the related Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)) radiopharmaceutical appears to only exhibit non-specific binding to human and animal serum albumins. Methods To further probe the structural basis for the species-dependence of this albumin binding interaction, protein binding of these three radiopharmaceuticals was examined in solutions of albumin and/or serum from a broader array of mammalian species (rat, sheep, donkey, rabbit, cow, pig, dog, baboon, mouse, cat, elephant). We also evaluated the albumin binding of several copper(II) bis(thiosemicarbazone) chelates offering more diverse substitution of the ligand backbone. Results Cu-PTSM and Cu-ATSM exhibit a strong interaction with HSA that is not apparent with the albumins of other species, while the binding of Cu-ETS to albumin is much less species-dependent. The strong interaction of Cu-PTSM with HSA does not appear to simply correlate with variation, relative to the animal albumins, of a single amino acid lining HSA's IIA site. Those agents that selectively interact with HSA share the common feature of only methyl or hydrogen substitution at the carbon atoms of the diimine fragment of the ligand backbone. Conclusions The interspecies variations in albumin binding of Cu-PTSM and Cu-ATSM are not simply explained by unique amino acid substitutions in the IIA binding pocket of the serum albumins. However, the specific affinity for this region of HSA is disrupted when substituents bulkier than a methyl group appear on the imine carbons of the copper bis(thiosemicarbazone) chelate. PMID:19520290

  18. Synthesis, structures, spectroscopy and antimicrobial properties of complexes of copper(II) with salicylaldehyde N-substituted thiosemicarbazones and 2,2'-bipyridine or 1,10-phenanthroline.

    PubMed

    Lobana, Tarlok S; Indoria, Shikha; Jassal, Amanpreet Kaur; Kaur, Harpreet; Arora, Daljit S; Jasinski, Jerry P

    2014-04-01

    Among the biometals (Cu, Co, Ni-cofactors in many enzymes), copper derivatives of O, N, S-donor salicylaldehyde thiosemicarbazones have received considerable attention owing to their potential biological applications. Eight new complexes of salicylaldehyde-N-substituted thiosemicarbazones [5-MeO-2-HO-C₆H₄-C(2)(H)N(3)-N(2)H-C(1)(S)-N(1)HR; R = Me, H2L(1); Et, H₂L(1), Ph, H₂L(3), H, H₂L(4)] with copper(II), namely, [Cu(κ(3)-O,N,S-L)( κ(2)-N,N-L')] {(L)(2-) = (L(1))(2-), L' = bipy, 1, phen, 2; (L)(2-) = (L(2))(2-), L' = bipy, 3, phen, 4; (L)(2-) = (L(3))(2-), L' = bipy, 5, phen, 6; (L)(2-) = (L(4))(2-), L' = bipy, 7, phen, 8} have been isolated. Complexes have slightly distorted square pyramidal geometry around the metal center (τ parameter = 0.243-0.357) and display weak to intense fluorescence in the region, 375-475 nm. These copper complexes have shown significant growth inhibitory activity (antimicrobial activity) against Staphylococcus aureus (MTCC740), methicillin resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae 1 (MTCC109), Shigella flexneri (MTCC1457), Pseudomonas aeruginosa (MTCC741) and Candida albicans (MTCC227). The activity against MRSA is an interesting observation as the commercially available gentamycin is found to be inactive against this bacterial strain. Specifically complex 5 formed by 5-methoxysalicylaldehyde-N-phenylthiosemicatbazone has shown novel antimicrobial activity against various bacteria and yeast investigated. PMID:24583354

  19. Influence of terminal substitution on structural, DNA, protein binding, anticancer and antibacterial activities of palladium(II) complexes containing 3-methoxy salicylaldehyde-4(N) substituted thiosemicarbazones.

    PubMed

    Kalaivani, P; Prabhakaran, R; Ramachandran, E; Dallemer, F; Paramaguru, G; Renganathan, R; Poornima, P; Vijaya Padma, V; Natarajan, K

    2012-02-28

    The variable chelating behavior of 3-methoxysalicylaldehyde-4(N)-substituted thiosemicarbazones was observed in equimolar reactions with [PdCl(2)(PPh(3))(2)]. The new complexes were characterized by various analytical, spectroscopic techniques (mass, (1)H-NMR, absorption, IR). All the new complexes were structurally characterized by single crystal X-ray diffraction. Crystallographic results showed that the ligands H(2)L(1) and H(2)L(4) are coordinated as binegative tridentate ONS donor ligands in the complexes 1 and 4 by forming six and five member rings. However, the ligands H(2)L(2) and H(2)L(3) bound to palladium in 2 and 3 as uninegative bidentate NS donors by forming a five member chelate ring. From this study, it was found that the substitution on terminal 4(N)-nitrogen may have an influence on the chelating ability of thiosemicarbazone. The presence of hydrogen bonding in 2 and 3 might be responsible for preventing the coordination of phenolic oxygen to the metal ion. The interaction of the complexes with calf-thymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an electrostatic binding mode of DNA has been proposed. The protein binding studies were monitored by quenching of tryptophan and tyrosine residues in the presence of complexes using Lysozyme as model protein. Antibacterial activity studies of the complexes have been screened against pathogenic bacteria such as Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa. MIC50 values of the complexes showed that they exhibited significant activity against the pathogens and among them, 3 exhibited higher activity. Further, anticancer activity of the complexes on the lung cancer cell line A549 has also been studied. PMID:22222360

  20. Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators: effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool.

    PubMed

    Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B; Kalinowski, Danuta S; Lovejoy, David B; Lane, Darius J R; Richardson, Des R

    2013-12-01

    Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50=4.45±1.70, 10.30±4.40, and 3.64±2.00μM, respectively) than DFO (IC50=23.43±3.40μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization.

  1. Computational study of the vibrational spectroscopic studies, natural bond orbital, frontier molecular orbital and second-order non-linear optical properties of acetophenone thiosemicarbazone molecule.

    PubMed

    Li, Xiao-Hong; Mei, Zheng; Zhang, Xian-Zhou

    2014-01-24

    The vibrational frequencies of acetophenone thiosemicarbazone in the ground state have been calculated using density functional method (B3LYP) with 6-31G(d), 6-31G(d,p) and 6-311++G(d,p) basis sets. The analysis of natural bond orbital was also performed. The IR spectra were obtained and interpreted by means of potential energies distributions (PEDs) using MOLVIB program. In addition, the results show that there exist N-H…N and N-H…S hydrogen bonds in the title compound, which play a major role in stabilizing the molecule and are confirmed by the natural bond orbital analysis. The predicted NLO properties show that the title compound is a good candidate as second-order NLO material. In addition, the frontier molecular orbitals were analyzed and the crystal structure obtained by molecular mechanics belongs to the Pbca space group, with lattice parameters Z=8, a=16.0735 Å, b=7.1719 Å, c=7.8725 Å, ρ=0.808 g/cm(3).

  2. Crystal structures of copper(II) chloride, copper(II) bromide, and copper(II) nitrate complexes with pyridine-2-carbaldehyde thiosemicarbazone

    SciTech Connect

    Chumakov, Yu. M.; Tsapkov, V. I.; Jeanneau, E.; Bairac, N. N.; Bocelli, G.; Poirier, D.; Roy, J.; Gulea, A. P.

    2008-09-15

    The crystal structures of chloro-(2-formylpyridinethiosemicarbazono)copper dimethyl sulfoxide solvate (I), bromo-(2-formylpyridinethiosemicarbazono)copper (II), and (2-formylpyridinethiosemicarbazono)copper(II) nitrate dimethyl sulfoxide solvate (III) are determined using X-ray diffraction. In the crystals, complexes I and II form centrosymmetric dimers in which the thiosemicarbazone sulfur atom serves as a bridge and occupies the fifth coordination site of the copper atom of the neighboring complex related to the initial complex through the center of symmetry. In both cases, the coordination polyhedron of the complexing ion is a distorted tetragonal bipyramid. Complex III in the crystal structure forms polymer chains in which the copper atom of one complex forms the coordination bond with the thicarbamide nitrogen atom of the neighboring complex. In this structure, the coordination polyhedron of the central atom is an elongated tetragonal bipyramid. It is established that complexes I-III at a concentration of 10{sup -5} mol/l selectively inhibit the growth of 60 to 90 percent of the cancer tumor cells of the human myeloid leukemia (HL-60).

  3. Simultaneous spectrophotometric determination of copper, cobalt, nickel and iron in foodstuffs and vegetables with a new bis thiosemicarbazone ligand using chemometric approaches.

    PubMed

    Rohani Moghadam, Masoud; Poorakbarian Jahromi, Sayedeh Maria; Darehkordi, Ali

    2016-02-01

    A newly synthesized bis thiosemicarbazone ligand, (2Z,2'Z)-2,2'-((4S,5R)-4,5,6-trihydroxyhexane-1,2-diylidene)bis(N-phenylhydrazinecarbothioamide), was used to make a complex with Cu(2+), Ni(2+), Co(2+) and Fe(3+) for their simultaneous spectrophotometric determination using chemometric methods. By Job's method, the ratio of metal to ligand in Ni(2+) was found to be 1:2, whereas it was 1:4 for the others. The effect of pH on the sensitivity and selectivity of the formed complexes was studied according to the net analyte signal (NAS). Under optimum conditions, the calibration graphs were linear in the ranges of 0.10-3.83, 0.20-3.83, 0.23-5.23 and 0.32-8.12 mg L(-1) with the detection limits of 2, 3, 4 and 10 μg L(-1) for Cu(2+), Co(2+), Ni(2+) and Fe(3+) respectively. The OSC-PLS1 for Cu(2+) and Ni(2+), the PLS1 for Co(2+) and the PC-FFANN for Fe(3+) were selected as the best models. The selected models were successfully applied for the simultaneous determination of elements in some foodstuffs and vegetables.

  4. Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP).

    PubMed

    Heng, Mok Piew; Sinniah, Saravana Kumar; Teoh, Wuen Yew; Sim, Kae Shin; Ng, Seik Weng; Cheah, Yoke Kqueen; Tan, Kong Wai

    2015-01-01

    Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism. PMID:26057090

  5. Gallium(III) complexes with 2-acetylpyridine-derived thiosemicarbazones: antimicrobial and cytotoxic effects and investigation on the interactions with tubulin.

    PubMed

    Lessa, Josane A; Soares, Marcella A; dos Santos, Raquel G; Mendes, Isolda C; Salum, Lívia B; Daghestani, Hikmat N; Andricopulo, Adriano D; Day, Billy W; Vogt, Andreas; Beraldo, Heloisa

    2013-02-01

    Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.

  6. Highly efficient ultrasonic-assisted removal of Hg(II) ions on graphene oxide modified with 2-pyridinecarboxaldehyde thiosemicarbazone: Adsorption isotherms and kinetics studies.

    PubMed

    Tadjarodi, Azadeh; Moazen Ferdowsi, Somayeh; Zare-Dorabei, Rouholah; Barzin, Ahmad

    2016-11-01

    A novel adsorbent, based on modifying graphene oxide (GO) chemically with 2-pyridinecarboxaldehyde thiosemicarbazone (2-PTSC) as ligand, was designed by facile process for removal of Hg(II) from aqueous solution. Characterization of the adsorbent was performed using various techniques, such as FT-IR, XRD, XPS, SEM and AFM analysis. The adsorption capacity was affected by variables such as adsorbent dosage, pH solution, Hg(2+) initial concentration and sonicating time. These variables were optimized by rotatable central composite design (CCD) under response surface methodology (RSM). The predictive model for Hg(II) adsorption was constructed and applied to find the best conditions at which the responses were maximized. In this conditions, the adsorption capacity of this adsorbent for Hg(2+) ions was calculated to be 309mgg(-1) that was higher than that of GO. Appling the ultrasound power combined with adsorption method was very efficient in shortening the removal time of Hg(2+) ions by enhancing the dispersion of adsorbent and metal ions in solution and effective interactions among them. The adsorption process was well described by second-order kinetic and Langmuir isotherm model in which the maximum adsorption capacity (Qm) was found to be 555mgg(-1) for adsorption of Hg(2+) ions over the obtained adsorbent. The performance of adsorbent was examined on the real wastewaters and confirmed the applicability of adsorbent for practical applications. PMID:27245963

  7. Evaluation of DNA-binding, DNA cleavage, antioxidant and cytotoxic activity of mononuclear ruthenium(II) carbonyl complexes of benzaldehyde 4-phenyl-3-thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    Sampath, Krishnan; Sathiyaraj, Subbaiyan; Jayabalakrishnan, Chinnasamy

    2013-11-01

    Two 4-phenyl-3-thiosemicarbazone ligands, (E)-2-(2-chlorobenzylidene)-N-phenylhydrazinecarbothioamide (HL1) and (E)-2-(2-nitrobenzylidene)-N-phenylhydrazinecarbothioamide (HL2), and its ruthenium(II) complexes were synthesized and characterized by physico-chemical and spectroscopic methods. The Schiff bases act as bidentate, monobasic chelating ligands with S and N as the donor sites and are preferably found in the thiol form in all the complexes studied. The molecular structure of HL1 and HL2 were determined by single crystal X-ray diffraction method. DNA binding of the compounds was investigated by absorption spectroscopy which indicated that the compounds bind to DNA via intercalation. The oxidative cleavage of the complexes with CT-DNA inferred that the effects of cleavage are dose dependent. Antioxidant study of the ligands and complexes showed significant antioxidant activity against DPPH radical. In addition, the in vitro cytotoxicity of the ligands and complexes assayed against HeLa and MCF-7 cell lines showed higher cytotoxic activity with the lower IC50 values indicating their efficiency in killing the cancer cells even at low concentrations.

  8. Mixed ligand ruthenium(III) complexes of benzaldehyde 4-methyl-3-thiosemicarbazones with triphenylphosphine/triphenylarsine co-ligands: Synthesis, DNA binding, DNA cleavage, antioxidative and cytotoxic activity

    NASA Astrophysics Data System (ADS)

    Sampath, K.; Sathiyaraj, S.; Raja, G.; Jayabalakrishnan, C.

    2013-08-01

    The new ruthenium(III) complexes with 4-methyl-3-thiosemicarbazone ligands, (E)-2-(2-chlorobenzylidene)-N-methylhydrazinecarbothioamide (HL1) and (E)-2-(2-nitrobenzylidene)-N-methylhydrazinecarbothioamide (HL2), were prepared and characterized by various physico-chemical and spectroscopic methods. The title compounds act as bidentate, monobasic chelating ligands with S and N as the donor sites and are preferably found in the thiol form in all the complexes studied. The molecular structure of HL1 and HL2 were determined by single crystal X-ray diffraction method. DNA binding of the ligands and complexes were investigated by absorption spectroscopy and IR spectroscopy. It reveals that the compounds bind to nitrogenous bases of DNA via intercalation. The oxidative cleavage of the complexes with CT-DNA inferred that the effects of cleavage are dose dependent. Antioxidant study of the ligands and complexes showed the significant antioxidant activity against DPPH radical. In addition, the in vitro cytotoxicity of the ligands and complexes against MCF-7 cell line was assayed which showed higher cytotoxic activity with the lower IC50 values indicating their efficiency in killing the cancer cells even at low concentrations.

  9. 4-Nitrobenzaldehyde thiosemicarbazone: a new compound derived from S-(-)-limonene that induces mitochondrial alterations in epimastigotes and trypomastigotes of Trypanosoma cruzi.

    PubMed

    Britta, Elizandra Aparecida; Scariot, Débora Botura; Falzirolli, Hugo; da Silva, Cleuza Conceição; Ueda-Nakamura, Tânia; Dias Filho, Benedito Prado; Borsali, Redouane; Nakamura, Celso Vataru

    2015-06-01

    Trypanosoma cruzi is the causative agent of Chagas' disease, a parasitic disease that remains a serious health concern with unsatisfactory treatment. Drugs that are currently used to treat Chagas' disease are partially effective in the acute phase but ineffective in the chronic phase of the disease. The aim of the present study was to evaluate the antitrypanosomal activity and morphological, ultrastructural and biochemical alterations induced by a new molecule, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-(-)-limonene against epimastigote, trypomastigote and intracellular amastigote forms of T. cruzi. BZTS inhibited the growth of epimastigotes (IC50 = 9·2 μ m), intracellular amastigotes (IC50 = 3·23 μ m) and inhibited the viability of trypomastigotes (EC50 = 1·43 μ m). BZTS had a CC50 of 37·45 μ m in LLCMK2 cells. BZTS induced rounding and distortion of the cell body and severely damaged parasite mitochondria, reflected by extensive swelling and disorganization in the inner mitochondrial membrane and the presence of concentric membrane structures inside the organelle. Cytoplasmic vacuolization, endoplasmic reticulum that surrounded organelles, the loss of mitochondrial membrane potential, and increased mitochondrial O2 •- production were also observed. Our results suggest that BZTS alters the ultrastructure and physiology of mitochondria, which could be closely related to parasite death.

  10. Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one thiosemicarbazone.

    PubMed

    Savithiri, S; Arockia doss, M; Rajarajan, G; Thanikachalam, V; Bharanidharan, S; Saleem, H

    2015-02-01

    In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c-diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground-state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6-31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED⩾10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (μ) and first hyperpolarizability (βo) values have been computed using DFT/B3LYP and HF methods. The calculated result (βo) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6-31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out. PMID:25448976

  11. Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Savithiri, S.; Arockia doss, M.; Rajarajan, G.; Thanikachalam, V.; Bharanidharan, S.; Saleem, H.

    2015-02-01

    In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c-diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground-state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6-31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED ⩾ 10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (μ) and first hyperpolarizability (βo) values have been computed using DFT/B3LYP and HF methods. The calculated result (βo) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6-31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out.

  12. Effects on rat testes of the thiosemicarbazone derivative Schiff base (4-(1-phenylmethylcyclobutane-3-yl)-2-(2-hydroxybenzylidenehydrazino)thiazole) and its cadmium(II) complex.

    PubMed

    Oner, Hakan; Karatepe, Mustafa; Karatas, Fikret; Oner, Jale; Yilmaz, Ibrahim; Cukurovali, Alaaddin

    2005-01-01

    The aim of this study was to investigate structural and biochemical changes in testes of rats treated with the thiosemicarbazone derivative thiazole ring Schiff base, (4-(1-phenyl-methylcyclobutane-3-yl)-2-(2-hydroxybenzylidene-hydrazino) thiazole (L), and its Cd(II) complex (CdL(2)). The animals were divided into three groups. Group I was designated as control. The rats in groups II and III were injected subcutaneously with L or CdL(2) respectively at 150-mg kg(-1) doses at 3-day intervals for 15 days. At the end of the study, blood samples were collected for biochemical analysis, and testes were removed for histological examinations. Serum levels of vitamin A, E and MDA of the L-injected group were similar to the control group. While CdL(2) treatment decreased serum vitamin A and E levels, it increased the MDA level compared to other groups. Histologically, the testes structures of L-treated animals were similar to the control. Spermatogenic cells in seminiferous tubules of CdL(2)-treated animals displayed necrosis. Nuclei of spermatogonia and primary spermatocytes were pyknotic and heterochromatic. Homogenous pink particles were present in place of the spermatids. The interstitial areas were oedematous and intertubular vessels were plugged. In conclusion, the present results indicate that L does not cause biochemical and morphological alterations, but its Cd(II) complex has degenerative effects in normal rat testes.

  13. Complexation of a 1-Indanone Thiosemicarbazone with Hydroxypropyl-β-Cyclodextrin Enhances Its Activity Against a Hepatitis C Virus Surrogate Model.

    PubMed

    Glisoni, Romina J; Castro, Eliana F; Cavallaro, Lucía V; Moglioni, Albertina G; Sosnik, Alejandro

    2015-06-01

    The current standard of care of the infection by hepatitis C virus (HCV) is effective in a limited number of patients and the high cost hinders therapy affordability and compliance. In this context, the research of new direct-acting antiviral agents (DAAs) for a more effective and long-lasting therapy is an urgent need and an area of active investigation. In an effort to develop novel DAAs, a series of 1-indanone thiosemicarbazones (TSCs) was synthesized and fully characterized. However, the high self-aggregation tendency and extremely poor aqueous solubility of these antiviral candidates often preclude their reliable biological evaluation in vitro. To maintain constant TSC concentrations over the biological assays, different TSC/cyclodextrin complexes were produced. In the present work, we report for the first time the cytotoxicity and antiviral activity of 5,6-dimethoxy TSC inclusion complexes with hydroxypropyl-β-cyclodextrin on bovine viral diarrhea virus (BVDV) as HCV surrogate model. Results showed a potent suppression of the virus replication, with greater activity for the inclusion complexes than the free compound. PMID:26369033

  14. Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles.

    PubMed

    Caneva, Chiara; Alfei, Silvana; De Maria, Monica; Ibba, Cristina; Delogu, Ilenia; Spallarossa, Andrea; Loddo, Roberta

    2015-11-01

    An unprecedented, highly convergent, high-yielding, one-pot synthesis of (acyl)hydrazones and thiosemicarbazones was carried out by the in situ condensation of isolable iminium chlorides of imidazolidin-2-(thio)one, tetrahydropyrimidin-2-thione and indole derivatives with nitrogen nucleophiles in the presence of a base. The developed reaction procedure is largely advantageous. It is highly parallelizable, no intermediates need to be isolated and minimal sample handling is required during the purification steps. Some relevant reaction parameters including reaction temperature and p[Formula: see text] of the base are discussed. NMR analysis was carried out to assess the stereochemistry of the obtained compounds. The stereochemical outcome of the reaction was found to be affected by the nature of the nitrogen-containing nucleophile being the majority of the derivatives isolated as single geometric isomers. The cytotoxicity and antiviral activities of the prepared compounds have been preliminary assessed. In cell-based screenings some of the derivatives proved to be cytotoxic at low micromolar concentrations and interesting anti-Reo-1 properties have been detected. PMID:26077842

  15. Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells

    PubMed Central

    Pessoto, Felipe S.; Yokomizo, Cesar H.; Prieto, Tatiana; Fernandes, Cleverton S.; Silva, Alan P.; Kaiser, Carlos R.; Basso, Ernani A.; Nantes, Iseli L.

    2015-01-01

    A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics. PMID:26075034

  16. Simultaneous spectrophotometric determination of copper, cobalt, nickel and iron in foodstuffs and vegetables with a new bis thiosemicarbazone ligand using chemometric approaches.

    PubMed

    Rohani Moghadam, Masoud; Poorakbarian Jahromi, Sayedeh Maria; Darehkordi, Ali

    2016-02-01

    A newly synthesized bis thiosemicarbazone ligand, (2Z,2'Z)-2,2'-((4S,5R)-4,5,6-trihydroxyhexane-1,2-diylidene)bis(N-phenylhydrazinecarbothioamide), was used to make a complex with Cu(2+), Ni(2+), Co(2+) and Fe(3+) for their simultaneous spectrophotometric determination using chemometric methods. By Job's method, the ratio of metal to ligand in Ni(2+) was found to be 1:2, whereas it was 1:4 for the others. The effect of pH on the sensitivity and selectivity of the formed complexes was studied according to the net analyte signal (NAS). Under optimum conditions, the calibration graphs were linear in the ranges of 0.10-3.83, 0.20-3.83, 0.23-5.23 and 0.32-8.12 mg L(-1) with the detection limits of 2, 3, 4 and 10 μg L(-1) for Cu(2+), Co(2+), Ni(2+) and Fe(3+) respectively. The OSC-PLS1 for Cu(2+) and Ni(2+), the PLS1 for Co(2+) and the PC-FFANN for Fe(3+) were selected as the best models. The selected models were successfully applied for the simultaneous determination of elements in some foodstuffs and vegetables. PMID:26304369

  17. Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells.

    PubMed

    Pessoto, Felipe S; Yokomizo, Cesar H; Prieto, Tatiana; Fernandes, Cleverton S; Silva, Alan P; Kaiser, Carlos R; Basso, Ernani A; Nantes, Iseli L

    2015-01-01

    A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics. PMID:26075034

  18. Halo-substituted thiosemicarbazones and their copper(II), nickel(II) complexes: Detailed spectroscopic characterization and study of antitumour activity against HepG2 human hepatoblastoma cells

    NASA Astrophysics Data System (ADS)

    Jagadeesh, M.; Kalangi, Suresh K.; Sivarama Krishna, L.; Reddy, A. Varada

    2014-01-01

    Copper(II) and nickel(II) complexes of two different halogen substituted thiosemicarbazone ligands were synthesized. The ligands 3,4-difluoroacetophenone thiosemicarbazone (1) and 2-bromo-4'-chloroacetophenone thiosemicarbazone (2) were characterized and confirmed spectroscopically by FT-IR, FT-Raman, UV-vis and fluorescence spectral analysis, while the respective copper(II) complexes [Cu(C9H9N3F2S)2Cl2] (1a), [Cu(C9H9N3ClBrS)2Cl2] (2a) and nickel(II) complexes [Ni(C9H9N3F2S)2] (1b), [Ni(C9H9N3ClBrS)2] (2b) were characterized by FT-IR, UV-vis and electron paramagnetic spectroscopy (EPR). The EPR spectra of the Cu(II) complexes provided the rhombic octahedral and axial symmetry of the complexes 1a and 2a respectively. For the complex 1a, the g values calculated as g1 = 2.1228, g2 = 2.0706 and g3 = 2.001 between 2900 and 3300 G. While for the complex 2a, a set of two resonance absorptions were observed. The synthesized compounds were tested for antitumor activity and showed that the ability to kill liver cancer cells significantly. Out of all the synthesized compounds, copper(II) complexes 1a and 2a showed high cytotoxic effect on liver cancer cells with 67.51% and 42.77% of cytotoxicity respectively at 100 μM.

  19. Metal complexes of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone: cytotoxic activity and investigation on the mode of action of the gold(III) complex.

    PubMed

    Sâmia, Luciana B P; Parrilha, Gabrieli L; Da Silva, Jeferson G; Ramos, Jonas P; Souza-Fagundes, Elaine M; Castelli, Silvia; Vutey, Venn; Desideri, Alessandro; Beraldo, Heloisa

    2016-06-01

    Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).

  20. Ligational behavior of thiosemicarbazone, semicarbazone and thiocarbohydrazone ligands towards VO(IV), Ce(III), Th(IV) and UO 2(VI) ions: Synthesis, structural characterization and biological studies

    NASA Astrophysics Data System (ADS)

    Shebl, M.; Seleem, H. S.; El-Shetary, B. A.

    2010-01-01

    Mono- and binuclear VO(IV), Ce(III), Th(IV) and UO 2(VI) complexes of thiosemicarbazone, semicarbazone and thiocarbohydrazone ligands derived from 4,6-diacetylresorcinol were synthesized. The structures of these complexes were elucidated by elemental analyses, IR, UV-vis, ESR, 1H NMR and mass spectra as well as conductivity and magnetic susceptibility measurements and thermal analyses. The thiosemicarbazone (H 4L 1) and the semicarbazone (H 4L 2) ligands behave as dibasic pentadentate ligands in case of VO(IV) and UO 2(VI) complexes, tribasic pentadentate in case of Ce(III) complexes and monobasic pentadentate in case of Th(IV) complexes. However, the thiocarbohydrazone ligand (H 3L 3) acts as a monobasic tridentate ligand in all complexes except the VO(IV) complex in which it acts as a dibasic tridentate ligand. The antibacterial and antifungal activities were also tested against Rhizobium bacteria and Fusarium-Oxysporium fungus. The metal complexes of H 4L 1 ligand showed a higher antibacterial effect than the free ligand while the other ligands (H 4L 2 and H 3L 3) showed a higher effect than their metal complexes. The antifungal effect of all metal complexes is lower than the free ligands.

  1. 2-Benzoylpyridine thiosemicarbazone as a novel reagent for the single pot synthesis of dinuclear Cu(I)-Cu(II) complexes: formation of stable copper(II)-iodide bonds.

    PubMed

    Lobana, Tarlok S; Khanna, Sonia; Butcher, Ray J

    2012-04-28

    2-Benzoylpyridine thiosemicarbazone {R(1)R(2)C(2)=N(2)·N(3)H-C(1)(=S)-N(4)H(2), R(1) = py-N(1), R(2) = Ph; Hbpytsc} with copper(I) iodide in acetonitrile-dichloromethane mixture has formed stable Cu(II)-I bonds in a dark green Cu(II) iodo-bridged dimer, [Cu(2)(II)(μ-I)(2)(η(3)-N(1),N(2),S-bpytsc)(2)] 1. Copper(I) bromide also formed similar Cu(II)-Br bonds in a dark green Cu(II) bromo-bridged dimer, [Cu(2)(II)(μ-Br)(2)(η(3)-N(1),N(2),S-bpytsc)(2)] 3. The formation of dimers 1 and 3 appears to be due to a proton coupled electron transfer (PCET) process wherein copper(I) loses an electron to form copper(II), and this is accompanied by a loss of -N(3)H proton of Hbpytsc ligand resulting in the formation of anionic bpytsc(-). When copper(I) iodide was reacted with triphenylphosphine (PPh(3)) in acetonitrile followed by the addition of 2-benzoylpyridine thiosemicarbazone in dichloromethane (Cu : PPh(3) : Hbpytsc in the molar ratio 1:1:1), both Cu(II) dimer 1 and an orange Cu(I) sulfur-bridged dimer, [Cu(2)(I)I(2)(μ-S-Hbpytsc)(2)(PPh(3))(2)] 2 were formed. Copper(I) bromide with PPh(3) and Hbpytsc also formed Cu(II) dimer 3 and an orange Cu(I) sulfur-bridged dimer, [Cu(2)(I)Br(2)(μ-S-Hbpytsc)(2)(PPh(3))(2)] 4. While complexes 2 and 4 exist as sulfur-bridged Cu(I) dimers, 1 and 3 are halogen-bridged. The central Cu(2)S(2) cores of 2 and 4 as well as Cu(2)X(2) of 1 (X = I) and 3 (X = Br) are parallelograms. One set of Cu(II)-I and Cu(II)-Br bonds are short, while the second set is very long {1, Cu-I, 2.565(1), 3.313(1) Å; 3, Cu-Br, 2.391(1), 3.111(1) Å}. The Cu···Cu separations are long in all four complexes {1, 4.126(1); 2, 3.857(1); 3, 3.227(1); 4, 3.285(1) Å}, more than twice the van der Waals radius of a Cu atom, 2.80 Å. The pyridyl group appears to be necessary for stabilizing the Cu(II)-I bond, as this group can accept π-electrons from the metal. PMID:22395858

  2. Antiviral activity against the hepatitis C virus (HCV) of 1-indanone thiosemicarbazones and their inclusion complexes with hydroxypropyl-β-cyclodextrin.

    PubMed

    Glisoni, Romina J; Cuestas, María L; Mathet, Verónica L; Oubiña, José R; Moglioni, Albertina G; Sosnik, Alejandro

    2012-10-01

    The hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis in humans. Approximately 5% of the infected people die from cirrhosis or hepatocellular carcinoma. The current standard therapy comprises a combination of pegylated-interferon alpha and ribavirin. Due to the relatively low effectiveness, the prohibitive costs and the extensive side effects of the treatment, an intense research for new direct-acting anti-HCV agents is taking place. Furthermore, NS3 protease inhibitors recently introduced into the market are not effective against all HCV subgenotypes. Thiosemicarbazones (TSCs) have shown antiviral activity against a wide range of DNA and RNA viruses. However, their extremely low aqueous solubility and high self-aggregation tendency often preclude their reliable biological evaluation in vitro. In this work, we investigated and compared for the first time the anti-HCV activity of two 1-indanone TSCs, namely 5,6-dimethoxy-1-indanone TSC and 5,6-dimethoxy-1-indanone N4-allyl TSC, and their inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβ-CD) in Huh-7.5 cells containing the full-length and the subgenomic subgenotype 1b HCV replicon system. Studies of physical stability in culture medium showed that free TSCs precipitated rapidly and formed submicron aggregates. Conversely, TSC complexation with HPβ-CD led to more stable systems with minimal size growth and drug concentration loss. More importantly, both TSCs and their inclusion complexes displayed a potent suppression of the HCV replication in both cell lines with no cytotoxic effects. The mechanism likely involves the inhibition of non-structural proteins of the virus. In addition, findings suggested that the cyclodextrin released the drug to the culture medium over time. This platform could be exploited for the study of the drug toxicity and pharmacokinetics animal models.

  3. Antiviral activity against the hepatitis C virus (HCV) of 1-indanone thiosemicarbazones and their inclusion complexes with hydroxypropyl-β-cyclodextrin.

    PubMed

    Glisoni, Romina J; Cuestas, María L; Mathet, Verónica L; Oubiña, José R; Moglioni, Albertina G; Sosnik, Alejandro

    2012-10-01

    The hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis in humans. Approximately 5% of the infected people die from cirrhosis or hepatocellular carcinoma. The current standard therapy comprises a combination of pegylated-interferon alpha and ribavirin. Due to the relatively low effectiveness, the prohibitive costs and the extensive side effects of the treatment, an intense research for new direct-acting anti-HCV agents is taking place. Furthermore, NS3 protease inhibitors recently introduced into the market are not effective against all HCV subgenotypes. Thiosemicarbazones (TSCs) have shown antiviral activity against a wide range of DNA and RNA viruses. However, their extremely low aqueous solubility and high self-aggregation tendency often preclude their reliable biological evaluation in vitro. In this work, we investigated and compared for the first time the anti-HCV activity of two 1-indanone TSCs, namely 5,6-dimethoxy-1-indanone TSC and 5,6-dimethoxy-1-indanone N4-allyl TSC, and their inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβ-CD) in Huh-7.5 cells containing the full-length and the subgenomic subgenotype 1b HCV replicon system. Studies of physical stability in culture medium showed that free TSCs precipitated rapidly and formed submicron aggregates. Conversely, TSC complexation with HPβ-CD led to more stable systems with minimal size growth and drug concentration loss. More importantly, both TSCs and their inclusion complexes displayed a potent suppression of the HCV replication in both cell lines with no cytotoxic effects. The mechanism likely involves the inhibition of non-structural proteins of the virus. In addition, findings suggested that the cyclodextrin released the drug to the culture medium over time. This platform could be exploited for the study of the drug toxicity and pharmacokinetics animal models. PMID:22885176

  4. Synthesis, characterization, and preliminary in vitro studies of vanadium(IV) complexes with a Schiff base and thiosemicarbazones as mixed-ligands.

    PubMed

    Lewis, Nerissa A; Liu, Fange; Seymour, Luke; Magnusen, Anthony; Erves, Travis R; Arca, Jessa Faye; Beckford, Floyd A; Venkatraman, Ramaiyer; González-Sarrías, Antonio; Fronczek, Frank R; Vanderveer, Don G; Seeram, Navindra P; Liu, Aimin; Jarrett, William L; Holder, Alvin A

    2012-02-01

    [VO(Sal-L-tryp)(H2O)] 1 (where sal-L-tryp = N-salicylidene-L-tryptophanate) was used as a precursor to produce the novel complexes, [VO(Sal-L-tryp)(MeATSC)].1.5C2H5OH 2 (where MeATSC = 9-Anthraldehyde-N(4)-methylthiosemicarbazone), [VO(Sal-L-tryp)(N-Ethhymethohcarbthio)].H2O 3 (where N-Ethhymethohcarbthio = (E)-N-ethyl-2-(4-hydroxy-3-methoxybenzylidene)hydrazinecarbothioamide), and [VO(Sal-L-tryp)(acetylethTSC)].C2H5OH 4 (where acetylethTSC = (E)-N-ethyl-2-(1-(thiazol-2-yl)ethylidene)hydrazinecarbothioamide), by reaction with the respective thiosemicarbazone. The chemical and structural properties of these ligands and complexes were characterised by elemental analysis, ESI MS, FT-IR, UV-visible, ESR, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. DMSO and DMSO-d6 solutions of compounds 1-4 were oxidised in air to produce vanadium(V) species which were verified by ESI MS and (51)V NMR spectroscopy. Anti-cancer properties of compounds 2-4 were examined with three colon cancer cell lines, HTC-116, Caco-2, and HT-29, and also with non-cancerous colonic myofibroblasts, CCD18-Co. Compounds 2-3 exhibited less inhibitory effects in the CCD-18Co cells, indicating a possible cytotoxic selectivity towards colon cancer cells. In general, those compounds which exhibited anti-proliferative activity on cancer cells, but did not affect non-cancerous cells, may have a potential in chemotherapy. PMID:23904789

  5. Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

    PubMed Central

    Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G.; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Šimůnek, Tomáš; Richardson, Des R.; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

  6. Spectrophotometric, voltammetric and cytotoxicity studies of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone and its N(4)-substituted derivatives: A combined experimental-computational study

    NASA Astrophysics Data System (ADS)

    Akgemci, Emine Guler; Saf, Ahmet Ozgur; Tasdemir, Halil Ugur; Türkkan, Ercan; Bingol, Haluk; Turan, Suna Ozbas; Akkiprik, Mustafa

    2015-02-01

    In this study, 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) and its novel N(4) substituted derivatives were synthesized and characterized by different techniques. The optical band gap of the compounds and the energy of HOMO were experimentally examined by UV-vis spectra and cyclic voltammetry measurements, respectively. Furthermore, the conformational spaces of the compounds were scanned with molecular mechanics method. The geometry optimization, HOMO and LUMO energies, the energy gap of the HOMO-LUMO, dipole moment of the compounds were theoretically calculated by the density functional theory B3LYP/6-311++G(d,p) level. The minimal electronic excitation energy and maximum wavelength calculations of the compounds were also performed by TD-DFT//B3LYP/6-311++G(d,p) level of theory. Theoretically calculated values were compared with the related experimental values. The combined results exhibit that all compounds have good electron-donor properties which affect anti-proliferative activity. The cytotoxic effects of the compounds were also evaluated against HeLa (cervical carcinoma), MCF-7 (breast carcinoma) and PC-3 (prostatic carcinoma) cell lines using the standard MTT assay. All tested compounds showed antiproliferative effect having IC50 values in different range. In comparison with that of HMAT, it was obtained that while ethyl group on 4(N)-substituted position decreased in potent anti-proliferative effect, the phenyl group on the position increased in anti-proliferative effect for the tested cancer cell line. Considering the molecular energy parameters, the cytotoxicity activities of the compounds were discussed.

  7. Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors.

    PubMed

    Zhai, Xin; Bao, Guanglong; Wang, Limei; Cheng, Mingke; Zhao, Meng; Zhao, Sijia; Zhou, Hongyang; Gong, Ping

    2016-03-15

    In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a-w, 26a-d and 30a-d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R(2) moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC50 values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC50=1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation. PMID:26897090

  8. Development of highly sensitive extractive spectrophotometric determination of nickel(II) in medicinal leaves, soil, industrial effluents and standard alloy samples using pyridoxal-4-phenyl-3-thiosemicarbazone.

    PubMed

    Sarma, Loka Subramanyam; Kumar, Jyothi Rajesh; Reddy, Koduru Janardhan; Thriveni, Thenepalli; Reddy, Ammireddy Varada

    2008-01-01

    Pyridoxal-4-phenyl-3-thiosemicarbazone (PPT) is proposed as a new sensitive reagent for the extractive spectrophotometric determination of nickel(II). PPT reacts with nickel(II) in the pH range 4.0-6.0 to form a reddish brown colored complex, which was well-extracted into n-butanol. The absorbance value of the Ni(II)-PPT complex was measured at different time intervals at 430nm, to ascertain the stability of the complex. The system obeyed Beer's law up to 0.5-5.0microgmL(-1) of nickel(II), with an excellent linearity in terms of the correlation coefficient value of 0.99. The molar absorptivity and Sandell's sensitivity of the extracted species are 1.92 x 10(4)Lmol(-1)cm(-1) and 0.003057microgcm(-2) respectively at 430nm. The detection limit of the method is 0.069microgmL(-1). To assess precision and accuracy of the developed method, determinations were carried out at different concentrations. The relative standard deviation of all measurements does not exceed 2.62%. The developed method has been satisfactorily applied for the determination of nickel(II), when present alone or in the presence of diverse ions, which are usually associated with nickel(II) in medicinal leaves, soil and industrial effluent samples. Various standard and certified reference materials (CM 247 LC, IN 718, BCS 233, 266, 253 and 251) have also been tested for the determination of nickel for the purpose of validation of the present method. The results of the proposed method are compared with those obtained from an atomic absorption spectrometer (AAS).

  9. Development of a highly sensitive extractive spectrophotometric method for the determination of nickel(II) from environmental matrices using N-ethyl-3-carbazolecarboxaldehyde-3-thiosemicarbazone.

    PubMed

    Ramachandraiah, C; Rajesh Kumar, J; Janardhan Reddy, K; Lakshmi Narayana, S; Varada Reddy, A

    2008-09-01

    Nickel(II) reacts with N-ethyl-3-carbazolecarboxaldehyde-3-thiosemicarbazone (ECCT) and forms a yellow colored complex, which was extracted into n-butanol from sodium acetate and acetic acid buffer at pH 6.0. The absorbance value of the Ni(II)-ECCT complex was measured at different intervals of time at 400 nm, to ascertain the time stability of the complex. The extraction of the complex into the solvent was instantaneous and stable for more than 72 h. The system obeyed Beer's law in the concentration range of 1.2-5.6 microg ml(-1) of nickel(II), with an excellent linearity and a correlation coefficient of 0.999. The molar absorptivity and Sandell's sensitivity of the extracted species were found to be 1.114 x 10(4)L mol(-1)cm(-1) and 5.29 x 10(-3)microg cm(-2) at 400 nm, respectively. Hence, a detailed study of the extraction of nickel(II) with ECCT has been undertaken with a view to developing a rapid and sensitive extractive spectrophotometric method for the determination of nickel(II) when present alone or in the presence of diverse ions which are usually associated with nickel(II) in environmental matrices like soil and industrial effluents. Various standard alloy samples (CM 247 LC, IN 718, BCS 233, 266, 253 and 251) have been tested for the determination of nickel for the purpose of validation of the present method. The results of the proposed method are comparable with those from atomic absorption spectrometry and were found to be in good agreement.

  10. Synthesis, structure and antifungal activity of thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) and nickel(II), copper(II) and cadmium(II) complexes: unsymmetrical coordination mode of nickel complex.

    PubMed

    Alomar, Kusaï; Landreau, Anne; Allain, Magali; Bouet, Gilles; Larcher, Gérald

    2013-09-01

    The reaction of nickel(II), copper(II) chlorides and cadmium(II) chloride and bromide with thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) (2,3BTSTCH2) leads to a series of new complexes: [Ni(2,3BTSTCH)]Cl, [Cu(2,3BTSTC)], [CdCl2(2,3BTSTCH2)] and [CdBr2(2,3BTSTCH2)]. The crystal structures of the ligand and of [Ni(2,3BTSTCH)]Cl complex have been determined. In this case, we remark an unusual non-symmetrical coordination mode for the two functional groups: one acting as a thione and the second as a deprotonated thiolate. All compounds have been tested for their antifungal activity against human pathogenic fungi: Candida albicans, Candida glabrata and Aspergillus fumigatus, the cadmium complexes exhibit the highest antifungal activity. Cytotoxicity was evaluated using two biological methods: human MRC5 cultured cells and brine shrimp Artemia salina bioassay.

  11. Electronic, epr and magnetic studies of Co(II), Ni(II) and Cu(II) complexes with thiosemicarbazone (L 1) and semicarbazone (L 2) derived from pyrole-2-carboxyaldehyde

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Kumar, Anil

    2007-07-01

    Co(II), Ni(II) and Cu(II) complexes are synthesized with thiosemicarbazone (L 1) and semicarbazone (L 2) derived from pyrole-2-carboxyaldehyde. These complexes are characterized by elemental analysis, molar conductance, magnetic susceptibility measurements, mass, IR, electronic and EPR spectral studies .The molar conductance measurements of the complexes in DMSO correspond to non-electrolytic nature except Co(L 1) 2(NO 3) 2 and Ni(L 1) 2(NO 3) 2 complexes which are 1:2 electrolytes. All the complexes are of high-spin type. On the basis of spectral studies an octahedral geometry may be assigned for Co(II) and Ni(II) complexes except Co(L 1) 2(NO 3) 2 and Ni(L 1) 2(NO 3) 2 which are of tetrahedral geometry. A tetragonal geometry may be suggested for Cu(II) complexes.

  12. Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Multidrug Resistance by a Novel Mechanism Involving the Hijacking of Lysosomal P-Glycoprotein (Pgp)*

    PubMed Central

    Jansson, Patric J.; Yamagishi, Tetsuo; Arvind, Akanksha; Seebacher, Nicole; Gutierrez, Elaine; Stacy, Alexandra; Maleki, Sanaz; Sharp, Danae; Sahni, Sumit; Richardson, Des R.

    2015-01-01

    Multidrug resistance (MDR) is a major obstacle in cancer treatment. More than half of human cancers express multidrug-resistant P-glycoprotein (Pgp), which correlates with a poor prognosis. Intriguingly, through an unknown mechanism, some drugs have greater activity in drug-resistant tumor cells than their drug-sensitive counterparts. Herein, we investigate how the novel anti-tumor agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes MDR. Four different cell types were utilized to evaluate the effect of Pgp-potentiated lysosomal targeting of drugs to overcome MDR. To assess the mechanism of how Dp44mT overcomes drug resistance, cellular studies utilized Pgp inhibitors, Pgp silencing, lysosomotropic agents, proliferation assays, immunoblotting, a Pgp-ATPase activity assay, radiolabeled drug uptake/efflux, a rhodamine 123 retention assay, lysosomal membrane permeability assessment, and DCF (2′,7′-dichlorofluorescin) redox studies. Anti-tumor activity and selectivity of Dp44mT in Pgp-expressing, MDR cells versus drug-sensitive cells were studied using a BALB/c nu/nu xenograft mouse model. We demonstrate that Dp44mT is transported by the lysosomal Pgp drug pump, causing lysosomal targeting of Dp44mT and resulting in enhanced cytotoxicity in MDR cells. Lysosomal Pgp and pH were shown to be crucial for increasing Dp44mT-mediated lysosomal damage and subsequent cytotoxicity in drug-resistant cells, with Dp44mT being demonstrated to be a Pgp substrate. Indeed, Pgp-dependent lysosomal damage and cytotoxicity of Dp44mT were abrogated by Pgp inhibitors, Pgp silencing, or increasing lysosomal pH using lysosomotropic bases. In vivo, Dp44mT potently targeted chemotherapy-resistant human Pgp-expressing xenografted tumors relative to non-Pgp-expressing tumors in mice. This study highlights a novel Pgp hijacking strategy of the unique dipyridylthiosemicarbazone series of thiosemicarbazones that overcome MDR via utilization of lysosomal Pgp transport

  13. Structure-antiproliferative activity studies on l-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes.

    PubMed

    Dobrova, Aliona; Platzer, Sonja; Bacher, Felix; Milunovic, Miljan N M; Dobrov, Anatolie; Spengler, Gabriella; Enyedy, Éva A; Novitchi, Ghenadie; Arion, Vladimir B

    2016-09-14

    Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone-homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L(1))Cl]Cl·H2O (2·H2O) and [Cu(H2L(1))Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L(2) and CuCl2·2H2O in methanol, the complex [Cu(H2L(2))Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L(1), 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L(1) and H2L(2) and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes. PMID:27485263

  14. Thiosemicarbazones as Aedes aegypti larvicidal.

    PubMed

    da Silva, João Bosco P; Navarro, Daniela Maria do A F; da Silva, Aluizio G; Santos, Geanne K N; Dutra, Kamilla A; Moreira, Diogo Rodrigo; Ramos, Mozart N; Espíndola, José Wanderlan P; de Oliveira, Ana Daura T; Brondani, Dalci José; Leite, Ana Cristina L; Hernandes, Marcelo Zaldini; Pereira, Valéria R A; da Rocha, Lucas F; de Castro, Maria Carolina A B; de Oliveira, Beatriz C; Lan, Que; Merz, Kenneth M

    2015-07-15

    A set of aryl- and phenoxymethyl-(thio)semicarbazones were synthetized, characterized and biologically evaluated against the larvae of Aedes aegypti (A. aegypti), the vector responsible for diseases like Dengue and Yellow Fever. (Q)SAR studies were useful for predicting the activities of the compounds not included to create the QSAR model as well as to predict the features of a new compound with improved activity. Docking studies corroborated experimental evidence of AeSCP-2 as a potential target able to explain the larvicidal properties of its compounds. The trend observed between the in silico Docking scores and the in vitro pLC50 (equals -log LC50, at molar concentration) data indicated that the highest larvicidal compounds, or the compounds with the highest values for pLC50, are usually those with the higher docking scores (i.e., greater in silico affinity for the AeSCP-2 target). Determination of cytotoxicity for these compounds in mammal cells demonstrated that the top larvicide compounds are non-toxic.

  15. Thiosemicarbazones as Aedes aegypti larvicidal.

    PubMed

    da Silva, João Bosco P; Navarro, Daniela Maria do A F; da Silva, Aluizio G; Santos, Geanne K N; Dutra, Kamilla A; Moreira, Diogo Rodrigo; Ramos, Mozart N; Espíndola, José Wanderlan P; de Oliveira, Ana Daura T; Brondani, Dalci José; Leite, Ana Cristina L; Hernandes, Marcelo Zaldini; Pereira, Valéria R A; da Rocha, Lucas F; de Castro, Maria Carolina A B; de Oliveira, Beatriz C; Lan, Que; Merz, Kenneth M

    2015-07-15

    A set of aryl- and phenoxymethyl-(thio)semicarbazones were synthetized, characterized and biologically evaluated against the larvae of Aedes aegypti (A. aegypti), the vector responsible for diseases like Dengue and Yellow Fever. (Q)SAR studies were useful for predicting the activities of the compounds not included to create the QSAR model as well as to predict the features of a new compound with improved activity. Docking studies corroborated experimental evidence of AeSCP-2 as a potential target able to explain the larvicidal properties of its compounds. The trend observed between the in silico Docking scores and the in vitro pLC50 (equals -log LC50, at molar concentration) data indicated that the highest larvicidal compounds, or the compounds with the highest values for pLC50, are usually those with the higher docking scores (i.e., greater in silico affinity for the AeSCP-2 target). Determination of cytotoxicity for these compounds in mammal cells demonstrated that the top larvicide compounds are non-toxic. PMID:26087027

  16. Synthesis, structure and antifungal activity of thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) and nickel(II), copper(II) and cadmium(II) complexes: unsymmetrical coordination mode of nickel complex.

    PubMed

    Alomar, Kusaï; Landreau, Anne; Allain, Magali; Bouet, Gilles; Larcher, Gérald

    2013-09-01

    The reaction of nickel(II), copper(II) chlorides and cadmium(II) chloride and bromide with thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) (2,3BTSTCH2) leads to a series of new complexes: [Ni(2,3BTSTCH)]Cl, [Cu(2,3BTSTC)], [CdCl2(2,3BTSTCH2)] and [CdBr2(2,3BTSTCH2)]. The crystal structures of the ligand and of [Ni(2,3BTSTCH)]Cl complex have been determined. In this case, we remark an unusual non-symmetrical coordination mode for the two functional groups: one acting as a thione and the second as a deprotonated thiolate. All compounds have been tested for their antifungal activity against human pathogenic fungi: Candida albicans, Candida glabrata and Aspergillus fumigatus, the cadmium complexes exhibit the highest antifungal activity. Cytotoxicity was evaluated using two biological methods: human MRC5 cultured cells and brine shrimp Artemia salina bioassay. PMID:23792913

  17. 3-methylcyclohexanone thiosemicarbazone: determination of E/Z isomerization barrier by dynamic high-performance liquid chromatography, configuration assignment and theoretical study of the mechanisms involved by the spontaneous, acid and base catalyzed processes.

    PubMed

    Carradori, Simone; Cirilli, Roberto; Dei Cicchi, Simona; Ferretti, Rosella; Menta, Sergio; Pierini, Marco; Secci, Daniela

    2012-12-21

    Here, we report on the simultaneous direct HPLC diastereo- and enantioseparation of 3-methylcyclohexanone thiosemicarbazone (3-MCET) on a polysaccharide-based chiral stationary phase under normal-phase conditions. The optimized chromatographic system was employed in dynamic HPLC experiments (DHPLC), as well as detection technique in a batch wise approach to determine the rate constants and the corresponding free energy activation barriers of the spontaneous, base- and acid-promoted E/Z diastereomerization of 3-MCET. The stereochemical characterization of four stereoisomers of 3-MCET was fully accomplished by integrating the results obtained by chemical correlation method with those derived by theoretical calculations and experimental investigations of circular dichroism (CD). As a final goal, a deepened analysis of the perturbing effect exercised by the stationary phase on rate constant values measured through DHPLC determinations as a function of the chromatographic separation factor α of the interconverting species was successfully accomplished. This revealed quite small deviations from the equivalent kinetic values obtained by off-column batch wise procedure, and suggested a possible effective correction of rate constants measured by DHPLC approach.

  18. Syntheses, structural and spectral studies of six-coordinate, [Ph 2SnCl(acpm)], and seven-coordinate, [ nBu 2Sn(dapm)], diorganotin(IV) complexes with N, N, S-tridentate and S, N, N, N, S-pentadentate N4-heterocyclic thiosemicarbazones

    NASA Astrophysics Data System (ADS)

    de Sousa, Gerimário F.; Manso, Luís Carlos C.; Lang, Ernesto S.; Gatto, Claudia C.; Mahieu, Bernard

    2007-01-01

    The reaction of the N, N, S-tridentate ligand 2-acetylpyridine ( N4-morpholyl thiosemicarbazones), Hacpm, with Ph 2SnCl 2 leads to the formation of the six-coordinate complex [Ph 2SnCl(acpm)] ( 1), whereas the reaction of the S, N, N, N, S-pentadentate ligand 2,6-diacetylpyridine bis( N4-morpholyl thiosemicarbazone), H 2dapm, with nBu 2SnCl 2 leads to the formation of the seven-coordinate complex [ nBu 2Sn(dapm)] ( 2). Both compounds were studied by microanalyses, IR, NMR ( 1H, 13C, 119Sn) and Mössbauer spectroscopy to investigate their structural properties. The organotin(IV) complexes were also studied by single crystal X-ray diffraction and the structure determination revealed that the phenyl derivative crystallizes in the triclinic space group (P1¯) as discrete neutral molecules, with the tin(IV) ion in a distorted octahedral geometry with the acpm 1- ligand in a meridional configuration and the phenyl groups in trans positions. X-ray analysis shows that the n-butyl complex crystallizes in the monoclinic space group ( P2 1/ c) as discrete neutral complexes, with the tin(IV) ion in a distorted pentagonal bipyramidal geometry. A correlation between Mössbauer and X-ray data based on the point-charge model is discussed.

  19. Synthesis, characterization antibacterial and antiproliferative activity of novel Cu(II) and Pd(II) complexes with 2-hydroxy-8-R-tricyclo[7.3.1.0.(2,7)]tridecane-13-one thiosemicarbazone.

    PubMed

    Rosu, Tudor; Pahontu, Elena; Pasculescu, Simona; Georgescu, Rodica; Stanica, Nicolae; Curaj, Adelina; Popescu, Alexandra; Leabu, Mircea

    2010-04-01

    Synthesis and biological activity investigation of complex compounds of Cu(II) are challenging issues because of the metal is not a xenobiotic one and the activity of ligands could be modulated by complexation. Complex combinations of Cu(II) and Pd(II) with thiosemicarbazone derivatives of 2-hydroxy-8-R-tricyclo[7.3.1.0.(2,7)]tridecane-13-one (where R=C(3)H(7), C(4)H(3)O) were synthesized. The characterization of the ligands and the newly formed compounds was done by (1)H NMR, (13)C NMR, UV-vis, IR, ESR spectroscopy, elemental analysis, molar electric conductibility and thermal studies. Experiments performed to identify the structures proved that the ligands coordinate to metal ions in different ways - neutral bidentate or mononegative bidentate. Also, if copper(II) acetate, copper(II) nitrate, copper(II) chloride and copper(II) thiocyanate were used, the ligands coordinated in a mononegative bidentate fashion. If copper(II) sulfate was used, the ligands coordinated in a neutral bidentate fashion. The biological activity for the copper(II) synthesized compounds was assessed in terms of antibacterial or antiproliferative activity. The antibacterial activity of the complexes against Staphylococcus aureus var. Oxford 6538, Escherichia coli ATCC 10536, Klebsielle pneumoniae ATCC 100131 and Candida albicans ATCC 10231 strains was studied and compared with that of free ligands. The effect of complex compounds on the proliferation of HeLa cells was tested. For all tested complexes an antiproliferative activity was noted at concentrations higher than 1 microM, but lower than 10 microM. Therefore, complex compounds of copper(II) were synthesized, structurally characterized and tested for biological activity, proving both antibacterial and antiproliferative activity. PMID:20096975

  20. Synthesis and evaluation of in vivo antioxidant, in vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazones.

    PubMed

    Thanh, Nguyen Dinh; Giang, Nguyen Thi Kim; Quyen, Tran Ha; Huong, Doan Thi; Toan, Vu Ngoc

    2016-11-10

    Some new isatin N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazones 4a-t with different substituents at 1-, 5- and 7-positions of isatin ring have been synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide 2 with corresponding isatins 3a-t. Compounds 4a-t were evaluated in vivo for antioxidant activity and in vitro for anti-microorganism activities. The MIC values were found for Gram positive bacteria (MIC = 1.56-6.25 μM), for Gram negative bacteria (MIC = 12.5 μM), and for fungi Aspergillus niger (MIC = 3.12-12.5 μM), Fusarium oxysporum (MIC = 6.25-12.5 μM) and Saccharomyces cerevisiae (MIC = 6.25-12.5 μM). Regarding the antioxidant activity, the SOD, GHS-Px and catalase activities of 4c-i and 4m-r were MIC = 10.57-10.85, 0.27-0.93 and 345.45-399.75 unit/mg protein, respectively. Compounds 4e-h had MIC values of 0.78, 1.56, and 3.12 μM for three clinical MRSA isolates. Compound 4e showed the selective cytotoxic effects against some cancer (LU-1, HepG2, MCF7, P338, SW480, KB) cell lines and normal fibroblast cell line NIH/3T3. PMID:27517802

  1. 3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies

    ClinicalTrials.gov

    2013-01-23

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia

  2. 3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-09-27

    Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  3. Lysosomal membrane stability plays a major role in the cytotoxic activity of the anti-proliferative agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT).

    PubMed

    Gutierrez, Elaine M; Seebacher, Nicole A; Arzuman, Laila; Kovacevic, Zaklina; Lane, Darius J R; Richardson, Vera; Merlot, Angelica M; Lok, Hiu; Kalinowski, Danuta S; Sahni, Sumit; Jansson, Patric J; Richardson, Des R

    2016-07-01

    The potent and selective anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), localizes in lysosomes and forms cytotoxic copper complexes that generate reactive oxygen species (ROS), resulting in lysosomal membrane permeabilization (LMP) and cell death. Herein, the role of lysosomal membrane stability in the anti-tumor activity of Dp44mT was investigated. Studies were performed using molecules that protect lysosomal membranes against Dp44mT-induced LMP, namely heat shock protein 70 (HSP70) and cholesterol. Up-regulation or silencing of HSP70 expression did not affect Dp44mT-induced LMP in MCF7 cells. In contrast, cholesterol accumulation in lysosomes induced by the well characterized cholesterol transport inhibitor, 3-β-[2-(diethyl-amino)ethoxy]androst-5-en-17-one (U18666A), inhibited Dp44mT-induced LMP and markedly and significantly (p<0.001) reduced the ability of Dp44mT to inhibit cancer cell proliferation (i.e., increased the IC(50)) by 140-fold. On the other hand, cholesterol extraction using methyl-β-cyclodextrin enhanced Dp44mT-induced LMP and significantly (p<0.01) increased its anti-proliferative activity. The protective effect of U18666A in increasing lysosomal cholesterol and preventing the cytotoxic activity of Dp44mT was not due to induced autophagy. Instead, U18666A was found to decrease lysosomal turnover, resulting in autophagosome accumulation. Moreover, preincubation with U18666A did not prevent the ability of Dp44mT to induce autophagosome synthesis, indicating that autophagic initiation via Dp44mT occurs independently of LMP. These studies demonstrate the significance of lysosomal membrane stability in relation to the ability of Dp44mT to execute tumor cell death and overcome pro-survival autophagy. Hence, lysosomal-dependent cell death induced by Dp44mT serves as an important anti-tumor strategy. These results are important for comprehensively understanding the mechanism of action of Dp44mT. PMID:27102538

  4. Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia† †Electronic supplementary information (ESI) available. CCDC 1001632–1001634. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5dt02537k Click here for additional data file. Click here for additional data file.

    PubMed Central

    Alam, Israt S.; Arrowsmith, Rory L.; Cortezon-Tamarit, Fernando; Twyman, Frazer; Kociok-Köhn, Gabriele; Botchway, Stanley W.; Dilworth, Jonathan R.

    2016-01-01

    We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under ‘cold’ and ‘hot’ biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. 68Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration. PMID:26583314

  5. Tables of thermospheric temperature, density and composition derived from satellite and ground based measurements. Volume 3: Ap=100

    NASA Technical Reports Server (NTRS)

    Hedin, A. E.

    1979-01-01

    The neutral temperature, neutral densities for N2, O2, O, Ar, He and H, mean molecular weight, and total mass density as predicted by the Mass Spectrometer and Incoherent Scatter empirical thermosphere model are presented in tabular form. The predictions are based on selected altitudes, latitudes, local times, days and other geophysical conditions. The model is dependent on a least squares fit to density data from mass spectrometers on five satellites and temperature data from four incoherent scatter stations, providing coverage for most of solar sunspot cycle 20.

  6. Coordination of Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) with 2,5-hexanedione bis(thiosemicarbazone), HBTS: Crystal structure of cis-[Pd(HBTS)]Cl2 and 1-(2,5-dimethyl-1H-pyrrol-yl)-thiourea

    NASA Astrophysics Data System (ADS)

    Jeragh, Bakir; El-Asmy, Ahmed A.

    2014-09-01

    Metal complexes of Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+, Pd2+ or Pt2+ with 2,5-hexanedione bis(thiosemicarbazone), HBTS; have been prepared and spectroscopically investigated. The empirical formulae of the complexes were suggested based on the elemental analysis. Single crystal of Pd(II) has been solved to be cis-form of square-planar geometry by the X-ray crystallography. 1H and 13C NMR spectra have been recorded for HBTS, Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) complexes, in DMSO-d6, showing the mode of chelation. The ligand acts as a neutral or a binegative tetradentate (N2S2) or neutral bidentate on the basis of FT-IR. The magnetic moments and electronic spectra provide information about the geometry of the complexes which supported by calculating the ligand field parameters for the Co(II) and Fe(III) complexes. The Ni(II) complex has subnormal magnetic moment (0.71 BM) indicative of a mixed stereochemistry of square-planar and tetrahedral structure. [Cu(HBTS-2H)] measured 0.93 BM indicating high interaction between the copper centers. The ligand may be ordered at the top of the spectrochemical series which giving high ligand field splitting energy (10Dq = 17,900 cm-1 for Co2+ complex). The mass spectra of some complexes proved their stable chemical formulae while the TGA depicts the degradation steps and the final residue. In evaporating the mother liquor during the preparation of HBTS, new compound is obtained naming 1-(2,5-dimethyl-1H-pyrrol-yl)thiourea and its crystal was solved.

  7. Coordination of Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) with 2,5-hexanedione bis(thiosemicarbazone), HBTS: crystal structure of cis-[Pd(HBTS)]Cl2 and 1-(2,5-dimethyl-1H-pyrrol-yl)-thiourea.

    PubMed

    Jeragh, Bakir; El-Asmy, Ahmed A

    2014-09-15

    Metal complexes of Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+, Pd2+ or Pt2+ with 2,5-hexanedione bis(thiosemicarbazone), HBTS; have been prepared and spectroscopically investigated. The empirical formulae of the complexes were suggested based on the elemental analysis. Single crystal of Pd(II) has been solved to be cis-form of square-planar geometry by the X-ray crystallography. 1H and 13C NMR spectra have been recorded for HBTS, Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) complexes, in DMSO-d6, showing the mode of chelation. The ligand acts as a neutral or a binegative tetradentate (N2S2) or neutral bidentate on the basis of FT-IR. The magnetic moments and electronic spectra provide information about the geometry of the complexes which supported by calculating the ligand field parameters for the Co(II) and Fe(III) complexes. The Ni(II) complex has subnormal magnetic moment (0.71 BM) indicative of a mixed stereochemistry of square-planar and tetrahedral structure. [Cu(HBTS-2H)] measured 0.93 BM indicating high interaction between the copper centers. The ligand may be ordered at the top of the spectrochemical series which giving high ligand field splitting energy (10 Dq=17,900 cm(-1) for Co2+ complex). The mass spectra of some complexes proved their stable chemical formulae while the TGA depicts the degradation steps and the final residue. In evaporating the mother liquor during the preparation of HBTS, new compound is obtained naming 1-(2,5-dimethyl-1H-pyrrol-yl)thiourea and its crystal was solved.

  8. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3) Mutants in Drosophila melanogaster

    PubMed Central

    Rodriguez-Fernandez, Imilce A.; Dell’Angelica, Esteban C.

    2015-01-01

    The Adaptor Protein (AP)-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs) such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions–which together covered most of the autosomal chromosomes–to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with molecules implicated in autophagy and small GTPase regulation. PMID:26565960

  9. 3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-16

    Accelerated Phase Chronic Myelogenous Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Primary Myelofibrosis; Relapsing Chronic Myelogenous Leukemia

  10. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3) Mutants in Drosophila melanogaster.

    PubMed

    Rodriguez-Fernandez, Imilce A; Dell'Angelica, Esteban C

    2015-01-01

    The Adaptor Protein (AP)-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs) such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions--which together covered most of the autosomal chromosomes-to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with molecules implicated in autophagy and small GTPase regulation.

  11. Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives

    PubMed Central

    de Almeida, Sinara Mônica Vitalino; Lafayette, Elizabeth Almeida; Gomes da Silva, Lúcia Patrícia Bezerra; Amorim, Cézar Augusto da Cruz; de Oliveira, Tiago Bento; Gois Ruiz, Ana Lucia Tasca; de Carvalho, João Ernesto; de Moura, Ricardo Olímpio; Beltrão, Eduardo Isidoro Carneiro; de Lima, Maria do Carmo Alves; de Carvalho Júnior, Luiz Bezerra

    2015-01-01

    In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a–h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 104 to 1.0 × 106 M−1 and quenching constants from −0.2 × 104 to 2.18 × 104 M−1 indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N-(4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties. PMID:26068233

  12. Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives.

    PubMed

    Loiseau, P M; Nguyen, D X

    1996-06-01

    Sixteen compounds were synthesized and evaluated on Plasmodium berghei in CD1 mouse. The nature of the salt associated to the active principle can give some advantages in the field of activity, bioavailability and toxicity. beta-Resorcylic acid was chosen in this study because of its previously described antimalarial activity and its expected enhancement of quinine antimalarial activity. While treatment with subcutaneous quinine sulphate at 1 mmol/kg cured 6/10 mice, quinine beta-resorcylate cured all the mice under identical conditions. Although such a result appeared promising, in vitro investigation should be performed to draw clear conclusions regarding a synergy between quinine and beta-resorcylate. Cinchonidine beta-resorcylate was also active; all mice were cured at 1 mmol/kg and the mean survival time was 13.8 +/- 2.4 days after a subcutaneous treatment at 0.5 mmol/kg in a single dose. In the series of acridines, (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine cured all mice at 50 mumol/kg under the same conditions. The maximum tolerated doses in mice ranged from 100 to 150 mumol/kg for these acridine derivatives. The chemotherapeutic index of (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine was estimated at 2-3. Other salts expected to reduce the toxicity, such as alpha-ketoglutarate and p-chlorophenoxyacetate, did not enhance the activity of the active principles. These results prompt us to further investigations including plasma kinetic evaluation in rats and in vitro on Plasmodium falciparum.

  13. [(64)Cu]diacetyl-bis(N(4)-methyl-thiosemicarbazone) - a radiotracer for tumor hypoxia.

    PubMed

    Wood, Katie A; Wong, Wai Lup; Saunders, Michele I

    2008-05-01

    Positron emission tomography scanning using the radiotracer-labeled copper (II)-diacetyl-bis(N(4)-methylthiosemicarbazone) has been proposed as a noninvasive method for evaluating tumor hypoxia. Tumor hypoxia results in a more aggressive tumor phenotype together with resistance to both radiotherapy and chemotherapy. A noninvasive technique for evaluation of tumor hypoxia is not currently available. Validation of this technique would provide clinicians with a tool for determining the most appropriate cancer therapy, prognostic information, and subvolume delineation for the radiotherapy dose escalation to the radioresistant hypoxic regions within a tumor. This review article describes the background to the development of this tracer, its proposed retention mechanism, biodistribution dosimetry and the preclinical and clinical studies to date. It outlines the potential use of this radiotracer for imaging in the field of oncology.

  14. Crystal structures of crotonaldehyde semicarbazone and crotonaldehyde thiosemicarbazone from X-ray powder diffraction data

    PubMed Central

    Arfan, Atef; Rukiah, Mwaffak

    2015-01-01

    Crotonaldehyde semicarbazone {systematic name: (E)-2-[(E)-but-2-en-1-yl­idene]hydrazinecarboxamide}, C5H9N3O, (I), and crotonaldehyde thio­semi­carba­zone {systematic name: (E)-2-[(E)-but-2-en-1-yldene]hydra­zinecarbo­­thio­amide}, C5H9N3S, (II), show the same E conformation around the imine C=N bond. Compounds (I) and (II) were obtained by the condensation of crotonaldehyde with semicarbazide hydro­chloride and thio­semicarbazide, respectively. Each mol­ecule has an intra­molecular N—H⋯N hydrogen bond, which generates an S(5) ring. In (I), the crotonaldehyde fragment is twisted by 2.59 (5)° from the semicarbazide mean plane, while in (II) the corresponding angle (with the thio­semicarbazide mean plane) is 9.12 (5)°. The crystal packing is different in the two compounds: in (I) inter­molecular N—H⋯O hydrogen bonds link the mol­ecules into layers parallel to the bc plane, while weak inter­molecular N—H⋯S hydrogen bonds in (II) link the mol­ecules into chains propagating in [110]. PMID:25878810

  15. Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives.

    PubMed

    de Almeida, Sinara Mônica Vitalino; Lafayette, Elizabeth Almeida; da Silva, Lúcia Patrícia Bezerra Gomes; Amorim, Cézar Augusto da Cruz; de Oliveira, Tiago Bento; Ruiz, Ana Lucia Tasca Gois; de Carvalho, João Ernesto; de Moura, Ricardo Olímpio; Beltrão, Eduardo Isidoro Carneiro; de Lima, Maria do Carmo Alves; de Carvalho Júnior, Luiz Bezerra

    2015-01-01

    In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties. PMID:26068233

  16. Synthesis, characterization, optical band gap, in vitro antimicrobial activity and DNA cleavage studies of some metal complexes of pyridyl thiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Yousef, T. A.; Abu El-Reash, G. M.; El-Gammal, O. A.; Bedier, R. A.

    2013-03-01

    A new series of Cr(III), Mn(II), Ni(II), Zn(II) and Hg(II) complexes of Schiff-bases derived from the condensation of 4-(2-pyridyl)-3-thiosemicarbazide and pyruvic acid (H2PTP) have been synthesized and characterized by spectroscopic studies. Schiff-base exhibit thiol-thione tautomerism wherein sulfur plays an important role in the coordination. The coordination possibility of the Schiff-bases towards metal ions have been proposed in the light of elemental analysis, spectral (IR, UV-vis, 1H NMR and 13C NMR), magnetic and thermal studies. IR spectra show that H2PTP is coordinated to the metal ions in a mononegative tridentate manner except in Cr(III) complex in which the ligand exhibits mononegative bidentate manner. The parameters total energy, binding energy, isolated atomic energy, electronic energy, heat of formation, dipole moment, HOMO and LUMO were calculated for the ligand and its complexes. Furthermore, the kinetic and thermodynamic parameters for the different decomposition steps were calculated using the Coats-Redfern and Horowitz-Metzger methods. Also, the optical band gap (Eg) of the metal complexes has been calculated. The optical transition energy (Eg) is direct and equals 3.20, 3.27 and 3.26 eV for Cr, Mn and Ni complexes, respectively. The synthesized ligand, in comparison to its metal complexes is screened for its antibacterial activity against the bacterial species, Bacillus thuringiensis, Staphylococcus aureus, Pseudomonas aeuroginosa and Escherichia coli. The results show that the metal complexes be more potent in activity antibacterial than the parent Shciff base ligand towards one or more bacterial species. Finally, the biochemical studies showed that, Mn complex have powerful and complete degradation effect on DNA.

  17. Evidence of desulfurization in the oxidative cyclization of thiosemicarbazones. Conversion to 1,3,4-oxadiazole derivatives.

    PubMed

    Gómez-Saiz, Patricia; García-Tojal, Javier; Maestro, Miguel A; Arnaiz, Francisco J; Rojo, Teófilo

    2002-03-25

    The addition of pyridine-2-carbaldehyde 4N-methylthiosemicarbazone (C8H10N4S) to an aqueous solution of copper(II) nitrate yields [[Cu(C8H9N4S)(NO3)]2] (1). This complex consists of centrosymmetric dinuclear entities containing square-pyramidal copper(II) ions bridged through the sulfur thioamide atoms. The oxidation of 1 with KBrO3 or KIO3 gives rise to a compound with formula [[Cu(C8H8N4O)(H2O)2(SO4)]2]*2H2O (2) (C8H8N4O = 2-methylamino-5-pyridin-2-yl-1,3,4-oxadiazole). The structure of 2 is made up of centrosymmetric dimers where the copper(II) ions exhibit a distorted octahedral coordination and are connected by the oxadiazole moiety. The metal ions in 2 can be removed by addition of K4[Fe(CN)6], and then the oxadiazole ligand can be isolated and recrystallized as (C8H8N4O)*3H2O (3). PMID:11896698

  18. Synthesis and spectroscopic characterization of 3,4-difluoroacetophenone-thiosemicarbazone and its palladium(II) complex: Evaluation of antimicrobial and antitumour activity

    NASA Astrophysics Data System (ADS)

    Jagadeesh, M.; Rashmi, H. K.; Subba Rao, Y.; Sreenath Reddy, A.; Prathima, B.; Uma Maheswari Devi, P.; Reddy, A. Varada

    2013-11-01

    A new cis-palladium(II)diaqua(3,4-difluoroacetophenonethiosemicarbazone complex (Pd(II) complex) is synthesized using 3,4-difluoroacetophenonethiosemicarbazone(L). The L and its Pd(II) complex are characterized and confirmed by elemental analyses, electrochemical analyses, FT-IR, FT-Raman, UV-Vis, HRMS and LC-MS techniques. Ligand L is further characterized by 1H, 13C and 19F NMR spectroscopy. The crystal structure of L is unambiguously characterized by single X-ray crystallography. The ligand (L) belongs to monoclinic system with P2(1)/C space group and the unit cell parameters are a(Å) = 9.1144(7), b(Å) = 13.7928(7), c(Å) = 8.4174(5), α(°) = 90, β(°) = 100.715, γ(°) = 90 and volume V(A3) = 1039.73(11). The Raman bands observed for the L and its Pd(II) complex are in good agreement with the FT-IR spectral data. The Pd(II) complex is found to be highly efficient in inhibiting the growth of human pathogens like Salmonella typhimurium and Klebsiella pneumonia with MIC value 10.0 μg/mL whose inhibition zones are almost comparable with the standard antibiotic. The synthesized compounds have shown antiproliferative activity against the human breast cancer cell lines MDA-MB231 by intermitting the regular pathway of ribonucleotidereductase.

  19. Vanadium-induced formation of thiadiazole and thiazoline compounds. Mononuclear and dinuclear oxovanadium(v) complexes with open-chain and cyclized thiosemicarbazone ligands.

    PubMed

    Rubcić, Mirta; Milić, Dalibor; Horvat, Gordan; Dilović, Ivica; Galić, Nives; Tomisić, Vladislav; Cindrić, Marina

    2009-11-28

    Reactions of the salicylaldehyde 4-phenylthiosemicarbazone (H(2)L) with selected vanadium(iv) and vanadium(v) precursors ([VO(acac)(2)], [VO(OAc)(2)], VOSO(4), [V(2)O(4)(acac)(2)]) were investigated under aerobic conditions in different alcohols (methanol, ethanol, propanol). In all examined cases mononuclear alkoxo vanadium(v) complexes [VOL(OR)] (1) (OR = OMe, OEt, OPr) were isolated as major products. On prolonged standing, mother liquids afforded dinuclear vanadium(v) complexes [V(2)O(3)(L(cycl))(2)(OR)(2)] (3) (OR = OMe, OEt, OPr), where L(cycl)(-) represents 1,3,4-thiadiazole ligand, formed by vanadium-induced oxidative cyclization of H(2)L. When [VO(acac)(2)] or [V(2)O(4)(acac)(2)] were used as precursors, in addition to products 1 and 3, a thiazoline derivative HL(acac)(cycl) (2) was isolated. This compound, formed by a reaction between acetylacetone and H(2)L, represented the second type of cyclic product. The products were characterized by IR and NMR spectroscopies, TG analysis, and in some cases by single-crystal X-ray diffraction. To the best of our knowledge, compounds [V(2)O(3)(L(cycl))(2)(OR)(2)] represent the first structurally characterized dinuclear vanadium(v) complexes with a thiadiazole moiety acting as a bridging ligand. Complexes 1 and 3, when dissolved in an appropriate alcohol, underwent substitution of the alkoxo ligand as confirmed by XRPD. The kinetics of reactions in methanolic solutions was qualitatively studied by UV-Vis and ESMS spectrometries. Under the experimental conditions applied, a relatively slow formation of the mononuclear complex [VOL(OMe)] and an even slower formation of the cyclic species 2 were observed, whereas the presence of dinuclear compound [V(2)O(3)(L(cycl))(2)(OMe)(2)] in the reaction mixture could not be detected.

  20. Synthesis, spectral characterization and biological evaluation of Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes with thiosemicarbazone ending by pyrazole and pyridyl rings

    NASA Astrophysics Data System (ADS)

    Yousef, T. A.; Abu El-Reash, G. M.; Al-Jahdali, M.; El-Rakhawy, El-Bastawesy R.

    2014-08-01

    Here we present the synthesis of the new Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes with chelating ligand (Z)-(2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene) hydrazinyl)(pyridin-2-ylamino)methanethiol. All the complexes were characterized by elemental analysis, IR, 1H NMR, UV-vis, magnetic susceptibility measurements and EPR spectral studies. IR spectra of complexes showed that the ligand behaves as NN neutral bidentate, NSN mononegative tridentate and NSNN mononegative tetradentate. The electronic spectra and the magnetic measurements suggested the octahedral geometry for all complexes as well as the EPR confirmed the tetragonal distorted octahedral for Cu(II) complex. Cd(II) complex showed the highest inhibitory antioxidant activity either using ABTS method. The SOD-like activity exhibited those Cd(II) and Zn(II) complexes have strong antioxidative properties. We tested the synthesized compounds for antitumor activity and showed that the ability to kill liver (HePG2) and breast (MCF-7) cancer cells definitely.

  1. Induction of antigen-specific immunity by pH-sensitive carbonate apatite as a potent vaccine carrier

    SciTech Connect

    Hebishima, Takehisa; Tada, Seiichi; Takeshima, Shin-nosuke; Akaike, Toshihiro; Ito, Yoshihiro; Aida, Yoko

    2011-12-02

    Highlights: Black-Right-Pointing-Pointer To develop effective vaccine, we examined the effects of CO{sub 3}Ap as an antigen carrier. Black-Right-Pointing-Pointer OVA contained in CO{sub 3}Ap was taken up by BMDCs more effectively than free OVA. Black-Right-Pointing-Pointer OVA-immunized splenocytes was activated by OVA contained in CO{sub 3}Ap effectively. Black-Right-Pointing-Pointer OVA contained in CO{sub 3}Ap induced strong OVA-specific immune responses to C57BL/6 mice. Black-Right-Pointing-Pointer CO{sub 3}Ap is promising antigen carrier for the achievement of effective vaccine. -- Abstract: The ability of carbonate apatite (CO{sub 3}Ap) to enhance antigen-specific immunity was examined in vitro and in vivo to investigate its utility as a vaccine carrier. Murine bone marrow-derived dendritic cells took up ovalbumin (OVA) containing CO{sub 3}Ap more effectively than free OVA. Interestingly, mice immunized with OVA-containing CO{sub 3}Ap produced OVA-specific antibodies more effectively than mice immunized with free OVA. Furthermore, immunization of C57BL/6 mice with OVA-containing CO{sub 3}Ap induced the proliferation and antigen-specific production of IFN-{gamma} by splenocytes more strongly than immunization with free OVA. Moreover, no significant differences were detected in the induction of delayed-type hypersensitivity responses, an immune reaction involving an antigen-specific, cell-mediated immune response between OVA-containing CO{sub 3}Ap and OVA-containing alumina salt (Alum), suggesting that CO{sub 3}Ap induced cell-mediated immune response to the same degree as Alum, which is commonly used for clinical applications. This study is the first to demonstrate the induction of antigen-specific immune responses in vivo by CO{sub 3}Ap.

  2. Gene Delivery Potential of Biofunctional Carbonate Apatite Nanoparticles in Lungs

    PubMed Central

    Alhaji, Suleiman Yusuf; Chowdhury, Ezharul Houque; Rosli, Rozita

    2014-01-01

    Existing nonviral gene delivery systems to lungs are inefficient and associated with dose limiting toxicity in mammalian cells. Therefore, carbonate apatite (CO3Ap) nanoparticles were examined as an alternative strategy for effective gene delivery to the lungs. This study aimed to (1) assess the gene delivery efficiency of CO3Ap in vitro and in mouse lungs, (2) evaluate the cytotoxicity effect of CO3Ap/pDNA in vitro, and (3) characterize the CO3Ap/pDNA complex formulations. A significantly high level of reporter gene expression was detected from the lung cell line transfected with CO3Ap/pDNA complex prepared in both serum and serum-free medium. Cytotoxicity analysis revealed that the percentage of the viable cells treated with CO3Ap to be almost similar to the untreated cells. Characterization analyses showed that the CO3Ap/pDNA complexes are in a nanometer range with aggregated spherical structures and tended to be more negatively charged. In the lung of mice, highest level of transgene expression was observed when CO3Ap (8 μL) was complexed with 40 μg of pDNA at day 1 after administration. Although massive reduction of gene expression was seen beyond day 1 post administration, the level of expression remained significant throughout the study period. PMID:25143941

  3. Coordination behavior of ligand based on NNS and NNO donors with ruthenium(III) complexes and their catalytic and DNA interaction studies

    NASA Astrophysics Data System (ADS)

    Manikandan, R.; Viswnathamurthi, P.

    2012-11-01

    Reactions of 2-acetylpyridine-thiosemicarbazone HL1, 2-acetylpyridine-4-methyl-thiosemicarbazone HL2, 2-acetylpyridine-4-phenyl-thiosemicarbazone HL3 and 2-acetylpyridine-semicarbazone HL4 with ruthenium(III) precursor complexes were studied and the products were characterized by analytical and spectral (FT-IR, electronic, EPR and EI-MS) methods. The ligands coordinated with the ruthenium(III) ion via pyridine nitrogen, azomethine nitrogen and thiolate sulfur/enolate oxygen. An octahedral geometry has been proposed for all the complexes based on the studies. All the complexes are redox active and display an irreversible and quasireversible metal centered redox processes. Further, the catalytic activity of the new complexes has been investigated for the transfer hydrogenation of ketones in the presence of isopropanol/KOH and the Kumada-Corriu coupling of aryl halides with aryl Grignard reagents. The DNA cleavage efficiency of new complexes has also been tested.

  4. The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways.

    PubMed

    Kovacevic, Zaklina; Menezes, Sharleen V; Sahni, Sumit; Kalinowski, Danuta S; Bae, Dong-Hun; Lane, Darius J R; Richardson, Des R

    2016-01-15

    N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors. PMID:26534963

  5. Histological Comparison in Rats between Carbonate Apatite Fabricated from Gypsum and Sintered Hydroxyapatite on Bone Remodeling

    PubMed Central

    Ayukawa, Yasunori; Suzuki, Yumiko; Tsuru, Kanji; Koyano, Kiyoshi; Ishikawa, Kunio

    2015-01-01

    Carbonate apatite (CO3Ap), the form of apatite found in bone, has recently attracted attention. The purpose of the present study was to histologically evaluate the tissue/cellular response toward the low-crystalline CO3Ap fabricated using a dissolution-precipitation reaction with set gypsum as a precursor. When set gypsum was immersed in a 100°C 1 mol/L Na3PO4 aqueous solution for 24 h, the set gypsum transformed into CO3Ap. Both CO3Ap and sintered hydroxyapatite (s-HAp), which was used as a control, were implanted into surgically created tibial bone defects of rats for histological evaluation. Two and 4 weeks after the implantation, histological sections were created and observed using light microscopy. The CO3Ap granules revealed both direct apposition of the bone matrix by osteoblasts and osteoclastic resorption. In contrast, the s-HAp granules maintained their contour even after 4 weeks following implantation which implied that there was a lack of replacement into the bone. The s-HAp granules were sometimes encapsulated with fibrous tissue, and macrophage polykaryon was occasionally observed directly apposed to the implanted granules. From the viewpoint of bone remodeling, the CO3Ap granules mimicked the bone matrix, suggesting that CO3Ap may be an appropriate bone substitute. PMID:26504813

  6. Vibrational predissociation and vibrationally induced isomerization of 3-aminophenol-ammonia

    SciTech Connect

    Heid, Cornelia G.; Merrill, Wyatt G.; Case, Amanda S. Crim, F. Fleming

    2015-01-07

    We investigate the vibrational predissociation dynamics of the hydrogen-bonded 3-aminophenol-ammonia cluster (3-AP-NH{sub 3}) in the OH and NH stretching regions. Vibrational excitation provides enough energy to dissociate the cluster into its constituent 3-AP and NH{sub 3} monomers, and we detect the 3-AP fragments via (1 + 1) resonance-enhanced multiphoton ionization (REMPI). The distribution of vibrational states of the 3-AP fragment suggests the presence of two distinct dissociation pathways. The first dissociation channel produces a broad, unstructured feature in the REMPI-action spectrum after excitation of any of the OH or NH stretching vibrations, pointing to a nearly statistical dissociation pathway with extensive coupling among the vibrations in the cluster during the vibrational predissociation. The second dissociation channel produces distinct, resolved features on top of the broad feature but only following excitation of the OH or symmetric NH{sub 3} stretch in the cluster. This striking mode-specificity is consistent with strong coupling of these two modes to the dissociation coordinate (the O–H⋯N bond). The presence of clearly resolved transitions to the electronic origin and to the 10a{sup 2} + 10b{sup 2} state of the cis-3-AP isomer shows that vibrational excitation is driving the isomerization of the trans-3-AP-NH{sub 3} isomer to the cis-3-AP-NH{sub 3} isomer in the course of the dissociation.

  7. Histological Comparison in Rats between Carbonate Apatite Fabricated from Gypsum and Sintered Hydroxyapatite on Bone Remodeling.

    PubMed

    Ayukawa, Yasunori; Suzuki, Yumiko; Tsuru, Kanji; Koyano, Kiyoshi; Ishikawa, Kunio

    2015-01-01

    Carbonate apatite (CO3Ap), the form of apatite found in bone, has recently attracted attention. The purpose of the present study was to histologically evaluate the tissue/cellular response toward the low-crystalline CO3Ap fabricated using a dissolution-precipitation reaction with set gypsum as a precursor. When set gypsum was immersed in a 100°C 1 mol/L Na3PO4 aqueous solution for 24 h, the set gypsum transformed into CO3Ap. Both CO3Ap and sintered hydroxyapatite (s-HAp), which was used as a control, were implanted into surgically created tibial bone defects of rats for histological evaluation. Two and 4 weeks after the implantation, histological sections were created and observed using light microscopy. The CO3Ap granules revealed both direct apposition of the bone matrix by osteoblasts and osteoclastic resorption. In contrast, the s-HAp granules maintained their contour even after 4 weeks following implantation which implied that there was a lack of replacement into the bone. The s-HAp granules were sometimes encapsulated with fibrous tissue, and macrophage polykaryon was occasionally observed directly apposed to the implanted granules. From the viewpoint of bone remodeling, the CO3Ap granules mimicked the bone matrix, suggesting that CO3Ap may be an appropriate bone substitute. PMID:26504813

  8. Induction of antigen-specific immunity by pH-sensitive carbonate apatite as a potent vaccine carrier.

    PubMed

    Hebishima, Takehisa; Tada, Seiichi; Takeshima, Shin-nosuke; Akaike, Toshihiro; Ito, Yoshihiro; Aida, Yoko

    2011-12-01

    The ability of carbonate apatite (CO(3)Ap) to enhance antigen-specific immunity was examined in vitro and in vivo to investigate its utility as a vaccine carrier. Murine bone marrow-derived dendritic cells took up ovalbumin (OVA) containing CO(3)Ap more effectively than free OVA. Interestingly, mice immunized with OVA-containing CO(3)Ap produced OVA-specific antibodies more effectively than mice immunized with free OVA. Furthermore, immunization of C57BL/6 mice with OVA-containing CO(3)Ap induced the proliferation and antigen-specific production of IFN-γ by splenocytes more strongly than immunization with free OVA. Moreover, no significant differences were detected in the induction of delayed-type hypersensitivity responses, an immune reaction involving an antigen-specific, cell-mediated immune response between OVA-containing CO(3)Ap and OVA-containing alumina salt (Alum), suggesting that CO(3)Ap induced cell-mediated immune response to the same degree as Alum, which is commonly used for clinical applications. This study is the first to demonstrate the induction of antigen-specific immune responses in vivo by CO(3)Ap.

  9. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    PubMed

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment.

  10. Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi.

    PubMed

    de Oliveira Filho, Gevanio Bezerra; de Oliveira Cardoso, Marcos Veríssimo; Espíndola, José Wanderlan Pontes; Ferreira, Luiz Felipe Gomes Rebello; de Simone, Carlos Alberto; Ferreira, Rafaela Salgado; Coelho, Pollyanne Lacerda; Meira, Cássio Santana; Magalhaes Moreira, Diogo Rodrigo; Soares, Milena Botelho Pereira; Lima Leite, Ana Cristina

    2015-12-01

    Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity. PMID:26549870

  11. Trypanocidal nitroimidazole derivatives: relationships among chemical structure and genotoxic activity.

    PubMed

    Buschini, Annamaria; Giordani, Federica; de Albuquerque, Cristina Northfleet; Pellacani, Claudia; Pelosi, Giorgio; Rossi, Carlo; Zucchi, Tânia Maria Araújo Domingues; Poli, Paola

    2007-05-15

    Human American trypanosomiasis is resurgent in Latin Americans, and new drugs are urgently required as current medications suffer from a number of drawbacks. Some nitroheterocycles have been demonstrated to exert a potent activity against trypanosomes. However, host toxicity issues halted their development as trypanocides. As part of the efforts to develop new compounds in order to treat parasitic infections, it is important to define their structure-activity relationship. In this study, 5-nitromegazol and two of its analogues, 4-nitromegazol, and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole-thiosemicarbazone, were tested and compared for in vitro induction of DNA damage in human leukocytes by the comet assay, performed at different pHs to better identify the types of damage. Specific oxidatively generated damage to DNA was also measured by using the comet assay with endonucleases. DNA damage was found in 5-nitromegazol-treated cells: oxidative stress appeared as the main source of DNA damage. 4-Nitromegazol did not produce any significant effect, thus confirming that 4-nitroimidazoles isomers have no important biological activity. The 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol. The central role in the reduction process played by the acidic hydrazine proton present in the thiosemicarbazone group but not in the cyclic (thiadiazole) form can contribute to rationalise our results. Given its versatility, thiosemicarbazone moiety could be involved in different reactions with nitrogenous bases (nucleophilic and/or electrophilic attacks).

  12. Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi.

    PubMed

    de Oliveira Filho, Gevanio Bezerra; de Oliveira Cardoso, Marcos Veríssimo; Espíndola, José Wanderlan Pontes; Ferreira, Luiz Felipe Gomes Rebello; de Simone, Carlos Alberto; Ferreira, Rafaela Salgado; Coelho, Pollyanne Lacerda; Meira, Cássio Santana; Magalhaes Moreira, Diogo Rodrigo; Soares, Milena Botelho Pereira; Lima Leite, Ana Cristina

    2015-12-01

    Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.

  13. 40 CFR 61.04 - Address.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... State, when appropriate, the authority to implement and enforce national emission standards...

  14. 40 CFR 61.04 - Address.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... State, when appropriate, the authority to implement and enforce national emission standards...

  15. 3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin.

    PubMed Central

    Li, Wei; Yuan, Xi-Ming; Ivanova, Svetlana; Tracey, Kevin J; Eaton, John W; Brunk, Ulf T

    2003-01-01

    Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH(3), protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia. PMID:12513695

  16. Human neuroblastoma (SH-SY5Y) cells are highly sensitive to the lysosomotropic aldehyde 3-aminopropanal.

    PubMed

    Yu, Zhengquan; Li, Wei; Hillman, Jan; Brunk, Ulf T

    2004-08-01

    3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH3 completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, alpha-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by alpha-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against

  17. Preparation, spectroscopy, EXAFS, electrochemistry and pharmacology of new ruthenium(II) carbonyl complexes containing ferrocenylthiosemicarbazone and triphenylphosphine/arsine

    NASA Astrophysics Data System (ADS)

    Prabhakaran, R.; Anantharaman, S.; Thilagavathi, M.; Kaveri, M. V.; Kalaivani, P.; Karvembu, R.; Dharmaraj, N.; Bertagnolli, H.; Dallemer, F.; Natarajan, K.

    2011-02-01

    A new series of new hetero-bimetallic complexes containing iron and ruthenium of the general formula [RuCl(CO)(B)(EPh 3)(L)] (where E = P or As; B = PPh 3, AsPh 3, py or pip; L = ferrocene derived monobasic bidentate thiosemicarbazone ligand) have been synthesized by the reaction between ferrocene-derived thiosemicarbazones and ruthenium(II) complexes of the type [RuHCl(CO)(B)(EPh 3) 2] (where E = P or As; B = PPh 3, AsPh 3, py or pip). The new complexes have been characterized by elemental analyses, IR, electronic, NMR ( 1H, 13C and 31P), EXAFS (extended X-ray absorption fine structure spectroscopy) and cyclic voltammetric techniques. Antibacterial activity of the new complexes has been screened against Escherichia coli, Vibrio cholerae, and Pseudomonas aeruginosa species.

  18. Computer-based approach to chelation therapy: a theoretical study of some chelating agents for the selective removal of toxic metal ions from plasma.

    PubMed

    Agarwal, R P; Perrin, D D

    1976-09-01

    COMICS is a computer programme for calculating equilibrium concentrations of metal complexes and reactive species in multi-metal-multi-ligand systems. Its usefulness for analysing metal ion equilibria in blood plasma has been improved by including albumin as a ligand. Using this model system the distribution and removal of copper(II) and zinc ions in histidinaemia, lead poisoning and Wilson's disease have been examined. The efficacy of TRIEN in removing excess copper(II) is shown. The use of specific tripeptides such as Gly-Gly-His methyl ester for the selective removal of copper(II) is suggested. A possible chemoprophylaxis of influenza based on complexation of zinc is discussed. Calculations confirm that thiosemicarbazones such as methisazone and 2-acetylpyridine thiosemicarbazone are effective competitors for heavy metal ions under physiological conditions. PMID:970298

  19. Effects of Intravenous Administration of Human Umbilical Cord Blood Stem Cells in 3-Acetylpyridine-Lesioned Rats

    PubMed Central

    Calatrava-Ferreras, Lucía; Gonzalo-Gobernado, Rafael; Herranz, Antonio S.; Reimers, Diana; Montero Vega, Teresa; Jiménez-Escrig, Adriano; Richart López, Luis Alberto; Bazán, Eulalia

    2012-01-01

    Cerebellar ataxias include a heterogeneous group of infrequent diseases characterized by lack of motor coordination caused by disturbances in the cerebellum and its associated circuits. Current therapies are based on the use of drugs that correct some of the molecular processes involved in their pathogenesis. Although these treatments yielded promising results, there is not yet an effective therapy for these diseases. Cell replacement strategies using human umbilical cord blood mononuclear cells (HuUCBMCs) have emerged as a promising approach for restoration of function in neurodegenerative diseases. The aim of this work was to investigate the potential therapeutic activity of HuUCBMCs in the 3-acetylpyridine (3-AP) rat model of cerebellar ataxia. Intravenous administered HuUCBMCs reached the cerebellum and brain stem of 3-AP ataxic rats. Grafted cells reduced 3-AP-induced neuronal loss promoted the activation of microglia in the brain stem, and prevented the overexpression of GFAP elicited by 3-AP in the cerebellum. In addition, HuUCBMCs upregulated the expression of proteins that are critical for cell survival, such as phospho-Akt and Bcl-2, in the cerebellum and brain stem of 3-AP ataxic rats. As all these effects were accompanied by a temporal but significant improvement in motor coordination, HuUCBMCs grafts can be considered as an effective cell replacement therapy for cerebellar disorders. PMID:23150735

  20. Synthesis and antimicrobial activity of new substituted anilinobenzimidazoles.

    PubMed

    Nofal, Z M; Fahmy, H H; Mohamed, H S

    2002-06-01

    A series of benzimidazole derivatives carrying different heterocycles such as 1,2,3-thiadiazole, 1,3,4-thiadiazole, thiazolidine, 2,3-dihydro-thiazole, 1,3,4-oxadiazole, semicarbazone and substituted thiosemi-carbazones were synthesized. Also a series of 1-methylbenzimidazole carrying hydroxy ethyl-amide, substituted sulfonyl hydrazide and benzoyl hydrazide from aminobenzoyl group at position 2 of 1-methylbenzimidazole were synthesized. The antimicrobial evaluation of some of the new compounds was carried out. PMID:12135093

  1. Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities.

    PubMed

    Cardoso, Marcos Veríssimo de Oliveira; Moreira, Diogo Rodrigo Magalhães; Oliveira Filho, Gevanio Bezerra; Cavalcanti, Suellen Melo Tiburcio; Coelho, Lucas Cunha Duarte; Espíndola, José Wanderlan Pontes; Gonzalez, Laura Rubio; Rabello, Marcelo Montenegro; Hernandes, Marcelo Zaldini; Ferreira, Paulo Michel Pinheiro; Pessoa, Cláudia; Alberto de Simone, Carlos; Guimarães, Elisalva Teixeira; Soares, Milena Botelho Pereira; Leite, Ana Cristina Lima

    2015-01-01

    The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups.

  2. Functional group analysis

    SciTech Connect

    Smith, W.T. Jr.; Patterson, J.M.

    1986-04-01

    Analytical methods for functional group analysis are reviewed. Literature reviewed is from the period of December 1983 through November 1985 and presents methods for determining the following compounds: acids, acid halides, active hydrogen, alcohols, aldehydes, ketones, amides, amines, amino acids, anhydrides, aromatic hydrocarbons, azo compounds, carbohydrates, chloramines, esters, ethers, halogen compounds, hydrazines, isothiocyanates, nitro compounds, nitroso compounds, organometallic compounds, oxiranes, peroxides, phenols, phosphorus compounds, quinones, silicon compounds, sulfates, sulfonyl chlorides, thioamides, thiols, and thiosemicarbazones. 150 references.

  3. In vitro and in vivo evaluation of bifunctional bisthiosemicarbazone 64Cu-complexes for the positron emission tomography imaging of hypoxia.

    PubMed

    Bonnitcha, Paul D; Vāvere, Amy L; Lewis, Jason S; Dilworth, Jonathan R

    2008-05-22

    The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis(N4-methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-amino-3-thiosemicarbazone) (H2ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with 64Cu (t1/2=12.7 h, beta+=19.3%). In vitro studies were performed on three of the compounds using EMT6 mammary carcinoma cells under hypoxic and normoxic conditions. All compounds displayed rapid cellular association and appreciable hypoxic selectivity with increased uptake under normoxic and hypoxic conditions when compared to 64Cu-ATSM. Biodistribution and small animal PET imaging studies were then carried out in vivo using two compounds in EMT6 tumor-bearing mice. The compounds showed high tumor uptake, but also substantial accumulation in the liver. These complexes demonstrate that H 2ATSM/A represents a novel and versatile synthetic platform that can be utilized to provide hypoxic cell selectivity through functionalization of the bisthiosemicarbazonate group.

  4. Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity.

    PubMed

    Buschini, Annamaria; Pinelli, Silvana; Pellacani, Claudia; Giordani, Federica; Ferrari, Marisa Belicchi; Bisceglie, Franco; Giannetto, Marco; Pelosi, Giorgio; Tarasconi, Pieralberto

    2009-05-01

    Thiosemicarbazones are versatile organic compounds that present considerable pharmaceutical interest because of a wide range of properties. In our laboratory we synthesised some new metal-complexes with thiosemicarbazones derived from natural aldehydes which showed peculiar biological activities. In particular, a nickel complex [Ni(S-tcitr)(2)] (S-tcitr=S-citronellalthiosemicarbazonate) was observed to induce an antiproliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC(50)=14.4microM). Therefore, we decided to study the interactions of this molecule with various cellular components and to characterise the induced apoptotic pathway. Results showed that [Ni(S-tcitr)(2)] causes programmed cell death via down-regulation of Bcl-2, alteration of mitochondrial membrane potential and caspase-3 activity, regardless of p53 function. The metal complex is not active on G(0) cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G(2)/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0microM), DNA damage, which could be partially ascribed to oxidative stress. [Ni(S-tcitr)(2)] is moreover able to strongly reduce the telomerase activity. Although the biological target of this metal complex is still unknown, the reported data suggest that [Ni(S-tcitr)(2)] could be a good model for the synthesis of new metal thiosemicarbazones with specific biological activity.

  5. Waste compatibility safety issues and final results for Tank 241-AP-103 grab samples

    SciTech Connect

    Nuzum, J.L.

    1997-10-02

    Three grab samples (3AP-97-2, 3AP-97-3, and 3AP-97-4) were taken from Riser 1 of Tank 241-AP-103 on August 21, 1997, and received by 222-S Laboratory on August 22, 1997. These samples were analyzed in accordance with Compatibility Grab Sampling and Analysis Plan for Fiscal Year 1997 (TSAP) (Field, 1997) and Data Quality Objectives for Tank Farms Waste and Compatibility Program (Mulkey et. al., 1995) (DQO) in support of the Waste Compatibility Program. No notifications were required based on sample results. Appearance and Sample Breakdown Attachment 1 illustrates subsamples generated in the laboratory for analyses and identifies their sources. Furthermore, this reference relates tank farm identification numbers to their corresponding 222-S Laboratory Information Management System sample numbers. Table 1 summarizes appearance information and over-the-top (OTR) dose readings performed on each sample. For each sample, two 20 ml subsamples were created for inorganic and radiochemical analyses.

  6. Photoaffinity labeling and photoaffinity cross-linking of phosphofructokinase-1 from Saccharomyces cerevisiae by 8-azidoadeninenucleotides.

    PubMed

    Knoche, M; Mönnich, K; Schäfer, H J; Kopperschläger, G

    2001-01-15

    Phosphofructokinase-1 from Saccharomyces cerevisiae is composed of four alpha- and four beta-subunits, each of them carrying catalytic and regulatory bindings sites for MgATP. In this paper, various photoaffinity labels, such as 8-azidoadenosine 5'-triphosphate, 8-azido-1,N6-ethenoadenosine 5'-triphosphate, and 8-N3-3'(2')-O-biotinyl-8-azidoadenosine 5'-triphosphate have been used to study their interaction with the enzyme in the dark and during irradiation. All nucleotidetriphosphates function as phosphate donor forming fructose 1,6-bisphosphate from fructose 6-phosphate. However, the kinetic analysis revealed distinctly differences between them. Photolabeling causes a decrease in enzyme activity to a similar extent, and ATP acts as competitive effector to inactivation. Three bifunctional diazidodiadeninedinucleotides (8-diN3AP4A, monoepsilon-8-diN3AP4A, and diepsilon-8-diN3AP4A) were applied for studying the spatial arrangement of the nucleotide binding sites. No cross-linking of the subunits was obtained by irradiation of the enzyme with 8-diN3AP4A. Photolabeling with diepsilon-8-diN3AP4A resulted in the formation of two alpha-beta cross-links with different mobilities in the SDS-polyacrylamide gel electrophoresis, while monoepsilon-8-diN3AP4A yielded only one alpha-beta cross-link. Because an interfacial location of the catalytic sites between two subunits is less likely, we suggest that the formation of cross-linked subunits may be the result of specific interactions of the bifunctional photolabels with regulatory sites at the interface of both subunits. PMID:11368011

  7. Reduction of GABA/sub B/ receptor binding induced by climbing fiber degeneration in the rat cerebellum

    SciTech Connect

    Kato, K.; Fukuda, H.

    1985-07-22

    When the rat cerebellar climbing fibers degenerated, as induced by lesioning the inferior olive with 3-acetylpyridine (3-AP), GABA/sub B/ receptor binding determined with /sup 3/H-(+/-)baclofen was reduced in the cerebellum but not in the cerebral cortex of rats. Computer analysis of saturation data revealed two components of the binding sites, and indicated that decrease of the binding in the cerebellum was due to reduction in receptor density, mainly of the high-affinity sites, the B/sub max/ of which was reduced to one-third that in the control animals. In vitro treatment with 3-AP, of the membranes prepared from either the cerebellum or the cerebral cortex, induced no alteration in the binding sites, thereby indicating that the alteration of GABA/sub B/ sites induced by in vivo treatment with 3-AP is not due to a direct action of 3-AP on the receptor. GABA/sub A/ and benzodiazepine receptor binding labelled with /sup 3/H-muscimol and /sup 3/H-diazepam, respectively, in both of brain regions was not affected by destruction of the inferior olive. These results provide evidence that some of the GABA/sub B/ sites but neither GABA/sub A/ nor benzodiazepine receptors in the cerebellum are located at the climbing fiber terminals. 28 references, 4 figures, 2 tables.

  8. 76 FR 67640 - Approval and Promulgation of Air Quality Implementation Plans; Pennsylvania; Attainment Plan for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... representation of weather conditions at the surface and aloft. e. Domain of the Model, Horizontal/Vertical..., Associate Director, Office of Air Planning Program, Mailcode 3AP30, U.S. Environmental Protection Agency... is not publicly available, i.e., CBI or other information whose disclosure is restricted by...

  9. 78 FR 78263 - Approval and Promulgation of Air Quality Implementation Plans; Pennsylvania; Update of the Motor...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-26

    ... using the Highway Mobile Source Emission Factor Model (MOBILE6.2). On March 2, 2010 (75 FR 9411), EPA...-2013-0058, Cristina Fernandez, Associate Director, Office of Air Program Planning, Mailcode 3AP30, U.S... the index, some information is not publicly available, i.e., CBI or other information whose...

  10. 77 FR 46990 - Approval and Promulgation of Air Quality Implementation Plans; Delaware; Attainment Demonstration...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-07

    ...-0930, Donna Mastro, Acting Associate Director, Office of Air Planning Program, Mailcode 3AP30, U.S.... Although listed in the index, some information is not publicly available, i.e., CBI or other information... contingency measures (elements of the June 13, 2007 attainment plan) were approved on April 8, 2010 (75...

  11. 77 FR 50966 - Approval and Promulgation of Air Quality Implementation Plans; Maryland; Attainment Demonstration...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-23

    ... Director, Office of Air Planning Program, Mailcode 3AP30, U.S. Environmental Protection Agency, Region III... is not publicly available, i.e., CBI or other information whose disclosure is restricted by statute... measures (elements of the June 4, 2007 attainment plan) were approved on June 11, 2010 (75 FR...

  12. Bacillus subtilis-based direct-fed microbials augment macrophage function in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study was conducted to evaluate the function of Bacillus subtilis-based direct-fed microbials (DFMs) on macrophage functions, i.e., nitric oxide (NO) production and phagocytosis in broiler chickens. DFMs used in this study were eight single strains designated as Bs2084, LSSAO1, 3AP4, Bs1...

  13. The effects of inferior olive lesion on strychnine seizure

    SciTech Connect

    Anderson, M.C.; Chung, E.Y.; Van Woert, M.H. )

    1990-10-01

    Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable ({sup 3}H)AMPA ((RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) binding in cerebella from inferior olive-lesioned rats was observed, but no difference in ({sup 3}H)AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10 imine) were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the ({sup 3}H)AMPA binding data.

  14. 40 CFR 61.04 - Address.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION..., Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103-2029. Region IV... authority to implement and enforce national emission standards for hazardous air pollutants for...

  15. 40 CFR 60.4 - Address.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... Pollution Control, Arkansas Department of Pollution Control and Ecology, 8001 National Drive, P.O. Box 9583..., CA 96101. Mojave Desert Air Quality Management District, 14306 Park Avenue, Victorville, CA...

  16. 77 FR 73575 - Approval and Promulgation of Air Quality Implementation Plans; West Virginia; Redesignation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-11

    ... ``Area'') be redesignated as attainment for the 1997 annual PM 2.5 national ambient air quality standard... 3AP30, U.S. Environmental Protection Agency, Region III, 1650 Arch Street, Philadelphia, Pennsylvania... hours at the Air Protection Division, U.S. Environmental Protection Agency, Region III, 1650 Arch...

  17. 40 CFR 60.4 - Address.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... Department of Pollution Control and Ecology, 8001 National Drive, P.O. Box 9583, Little Rock, AR 72209. (F... Management District, 14306 Park Avenue, Victorville, CA 92392-2310. Monterey Bay Unified Air...

  18. 40 CFR 60.4 - Address.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... Department of Pollution Control and Ecology, 8001 National Drive, P.O. Box 9583, Little Rock, AR 72209. (F... Management District, 14306 Park Avenue, Victorville, CA 92392-2310. Monterey Bay Unified Air...

  19. 40 CFR 60.4 - Address.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103-2029. Region IV... Pollution Control and Ecology, 8001 National Drive, P.O. Box 9583, Little Rock, AR 72209. (F) California... Management District, 14306 Park Avenue, Victorville, CA 92392-2310. Monterey Bay Unified Air...

  20. 40 CFR 61.04 - Address.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION... Virginia), Director, Air Protection Division, Mail Code 3AP00, 1650 Arch Street, Philadelphia, PA 19103... Administrator to delegate to each State, when appropriate, the authority to implement and enforce...

  1. 76 FR 58206 - Approval and Promulgation of Air Quality Implementation Plans; District of Columbia, Maryland...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ..., Maryland, and Virginia; Determinations of Attainment of the 1997 8-Hour Ozone National Ambient Air Quality... National Ambient Air Quality Standard (NAAQS). This proposed determination is based upon complete, quality..., Mailcode 3AP30, U.S. Environmental Protection Agency, Region III, 1650 Arch Street,...

  2. Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

    PubMed

    Kerdjoudj, R; Pniok, M; Alliot, C; Kubíček, V; Havlíčková, J; Rösch, F; Hermann, P; Huclier-Markai, S

    2016-01-28

    The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

  3. Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

    PubMed

    Kerdjoudj, R; Pniok, M; Alliot, C; Kubíček, V; Havlíčková, J; Rösch, F; Hermann, P; Huclier-Markai, S

    2016-01-28

    The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine. PMID:26675416

  4. Directed Molecular Evolution of an Engineered Gammaretroviral Envelope Protein with Dual Receptor Use Shows Stable Maintenance of Both Receptor Specificities

    PubMed Central

    Friis, Kristina Pagh; Iturrioz, Xavier; Thomsen, Jonas; Alvear-Perez, Rodrigo; Bahrami, Shervin; Llorens-Cortes, Catherine

    2015-01-01

    ABSTRACT We have previously reported the construction of a murine leukemia virus-based replication-competent gammaretrovirus (SL3-AP) capable of utilizing the human G protein-coupled receptor APJ (hAPJ) as its entry receptor and its natural receptor, the murine Xpr1 receptor, with equal affinities. The apelin receptor has previously been shown to function as a coreceptor for HIV-1, and thus, adaptation of the viral vector to this receptor is of significant interest. Here, we report the molecular evolution of the SL3-AP envelope protein when the virus is cultured in cells harboring either the Xpr1 or the hAPJ receptor. Interestingly, the dual receptor affinity is maintained even after 10 passages in these cells. At the same time, the chimeric viral envelope protein evolves in a distinct pattern in the apelin cassette when passaged on D17 cells expressing hAPJ in three separate molecular evolution studies. This pattern reflects selection for reduced ligand-receptor interaction and is compatible with a model in which SL3-AP has evolved not to activate hAPJ receptor internalization. IMPORTANCE Few successful examples of engineered retargeting of a retroviral vector exist. The engineered SL3-AP envelope is capable of utilizing either the murine Xpr1 or the human APJ receptor for entry. In addition, SL3-AP is the first example of an engineered retrovirus retaining its dual tropism after several rounds of passaging on cells expressing only one of its receptors. We demonstrate that the virus evolves toward reduced ligand-receptor affinity, which sheds new light on virus adaptation. We provide indirect evidence that such reduced affinity leads to reduced receptor internalization and propose a novel model in which too rapid receptor internalization may decrease virus entry. PMID:26608314

  5. 3-acetylpyridine-induced degeneration in the adult ascidian neural complex: Reactive and regenerative changes in glia and blood cells.

    PubMed

    Medina, Bianca N S P; Santos de Abreu, Isadora; Cavalcante, Leny A; Silva, Wagner A B; da Fonseca, Rodrigo N; Allodi, Silvana; de Barros, Cintia M

    2015-08-01

    Ascidians are interesting neurobiological models because of their evolutionary position as a sister-group of vertebrates and the high regenerative capacity of their central nervous system (CNS). We investigated the degeneration and regeneration of the cerebral ganglion complex of the ascidian Styela plicata following injection of the niacinamide antagonist 3-acetylpyridine (3AP), described as targeting the CNS of several vertebrates. For the analysis and establishment of a new model in ascidians, the ganglion complex was dissected and prepared for transmission electron microscopy (TEM), routine light microscopy (LM), immunohistochemistry and Western blotting, 1 or 10 days after injection of 3AP. The siphon stimulation test (SST) was used to quantify the functional response. One day after the injection of 3AP, CNS degeneration and recruitment of a non-neural cell type to the site of injury was observed by both TEM and LM. Furthermore, weaker immunohistochemical reactions for astrocytic glial fibrillary acidic protein (GFAP) and neuronal βIII-tubulin were observed. In contrast, the expression of caspase-3, a protein involved in the apoptotic pathway, and the glycoprotein CD34, a marker for hematopoietic stem cells, increased. Ten days after the injection of 3AP, the expression of markers tended toward the original condition. The SST revealed attenuation and subsequent recovery of the reflexes from 1 to 10 days after 3AP. Therefore, we have developed a new method to study ascidian neural degeneration and regeneration, and identified the decreased expression of GFAP and recruitment of blood stem cells to the damaged ganglion as reasons for the success of neuroregeneration in ascidians.

  6. Iron-Targeting Antitumor Activity of Gallium Compounds and Novel Insights Into Triapine®-Metal Complexes

    PubMed Central

    Antholine, William E.

    2013-01-01

    Abstract Significance: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Recent Advances: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine® has demonstrated activity against other tumors. Critical Issues: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed. Future Directions: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it. Antioxid. Redox Signal. 00, 000–000. PMID:22900955

  7. Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II) - Potential combination agents for the PET imaging of hypoxia.

    PubMed

    Bonnitcha, Paul D; Bayly, Simon R; Theobald, Mark B M; Betts, Helen M; Lewis, Jason S; Dilworth, Jonathan R

    2010-02-01

    Combination agents comprising two different pharmacophores with the same biological target have the potential to show additive or synergistic activity. Bis(thiosemicarbazonato)copper(II) complexes (e.g. (64)Cu-ATSM) and nitroimidazoles (e.g. (18)F-MISO) are classes of tracer used for the delineation of tumor hypoxia by positron emission tomography (PET). Three nitroimidazole-bis(thiosemicarbazonato)copper(II) conjugates were produced in order to investigate their potential as combination hypoxia imaging agents. Two were derived from the known bifunctional bis(thiosemicarbazone) H(2)ATSM/A and the third from the new precursor diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-ethylamino-3-thiosemicarbazone) - H(2)ATSM/en. Oxygen-dependent uptake studies were performed using the (64)Cu radiolabelled complexes in EMT6 carcinoma cells. All the complexes displayed appreciable hypoxia selectivity, with the nitroimidazole conjugates displaying greater selectivity than a simple propyl derivative used as a control. Participation of the nitroimidazole group in the trapping mechanism is indicated by the increased hypoxic uptake of the 2- vs. the 4-substituted (64)Cu-ATSM/A derivatives. The 2-nitroimidazole derivative of (64)Cu-ATSM/en demonstrated superior hypoxia selectivity to (64)Cu-ATSM over the range of oxygen concentrations tested. Biodistribution of the radiolabelled 2-nitroimidazole conjugates was carried out in EMT6 tumor-bearing mice. The complexes showed significantly different uptake trends in comparison to each other and previously studied Cu-ATSM derivatives. Uptake of the Cu-ATSM/en conjugate in non-target organs was considerably lower than for derivatives based on Cu-ATSM/A.

  8. Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter.

    PubMed

    Seebacher, Nicole A; Lane, Darius J R; Jansson, Patric J; Richardson, Des R

    2016-02-19

    Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in

  9. Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter.

    PubMed

    Seebacher, Nicole A; Lane, Darius J R; Jansson, Patric J; Richardson, Des R

    2016-02-19

    Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in

  10. Synthesis, structures and anti-malaria activity of some gold(I) phosphine complexes containing seleno- and thiosemicarbazonato ligands.

    PubMed

    Molter, Anja; Rust, Jörg; Lehmann, Christian W; Deepa, Ganesh; Chiba, Peter; Mohr, Fabian

    2011-10-14

    A series of both mono- and dinuclear gold(I) phosphine complexes containing monoanionic seleno- and thiosemicarbazones as ligands were prepared and fully characterized by spectroscopic methods and, in some cases, by single crystal X-ray diffraction. The in vitro anti-malaria activity of some of these compounds was investigated in chloroquine sensitive strains of Plasmodium falciparum. The IC(50) results show that the sulfur containing compounds exhibit activity similar to that of chloroquine, whilst the selenium derivatives display only moderate anti-malaria activity. PMID:21879088

  11. Synthesis, structures and anti-malaria activity of some gold(I) phosphine complexes containing seleno- and thiosemicarbazonato ligands.

    PubMed

    Molter, Anja; Rust, Jörg; Lehmann, Christian W; Deepa, Ganesh; Chiba, Peter; Mohr, Fabian

    2011-10-14

    A series of both mono- and dinuclear gold(I) phosphine complexes containing monoanionic seleno- and thiosemicarbazones as ligands were prepared and fully characterized by spectroscopic methods and, in some cases, by single crystal X-ray diffraction. The in vitro anti-malaria activity of some of these compounds was investigated in chloroquine sensitive strains of Plasmodium falciparum. The IC(50) results show that the sulfur containing compounds exhibit activity similar to that of chloroquine, whilst the selenium derivatives display only moderate anti-malaria activity.

  12. Crystal structure of 3-(prop-2-en-1-yl)-1-{[(1E)-1,2,3,4-tetra-hydro-naphthalen-1-yl-idene]amino}-thio-urea.

    PubMed

    Mague, Joel T; Mohamed, Shaaban K; Akkurt, Mehmet; Hassan, Alaa A; Abdel-Aziz, Ahmed T; Albayati, Mustafa R

    2015-12-01

    In the title compound, C14H17N3S, the dihedral angle between the planes of the benzene ring and the thio-semicarbazone group (r.m.s. deviation = 0.031 Å) is 8.45 (4)°. A short intra-molcular N-H⋯N contact is seen. In the crystal, weak N-H⋯S hydrogen bonds connect the mol-ecules into C(4) chains propagating in the [010] direction, with adjacent mol-ecules in the chain related by 21 screw-axis symmetry. PMID:26870559

  13. Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells.

    PubMed

    Adsule, Shreelekha; Barve, Vivek; Chen, Di; Ahmed, Fakhara; Dou, Q Ping; Padhye, Subhash; Sarkar, Fazlul H

    2006-11-30

    We report the synthesis of novel 1:1 Schiff base copper complexes of quinoline-2-carboxaldehyde showing dose-dependent, antiproliferative, and proapoptotic activity in PC-3 and LNCaP prostate cancer cells. We found that quinoline thiosemicarbazone 2 (FPA-137) was the most potent and inhibited proteosome activity in intact human prostate cancer PC-3 and LNCaP cells (IC50 of 4 and 3.2 microM, respectively) compared to clioquinol and pyrrolidine dithiocarbamate (IC50 of 10 and 20 microM), supporting the novelty of 2. PMID:17125278

  14. Synthesis, structure, and electrochemical characterization of a mixed-ligand diruthenium(III,II) complex with an unusual arrangement of the bridging ligands.

    PubMed

    Ngubane, Siyabonga; Kadish, Karl M; Bear, John L; Van Caemelbecke, Eric; Thuriere, Antoine; Ramirez, Kevin P

    2013-03-14

    A mixed-ligand metal-metal bonded diruthenium complex having the formula Ru(2)(2,4,6-(CH(3))(3)ap)(3)(O(2)CCH(3))Cl where ap is the anilinopyridinate anion was synthesized from the reaction of Ru(2)(O(2)CCH(3))(4)Cl and H(2,4,6-(CH(3))(3)ap), after which the isolated product was structurally, spectroscopically and electrochemically characterized. The crystal structure reveals an unusual arrangement of the bridging ligands around the dimetal unit where one ruthenium atom is coordinated to one anilino and two pyridyl nitrogen atoms while the other ruthenium atom is coordinated to one pyridyl and two anilino nitrogen atoms. To our knowledge, Ru(2)(2,4,6-(CH(3))(3)ap)(3)(O(2)CCH(3))Cl is the only example of a mixed-ligand diruthenium complex of the type [Ru(2)L(3)(O(2)CCH(3))](+), where L is an unsymmetrical anionic bridging ligand that has been structurally characterized with a "(2,1)" geometric conformation of the bridging ligands, all others being "(3,0)". The initial Ru(2)(5+) compound in CH(2)Cl(2) or CH(3)CN containing 0.1 M tetra-n-butylammonium perchlorate (TBAP) undergoes up to four one-electron redox processes involving the dimetal unit. The Ru(2)(5+/4+) and Ru(2)(5+/6+) processes were characterized under N(2) using thin-layer UV-visible spectroelectrochemistry and this data is compared to UV-visible spectral changes obtained during similar electrode reactions for related diruthenium compounds having the formula Ru(2)L(4)Cl or Ru(2)L(3)(O(2)CCH(3))Cl where L is an anionic bridging ligand. Ru(2)(2,4,6-(CH(3))(3)ap)(3)(O(2)CCH(3))Cl was also examined by UV-visible and FTIR spectroelectrochemistry under a CO atmosphere and two singly reduced Ru(2)(4+) species, [Ru(2)(2,4,6-(CH(3))(3)ap)(3)(O(2)CCH(3))(CO)Cl](-) and Ru(2)(2,4,6-(CH(3))(3)ap)(3)(O(2)CCH(3))(CO) were in situ generated for further characterization. The CO-bound complexes could be further reduced and exhibited additional reductions to their Ru(2)(3+) and Ru(2)(2+) oxidation states. PMID:23283183

  15. Synthesis and In Vitro Antitumor Activity of Two Mixed-Ligand Oxovanadium(IV) Complexes of Schiff Base and Phenanthroline

    PubMed Central

    Zhang, Yongli; Wang, Xiangsheng; Fang, Wei; Cai, Xiaoyan; Chu, Fujiang; Liao, Xiangwen; Lu, Jiazheng

    2013-01-01

    Two oxovanadium(IV) complexes of [VO(msatsc)(phen)], (1) (msatsc = methoxylsalicylaldehyde thiosemicarbazone, phen = phenanthroline) and its novel derivative [VO (4-chlorosatsc)(phen)], (2) (4-chlorosatsc = 4-chlorosalicylaldehyde thiosemicarbazone), have been synthesized and characterized by elemental analysis, IR, ES-MS, 1H NMR, and magnetic susceptibility measurements. Their antitumor effects on BEL-7402, HUH-7, and HepG2 cells were studied by MTT assay. The antitumor biological mechanism of these two complexes was studied in BEL-7402 cells by cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay, and detection of mitochondrial membrane potential (ΔΨm). The results showed that the growth of cancer cells was inhibited significantly, and complexes 1 and 2 mainly caused in BEL-7402 cells G0/G1 cell cycle arrest and induced apoptosis. Both 1 and 2 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Complex 2 showed greater antitumor efficiency than that of complex 1. PMID:23424390

  16. Anticancer activity and biophysical reactivity of copper complexes of 2-(benzo[d][1,3]dioxol-5-ylmethylene)-N-alkylhydrazinecarbothioamides

    PubMed Central

    Beckford, Floyd A.; Thessing, Jeffrey; Stott, Alyssa; Holder, Alvin A.; Poluektov, Oleg G.; Li, Liya; Seeram., Navindra P.

    2012-01-01

    A series of copper complexes were synthesized from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) thio-semicarbazones (RHpTSC where R=H, CH3, C2H5 or C6H5 (Ph)). The complexes show interesting variations in geometry depending on the thiosemicarbazone; a dinuclear complex [Cu(HpTSC)Cl]2, a mononuclear complex [Cu(RHpTSC)2Cl2] (R=CH3 or C2H5) and another mononuclear complex [Cu(PhHpTSC)(PhpTSC)Cl] was generated. The complexes bind in a moderately strong fashion to DNA with binding constants on the order of 104M‒1. They are also strong binders of human serum albumin with binding constants near 104 M‒1. The complexes show good in vitro cytotoxic profiles against two human colon cancer cell lines (HCT-116 and HT29) and two human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values in the low millimolar concentration range. PMID:23440300

  17. Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention

    PubMed Central

    2016-01-01

    One of the most promising classes of iron chelators are α-N-heterocyclic thiosemicarbazones with Triapine as the most prominent representative. In several clinical trials Triapine showed anticancer activity against hematological diseases, however, studies on solid tumors failed due to widely unknown reasons. Some years ago, it was recognized that “terminal dimethylation” of thiosemicarbazones can lead to a more than 100-fold increased activity, probably due to interactions with cellular copper depots. To better understand the structural requirements for the switch to nanomolar cytotoxicity, we systematically synthesized all eight possible N-methylated derivatives of Triapine and investigated their potential against Triapine-sensitive as well as -resistant cell lines. While only the “completely” methylated compound exerted nanomolar activity, the data revealed that all compounds with at least one N-dimethylation were not affected by acquired Triapine resistance. In addition, these compounds were highly synergistic with copper treatment accompanied by induction of reactive oxygen species and massive necrotic cell death. PMID:27336684

  18. Iodido{4-phenyl-1-[1-(1,3-thia-zol-2-yl-κN)ethyl-idene]thio-semicarbazidato-κ(2) N',S}{4-phenyl-1-[1-(1,3-thia-zol-2-yl)ethyl-idene]thio-semicarbazide-κS}cadmium(II).

    PubMed

    Venkatraman, Ramaiyer; Samuel, Dasary S; Arslan, Zikri; Hossain, Md Alamgir; Fronczek, Frank R

    2013-05-01

    In the title complex, [Cd(C12H11N4S2)I(C12H12N4S2)], the Cd(II) ion is penta-coordinated by two thio-semicarbazone ligands (one neutral and the other anionic) and one iodide ion in a distorted square pyramidal (τ = 0.35) geometry. The central ion is coordinated by the thia-zole N atom, the thio-ureido N and the S atom of the deprotonated thio-semicarbazone ligand. The other ligand is linked with the central ion through the C=S group. The deprotonated ligand intra-molecularly hydrogen bonds to the thia-zole ring N atom, while the ligand forms an inter-molecular hydrogen bond to the thiol-ate S atom of the second ligand. The deprotonation of the tridentate ligand and its coordination to the Cd(II) ion via the S atom strikingly affects the C-S bond lengths. The C-S bond lengths in the neutral and deprotonated ligands in the metal complex are 1.709 (3) and 1.748 (2) Å, respectively, whereas it is 1.671 (3) Å in the free ligand. In the metal complex, the Cd-S distances are 2.6449 (6) and 2.5510 (6) Å. The Cd-I bond length is 2.7860 (2) Å. PMID:23723762

  19. Beyond Metal-Hydrides: Non-Transition-Metal and Metal-Free Ligand-Centered Electrocatalytic Hydrogen Evolution and Hydrogen Oxidation.

    PubMed

    Haddad, Andrew Z; Garabato, Brady D; Kozlowski, Pawel M; Buchanan, Robert M; Grapperhaus, Craig A

    2016-06-29

    A new pathway for homogeneous electrocatalytic H2 evolution and H2 oxidation has been developed using a redox active thiosemicarbazone and its zinc complex as seminal metal-free and transition-metal-free examples. Diacetyl-bis(N-4-methyl-3-thiosemicarbazone) and zinc diacetyl-bis(N-4-methyl-3-thiosemicarbazide) display the highest reported TOFs of any homogeneous ligand-centered H2 evolution catalyst, 1320 and 1170 s(-1), respectively, while the zinc complex also displays one of the highest reported TOF values for H2 oxidation, 72 s(-1), of any homogeneous catalyst. Catalysis proceeds via ligand-centered proton-transfer and electron-transfer events while avoiding traditional metal-hydride intermediates. The unique mechanism is consistent with electrochemical results and is further supported by density functional theory. The results identify a new direction for the design of electrocatalysts for H2 evolution and H2 oxidation that are not reliant on metal-hydride intermediates. PMID:27326672

  20. Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

    PubMed Central

    2013-01-01

    Abstract Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 00, 000–000. PMID:22900902

  1. Synthesis and biological evaluation of some novel thiazole compounds as potential anti-inflammatory agents.

    PubMed

    Helal, M H M; Salem, M A; El-Gaby, M S A; Aljahdali, M

    2013-07-01

    In the present investigation, furo[2,3-d]thiazol-5(2H)-one 5 was obtained from reaction of thiosemicarbazone derivative 2 with diethyl acetylene dicarboxylate. A series of newly synthesized 2-(hydrazinyl)thiazol-4(5H)-one 6, 7 &8 and 2-(4-(substituted)-thiazol-2-yl)hydrazono derivatives 9a, b &10 were synthesized from treatment of thiosemicarbazone derivative 2 with appropriate α-halogenated compounds. Also, a one pot synthesis of thiazole derivatives 13 &15 was achieved from three components reaction of hydrazone derivative 11 with phenyl isothiocyanate and α-halogenated compounds catalyzed by DMF/KOH. 4-(4-Morpholino phenyl) thiazol-2-amino 17 was obtained via the reaction of acetophenone derivative 1 with thiourea in presence of iodine. The reactivity of 2-aminothiazole 17 toward some electrophilic reagents was investigated. The structure of the newly compounds was confirmed on the basis of elemental analysis and spectral data. The antibacterial activity towards two Gram negative (Proteus mirabilis &Serratia marcesens) and two Gram positive (Staphylococcus aureus &Bacillus cereus) bacteria was investigated. The anti-inflammatory activity was also investigated and the inhibition of the carrageenin-induced oedema by these compounds was established.

  2. Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks.

    PubMed

    Song, Jiangli; Jones, Lindsay M; Chavarria, Gustavo E; Charlton-Sevcik, Amanda K; Jantz, Adam; Johansen, Audra; Bayeh, Liela; Soeung, Victoria; Snyder, Lindsey K; Lade, Shawn D; Chaplin, David J; Trawick, Mary Lynn; Pinney, Kevin G

    2013-05-01

    Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl-alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure-activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 <500 nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC50=164 nM. All of the compounds evaluated were inactive (IC50 >10,000 nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.

  3. Novel Zinc(II) Complexes [Zn(atc-Et)₂] and [Zn(atc-Ph)₂]: In Vitro and in Vivo Antiproliferative Studies.

    PubMed

    Lopes, Erica de O; Oliveira, Carolina G de; Silva, Patricia B da; Eismann, Carlos E; Suárez, Carlos A; Menegário, Amauri A; Leite, Clarice Q F; Deflon, Victor M; Pavan, Fernando R

    2016-01-01

    Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research. PMID:27213368

  4. Potent 5-nitrofuran derivatives inhibitors of Trypanosoma cruzi growth: Electrochemical, spectroscopic and biological studies

    NASA Astrophysics Data System (ADS)

    Maria Aravena, C.; Claudio Olea, A.; Cerecetto, Hugo; González, Mercedes; Maya, Juan Diego; Rodríguez-Becerra, Jorge

    2011-07-01

    Cyclic voltammetry and electron spin resonance techniques were used in the investigation of several potential antiprotozoal containing thiosemicarbazone and carbamate nitrofurans. In the electrochemical behaviour, a self-protonation process involving the nitro group was observed. The reactivity of the nitro anion radical for these derivatives with glutathione, a biological relevant thiol, was also studied in means of cyclic voltammetry. These studies demonstrated that glutathione could react with radical species from 5-nitrofuryl system. Furthermore, from the voltammetric results, some parameters of biological significance as E71 (indicative of the biological nitro anion radical formation), and K (thermodynamic indicator the of oxygen redox cycling) have been calculated. We also evaluated the stability of the nitro anion radical in terms of the dimerization constant ( kd). The nitrofuran-free radicals from cyclic voltammetry were characterized by electron spin resonance. A clear dependence between both the thiosemicarbazone or carbamate substructure and the length of the linker, furyl- or furylpropenyl-spacer, and the delocalization of the unpaired electron was observed. Through of biological assays we obtained important parameters that account for the selective anti-trypanosomal activity of these derivatives. The trypomastigote viability study showed that all derivatives are as active as in the epimastigote form of the parasite in a doses dependent manner.

  5. cis-Dioxomolybdenum(VI) complexes of a new ONN chelating thiosemicarbazidato ligand; Synthesis, characterization, crystal, molecular structures and antioxidant activities

    NASA Astrophysics Data System (ADS)

    İlhan Ceylan, Berat; Deniz, Nahide Gulsah; Kahraman, Sibel; Ulkuseven, Bahri

    2015-04-01

    5-Chloro-4-methyl-2-hydroxybenzophenone S-propyl-4-phenyl-thiosemicarbazone (H2L) and its cis-dioxomolybdenum(VI) complexes, in the general formula [MoO2(L)R-OH)] (R: methyl, 1; ethyl, 2; n-propyl, 3; n-butyl, 4; n-pentyl, 5), were synthesized and characterized by micro analysis, electronic, infrared and 1H and 13C NMR spectra. The crystal structures of complexes, 1 and 3, have been solved by direct methods (SIR92) and refined to the residual indexes R1 = 0.098 and R1 = 0.052 respectively. Complexes 1 and 3 are crystallized in the triclinic space group P-1 with Z = 2. The crystal study of complex 1 showed the first example of intermolecular hydrogen bond for this type of molybdenum-thiosemicarbazone complexes. The hydrogen bond is between the hydroxyl proton of attached alcohol and an oxo oxygen (in MoO22+ unit) of another complex molecule, and its bond distance (1.767(1) Å) is shorter than from the σ-coordination bonds in complex 1. Antioxidant activities of the compounds were determined by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. Ligand showed 23.61% DPPH radical scavenging activity at 250 mg/L concentration. Cupric Reducing Antioxidant Capacity (CUPRAC) was also evaluated and trolox-equivalent antioxidant capacity (TEAC) values were found for ligand, 1 and 3 as 0.51, 0.33 and 0.30 respectively.

  6. Novel Zinc(II) Complexes [Zn(atc-Et)2] and [Zn(atc-Ph)2]: In Vitro and in Vivo Antiproliferative Studies

    PubMed Central

    Lopes, Erica de O.; de Oliveira, Carolina G.; da Silva, Patricia B.; Eismann, Carlos E.; Suárez, Carlos A.; Menegário, Amauri A.; Leite, Clarice Q. F.; Deflon, Victor M.; Pavan, Fernando R.

    2016-01-01

    Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (ZnII) thiosemicarbazone complexes [Zn(atc-Et)2] (1) and [Zn(atc-Ph)2] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (1H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research. PMID:27213368

  7. Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization.

    PubMed

    Al-Eisawi, Zaynab; Stefani, Christian; Jansson, Patric J; Arvind, Akanksha; Sharpe, Philip C; Basha, Maram T; Iskander, George M; Kumar, Naresh; Kovacevic, Zaklina; Lane, Darius J R; Sahni, Sumit; Bernhardt, Paul V; Richardson, Des R; Kalinowski, Danuta S

    2016-01-14

    Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent. PMID:26645570

  8. Optimization of the 8 GeV AP3-P1 Lattice for Antiproton Transfers

    SciTech Connect

    McGinnis, Dave; /Fermilab

    2001-01-22

    During 8 GeV antiproton transfers between the Accumulator to the Main Injector, the antiprotons must travel through four separate beam lines, AP3, AP1, P2, and P1. This note describes the optimization of a single lattice that describes these beam lines for 8 GeV antiproton transfers from the Accumulator to the Main Injector and 8 GeV proton transfers from the Main Injector to the Accumulator.

  9. Towards the rational design of organic/inorganic interface for solid supported CO2 capture

    NASA Astrophysics Data System (ADS)

    He, Feng

    Monoethanolamine (MEA, HO(CH2)2NH2) aqueous solution based CO2 capture is the current technology used to mitigate power plants' green house gas emission. Solid based CO2 capture technique is regarded as a promising alternative, because it is more cost-effective and environmentally friendly than the solution based technique. Recently, solid-supported CO2 capture on MEA modified TiO 2 powders has been demonstrated [1]. It is believed that the main reaction pathway involved in solid-supported amine based CO2 capture is similar to the reaction in the amine solution, where the amine group reacts with CO2 to form carbamate (--NHCOO--). From the previous work on the MEA/TiO2 (110) system [2], it is found that MEA covered rutile TiO2 (110) did not capture CO 2. The main reaction pathway in this system was blocked because the amine group attached to the surface. In order to design a functional system, we proposed two possible mechanisms to free --NH2 from rutile TiO2 (110) surface. In this work, we investigated one of our six candidates, the 3-Amino-1-propanol (3AP, HO(CH2) 3NH2) molecule. The classical reactive force field (ReaxFF) [3] method has been employed to investigate the 3AP/TiO2 (110) system with emphasis on binding configurations and binding energies. We found that the amine group of 3AP did not attach to the rutile TiO2 (110) surface, indicating the CO2 capture capability of the 3AP/TiO 2 (110) system, which was confirmed by our experimental collaborators [4].

  10. Detecting necrotic neurons with fluoro-jade stain.

    PubMed

    Krinke, G J; Classen, W; Vidotto, N; Suter, E; Würmlin, C H

    2001-10-01

    Fluoro-jade, a novel stain for detection of neuropathic lesions by fluorescence microscopy, was validated on the models of toxic neuropathy induced with 3-acetylpyridine (3-AP) or with acrylamide (ACR). Groups of male and female albino rats of Wistar strain were either exposed to a single administration of 80 mg/kg i.p. 3-AP followed 5 hours later by 300 mg/kg of nicotinamide i.p. and examined at days 3 and 15, or to 15 daily doses of 30 mg/kg p.o. ACR and examined at day 15. Following in-life behavioral observations and measurements, the rats were fixed by perfusion with formalin. Additional animals treated with same dose of 3-AP and nicotinamide were submitted to purposeful autolysis for 4 or 16 hours before immersion fixation with formalin on test day 3. In-life observations showed in 3-AP-treated animals signs of severe general toxicity, sensorimotor dysfunction and decreased motor activity starting shortly after the treatment and persisting throughout the observation period. ACR-treated rats started to develop abnormal gait on test day 8 and by day 15 developed reduced grip strength, increased landing footsplay and decreased motor activity. Fluoro-jade, applied to paraffin sections of the nervous system, detected selectively and sensitively the necrotic neurons in the brain, especially those in the inferior olivary nucleus of animals treated with 3-AP, at test day 3, as well as the necrotic Purkinje cells in the cerebellum of ACR-treated animals at test day 15. Chromatolytic neurons in the dorsal root ganglia of ACR-treated animals did not stain positively, indicating that this kind of reversible neuronal remodeling is not detectable using fluoro-jade. Necrotic neurons were still stained by fluoro-jade after 4 hour autolysis, but following 16 hour autolysis the results became false negative. There was no false positive fluorescence in fresh or autolytic tissues, except that emitted by red blood cells in unperfused specimens. The study confirmed the validity of

  11. 1-(4-Carb­oxy­butan-2-yl­idene)-4-phenyl­thio­semicarbazide

    PubMed Central

    Mendoza-Meroño, Rafael; Menéndez-Taboada, Laura; García-Granda, Santiago

    2012-01-01

    The mol­ecule of the title compound, C12H15N3O2S, which belongs to the family of thio­semicarbazones, containing an acid group, adopts a semi-closed conformation with an intramolecular N—H⋯N hydrogen bond. In the crystal, molecules are linked by strong N—H⋯O and O—H⋯S hydrogen bonds between the acid group and thiosemicarbazone unit, with one additional intermolecular hydrogen C—H⋯O interaction. These three interactions form R 2 2(8) and a R 2 1(7) rings and the molecules related by the c-glide plane are linked into a zigzag chain along [001]. PMID:22719696

  12. ESR of copper and iron complexes with antitumor and cytotoxic properties.

    PubMed

    Antholine, W E; Kalyanaraman, B; Petering, D H

    1985-12-01

    The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of oxygen to produce radicals. Structural features of these reactions are identified by ESR spectroscopy in model systems and often in cells. Furthermore, ESR spectroscopy has been most useful to probe the environment of the complexes in cells and to measure the rate of reduction of their oxidized forms. As a result of these studies, it is anticipated that more attention will be given to the exploration of redox-active metal complexes as drugs.

  13. New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi.

    PubMed

    de Moraes Gomes, Paulo André Teixeira; de Oliveira Barbosa, Miria; Farias Santiago, Edna; de Oliveira Cardoso, Marcos Veríssimo; Capistrano Costa, Natáli Tereza; Hernandes, Marcelo Zaldini; Moreira, Diogo Rodrigo Magalhães; da Silva, Aline Caroline; Dos Santos, Thiago André Ramos; Pereira, Valéria Rêgo Alves; Brayner Dos Santosd, Fábio André; do Nascimento Pereira, Glaécia Aparecida; Ferreira, Rafaela Salgado; Leite, Ana Cristina Lima

    2016-10-01

    In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites. PMID:27295485

  14. Four copper(II) compounds synthesized by anion regulation: Structure, anticancer function and anticancer mechanism.

    PubMed

    Zhang, Zhenlei; Gou, Yi; Wang, Jun; Yang, Kun; Qi, Jinxu; Zhou, Zuping; Liang, Shichu; Liang, Hong; Yang, Feng

    2016-10-01

    Copper (Cu) compounds are a promising candidate for next generation metal anticancer drugs. Therefore, we regulated anions to synthesize four mononuclear and binuclear Cu(II) compounds derived from thiosemicarbazone Schiff base ligands and characterized them. Four of these compounds showed very high cytotoxicity to cancer cell lines in vitro. These Cu(II) compounds strongly promoted the apoptosis of BEL-7404 cells and had a capacity to arrest the cell cycle at S phase of those cells. Furthermore, reactive oxygen species (ROS), mitochondrial membrane potential and Western blot analyses revealed that these Cu(II) compounds exert their cytotoxicity through an ROS-mediated intrinsic mitochondrial pathway accompanied by the regulation of Bcl-2 family proteins. PMID:27309677

  15. Mn(II) and Cu(II) complexes of a bidentate Schiff's base ligand: Spectral, thermal, molecular modelling and mycological studies

    NASA Astrophysics Data System (ADS)

    Tyagi, Monika; Chandra, Sulekh; Tyagi, Prateek

    2014-01-01

    Complexes of manganese(II) and copper(II) of general composition M(L)2X2 have been synthesized [L = 2-acetyl thiophene thiosemicarbazone and X = Cl- and NO3-]. The elemental analysis, molar conductance measurements, magnetic susceptibility measurements, mass, IR, UV, NMR and EPR spectral studies of the compounds led to the conclusion that the ligand acts as a bidentate manner. The Schiff's base ligand forms hexacoordinated complexes having octahedral geometry for Mn(II) and tetragonal geometry for Cu(II) complexes. The thermal studies suggested that the complexes are more stable as compared to ligand. In molecular modelling the geometries of Schiff's base and metal complexes were fully optimized with respect to the energy using the 6-31g(d,p) basis set. The mycological studies of the compounds were examined against the plant pathogenic fungi i.e. Rhizoctonia bataticola, Macrophomina phaseolina, Fusarium odum.

  16. Synthesis, NMR spectral and antimicrobial studies of some [N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-ylidine]-5‧-methylthiazolidine-4-ones

    NASA Astrophysics Data System (ADS)

    Prakash, S. M.; Pandiarajan, K.; Kumar, S.

    2013-06-01

    Four new [N-methyl-3t-alkyl-2r,6c-diaryl-4-ylidine]-5'-methylthiozolidin-4-ones 9-12 have been synthesized by the condensation of N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-one thiosemicarbazones with ethyl 2-bromopropionate. These compounds have been characterized using FT-IR, 1H NMR, 13C NMR spectral techniques. HOMOCOSY, HSQC and HMBC spectral study have been done for [N-methyl-3,3-dimethyl-2r,6c-bis(p-methoxyphenyl)piperidin-4-ylidine]-5'-methylthiazolidine-4-one (12). Two geometrical isomers are formed in this reaction. In all these compounds piperidin rings adopt chair conformation. The rotation of the aryl group at C-2 is rather slow in 10-12. Antimicrobial activities have also been studied for 9-12. These compounds are active against all the tested bacterial and fungal strains.

  17. Activation of the IFN-inducible enzyme RNase L causes apoptosis of animal cells.

    PubMed

    Díaz-Guerra, M; Rivas, C; Esteban, M

    1997-09-29

    The interferon (IFN)-induced enzyme RNase L produced by a recombinant vaccinia virus (VV) causes death of mammalian cells with morphological and biochemical characteristics of apoptosis. Coexpression of 2-5A-synthetase enhances apoptosis induced by RNase L Activation of endogenous RNase L by infection with a VV ts mutant (ts22) or with wild-type virus in the presence of the antipoxvirus drug isatin-beta-thiosemicarbazone, a treatment known to significantly increase the amount of double-stranded RNA late during infection, also causes pronounced apoptosis of infected cells. The effects observed with recombinant virus-derived RNase L or with the endogenous enzyme are specific, since apoptosis also occurs in cells derived from mice lacking the IFN-induced protein kinase (PKR). The apoptosis antagonist Bcl-2 prevents induction of cell death by RNase L activation. Apoptosis of mammalian cells by RNase L activation could be a mechanism mediating anticellular actions of IFN.

  18. Arylthiosemicarbazones as antileishmanial agents.

    PubMed

    Manzano, José Ignacio; Cochet, Florent; Boucherle, Benjamin; Gómez-Pérez, Verónica; Boumendjel, Ahcène; Gamarro, Francisco; Peuchmaur, Marine

    2016-11-10

    Based on a screening process, we targeted substituted thiosemicarbazone as potential antileishmanial agents. Our objective was to identify the key structural elements contributing to the anti-parasite activity that might be used for development of effective drugs. A series of 32 compounds was synthesized and their efficacy was evaluated against the clinically relevant intracellular amastigotes of Leishmania donovani. From these, 22 compounds showed EC50 values below 10 μM with the most active derivative (compound 14) showing an EC50 of 0.8 μM with very low toxicity on two different mammalian cell lines. The most relevant structural elements required for higher activity indicate that the presence of a fused bicyclic aromatic ring such as a naphthalene bearing an alkyl or an alkoxy group substituent are prerequisites. Owing to the easy synthesis, high activity and low toxicity, the most active compounds could be considered as a lead for further development.

  19. New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi.

    PubMed

    de Moraes Gomes, Paulo André Teixeira; de Oliveira Barbosa, Miria; Farias Santiago, Edna; de Oliveira Cardoso, Marcos Veríssimo; Capistrano Costa, Natáli Tereza; Hernandes, Marcelo Zaldini; Moreira, Diogo Rodrigo Magalhães; da Silva, Aline Caroline; Dos Santos, Thiago André Ramos; Pereira, Valéria Rêgo Alves; Brayner Dos Santosd, Fábio André; do Nascimento Pereira, Glaécia Aparecida; Ferreira, Rafaela Salgado; Leite, Ana Cristina Lima

    2016-10-01

    In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites.

  20. Mechanistic insights into mode of action of novel natural cathepsin L inhibitors

    PubMed Central

    2013-01-01

    Background Development of a cancerous cell takes place when it ceases to respond to growth-inhibiting signals and multiplies uncontrollably and can detach and move to other parts of the body; the process called as metastasis. A particular set of cysteine proteases are very active during cancer metastasis, Cathepsins being one of them. They are involved in tumor growth and malignancy and have also been reported to be overexpressed in tumor cell lines. In the present study, a combinatorial approach comprising three-dimensional quantitative structure-activity relationship (3D QSAR), ligand-based pharmacophore modelling and search followed by cathepsin L structure-based high throughput screening was carried out using an initial set of 28 congeneric thiosemicarbazone derivatives as cathepsin L inhibitors. A 3D QSAR was derived using the alignment of a common thiosemicarbazone substructure. Essential structural features responsible for biological activity were taken into account for development of a pharmacophore model based on 29 congeneric thiosemicarbazone derivatives. This model was used to carry out an exhaustive search on a large dataset of natural compounds. A further cathepsin L structure-based screen identified two top scoring compounds as potent anti-cancer leads. Results The generated 3D QSAR model showed statistically significant results with an r2 value of 0.8267, cross-validated correlation coefficient q2 of 0.7232, and a pred_r2 (r2 value for test set) of 0.7460. Apart from these, a high F test value of 30.2078 suggested low probability of the model's failure. The pharmacophoric hypothesis chosen for searching the natural compound libraries was identified as DDHRR, where two Ds denote 2 hydrogen donors, H represents a hydrophobic group and two Rs represent aromatic rings, all of which are essential for the biological activity. We report two potential drug leads ZINC08764437 (NFP) and ZINC03846634 (APQ) obtained after a combined approach of pharmacophore

  1. Use of fluorescein hydrazide and fluorescein thiosemicarbazide reagents for the fluorometric determination of protein carbonyl groups and for the detection of oxidized protein on polyacrylamide gels.

    PubMed

    Ahn, B; Rhee, S G; Stadtman, E R

    1987-03-01

    Highly fluorescent thiosemicarbazide and hydrazide prepared by reaction of fluorescein isothiocyanate with hydrazine or adipic acid dihydrazide have been used to monitor the presence of carbonyl groups in oxidatively modified proteins. After oxidation, proteins react with these reagents under anaerobic conditions in the dark to yield fluorescent protein conjugates (presumably thiosemicarbazones or hydrazones) which can be visualized as fluorescent bands following electrophoresis (0-4 degrees C) on lithium dodecyl sulfate-polyacrylamide gels. These reagents do not react with unoxidized proteins. The conjugates formed dissociate readily at room temperature but are fairly stable at pH 6-9, 0 degrees C. Current data suggest that these reagents will be useful in the detection and quantitation of oxidatively modified proteins in biological systems. PMID:2883911

  2. ESR of copper and iron complexes with antitumor and cytotoxic properties.

    PubMed Central

    Antholine, W E; Kalyanaraman, B; Petering, D H

    1985-01-01

    The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of oxygen to produce radicals. Structural features of these reactions are identified by ESR spectroscopy in model systems and often in cells. Furthermore, ESR spectroscopy has been most useful to probe the environment of the complexes in cells and to measure the rate of reduction of their oxidized forms. As a result of these studies, it is anticipated that more attention will be given to the exploration of redox-active metal complexes as drugs. PMID:2420582

  3. Flow Injection Analysis of Mercury Using 4-(Dimethylamino) Benzaldehyde-4-Ethylthiosemicarbazone as the Ionophore of a Coated Wire Electrode

    PubMed Central

    Tahir, Tara F.; Salhin, Abdussalam; Ghani, Sulaiman Ab

    2012-01-01

    A flow injection analysis (FIA) incorporating a thiosemicarbazone-based coated wire electrode (CWE) was developed method for the determination of mercury(II). A 0.1 M KNO3 carrier stream with pH between 1 and 5 and flow rate of 1 mL·min−1 were used as optimum parameters. A linear plot within the concentration range of 5 × 10−6–0.1 M Hg(II), slope of 27.8 ± 1 mV per decade and correlation coefficient (R2) of 0.984 were obtained. The system was successfully applied for the determination of mercury(II) in dental amalgam solutions and spiked environmental water samples. Highly reproducible measurements with relative standard deviation (RSD < 1% (n = 3)) were obtained, giving a typical throughput of 30 samples·h−1. PMID:23202196

  4. Synthesis and in vitro evaluation of new benzothiazole derivatives as schistosomicidal agents.

    PubMed

    Mahran, Mona A; William, Samia; Ramzy, Fatem; Sembel, Amira M

    2007-01-01

    A series of benzothiazol-2-yl-dithiocarbamates 3a-d along with their copper complexes 4a-c were synthesized via the reaction of suitable alkyl, aralkyl or heteroaryl halides with the sodium salt of benzothiazol-2-yl-dithiocarbamic acid, followed by complexation with copper sulphate. N-(4-Acetyl-5-aryl-4,5-dihydro-1,3,4-thiadiazol-2-yl)-N-benzothiazol-2-yl-acetamides 7a-c were synthesized by cyclization of the appropriate thiosemicarbazones 6a-c in acetic anhydride. Selected compounds were screened for in vitro schistosomicidal activity against Schistosoma mansoni at three different dosage levels (10, 50 and 100 microg/mL). Three of these products, 4a-c, showed schistosomicidal activity similar to praziquantel, with 100% worm mortality at 10 microg/mL. These compounds would constitute a new class of potent schistosomicidal agents. PMID:17851416

  5. Synthesis, spectral, catalytic and antimicrobial studies of PPh 3/AsPh 3 complexes of Ru(II) with dibasic tridentate O, N, S donor ligands

    NASA Astrophysics Data System (ADS)

    Balasubramanian, K. P.; Karvembu, R.; Prabhakaran, R.; Chinnusamy, V.; Natarajan, K.

    2007-09-01

    Complexes of the type [Ru(CO)(EPh 3)(B)(L)] (E = P or As; B = PPh 3, AsPh 3, py or pip; L = dianion of the Schiff bases derived from thiosemicarbazone with acetoacetanilide, acetoacet- o-toluidide and o-chloro acetoacetanilide) have been synthesized from the reactions of equimolar amounts of [RuHCl(CO)(EPh 3) 2(B)] and Schiff bases in benzene. The new complexes have been characterized by analytical and spectral (IR, electronic, NMR) data. The arrangement of PPh 3 groups around ruthenium metal was determined from 31P NMR spectra. An octahedral structure has been assigned for all the new complexes. All the complexes exhibited catalytic activity for the oxidation of benzyl alcohol and cyclohexanol in presence of N-methylmorpholine- N-oxide as co-oxidant. The complexes also exhibited antibacterial activity against E. coli, Aeromonas hydrophilla and Salmonella typhi. The activity was compared with standard streptomycin.

  6. Synthesis, spectral, catalytic and antimicrobial studies of PPh3/AsPh3 complexes of Ru(II) with dibasic tridentate O, N, S donor ligands.

    PubMed

    Balasubramanian, K P; Karvembu, R; Prabhakaran, R; Chinnusamy, V; Natarajan, K

    2007-09-01

    Complexes of the type [Ru(CO)(EPh(3))(B)(L)] (E = P or As; B = PPh(3), AsPh(3), py or pip; L=dianion of the Schiff bases derived from thiosemicarbazone with acetoacetanilide, acetoacet-o-toluidide and o-chloro acetoacetanilide) have been synthesized from the reactions of equimolar amounts of [RuHCl(CO)(EPh(3))(2)(B)] and Schiff bases in benzene. The new complexes have been characterized by analytical and spectral (IR, electronic, NMR) data. The arrangement of PPh(3) groups around ruthenium metal was determined from (31)P NMR spectra. An octahedral structure has been assigned for all the new complexes. All the complexes exhibited catalytic activity for the oxidation of benzyl alcohol and cyclohexanol in presence of N-methylmorpholine-N-oxide as co-oxidant. The complexes also exhibited antibacterial activity against E. coli, Aeromonas hydrophilla and Salmonella typhi. The activity was compared with standard streptomycin. PMID:17182271

  7. Crystal structure of chlorido-(2-{[2-(phenyl-car-bamo-thioyl)hydrazin-1-ylidene](pyridin-2-yl)methyl}pyridin-1-ium)gold(I) chloride sesqui-hydrate.

    PubMed

    Gatto, Claudia C; Lima, Iariane J

    2015-09-01

    The title complex, [AuCl(C18H16N5S)]Cl·1.5H2O, may be considered as a gold(I) compound with the corresponding metal site coordinated by a thio-semicarbazone ligand through the S atom. The ligand adopts an E conformation and the gold(I) atom displays the expected linear geometry with a Cl atom also bonded to the metal ion [Cl-Au-S = 174.23 (5)°]. One of the pyridyl rings is protonated, giving the gold complex an overall positive charge. Two solvent water mol-ecules, one of which is located on a twofold rotation axis, and a non-coordinating chloride ion complete the structural assembly. The mol-ecular structure is stabilized by intra-molecular and inter-molecular N-H⋯Cl, N-H⋯N, O-H⋯Cl and O-H⋯O hydrogen bonding. PMID:26396851

  8. The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals.

    PubMed

    Donnelly, Paul S

    2011-02-01

    There are several isotopes of copper and rhenium that are of interest in the development of new molecular imaging or radiotherapeutic agents. This perspective article highlights the role of coordination chemistry in the design of copper and rhenium radiopharmaceuticals engineered to selectively target tissue of interest such as cancer cells or pathological features associated with Alzheimer's disease. The coordination chemistry of copper bis(thiosemicarbazone) derivatives and copper macrocyclic complexes is discussed in terms of their potential application as targeted positron emission tomography tracers for non-invasive diagnostic imaging. A range of rhenium complexes with different ligands with rhenium in different oxidation states are introduced and their potential to be translated to new radiotherapeutic agents discussed.

  9. Water-soluble ruthenium complexes bearing activity against protozoan parasites.

    PubMed

    Sarniguet, Cynthia; Toloza, Jeannette; Cipriani, Micaella; Lapier, Michel; Vieites, Marisol; Toledano-Magaña, Yanis; García-Ramos, Juan Carlos; Ruiz-Azuara, Lena; Moreno, Virtudes; Maya, Juan Diego; Azar, Claudio Olea; Gambino, Dinorah; Otero, Lucía

    2014-06-01

    Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites. PMID:24740394

  10. Water-soluble ruthenium complexes bearing activity against protozoan parasites.

    PubMed

    Sarniguet, Cynthia; Toloza, Jeannette; Cipriani, Micaella; Lapier, Michel; Vieites, Marisol; Toledano-Magaña, Yanis; García-Ramos, Juan Carlos; Ruiz-Azuara, Lena; Moreno, Virtudes; Maya, Juan Diego; Azar, Claudio Olea; Gambino, Dinorah; Otero, Lucía

    2014-06-01

    Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 μM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.

  11. Potentiating the cellular targeting and anti-tumor activity of Dp44mT via binding to human serum albumin: two saturable mechanisms of Dp44mT uptake by cells

    PubMed Central

    Merlot, Angelica M.; Sahni, Sumit; Lane, Darius J.R.; Fordham, Ashleigh M.; Pantarat, Namfon; Hibbs, David E.; Richardson, Vera; Doddareddy, Munikumar R.; Ong, Jennifer A.; Huang, Michael L.H.

    2015-01-01

    Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) demonstrates potent anti-cancer activity. We previously demonstrated that 14C-Dp44mT enters and targets cells through a carrier/receptor-mediated uptake process. Despite structural similarity, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and pyridoxal isonicotinoyl hydrazone (PIH) enter cells via passive diffusion. Considering albumin alters the uptake of many drugs, we examined the effect of human serum albumin (HSA) on the cellular uptake of Dp44mT, Bp4eT and PIH. Chelator-HSA binding studies demonstrated the following order of relative affinity: Bp4eT≈PIH>Dp44mT. Interestingly, HSA decreased Bp4eT and PIH uptake, potentially due to its high affinity for the ligands. In contrast, HSA markedly stimulated Dp44mT uptake by cells, with two saturable uptake mechanisms identified. The first mechanism saturated at 5-10 μM (Bmax:1.20±0.04 × 107 molecules/cell; Kd:33±3 μM) and was consistent with a previously identified Dp44mT receptor/carrier. The second mechanism was of lower affinity, but higher capacity (Bmax:2.90±0.12 × 107 molecules/cell; Kd:65±6 μM), becoming saturated at 100 μM and was only evident in the presence of HSA. This second saturable Dp44mT uptake process was inhibited by excess HSA and had characteristics suggesting it was mediated by a specific binding site. Significantly, the HSA-mediated increase in the targeting of Dp44mT to cancer cells potentiated apoptosis and could be important for enhancing efficacy. PMID:25848850

  12. Spectral, magnetic, biocidal screening, DNA binding and photocleavage studies of mononuclear Cu(II) and Zn(II) metal complexes of tricoordinate heterocyclic Schiff base ligands of pyrazolone and semicarbazide/thiosemicarbazide based derivatives

    NASA Astrophysics Data System (ADS)

    Raman, N.; Selvan, A.; Manisankar, P.

    2010-07-01

    We depict the synthesis and characterization of copper(II) and zinc(II) coordination compounds of 4-(3',4'-dimethoxybenzaldehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-semicarbazone ( 1a), 4-(3',4'-dimethoxybenzaldehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-thiosemicarbazone ( 1b), 4-(3'-hydroxy-4'-nitrobenzaldehydene)2-3-dimeth yl-1-phenyl-3-pyrazolin-5-semicarbazone ( 1c) and 4-(3'-hydroxy-4'-nitrobenzal dehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-thiosemicarbazone ( 1d). All the remote compounds have the general composition [ML 2] (M = Cu(II) and Zn(II)); L = Schiff base ( 1a- 1d). All the complexes were characterized by elemental analysis, molar conductivity, IR, 1H NMR, UV-vis, ESI-Mass, magnetic susceptibility measurements, cyclic voltammetric measurements, and EPR spectral studies. It has been originated that the Schiff bases with Cu(II) and Zn(II) ions form mononuclear complexes on 1:2 (metal:ligand) stoichiometry. Distorted octahedral environment is suggested for the metal complexes. The conductivity data confirm the non-electrolytic nature of the complexes. The interaction of CuL 21a- 1d complexes with CT DNA was investigated by spectroscopic, electrochemical and viscosity measurements. Results suggest that the copper complexes bind to DNA via an intercalative mode. Moreover, the complexes have been found to promote the photocleavage of plasmid DNA pBR322 under irradiation at 365 nm. The Schiff bases and their metal complexes were screened for their antifungal and antibacterial activities against different species of pathogenic fungi and bacteria and their biopotency has been discussed.

  13. Photolysis of Nitrate and Nitrite in Artificial Snow and Artificial Ice

    NASA Astrophysics Data System (ADS)

    Shi, W.; Green, S. A.

    2003-12-01

    It is well known that nitrate and nitrite undergo photolysis in aqueous solution. Recent studies show that these reactions are likely to occur in natural snow as well. Therefore it is of interest to measure rates of photolysis of nitrate and nitrite in snow and ice. In this study artificial snow was made by spraying a solution onto the wall of a reservoir containing liquid nitrogen. Artificial snow and ice were irradiated in a sealed quartz tube with a UV lamp and production of hydroxyl radicals was quantified. Hydroxyl radicals produced in these processes react with dimethyl sulfoxide to release methyl radicals, which were trapped by 3-amino-2,2,5,5-tetramethyl-1-pyrrolidinyloxy free radical (3AP). The 3AP-CH3 compound was later derivatized to produce a highly fluorescent adduct, which was measured by HPLC. Snow produced the highest yield of hydroxyl radicals and ice the lowest. Nitrite had higher yield than nitrate. The calculation of photolysis rates for nitrate and nitrite in snow and ice is discussed.

  14. Acetyl Radical Generation in Cigarette Smoke: Quantification and Simulations.

    PubMed

    Hu, Na; Green, Sarah A

    2014-10-01

    Free radicals are present in cigarette smoke and can have a negative effect on human health. However, little is known about their formation mechanisms. Acetyl radicals were quantified in tobacco smoke and mechanisms for their generation were investigated by computer simulations. Acetyl radicals were trapped from the gas phase using 3-amino-2, 2, 5, 5-tetramethyl-proxyl (3AP) on solid support to form stable 3AP adducts for later analysis by high performance liquid chromatography (HPLC), mass spectrometry/tandem mass spectrometry (MS-MS/MS) and liquid chromatography-mass spectrometry (LC-MS). Simulations were performed using the Master Chemical Mechanism (MCM). A range of 10-150 nmol/cigarette of acetyl radical was measured from gas phase tobacco smoke of both commerial and research cigarettes under several different smoking conditions. More radicals were detected from the puff smoking method compared to continuous flow sampling. Approximately twice as many acetyl radicals were trapped when a glass filber particle filter (GF/F specifications) was placed before the trapping zone. Simulations showed that NO/NO2 reacts with isoprene, initiating chain reactions to produce hydroxyl radical, which abstracts hydrogen from acealdehyde to generate acetyl radical. These mechanisms can account for the full amount of acetyl radical detected experimentally from cigarette smoke. Similar mechanisms may generate radicals in second hand smoke. PMID:25253993

  15. Acetyl radical generation in cigarette smoke: Quantification and simulations

    NASA Astrophysics Data System (ADS)

    Hu, Na; Green, Sarah A.

    2014-10-01

    Free radicals are present in cigarette smoke and can have a negative effect on human health. However, little is known about their formation mechanisms. Acetyl radicals were quantified in tobacco smoke and mechanisms for their generation were investigated by computer simulations. Acetyl radicals were trapped from the gas phase using 3-amino-2, 2, 5, 5-tetramethyl-proxyl (3AP) on solid support to form stable 3AP adducts for later analysis by high-performance liquid chromatography (HPLC), mass spectrometry/tandem mass spectrometry (MS-MS/MS) and liquid chromatography-mass spectrometry (LC-MS). Simulations were performed using the Master Chemical Mechanism (MCM). A range of 10-150 nmol/cigarette of acetyl radical was measured from gas phase tobacco smoke of both commercial and research cigarettes under several different smoking conditions. More radicals were detected from the puff smoking method compared to continuous flow sampling. Approximately twice as many acetyl radicals were trapped when a glass fiber particle filter (GF/F specifications) was placed before the trapping zone. Simulations showed that NO/NO2 reacts with isoprene, initiating chain reactions to produce hydroxyl radical, which abstracts hydrogen from acetaldehyde to generate acetyl radical. These mechanisms can account for the full amount of acetyl radical detected experimentally from cigarette smoke. Similar mechanisms may generate radicals in second hand smoke.

  16. GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development.

    PubMed

    Kuwahara, Kazuhiko; Yamamoto-Ibusuki, Mutsuko; Zhang, Zhenhuan; Phimsen, Suchada; Gondo, Naomi; Yamashita, Hiroko; Takeo, Toru; Nakagata, Naomi; Yamashita, Daisuke; Fukushima, Yoshimi; Yamamoto, Yutaka; Iwata, Hiroji; Saya, Hideyuki; Kondo, Eisaku; Matsuo, Keitaro; Takeya, Motohiro; Iwase, Hirotaka; Sakaguchi, Nobuo

    2016-04-01

    Human chromosome 21 is known to be associated with the high risk of hematological malignancy but with resistance to breast cancer in the study of Down syndrome. In human cancers, we previously observed the significant alterations of the protein expression encoded by the ganp/MCM3AP gene on human chromosome 21q22.3. Here, we investigated GANP protein alterations in human breast cancer samples (416 cases) at various stages by immunohistochemical analysis. This cohort study clearly showed that expression of GANP is significantly decreased in human breast cancer cases with poor prognosis as an independent risk factor (relapse-free survival, hazard ratio = 2.37, 95% confidence interval, 1.27-4.42, P = 0.007 [univariate analysis]; hazard ratio = 2.70, 95% confidence interval, 1.42-5.13, P = 0.002 [multivariate analysis]). To investigate whether the altered GANP expression is associated with mammary tumorigenesis, we created mutant mice that were conditionally deficient in the ganp/MCM3AP gene using wap-cre recombinase transgenic mice. Mammary gland tumors occurred at a very high incidence in female mammary gland-specific GANP-deficient mice after severe impairment of mammary gland development during pregnancy. Moreover, tumor development also occurred in female post parous GANP-heterodeficient mice. GANP has a significant role in the suppression of DNA damage caused by estrogen in human breast cancer cell lines. These results indicated that the GANP protein is associated with breast cancer resistance. PMID:26749495

  17. Role of direction of charge transfer on the nonlinear optical behavior of pyridine substituted chalcone derivatives

    NASA Astrophysics Data System (ADS)

    Menezes, Anthoni Praveen; Jayarama, A.

    2014-10-01

    High quality single crystals of an efficient novel nonlinear optical (NLO) chalcone derivative 3-(4-nitrophenyl)-1-(pyridine-3-yl) prop-2-en-1-one (4NP3AP) that are transparent in the entire visible and infrared region are grown by the slow evaporation solution growth method at ambient temperature. The single crystal XRD studies reveal that the crystal belongs to monoclinic system with the noncentrosymmetric space group P21. The presence of functional groups in the compound is confirmed by different spectroscopic techniques. The surface morphology of the crystal is studied by scanning electron microscopy. The second harmonic generation (SHG) efficiency of 4NP3AP determined by Perry and Kurtz method is 56% that of potassium dihydrogen phosphate (KDP) single crystals. The static and frequency dependent molecular hyperpolarizabilities were computed using MOPAC 2012. Thermal analysis confirms that the crystal is thermally stable up to 177 °C. The origin of nonlinearity and the role of charge transfer direction on the nonlinearity of the chalcone have been discussed in detail.

  18. The interplay of solvation, molecular conformation and supramolecular assembly in 1,1'-({[(ethane-1,2-diyl)dioxy](1,2-phenylene)}bis(methanylylidene))bis(thiosemicarbazide) and its N,N-dimethylformamide disolvate.

    PubMed

    Mohamed, Shaaban K; Younes, Sabry H H; Abdel-Raheem, Eman M M; Mague, Joel T; Akkurt, Mehmet; Glidewell, Christopher

    2015-11-01

    The wide diversity of applications of thiosemicarbazones and bis(thiosemicarbazones) has seen them used as anticancer and antitubercular agents, and as ligands in metal complexes designed to act as site-specific radiopharmaceuticals. Molecules of 1,1'-({[(ethane-1,2-diyl)dioxy](1,2-phenylene)}bis(methanylylidene))bis(thiosemicarbazide) {alternative name: 2,2'-[ethane-1,2-diylbis(oxy)]dibenzaldehyde bis(thiosemicarbazide)}, C18H20N6O2S2, (I), lie across twofold rotation axes in the space group C2/c, with an O-C-C-O torsion angle of -59.62 (13)° and a trans-planar arrangement of the thiosemicarbazide fragments relative to the adjacent aryl rings. The molecules of (I) are linked by N-H...S hydrogen bonds to form sheets containing R(2)4(38) rings and two types of R(2)2(8) ring. In the N,N-dimethylformamide disolvate, C18H20N6O2S2·2C3H7NO, (II), the independent molecular components all lie in general positions, but one of the solvent molecules is disordered over two sets of atomic sites having occupancies of 0.839 (3) and 0.161 (3). The O-C-C-O torsion angle in the ArOCH2CH2OAr component is -75.91 (14)° and the independent thiosemicarbazide fragments both adopt a cis-planar arrangement relative to the adjacent aryl rings. The ArOCH2CH2OAr components in (II) are linked by N-H...S hydrogen bonds to form deeply puckered sheets containing R(2)2(8), R(2)4(8) and two types of R(2)2(38) rings, and which contain cavities which accommodate all of the solvent molecules in the interior of the sheets. Comparisons are made with some related compounds. PMID:26524167

  19. Regulation of urokinase-type plasminogen activator gene transcription by macrophage colony-stimulating factor.

    PubMed Central

    Stacey, K J; Fowles, L F; Colman, M S; Ostrowski, M C; Hume, D A

    1995-01-01

    The mouse urokinase-type plasminogen activator (uPA) gene was used as a model macrophage colony-stimulating factor 1 (CSF-1)-inducible gene to investigate CSF-1 signalling pathways. Nuclear run-on analysis showed that induction of uPA mRNA by CSF-1 and phorbol myristate acetate (PMA) was at the transcriptional level in bone marrow-derived macrophages. CSF-1 and PMA synergized strongly in the induction of uPA mRNA, showing that at least some components of CSF-1 action are mediated independently of protein kinase C. Promoter targets of CSF-1 signalling were investigated with NIH 3T3 cells expressing the human CSF-1 receptor (c-fms). uPA mRNA was induced in these cells by treatment with CSF-1, and a PEA3/AP-1 element at -2.4 kb in the uPA promoter was involved in this response. Ets transcription factors can act through PEA3 sequences, and the involvement of Ets factors in the induction of uPA was confirmed by use of a dominant negative Ets-2 factor. Expression of the DNA binding domain of Ets-2 fused to the lacZ gene product prevented CSF-1-mediated induction of uPA mRNA in NIH 3T3 cells expressing the CSF-1 receptor. Examination of ets-2 mRNA expression in macrophages showed that it was also induced synergistically by CSF-1 and PMA. In the macrophage cell line RAW264, the uPA PEA3/AP-1 element mediated a response to both PMA and cotransfected Ets-2. uPA promoter constructs were induced 60- to 130-fold by Ets-2 expression, and the recombinant Ets-2 DNA binding domain was able to bind to the uPA PEA3/AP-1 element. This work is consistent with a proposed pathway for CSF-1 signalling involving sequential activation of fms, ras, and Ets factors. PMID:7760840

  20. Crystal structure of cis-bis-{4-phenyl-1-[(3R)-1,7,7-tri-methyl-2-oxobi-cyclo-[2.2.1]heptan-3-ylidene]thio-semicarbazidato-κ(3) O,N (1),S}cadmium(II) with an unknown solvent mol-ecule.

    PubMed

    Nogueira, Vanessa Senna; Bresolin, Leandro; Näther, Christian; Jess, Inke; de Oliveira, Adriano Bof

    2015-12-01

    The reaction between the racemic mixture of the camphor-4-phenyl-thio-semicarbazone derivative and cadmium acetate dihydrate yielded the title compound, [Cd(C17H20N3OS)2]. The Cd(II) ion is six-coordinated in a distorted octa-hedral environment by two deprotonated thio-semicarbazone ligands acting as an O,N,S-donor in a tridentate chelating mode, forming five-membered chelate rings. In the crystal, the mol-ecules are connected via pairs of N-H⋯S and C-H⋯S inter-actions, building centrosymmetric dimers. One of the ligands is disordered in the campher unit over two sets of sites with site-occupancy factors of 0.7 and 0.3. The structure contains additional solvent mol-ecules, which are disordered and for which no reasonable split model was found. Therefore, the data were corrected for disordered solvent using the SQUEEZE routine [Spek (2015 ▸). Acta Cryst. C71, 9-18] in PLATON. Since the disordered solvents were removed by data processing, and the number of solvent entities was a suggestion only, they were not considered in the chemical formula and subsequent chemical or crystal information. PMID:26870441

  1. Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics

    PubMed Central

    Goytia, Maira M.; Donnelly, Paul S.; Shafer, William M.

    2015-01-01

    There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen. PMID:26239980

  2. Synthesis and fluorine-mediated interactions in methanol-encapsulated solid state self-assembly of an isatin-thiazoline hybrid

    NASA Astrophysics Data System (ADS)

    Pervez, Humayun; Ahmad, Maqbool; Hadda, Taibi B.; Toupet, Loic; Naseer, Muhammad Moazzam

    2015-10-01

    An exciting isatin-thiazoline hybrid molecule 2 having -Cdbnd N-Ndbnd C- linkage has been synthesized in 88% yield by the reaction of 5-fluoroisatin with N-(4-fluorophenyl)hydrazinecarbothioamide followed by condensation of the resultant isatin-thiosemicarbazone intermediate with p-chlorophenacyl bromide. The solid state self-assembly of this hybrid molecule was studied by X-ray crystallographic technique. A layered assembly composed of 1D-chains with methanol molecules encapsulated between every two chains is obtained, making a bi-chain sandwich like structure. The supramolecular forces involved in the stabilization of this structure are importantly fluorine-mediated interactions (C-H⋯F, F⋯S and F⋯π) along with others i.e. N-H⋯O, O-H⋯O, C-H⋯O, Cl⋯π, C-H⋯π and π⋯π interactions. To the best of our knowledge, this is the first example of solid state fluorine-mediated C-H⋯F, F⋯S and F⋯π interactions found in a family of isatin-based compounds.

  3. A metal-organic tetrahedron as a redox vehicle to encapsulate organic dyes for photocatalytic proton reduction.

    PubMed

    Jing, Xu; He, Cheng; Yang, Yang; Duan, Chunying

    2015-03-25

    The design of artificial systems that mimic highly evolved and finely tuned natural photosynthetic systems is a subject of intensive research. We report herein a new approach to constructing supramolecular systems for the photocatalytic generation of hydrogen from water by encapsulating an organic dye molecule into the pocket of a redox-active metal-organic polyhedron. The assembled neutral Co4L4 tetrahedron consists of four ligands and four cobalt ions that connect together in alternating fashion. The cobalt ions are coordinated by three thiosemicarbazone NS chelators and exhibit a redox potential suitable for electrochemical proton reduction. The close proximity between the redox site and the photosensitizer encapsulated in the pocket enables photoinduced electron transfer from the excited state of the photosensitizer to the cobalt-based catalytic sites via a powerful pseudo-intramolecular pathway. The modified supramolecular system exhibits TON values comparable to the highest values reported for related cobalt/fluorescein systems. Control experiments based on a smaller tetrahedral analogue of the vehicle with a filled pocket and a mononuclear compound resembling the cobalt corner of the tetrahedron suggest an enzymatic dynamics behavior. The new, well-elucidated reaction pathways and the increased molarity of the reaction within the confined space render these supramolecular systems superior to other relevant systems.

  4. Design, synthesis and biological evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents.

    PubMed

    Ramachandran, R; Rani, M; Kabilan, S

    2009-05-15

    New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (9-16) obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (1-8) upon cyclization with ethylbromoacetate in the presence of sodium acetate-acetic acid buffer afforded novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones (17-24). The synthesized compounds have been characterized by their elemental, analytical and spectral studies. Besides, the reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that compounds 11/18/20/23 against Staphylococcus aureus, 19/20/24 against Salmonella typhi show maximum inhibition potency at low concentration (6.25microg/ml) whereas 18/19 against Candida albicans and 19/20/21 against Rhizopus sp. showed beneficial antifungal activity at minimum concentration. PMID:19361987

  5. Synthesis and antioxidant activities of transition metal complexes based 3-hydroxysalicylaldehyde-S-methylthiosemicarbazone

    NASA Astrophysics Data System (ADS)

    Bal-Demirci, Tülay; Şahin, Musa; Kondakçı, Esin; Özyürek, Mustafa; Ülküseven, Bahri; Apak, Reşat

    2015-03-01

    The nickel(II), iron(III), oxovanadium(IV) complexes of the 3-hydroxysalicylidene-S-methyl-thiosemicarbazone (L) were obtained from the 3-hydroxysalicyldehyde-S-methylthiosemicarbazone with the R1-substituted-salicylaldehyde (R1: H, 3-OH) in the presence of Ni(II), Fe(III), VO(IV) as template ion. The ligand and its complexes were characterized by elemental analysis, electronic, UV/Vis., 1H NMR, EPR and IR studies. The free ligand and its metal complexes have been tested for in vitro antioxidant capacity by reduction of copper(II) neocuproine (Cu(II)-Nc) using the CUPRAC method. The ligand exhibited more potent in vitro antioxidant capacity than its complexes. The obtained trolox equivalent antioxidant capacity (TEAC) value of the iron(III) complex (TEACCUPRAC = 3.27) was higher than those of other complexes. Furthermore, the antioxidant activity of the free ligand and its complexes were determined by in vitro methods measuring the scavenging activity of reactive oxygen species (ROS) including hydroxyl radical (radOH), superoxide anion radical (O2rad -), and hydrogen peroxide (H2O2), showing that especially the V(IV) and Fe(III) complexes had significant scavenging activity for ROS.

  6. Microwave assisted synthesis, characterization and biological evaluation of palladium and platinum complexes with azomethines

    NASA Astrophysics Data System (ADS)

    Sharma, Krishna; Singh, Ritu; Fahmi, Nighat; Singh, R. V.

    2010-01-01

    Reactions of 3-acetyl-2,5-dimethylthiophene with thiosemicarbazide and semicarbazide hydrochloride resulted in the formation of new heterocyclic ketimines, 3-acetyl-2,5-dimethylthiophene thiosemicarbazone (C 9H 13N 3OS 2 or L 1H) and 3-acetyl-2,5- dimethylthiophene semicarbazone (C 9H 13N 3OS or L 2H), respectively. The Pd(II) and Pt(II) complexes have been synthesized by mixing metal salts in 1:2 molar ratios with these ligands by using microwave as well as conventional heating method for comparison purposes. The authenticity of these ligands and their complexes has been established on the basis of elemental analysis, melting point determinations, molecular weight determinations, IR, 1H NMR and UV spectral studies. These studies showed that the ligands coordinate to the metal atom in a monobasic bidentate manner and square planar environment around the metal atoms has been proposed to the complexes. Both the ligands and their complexes have been screened for their antimicrobial activities. The antiamoebic activity of both the ligands and their palladium compounds against the protozoan parasite Entamoeba histolytica has been tested.

  7. A cell-based screening system for anti-influenza A virus agents

    PubMed Central

    Wong, Wan Ying; Loh, Sheng Wei; Ng, Wei Lun; Tan, Ming Cheang; Yeo, Kok Siong; Looi, Chung Yeng; Maah, Mohd Jamil; Ea, Chee-Kwee

    2015-01-01

    Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell-based screening system for anti-IAV replication inhibitors using a non-replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-κB in response to different stimuli, such as LPS and TNFα. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-κB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication. PMID:25728279

  8. A microsomal ecdysone-binding cytochrome P450 from the insect Locusta migratoria purified by sequential use of type-II and type-I ligands.

    PubMed

    Winter, J; Eckerskorn, C; Waditschatka, R; Kayser, H

    2001-11-01

    A dual-affinity method was established to purify, for the first time, a microsomal ecdysone-binding cytochrome P450 protein from locust Malpighian tubules. This method involved, after prepurification on omega-octylamino-agarose and hydroxylapatite, binding of cytochrome P450 to an immobilized triazole-based general P450 inhibitor (type-II ligand) followed by elution with the substrate ecdysone (type-I ligand) of the bound cytochrome. The isolated material showed a typical cytochrome P450 spectrum, a specific heme content of 13 nmol/mg protein, and a prominent protein of about 60 kDa on SDS-PAGE. Based on a tryptic undecapeptide sequence the isolated protein may be identical to CYP6H1, a putative ecdysone 20-monooxygenase recently cloned from the same tissue. Ecdysone 20-monooxygenase activity could be partially reconstituted from microsomal detergent extracts, when supplemented with purified bovine cytochrome P450 reductase and detergent-extracted microsomes; reconstitution was not successful with any chromatographic fraction, however. Therefore, purification of the locust cytochrome P450 was monitored by ecdysone-induced type-I difference spectra, whenever applicable, in addition to carbon monoxide spectra. Affinity columns with matrix-bound diethylstilbestrol and testosterone 3-thiosemicarbazone, but not with the 17beta-hemisuccinate, yielded elution profiles with ecdysone that were comparable to those of the triazole matrix. The concept of dual-affinity chromatography described here may be generally applicable to the isolation of cytochromes P450.

  9. Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues.

    PubMed

    Silva, Fredson T; Franco, Caio H; Favaro, Denize C; Freitas-Junior, Lucio H; Moraes, Carolina B; Ferreira, Elizabeth I

    2016-10-01

    Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease. PMID:27318979

  10. Antimicrobial effects of copper(II) bis(thiosemicarbazonato) complexes provide new insight into their biochemical mode of action.

    PubMed

    Djoko, Karrera Y; Paterson, Brett M; Donnelly, Paul S; McEwan, Alastair G

    2014-04-01

    The copper(II) complexes of bis-thiosemicarbazones (Cu(btsc)) such as Cu(atsm) and Cu(gtsm) are neutral, lipophilic compounds that show promise as therapeutics for the treatment of certain neurological diseases and cancers. Although the effects of these compounds have been described at the cellular level, there is almost no information about their biochemical mode of action. In this work, we showed that Cu(atsm) and Cu(gtsm) displayed antimicrobial activities against the human obligate pathogen Neisseria gonorrhoeae that were more than 100 times more potent than Cu(NO3)2 salt alone. Treatment with Cu(btsc) also produced phenotypes that were consistent with copper poisoning, but the levels of intracellular copper were undetectable by ICP MS. We observed that Cu(btsc) interacted with proteins in the cell membrane. Systematic measurements of O2 uptake further demonstrated that treatment with both Cu(atsm) and Cu(gtsm) led to dose-dependent inhibition of respiratory electron transfer processes via succinate and NADH dehydrogenases. These dehydrogenases were not inhibited by a non-btsc source of Cu(II). The results led us to conclude that the biochemical mechanism of Cu(btsc) action is likely more complex than the present, simplistic model of copper release into the cytoplasm. PMID:24435165

  11. Analysis of the Interaction of Dp44mT with Human Serum Albumin and Calf Thymus DNA Using Molecular Docking and Spectroscopic Techniques

    PubMed Central

    Xu, Zhongjie; Liu, Youxun; Zhou, Sufeng; Fu, Yun; Li, Changzheng

    2016-01-01

    Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) exhibits significant antitumor activity. However, the mechanism of its pharmacological interaction with human serum albumin (HSA) and DNA remains poorly understood. Here, we aimed to elucidate the interactions of Dp44mT with HSA and DNA using MTT assays, spectroscopic methods, and molecular docking analysis. Our results indicated that addition of HSA at a ratio of 1:1 did not alter the cytotoxicity of Dp44mT, but did affect the cytotoxicity of the Dp44mT-Cu complex. Data from fluorescence quenching and UV-VIS absorbance measurements demonstrated that Dp44mT could bind to HSA with a moderate affinity (Ka = approximately 104 M−1). CD spectra revealed that Dp44mT could slightly disrupt the secondary structure of HSA. Dp44mT could also interact with Ct-DNA, but had a moderate binding constant (KEB = approximately 104 M−1). Docking studies indicated that the IB site of HSA, but not the IIA and IIIA sites, could be favorable for Dp44mT and that binding of Dp44mT to HSA involved hydrogen bonds and hydrophobic force, consistent with thermodynamic results from spectral investigations. Thus, the moderate binding affinity of Dp44mT with HSA and DNA partially contributed to its antitumor activity and may be preferable in drug design approaches. PMID:27376275

  12. Microwave assisted synthesis, spectroscopic, electrochemical and DNA cleavage studies of lanthanide(III) complexes with coumarin based imines.

    PubMed

    Kapoor, Puja; Fahmi, Nighat; Singh, R V

    2011-12-01

    The present work stems from our interest in the synthesis, characterization and biological evaluation of lanthanide(III) complexes of a class of coumarin based imines which have been prepared by the interaction of hydrated lanthanide(III) chloride with the sodium salts of 3-acetylcoumarin thiosemicarbazone (ACTSZH) and 3-acetylcoumarin semicarbazone (ACSZH) in 1:3 molar ratio using thermal as well as microwave method. Characterization of the ligands as well as the metal complexes have been carried out by elemental analysis, melting point determinations, molecular weight determinations, magnetic moment, molar conductance, IR, (1)H NMR, (13)C NMR, electronic, EPR, X-ray powder diffraction and mass spectral studies. Spectral studies confirm ligands to be monofunctional bidentate and octahedral environment around metal ions. The redox behavior of one of the synthesized metal complex was investigated by cyclic voltammetry. Further, free ligands and their metal complexes have been screened for their antimicrobial as well as DNA cleavage activity. The results of these findings have been presented and discussed.

  13. Steroidal pyrimidines: Synthesis, characterization, molecular docking studies with DNA and in vitro cytotoxicity

    NASA Astrophysics Data System (ADS)

    Shamsuzzaman; Dar, Ayaz Mahmood; Yaseen, Zahid; Alam, Khursheed; Hussain, Altaf; Gatoo, Manzoor Ahmad

    2013-08-01

    A series of new steroid pyrimidines (7-9) were synthesized by reacting steroidal thiosemicarbazones (4-6) with diethyl malonate. The new compounds were characterized by IR, 1H NMR, 13C NMR, MS and analytical data. The interaction studies of compounds (7-9) with DNA were carried out by employing gel electrophoresis, UV-vis and fluorescence spectroscopy. The acting force between the compounds (7-9) and DNA was mainly hydrophobic while the other interactions like van der Waals, hydrogen bonding cannot be ruled out. The gel electrophoresis pattern also demonstrated that the compound 7 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. The docking study of compounds (7-9) suggested that the intercalation of compounds in between the nucleotide base pairs might be due to the presence of pyrimidine moiety in steroid molecule. MTT assay was carried out to check the toxicity of new compounds (7-9) against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC and HPLF. Apoptotic degradation of DNA in presence of steroidal pyrimidines (7-9) was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).

  14. Crystal structure of cis-bis-{4-phenyl-1-[(3R)-1,7,7-tri-methyl-2-oxobi-cyclo-[2.2.1]heptan-3-ylidene]thio-semicarbazidato-κ(3) O,N (1),S}cadmium(II) with an unknown solvent mol-ecule.

    PubMed

    Nogueira, Vanessa Senna; Bresolin, Leandro; Näther, Christian; Jess, Inke; de Oliveira, Adriano Bof

    2015-12-01

    The reaction between the racemic mixture of the camphor-4-phenyl-thio-semicarbazone derivative and cadmium acetate dihydrate yielded the title compound, [Cd(C17H20N3OS)2]. The Cd(II) ion is six-coordinated in a distorted octa-hedral environment by two deprotonated thio-semicarbazone ligands acting as an O,N,S-donor in a tridentate chelating mode, forming five-membered chelate rings. In the crystal, the mol-ecules are connected via pairs of N-H⋯S and C-H⋯S inter-actions, building centrosymmetric dimers. One of the ligands is disordered in the campher unit over two sets of sites with site-occupancy factors of 0.7 and 0.3. The structure contains additional solvent mol-ecules, which are disordered and for which no reasonable split model was found. Therefore, the data were corrected for disordered solvent using the SQUEEZE routine [Spek (2015 ▸). Acta Cryst. C71, 9-18] in PLATON. Since the disordered solvents were removed by data processing, and the number of solvent entities was a suggestion only, they were not considered in the chemical formula and subsequent chemical or crystal information.

  15. The anticancer drug Dp44mT inhibits T-cell activation and CD25 through a copper-dependent mechanism.

    PubMed

    Gundelach, Justin H; Madhavan, Ajay A; Wettstein, Peter J; Bram, Richard J

    2013-02-01

    The di-2-pyridylketone thiosemicarbazone Dp44mT is a metal-chelating compound that has been demonstrated to have potent activity as an anticancer agent. Here we report that it also has a dramatic inhibitory effect on T-cell activation in vitro. We found that 10 nM Dp44mT (IC(50) 3.2 nM) prevented the up-regulation of surface CD25, and completely suppressed the activation and proliferation of splenic T cells isolated from Mus musculus that were stimulated with either T-cell receptor (TCR) cross-linking antibodies or phorbol ester plus ionomycin. In contrast, Dp44mT had no adverse effects on the survival of resting T cells. In addition, T cells stimulated in the presence of Dp44mT maintained the ability to up-regulate CD69 surface expression and secrete interleukin-2. Consistent with these observations, Dp44mT did not inhibit multiple canonical signals downstream of the TCR, including the nuclear factor of activated T cells. The effects of Dp44mT were easily mitigated by addition of nontoxic copper chelators or N-acetylcysteine, indicating a role for copper and reactive oxygen species in its actions. Together, these findings suggest that Dp44mT may serve as a potent immunosuppressive agent that could complicate its use as a cancer therapeutic agent, but might have utility in the treatment of autoimmunity.

  16. Spectroscopic, cyclic voltammetric and biological studies of transition metal complexes with mixed nitrogen-sulphur (NS) donor macrocyclic ligand derived from thiosemicarbazide

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Gupta, Lokesh Kumar; Sangeetika

    2005-11-01

    The complexation of new mixed thia-aza-oxa macrocycle viz., 2,12-dithio-5,9,14,18-tetraoxo-7,16-dithia-1,3,4,10,11,13-hexaazacyclooctadecane containing thiosemicarba-zone unit with a series of transition metals Co(II), Ni(II) and Cu(II) has been investigated, by different spectroscopic techniques. The structural features of the ligand have been studied by EI-mass, 1H NMR and IR spectral techniques. Elemental analyses, magnetic moment susceptibility, molar conductance, IR, electronic, and EPR spectral studies characterized the complexes. Electronic absorption and IR spectra of the complexes indicate octahedral geometry for chloro, nitrato, thiocyanato or acetato complexes. The dimeric and neutral nature of the sulphato complexes are confirmed from magnetic susceptibility and low conductance values. Electronic spectra suggests square-planar geometry for all sulphato complexes. The redox behaviour was studied by cyclic voltammetry, show metal-centered reduction processes for all complexes. The complexes of copper show both oxidation and reduction process. The redox potentials depend on the conformation of central atom in the macrocyclic complexes. Newly synthesized macrocyclic ligand and its transition metal complexes show markedly growth inhibitory activity against pathogenic bacterias and plant pathogenic fungi under study. Most of the complexes have higher activity than that of the metal free ligand.

  17. Simultaneous preconcentration of copper and mercury in water samples by cloud point extraction and their determination by inductively coupled plasma atomic emission spectrometry.

    PubMed

    Shoaee, Hamta; Roshdi, Mina; Khanlarzadeh, Nasibeh; Beiraghi, Asadollah

    2012-12-01

    A cloud-point extraction process coupled to ICP-OES by using 3-nitro benzaldehyde thiosemicarbazone (3-NBT) as complexing agent was developed for the simultaneous preconcentration and determination of copper and mercury in water samples. The variables affecting the complexation and extraction steps were optimized. Under the optimum conditions (i.e. 1.5×10(-5) mol L(-1) ligand, 0.3% (v/v) Triton X-114, 55 °C equilibrium temperature, incubation time of 30 min) the calibration graphs were linear in the range of 5-120 and 10-100 ng mL(-1) with enhancement factor of 82.7 and 51.3 for Cu(2+) and Hg(2+), respectively. The preconcentration factors were 28.6 in both cases and detection limits were obtained 0.48 for Cu and 1.1 ng mL(-1) for Hg. The precisions (R.S.D.%) for five replicate determinations at 50 ng mL(-1) of copper and mercury were better than 1.8% and 3.2%, respectively. The accuracy of the proposed method is validated by analyzing a certified reference material of water (RTC-QCI-049) with satisfactory results. Finally, the proposed method was utilized successfully for the determination of copper and mercury in surface water (river), tap water and bottled mineral water samples.

  18. Simultaneous preconcentration of copper and mercury in water samples by cloud point extraction and their determination by inductively coupled plasma atomic emission spectrometry

    NASA Astrophysics Data System (ADS)

    Shoaee, Hamta; Roshdi, Mina; Khanlarzadeh, Nasibeh; Beiraghi, Asadollah

    2012-12-01

    A cloud-point extraction process coupled to ICP-OES by using 3-nitro benzaldehyde thiosemicarbazone (3-NBT) as complexing agent was developed for the simultaneous preconcentration and determination of copper and mercury in water samples. The variables affecting the complexation and extraction steps were optimized. Under the optimum conditions (i.e. 1.5 × 10-5 mol L-1 ligand, 0.3% (v/v) Triton X-114, 55 °C equilibrium temperature, incubation time of 30 min) the calibration graphs were linear in the range of 5-120 and 10-100 ng mL-1 with enhancement factor of 82.7 and 51.3 for Cu2+ and Hg2+, respectively. The preconcentration factors were 28.6 in both cases and detection limits were obtained 0.48 for Cu and 1.1 ng mL-1 for Hg. The precisions (R.S.D.%) for five replicate determinations at 50 ng mL-1 of copper and mercury were better than 1.8% and 3.2%, respectively. The accuracy of the proposed method is validated by analyzing a certified reference material of water (RTC-QCI-049) with satisfactory results. Finally, the proposed method was utilized successfully for the determination of copper and mercury in surface water (river), tap water and bottled mineral water samples.

  19. Application of Cloud Point Extraction for Cadmium in Biological Samples of Occupationally Exposed Workers: Relation Between Cadmium Exposure and Renal Lesion.

    PubMed

    Mortada, Wael I; Hassanien, Mohamed M; Donia, Ahmed F; Shokeir, Ahmed A

    2015-12-01

    Cadmium (Cd) level in blood and urine of soldering iron workers (n=49) and 41 matched healthy controls has been assessed. Cloud point extraction was employed for preconcentration of Cd. The Cd ions formed hydrophobic complex with 9,10-phenanthraquinone monoethyl thiosemicarbazone that was extracted by surfactant-rich phases in the nonionic surfactant Triton X-114. The surfactant-rich phase was diluted with 1 M HNO3 in methanol prior to its analysis by graphite furnace atomic absorption spectrometry. The parameters affecting the extraction efficiency of the proposed method, such as solution pH, amount of complexing agent, surfactant concentration, temperature, and incubation time, were optimized. Under the optimum experimental conditions, the detection limit and the enrichment factor were 0.04 μg L(-1) and 61, respectively. Relative standard deviation of 10 μg L(-1) Cd was less than 3.0%. The accuracy of the method was examined by analysis of certified reference materials. It was observed that soldering iron workers are liable to Cd overload as indicated by higher levels of Cd in blood and urine when compared with the controls. This exposure may lead to kidney damage indicated by elevation of urinary excretion of both N-acetyl-β-D-glucosaminidase and β2-microglobulin.

  20. Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi.

    PubMed

    Guido, Rafael V C; Trossini, Gustavo H G; Castilho, Marcelo S; Oliva, Glaucius; Ferreira, Elizabeth I; Andricopulo, Adriano D

    2008-12-01

    Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q(2) = 0.75 and r(2) = 0.96; classical QSAR, q(2) = 0.72 and r(2) = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.95; classical QSAR, r(2)(pred) = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.

  1. Synthesis and characterisation of thiosemicarbazonato molybdenum(VI) complexes and their in vitro antitumor activity.

    PubMed

    Vrdoljak, Visnja; Dilović, Ivica; Rubcić, Mirta; Kraljević Pavelić, Sandra; Kralj, Marijeta; Matković-Calogović, Dubravka; Piantanida, Ivo; Novak, Predrag; Rozman, Andrea; Cindrić, Marina

    2010-01-01

    New dioxomolybdenum(VI) complexes were obtained by the reaction of [MoO2(acac)2] with thiosemicarbazone ligands derived from 3-thiosemicarbazide and 4-(diethylamino)salicylaldehyde (H2L1), 2-hydroxy-3-methoxybenzaldehyde (H2L2) or 2-hydroxy-1-naphthaldehyde (H2L3). In all complexes thiosemicarbazonato ligands are coordinated to molybdenum as tridentate ONS-donors. Octahedral coordination of each molybdenum atom is completed by methanol molecule (in 1a-3a) or by oxygen atom of Mo=O unit from the neighbouring molecule (in 1-3). All complexes were characterized by means of chemical analyses, IR spectroscopy, TG and NMR measurements. The molecular structures of the ligand H2L2 and complex [MoO2L2(CH3OH)].CH3OH (2a) have been determined by single crystal X-ray crystallography. The characterisation of thiosemicarbazonato molybdenum(VI) complexes (1-4) as well as of the 4-phenylthisemicarbazonato molybdenum(VI) complexes (5-8) in aqueous medium revealed that upon dissolving complexes in water, most likely to some extent dissociation took place, although experimental data didn't allow exact quantification of dissociation. The antiproliferative effects of studied molybdenum(VI) complexes (1-8) on the human cell lines were identical to the activity of their corresponding ligands.

  2. Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro.

    PubMed

    Dearling, J L; Lewis, J S; Mullen, G E; Rae, M T; Zweit, J; Blower, P J

    1998-07-01

    The well-known perfusion tracer CuPTSM, labelled with 62Cu or 64Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare 64Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that both series of complexes offer a basis for development of hypoxia-targeting radiopharmaceuticals for positron emission tomography (60Cu, 61Cu, 62Cu, 64Cu) and targeted radiotherapy (64Cu, 67Cu).

  3. Inhibition of Chikungunya Virus Replication by 1-[(2-Methylbenzimidazol-1-yl) Methyl]-2-Oxo-Indolin-3-ylidene] Amino] Thiourea(MBZM-N-IBT)

    PubMed Central

    Mishra, Priyadarsee; Kumar, Abhishek; Mamidi, Prabhudutta; Kumar, Sameer; Basantray, Itishree; Saswat, Tanuja; Das, Indrani; Nayak, Tapas Kumar; Chattopadhyay, Subhasis; Subudhi, Bharat Bhusan; Chattopadhyay, Soma

    2016-01-01

    Chikungunya virus (CHIKV) infection is one of the most challenging human Arboviral infections with global significance and without any specific antiviral. In this investigation, 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (MBZM-N-IBT) was synthesised as a molecular hybrid of 2-methyl benzimidazole and isatin-β-thiosemicarbazone and its anti-CHIKV property was evaluated. The release of infectious virus particles was calculated by plaque assay, expression profile of viral RNA was estimated by RT-PCR and viral protein profiles were assessed by Western blot and FACS analyses. The safety index of MBZM-N-IBT was found to be >21. The CHIKV infectious viral particle formation was abrogated around 76.02% by MBZM-N-IBT during infection in mammalian system and the viral RNA synthesis was reduced by 65.53% and 23.71% for nsP2 and E1 respectively. Surprisingly, the viral protein levels were reduced by 97% for both nsP2 and E2. In the time-of-addition experiment it abrogated viral infection at early as well as late phase of viral life cycle, which indicates about multiple mechanisms for its anti-CHIKV action. In silico analysis justified development of MBZM-N-IBT with good affinities for potential target proteins of CHIKV and related virus. With predictions of good drug-likeness property, it shows potential of a drug candidate which needs further experimental validation. PMID:26843462

  4. Vibrational spectra, molecular structure, natural bond orbital, first order hyperpolarizability, thermodynamic analysis and normal coordinate analysis of Salicylaldehyde p-methylphenylthiosemicarbazone by density functional method.

    PubMed

    Porchelvi, E Elamurugu; Muthu, S

    2015-01-01

    The thiosemicarbazone compound, Salicylaldehyde p-methylphenylthiosemicarbazone (abbreviated as SMPTSC) was synthesized and characterized by FTIR, FT-Raman and UV. Density functional (DFT) calculations have been carried out for the title compound by performing DFT level of theory using B3LYP/6-31++G(d,p) basis set. The molecular geometry and vibrational frequencies were calculated and compared with the experimental data. The detailed interpretation of the vibrational spectra has been carried out with aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology. The electronic dipole moment (μD) and the first hyperpolarizability (βtot) values of the investigated molecule were computed using density functional theory (DFT/B3LYP) with 6-311++G(d,p) basis set. The stability and charge delocalization of the molecule was studied by natural bond orbital (NBO) analysis. Thearomaticities of the phenyl rings were studied using the standard harmonic oscillator model of aromaticity (HOMA) index. Mulliken population analysis on atomic charges is also calculated. The molecule orbital contributions are studied by density of energy states (DOSs).

  5. A microsomal ecdysone-binding cytochrome P450 from the insect Locusta migratoria purified by sequential use of type-II and type-I ligands.

    PubMed

    Winter, J; Eckerskorn, C; Waditschatka, R; Kayser, H

    2001-11-01

    A dual-affinity method was established to purify, for the first time, a microsomal ecdysone-binding cytochrome P450 protein from locust Malpighian tubules. This method involved, after prepurification on omega-octylamino-agarose and hydroxylapatite, binding of cytochrome P450 to an immobilized triazole-based general P450 inhibitor (type-II ligand) followed by elution with the substrate ecdysone (type-I ligand) of the bound cytochrome. The isolated material showed a typical cytochrome P450 spectrum, a specific heme content of 13 nmol/mg protein, and a prominent protein of about 60 kDa on SDS-PAGE. Based on a tryptic undecapeptide sequence the isolated protein may be identical to CYP6H1, a putative ecdysone 20-monooxygenase recently cloned from the same tissue. Ecdysone 20-monooxygenase activity could be partially reconstituted from microsomal detergent extracts, when supplemented with purified bovine cytochrome P450 reductase and detergent-extracted microsomes; reconstitution was not successful with any chromatographic fraction, however. Therefore, purification of the locust cytochrome P450 was monitored by ecdysone-induced type-I difference spectra, whenever applicable, in addition to carbon monoxide spectra. Affinity columns with matrix-bound diethylstilbestrol and testosterone 3-thiosemicarbazone, but not with the 17beta-hemisuccinate, yielded elution profiles with ecdysone that were comparable to those of the triazole matrix. The concept of dual-affinity chromatography described here may be generally applicable to the isolation of cytochromes P450. PMID:11767943

  6. Exploring oxorhenium '3+1' mixed-ligand complexes carrying the S-benzyl-3-[(2-hydroxyphenyl)methylene]dithiocarbazate [ONS]/monothiol [S] donor set: synthesis and characterization.

    PubMed

    Chen, Xiaoyuan; Femia, Frank J; Babich, John W; Zubieta, Jon

    2000-09-11

    The reaction of ReOCl(3)(PPh(3))(2) with the potentially tridentate ligand S-benzyl-3-[(2-hydroxyphenyl)methylene]dithiocarbazate ([ONS] donor set) and para-substituted benzenethiols [C(6)H(4)X-4-SH] (where X=H, F, Cl, Br and OCH(3)) in the presence of Et(3)N afforded a series of integrated '3+1' oxorhenium(V) complexes with general formula [ReO{eta(3)-OC(6)H(4)-2-CH=N-N=C(SCH(2)Ph)-S}(eta(1)-C(6)H(4)X-4-S)]. The molecular structure of [ReO{eta(3)-OC(6)H(4)-2-CH=N-N=C(SCH(2)Ph)-S}(eta(1)-C(6)H(4)F-4-S)] (4) was determined by single-crystal X-ray analysis. Complex 4 consists of a central oxorhenium(V) core with phenolic oxygen, azomethine nitrogen and thiol sulfur donor from the thiosemicarbazone Schiff base ligand and one sulfur donor from monothiol ligand completing a distorted square pyramidal environment. Crystal data for 4, C(21)H(16)FN(2)O(2)S(3)Re: orthorhombic, P2(1)2(1)2(1), a=5.6682(3), b=11.6600(6), c=31.697(2) A, V=2094.9(2) A(3), Z=4. PMID:20592952

  7. Targeting cancer by binding iron: Dissecting cellular signaling pathways

    PubMed Central

    Lui, Goldie Y.L.; Kovacevic, Zaklina; Richardson, Vera; Merlot, Angelica M.; Kalinowski, Danuta S.; Richardson, Des R.

    2015-01-01

    Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID:26125440

  8. Microwave assisted synthesis, spectroscopic, electrochemical and DNA cleavage studies of lanthanide(III) complexes with coumarin based imines

    NASA Astrophysics Data System (ADS)

    Kapoor, Puja; Fahmi, Nighat; Singh, R. V.

    2011-12-01

    The present work stems from our interest in the synthesis, characterization and biological evaluation of lanthanide(III) complexes of a class of coumarin based imines which have been prepared by the interaction of hydrated lanthanide(III) chloride with the sodium salts of 3-acetylcoumarin thiosemicarbazone (ACTSZH) and 3-acetylcoumarin semicarbazone (ACSZH) in 1:3 molar ratio using thermal as well as microwave method. Characterization of the ligands as well as the metal complexes have been carried out by elemental analysis, melting point determinations, molecular weight determinations, magnetic moment, molar conductance, IR, 1H NMR, 13C NMR, electronic, EPR, X-ray powder diffraction and mass spectral studies. Spectral studies confirm ligands to be monofunctional bidentate and octahedral environment around metal ions. The redox behavior of one of the synthesized metal complex was investigated by cyclic voltammetry. Further, free ligands and their metal complexes have been screened for their antimicrobial as well as DNA cleavage activity. The results of these findings have been presented and discussed.

  9. Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics.

    PubMed

    Djoko, Karrera Y; Goytia, Maira M; Donnelly, Paul S; Schembri, Mark A; Shafer, William M; McEwan, Alastair G

    2015-10-01

    There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen. PMID:26239980

  10. Targeting cancer by binding iron: Dissecting cellular signaling pathways.

    PubMed

    Lui, Goldie Y L; Kovacevic, Zaklina; Richardson, Vera; Merlot, Angelica M; Kalinowski, Danuta S; Richardson, Des R

    2015-08-01

    Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID:26125440

  11. Crystal structure of 1-(4-methyl-phen-yl)-3-(propan-2-yl-idene-amino)-thio-urea.

    PubMed

    Jotani, Mukesh M; Yeo, Chien Ing; Tiekink, Edward R T

    2015-10-01

    In the title thio-semicarbazone, C11H15N3S, the p-tolyl-N-H and imino-N-H groups are anti and syn, respectively, to the central thione-S atom. This allows for the formation of an intra-molecular p-tolyl-N-H⋯N(imino) hydrogen bond. The mol-ecule is twisted with the dihedral angle between the p-tolyl ring and the non-hydrogen atoms of the N=CMe2 residue being 29.27 (8)°. The crystal packing features supra-molecular layers lying in the bc plane whereby centrosymmetric aggregates sustained by eight-membered thio-amide {⋯HNCS}2 synthons are linked by further N-H⋯S hydrogen bonds. Layers are connected via methyl-C-H⋯π inter-actions. The supra-molecular aggregation was further investigated by an analysis of the Hirshfeld surface and comparison made to related structures. PMID:26594415

  12. Biological evaluation and molecular docking of some chromenyl-derivatives as potential antimicrobial agents.

    PubMed

    Ionuţ, Ioana; Vodnar, Dan Cristian; Oniga, Ilioara; Oniga, Ovidiu; Tiperciuc, Brînduşa; Tamaian, Radu

    2016-01-01

    Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (molecular docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties. PMID:27005495

  13. A119Sn Mössbauer study of heptacoordinated tin complexes with multidentate ligands

    NASA Astrophysics Data System (ADS)

    Abras, A.; de Sousa, Gerimário F.; Filgueiras, Carlos A. L.

    1994-12-01

    Three novel heptacoordinated tin complexes with multidentate ligands were prepared and studied by Mössbauer spectroscopy. The complexes were identified as [MeSnCl(Hdaptsc)]Cl·MeOH, [MeSnCl(H2dapsc)]Cl2·2H2O and [ClSnCl(Hdaptsc)]Cl, where H2daptsc= 2,6-diacetylpyridinebis (thiosemicarbazone) and H2dapsc=2,6-diacetylpyridinebis (semicarbazone). The structures of the first two complexes were determined by X-ray crystallography. The ligand H2dapsc originated a fourth complex, which was characterised as [(Me2SnCl2)2(H2dapsc)] in which the two Sn atoms are probably hexacoordinated, as suggested by Mössbauer data. The isomer shifts and the quadrupole splittings of the complexes are consistent with the structural interpretation, and correlate well with other literature examples and with X-ray data whenever available. The correlation between Mössbauer results and structural information is important considering the paucity of published data for heptacoordinated species.

  14. Crystal structure of 1-{(Z)-[(2E)-3-(4-chloro-phen-yl)-1-phenyl-prop-2-en-1-yl-idene]amino}-3-ethyl-thio-urea.

    PubMed

    Tan, Ming Yueh; Crouse, Karen A; Ravoof, Thahira Begum S A; Tiekink, Edward R T

    2015-12-01

    In the title thio-semicarbazone compound, C18H18ClN3S, the CN3S residue is almost planar (r.m.s. deviation = 0.0031 Å) and forms dihedral angles of 65.99 (7) and 34.60 (10)° with the phenyl and chloro-benzene rings, respectively; the dihedral angle between the aromatic rings is 85.13 (8)°. The conformation about the C=N bond is Z, and that about the C=C bonds is E. The imine N and ethyl N atoms are syn and are linked by an eth-yl-imine N-H⋯N hydrogen bond. This H atom also forms an inter-molecular hydrogen bond to the thione S atom, resulting in a supra-molecular helical chain propagating along the b axis. The chains are consolidated into a three-dimensional architecture by phenyl-C-H⋯Cl contacts and weak π-π inter-actions between centrosymmetrically related chloro-benzene rings [inter-centroid distance = 3.9127 (15) Å]. PMID:26870491

  15. Endocytic structures and synaptic vesicle recycling at a central synapse in awake rats.

    PubMed

    Körber, Christoph; Horstmann, Heinz; Sätzler, Kurt; Kuner, Thomas

    2012-12-01

    The synaptic vesicle (SV) cycle has been studied extensively in cultured cells and slice preparations, but not much is known about the roles and relative contributions of endocytic pathways and mechanisms of SV recycling in vivo, under physiological patterns of activity. We employed horseradish peroxidase (HRP) as an in vivo marker of endocytosis at the calyx of Held synapse in the awake rat. Ex vivo serial section scanning electron microscopy and 3D reconstructions revealed two categories of labelled structures: HRP-filled SVs and large cisternal endosomes. Inhibition of adaptor protein complexes 1 and 3 (AP-1, AP-3) by in vivo application of Brefeldin A (BFA) disrupted endosomal SV budding while SV recycling via clathrin-mediated endocytosis (CME) remained unaffected. In conclusion, our study establishes cisternal endosomes as an intermediate of the SV cycle and reveals CME and endosomal budding as the predominant mechanisms of SV recycling in a tonically active central synapse in vivo.

  16. Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold.

    PubMed

    Xiao, Zhu-Ping; Wei, Wei; Wang, Peng-Fei; Shi, Wei-Kang; Zhu, Na; Xie, Me-Qun; Sun, Yu-Wen; Li, Ling-Xia; Xie, Yong-Xiang; Zhu, Liang-Song; Tang, Nian; Ouyang, Hui; Li, Xian-Hui; Wang, Guang-Cheng; Zhu, Hai-Liang

    2015-09-18

    Tyrosyl-tRNA synthetase (TyrRS), an essential enzyme in bacterial protein biosynthesis, is an attractive therapeutic target for finding novel antibacterial agents, and a series of N2-(arylacetyl)glycinanilides has been herein synthesized and identified as TyrRS inhibitors. These efforts yielded several compounds, with IC50 in the low micromolar range against TyrRS from Staphylococcus aureus. Out of the obtained compounds, 3ap is the most active and exhibits excellent activity against both Gram-positive (S. aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains. In comparison with the parent scaffold 3-arylfuran-2(5H)-one, N2-(arylacetyl)glycinanilide significantly improved the potency against Gram-negative bacterial strains, indicating that this scaffold offers a significant potential for developing new antibacterial drugs.

  17. Activation of the Arabidopsis B class homeotic genes by APETALA1.

    PubMed

    Ng, M; Yanofsky, M F

    2001-04-01

    Proper development of petals and stamens in Arabidopsis flowers requires the activities of APETALA3 (AP3) and PISTILLATA (PI), whose transcripts can be detected in the petal and stamen primordia. Localized expression of AP3 and PI requires the activities of at least three genes: APETALA1 (AP1), LEAFY (LFY), and UNUSUAL FLORAL ORGANS (UFO). It has been proposed that UFO provides spatial cues and that LFY specifies competence for AP3 and PI expression in the developing flower. To understand the epistatic relationship among AP1, LFY, and UFO in regulating AP3 and PI expression, we generated two versions of AP1 that have strong transcriptional activation potential. Genetic and molecular analyses of transgenic plants expressing these activated AP1 proteins show that the endogenous AP1 protein acts largely as a transcriptional activator in vivo and that AP1 specifies petals by regulating the spatial domains of AP3 and PI expression through UFO. PMID:11283333

  18. Activation of the Arabidopsis B class homeotic genes by APETALA1.

    PubMed

    Ng, M; Yanofsky, M F

    2001-04-01

    Proper development of petals and stamens in Arabidopsis flowers requires the activities of APETALA3 (AP3) and PISTILLATA (PI), whose transcripts can be detected in the petal and stamen primordia. Localized expression of AP3 and PI requires the activities of at least three genes: APETALA1 (AP1), LEAFY (LFY), and UNUSUAL FLORAL ORGANS (UFO). It has been proposed that UFO provides spatial cues and that LFY specifies competence for AP3 and PI expression in the developing flower. To understand the epistatic relationship among AP1, LFY, and UFO in regulating AP3 and PI expression, we generated two versions of AP1 that have strong transcriptional activation potential. Genetic and molecular analyses of transgenic plants expressing these activated AP1 proteins show that the endogenous AP1 protein acts largely as a transcriptional activator in vivo and that AP1 specifies petals by regulating the spatial domains of AP3 and PI expression through UFO.

  19. Deciphering simultaneous bioelectricity generation and dye decolorization using Proteus hauseri.

    PubMed

    Chen, Bor-Yann; Wang, Yu-Min; Ng, I-Son; Liu, Shi-Qi; Hung, Jhao-Yin

    2012-04-01

    This first-attempt study disclosed how and why electron-shuttling mediators were capable to stimulate bioelectricity-generating capabilities of dye-bearing microbial fuel cells (MFCs) using Proteus hauseri. Due to significant biotoxicity of 4-aminophenol (4AP) and the absence of electron-mediating potential of 3AP, only 2AP among all isomers could work as an exogenous mediator to stimulate bioelectricity generation of P. hauseri. Dye toxicity to cells on anodic biofilm in MFCs apparently affected the performance of simultaneous bioelectricity production and color removal (SBP&CR) in MFCs. Plus, dose-response analysis upon toxicity potency of reactive blue 160 revealed that cells on anodic biofilm in MFCs had a higher tolerance to reactive blue 160 than suspended cells. Apparently, augmentation of electron mediator(s) with low toxicity was a feasible means to facilitate bioelectricity-generating capability of SBP&CR.

  20. Multimodal two-photon imaging using a second harmonic generation-specific dye

    PubMed Central

    Nuriya, Mutsuo; Fukushima, Shun; Momotake, Atsuya; Shinotsuka, Takanori; Yasui, Masato; Arai, Tatsuo

    2016-01-01

    Second harmonic generation (SHG) imaging can be used to visualize unique biological phenomena, but currently available dyes limit its application owing to the strong fluorescent signals that they generate together with SHG. Here we report the first non-fluorescent and membrane potential-sensitive SHG-active organic dye Ap3. Ap3 is photostable and generates SH signals at the plasma membrane with virtually no fluorescent signals, in sharp contrast to the previously used fluorescent dye FM4-64. When tested in neurons, Ap3-SHG shows linear membrane potential sensitivity and fast responses to action potentials, and also shows significantly reduced photodamage compared with FM4-64. The SHG-specific nature of Ap3 allows simultaneous and completely independent imaging of SHG signals and fluorescent signals from various reporter molecules, including markers of cellular organelles and intracellular calcium. Therefore, this SHG-specific dye enables true multimodal two-photon imaging in biological samples. PMID:27156702

  1. Statistics and variability of the altitude of elves

    NASA Astrophysics Data System (ADS)

    van der Velde, Oscar A.; Montanyà, Joan

    2016-05-01

    From June 2008 to January 2016 nearly 800 elves have been recorded by a low-light camera in northeastern Spain. Elves occur in this region mainly over the lower topped cold air mass maritime thunderstorms, peaking from November to January. Cloud-to-ground strokes still produce elves when maritime winter storms are carried inland, suggesting that the cold season thunderstorm charge configuration favors strokes with large electromagnetic pulses. Altitudes of 389 elves were determined using optical data combined with a lightning location network. The overall median altitude was 87.1 km, near the typical OH airglow height, but average heights during individual nights ranged between 83 and 93 km. The lower elve nights (~84 km) occurred during slightly elevated geomagnetic conditions (Kp >3-, Ap-index >10). Elve altitude often shifts by several kilometers during the night, apparently in response to changing background conditions in the upper mesosphere.

  2. Characterization of GABA/sub A/ receptor-mediated /sup 36/chloride uptake in rat brain synaptoneurosomes

    SciTech Connect

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-09-07

    ..gamma..-Aminobutyric acid (GABA) receptor-mediated /sup 36/chloride (/sup 36/Cl/sup -/) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated /sup 36/Cl/sup -/ uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated /sup 36/Cl/sup -/ uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated /sup 36/Cl/sup -/ uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br/sup -/>Cl/sup -/greater than or equal toNO/sub 3//sup -/>I/sup -/greater than or equal toSCN/sup -/>>C/sub 3/H/sub 5/OO/sup -/greater than or equal toClO/sub 4//sup -/>F/sup -/, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl/sup -/ channel. 43 references, 4 figures, 3 tables.

  3. ssDNA Aptamer Specifically Targets and Selectively Delivers Cytotoxic Drug Doxorubicin to HepG2 Cells

    PubMed Central

    Yu, Ge; Li, Huan; Yang, Shuanghui; Wen, Jianguo; Niu, Junqi; Zu, Youli

    2016-01-01

    Hepatocellular carcinoma (HCC) is the third leading cause of death due to cancer worldwide with over 500,000 people affected annually. Although chemotherapy has been widely used to treat patients with HCC, alternate modalities to specifically deliver therapeutic cargos to cancer cells have been sought in recent years due to the severe side effects of chemotherapy. In this respect, aptamer-based tumor targeted drug delivery has emerged as a promising approach to increase the efficacy of chemotherapy and reduce or eliminate drug toxicity. In this study, we developed a new HepG2-specific aptamer (HCA#3) by a procedure known as systematic evolution of ligands by exponential enrichment (SELEX) and exploited its role as a targeting ligand to deliver doxorubicin (Dox) to HepG2 cells in vitro. The selected 76-base nucleotide aptamer preferentially bound to HepG2 hepatocellular carcinoma cells but not to control cells. The aptamer HCA#3 was modified with paired CG repeats at the 5′-end to carry and deliver a high payload of intercalated Dox molecules at the CG sites. Four Dox molecules (mol/mol) were fully intercalated in each conjugate aptamer-Dox (ApDC) molecule. Biostability analysis showed that the ApDC molecules are stable in serum. Functional analysis showed that ApDC specifically targeted and released Dox within HepG2 cells but not in control cells, and treatment with HCA#3 ApDC induced HepG2 cell apoptosis but had minimal effect on control cells. Our study demonstrated that HCA#3 ApDC is a promising aptamer-targeted therapeutic that can specifically deliver and release a high doxorubicin payload in HCC cells. PMID:26808385

  4. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study

    NASA Technical Reports Server (NTRS)

    Kwan, Jun; Shiota, Takahiro; Agler, Deborah A.; Popovic, Zoran B.; Qin, Jian Xin; Gillinov, Marc A.; Stewart, William J.; Cosgrove, Delos M.; McCarthy, Patrick M.; Thomas, James D.

    2003-01-01

    BACKGROUND: This study was conducted to elucidate the geometric differences of the mitral apparatus in patients with significant mitral regurgitation caused by ischemic cardiomyopathy (ICM-MR) and by idiopathic dilated cardiomyopathy (DCM-MR) by use of real-time 3D echocardiography (RT3DE). METHODS AND RESULTS: Twenty-six patients with ICM-MR caused by posterior infarction, 18 patients with DCM-MR, and 8 control subjects were studied. With the 3D software, commissure-commissure plane and 3 perpendicular anteroposterior (AP) planes were generated for imaging the medial, central, and lateral sides of the mitral valve (MV) during mid systole. In 3 AP planes, the angles between the annular plane and each leaflet (anterior, Aalpha; posterior, Palpha) were measured. In ICM-MR, Aalpha measured in the medial and central planes was significantly larger than that in the lateral plane (39+/-5 degrees, 34+/-6 degrees, and 27+/-5 degrees, respectively; P<0.01), whereas Palpha showed no significant difference in any of the 3 AP planes (61+/-7 degrees, 57+/-7 degrees, and 56+/-7 degrees, P>0.05). In DCM-MR, both Aalpha (38+/-8 degrees, 37+/-9 degrees, and 36+/-7 degrees, P>0.05) and Palpha (59+/-6 degrees, 58+/-5 degrees, and 57+/-6 degrees, P>0.05) revealed no significant differences in the 3 planes. CONCLUSIONS: The pattern of MV deformation from the medial to the lateral side was asymmetrical in ICM-MR, whereas it was symmetrical in DCM-MR. RT3DE is a helpful tool for differentiating the geometry of the mitral apparatus between these 2 different types of functional mitral regurgitation.

  5. Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

    PubMed

    Lambert, C S; Philpot, R M; Engberg, M E; Johns, B E; Wecker, L

    2015-09-15

    Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle.

  6. Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

    PubMed

    Lambert, C S; Philpot, R M; Engberg, M E; Johns, B E; Wecker, L

    2015-09-15

    Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle. PMID:26049061

  7. Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations

    PubMed Central

    Jones, RL; Woodward, DF; Wang, JW; Clark, RL

    2011-01-01

    BACKGROUND AND PURPOSE The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. EXPERIMENTAL APPROACH Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. KEY RESULTS L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L-798106 (EP3), L-826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar. CONCLUSIONS AND IMPLICATIONS High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed. PMID:20973775

  8. Applications of "Hot" and "Cold" Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging.

    PubMed

    Cortezon-Tamarit, Fernando; Sarpaki, Sophia; Calatayud, David G; Mirabello, Vincenzo; Pascu, Sofia I

    2016-06-01

    The applications of coordination chemistry to molecular imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in molecular imaging have mainly been focused on compounds with aliphatic backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomography) using (64) CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compound entered clinical trials in the US and the UK during the first decade of the 21(st) century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to aromatic groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliphatic ATSM complexes, allows the stabilization of a number of imaging probes, with special interest in "cold" and "hot" Cu(II) and Ga(III) derivatives for PET applications and (111) In(III) derivatives for SPECT (single-photon emission computed tomography) applications, whilst Zn(II) derivatives display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications. PMID:27149900

  9. Increasing intracellular bioavailable copper selectively targets prostate cancer cells.

    PubMed

    Cater, Michael A; Pearson, Helen B; Wolyniec, Kamil; Klaver, Paul; Bilandzic, Maree; Paterson, Brett M; Bush, Ashley I; Humbert, Patrick O; La Fontaine, Sharon; Donnelly, Paul S; Haupt, Ygal

    2013-07-19

    The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from Cu(II)(gtsm) but is retained by Cu(II)(atsm). We further demonstrated that intracellular H2gtsm [reduced Cu(II)(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both Cu(II)(gtsm) and Cu(II)(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both Cu(II)(gtsm) and Cu(II)(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with Cu(II)(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden (∼70%) and severity (grade), while treatment with Cu(II)(atsm) (30 mg/kg) was ineffective at the given dose. However, Cu(II)(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that Cu(II)(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.

  10. Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.

    PubMed

    da Costa, Patrícia Marçal; da Costa, Marcilia Pinheiro; Carvalho, Adriana Andrade; Cavalcanti, Suellen Melo Tibúrcio; de Oliveira Cardoso, Marcos Veríssimo; de Oliveira Filho, Gevânio Bezerra; de Araújo Viana, Daniel; Fechine-Jamacaru, Francisco Vagnaldo; Leite, Ana Cristina Lima; de Moraes, Manoel Odorico; Pessoa, Claudia; Ferreira, Paulo Michel Pinheiro

    2015-09-01

    The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.

  11. Exploring the interaction of N/S compounds with a dicopper center: tyrosinase inhibition and model studies.

    PubMed

    Buitrago, Elina; Vuillamy, Alexandra; Boumendjel, Ahcène; Yi, Wei; Gellon, Gisèle; Hardré, Renaud; Philouze, Christian; Serratrice, Guy; Jamet, Hélène; Réglier, Marius; Belle, Catherine

    2014-12-15

    Tyrosinase (Ty) is a copper-containing enzyme widely present in plants, bacteria, and humans, where it is involved in biosynthesis of melanin-type pigments. Development of Ty inhibitors is an important approach to control the production and the accumulation of pigments in living systems. In this paper, we focused our interest in phenylthiourea (PTU) and phenylmethylene thiosemicarbazone (PTSC) recognized as inhibitors of tyrosinase by combining enzymatic studies and coordination chemistry methods. Both are efficient inhibitors of mushroom tyrosinase and they can be considered mainly as competitive inhibitors. Computational studies verify that PTSC and PTU inhibitors interact with the metal center of the active site. The KIC value of 0.93 μM confirms that PTSC is a much more efficient inhibitor than PTU, for which a KIC value of 58 μM was determined. The estimation of the binding free energies inhibitors/Ty confirms the high inhibitor efficiency of PTSC. Binding studies of PTSC along with PTU to a dinuclear copper(II) complex ([Cu2(μ-BPMP)(μ-OH)](ClO4)2 (1); H-BPMP = 2,6-bis-[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) known to be a structural and functional model for the tyrosinase catecholase activity, have been performed. Interactions of the compounds with the dicopper model complex 1 were followed by spectrophotometry and electrospray ionization (ESI). The molecular structure of 1-PTSC and 1-PTU adducts were determined by single-crystal X-ray diffraction analysis showing for both an unusual bridging binding mode on the dicopper center. These results reflect their adaptable binding mode in relation to the geometry and chelate size of the dicopper center. PMID:25415587

  12. Recent advances on antimony(III/V) compounds with potential activity against tumor cells.

    PubMed

    Hadjikakou, S K; Ozturk, I I; Banti, C N; Kourkoumelis, N; Hadjiliadis, N

    2015-12-01

    Antimony one of the heavier pnictogens, has been in medical use against microbes and parasites as well. Antimony-based drugs have been prescribed against leishmaniasis since the parasitic transmission of the tropical disease was understood in the beginning of the 20th century. The activity of arsenic against visceral leishmaniasis led to the synthesis of an array of arsenic-containing parasitic agents, among them the less toxic pentavalent antimonials: Stibosan, Neostibosan, and Ureastibamine. Other antimony drugs followed: sodium stibogluconate (Pentostam) and melglumine antimoniate (Glucantim or Glucantime); both continue to be in use today despite their toxic side effects and increasing loss in potency due to the growing resistance of the parasite against antimony. Antimony compounds and their therapeutic potentials are under consideration from many research groups, while a number of early reviews recording advances of antimony biomedical applications are also available. However, there are only few reports on the screening for antitumor potential of antimony compounds. This review focuses upon results obtained on the anti-proliferative activity of antimony compounds in the past years. This survey shows that antimony(III/V) complexes containing various types of ligands such as thiones, thiosemicarbazones, dithiocarbamates, carboxylic acids, or ketones, nitrogen donor ligands, exhibit selectivity against a variety of cancer cells. The role of the ligand type of the complex is elucidated within this review. The complexes and their biological activity are already reported elsewhere. However quantitative structure-activity relationship (QSAR) modeling studies have been carried out and they are reported for the first time here. PMID:26092367

  13. Abnormal brain aging as a radical-related disease: A new target for nuclear medicine

    SciTech Connect

    Fujibayashi, Y.; Yamamoto, S.; Waki, A. |

    1996-05-01

    DNA damages caused by endogenously produced radicals are closely correlated with aging. Among them, mitochondrial DNA (mtDNA) deletions have been reported as a memory of DNA damage by oxygen radicals. In fact, clinical as well as experimental studies indicated the accumulation of deleted mtDNA in the brain, myocardium and son on, in aged subjects. In our previous work, radioiodinated radical trapping agent, p-iodophenyl-N-t-butylnitrone, and hypoxia imaging agent, Cu-62 diacetyl-bis-N-4-methyl-thiosemicarbazone have been developed for the diagnosis of radical-related diseases, such as ischemic, inflammation, cancer or aging. The aim of the present work was to evaluate these agents for brain aging studies. In our university, an unique animal model, a senescence accelerated model mouse (SAM), has been established. Among the various substrains, SAMP8 showing memory deterioration in its young age ({approximately}3 month) was basically evaluated as an abnormal brain aging model with mtDNA deletion. As controls, SAMR1 showing normal aging and ddY mice were used. MtDNA deletion n the brain was analyzed with polymerase-chain reaction (PCR) method, and relationship between mtDNA deletion and brain uptake of IPBN or Cu-62-ATSM was studied. In 1-3 month old SAMP8 brain, multiple mtDNa deletions were already found and their content was significantly higher than that of SAMR1 or age-matched ddY control. Thus, it was cleared that SAMP8 brain has high tendency to be attacked by endogenously produced oxygen radicals, possibly from its birth. Both IPBN and Cu-ATSM showed significantly higher accumulation in the SAMP8 brain than in the SAMR1 brain, indicating that these agents have high possibility for the early detection of abnormal brain aging as a radical-related disease.

  14. Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.

    PubMed

    da Costa, Patrícia Marçal; da Costa, Marcilia Pinheiro; Carvalho, Adriana Andrade; Cavalcanti, Suellen Melo Tibúrcio; de Oliveira Cardoso, Marcos Veríssimo; de Oliveira Filho, Gevânio Bezerra; de Araújo Viana, Daniel; Fechine-Jamacaru, Francisco Vagnaldo; Leite, Ana Cristina Lima; de Moraes, Manoel Odorico; Pessoa, Claudia; Ferreira, Paulo Michel Pinheiro

    2015-09-01

    The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b. PMID:26134001

  15. Imaging hypoxia in tumors.

    PubMed

    Ballinger, J R

    2001-10-01

    For many years, it has been known that hypoxia affects the response to radiotherapy in human cancers. Hypoxic regions can develop as a tumor grows beyond the ability of its blood supply to deliver oxygen to the full extent of the tumor, exacerbated by vascular spasm or compression caused by increased interstitial fluid pressure. However, hypoxia is heterogeneous, and tumors that appear identical by clinical and radiographic criteria can vary greatly in their extent of hypoxia. Several invasive procedures to measure hypoxia in tumors have been developed and are predictive of response to therapy, but none of these is in routine clinical use because of technical complexity, inconvenience, and inability to obtain repeated measures. Noninvasive imaging with a hypoxia-directed radiopharmaceutical could be of great clinical utility. Most such radiopharmaceuticals under development use 2-nitroimidazole as the targeting moiety. 2-Nitroimidazole, which is selectively reduced and bound in hypoxic tissues, has been labeled with F-18, Cu-64/67, I-123, and Tc-99m. Of these, F-18-fluoromisonidazole and I-123-iodoazomycin arabinoside (IAZA) have been most widely studied clinically. Non-nitro-containing bioreductive complexes, such as the Cu-60/62/64 thiosemicarbazone ATSM and Tc-99m butylene amineoxime (BnAO or HL91), have also been evaluated. In particular, 1-123-IAZA and Cu-60-ATSM have shown correlation with response to radiotherapy in preliminary clinical studies. However, more preclinical studies comparing imaging with validated invasive methods and clinical studies with outcome measures are required. Nuclear medicine is poised to play an important role in optimizing the therapy of patients with hypoxic tumors.

  16. Subcellular localization of a fluorescent derivative of CuII(atsm) offers insight into the neuroprotective action of CuII(atsm).

    PubMed

    Price, Katherine Ann; Crouch, Peter J; Lim, SinChun; Paterson, Brett M; Liddell, Jeffrey R; Donnelly, Paul S; White, Anthony R

    2011-12-01

    Copper complexes of bis(thiosemicarbazone) (Cu(II)(btsc)s) have been studied as potential anti-cancer agents and hypoxia imaging agents. More recently, Cu(II)(btsc)s have been identified as possessing potent neuroprotective properties in cell and animal models of neurodegenerative disease. Despite their broad range of pharmacological activity little is known about how cells traffic Cu(II)(btsc)s and how this relates to potential anti-cancer or neuroprotective outcomes. One method of investigating sub-cellular localization of metal complexes is through confocal fluorescence imaging of the compounds in cells. Previously we harnessed the fluorescence of a pyrene group attached to diacetyl-bis(N4-methylthiosemicarbazonato)copper(ii)) (Cu(II)(atsm)), (Cu(II)L(1)). We demonstrated that Cu(II)L(1) was partially localized to lysosomes in HeLa cancer epithelial cells. Here we extend these studies to map the sub-cellular localization of Cu(II)L(1) in M17 neuroblastoma cells. Treatment of M17 or HeLa cells led to rapid association of the Cu-complex into distinct punctate structures that partially co-localized with lysosomes as assessed by co-localization with Lysotracker and acridine orange. No localization to early or late endosomes, the nucleus or mitochondria was observed. We also found evidence for a limited association of Cu(II)L(1) with autophagic structures, however, this did not account for the majority of the punctate localization of Cu(II)L(1). In addition, Cu(II)L(1) revealed partial localization with ER Tracker and was found to inhibit ER stress induced by tunicamycin. This is the first report to comprehensively characterize the sub-cellular localization of a Cu(II)(atsm) derivative in cells of a neuronal origin and the partial association with lysosome/autophagic structures and the ER may have a potential role in neuroprotection.

  17. Comparative study of ZnO nanorods and thin films for chemical and biosensing applications and the development of ZnO nanorods based potentiometric strontium ion sensor

    NASA Astrophysics Data System (ADS)

    Khun, K.; Ibupoto, Z. H.; Chey, C. O.; Lu, Jun.; Nur, O.; Willander, M.

    2013-03-01

    In this study, the comparative study of ZnO nanorods and ZnO thin films were performed regarding the chemical and biosensing properties and also ZnO nanorods based strontium ion sensor is proposed. ZnO nanorods were grown on gold coated glass substrates by the hydrothermal growth method and the ZnO thin films were deposited by electro deposition technique. ZnO nanorods and thin films were characterised by field emission electron microscopy [FESEM] and X-ray diffraction [XRD] techniques and this study has shown that the grown nanostructures are highly dense, uniform and exhibited good crystal quality. Moreover, transmission electron microscopy [TEM] was used to investigate the quality of ZnO thin film and we observed that ZnO thin film was comprised of nano clusters. ZnO nanorods and thin films were functionalised with selective strontium ionophore salicylaldehyde thiosemicarbazone [ST] membrane, galactose oxidase, and lactate oxidase for the detection of strontium ion, galactose and L-lactic acid, respectively. The electrochemical response of both ZnO nanorods and thin films sensor devices was measured by using the potentiometric method. The strontium ion sensor has exhibited good characteristics with a sensitivity of 28.65 ± 0.52 mV/decade, for a wide range of concentrations from 1.00 × 10-6 to 5.00 × 10-2 M, selectivity, reproducibility, stability and fast response time of 10.00 s. The proposed strontium ion sensor was used as indicator electrode in the potentiometric titration of strontium ion versus ethylenediamine tetra acetic acid [EDTA]. This comparative study has shown that ZnO nanorods possessed better performance with high sensitivity and low limit of detection due to high surface area to volume ratio as compared to the flat surface of ZnO thin films.

  18. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites

    PubMed Central

    Potůčková, Eliška; Roh, Jaroslav; Macháček, Miloslav; Sahni, Sumit; Stariat, Ján; Šesták, Vít; Jansová, Hana; Hašková, Pavlína; Jirkovská, Anna; Vávrová, Kateřina; Kovaříková, Petra; Kalinowski, Danuta S.; Richardson, Des R.; Šimůnek, Tomáš

    2015-01-01

    Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents. PMID:26460540

  19. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

    PubMed

    Potůčková, Eliška; Roh, Jaroslav; Macháček, Miloslav; Sahni, Sumit; Stariat, Ján; Šesták, Vít; Jansová, Hana; Hašková, Pavlína; Jirkovská, Anna; Vávrová, Kateřina; Kovaříková, Petra; Kalinowski, Danuta S; Richardson, Des R; Šimůnek, Tomáš

    2015-01-01

    Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents. PMID:26460540

  20. Differential targeting of the cyclin-dependent kinase inhibitor, p21CIP1/WAF1, by chelators with anti-proliferative activity in a range of tumor cell-types

    PubMed Central

    Moussa, Rayan S.; Kovacevic, Zaklina; Richardson, Des R.

    2015-01-01

    Chelators such as 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) target tumor cell iron pools and inhibit proliferation. These agents also modulate multiple targets, one of which is the cyclin-dependent kinase inhibitor, p21. Hence, this investigation examined the mechanism of action of these compounds in targeting p21. All the chelators up-regulated p21 mRNA in the five tumor cell-types assessed. In contrast, examining their effect on total p21 protein levels, these agents induced either: (1) down-regulation in MCF-7 cells; (2) up-regulation in SK-MEL-28 and CFPAC-1 cells; or (3) had no effect in LNCaP and SK-N-MC cells. The nuclear localization of p21 was also differentially affected by the ligands depending upon the cell-type, with it being decreased in MCF-7 cells, but increased in SK-MEL-28 and CFPAC-1 cells. Further studies assessing the mechanisms responsible for these effects demonstrated that p21 expression was not correlated with p53 status, suggesting a p53-independent mechanism. Considering this, we examined proteins that modulate p21 independently of p53, namely NDRG1, MDM2 and ΔNp63. These studies demonstrated that a dominant negative MDM2 isoform (p75MDM2) closely resembled p21 expression in response to chelation in three cell lines. These data suggest MDM2 may be involved in the regulation of p21 by chelators. PMID:26335183

  1. Differential targeting of the cyclin-dependent kinase inhibitor, p21CIP1/WAF1, by chelators with anti-proliferative activity in a range of tumor cell-types.

    PubMed

    Moussa, Rayan S; Kovacevic, Zaklina; Richardson, Des R

    2015-10-01

    Chelators such as 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) target tumor cell iron pools and inhibit proliferation. These agents also modulate multiple targets, one of which is the cyclin-dependent kinase inhibitor, p21. Hence, this investigation examined the mechanism of action of these compounds in targeting p21. All the chelators up-regulated p21 mRNA in the five tumor cell-types assessed. In contrast, examining their effect on total p21 protein levels, these agents induced either: (1) down-regulation in MCF-7 cells; (2) up-regulation in SK-MEL-28 and CFPAC-1 cells; or (3) had no effect in LNCaP and SK-N-MC cells. The nuclear localization of p21 was also differentially affected by the ligands depending upon the cell-type, with it being decreased in MCF-7 cells, but increased in SK-MEL-28 and CFPAC-1 cells. Further studies assessing the mechanisms responsible for these effects demonstrated that p21 expression was not correlated with p53 status, suggesting a p53-independent mechanism. Considering this, we examined proteins that modulate p21 independently of p53, namely NDRG1, MDM2 and ΔNp63. These studies demonstrated that a dominant negative MDM2 isoform (p75(MDM2)) closely resembled p21 expression in response to chelation in three cell lines. These data suggest MDM2 may be involved in the regulation of p21 by chelators. PMID:26335183

  2. Phenolic thio- and selenosemicarbazones as multi-target drugs.

    PubMed

    Calcatierra, Verónica; López, Óscar; Fernández-Bolaños, José G; Plata, Gabriela B; Padrón, José M

    2015-04-13

    A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon their in vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 μM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 μM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 μM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 μM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 μM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin. PMID:25752525

  3. A hexadentate bis(thiosemicarbazonato) ligand: rhenium(V), iron(III) and cobalt(III) complexes.

    PubMed

    Paterson, Brett M; White, Jonathan M; Donnelly, Paul S

    2010-03-21

    A new 1,3-diaminopropane bridged bis(thiosemicarbazone) ligand (H(4)L) has been synthesised. The new hexadentate ligand is capable of forming six coordinate complexes with rhenium(V), iron(III) and cobalt(III). In the case of the iron(III) and cobalt(III) complexes the ligand doubly deprotonates to give the monocations [Fe(III)(H(2)L)](+) and [Co(III)(H(2)L)](+) in which the metal ion is in a distorted octahedral environment. In the rhenium(V) complex the ligand loses four protons by deprotonation of both secondary amine nitrogen atoms to give [Re(V)(L)](+) with the metal ion in a distorted trigonal prismatic coordination environment. [Re(V)(L)](+) represents a rare example of a rhenium(V) complex that does not contain one of the ReO(3+), ReN(2+) or Re(NPh)(2+) cores. The new ligand and metal complexes have been characterised by a combination of NMR spectroscopy, X-ray crystallography, mass spectrometry and microanalysis. The electrochemistry of [Fe(III)(H(2)L)](+), [Co(III)(H(2)L)](+) and [Re(V)(L)](+) has been investigated by cyclic voltammetry with each complex undergoing a single electron reduction event. It is possible to prepare the rhenium(V) complex from ReOCl(3)(PPh(3))(2) or directly from [ReO(4)](-) with the addition of a reductant, which suggests the new ligand may be of interest in the development of rhenium radiopharmaceuticals.

  4. Neurotoxicity of reactive aldehydes: the concept of "aldehyde load" as demonstrated by neuroprotection with hydroxylamines.

    PubMed

    Wood, Paul L; Khan, M Amin; Kulow, Sarah R; Mahmood, Siddique A; Moskal, Joseph R

    2006-06-20

    The concept of "oxidative stress" has become a mainstay in the field of neurodegeneration but has failed to differentiate critical events from epiphenomena and sequalae. Furthermore, the translation of current concepts of neurodegenerative mechanisms into effective therapeutics for neurodegenerative diseases has been meager and disappointing. A corollary of current concepts of "oxidative stress" is that of "aldehyde load". This relates to the production of reactive aldehydes that covalently modify proteins, nucleic acids, lipids and carbohydrates and activate apoptotic pathways. However, reactive aldehydes can also be generated by mechanisms other than "oxidative stress". We therefore hypothesized that agents that can chemically neutralize reactive aldehydes should demonstrate superior neuroprotective actions to those of free radical scavengers. To this end, we evaluated hydroxylamines as aldehyde-trapping agents in an in vitro model of neurodegeneration induced by the reactive aldehyde, 3-aminopropanal (3-AP), a product of polyamine oxidase metabolism of spermine and spermidine. In this model, the hydroxylamines N-benzylhydroxylamine, cyclohexylhydroxylamine and t-butylhydroxylamine were shown to protect, in a concentration-dependent manner, against 3-AP neurotoxicity. Additionally, a therapeutic window of 3 h was demonstrated for delayed administration of the hydroxylamines. In contrast, the free radical scavengers TEMPO and TEMPONE and the anti-oxidant ascorbic acid were ineffective in this model. Extending these tissue culture findings in vivo, we examined the actions of N-benzylhydroxylamine in the trimethyltin (TMT) rat model of hippocampal CA3 neurodegeneration. This model involves augmented polyamine metabolism resulting in the generation of reactive aldehydes that compromise mitochondrial integrity. In the rat TMT model, NBHA (50 mg/kg, sc, daily) provided 100% protection against neurodegeneration, as reflected by measurements of KCl-evoked glutamate

  5. Sources, Sinks and Cycling of Acetyl Radicals in Tobacco Smoke: A Model for Biomass Burning Chemistry

    NASA Astrophysics Data System (ADS)

    Hu, N.; Green, S. A.

    2012-12-01

    Smoke near the source of biomass burning contains high concentrations of reactive compounds, with NO and CH3CHO concentrations four to six orders of magnitude higher than those in the ambient atmosphere. Tobacco smoke represents a special case of biomass burning that is quite reproducible in the lab and may elucidate early processes in smoke from other sources. The origins, identities, and reactions of radical species in tobacco smoke are not well understood, despite decades of study on the concentrations and toxicities of the relatively stable compounds in smoke. We propose that reactions of NO2 and aldehydes are a primary source for transient free radicals in tobacco smoke, which contrasts with the long-surmised mechanism of reaction between NO2 and dienes. The objective of this study was to investigate the sources, sinks and cycling of acetyl radical in tobacco smoke. Experimentally, the production of acetyl radical was demonstrated both in tobacco smoke and in a simplified mixture of air combined with NO and acetaldehyde, both of which are significant components of smoke. Acetyl radicals were trapped from the gas phase using 3-amino-2, 2, 5, 5-tetramethyl-proxyl (3AP) on solid support to form stable 3AP adducts for later analysis by high performance liquid chromatography (HPLC), mass spectrometry/tandem mass spectrometry (MS-MS/MS) and liquid chromatography-mass spectrometry (LC-MS). The dynamic nature of radical cycling in smoke makes it impossible to define a fixed concentration of radical species; 2.15×e13-3.18×e14 molecules/cm3 of acetyl radicals were measured from different cigarette samples and smoking conditions. Matlab was employed to simulate reactions of NO, NO2, O2, and a simplified set of organic compounds known to be present in smoke, with a special emphasis on acetaldehyde and the acetyl radical. The NO2/acetaldehyde mechanism initiates a cascade of chain reactions, which accounts for the most prevalent known carbon-centered radicals found in

  6. Temporal Analysis of Gene Expression in the Murine Schwann Cell Lineage and the Acutely Injured Postnatal Nerve

    PubMed Central

    Touahri, Yacine; Stratton, Jo Anne; Biernaskie, Jeff; Schuurmans, Carol

    2016-01-01

    Schwann cells (SCs) arise from neural crest cells (NCCs) that first give rise to SC precursors (SCPs), followed by immature SCs, pro-myelinating SCs, and finally, non-myelinating or myelinating SCs. After nerve injury, mature SCs ‘de-differentiate’, downregulating their myelination program while transiently re-activating early glial lineage genes. To better understand molecular parallels between developing and de-differentiated SCs, we characterized the expression profiles of a panel of 12 transcription factors from the onset of NCC migration through postnatal stages, as well as after acute nerve injury. Using Sox10 as a pan-glial marker in co-expression studies, the earliest transcription factors expressed in E9.0 Sox10+ NCCs were Sox9, Pax3, AP2α and Nfatc4. E10.5 Sox10+ NCCs coalescing in the dorsal root ganglia differed slightly, expressing Sox9, Pax3, AP2α and Etv5. E12.5 SCPs continued to express Sox10, Sox9, AP2α and Pax3, as well as initiating Sox2 and Egr1 expression. E14.5 immature SCs were similar to SCPs, except that they lost Pax3 expression. By E18.5, AP2α, Sox2 and Egr1 expression was turned off in the nerve, while Jun, Oct6 and Yy1 expression was initiated in pro-myelinating Sox9+/Sox10+ SCs. Early postnatal and adult SCs continued to express Sox9, Jun, Oct6 and Yy1 and initiated Nfatc4 and Egr2 expression. Notably, at all stages, expression of each marker was observed only in a subset of Sox10+ SCs, highlighting the heterogeneity of the SC pool. Following acute nerve injury, Egr1, Jun, Oct6, and Sox2 expression was upregulated, Egr2 expression was downregulated, while Sox9, Yy1, and Nfatc4 expression was maintained at similar frequencies. Notably, de-differentiated SCs in the injured nerve did not display a transcription factor profile corresponding to a specific stage in the SC lineage. Taken together, we demonstrate that uninjured and injured SCs are heterogeneous and distinct from one another, and de-differentiation recapitulates

  7. Proteomics and Transcriptomics of BJAB Cells Expressing the Epstein-Barr Virus Noncoding RNAs EBER1 and EBER2

    PubMed Central

    Pimienta, Genaro; Fok, Victor; Haslip, Maria; Nagy, Maria; Takyar, Seyedtaghi; Steitz, Joan A

    2015-01-01

    In Epstein-Barr virus (EBV) latent infection, the EBV-encoded RNAs EBER1 and EBER2 accumulate in the host cell nucleus to ~106 copies. While the expression of EBERs in cell lines is associated with transformation, a mechanistic explanation of their roles in EBV latency remains elusive. To identify EBER-specific gene expression features, we compared the proteome and mRNA transcriptome from BJAB cells (an EBV-negative B lymphoma cell line) stably transfected with an empty plasmid or with one carrying both EBER genes. We identified ~1800 proteins with at least 2 SILAC pair measurements, of which only 8 and 12 were up- and downregulated ≥ 2-fold, respectively. One upregulated protein was PIK3AP1, a B-cell specific protein adapter known to activate the PI3K-AKT signaling pathway, which regulates alternative splicing and translation in addition to its pro-survival effects. In the mRNA-seq data, the mRNA levels for some of the proteins changing in the SILAC data did not change. We instead observed isoform switch events. We validated the most relevant findings with biochemical assays. These corroborated the upregulation of PIK3AP1 and AKT activation in BJAB cells expressing high levels of both EBERs and EBNA1 (a surrogate of Burkitt’s lymphoma EBV latency I) relative to those expressing only EBNA1. The mRNA-seq data in these cells showed multiple upregulated oncogenes whose mRNAs are enriched for 3´-UTR AU-rich elements (AREs), such as ccl3, ccr7, il10, vegfa and zeb1. The CCL3, CCR7, IL10 and VEGFA proteins promote cell proliferation and are associated with EBV-mediated lymphomas. In EBV latency, ZEB1 represses the transcription of ZEBRA, an EBV lytic phase activation factor. We previously found that EBER1 interacts with AUF1 in vivo and proposed stabilization of ARE-containing mRNAs. Thus, the ~106 copies of EBER1 may promote not only cell proliferation due to an increase in the levels of ARE-containing genes like ccl3, ccr7, il10, and vegfa, but also the

  8. Proteomics and Transcriptomics of BJAB Cells Expressing the Epstein-Barr Virus Noncoding RNAs EBER1 and EBER2.

    PubMed

    Pimienta, Genaro; Fok, Victor; Haslip, Maria; Nagy, Maria; Takyar, Seyedtaghi; Steitz, Joan A

    2015-01-01

    In Epstein-Barr virus (EBV) latent infection, the EBV-encoded RNAs EBER1 and EBER2 accumulate in the host cell nucleus to ~10(6) copies. While the expression of EBERs in cell lines is associated with transformation, a mechanistic explanation of their roles in EBV latency remains elusive. To identify EBER-specific gene expression features, we compared the proteome and mRNA transcriptome from BJAB cells (an EBV-negative B lymphoma cell line) stably transfected with an empty plasmid or with one carrying both EBER genes. We identified ~1800 proteins with at least 2 SILAC pair measurements, of which only 8 and 12 were up- and downregulated ≥ 2-fold, respectively. One upregulated protein was PIK3AP1, a B-cell specific protein adapter known to activate the PI3K-AKT signaling pathway, which regulates alternative splicing and translation in addition to its pro-survival effects. In the mRNA-seq data, the mRNA levels for some of the proteins changing in the SILAC data did not change. We instead observed isoform switch events. We validated the most relevant findings with biochemical assays. These corroborated the upregulation of PIK3AP1 and AKT activation in BJAB cells expressing high levels of both EBERs and EBNA1 (a surrogate of Burkitt's lymphoma EBV latency I) relative to those expressing only EBNA1. The mRNA-seq data in these cells showed multiple upregulated oncogenes whose mRNAs are enriched for 3´-UTR AU-rich elements (AREs), such as ccl3, ccr7, il10, vegfa and zeb1. The CCL3, CCR7, IL10 and VEGFA proteins promote cell proliferation and are associated with EBV-mediated lymphomas. In EBV latency, ZEB1 represses the transcription of ZEBRA, an EBV lytic phase activation factor. We previously found that EBER1 interacts with AUF1 in vivo and proposed stabilization of ARE-containing mRNAs. Thus, the ~10(6) copies of EBER1 may promote not only cell proliferation due to an increase in the levels of ARE-containing genes like ccl3, ccr7, il10, and vegfa, but also the

  9. Formation and decomplexation kinetics of copper(ii) complexes with cyclen derivatives having mixed carboxylate and phosphonate pendant arms.

    PubMed

    Ševčík, R; Vaněk, J; Michalicová, R; Lubal, P; Hermann, P; Santos, I C; Santos, I; Campello, M P C

    2016-08-01

    The kinetic properties of Cu(ii) complexes of H4dota and its analogues with one (H5do3ap), two in the 1,7-position (trans-H6do2a2p), three (H7doa3p) and four (H8dotp) phosphonic acid pendant arms were investigated. The formation of a Cu(ii) complex with H4dota, trans-H6do2a2p and H8dotp at a slightly acidic pH is faster for the phosphonic acid derivatives than for H4dota, but with no simple dependence on the number of -CH2PO3H2 substituents (trans-H6do2a2p > H8dotp > H4dota; pH 4-6). Relative differences in the reactivity among the differently protonated species (HnL(x-)) of the same ligand are successively decreased with the more phosphonic acid groups in the ligand. The faster complexation is probably caused by the higher ability of phosphonates to bind the metal ion and/or to assist in the transfer of protons from the ring amine groups to the bulk water. The acid-assisted decomplexation kinetics of the complexes was followed in highly acidic solutions ([H(+)] = 0.01-5 M) and at different temperatures (15-70 °C) to determine the activation parameters of the reaction. The kinetic inertness of the Cu(ii) complexes follows the order: H4dota > H5do3ap > trans-H6do2a2p > H7doa3p > H8dotp. To obtain information on the influence of additional pendant arms, analogous data were obtained for trans-H2do2a. The ligand is less reactive than H4dota, but the kinetic inertness of its Cu(ii) complex is similar to that of the H4dota complex. As it was considered that the published thermodynamics data on the Cu(ii)-H8dotp system are probably incorrect, the system was re-investigated. It showed a very high stability for the [Cu(dotp)](6-) species and the easy formation of several Cu2L species in the presence of an excess of the metal ion. Also, the structure of the (H6doa3p)(-) anion in the solid state was determined. These experimental data demonstrate that the substitution of acetic acid pendant arms by methylphosphonic acid ones in H4dota-like ligands increases the rate of

  10. Phase equilibria, crystal structure and oxygen content of intermediate phases in the Y-Ba-Co-O system

    NASA Astrophysics Data System (ADS)

    Urusova, A. S.; Cherepanov, V. A.; Aksenova, T. V.; Gavrilova, L. Ya.; Kiselev, E. A.

    2013-06-01

    The phase equilibria in the Y-Ba-Co-O system were systematically studied at 1373 K in air. The intermediate phases formed in the Y-Ba-Co-O system at 1373 K in air were: YBaCo2O5+δ, YBaCo4O7 and BaCo1-yYyO3-δ (0.09≤y≤0.42). It was shown that YBaCo2O5+δ possesses tetragonal structure with the 3ap×3ap×2ap superstructure (sp. gr. P4/mmm). High-temperature X-ray diffraction analysis of the YBaCo2O5+δ in the temperature range from 298 K up to 1073 K under Po2=0.21 аtm has not shown any phase transformations. The value of oxygen content for the YBaCo2O5+δ at room temperature was estimated as 5.40 and at 1323 K it was equal to 5.04. Thermal expansion of sample shows a linear characteristics and the average thermal expansion coefficient (TEC) is about 13.8×10-6, K-1 in the temperature range 298-1273 K. The homogeneity range and crystal structure of the BaCo1-yYyO3-δ (0.09≤y≤0.42) solid solutions were determined by X-ray diffraction of quenched samples. All BaCo1-yYyO3-δ solid solutions were found to have cubic structure (sp. gr. Pm3m). The unit cell parameters were refined using Rietveld full-profile analysis. Oxygen nonstoichiometry of BaCo1-yYyO3-δ solid solutions with 0.1≤y≤0.4 was measured by means of thermogravimetric technique within the temperature range 298-1373 K in air. Thermal expansion of BaCo1-yYyO3-δ (у=0.0; 0.1; 0.2; 0.3) samples was studied within the temperature range 298-1200 K in air. The projection of isothermal-isobaric phase diagram for the Y-Ba-Co-O system to the compositional triangle of metallic components was presented.

  11. Temporal Analysis of Gene Expression in the Murine Schwann Cell Lineage and the Acutely Injured Postnatal Nerve.

    PubMed

    Balakrishnan, Anjali; Stykel, Morgan G; Touahri, Yacine; Stratton, Jo Anne; Biernaskie, Jeff; Schuurmans, Carol

    2016-01-01

    Schwann cells (SCs) arise from neural crest cells (NCCs) that first give rise to SC precursors (SCPs), followed by immature SCs, pro-myelinating SCs, and finally, non-myelinating or myelinating SCs. After nerve injury, mature SCs 'de-differentiate', downregulating their myelination program while transiently re-activating early glial lineage genes. To better understand molecular parallels between developing and de-differentiated SCs, we characterized the expression profiles of a panel of 12 transcription factors from the onset of NCC migration through postnatal stages, as well as after acute nerve injury. Using Sox10 as a pan-glial marker in co-expression studies, the earliest transcription factors expressed in E9.0 Sox10+ NCCs were Sox9, Pax3, AP2α and Nfatc4. E10.5 Sox10+ NCCs coalescing in the dorsal root ganglia differed slightly, expressing Sox9, Pax3, AP2α and Etv5. E12.5 SCPs continued to express Sox10, Sox9, AP2α and Pax3, as well as initiating Sox2 and Egr1 expression. E14.5 immature SCs were similar to SCPs, except that they lost Pax3 expression. By E18.5, AP2α, Sox2 and Egr1 expression was turned off in the nerve, while Jun, Oct6 and Yy1 expression was initiated in pro-myelinating Sox9+/Sox10+ SCs. Early postnatal and adult SCs continued to express Sox9, Jun, Oct6 and Yy1 and initiated Nfatc4 and Egr2 expression. Notably, at all stages, expression of each marker was observed only in a subset of Sox10+ SCs, highlighting the heterogeneity of the SC pool. Following acute nerve injury, Egr1, Jun, Oct6, and Sox2 expression was upregulated, Egr2 expression was downregulated, while Sox9, Yy1, and Nfatc4 expression was maintained at similar frequencies. Notably, de-differentiated SCs in the injured nerve did not display a transcription factor profile corresponding to a specific stage in the SC lineage. Taken together, we demonstrate that uninjured and injured SCs are heterogeneous and distinct from one another, and de-differentiation recapitulates

  12. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-05-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3-AP, Adalimumab, adefovir dipivoxil, AeroDose albuterol inhaler, agalsidase alfa, alemtuzumab, aminolevulinic acid methyl ester, anidulafungin, anthrax vaccine, anti-CTLA-4 MAb, azimilide hydrochloride; Bevacizumab, BG-12, bimatoprost, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, ceftobiprole, certolizumab pegol, CG-53135, cilansetron; Darbepoetin alfa, degarelix acetate, dimethylfumarate, duloxetine hydrochloride, dutasteride; Eicosapentaenoic acid/docosahexaenoic acid, eletriptan, entecavir, esomeprazole magnesium, exatecan mesilate, exenatide, ezetimibe; Falecalcitriol, fampridine, fondaparinux sodium, fontolizumab; Gefitinib, gepirone hydrochloride; Human insulin; IDEA-070, imatinib mesylate, iodine (I131) tositumomab; Lanthanum carbonate, lubiprostone; Mafosfamide cyclohexylamine salt, melatonin; NC-531, nemifitide ditriflutate, neridronic acid, nolatrexed dihydrochloride; Oral insulin; Palifermin, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, plerixafor hydrochloride, posaconazole, pramlintide acetate, pregabalin, PT-141; Quercetin; Ranibizumab, renzapride hydrochloride, RSD-1235; Sabarubicin hydrochloride, semapimod hydrochloride, Semax, SHL-749; Tegaserod maleate, tenatoprazole, tetrodotoxin, tolevamer sodium, trabectedin, travoprost, travoprost/timolol; Valdecoxib, visilizumab, Xcellerated T cells, XP-828L; Zoledronic acid monohydrate.

  13. Functional analysis of the two Brassica AP3 genes involved in apetalous and stamen carpelloid phenotypes.

    PubMed

    Zhang, Yanfeng; Wang, Xuefang; Zhang, Wenxue; Yu, Fei; Tian, Jianhua; Li, Dianrong; Guo, Aiguang

    2011-01-01

    The Arabidopsis homeotic genes APETALA3 (AP3) and PISTILLATA (PI) are B genes which encode MADS-box transcription factors and specify petal and stamen identities. In the current study, the stamen carpelloid (SC) mutants, HGMS and AMS, of B. rapa and B. napus were investigated and two types of AP3 genes, B.AP3.a and B.AP3.b, were functional characterized. B.AP3.a and B.AP3.b share high similarity in amino acid sequences except for 8 residues difference located at the C-terminus. Loss of this 8 residues in B.AP3.b led to the change of PI-derived motifs. Meanwhile, B.AP3.a specified petal and stamen development, whereas B.AP3.b only specified stamen development. In B. rapa, the mutations of both genes generated the SC mutant HGMS. In B. napus that contained two B.AP3.a and two B.AP3.b, loss of the two B.AP3.a functions was the key reason for the apetalous mutation, however, the loss-of-function in all four AP3 was related to the SC mutant AMS. We inferred that the 8 residues or the PI-derived motif in AP3 gene probably relates to petal formation.

  14. Development of amplified consensus genetic markers (ACGM) in Brassica napus from Arabidopsis thaliana sequences of known biological function.

    PubMed

    Brunel, D; Froger, N; Pelletier, G

    1999-06-01

    A method for the development of consensus genetic markers between species of the same taxonomic family is described in this paper. It is based on the conservation of the peptide sequences and on the potential polymorphism within non-coding sequences. Six loci sequenced from Arabidopsis thaliana, AG, LFY3, AP3, FAD7, FAD3, and ADH, were analysed for one ecotype of A. thaliana, four lines of Brassica napus, and one line for each parental species, Brassica oleracea and Brassica rapa. Positive amplifications with the degenerate primers showed one band for A. thaliana, two to four bands in rapeseed, and one to two bands in the parental species. Direct sequencing of the PCR products confirms their peptide similarity with the "mother" sequence. By comparison of intron sequences, the correspondence between each rapeseed gene and its homologue in one of the parental species can be determined without ambiguity. Another important result is the presence of a polymorphism inside these fragments between the rapeseed lines. This variability could generally be detected by differences of electrophoretic migration on long non-denaturing polyacrylamide gels. This method enables a quick and easy shuttle between A. thaliana and Brassica species without cloning.

  15. Functional divergence within the APETALA3/PISTILLATA floral homeotic gene lineages

    PubMed Central

    Lamb, Rebecca S.; Irish, Vivian F.

    2003-01-01

    Changes in homeotic gene expression patterns or in the functions of the encoded proteins are thought to play a prominent role in the evolution of new morphologies. The floral homeotic APETALA3 (AP3) and PISTILLATA (PI) genes encode MADS domain-containing transcription factors required to specify petal and stamen identities in Arabidopsis. We have previously shown that perianth expression of AP3 and PI homologs varies in different groups of angiosperms with diverse floral structures, suggesting that changes in expression may contribute to changing morphology. We have investigated the possibility that changes in the functions of the encoded gene products may also have played a role in the evolution of different floral morphologies. AP3 and PI are members of paralogous gene lineages and share extensive similarity along the length of the protein products. Genes within these lineages encode products with characteristic C-terminal motifs that we show are critical for functional specificity. In particular, the C terminus of AP3 is sufficient to confer AP3 functionality on the heterologous PI protein. Furthermore, we have shown that the evolution of the divergent AP3 C-terminal domain in the core eudicots is correlated with the acquisition of a role in specifying perianth structures. These results suggest that divergence in these sequence motifs has contributed to the evolution of distinct functions for these floral homeotic gene products. PMID:12746493

  16. Global identification of target genes regulated by APETALA3 and PISTILLATA floral homeotic gene action.

    PubMed

    Zik, Moriyah; Irish, Vivian F

    2003-01-01

    Identifying the genes regulated by the floral homeotic genes APETALA3 (AP3) and PISTILLATA (PI) is crucial for understanding the molecular mechanisms that lead to petal and stamen formation. We have used microarray analysis to conduct a broad survey of genes whose expression is affected by AP3 and PI activity. DNA microarrays consisting of 9216 Arabidopsis ESTs were screened with probes corresponding to mRNAs from different mutant and transgenic lines that misexpress AP3 and/or PI. The microarray results were further confirmed by RNA gel blot analyses. Our results suggest that AP3 and PI regulate a relatively small number of genes, implying that many genes used in petal and stamen development are not tissue specific and likely have roles in other processes as well. We recovered genes similar to previously identified petal- and stamen-expressed genes as well as genes that were not implicated previously in petal and stamen development. A very low percentage of the genes recovered encoded transcription factors. This finding suggests that AP3 and PI act relatively directly to regulate the genes required for the basic cellular processes responsible for petal and stamen morphogenesis.

  17. Effects of modulation of pentose-phosphate pathway on biosynthesis of ansamitocins in Actinosynnema pretiosum.

    PubMed

    Fan, Yuxiang; Hu, Fengxian; Wei, Liujing; Bai, Linquan; Hua, Qiang

    2016-07-20

    Ansamitocins, produced by Actinosynnema pretiosum, are a group of maytansinoid antibiotics that block the assembly of tubulin into functional microtubules. The precursors of ansamitocin biosynthesis are generally derived from the Embden-Meyerhof-Parnas (EMP) pathway and the tricarboxylic acid cycle. In this study, central carbon flux distributions were analyzed by (13)C-based flux analysis to reveal the contribution of individual central carbon metabolism pathways. To direct more carbon flux into ansamitocin biosynthesis, pentose phosphate (PP) pathway only and the combination of PP pathway and Entner-Doudoroff (ED) pathway were weakened, respectively. Ansamitocin P-3 (AP-3) productions by both kinds of pathways weakened mutant strains were significantly enhanced in chemically defined medium. In order to draw metabolic flux to the biosynthesis of ansamitocins more efficiently, heterologous phosphoglucomutase was subsequently overexpressed based on a mutant strain with combinational regulation of PP pathway and ED pathway. More fluxes were successfully directed into the UDP-glucose synthetic pathway and the AP-3 production was further improved in this case, reaching approximately 185mg/L in fermentation medium. It was demonstrated that eliminating the bypass pathways and favoring the precursor synthetic pathway could effectively improve ansamitocin production by A. pretiosum, suggesting a promising role of metabolic strategy in improving secondary metabolite production.

  18. A Cucumber DELLA Homolog CsGAIP May Inhibit Staminate Development through Transcriptional Repression of B Class Floral Homeotic Genes

    PubMed Central

    Zhang, Yan; Liu, Bin; Yang, Sen; An, Jingbo; Chen, Chunhua; Zhang, Xiaolan; Ren, Huazhong

    2014-01-01

    In hermaphroditic Arabidopsis, the phytohormone gibberellin (GA) stimulates stamen development by opposing the DELLA repression of B and C classes of floral homeotic genes. GA can promote male flower formation in cucumber (Cucumis sativus L.), a typical monoecious vegetable with unisexual flowers, and the molecular mechanism remains unknown. Here we characterized a DELLA homolog CsGAIP in cucumber, and we found that CsGAIP is highly expressed in stem and male flower buds. In situ hybridization showed that CsGAIP is greatly enriched in the stamen primordia, especially during the hermaphrodite stage of flower development. Further, CsGAIP protein is located in nucleus. CsGAIP can partially rescue the plant height, stamen development and fertility phenotypes of Arabidopsis rga-24/gai-t6 mutant, and ectopic expression of CsGAIP in wide-type Arabidopsis results in reduced number of stamens and decreased transcription of B class floral homeotic genes APETALA3 (AP3) and PISTILLATA (PI). Our data suggest that monoecious CsGAIP may inhibit staminate development through transcriptional repression of B class floral homeotic genes in Arabidopsis. PMID:24632777

  19. Phylogeny and divergence of basal angiosperms inferred from APETALA3- and PISTILLATA-like MADS-box genes.

    PubMed

    Aoki, Seishiro; Uehara, Koichi; Imafuku, Masao; Hasebe, Mitsuyasu; Ito, Motomi

    2004-06-01

    The B-class MADS-box genes composed of APETALA3 ( AP3) and PISTILLATA ( PI) lineages play an important role in petal and stamen identity in previously studied flowering plants. We investigated the diversification of the AP3-like and PI-like MADS-box genes of eight species in five basal angiosperm families: Amborella trichopoda (Amborellaceae); Brasenia schreberi and Cabomba caroliniana (Cabombaceae); Euryale ferox, Nuphar japonicum, and Nymphaea tetragona (Nymphaeaceae); Illicium anisatum (Illiciaceae); and Kadsura japonica (Schisandraceae). Sequence analysis showed that a four amino acid deletion in the K domain, which was found in all previously reported angiosperm PI genes, exists in a PI homologue of Schisandraceae, but not in six PI homologues of the Amborellaceae, Cabombaceae, and Nymphaeaceae, suggesting that the Amborellaceae, Cabombaceae, and Nymphaeaceae are basalmost lineages in angiosperms. The results of molecular phylogenetic analyses were not inconsistent with this hypothesis. The AP3 and PI homologues from Amborella share a sequence of five amino acids in the 5' region of exon 7. Using the linearized tree and likelihood methods, the divergence time between the AP3 and PI lineages was estimated as somewhere between immediately after to several tens of millions of years after the split between angiosperms and extant gymnosperms. Estimates of the age of the most recent common ancestor of all extant angiosperms range from approximately 140-210 Ma, depending on the trees used and assumptions made.

  20. Endosome-mediated endocytic mechanism replenishes the majority of synaptic vesicles at mature CNS synapses in an activity-dependent manner.

    PubMed

    Park, Joohyun; Cho, Oh Yeon; Kim, Jung Ah; Chang, Sunghoe

    2016-01-01

    Whether synaptic vesicles (SVs) are recovered via endosome-mediated pathways is a matter of debate; however, recent evidence suggests that clathrin-independent bulk endocytosis (CIE) via endosomes is functional and preferentially replenishes SV pools during strong stimulation. Here, using brefeldin-A (BFA) to block CIE, we found that CIE retrieved a minority of SVs at developing CNS synapses during strong stimulation, but its contribution increased up to 61% at mature CNS synapses. Contrary to previous views, BFA not only blocked SV formation from the endosome but also blocked the endosome formation at the plasma membrane. Adaptor protein 1 and 3 (AP-1/3) have key roles in SV reformation from endosomes during CIE, and AP-1 also affects bulk endosome formation from the plasma membrane. Finally, temporary blocking of chronic or acute neuronal activity with tetrodotoxin in mature neurons redirected most SV retrieval to endosome-independent pathways. These results show that during high neuronal activity, CIE becomes the major endocytic pathway at mature CNS synapses. Moreover, mature neurons use clathrin-mediated endocytosis and the CIE pathway to different extents depending on their previous activity; this may result in activity-dependent alterations of the SV composition which ultimately influence transmitter release and contribute to synaptic plasticity. PMID:27534442

  1. A ventilation capacity test for the Eustachian tube using a soundproof pressure chamber.

    PubMed

    Kodama, A; Kitahara, M; Ozawa, H; Izukura, H

    1994-01-01

    Using a soundproof pressure chamber, we performed Békésy air conduction audiometry at 1000 Hz under the following pressure conditions: 1) from atmospheric pressure (AP) to 200 mmH2O below AP, 2) AP to 200 mmH2O above AP, 3) AP to 700 mmH2O below AP, and 4) AP to 700 mmH2O above AP. In conditions 1) and 2), the patient was instructed not to swallow until the pressure change was complete, then to swallow once every 15 seconds. The number of swallows required for hearing to return to the baseline level was counted. In conditions 3) and 4), the patient was told to swallow as many times as possible both before and after completion of the pressure change; maximum hearing level and the time needed for return to the baseline level were measured. Although all except one of the seven patients with suspected tubal dysfunction showed normal results with catheter insufflation and tympanometry, six of the seven showed abnormality and one reported the disappearance of ear stuffiness after the ventilation capacity test. We concluded that this test is useful not only for the diagnosis of tubal dysfunction but also as a possible therapy for aiding adaptation to changing environmental pressure.

  2. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

    PubMed Central

    Wu, Shaowei; Fu, Xiong; Brennan, Margaret A.; Brennan, Charles S.; Chun, Chen

    2016-01-01

    Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

  3. An Arabidopsis F-box protein acts as a transcriptional co-factor to regulate floral development.

    PubMed

    Chae, Eunyoung; Tan, Queenie K-G; Hill, Theresa A; Irish, Vivian F

    2008-04-01

    Plants flower in response to both environmental and endogenous signals. The Arabidopsis LEAFY (LFY) transcription factor is crucial in integrating these signals, and acts in part by activating the expression of multiple floral homeotic genes. LFY-dependent activation of the homeotic APETALA3 (AP3) gene requires the activity of UNUSUAL FLORAL ORGANS (UFO), an F-box component of an SCF ubiquitin ligase, yet how this regulation is effected has remained unclear. Here, we show that UFO physically interacts with LFY both in vitro and in vivo, and this interaction is necessary to recruit UFO to the AP3 promoter. Furthermore, a transcriptional repressor domain fused to UFO reduces endogenous LFY activity in plants, supporting the idea that UFO acts as part of a transcriptional complex at the AP3 promoter. Moreover, chemical or genetic disruption of proteasome activity compromises LFY-dependent AP3 activation, indicating that protein degradation is required to promote LFY activity. These results define an unexpected role for an F-box protein in functioning as a DNA-associated transcriptional co-factor in regulating floral homeotic gene expression. These results suggest a novel mechanism for promoting flower development via protein degradation and concomitant activation of the LFY transcription factor. This mechanism may be widely conserved, as homologs of UFO and LFY have been identified in a wide array of plant species. PMID:18287201

  4. Ectopic expression of SUPERMAN suppresses development of petals and stamens.

    PubMed

    Yun, Jae-Young; Weigel, Detlef; Lee, Ilha

    2002-01-01

    The floral regulatory gene SUPERMAN (SUP) encodes a C2H2 type zinc finger protein that is required for maintaining boundaries between floral organs in Arabidopsis. It has been proposed that the main function of SUP is to balance cell proliferation in the third and fourth whorl of developing flowers, thereby maintaining the boundaries between the two whorls. To gain further insight into the function of SUP, we have ectopically expressed SUP using the promoter of APETALA1 (AP1), a gene that is initially expressed throughout floral meristems and later becomes restricted to the first and second whorls. Flowers of AP1::SUP plants have fewer floral organs, consistent with an effect of SUP on cell proliferation. In addition, the AP1::SUP transgene caused the conversion of petals to sepals and suppressed the development of stamens. The expression of the B function homeotic gene APETALA3 (AP3) and its regulator UNUSUAL FLORAL ORGANS (UFO) were delayed and reduced in AP1::SUP flowers. However, SUP does not act merely through UFO, as constitutive expression of UFO did not rescue the defects in petal and stamen development in AP1::SUP flowers. Together, these results suggest that SUP has both indirect and direct effects on the expression of B function homeotic genes. PMID:11828022

  5. The COP9 signalosome interacts with SCF UFO and participates in Arabidopsis flower development.

    PubMed

    Wang, Xiping; Feng, Suhua; Nakayama, Naomi; Crosby, W L; Irish, Vivian; Deng, Xing Wang; Wei, Ning

    2003-05-01

    The COP9 signalosome (CSN) is involved in multiple developmental processes. It interacts with SCF ubiquitin ligases and deconjugates Nedd8/Rub1 from cullins (deneddylation). CSN is highly expressed in Arabidopsis floral tissues. To investigate the role of CSN in flower development, we examined the expression pattern of CSN in developing flowers. We report here that two csn1 partially deficient Arabidopsis strains exhibit aberrant development of floral organs, decline of APETALA3 (AP3) expression, and low fertility in addition to defects in shoot and inflorescence meristems. We show that UNUSUAL FLORAL ORGANS (UFO) forms a SCF(UFO) complex, which is associated with CSN in vivo. Genetic interaction analysis indicates that CSN is necessary for the gain-of-function activity of the F-box protein UFO in AP3 activation and in floral organ transformation. Compared with the previously reported csn5 antisense and csn1 null mutants, partial deficiency of CSN1 causes a reduction in the level of CUL1 in the mutant flowers without an obvious defect in CUL1 deneddylation. We conclude that CSN is an essential regulator of Arabidopsis flower development and suggest that CSN regulates Arabidopsis flower development in part by modulating SCF(UFO)-mediated AP3 activation. PMID:12724534

  6. The ASK1 gene regulates B function gene expression in cooperation with UFO and LEAFY in Arabidopsis.

    PubMed

    Zhao, D; Yu, Q; Chen, M; Ma, H

    2001-07-01

    The Arabidopsis floral regulatory genes APETALA3 (AP3) and PISTILLATA (PI) are required for the B function according to the ABC model for floral organ identity. AP3 and PI expression are positively regulated by the LEAFY (LFY) and UNUSUAL FLORAL ORGANS (UFO) genes. UFO encodes an F-box protein, and we have shown previously that UFO genetically interacts with the ASK1 gene encoding a SKP1 homologue; both the F-box containing protein and SKP1 are subunits of ubiquitin ligases. We show here that the ask1-1 mutation can enhance the floral phenotypes of weak lfy and ap3 mutants; therefore, like UFO, ASK1 also interacts with LFY and AP3 genetically. Furthermore, our results from RNA in situ hybridizations indicate that ASK1 regulates early AP3 and PI expression. These results support the idea that UFO and ASK1 together positively regulate AP3 and PI expression. We propose that the UFO and ASK1 proteins are components of a ubiquitin ligase that mediates the proteolysis of a repressor of AP3 and PI expression. Our genetic studies also indicate that ASK1 and UFO play a role in regulating the number of floral organ primordia, and we discuss possible mechanisms for such a regulation. PMID:11526079

  7. A microsuspension adaptation of the Bacillus subtilis ''rec'' assay. [Detection of chemically induced DNA damage

    SciTech Connect

    McCarroll, N.E.; Keech, B.H.; Piper, C.E.

    1981-01-01

    We have demonstrated the utility of an Escherichia coli microsuspension assay to detect and characterize chemical mediation of DNA damage by a wide variety of mutagens and carcinogens. The assay have been improved by the development of a microsuspension modification to the Bacillus subtilis ''rec'' assay. The addition of these gram-positive organisms has allowed detection of DNA damage induced by benzo(a)pyrene (B(a)P), 3-aminopyrene (3-AP), 7, 12-dimethylbenz(a)anthrancene (DMBA), 3-methylcholanthrene (3-MC), and 4-nitrobiphenyl (4-NBP). Data presented in this paper from tests of 61 additional compounds, including a representative number of direct and promutagenic agents, indicate that the B subtilis H17 and M45 strains provide an effective microbial system for identification of DNA damage susceptible to postreplicational repair. The results of this study further suggests that the inclusion of these strains in the microsuspension assay for DNA damage will markedly enhance the detection of agents which cannot readily penetrate the intact cell wall of E coli.

  8. Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis.

    PubMed

    Li, J; Xiong, J; Yang, B; Zhou, Q; Wu, Y; Luo, H; Zhou, H; Liu, N; Li, Y; Song, Z; Zheng, Q

    2015-12-01

    Endothelial cells (ECs) apoptosis is an initial event in transplant arteriosclerosis (TA), resulting in allograft function loss. To elucidate the precise mechanisms of ECs apoptosis leading to neointimal smooth muscle cells (SMCs) accumulation during TA. We induced apoptosis in cultured ECs by overexpressing p53 through lentivirus-mediated transfection. ECs apoptosis induced the production of transforming growth factor (TGF)-β1 in both apoptotic and neighboring viable cells, leading to increased TGF-β1 in the culture media. Conditioned media from Ltv-p53-transfected ECs further promoted transition of cultured ECs to SM-like cells by activating TGF-β/Smad3, PI3K/Akt/mTOR, and MAPK/ERK signaling in a TGF-β-dependent manner. In transgenic rat aorta transplantation models, inhibition of ECs apoptosis in Bcl-xL(+/+) knock-in rat aortic allografts significantly reduced TGF-β1 production both in allograft endothelia and in blood plasma, which in turn decreased accumulation of SM22α+ cells from transgenic recipient ECs originally marked with EGFP knock-in in neointima and alleviated TA. Systemic treatment with SIS3, AP23573, or PD98059 also prevented recipient ECs-originated SM-like cells accumulation and intima hyperplasia in aortic allografts. These data suggest that allograft EC apoptosis induced recipient endothelial-mesenchymal (smooth muscle) transition via TGF-β signaling, resulting in recipient EC-derived SMC accumulation as a major mechanism of vascular remodeling during TA.

  9. Lysosomal Targeting of Cystinosin Requires AP-3.

    PubMed

    Andrzejewska, Zuzanna; Névo, Nathalie; Thomas, Lucie; Bailleux, Anne; Chauvet, Véronique; Benmerah, Alexandre; Antignac, Corinne

    2015-07-01

    Cystinosin is a lysosomal cystine transporter defective in cystinosis, an autosomal recessive lysosomal storage disorder. It is composed of seven transmembrane (TM) domains and contains two lysosomal targeting motifs: a tyrosine-based signal (GYDQL) in its C-terminal tail and a non-classical motif in its fifth inter-TM loop. Using the yeast two-hybrid system, we showed that the GYDQL motif specifically interacted with the μ subunit of the adaptor protein complex 3 (AP-3). Moreover, cell surface biotinylation and total internal reflection fluorescence microscopy revealed that cystinosin was partially mislocalized to the plasma membrane (PM) in AP-3-depleted cells. We generated a chimeric CD63 protein to specifically analyze the function of the GYDQL motif. This chimeric protein was targeted to lysosomes in a manner similar to cystinosin and was partially mislocalized to the PM in AP-3 knockdown cells where it also accumulated in the trans-Golgi network and early endosomes. Together with the fact that the surface levels of cystinosin and of the CD63-GYDQL chimeric protein were not increased when clathrin-mediated endocytosis was impaired, our data show that the tyrosine-based motif of cystinosin is a 'strong' AP-3 interacting motif responsible for lysosomal targeting of cystinosin by a direct intracellular pathway.

  10. Multiresidue analysis of environmental pollutants in edible vegetable oils by gas chromatography-tandem mass spectrometry.

    PubMed

    Zhou, Rui-Ze; Jiang, Jie; Mao, Ting; Zhao, Ya-Song; Lu, Yong

    2016-09-15

    A novel multiresidue determination of polycyclic aromatic hydrocarbons (PAHs), phthalate esters (PAEs) and alkylphenols (APs) in edible vegetable oils was developed. The samples were extracted with hexane-saturated acetonitrile, and after concentration, the extract was directly qualitatively and quantitatively analyzed by gas chromatography-tandem mass spectrometry (GC-MS/MS) with multiple reaction monitoring (MRM) in positive ion mode. The calibration curve displayed good linearity in the range of 2-100 μg/L, with correlation coefficients greater than 0.99. The mean recoveries were 70.0-110.8% by analysis of spiked oil, and the relative standard deviations (RSDs) were 2.1-10.2% (n=6), respectively. The limits of detection (LODs) for the 23 PAHs, 17 PAEs and 3 APs were 0.1-1.0 μg/kg, 0.1-4.0 μg/kg and 1.2-3.0 μg/kg, respectively. The established method effectively avoided interference from large amounts of lipids and pigments. It was applied to real sample and shown to be a rapid and reliable alternative for determination and confirmation in routine analysis.

  11. Hairpin-dimer equilibrium of a parallel-stranded DNA hairpin: formation of a four-stranded complex.

    PubMed Central

    Dornberger, U; Behlke, J; Birch-Hirschfeld, E; Fritzsche, H

    1997-01-01

    The 24mer deoxyoligonucleotide 3'-d(T)10-5'-5'-d(C)4- d(A)10-3'(psC4) with an uncommon 5'-p-5'phosphodiester linkage was designed to enable the formation of a hairpin structure with unusual parallel-stranded stem. As reference hairpin structure with an antiparallel-stranded stem, the 24mer 5'-d(T)10-d(C)4-d(A)10-3'(apsC4) was chosen. The behaviour of these oligonucleotides at different temperatures, DNA and salt concentrations was characterised by a combination of UV melting, CD, CD melting, infrared and Raman spectroscopy, infrared melting and analytical ultracentrifugation. The parallel-stranded hairpin structure was found to be formed by psC4 only under conditions of low DNA concentration and low salt concentration. Increase of the NaCl concentration beyond the physiological level or high DNA concentration supports the formation of intermolecular multi-stranded structures. The experimental data are in agreement with a four-stranded complex formed by two molecules of psC4. The base pairing model of this asymmetric four-stranded complex is based on the pyrimidine motif of a triple helix with two bifurcated hydrogen bonds at the O4 of the thymine each directed towards one of the amino protons of both adenines. In contrast, the reference oligonucleotide apsC4 forms only an antiparallel-stranded hairpin under all experimental conditions. PMID:9016633

  12. Hairpin-dimer equilibrium of a parallel-stranded DNA hairpin: formation of a four-stranded complex.

    PubMed

    Dornberger, U; Behlke, J; Birch-Hirschfeld, E; Fritzsche, H

    1997-02-15

    The 24mer deoxyoligonucleotide 3'-d(T)10-5'-5'-d(C)4- d(A)10-3'(psC4) with an uncommon 5'-p-5'phosphodiester linkage was designed to enable the formation of a hairpin structure with unusual parallel-stranded stem. As reference hairpin structure with an antiparallel-stranded stem, the 24mer 5'-d(T)10-d(C)4-d(A)10-3'(apsC4) was chosen. The behaviour of these oligonucleotides at different temperatures, DNA and salt concentrations was characterised by a combination of UV melting, CD, CD melting, infrared and Raman spectroscopy, infrared melting and analytical ultracentrifugation. The parallel-stranded hairpin structure was found to be formed by psC4 only under conditions of low DNA concentration and low salt concentration. Increase of the NaCl concentration beyond the physiological level or high DNA concentration supports the formation of intermolecular multi-stranded structures. The experimental data are in agreement with a four-stranded complex formed by two molecules of psC4. The base pairing model of this asymmetric four-stranded complex is based on the pyrimidine motif of a triple helix with two bifurcated hydrogen bonds at the O4 of the thymine each directed towards one of the amino protons of both adenines. In contrast, the reference oligonucleotide apsC4 forms only an antiparallel-stranded hairpin under all experimental conditions.

  13. 1H NMR global metabolic phenotyping of acute pancreatitis in the emergency unit.

    PubMed

    Villaseñor, Alma; Kinross, James M; Li, Jia V; Penney, Nicholas; Barton, Richard H; Nicholson, Jeremy K; Darzi, Ara; Barbas, Coral; Holmes, Elaine

    2014-12-01

    We have investigated the urinary and plasma metabolic phenotype of acute pancreatitis (AP) patients presenting to the emergency room at a single center London teaching hospital with acute abdominal pain using (1)H NMR spectroscopy and multivariate modeling. Patients were allocated to either the AP (n = 15) or non-AP patients group (all other causes of abdominal pain, n = 21) on the basis of the national guidelines. Patients were assessed for three clinical outcomes: (1) diagnosis of AP, (2) etiology of AP caused by alcohol consumption and cholelithiasis, and (3) AP severity based on the Glasgow score. Samples from AP patients were characterized by high levels of urinary ketone bodies, glucose, plasma choline and lipid, and relatively low levels of urinary hippurate, creatine and plasma-branched chain amino acids. AP could be reliably identified with a high degree of sensitivity and specificity (OPLS-DA model R(2) = 0.76 and Q(2)Y = 0.59) using panel of discriminatory biomarkers consisting of guanine, hippurate and creatine (urine), and valine, alanine and lipoproteins (plasma). Metabolic phenotyping was also able to distinguish between cholelithiasis and colonic inflammation among the heterogeneous non-AP group. This work has demonstrated that combinatorial biomarkers have a strong diagnostic and prognostic potential in AP with relevance to clinical decision making in the emergency unit. PMID:25160714

  14. Ectopic Expression of a WRKY Homolog from Glycine soja Alters Flowering Time in Arabidopsis

    PubMed Central

    Liu, Baohui; Zhu, Dan; Bai, Xi; Cai, Hua; Ji, Wei; Cao, Lei; Wu, Jing; Wang, Mingchao; Ding, Xiaodong; Zhu, Yanming

    2013-01-01

    Flowering is a critical event in the life cycle of plants; the WRKY-type transcription factors are reported to be involved in many developmental processes sunch as trichome development and epicuticular wax loading, but whether they are involved in flowering time regulation is still unknown. Within this study, we provide clear evidence that GsWRKY20, a member of WRKY gene family from wild soybean, is involved in controlling plant flowering time. Expression of GsWRKY20 was abundant in the shoot tips and inflorescence meristems of wild soybean. Phenotypic analysis showed that GsWRKY20 over-expression lines flowered earlier than the wild-type plants under all conditions: long-day and short-day photoperiods, vernalization, or exogenous GA3 application, indicating that GsWRKY20 may mainly be involved in an autonomous flowering pathway. Further analyses by qRT-PCR and microarray suggests that GsWRKY20 accelerating plant flowering might primarily be through the regulation of flowering-related genes (i.e., FLC, FT, SOC1 and CO) and floral meristem identity genes (i.e., AP1, SEP3, AP3, PI and AG). Our results provide the evidence demonstrating the effectiveness of manipulating GsWRKY20 for altering plant flowering time. PMID:23991184

  15. Comparison of gas-phase free-radical populations in tobacco smoke and model systems by HPLC.

    PubMed Central

    Flicker, T M; Green, S A

    2001-01-01

    We used an improved method for trapping carbon-centered radicals (.R) from the gas-phase to compare radical suites trapped from various tobacco smoke and model smoke systems. Using a nitroxide trap, 3-amino-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3AP), on solid support, we trapped radicals directly from the gas phase, washed them off the support, and analyzed them with HPLC. Separation of the trapped radicals showed that each tobacco type produced a unique radical suite of 4-10 distinct peaks. Gas mixtures used to model tobacco smoke consisted of nitric oxide, air, isoprene, and methanol. The model systems produced radical suites of four major and several minor peaks, two of which matched peaks in tobacco smoke chromatograms. Quantities of radicals trapped from tobacco smoke were: 54 +/- 2 nmol .R per Marlboro cigarette, 66 +/- 9 nmol .R per Djarum clove cigarette, and 185 +/- 9 nmol .R per Swisher Sweet cigar. In these experiments oxygen competes with the nitroxide trap for gas-phase radicals. A kinetic analysis of the O2 competition shows that actual radical concentrations in the smoke were approximately 100-fold higher than measured. PMID:11564610

  16. Multiresidue analysis of environmental pollutants in edible vegetable oils by gas chromatography-tandem mass spectrometry.

    PubMed

    Zhou, Rui-Ze; Jiang, Jie; Mao, Ting; Zhao, Ya-Song; Lu, Yong

    2016-09-15

    A novel multiresidue determination of polycyclic aromatic hydrocarbons (PAHs), phthalate esters (PAEs) and alkylphenols (APs) in edible vegetable oils was developed. The samples were extracted with hexane-saturated acetonitrile, and after concentration, the extract was directly qualitatively and quantitatively analyzed by gas chromatography-tandem mass spectrometry (GC-MS/MS) with multiple reaction monitoring (MRM) in positive ion mode. The calibration curve displayed good linearity in the range of 2-100 μg/L, with correlation coefficients greater than 0.99. The mean recoveries were 70.0-110.8% by analysis of spiked oil, and the relative standard deviations (RSDs) were 2.1-10.2% (n=6), respectively. The limits of detection (LODs) for the 23 PAHs, 17 PAEs and 3 APs were 0.1-1.0 μg/kg, 0.1-4.0 μg/kg and 1.2-3.0 μg/kg, respectively. The established method effectively avoided interference from large amounts of lipids and pigments. It was applied to real sample and shown to be a rapid and reliable alternative for determination and confirmation in routine analysis. PMID:27080878

  17. Effects of modulation of pentose-phosphate pathway on biosynthesis of ansamitocins in Actinosynnema pretiosum.

    PubMed

    Fan, Yuxiang; Hu, Fengxian; Wei, Liujing; Bai, Linquan; Hua, Qiang

    2016-07-20

    Ansamitocins, produced by Actinosynnema pretiosum, are a group of maytansinoid antibiotics that block the assembly of tubulin into functional microtubules. The precursors of ansamitocin biosynthesis are generally derived from the Embden-Meyerhof-Parnas (EMP) pathway and the tricarboxylic acid cycle. In this study, central carbon flux distributions were analyzed by (13)C-based flux analysis to reveal the contribution of individual central carbon metabolism pathways. To direct more carbon flux into ansamitocin biosynthesis, pentose phosphate (PP) pathway only and the combination of PP pathway and Entner-Doudoroff (ED) pathway were weakened, respectively. Ansamitocin P-3 (AP-3) productions by both kinds of pathways weakened mutant strains were significantly enhanced in chemically defined medium. In order to draw metabolic flux to the biosynthesis of ansamitocins more efficiently, heterologous phosphoglucomutase was subsequently overexpressed based on a mutant strain with combinational regulation of PP pathway and ED pathway. More fluxes were successfully directed into the UDP-glucose synthetic pathway and the AP-3 production was further improved in this case, reaching approximately 185mg/L in fermentation medium. It was demonstrated that eliminating the bypass pathways and favoring the precursor synthetic pathway could effectively improve ansamitocin production by A. pretiosum, suggesting a promising role of metabolic strategy in improving secondary metabolite production. PMID:27173582

  18. Endosome-mediated endocytic mechanism replenishes the majority of synaptic vesicles at mature CNS synapses in an activity-dependent manner

    PubMed Central

    Park, Joohyun; Cho, Oh Yeon; Kim, Jung Ah; Chang, Sunghoe

    2016-01-01

    Whether synaptic vesicles (SVs) are recovered via endosome-mediated pathways is a matter of debate; however, recent evidence suggests that clathrin-independent bulk endocytosis (CIE) via endosomes is functional and preferentially replenishes SV pools during strong stimulation. Here, using brefeldin-A (BFA) to block CIE, we found that CIE retrieved a minority of SVs at developing CNS synapses during strong stimulation, but its contribution increased up to 61% at mature CNS synapses. Contrary to previous views, BFA not only blocked SV formation from the endosome but also blocked the endosome formation at the plasma membrane. Adaptor protein 1 and 3 (AP-1/3) have key roles in SV reformation from endosomes during CIE, and AP-1 also affects bulk endosome formation from the plasma membrane. Finally, temporary blocking of chronic or acute neuronal activity with tetrodotoxin in mature neurons redirected most SV retrieval to endosome-independent pathways. These results show that during high neuronal activity, CIE becomes the major endocytic pathway at mature CNS synapses. Moreover, mature neurons use clathrin-mediated endocytosis and the CIE pathway to different extents depending on their previous activity; this may result in activity-dependent alterations of the SV composition which ultimately influence transmitter release and contribute to synaptic plasticity. PMID:27534442

  19. Celery oil modulates DEHP-induced reproductive toxicity in male rats.

    PubMed

    Helal, Mona A M

    2014-09-01

    The objective of the study was to investigate the protective effect of Apium graveolens (AP) against di-(2-ethylhexyl) phthalate (DEHP)-induced testes injury in rats. Adult rats were divided into nine groups: (1) control group (no treatment); (2) corn oil (60 μg/kg body weight - bwt); (3) AP (50 μg/kg bwt); (4) 300 mg DEHP/kg bwt; (5) 500 mg DEHP/kg bwt; (6) 1000 mg DEHP/kg bwt; (7) 300 mg DEHP/kg bwt+AP; (8) 500 mg DEHP/kg bwt+AP; and (9) 1000 mg DEHP/kg bwt+AP. Oral administration of treatments was performed daily for 6 weeks. DEHP decreased (p<0.01) body weight, testis weight and serum concentrations of testosterone, cholesterol and total proteins. Moreover, DEHP increased (p<0.001) total antioxidant capacity in the testis and plasma DEHP level. In addition, DEHP decreased mRNA expression of two testicular steroidogenic enzymes: 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. DEHP also caused atrophy, vacuolar degeneration and aspermia of the seminiferous tubules. AP administered concurrently with DEHP effectively alleviated most of the DEHP-induced effects. In conclusion, in male rats, DEHP had adverse effects on the testis including inhibition of androgen production. A concurrent administration of A. graveolens (celery oil) protected the testis against DEHP-induced toxicity.

  20. DISSECTING THE ROLE OF THE FOXP3 GENE IN THE JOINT GENETIC SUSCEPTIBILITY TO AUTOIMMUNE THYROIDITIS AND DIABETES:A GENETIC AND FUNCTIONAL ANALYSIS

    PubMed Central

    Li, Cheuk Wun; Concepcion, Erlinda; Tomer, Yaron

    2014-01-01

    We have previously shown that a (TC)n microsatellite in intron 5 of the Forkhead Box Protein 3 (FOXP3) gene was associated with a variant of the autoimmune polyglandular syndrome type 3 (APS3v), that is defined as the co-occurrence of type 1 diabetes (T1D) and autoimmune thyroiditis (AITD). Allele 10, containing 25 repeats of the microsatellite (long repeats), is preferentially transmitted to offspring with APS3v, while allele 2, containing 14 repeats of the microsatellite (short repeats), is protective. We hypothesized that the long repeats of the intron 5 microsatellite decrease FOXP3 splicing and function, thereby reducing regulatory T cell activity and promoting the development of APS3v. We cloned genomic DNA from two males hemizygous for the long and short repeats of the microsatellite on their X-chromosomes and transfected them into human embryonic kidney 293 (HEK 293) cells to perform direct splicing analysis. We identified a novel splice variant of FOXP3 lacking exon 6, and showed that it is expressed in human thymus and lymph node. However, the length of the repeats in the microsatellite did not significantly influence the expression of this FOXP3 splice variant in vitro. Interestingly, this splice variant was expressed in human regulatory T cells, suggesting it may play a role in their function. In conclusion, we identified a novel splice variant FOXP3Δ6. The role of its expression in regulatory T cells in the development of autoimmunity remains to be determined. PMID:25481456

  1. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions.

    PubMed

    Wu, Shaowei; Fu, Xiong; Brennan, Margaret A; Brennan, Charles S; Chun, Chen

    2016-01-01

    Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 10⁴ Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

  2. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.

    PubMed

    Ammann, Sandra; Schulz, Ansgar; Krägeloh-Mann, Ingeborg; Dieckmann, Nele M G; Niethammer, Klaus; Fuchs, Sebastian; Eckl, Katja Martina; Plank, Roswitha; Werner, Roland; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Bank, Julia; Strauss, Anne; von Bernuth, Horst; Zur Stadt, Udo; Grieve, Samantha; Griffiths, Gillian M; Lehmberg, Kai; Hennies, Hans Christian; Ehl, Stephan

    2016-02-25

    Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3δ subunit of the complex, which is essential for both forms. In contrast, the AP3β3A subunit, affected in HPS2 patients, is substituted by AP3β3B in the neuron-specific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10. PMID:26744459

  3. Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency.

    PubMed

    Prandini, Alberto; Salvi, Valentina; Colombo, Francesca; Moratto, Daniele; Lorenzi, Luisa; Vermi, William; De Francesco, Maria Antonia; Notarangelo, Lucia Dora; Porta, Fulvio; Plebani, Alessandro; Facchetti, Fabio; Sozzani, Silvano; Badolato, Raffaele

    2016-06-30

    Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-β/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2. PMID:27207797

  4. An Arabidopsis F-box protein acts as a transcriptional co-factor to regulate floral development.

    PubMed

    Chae, Eunyoung; Tan, Queenie K-G; Hill, Theresa A; Irish, Vivian F

    2008-04-01

    Plants flower in response to both environmental and endogenous signals. The Arabidopsis LEAFY (LFY) transcription factor is crucial in integrating these signals, and acts in part by activating the expression of multiple floral homeotic genes. LFY-dependent activation of the homeotic APETALA3 (AP3) gene requires the activity of UNUSUAL FLORAL ORGANS (UFO), an F-box component of an SCF ubiquitin ligase, yet how this regulation is effected has remained unclear. Here, we show that UFO physically interacts with LFY both in vitro and in vivo, and this interaction is necessary to recruit UFO to the AP3 promoter. Furthermore, a transcriptional repressor domain fused to UFO reduces endogenous LFY activity in plants, supporting the idea that UFO acts as part of a transcriptional complex at the AP3 promoter. Moreover, chemical or genetic disruption of proteasome activity compromises LFY-dependent AP3 activation, indicating that protein degradation is required to promote LFY activity. These results define an unexpected role for an F-box protein in functioning as a DNA-associated transcriptional co-factor in regulating floral homeotic gene expression. These results suggest a novel mechanism for promoting flower development via protein degradation and concomitant activation of the LFY transcription factor. This mechanism may be widely conserved, as homologs of UFO and LFY have been identified in a wide array of plant species.

  5. The ASK1 gene regulates B function gene expression in cooperation with UFO and LEAFY in Arabidopsis.

    PubMed

    Zhao, D; Yu, Q; Chen, M; Ma, H

    2001-07-01

    The Arabidopsis floral regulatory genes APETALA3 (AP3) and PISTILLATA (PI) are required for the B function according to the ABC model for floral organ identity. AP3 and PI expression are positively regulated by the LEAFY (LFY) and UNUSUAL FLORAL ORGANS (UFO) genes. UFO encodes an F-box protein, and we have shown previously that UFO genetically interacts with the ASK1 gene encoding a SKP1 homologue; both the F-box containing protein and SKP1 are subunits of ubiquitin ligases. We show here that the ask1-1 mutation can enhance the floral phenotypes of weak lfy and ap3 mutants; therefore, like UFO, ASK1 also interacts with LFY and AP3 genetically. Furthermore, our results from RNA in situ hybridizations indicate that ASK1 regulates early AP3 and PI expression. These results support the idea that UFO and ASK1 together positively regulate AP3 and PI expression. We propose that the UFO and ASK1 proteins are components of a ubiquitin ligase that mediates the proteolysis of a repressor of AP3 and PI expression. Our genetic studies also indicate that ASK1 and UFO play a role in regulating the number of floral organ primordia, and we discuss possible mechanisms for such a regulation.

  6. The COP9 signalosome interacts with SCF UFO and participates in Arabidopsis flower development.

    PubMed

    Wang, Xiping; Feng, Suhua; Nakayama, Naomi; Crosby, W L; Irish, Vivian; Deng, Xing Wang; Wei, Ning

    2003-05-01

    The COP9 signalosome (CSN) is involved in multiple developmental processes. It interacts with SCF ubiquitin ligases and deconjugates Nedd8/Rub1 from cullins (deneddylation). CSN is highly expressed in Arabidopsis floral tissues. To investigate the role of CSN in flower development, we examined the expression pattern of CSN in developing flowers. We report here that two csn1 partially deficient Arabidopsis strains exhibit aberrant development of floral organs, decline of APETALA3 (AP3) expression, and low fertility in addition to defects in shoot and inflorescence meristems. We show that UNUSUAL FLORAL ORGANS (UFO) forms a SCF(UFO) complex, which is associated with CSN in vivo. Genetic interaction analysis indicates that CSN is necessary for the gain-of-function activity of the F-box protein UFO in AP3 activation and in floral organ transformation. Compared with the previously reported csn5 antisense and csn1 null mutants, partial deficiency of CSN1 causes a reduction in the level of CUL1 in the mutant flowers without an obvious defect in CUL1 deneddylation. We conclude that CSN is an essential regulator of Arabidopsis flower development and suggest that CSN regulates Arabidopsis flower development in part by modulating SCF(UFO)-mediated AP3 activation.

  7. Ectopic expression of SUPERMAN suppresses development of petals and stamens.

    PubMed

    Yun, Jae-Young; Weigel, Detlef; Lee, Ilha

    2002-01-01

    The floral regulatory gene SUPERMAN (SUP) encodes a C2H2 type zinc finger protein that is required for maintaining boundaries between floral organs in Arabidopsis. It has been proposed that the main function of SUP is to balance cell proliferation in the third and fourth whorl of developing flowers, thereby maintaining the boundaries between the two whorls. To gain further insight into the function of SUP, we have ectopically expressed SUP using the promoter of APETALA1 (AP1), a gene that is initially expressed throughout floral meristems and later becomes restricted to the first and second whorls. Flowers of AP1::SUP plants have fewer floral organs, consistent with an effect of SUP on cell proliferation. In addition, the AP1::SUP transgene caused the conversion of petals to sepals and suppressed the development of stamens. The expression of the B function homeotic gene APETALA3 (AP3) and its regulator UNUSUAL FLORAL ORGANS (UFO) were delayed and reduced in AP1::SUP flowers. However, SUP does not act merely through UFO, as constitutive expression of UFO did not rescue the defects in petal and stamen development in AP1::SUP flowers. Together, these results suggest that SUP has both indirect and direct effects on the expression of B function homeotic genes.

  8. Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency.

    PubMed

    Prandini, Alberto; Salvi, Valentina; Colombo, Francesca; Moratto, Daniele; Lorenzi, Luisa; Vermi, William; De Francesco, Maria Antonia; Notarangelo, Lucia Dora; Porta, Fulvio; Plebani, Alessandro; Facchetti, Fabio; Sozzani, Silvano; Badolato, Raffaele

    2016-06-30

    Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-β/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2.

  9. Molecular phenotypes associated with anomalous stamen development in Alternanthera philoxeroides

    PubMed Central

    Zhu, Zhu; Zhou, Chengchuan; Yang, Ji

    2015-01-01

    Alternanthera philoxeroides is a perennial amphibious weed native to South America but has now spread to diverse parts of the world. A. philoxeroides reproduces both sexually and asexually in its native range, but propagates solely through vegetative means in its introduced range. Traits associated with sexual reproduction become degraded for sexual dysfunction, with flowers possessing either pistillate stamens or male-sterile anthers. Degradations of sexual characters for loss of sexuality commonly take place in clonal plants. The underlying molecular-genetic processes remain largely unknown. We compared the gene expression profiles of abnormal stamens with that of normal stamens by RNA-Seq analysis, and identified a large number of differentially expressed genes between abnormal and normal stamens. In accordance with flower morphology, the expression of B-class MADS-box genes (ApAP3, ApTM6, and ApPI) was markedly reduced in pistillate stamens. However, most of the genes involved in meiosis were expressed normally in stamens with male-sterile anthers. In addition to verifying the expression patterns of genes previously known to be related to stamen and pollen grain development, we also identified previously unknown molecular phenotypes associated with sexual dysfunction in A. philoxeroides, that is helpful for dissecting the molecular mechanisms underpinning various male-sterile phenotypes and the molecular processes underlying the transition from sexuality to asexuality in clonal plants. PMID:25926842

  10. Ectopic expression of a WRKY homolog from Glycine soja alters flowering time in Arabidopsis.

    PubMed

    Luo, Xiao; Sun, Xiaoli; Liu, Baohui; Zhu, Dan; Bai, Xi; Cai, Hua; Ji, Wei; Cao, Lei; Wu, Jing; Wang, Mingchao; Ding, Xiaodong; Zhu, Yanming

    2013-01-01

    Flowering is a critical event in the life cycle of plants; the WRKY-type transcription factors are reported to be involved in many developmental processes sunch as trichome development and epicuticular wax loading, but whether they are involved in flowering time regulation is still unknown. Within this study, we provide clear evidence that GsWRKY20, a member of WRKY gene family from wild soybean, is involved in controlling plant flowering time. Expression of GsWRKY20 was abundant in the shoot tips and inflorescence meristems of wild soybean. Phenotypic analysis showed that GsWRKY20 over-expression lines flowered earlier than the wild-type plants under all conditions: long-day and short-day photoperiods, vernalization, or exogenous GA3 application, indicating that GsWRKY20 may mainly be involved in an autonomous flowering pathway. Further analyses by qRT-PCR and microarray suggests that GsWRKY20 accelerating plant flowering might primarily be through the regulation of flowering-related genes (i.e., FLC, FT, SOC1 and CO) and floral meristem identity genes (i.e., AP1, SEP3, AP3, PI and AG). Our results provide the evidence demonstrating the effectiveness of manipulating GsWRKY20 for altering plant flowering time.

  11. Ectopic expression of FaesAP3, a Fagopyrum esculentum (Polygonaceae) AP3 orthologous gene rescues stamen development in an Arabidopsis ap3 mutant.

    PubMed

    Fang, Zheng-wu; Qi, Rui; Li, Xiao-fang; Liu, Zhi-xiong

    2014-10-25

    Arabidopsis thaliana APETALA3 (AP3) and Antirrhinum majus DEFICIENS (DEF) MADS box genes are required to specify petal and stamen identity. AP3 and DEF are members of the euAP3 lineage, which arose by gene duplication coincident with radiation of the core eudicots. In order to investigate the molecular mechanisms underlying organ development in early diverging clades of core eudicots, we isolated and identified an AP3 homolog, FaesAP3, from Fagopyrum esculentum (buckwheat, Polygonaceae), a multi-food-use pseudocereal with healing benefits. Protein sequence alignment and phylogenetic analyses revealed that FaesAP3 grouped into the euAP3 lineage. Expression analysis showed that FaesAP3 was transcribed only in developing stamens, and differed from AP3 and DEF, which expressed in developing petals and stamens. Moreover, ectopic expression of FaesAP3 rescued stamen development without complementation of petal development in an Arabidopsis ap3 mutant. Our results suggest that FaesAP3 is involved in the development of stamens in buckwheat. These results also suggest that FaesAP3 holds some potential for biotechnical engineering to create a male sterile line of F. esculentum. PMID:25149019

  12. The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin

    PubMed Central

    Arnold, Miranda; Cross, Rebecca; Singleton, Kaela S.; Zlatic, Stephanie; Chapleau, Christopher; Mullin, Ariana P.; Rolle, Isaiah; Moore, Carlene C.; Theibert, Anne; Pozzo-Miller, Lucas; Faundez, Victor; Larimore, Jennifer

    2016-01-01

    AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse ortholog of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function. PMID:27713690

  13. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2005-03-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3-AP, 667-coumate, 9-aminocamptothecin; Ad5CMV-p53, AES-14, alefacept, anecortave acetate, APC-8024, APD-356, asoprisnil; Bevacizumab, bimakalim, bimatoprost, BLP-25, BR-1; Caspofungin acetate, cetuximab, cypher; Darbepoetin alfa, dexanabinol, dextromethorphan/quinidine sulfate, DNA.HIVA; Efaproxiral sodium, ertapenem sodium; Frovatriptan; HuMax-EGFr, HYB-2055, gamma-hydroxybutyrate sodium, Id-KLH vaccine, imatinib mesylate; Lapatinib, lonafarnib, Motexafin lutetium, MVA.HIVA, mycophenolic acid sodium salt; Nesiritide, NS-2330; Olmesartan medoxomil; Peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, perifosine, pimecrolimus, pregabalin; QbG-10; Ralfinamide, rasburicase, rFGF-2, Ro-31-7453; Sitaxsentan sodium, sorafenib; Tadalafil, TC-1734, telmisartan/hydrochlorothiazide, tenofovir disoproxil fumarate, thymus nuclear protein, tipifarnib; Vandetanib, vibriolysin, vildagliptin, voriconazole. PMID:15834466

  14. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-05-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3-AP, Adalimumab, adefovir dipivoxil, AeroDose albuterol inhaler, agalsidase alfa, alemtuzumab, aminolevulinic acid methyl ester, anidulafungin, anthrax vaccine, anti-CTLA-4 MAb, azimilide hydrochloride; Bevacizumab, BG-12, bimatoprost, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, ceftobiprole, certolizumab pegol, CG-53135, cilansetron; Darbepoetin alfa, degarelix acetate, dimethylfumarate, duloxetine hydrochloride, dutasteride; Eicosapentaenoic acid/docosahexaenoic acid, eletriptan, entecavir, esomeprazole magnesium, exatecan mesilate, exenatide, ezetimibe; Falecalcitriol, fampridine, fondaparinux sodium, fontolizumab; Gefitinib, gepirone hydrochloride; Human insulin; IDEA-070, imatinib mesylate, iodine (I131) tositumomab; Lanthanum carbonate, lubiprostone; Mafosfamide cyclohexylamine salt, melatonin; NC-531, nemifitide ditriflutate, neridronic acid, nolatrexed dihydrochloride; Oral insulin; Palifermin, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, plerixafor hydrochloride, posaconazole, pramlintide acetate, pregabalin, PT-141; Quercetin; Ranibizumab, renzapride hydrochloride, RSD-1235; Sabarubicin hydrochloride, semapimod hydrochloride, Semax, SHL-749; Tegaserod maleate, tenatoprazole, tetrodotoxin, tolevamer sodium, trabectedin, travoprost, travoprost/timolol; Valdecoxib, visilizumab, Xcellerated T cells, XP-828L; Zoledronic acid monohydrate. PMID:16082427

  15. Degradation of octylphenol and nonylphenol by ozone - part I: direct reaction.

    PubMed

    Ning, Bo; Graham, Nigel J D; Zhang, Yanping

    2007-06-01

    This aqueous reaction between ozone and two alkylphenols (APs), namely octylphenol (OP) and nonylphenol (NP), has been investigated. Both compounds are important endocrine disrupting chemicals, which arise from the biodegradation of alkylphenol ethoxylates and are often found at relatively high concentrations in wastewater effluents. In this paper the results of an experimental study are presented which provide values for the reaction rate constants between molecular ozone and undissociated OP and NP, and overall reaction rate constants for the degradation of the two APs at pH values in the range of 7-9. The kinetic rate constants for OP and NP degradation by molecular ozone were 4.33(+/-0.18) x 10(4) and 3.90(+/-0.10) x 10(4) M(-1) s(-1), and the reaction stoichiometry was similar in both cases and equal to approximately 1.3:1 ([O3]:[AP]). The overall second order reaction rate constants for the two APs increased significantly with increasing pH, which is believed to be mainly due to the increasing influence of indirect radical reaction with increasing pH; this aspect is considered in more detail in a companion paper. A preliminary investigation of the reaction mechanism suggests that an initial product of ozonation is hydroxyl-alkyl phenol. PMID:17349676

  16. Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

    PubMed Central

    Jandial, Danielle D.; Blair, Christopher A.; Zhang, Saiyang; Krill, Lauren S.; Zhang, Yan-Bing; Zi, Xiaolin

    2014-01-01

    There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID:24467530

  17. Prokineticin Receptor 1 Antagonist PC-10 as a Biomarker for Imaging Inflammatory Pain

    PubMed Central

    Jacobson, Orit; Weiss, Ido D.; Niu, Gang; Balboni, Gianfranco; Congiu, Cenzo; Onnis, Valentina; Kiesewetter, Dale O.; Lattanzi, Roberta; Salvadori, Severo; Chen, Xiaoyuan

    2013-01-01

    Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumor-supporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo. Methods A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine, which contains a free guanidine group, was labeled with 18F by reacting the guanidine function with N-succinimidyl-4-18F-fluorobenzoate to give the guanidinyl amide N-(4-18F-fluoro-benzoyl)-N′-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine (18F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with 18F-PC-10, 18F-FDG, and 64Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) (64Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device. Results 18F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). 18F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with 18F-PC-10, 18F-FDG and 64Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. 18F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract. Conclusion 18F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of 18F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility. PMID:21421710

  18. Evolutionary Dynamics of Floral Homeotic Transcription Factor Protein-Protein Interactions.

    PubMed

    Bartlett, Madelaine; Thompson, Beth; Brabazon, Holly; Del Gizzi, Robert; Zhang, Thompson; Whipple, Clinton

    2016-06-01

    Protein-protein interactions (PPIs) have widely acknowledged roles in the regulation of development, but few studies have addressed the timing and mechanism of shifting PPIs over evolutionary history. The B-class MADS-box transcription factors, PISTILLATA (PI) and APETALA3 (AP3) are key regulators of floral development. PI-like (PI(L)) and AP3-like (AP3(L)) proteins from a number of plants, including Arabidopsis thaliana (Arabidopsis) and the grass Zea mays (maize), bind DNA as obligate heterodimers. However, a PI(L) protein from the grass relative Joinvillea can bind DNA as a homodimer. To ascertain whether Joinvillea PI(L) homodimerization is an anomaly or indicative of broader trends, we characterized PI(L) dimerization across the Poales and uncovered unexpected evolutionary lability. Both obligate B-class heterodimerization and PI(L) homodimerization have evolved multiple times in the order, by distinct molecular mechanisms. For example, obligate B-class heterodimerization in maize evolved very recently from PI(L) homodimerization. A single amino acid change, fixed during domestication, is sufficient to toggle one maize PI(L) protein between homodimerization and obligate heterodimerization. We detected a signature of positive selection acting on residues preferentially clustered in predicted sites of contact between MADS-box monomers and dimers, and in motifs that mediate MADS PPI specificity in Arabidopsis. Changing one positively selected residue can alter PI(L) dimerization activity. Furthermore, ectopic expression of a Joinvillea PI(L) homodimer in Arabidopsis can homeotically transform sepals into petals. Our results provide a window into the evolutionary remodeling of PPIs, and show that novel interactions have the potential to alter plant form in a context-dependent manner. PMID:26908583

  19. Mycobacterium avium MAV_2941 mimics Phosphoinositol-3-Kinase to interfere with macrophage phagosome maturation

    PubMed Central

    Danelishvili, Lia; Bermudez, Luiz E.

    2015-01-01

    Mycobacterium avium subsp hominissuis (M. avium) is a pathogen that infects and survives in macrophages. Previously, we have identified the M. avium MAV_2941 gene encoding a 73 amino acid protein exported by the oligopeptide transporter OppA to the macrophage cytoplasm. Mutations in MAV_2941 were associated with significant impairment of M. avium growth in THP-1 macrophages. In this study, we investigated the molecular mechanism of MAV_2941 action and demonstrated that MAV_2941 interacts with the vesicle trafficking proteins syntaxin-8 (STX8), adaptor-related protein complex 3 (AP-3) complex subunit beta-1 (AP3B1) and Archain 1 (ARCN1) in mononuclear phagocytic cells. Sequencing analysis revealed that the binding site of MAV_2941 is structurally homologous to the human phosphatidylinositol 3-kinase (PI3K) chiefly in the region recognized by vesicle trafficking proteins. The β3A subunit of AP-3, encoded by AP3B1, is essential for trafficking cargo proteins, including lysosomal-associated membrane protein 1 (LAMP-1), to the phagosome and lysosome-related organelles. Here, we show that while the heat-killed M. avium when ingested by macrophages co-localizes with LAMP-1 protein, transfection of MAV_2941 in macrophages results in significant decrease of LAMP-1 co-localization with the heat-killed M. avium phagosomes. Mutated MAV_2941, where the amino acids homologous to the binding region of PI3K were changed, failed to interact with trafficking proteins. Inactivation of the AP3B1 gene led to alteration in the trafficking of LAMP-1. These results suggest that M. avium MAV_2941 interferes with the protein trafficking within macrophages altering the maturation of phagosome. PMID:26043821

  20. Glutathione-S-transferase profiles in the emerald ash borer, Agrilus planipennis.

    PubMed

    Rajarapu, Swapna Priya; Mittapalli, Omprakash

    2013-05-01

    The emerald ash borer, Agrilus planipennis Fairmaire is a recently discovered invasive insect pest of ash, Fraxinus spp. in North America. Glutathione-S-transferases (GST) are a multifunctional superfamily of enzymes which function in conjugating toxic compounds to less toxic and excretable forms. In this study, we report the molecular characterization and expression patterns of different classes of GST genes in different tissues and developmental stages plus their specific activity. Multiple sequence alignment of all six A. planipennis GSTs (ApGST-E1, ApGST-E2, ApGST-E3, ApGST-O1, ApGST-S1 and ApGST-μ1) revealed conserved features of insect GSTs and a phylogenetic analysis grouped the GSTs within the epsilon, sigma, omega and microsomal classes of GSTs. Real time quantitative PCR was used to study field collected samples. In larval tissues high mRNA levels for ApGST-E1, ApGST-E3 and ApGST-O1 were obtained in the midgut and Malpighian tubules. On the other hand, ApGST-E2 and ApGST-S1 showed high mRNA levels in fat body and ApGST-μ1 showed constitutive levels in all the tissues assayed. During development, mRNA levels for ApGST-E2 were observed to be the highest in feeding instars, ApGST-S1 in prepupal instars; while the others showed constitutive patterns in all the developmental stages examined. At the enzyme level, total GST activity was similar in all the tissues and developmental stages assayed. Results obtained suggest that A. planipennis is potentially primed with GST-driven detoxification to metabolize ash allelochemicals. To our knowledge this study represents the first report of GSTs in A. planipennis and also in the family of wood boring beetles. PMID:23499941

  1. Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities.

    PubMed

    Gómez-Martín, Antonio; Hernández, Antonio F; Martínez-González, Luis Javier; González-Alzaga, Beatriz; Rodríguez-Barranco, Miguel; López-Flores, Inmaculada; Aguilar-Garduno, Clemente; Lacasana, Marina

    2015-11-01

    Polymorphisms in genes encoding xenobiotic-metabolizing enzymes (XME) are important parameters accounting for the wide inter-individual variability to environmental exposures. Paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and Cytochrome-P450 constitute major classes of XME involved in the detoxification of pesticide chemicals, in particular organophosphates. This study explored the allelic frequency, linkage disequilibrium and haplotype analysis of ten common polymorphic variants of seven key genes involved in organophosphate metabolism (BCHE-K, BCHE-A, PON1 Q192R, PON1 L55M, PON1 -108C/T, CYP2C19 G681A, CYP2D6 G1846A, CYP3AP1 -44G/A, GSTM1∗0 and GSTT1∗0) in a children population living near an intensive agriculture area in Spain. It was hypothesized that individuals with unfavorable combinations of gene variants will be more susceptible to adverse effects from organophosphate exposure. Genomic DNA from 496 healthy children was isolated and amplified by PCR. Hydrolysis probes were used for the detection of eight specific SNPs and two copy number variants (CNVs) by using TaqMan® Assay-based real-time PCR. Frequencies of SNPs and CNVs in the target genes were in Hardy-Weinberg equilibrium and broadly consistent with European populations. Linkage disequilibrium was found between the three PON1 genetic polymorphisms studied and between BCHE-K and BCHE-A. The adverse genotype combination (unusual BCHE variants, PON1 55MM/-108TT and null genotype for both GSTM1 and GSTT1) potentially conferring a greater genetic risk from exposure to organophosphates was observed in 0.2% of our study population. This information allows broadening our knowledge about differential susceptibility toward environmental toxicants and may be helpful for further research to understand the inter-individual toxicokinetic variability in response to organophosphate pesticides exposure.

  2. Localization of candidate regions for a novel gene for Kartagener syndrome.

    PubMed

    Gutierrez-Roelens, Ilse; Sluysmans, Thierry; Jorissen, Mark; Amyere, Mustapha; Vikkula, Miikka

    2006-07-01

    Asymmetric positioning of internal organs is a characteristics of vertebrates. The normal left-right anatomic positioning, situs solitus, sometimes does not occur normaly, leading to laterality defects. Studies in animal models have shown that laterality decisions are mediated by a cascade of genes that lead to the asymmetric expression of Nodal, LEFTA, LEFTB and PITX2 in the lateral plate mesoderm. A search for mutations in genes implicated in left-right patterning in animal models allowed genes associated with heterotaxia defects in humans to be identified. However, these genes explain only a small percentage of human situs defects, suggesting that other genes must play a role. In this study, we report a consanguineous family of Turkish origin, composed of two unaffected parents and three children, two of whom presented Kartagener syndrome. On the basis of their family history, we hypothesize autosomal recessive mode of inheritance. A genotype analysis with polymorphic markers did not show linkage with any known genes or loci causing laterality disorders. Array CGH did not detect a duplication or microdeletion greater than 1 Mb as a possible cause. Genome wide screening using 10 K Affymetrix SNP chips was performed, allowing the identification of two regions of autozygosity, one in chromosome 1 and the other on chromosome 7. In the chromosome 1 locus, a strong candidate gene, encoding the kinesin-associated protein 3 (KIF3AP) was not mutated, based on SSCP/heteroduplex analysis and direct sequencing. These data provide a basis for the identification of a novel gene implicated in Kartagener syndrome.

  3. Association Studies of the GPR103 and BCL2L15 Genes in Autoimmune Thyroid Disease in the Japanese Population

    PubMed Central

    Ban, Yoshiyuki; Tozaki, Teruaki; Nakano, Yasuko

    2016-01-01

    While the past genome-wide association study (GWAS) for autoimmune thyroid diseases (AITDs) was done in Caucasians, a recent GWAS in Caucasian patients with both AITD and type 1 diabetes [a variant of autoimmune polyglandular syndrome type 3 (APS3v)] identified five non-HLA genes: BCL2L15, MAGI3, PHTF1, PTPN22, and GPR103. The aim of our study was to replicate these associations with AITD in a Japanese population. Since analyzing the rs2476601 single-nucleotide polymorphism (SNP) within the PTPN22 gene revealed no polymorphism in the Japanese, we analyzed four SNPs, rs2358994 (in BCL2L15), rs2153977 (in MAGI3), rs1111695 (in PHTF1), and rs7679475 (in GPR103) genotypes in a case–control study based on 447 Japanese AITD patients [277 Graves’ disease (GD) and 170 Hashimoto’s thyroiditis (HT) patients] and 225 matched Japanese controls using the high-resolution melting and unlabeled probe methods. Case–control association studies were performed using the χ2 and Fisher’s exact tests with Yates correction. The G allele of rs7679475 (A/G) was associated with HT compared with controls [P = 0.022, odds ratio (OR) = 0.69]. GD showed no significant associations with any SNPs. However, when patients with GD were stratified according to Graves’ ophthalmopathy (GO), the G allele of rs2358994 (A/G) was associated with GO vs. controls (P = 0.018, OR = 1.52). These findings suggest that in the Japanese population the GPR103 gene may contribute to the pathogenesis of HT. Moreover, this study demonstrated that the SNP rs2358994 within BCL2L15 gene is associated with GO in the Japanese population. PMID:27486433

  4. A novel comparative pattern count analysis reveals a chronic ethanol-induced dynamic shift in immediate early NF-κB genome-wide promoter binding during liver regeneration.

    PubMed

    Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B; Vadigepalli, Rajanikanth

    2016-03-01

    Liver regeneration after partial hepatectomy is a clinically important process that is impaired by adaptation to chronic alcohol intake. We focused on the initial time points following partial hepatectomy (PHx) to analyze the genome-wide binding activity of NF-κB, a key immediate early regulator. We investigated the effect of chronic alcohol intake on immediate early NF-κB genome-wide localization, in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found many ethanol-specific NF-κB binding target promoters in the ethanol-adapted state, corresponding to the regulation of biosynthetic processes, oxidation-reduction and apoptosis. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns in ethanol and pair-fed control groups. The highest pattern count corresponded to promoters with NF-κB binding exclusively in the ethanol group at 1 h post PHx. This set was associated with the regulation of cell death, response to oxidative stress, histone modification, mitochondrial function, and metabolic processes. Integration with the global gene expression profiles to identify putative transcriptional consequences of NF-κB binding patterns revealed that several of ethanol-specific 1 h binding targets showed ethanol-specific differential expression through 6 h post PHx. Motif analysis yielded co-incident binding loci for STAT3, AP-1, CREB, C/EBP-β, PPAR-γ and C/EBP-α, likely participating in co-regulatory modules with NF-κB in shaping the immediate early response to PHx. We conclude that adaptation to chronic ethanol intake disrupts the NF-κB promoter binding landscape with consequences for the immediate early gene regulatory response to the acute challenge of PHx.

  5. Disruption of the petal identity gene APETALA3-3 is highly correlated with loss of petals within the buttercup family (Ranunculaceae).

    PubMed

    Zhang, Rui; Guo, Chunce; Zhang, Wengen; Wang, Peipei; Li, Lin; Duan, Xiaoshan; Du, Qinggao; Zhao, Liang; Shan, Hongyan; Hodges, Scott A; Kramer, Elena M; Ren, Yi; Kong, Hongzhi

    2013-03-26

    Absence of petals, or being apetalous, is usually one of the most important features that characterizes a group of flowering plants at high taxonomic ranks (i.e., family and above). The apetalous condition, however, appears to be the result of parallel or convergent evolution with unknown genetic causes. Here we show that within the buttercup family (Ranunculaceae), apetalous genera in at least seven different lineages were all derived from petalous ancestors, indicative of parallel petal losses. We also show that independent petal losses within this family were strongly associated with decreased or eliminated expression of a single floral organ identity gene, APETALA3-3 (AP3-3), apparently owing to species-specific molecular lesions. In an apetalous mutant of Nigella, insertion of a transposable element into the second intron has led to silencing of the gene and transformation of petals into sepals. In several naturally occurring apetalous genera, such as Thalictrum, Beesia, and Enemion, the gene has either been lost altogether or disrupted by deletions in coding or regulatory regions. In Clematis, a large genus in which petalous species evolved secondarily from apetalous ones, the gene exhibits hallmarks of a pseudogene. These results suggest that, as a petal identity gene, AP3-3 has been silenced or down-regulated by different mechanisms in different evolutionary lineages. This also suggests that petal identity did not evolve many times independently across the Ranunculaceae but was lost in numerous instances. The genetic mechanisms underlying the independent petal losses, however, may be complex, with disruption of AP3-3 being either cause or effect.

  6. Comparative Transcript Profiling of a Male Sterile Cybrid Pummelo and Its Fertile Type Revealed Altered Gene Expression Related to Flower Development

    PubMed Central

    Zheng, Bei-Bei; Wu, Xiao-Meng; Ge, Xiao-Xia; Deng, Xiu-Xin; Grosser, Jude W.; Guo, Wen-Wu

    2012-01-01

    Male sterile and seedless characters are highly desired for citrus cultivar improvement. In our breeding program, a male sterile cybrid pummelo, which could be considered as a variant of male fertile pummelo, was produced by protoplast fusion. Herein, ecotopic stamen primordia initiation and development were detected in this male sterile cybrid pummelo. Histological studies revealed that the cybrid showed reduced petal development in size and width, and retarded stamen primordia development. Additionally, disorganized cell proliferation was also detected in stamen-like structures (fused to petals and/or carpel). To gain new insight into the underlying mechanism, we compared, by RNA-Seq analysis, the nuclear gene expression profiles of floral buds of the cybrid with that of fertile pummelo. Gene expression profiles which identified a large number of differentially expressed genes (DEGs) between the two lines were captured at both petal primordia and stamen primordia distinguishable stages. For example, nuclear genes involved in nucleic acid binding and response to hormone synthesis and metabolism, genes required for floral bud identification and expressed in particular floral whorls. Furthermore, in accordance with flower morphology of the cybrid, expression of PISTILLATA (PI) was reduced in stamen-like structures, even though it was restricted to correct floral whorls. Down-regulated expression of APETALA3 (AP3) coincided with that of PI. These finding indicated that, due to their whorl specific effects in flower development, citrus class-B MADS-box genes likely constituted ‘perfect targets’ for CMS retrograde signaling, and that dysfunctional mitochondria seemed to cause male sterile phenotype in the cybrid pummelo. PMID:22952758

  7. pistillata-5, an Arabidopsis B class mutant with strong defects in petal but not in stamen development.

    PubMed

    Yang, Yingzhen; Xiang, Hongjun; Jack, Thomas

    2003-01-01

    The Arabidopsis floral organ identity genes APETALA3 (AP3) and PISTILLATA (PI) encode related DNA-binding proteins of the MADS family. Considerable evidence supports the hypothesis that a heterodimer of AP3 and PI is an essential component of B class activity. All ap3 and pi alleles characterized to date exhibit equivalent phenotypic defects in both whorls 2 and 3. In strong ap3 and pi mutants, petals and stamens are missing and sepals and carpels develop in their place. Weak ap3 and pi mutants exhibit partial conversions of petals to sepals and stamens to carpels. In this report, we describe the isolation and characterization of pi-5, an unusual B class mutant that exhibits defects in whorl 2 where sepals develop in place of petals, but third whorl stamens are most often normal. pi-5 flowers resemble those from 35S::SEP3 antisense plants. pi-5 contains missense mutation in the K domain (PIE125K). PIE125K exhibits defects in heterodimerization with its partner protein AP3. Via a reverse yeast two-hybrid screen, AP3K139E was isolated as a compensatory mutant of PIE125K. The compensatory interaction between PIE125K and AP3K139E is observed both in yeast two-hybrid assays and in planta. On its own, AP3K139E exhibits defects in specifying both petal and stamen identity. In addition, PIE125K is defective in interaction with SEPALLATA proteins in both two- and three-hybrid assays suggesting that PIE125K is defective in forming higher order complexes of MADS proteins. The decreased concentration of PI/AP3/SEP complexes offers an explanation for the petal defects observed in both pi-5 and 35S::SEP3 antisense plants. PMID:12943551

  8. Novel Comparative Pattern Count Analysis Reveals a Chronic Ethanol-Induced Dynamic Shift in Immediate Early NF-κB Genome-wide Promoter Binding During Liver Regeneration

    PubMed Central

    Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B; Vadigepalli, Rajanikanth

    2016-01-01

    Liver regeneration after partial hepatectomy is a clinically important process that is impaired by adaptation to chronic alcohol intake. We focused on the initial time points following partial hepatectomy (PHx) to analyze genome-wide binding activity of NF-κB, a key immediate early regulator. We investigated the effect of chronic alcohol intake on immediate early NF-κB genome-wide localization, in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found many ethanol-specific NF-κB binding target promoters in the ethanol-adapted state, corresponding to regulation of biosynthetic processes, oxidation-reduction and apoptosis. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns in ethanol and pair-fed control groups. The highest pattern count corresponded to promoters with NF-κB binding exclusively in the ethanol group at 1h post PHx. This set was associated with regulation of cell death, response to oxidative stress, histone modification, mitochondrial function, and metabolic processes. Integration with the global gene expression profiles to identify putative transcriptional consequences of NF-κB binding patterns revealed that several of ethanol-specific 1h binding targets showed ethanol-specific differential expression through 6h post PHx. Motif analysis yielded co-incident binding loci for STAT3, AP-1, CREB, C/EBP-β, PPAR-γ and C/EBP-α, likely participating in co-regulatory modules with NF-κB in shaping the immediate early response to PHx. We conclude that adaptation to chronic ethanol intake disrupts the NF-κB promoter binding landscape with consequences for the immediate early gene regulatory response to the acute challenge of PHx. PMID:26847025

  9. Neoplasms with schwannian differentiation express transcription factors known to regulate normal schwann cell development.

    PubMed

    Pytel, Peter; Karrison, Theodore; Can Gong; Tonsgard, James H; Krausz, Thomas; Montag, Anthony G

    2010-12-01

    A number of transcription factors have been identified as important in guiding normal Schwann cell development. This study used immunohistochemistry on tissue arrays to assess the expression of some of these transcription factors (Sox5, Sox9, Sox10, AP-2α, Pax7, and FoxD3) on 76 schwannomas, 105 neurofibromas, and 34 malignant peripheral nerve sheath tumors (MPNSTs). Sox9 and Sox10 were found to be widely expressed in all tumor types. FoxD3 reactivity was stronger and more frequently found in schwannomas and MPNSTs than neurofibromas. AP-2α was positive in 31% to 49% of all tumors, but strong reactivity was limited to MPNSTs and schwannomas. Pax7 and Sox5 expression was restricted to subsets of MPNSTs. Statistical analysis showed significant differences between the 3 tumor types in the expression of these markers. No differences were found in the analyzed tumor subgroups, including schwannomas of different sites, schwannomas with or without NF2 association, neurofibromas of different types, or sporadic versus NF1-associated MPNSTs. These results suggest that the transcription factors that guide normal Schwann cell development also play a role in the biology of neoplastic cells with Schwannian differentiation. FoxD3, AP-2α, Pax7, and Sox5 are upregulated in MPNSTs compared with neurofibromas and may be markers of malignant transformation. Screening the expression of FoxD3, Sox9, and Sox10 on 23 cases of other spindle-cell proliferations that may be considered in the differential diagnosis of MPNST, including synovial sarcoma and spindle cell melanoma, suggests that these 3 are helpful markers of Schwannian differentiation in the context of diagnosing MPNSTs.

  10. Calcium channels in the high resistivity axonal membrane of photoreceptors of the giant barnacle.

    PubMed Central

    Edgington, D R; Stuart, A E

    1979-01-01

    1. The distribution of calcium channels in the cell membrane of the photoreceptor neurone of the giant barnacle, Balanus nubilus, was studied by recording intracellularly in or near the soma, in the axon, and near the presynaptic terminals. The membrane properties of these different regions of the cell could be studied by separately superfusing each region with test salines or by cutting the axon between two regions. 2. In the presence of tetraethylammonium (TEA) or 3-aminopyridine (3-AP), but not in their absence, Ca dependent action potentials could be evoked with depolarizing current pulses in the somatic, axonal, and terminal regions. Consequently, voltage-sensitive Ca channels and TEA-sensitive channels are present in all three regions of the cell. 3. The action potentials recorded from the three regions were similar in their slow times-to-peak (30-300 msec), long durations (0.2-2 sec in 100 mM-TEA), and long-lasting (0.2-10 sec) undershoots. The action potentials were inhibited by extracellular Co. 4. Clear differences were consistently observed between terminal action potentials and axonal or somatic action potentials in TEA. Terminal action potentials displayed a lower voltage threshold, faster rate of rise, and were less sensitive to inhibition by extracellular cobalt, suggesting that the Ca current is greater in the terminal region. 5. Bathing the receptor axon in low Ca or Co solutions led to a greater attenuation of large depolarizing components of the visual signal as they spread to the presynaptic terminals. PMID:512951

  11. Disruption of the petal identity gene APETALA3-3 is highly correlated with loss of petals within the buttercup family (Ranunculaceae)

    PubMed Central

    Zhang, Rui; Guo, Chunce; Zhang, Wengen; Wang, Peipei; Li, Lin; Duan, Xiaoshan; Zhao, Liang; Shan, Hongyan; Hodges, Scott A.; Kramer, Elena M.; Ren, Yi; Kong, Hongzhi

    2013-01-01

    Absence of petals, or being apetalous, is usually one of the most important features that characterizes a group of flowering plants at high taxonomic ranks (i.e., family and above). The apetalous condition, however, appears to be the result of parallel or convergent evolution with unknown genetic causes. Here we show that within the buttercup family (Ranunculaceae), apetalous genera in at least seven different lineages were all derived from petalous ancestors, indicative of parallel petal losses. We also show that independent petal losses within this family were strongly associated with decreased or eliminated expression of a single floral organ identity gene, APETALA3-3 (AP3-3), apparently owing to species-specific molecular lesions. In an apetalous mutant of Nigella, insertion of a transposable element into the second intron has led to silencing of the gene and transformation of petals into sepals. In several naturally occurring apetalous genera, such as Thalictrum, Beesia, and Enemion, the gene has either been lost altogether or disrupted by deletions in coding or regulatory regions. In Clematis, a large genus in which petalous species evolved secondarily from apetalous ones, the gene exhibits hallmarks of a pseudogene. These results suggest that, as a petal identity gene, AP3-3 has been silenced or down-regulated by different mechanisms in different evolutionary lineages. This also suggests that petal identity did not evolve many times independently across the Ranunculaceae but was lost in numerous instances. The genetic mechanisms underlying the independent petal losses, however, may be complex, with disruption of AP3-3 being either cause or effect. PMID:23479615

  12. AP-3 mediated trafficking of TLR2 ligands controls specificity of inflammatory responses but not adaptor complex assembly

    PubMed Central

    Petnicki-Ocwieja, Tanja; Kern, Aurelie; Killpack, Tess L.; Bunnell, Stephen C.; Hu, Linden T.

    2015-01-01

    Innate immune engagement results in the activation of host defenses that produce microbe-specific inflammatory responses. A long-standing interest in the field of innate immunity is to understand how varied host responses are generated through the signaling of just a limited number of receptors. Recently, intracellular trafficking and compartmental partitioning have been identified as mechanism that provide signaling specificity for receptors by regulating signaling platform assembly. We show that cytokine activation as a result of Toll-like receptor 2 (TLR2) stimulation occurs at different intracellular locations and is mediated by the phagosomal trafficking molecule AP-3. AP-3 is required for trafficking TLR2 purified ligands or the Lyme disease causing bacterium, Borrelia burgdorferi, to LAMP-1 lysosomal compartments. The presence of AP-3 is necessary for the activation of cytokines such as IL-6 but not TNF-α or type I interferons, suggesting induction of these cytokines occurs from a different compartment. Lack of AP-3 does not interfere with the recruitment of TLR signaling adaptors TRAM and MyD88 to the phagosome, indicating that the TLR-MyD88 signaling complex is assembled at a pre-lysosomal stage and that IL-6 activation depends on proper localization of signaling molecules downstream of MyD88. Finally, infection of AP-3 deficient mice with B. burgdorferi resulted in altered joint inflammation during murine Lyme arthritis. Our studies further elucidate the effects of phagosomal trafficking on tailoring immune responses in vitro and in vivo. PMID:26423153

  13. Glutathione-S-transferase profiles in the emerald ash borer, Agrilus planipennis.

    PubMed

    Rajarapu, Swapna Priya; Mittapalli, Omprakash

    2013-05-01

    The emerald ash borer, Agrilus planipennis Fairmaire is a recently discovered invasive insect pest of ash, Fraxinus spp. in North America. Glutathione-S-transferases (GST) are a multifunctional superfamily of enzymes which function in conjugating toxic compounds to less toxic and excretable forms. In this study, we report the molecular characterization and expression patterns of different classes of GST genes in different tissues and developmental stages plus their specific activity. Multiple sequence alignment of all six A. planipennis GSTs (ApGST-E1, ApGST-E2, ApGST-E3, ApGST-O1, ApGST-S1 and ApGST-μ1) revealed conserved features of insect GSTs and a phylogenetic analysis grouped the GSTs within the epsilon, sigma, omega and microsomal classes of GSTs. Real time quantitative PCR was used to study field collected samples. In larval tissues high mRNA levels for ApGST-E1, ApGST-E3 and ApGST-O1 were obtained in the midgut and Malpighian tubules. On the other hand, ApGST-E2 and ApGST-S1 showed high mRNA levels in fat body and ApGST-μ1 showed constitutive levels in all the tissues assayed. During development, mRNA levels for ApGST-E2 were observed to be the highest in feeding instars, ApGST-S1 in prepupal instars; while the others showed constitutive patterns in all the developmental stages examined. At the enzyme level, total GST activity was similar in all the tissues and developmental stages assayed. Results obtained suggest that A. planipennis is potentially primed with GST-driven detoxification to metabolize ash allelochemicals. To our knowledge this study represents the first report of GSTs in A. planipennis and also in the family of wood boring beetles.

  14. Evolutionary Dynamics of Floral Homeotic Transcription Factor Protein–Protein Interactions

    PubMed Central

    Bartlett, Madelaine; Thompson, Beth; Brabazon, Holly; Del Gizzi, Robert; Zhang, Thompson; Whipple, Clinton

    2016-01-01

    Protein–protein interactions (PPIs) have widely acknowledged roles in the regulation of development, but few studies have addressed the timing and mechanism of shifting PPIs over evolutionary history. The B-class MADS-box transcription factors, PISTILLATA (PI) and APETALA3 (AP3) are key regulators of floral development. PI-like (PIL) and AP3-like (AP3L) proteins from a number of plants, including Arabidopsis thaliana (Arabidopsis) and the grass Zea mays (maize), bind DNA as obligate heterodimers. However, a PIL protein from the grass relative Joinvillea can bind DNA as a homodimer. To ascertain whether Joinvillea PIL homodimerization is an anomaly or indicative of broader trends, we characterized PIL dimerization across the Poales and uncovered unexpected evolutionary lability. Both obligate B-class heterodimerization and PIL homodimerization have evolved multiple times in the order, by distinct molecular mechanisms. For example, obligate B-class heterodimerization in maize evolved very recently from PIL homodimerization. A single amino acid change, fixed during domestication, is sufficient to toggle one maize PIL protein between homodimerization and obligate heterodimerization. We detected a signature of positive selection acting on residues preferentially clustered in predicted sites of contact between MADS-box monomers and dimers, and in motifs that mediate MADS PPI specificity in Arabidopsis. Changing one positively selected residue can alter PIL dimerization activity. Furthermore, ectopic expression of a Joinvillea PIL homodimer in Arabidopsis can homeotically transform sepals into petals. Our results provide a window into the evolutionary remodeling of PPIs, and show that novel interactions have the potential to alter plant form in a context-dependent manner. PMID:26908583

  15. Histone acetylation accompanied with promoter sequences displaying differential expression profiles of B-class MADS-box genes for phalaenopsis floral morphogenesis.

    PubMed

    Hsu, Chia-Chi; Wu, Pei-Shan; Chen, Tien-Chih; Yu, Chun-Wei; Tsai, Wen-Chieh; Wu, Keqiang; Wu, Wen-Luan; Chen, Wen-Huei; Chen, Hong-Hwa

    2014-01-01

    Five B-class MADS-box genes, including four APETALA3 (AP3)-like PeMADS2∼5 and one PISTILLATA (PI)-like PeMADS6, specify the spectacular flower morphology in orchids. The PI-like PeMADS6 ubiquitously expresses in all floral organs. The four AP3-like genes, resulted from two duplication events, express ubiquitously at floral primordia and early floral organ stages, but show distinct expression profiles at late floral organ primordia and floral bud stages. Here, we isolated the upstream sequences of PeMADS2∼6 and studied the regulatory mechanism for their distinct gene expression. Phylogenetic footprinting analysis of the 1.3-kb upstream sequences of AP3-like PeMADS2∼5 showed that their promoter regions have sufficiently diverged and contributed to their subfunctionalization. The amplified promoter sequences of PeMADS2∼6 could drive beta-glucuronidase (GUS) gene expression in all floral organs, similar to their expression at the floral primordia stage. The promoter sequence of PeMADS4, exclusively expressed in lip and column, showed a 1.6∼3-fold higher expression in lip/column than in sepal/petal. Furthermore, we noted a 4.9-fold increase in histone acetylation (H3K9K14ac) in the translation start region of PeMADS4 in lip as compared in petal. All these results suggest that the regulation via the upstream sequences and increased H3K9K14ac level may act synergistically to display distinct expression profiles of the AP3-like genes at late floral organ primordia stage for Phalaenopsis floral morphogenesis. PMID:25501842

  16. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2004-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, 3-AP, AP-12009, APC-8015, L-Arginine hydrochloride, aripiprazole, arundic acid, avasimibe; Bevacizumab, bivatuzumab, BMS-181176, BMS-184476, BMS-188797, bortezomib, bosentan, botulinum toxin type B, BQ-123, BRL-55730, bryostatin 1; CEP-1347, cetuximab, cinacalcet hydrochloride, CP-461, CpG-7909; D-003, dabuzalgron hydrochloride, darbepoetin alfa, desloratadine, desoxyepothilone B, dexmethylphenidate hydrochloride, DHA-paclitaxel, diflomotecan, DN-101, DP-b99, drotrecogin alfa (activated), duloxetine hydrochloride, duramycin; Eculizumab, Efalizumab, EKB-569, elcometrine, enfuvirtide, eplerenone, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, exatecan mesilate, ezetimibe; Fenretinide, fosamprenavir calcium, frovatriptan; GD2L-KLH conjugate vaccine, gefitinib, glufosfamide, GTI-2040; Hexyl insulin M2, human insulin, hydroquinone, gamma-Hydroxybutyrate sodium; IL-4(38-37)-PE38KDEL, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; KRN-5500; LY-544344; MDX-210, melatonin, mepolizumab, motexafin gadolinium; Natalizumab, NSC-330507, NSC-683864; 1-Octanol, omalizumab, ortataxel; Pagoclone, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, phenoxodiol, pimecrolimus, plevitrexed, polyphenon E, pramlintide acetate, prasterone, pregabalin, PX-12; QS-21; Ragaglitazar, ranelic acid distrontium salt, RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, repinotan hydrochloride, rhEndostatin, rh-Lactoferrin, (R)-roscovitine; S-8184, semaxanib, sitafloxacin hydrate, sitaxsentan sodium, sorafenib, synthadotin

  17. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-09-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 101M, 166Ho-DOTMP, 3-AP; Abatacept, abetimus sodium, ACR-16, adefovir dipivoxil, alefacept, AMD-070, aminolevulinic acid hexyl ester, anatumomab mafenatox, anti-CTLA-4 MAb, antigastrin therapeutic vaccine, AP-12009, AP-23573, APC-8024, aripiprazole, ATL-962, atomoxetine hydrochloride; Bevacizumab, bimatoprost, bortezomib, bosentan, BR-1; Calcipotriol/betamethasone dipropionate, cinacalcet hydrochloride, clofazimine, colchicine, cold-adapted influenza vaccine trivalent, CRM197; Desloratadine, desoxyepothilone B, diethylhomospermine; Edodekin alfa, efalizumab, elcometrine, eletriptan, enfuvirtide, entecavir, EP-2101, eplerenone, erlotinib hydrochloride, etoricoxib, everolimus, exherin, ezetimibe; Febuxostat, fluorescein lisicol, fosamprenavir calcium, frovatriptan; Hemoglobin raffimer, HSPPC-96, human insulin; Imatinib mesylate, insulin detemir, insulin glargine, IRX-2, istradefylline, IV gamma-globulin, ixabepilone; Kahalalide F; L-759274, levodopa/carbidopa/entacapone, licofelone, lonafarnib, lopinavir, lurtotecan, LY-156735; MAb G250, mecasermin, melatonin, midostaurin, muraglitazar; Nesiritide, nitronaproxen; O6-Benzylguanine, olmesartan medoxomil, olmesartan medoxomil/hydrochlorothiazide, omapatrilat, oral insulin; Parecoxib sodium, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pemetrexed disodium, peptide YY3-36, PG-CPT, phenoxodiol, pimecrolimus, posaconazole; Rasagiline mesilate, rDNA insulin, RG228, rimonabant hydrochloride, rosuvastatin calcium, rotigotine hydrochloride; S-3304, safinamide mesilate, salcaprozic acid sodium salt, SDZ-SID-791, SGN-30, soblidotin

  18. Functional divergence within class B MADS-box genes TfGLO and TfDEF in Torenia fournieri Lind

    PubMed Central

    Sasaki, Katsutomo; Aida, Ryutaro; Yamaguchi, Hiroyasu; Shikata, Masahito; Niki, Tomoya; Nishijima, Takaaki

    2010-01-01

    Homeotic class B genes GLOBOSA (GLO)/PISTILLATA (PI) and DEFICIENS (DEF)/APETALA3 (AP3) are involved in the development of petals and stamens in Arabidopsis. However, functions of these genes in the development of floral organs in torenia are less well known. Here, we demonstrate the unique floral phenotypes of transgenic torenia formed due to the modification of class B genes, TfGLO and TfDEF. TfGLO-overexpressing plants showed purple-stained sepals that accumulated anthocyanins in a manner similar to that of petals. TfGLO-suppressed plants showed serrated petals and TfDEF-suppressed plants showed partially decolorized petals. In TfGLO-overexpressing plants, cell shapes on the surfaces of sepals were altered to petal-like cell shapes. Furthermore, TfGLO- and TfDEF-suppressed plants partially had sepal-like cells on the surfaces of their petals. We isolated putative class B gene-regulated genes and examined their expression in transgenic plants. Three xyloglucan endo-1,4-beta-d-glucanase genes were up-regulated in TfGLO- and TfDEF-overexpressing plants and down-regulated in TfGLO- and TfDEF-suppressed plants. In addition, 10 anthocyanin biosynthesis-related genes, including anthocyanin synthase and chalcone isomerase, were up-regulated in TfGLO-overexpressing plants and down-regulated in TfGLO-suppressed plants. The expression patterns of these 10 genes in TfDEF transgenic plants were diverse and classified into several groups. HPLC analysis indicated that sepals of TfGLO-overexpressing plants accumulate the same type of anthocyanins and flavones as wild-type plants. The difference in phenotypes and expression patterns of the 10 anthocyanin biosynthesis-related genes between TfGLO and TfDEF transgenic plants indicated that TfGLO and TfDEF have partial functional divergence, while they basically work synergistically in torenia. Electronic supplementary material The online version of this article (doi:10.1007/s00438-010-0574-z) contains supplementary material, which

  19. The C-Terminal Sequence and PI motif of the Orchid (Oncidium Gower Ramsey) PISTILLATA (PI) Ortholog Determine its Ability to Bind AP3 Orthologs and Enter the Nucleus to Regulate Downstream Genes Controlling Petal and Stamen Formation.

    PubMed

    Mao, Wan-Ting; Hsu, Hsing-Fun; Hsu, Wei-Han; Li, Jen-Ying; Lee, Yung-I; Yang, Chang-Hsien

    2015-11-01

    This study focused on the investigation of the effects of the PI motif and C-terminus of the Oncidium Gower Ramsey MADS box gene 8 (OMADS8), a PISTILLATA (PI) ortholog, on floral organ formation. 35S::OMADS8 completely rescued and 35S::OMADS8-PI (with the PI motif deleted) partially rescued petal/stamen formation, whereas these deficiencies were not rescued by 35S::OMADS8-C (C-terminal 29 amino acids deleted) in pi-1 mutants. OMADS8 could interact with Arabidopsis APETALA3 (AP3) and enter the nucleus. The nuclear entry efficiency was reduced for OMADS8-PI/AP3 and OMADS8-C/AP3. OMADS8 could also interact with OMADS5/OMADS9 (the Oncidium AP3 ortholog) and enter the nucleus with an efficiency only slightly affected by the deletion of the C-terminal sequence or PI motif. However, the stability of the OMADS8/OMADS5 and OMADS8/OMADS9 complexes was significantly reduced by deletion of the C-terminal sequence or PI motif. Further analysis indicated that the expression of genes downstream of AP3/PI (BNQ1/BNQ2/GNC/At4g30270) was compensated by 35S::OMADS8 and 35S::OMADS8-PI to a level similar to wild-type plants but was not affected by 35S::OMADS8-C in the pi-1 mutants. A similar FRET (fluorescence resonance energy transfer) efficiency was observed for Arabidopsis AGAMOUS (AG) and the Oncidium AG ortholog OMADS4 for OMADS8, OMADS8-PI and OMADS8-C. These results indicated that the OMADS8 PI motif and C-terminus were valuable for the interaction of OMADS8 with the AP3 orthologs to form higher order heterotetrameric complexes that regulated petal/stamen formation in both Oncidium orchids and transgenic Arabidopsis. However, the C-terminal sequence and PI motif were dispensable for the interaction of OMADS8 with the AG orthologs.

  20. Molecular and Functional Characterization of ssDNA Aptamers that Specifically Bind Leishmania infantum PABP

    PubMed Central

    Guerra-Pérez, Natalia; Ramos, Edurne; García-Hernández, Marta; Pinto, Celia; Soto, Manuel; Martín, M. Elena; González, Víctor M.

    2015-01-01

    Summary A poly (A)-binding protein from Leishmania infantum (LiPABP) has been recently cloned and characterized in our laboratory. Although this protein shows a very high homology with PABPs from other eukaryotic organisms including mammals and other parasites, exist divergences along the sequence that convert them in potential diagnostic markers and/or therapeutics targets. Aptamers are oligonucleotide ligands that are selected in vitro by their affinity and specificity for the target as a consequence of the particular tertiary structure that they are able to acquire depending on their sequence. Development of high-affinity molecules with the ability to recognize specifically Leishmania proteins is essential for the progress of this kind of study. Results We have selected a ssDNA aptamer population against a recombinant 6xHIS–LiPABP protein (rLiPABP) that is able to recognize the target with a low Kd. Cloning, sequencing and in silico analysis of the aptamers obtained from the population yielded three aptamers (ApPABP#3, ApPABP#7 and ApPABP#11) that significantly bound to PABP with higher affinity than the naïve population. These aptamers were analyzed by ELONA and slot blot to establish affinity and specificity for rLiPABP. Results demonstrated that the three aptamers have high affinity and specificity for the target and that they are able to detect an endogenous LiPABP (eLiPABP) protein amount corresponding to 2500 L. infantum promastigotes in a significant manner. The functional analysis of the aptamers also revealed that ApPABP#11 disrupts the binding of both Myc-LiPABP and eLiPABP to poly (A) in vitro. On the other hand, these aptamers are able to bind and purify LiPABP from complex mixes. Conclusion Results presented here demonstrate that aptamers represent new reagents for characterization of LiPABP and that they can affect LiPABP activity. At this respect, the use of these aptamers as therapeutic tool affecting the physiological role of PABP has to be

  1. Gallium(III) complexes of NOTA-bis (phosphonate) conjugates as PET radiotracers for bone imaging.

    PubMed

    Holub, Jan; Meckel, Marian; Kubíček, Vojtěch; Rösch, Frank; Hermann, Petr

    2015-01-01

    Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.

  2. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

    PubMed

    Hannan, Fadil M; Howles, Sarah A; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M; Babinsky, Valerie N; Reed, Anita A; Thakker, Clare E; Bockenhauer, Detlef; Brown, Rosalind S; Connell, John M; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J; McKnight, John A; Morrison, Patrick J; Mughal, M Zulf; O'Halloran, Domhnall; Pearce, Simon H; Porteous, Mary E; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; Van't Hoff, William G; Wang, Timothy; Whyte, Michael P; Nesbit, M Andrew; Thakker, Rajesh V

    2015-09-15

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. PMID:26082470

  3. Pooled Analysis of Phosphatidylinositol 3-kinase Pathway Variants and Risk of Prostate Cancer

    PubMed Central

    Koutros, Stella; Schumacher, Fredrick R.; Hayes, Richard B.; Ma, Jing; Huang, Wen-Yi; Albanes, Demetrius; Canzian, Federico; Chanock, Stephen J.; Crawford, E. David; Diver, W. Ryan; Feigelson, Heather Spencer; Giovanucci, Edward; Haiman, Christopher A.; Henderson, Brian E.; Hunter, David J.; Kaaks, Rudolf; Kolonel, Laurence N.; Kraft, Peter; Le Marchand, Loïc; Riboli, Elio; Siddiq, Afshan; Stampfer, Mier J.; Stram, Daniel O.; Thomas, Gilles; Travis, Ruth C.; Thun, Michael J.; Yeager, Meredith; Berndt, Sonja I.

    2010-01-01

    The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking and may impact prostate carcinogenesis. Thus, we explored the association between single nucleotide polymorphisms (SNPs) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk (ORper allele=1.08 (95% CI: 1.03, 1.14), p-trend = 0.0017) after adjustment for multiple testing (Padj=0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association (ORper allele=1.21 (95% CI: 1.09, 1.34); p-trend =0.0003). The adjusted association was stronger for men who were diagnosed before 65 years (ORper allele= 1.47 (95% CI: 1.20, 1.79), p-trend = 0.0001) or had a family history (ORper allele= 1.57 (95% CI: 1.11, 2.23), p-trend = 0.0114), and was strongest in those with both characteristics (ORper allele= 2.31 (95% CI: 1.07, 5.07), p-interaction = 0.005). Increased risks were observed among men in the top tertile of circulating insulin like growth factor-1 (IGF-1) levels (ORper allele= 1.46 (95% CI: 1.04, 2.06), p-trend=0.075). No differences were observed with disease aggressiveness (≥8/stage T3/T4/fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early onset disease, which may be attributable to IGF-dependent PI3K signaling. PMID:20197460

  4. Effects of Instability Versus Traditional Resistance Training on Strength, Power and Velocity in Untrained Men

    PubMed Central

    Maté-Muñoz, José Luis; Monroy, Antonio J. Antón; Jodra Jiménez, Pablo; Garnacho-Castaño, Manuel V.

    2014-01-01

    The purpose of this study was compare the effects of a traditional and an instability resistance circuit training program on upper and lower limb strength, power, movement velocity and jumping ability. Thirty-six healthy untrained men were assigned to two experimental groups and a control group. Subjects in the experimental groups performed a resistance circuit training program consisting of traditional exercises (TRT, n = 10) or exercises executed in conditions of instability (using BOSU® and TRX®) (IRT, n = 12). Both programs involved three days per week of training for a total of seven weeks. The following variables were determined before and after training: maximal strength (1RM), average (AV) and peak velocity (PV), average (AP) and peak power (PP), all during bench press (BP) and back squat (BS) exercises, along with squat jump (SJ) height and counter movement jump (CMJ) height. All variables were found to significantly improve (p <0.05) in response to both training programs. Major improvements were observed in SJ height (IRT = 22.1%, TRT = 20.1%), CMJ height (IRT = 17.7%, TRT = 15.2%), 1RM in BS (IRT = 13.03%, TRT = 12.6%), 1RM in BP (IRT = 4.7%, TRT = 4.4%), AP in BS (IRT = 10.5%, TRT = 9.3%), AP in BP (IRT = 2.4%, TRT = 8.1%), PP in BS (IRT=19.42%, TRT = 22.3%), PP in BP (IRT = 7.6%, TRT = 11.5%), AV in BS (IRT = 10.5%, TRT = 9.4%), and PV in BS (IRT = 8.6%, TRT = 4.5%). Despite such improvements no significant differences were detected in the posttraining variables recorded for the two experimental groups. These data indicate that a circuit training program using two instability training devices is as effective in untrained men as a program executed under stable conditions for improving strength (1RM), power, movement velocity and jumping ability. Key Points Similar adaptations in terms of gains in strength, power, movement velocity and jumping ability were produced in response to both training programs. Both the stability and instability approaches

  5. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

    PubMed

    Hannan, Fadil M; Howles, Sarah A; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M; Babinsky, Valerie N; Reed, Anita A; Thakker, Clare E; Bockenhauer, Detlef; Brown, Rosalind S; Connell, John M; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J; McKnight, John A; Morrison, Patrick J; Mughal, M Zulf; O'Halloran, Domhnall; Pearce, Simon H; Porteous, Mary E; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; Van't Hoff, William G; Wang, Timothy; Whyte, Michael P; Nesbit, M Andrew; Thakker, Rajesh V

    2015-09-15

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

  6. Chronic low back pain is associated with reduced vertebral bone mineral measures in community-dwelling adults

    PubMed Central

    2012-01-01

    Background Chronic low back pain (CLBP) experienced in middle-age may have important implications for vertebral bone health, although this issue has not been investigated as a primary aim previously. This study investigated the associations between CLBP and dual energy X-ray absorptiometry (DXA)-derived vertebral bone mineral measures acquired from postero-anterior and lateral-projections, among community-dwelling, middle-aged adults. Methods Twenty-nine adults with CLBP (11 male, 18 female) and 42 adults with no history of LBP in the preceding year (17 male, 25 female) were evaluated. Self-reported demographic and clinical data were collected via questionnaires. Areal bone mineral density (aBMD) was measured in the lumbar spine by DXA. Apparent volumetric (ap.v) BMD in the lumbar spine was also calculated. Multiple linear regression models were used to examine associations between study group (CLBP and control) and vertebral DXA variables by gender, adjusting for height, mass and age. Results There was no difference between groups by gender in anthropometrics or clinical characteristics. In the CLBP group, the mean (SD) duration of CLBP was 13.3 (10.4) years in males and 11.6 (9.9) years in females, with Oswestry Disability Index scores of 16.2 (8.7)% and 15.4 (9.1)%, respectively. Males with CLBP had significantly lower adjusted lateral-projection aBMD and lateral-projection ap.vBMD than controls at L3 with mean differences (standard error) of 0.09 (0.04) g/cm2 (p = 0.03) and 0.02 (0.01) g/cm3 (p = 0.04). These multivariate models accounted for 55% and 53% of the variance in lateral-projection L3 aBMD and lateral-projection L3 ap.vBMD. Conclusions CLBP in males is associated with some lumbar vertebral BMD measures, raising important questions about the mechanism and potential clinical impact of this association. PMID:22458361

  7. [Accidental Dural Puncture and Post-dural Puncture Headache in the Obstetric Population: Eight Years of Experience].

    PubMed

    Antunes, Maria Vaz; Moreira, Adriano; Sampaio, Catarina; Faria, Aida

    2016-04-01

    Introdução: A punção acidental da dura é uma importante complicação da anestesia regional e a cefaleia pós-punção continua a ser causa de morbilidade na população obstétrica. O objetivo do nosso estudo foi calcular a incidência de punção acidental e cefaleia pós-punção no nosso Centro Hospitalar e avaliar a sua abordagem entre os anestesiologistas obstétricos. Material e Métodos: Realizámos uma auditoria retrospetiva, entre janeiro de 2007 e dezembro de 2014. Revimos as folhas de registo das doentes em que ocorreu punção inadvertida da dura ou cefaleia pós-punção. Excluímos as doentes submetidas a bloqueio subaracnoideu. Utilizámos o SPSS 22.0 no tratamento estatístico dos dados. Resultados: Obtivémos 18 497 bloqueios neuro-axiais e 58 punções acidentais da dura (0,3%). Após punção detetada, em 71,4% o cateter epidural foi re-posicionado e 21,4% tiveram cateteres intra-tecais. Quarenta e cinco (77,6%) desenvolveram cefaleia e a instituição de medidas profiláticas ocorreu em 76,1%. O tratamento conservador foi efetuado em todas as doentes. O blood patch epidural foi realizado em 32,8% com um sucesso de 84,2%. Discussão: A incidência de cefaleia pós-punção não está relacionada com o tipo de parto ou a inserção do cateter intra-tecal. A re-colocação do cateter epidural mantém-se a abordagem de eleição após punção. A instituição de medidas profiláticas é uma prática comum, apesar do baixo grau de eficácia. Realizámos blood patch epidural após falência do tratamento conservador. Conclusão: A incidência de punção inadvertida e cefaleia pós-punção foi semelhante à da literatura. Apesar de ser uma complicação comum, existe falta de consenso na sua abordagem.

  8. Probiotics Prevent Intestinal Barrier Dysfunction in Acute Pancreatitis in Rats via Induction of Ileal Mucosal Glutathione Biosynthesis

    PubMed Central

    Lutgendorff, Femke; Nijmeijer, Rian M.; Sandström, Per A.; Trulsson, Lena M.; Magnusson, Karl-Eric; Timmerman, Harro M.; van Minnen, L. Paul; Rijkers, Ger T.; Gooszen, Hein G.; Akkermans, Louis M. A.; Söderholm, Johan D.

    2009-01-01

    Background During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. Methodology/Principal Findings Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and 51Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4±33.5 vs. placebo 223.7±93.7 a.u.; P<0.001), 51Cr-EDTA flux (16.7±10.1 vs. 32.1±10.0 cm/s10−6; P<0.005), apoptosis, lipid peroxidation (0.42±0.13 vs. 1.62±0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33±1.47 vs. 8.82±1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33±1.47 vs. 10.70±1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88±1.21 vs. placebo 1.94±0.55 nmol/min/mg protein; P<0

  9. Endovascular Treatment of Aortic Aneurysms and Blood Transfusion. What do We Need?

    PubMed

    Machado, Rui; Loureiro, Luís; Antunes, Inês; Coutinho, Jorge; Almeida, Rui

    2016-05-01

    Introdução: O tratamento endovascular dos aneurismas da aorta reduziu as taxas de transfusão. Não existem recomendações relativamente às unidades de glóbulos vermelhos a serem tipadas por crossmatch pré-operatoriamente. O nosso objetivo é contribuir para a análise das unidades de glóbulos vermelhos necessárias no tratamento endovascular dos aneurismas da aorta e na cirurgia híbrida de aneurismas da aorta e definir um protocolo do Maximum Surgical Blood Orders Schedule. Material e Métodos: Analisámos retrospetivamente a base de dados prospectiva dos doentes tratados eletivamente por tratamento endovascular dos aneurismas da aorta, entre 2001 e 2012. Analisamos idade, género, classe ASA, Maximum Surgical Blood Orders Schedule, unidades de glóbulos vermelhos transfundidas e tempos, endoprótese, relação unidades de glóbulos vermelhos consumidas/endoprótese, relação unidades crossmatched/transfundidas, conversão para cirurgia convencional, hemoglobina pré-operatória e na alta. Resultados: Selecionamos para análise 187 doentes, 90% homens, idade média 73,1, classe ASA III mais frequente. Usamos próteses aorto-bi-iliaca em 71%, aorto-uni-iliaca 23% e torácica 6%. Não necessitaram transfusão 72,6%. Transfundimos 171 unidades de glóbulos vermelhos. A relação unidades crossmatched/transfundidas foi 10,1 até 2010 e 7,3 após. A relação unidades de glóbulos vermelhos consumidas/endoprótese nas primeiras 24 horas foi 0,21 unidades de glóbulos vermelhos/aorto-bi-iliaca, 0,46 unidades de glóbulos vermelhos/aorto-uni-iliaca, 0,8 unidades de glóbulos vermelhos/torácica, 1,3 unidades de glóbulos vermelhos/híbrida-torácica e duas unidades de glóbulos vermelhos/híbrida-aorto-bi-iliaca. Obtivemos relação estatisticamente significativa entre unidades de glóbulos vermelhos transfundidas/endoprótese (p < 0,001) e entre classificação ASA e unidades de glóbulos vermelhos transfundidas após 24 h (p < 0,01). Discussão: As recomenda