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Sample records for pyrrolidine dithiocarbamate complex

  1. Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity

    SciTech Connect

    Milacic, Vesna; Chen Di; Giovagnini, Lorena; Diez, Alejandro; Fregona, Dolores; Dou, Q. Ping

    2008-08-15

    Zinc and copper are trace elements essential for proper folding, stabilization and catalytic activity of many metalloenzymes in living organisms. However, disturbed zinc and copper homeostasis is reported in many types of cancer. We have previously demonstrated that copper complexes induced proteasome inhibition and apoptosis in cultured human cancer cells. In the current study we hypothesized that zinc complexes could also inhibit the proteasomal chymotrypsin-like activity responsible for subsequent apoptosis induction. We first showed that zinc(II) chloride was able to inhibit the chymotrypsin-like activity of a purified 20S proteasome with an IC{sub 50} value of 13.8 {mu}M, which was less potent than copper(II) chloride (IC{sub 50} 5.3 {mu}M). We then compared the potencies of a pyrrolidine dithiocarbamate (PyDT)-zinc(II) complex and a PyDT-copper(II) complex to inhibit cellular proteasomal activity, suppress proliferation and induce apoptosis in various human breast and prostate cancer cell lines. Consistently, zinc complex was less potent than copper complex in inhibiting the proteasome and inducing apoptosis. Additionally, zinc and copper complexes appear to use somewhat different mechanisms to kill tumor cells. Zinc complexes were able to activate calpain-, but not caspase-3-dependent pathway, while copper complexes were able to induce activation of both proteases. Furthermore, the potencies of these PyDT-metal complexes depend on the nature of metals and also on the ratio of PyDT to the metal ion within the complex, which probably affects their stability and availability for interacting with and inhibiting the proteasome in tumor cells.

  2. Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate.

    PubMed

    Shin, Eun-Joo; Jhoo, Jin Hyeong; Kim, Won-Ki; Jhoo, Wang Kee; Lee, Chaeyoung; Jung, Bae Dong; Kim, Hyoung-Chun

    2004-01-01

    The effect of pyrrolidine dithiocarbamate (PDTC) on kainate (KA)-induced neurotoxicity was examined in Sprague-Dawley rats. At 10 mg/kg, i.p., KA produced seizures accompanied by neuronal loss in the hippocampus and increased levels of malondialdehyde (MDA) and protein carbonyl. Pretreatment with PDTC (100 or 200 mg/kg, p.o., every 12 h x 5) blocked KA-induced neurotoxicities (seizures, increases in MDA and protein carbonyl and neuronal losses) in a dose-dependent manner. These effects were counteracted by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 micro g/kg, i.p.), but not by the A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg, i.p.) or the A(2B) receptor antagonist alloxazine (1.5 or 3.0 mg/kg, i.p.). Our results suggest that the anticonvulsant and neuroprotective effects of PDTC are mediated, at least in part, via adenosine A(1) receptor stimulation.

  3. Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation

    PubMed Central

    Cuzzocrea, Salvatore; Chatterjee, Prabal K; Mazzon, Emanuela; Dugo, Laura; Serraino, Ivana; Britti, Domenico; Mazzullo, Giuseppe; Caputi, Achille P; Thiemermann, Christoph

    2002-01-01

    The nuclear factor-κB (NF-κB) is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are antioxidants which are potent inhibitors of NF-κB. We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate inflammation. In the present study we investigate the effects of PDTC in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that PDTC (given at 100, 30 or 10 mg kg−1 i.p. in the pleurisy model or at 10 mg kg−1 i.p. every 48 h in the arthritis model) exerts potent anti-inflammatory effects (e.g. significant reduction of (A) pleural exudate formation, (B) polymorphonuclear cell infiltration, (C) lipid peroxidation, (D) inducible nitric oxide synthase (iNOS) activity and nitric oxide production (E) plasma and pleural exudates levels of interleukin-1β and tumour necrosis factor-α, (F) histological injury and (G) delayed development of clinical indicators). Furthermore, PDTC reduced immunohistochemical evidence of (A) formation of nitrotyrosine, (B) activation of poly (ADP-ribose) polymerase (PARP), (C) expression of iNOS and (D) expression of cyclo-oxygenase-2 (COX-2) in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. Additionally, Western blotting and immunohistochemical analysis of lung tissue revealed that PDTC prevented degradation of IKB-α and translocation of NF-κB from the cytoplasm into the nucleus. Taken together, our results clearly demonstrate that prevention of the activation of NF-κB by PDTC reduces the development of acute and chronic inflammation. Therefore, inhibition of NF-κB may represent a novel approach for the therapy of inflammation. PMID:11815386

  4. Therapy of experimental influenza virus infection with pyrrolidine dithiocarbamate.

    PubMed

    Wiesener, Nadine; Zimmer, Christin; Jarasch-Althof, Nadine; Wutzler, Peter; Henke, Andreas

    2011-05-01

    The search for new antiviral strategies to treat influenza A virus (IAV) infections is one major international health care activity. Hereby, the IAV-caused misuse of cellular nuclear factor kappa B (NF-κB) signaling pathways in infected cells represents one target for antiviral therapy. In the present study, pyrrolidine dithiocarbamate (PDTC), which is known as an antioxidant and as an inhibitor of IAV-induced NF-κB activation, was studied in vivo. After the antiviral activity of PDTC was confirmed in MDCK cells, mice-infected with the mouse-adapted strain of IAV A/PR/8/34 (H1N1)-were treated intraperitoneally simultaneously with PDTC (75, 150, 200 mg/kg body weight). The influence of PDTC administrations was evaluated on viral replication and inflammatory reactions in lung tissue up to 14 days postinfection (p. i.). This therapy increased survival up to 80% and reduced IAV-caused weight loss and viral replication in lung tissue in a dose-dependent manner. Protective effects were less pronounced, if the therapy started later on during an ongoing IAV infection. In addition, simultaneous PDTC treatment also limited IAV-caused infiltration of immune cells as well as local interferon-γ expression in lung tissue. These results imply that PDTC decreases IAV-caused disease in mice significantly. Therefore, the development of drugs like PDTC that interfere with NF-κB signaling may represent a modern focus of anti-IAV therapy.

  5. Antiviral Effects of Pyrrolidine Dithiocarbamate on Human Rhinoviruses

    PubMed Central

    Gaudernak, Elisabeth; Seipelt, Joachim; Triendl, Andrea; Grassauer, Andreas; Kuechler, Ernst

    2002-01-01

    Human rhinoviruses (HRVs) are the predominant cause of the common cold. The frequency of HRV infections in industrial countries and the lack of effective therapeutical treatment underline the importance of research for new antiviral substances. As viral infections are often accompanied by the generation of oxidative stress inside the infected cells, several redox-active substances were tested as potential antivirals. In the course of these studies it was discovered that pyrrolidine dithiocarbamate (PDTC) is an extremely potent compound against HRV and poliovirus infection in cell culture. Besides the ability to dramatically reduce HRV production by interfering with viral protein expression, PDTC promotes cell survival and abolishes cytopathic effects in infected cells. PDTC also protects cells against poliovirus infection. These effects were highly specific, as several other antioxidants (vitamin C, Trolox, 2-mercaptoethanol, and N-acetyl-l-cysteine) are inactive against HRV infection. Synthesis of HRV proteins and cleavage of eucaryotic initiation factor 4G responsible for host cell shutoff of cellular protein synthesis are severely inhibited in the presence of PDTC. PMID:12021333

  6. INHIBITION OF TOXOPLASMA GONDII GROWTH BY PYRROLIDINE DITHIOCARBAMATE IS CELL CYCLE SPECIFIC AND LEADS TO POPULATION SYNCHRONIZATION

    PubMed Central

    Conde de Felipe, Magnolia M.; Lehmann, Margaret M.; Jerome, Maria E.; White, Michael W.

    2008-01-01

    Successful completion of the Toxoplasma cell cycle requires the coordination of a series of complex and ordered processes that results in the formation of two daughters by internal budding. Although we now understand the order and timing of intracellular events associated with the parasite cell cycle, the molecular details of the checkpoints that regulate each step in T. gondii division is still uncertain. In other eukaryotic cells, the use of cytostatic inhibitors that are able to arrest replication at natural checkpoints have been exploited to induce synchronization of population growth. Herein, we describe a novel method to synchronize T. gondii tachyzoites based on the reversible growth inhibition by the drug, pyrrolidine dithiocarbamate. This method is an improvement over other strategies developed for this parasite as no prior genetic manipulation of the parasite was required. RH tachyzoites blocked by pyrrolidine dithiocarbamate exhibited a near uniform haploid DNA content and single centrosome indicating that this compound arrests parasites in the G1 phase of the tachyzoite cell cycle with a minor block in late cytokinesis. Thus, these studies support the existence of a natural checkpoint that regulates passage through the G1 period of the cell cycle. Populations released from pyrrolidine dithiocarbamate inhibition completed progression through G1 and entered S phase ~2 hours post-drug release. The transit of drug-synchronized populations through S phase and mitosis followed a similar timeframe to previous studies of the tachyzoite cell cycle. Tachyzoites treated with pyrrolidine dithiocarbamate were fully viable and completed two identical division cycles post-drug release demonstrating that this is a robust method for synchronizing population growth in Toxoplasma. PMID:17976834

  7. Effect of pyrrolidine dithiocarbamate on photo-induced proton transport through chloroplast membranes.

    PubMed

    Po, E S; Ho, J W

    1997-12-01

    pH changes produced by photo-induced proton transport through chloroplast membranes in spinach were measured by a glass microelectrode. Effect of pyrrolidine dithiocarbamate on proton translocation through chloroplast membranes has been studied. Kinetic analysis of proton translocation shows that the rate is reduced as the carbamate concentration increases. The rate of proton uptake follows first-order kinetics and diminishes with increasing carbamate concentrations. The outward leakage of accumulated protons through thylakoid membranes in the dark also decreases likewise. However, the leakage of protons takes a much longer time. Pyrrolidine dithiocarbamate is an effective inhibitor of proton transport through chloroplast membranes. The results suggest that the photo-induced proton translocation is regulated by conformation change in the membrane. Higher concentration of carbamate disrupts the tertiary conformation of the membrane. The inhibition of proton transport would affect ATPase function; thus, an excess use or accumulation of pyrrolidine thiocarbamate may compromise ATP production.

  8. The characteristic long-term upregulation of hippocampal NF-κB complex in PTSD-like behavioral stress response is normalized by high-dose corticosterone and pyrrolidine dithiocarbamate administered immediately after exposure.

    PubMed

    Cohen, Hagit; Kozlovsky, Nitsan; Matar, Michael A; Zohar, Joseph; Kaplan, Zeev

    2011-10-01

    Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor for genes involved in cell survival, differentiation, inflammation, and growth. This study examined the role of NF-κB pathway in stress-induced PTSD-like behavioral response patterns in rats. Immunohistochemical technique was used to detect the expression of the NF-κB p50 and p65 subunits, I-κBα, p38, and phospho-p38 in the hippocampal subregions at 7 days after exposure to predator scent stress. Expression of p65 nuclear translocation was quantified by western blot as the level of NF-κB activation. The effects of intraperitoneally administered corticosterone or a selective NF-κB inhibitor (pyrrolidine dithiocarbamate (PDTC)) at 1 h post exposure on behavioral tests (elevated plus-maze and acoustic startle response) were evaluated 7 days later. Hippocampal expressions of those genes were subsequently evaluated. All data were analyzed in relation to individual behavior patterns. Extreme behavioral responder animals displayed significant upregulation of p50 and p65 with concomitant downregulation of I-κBα, p38, and phospho-p38 levels in hippocampal structures compared with minimal behavioral responders and controls. Immediate post-exposure treatment with high-dose corticosterone and PDTC significantly reduced prevalence rates of extreme responders and normalized the expression of those genes. Stress-induced upregulation of NF-κB complex in the hippocampus may contribute to the imbalance between what are normally precisely orchestrated and highly coordinated physiological and behavioral processes, thus associating it with stress-related disorders.

  9. An experimental study on effects of pyrrolidine dithiocarbamate on ischemia-reperfusion injury in testis

    PubMed Central

    Kemahli, Eray; Yildiz, Mevlüt; Firat, Tülin; Özyalvaçli, Mehmet Emin; Üyetürk, Uğur; Yilmaz, Burak; Gücük, Adnan

    2016-01-01

    Introduction: The aim of this experimental study was to investigate the histopathological and biochemical effects of pyrrolidine dithiocarbamate, an antioxidant and inhibitor of NF-kβ, on ischemiareperfusion injury in rats. Methods: A total of 21 male Wistar-Albino rats were randomly distributed into three groups as sham group (Group 1), ischemia-reperfusion (I/R) group (Group 2) and I/R with pyrrolidine dithiocarbamate (PDTC) group (Group 3). Left testicles of rats in Groups 2 and 3 underwent testicular torsion of 720° for four hours and 100 mg/kg of PDTC was administered intraperitoneally prior to detorsion in Group 3. An hour after detorsion process, left orchiectomies were performed and 5 ml of intracardiac blood samples were drawn from rats in all three groups. Histopathological examination of testis tissues performed and measurement of superoxide dismutase (SOD) and malondialdehyde (MDA) levels in blood samples were taken. Results: Elevated levels of MDA and decreased SOD activity, together with decreased Johnson tubular biopsy scores consistent with I/R injury were observed in Group 2 (p<0.05). Group 1 and Group 3 were similar in terms of MDA levels, SOD activity, and Johnson scores (p>0.05). Conclusions: Our results indicated that PDTC may have beneficial effects for alleviation of I/R injury in testicular tissue in rats. Understanding the underlying mechanisms and exploration of its diagnostic and therapeutic potential requires further randomized, controlled trials on a larger scale. PMID:27330576

  10. Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats

    PubMed Central

    Kan, Min Hui; Yang, Ting; Fu, Hui Qun; Fan, Long; Wu, Yan; Terrando, Niccolò; Wang, Tian-Long

    2016-01-01

    Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1β expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure. PMID:27493629

  11. Potentiation of bacterial killing activity of zinc chloride by pyrrolidine dithiocarbamate.

    PubMed

    Choi, Eun-Kyoung; Lee, Hye-Hyang; Kang, Mi-Sun; Kim, Byung-Gook; Lim, Hoi-Soon; Kim, Seon-Mi; Kang, In-Chol

    2010-02-01

    Zinc has antimicrobial activity and zinc salts including zinc chloride (ZnCl(2)) have been used for the control of oral malodor. In this study, we hypothesized that pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, may enhance antimicrobial efficacy of ZnCl(2). The bactericidal effectiveness of ZnCl(2) alone (0.5-8 mM) or in combination with PDTC (1 or 10 microM) was evaluated by in vitro short (1 h) time-killing assays against Fusobacterium nucleatum and Porphyromonas gingivalis. Only a slight viability decrease was observed with ZnCl(2) or PDTC alone after 1-h incubation. By contrast, combination of ZnCl(2) and PDTC could achieve a more than 100-fold viability reduction compared with ZnCl(2) or PDTC alone in F. nucleatum and P. gingivalis. Therefore, PDTC greatly enhanced the bactericidal activity of ZnCl(2) against the oral malodor-producing bacteria. These results suggest that use of PDTC may be useful for enhancing bactericidal activity of antimalodor regimens of zinc salts.

  12. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria

    PubMed Central

    Tapia, Edilia; Sánchez-González, Dolores J.; Medina-Campos, Omar N.; Soto, Virgilia; Ávila-Casado, Carmen; Martínez-Martínez, Claudia M.; Johnson, Richard J.; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Franco, Martha; Sánchez-Lozada, Laura G.

    2008-01-01

    We evaluated whether the blockade of the proinflammatory transcription factor NF-κB would modify the oxidative stress, inflammation, and structural and hemodynamic alterations found in the kidney as a result of massive proteinuria. Twenty male Sprague-Dawley rats were injected with 2 g of BSA intraperitoneally daily for 2 wk. Ten of them received in addition the inhibitor of NF-κB activation pyrrolidine dithiocarbamate (PDTC; 200 mg·kg−1·day−1 sc) and the rest received vehicle. Seven rats that received intraperitoneal saline were used as controls. Glomerular hemodynamics were studied after 14 days. Markers of oxidative stress (NF-κB subunit p65+ cells, 3-nitrotyrosine, and 4-hydroxynonenal), inflammation (cortical CD68+ cells and NOS-II), and afferent arteriole damage were assessed by immunohistochemistry and morphometry. Activity of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase was evaluated in renal cortex and medulla. Albumin overload induced massive proteinuria, oxidative stress with reduced activity of antioxidant enzymes, NF-κB activation, inflammatory cell infiltration, a significant presence of proteinaceous casts, systemic and glomerular hypertension, as well as arteriolar remodeling. Treatment with PDTC prevented or improved all of these findings. In this model of nephrotic syndrome, we demonstrate a key role for oxidative stress and inflammation in causing systemic and glomerular hypertension and proteinuria. Oxidative stress and inflammation may have a key role in accelerating renal injury associated with intense proteinuria. PMID:18753301

  13. Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells.

    PubMed

    Jakubowska-Mućka, Anna; Sieńko, Jacek; Zapała, Łukasz; Wolny, Rafał; Lasek, Witold

    2012-04-01

    Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models.

  14. Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells

    PubMed Central

    JAKUBOWSKA-MUĆKA, ANNA; SIEŃKO, JACEK; ZAPAŁA, ŁUKASZ; WOLNY, RAFAŁ; LASEK, WITOLD

    2012-01-01

    Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by Western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models. PMID:22266802

  15. Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

    PubMed Central

    VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James A.

    2016-01-01

    Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. PMID:27449092

  16. Copper uptake is required for pyrrolidine dithiocarbamate-mediated oxidation and protein level increase of p53 in cells.

    PubMed Central

    Furuta, Saori; Ortiz, Fausto; Zhu Sun, Xiu; Wu, Hsiao-Huei; Mason, Andrew; Momand, Jamil

    2002-01-01

    The p53 tumour-suppressor protein is a transcription factor that activates the expression of genes involved in cell cycle arrest, apoptosis and DNA repair. The p53 protein is vulnerable to oxidation at cysteine thiol groups. The metal-chelating dithiocarbamates, pyrrolidine dithiocarbamate (PDTC), diethyldithiocarbamate, ethylene(bis)dithiocarbamate and H(2)O(2) were tested for their oxidative effects on p53 in cultured human breast cancer cells. Only PDTC oxidized p53, although all oxidants tested increased the p53 level. Inductively coupled plasma MS analysis indicated that the addition of 60 microM PDTC increased the cellular copper concentration by 4-fold, which was the highest level of copper accumulated amongst all the oxidants tested. Bathocuproinedisulphonic acid, a membrane-impermeable Cu(I) chelator inhibited the PDTC-mediated copper accumulation. Bathocuproinedisulphonic acid as well as the hydroxyl radical scavenger d-mannitol inhibited the PDTC-dependent increase in p53 protein and oxidation. Our results show that a low level of copper accumulation in the range of 25-40 microg/g of cellular protein increases the steady-state levels of p53. At copper accumulation levels higher than 60 microg/g of cellular protein, p53 is oxidized. These results suggest that p53 is vulnerable to free radical-mediated oxidation at cysteine residues. PMID:11964141

  17. Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

    PubMed Central

    Ta, Michelle H. T.; Rao, Padmashree; Korgaonkar, Mayuresh; Foster, Sheryl F.; Peduto, Anthony; Harris, David C. H.; Rangan, Gopala K.

    2014-01-01

    Abstract Heterocyclic dithiocarbamates have anti‐inflammatory and anti‐proliferative effects in rodent models of chronic kidney disease. In this study, we tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) reduces the progression of polycystic kidney disease (PKD). Male Lewis polycystic kidney (LPK) rats (an ortholog of Nek8/NPHP9) received intraperitoneal injections of either saline vehicle or PDTC (40 mg/kg once or twice daily) from postnatal weeks 4 until 11. By serial magnetic resonance imaging at weeks 5 and 10, the relative within‐rat increase in total kidney volume and cyst volume were 1.3‐fold (P =0.01) and 1.4‐fold (P < 0.01) greater, respectively, in LPK + Vehicle compared to the LPK + PDTC(40 mg/kg twice daily) group. At week 11 in LPK rats, PDTC attenuated the increase in kidney weight to body weight ratio by 25% (P < 0.01) and proteinuria by 66% (P < 0.05 vs. LPK + Vehicle) but did not improve renal dysfunction. By quantitative whole‐slide image analysis, PDTC did not alter interstitial CD68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor (NF)‐κB subunit, p105, was increased in cystic epithelial cells of LPK rats, but was not altered by PDTC. Moreover, PDTC did not significantly alter nuclear expression of the p50 subunit or NF‐κB (p65)‐DNA binding. Kidney enlargement in LPK rats was resistant to chronic treatment with a proteasome inhibitor, bortezomib. In conclusion, PDTC reduced renal cystic enlargement and proteinuria but lacked anti‐inflammatory effects in LPK rats. PMID:25501440

  18. Crystal structure and carrier transport properties of a new 3D mixed-valence Cu(I)-Cu(II) coordination polymer including pyrrolidine dithiocarbamate ligand.

    PubMed

    Okubo, Takashi; Tanaka, Naoya; Kim, Kyung Ho; Anma, Haruho; Seki, Shu; Saeki, Akinori; Maekawa, Masahiko; Kuroda-Sowa, Takayoshi

    2011-03-14

    A novel mixed-valence Cu(i)-Cu(ii) coordination polymer having an infinite three-dimensional (3D) structure, {[Cu(I)(4)Cu(II)(2)Br(4)(Pyr-dtc)(4)]·CHCl(3)}(n) (1) (Pyr-dtc(-) = pyrrolidine dithiocarbamate), has been prepared and structurally characterized via X-ray diffraction. This complex consists of 1D Cu(i)-Br chains and bridging mononuclear copper(ii) units of Cu(II)(Pyr-dtc)(2), which form an infinite 3D network. A magnetic study indicates that this complex includes copper(ii) ions exhibiting a weak antiferromagnetic interaction (θ = -0.086 K) between the unpaired electrons of the copper(ii) ions present in the diamagnetic Cu(i)-Br chains. The carrier transport properties of 1 are investigated using an impedance spectroscopy technique and flash-photolysis time-resolved microwave conductivity measurement (FP-TRMC). The impedance spectroscopy reveals that this complex exhibits intriguing semiconducting properties at a small activation energy (E(a) = 0.29 eV (bulk)). The sum of the mobilities of the negative and positive carriers estimated via FP-TRMC is Σμ∼ 0.4 cm(2) V(-1) s(-1).

  19. Pyrrolidine dithiocarbamate inhibits UVB-induced skin inflammation and oxidative stress in hairless mice and exhibits antioxidant activity in vitro.

    PubMed

    Ivan, Ana L M; Campanini, Marcela Z; Martinez, Renata M; Ferreira, Vitor S; Steffen, Vinicius S; Vicentini, Fabiana T M C; Vilela, Fernanda M P; Martins, Frederico S; Zarpelon, Ana C; Cunha, Thiago M; Fonseca, Maria J V; Baracat, Marcela M; Georgetti, Sandra R; Verri, Waldiceu A; Casagrande, Rúbia

    2014-09-05

    Ultraviolet B (UVB) irradiation may cause oxidative stress- and inflammation-dependent skin cancer and premature aging. Pyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibits nuclear factor-κB (NF-κB) activation. In the present study, the mechanisms of PDTC were investigated in cell free oxidant/antioxidant assays, in vivo UVB irradiation in hairless mice and UVB-induced NFκB activation in keratinocytes. PDTC presented the ability to scavenge 2,2'-azinobis-(3-ethyl benzothiazoline-6-sulfonic acid) radical (ABTS), 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH) and hydroxyl radical (OH); and also efficiently inhibited iron-dependent and -independent lipid peroxidation as well as chelated iron. In vivo, PDTC treatment significantly decreased UVB-induced skin edema, myeloperoxidase (MPO) activity, production of the proinflammatory cytokine interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), increase of reduced glutathione (GSH) levels and antioxidant capacity of the skin tested by the ferric reducing antioxidant power (FRAP) and ABTS assays. PDTC also reduced UVB-induced IκB degradation in keratinocytes. These results demonstrate that PDTC presents antioxidant and anti-inflammatory effects in vitro, which line up well with the PDTC inhibition of UVB irradiation-induced skin inflammation and oxidative stress in mice. These data suggest that treatment with PDTC may be a promising approach to reduce UVB irradiation-induced skin damages and merits further pre-clinical and clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells.

    PubMed

    Thompson, John S; Asmis, Reto; Tapp, Andrea A; Nelson, Brandy; Chu, Yanxia; Glass, Judith; Moneyhon, Micheal; Brown, Stephen A

    2010-06-01

    Ionizing radiation (IR) is a pro-oxidant that kills cells by both apoptotic and necrotic mechanisms. Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that may act either as a pro- or anti-oxidant depending on the experimental conditions. This study was designed to determine whether PDTC would reduce or enhance IR-induced cell death of freshly-isolated normal mouse B6/129 spleen cells (NMSC). We determined the effect of increasing doses of IR, PDTC alone and PDTC followed by IR on the viability of NMSC. Annexin V and propidium iodide (Annexin V/PI) staining demonstrated a dose and time-dependent relationship in which PDTC enhanced the percentage of IR-induced apoptotic/necrotic NMSC. Trypan blue dye inclusion confirmed that a loss of membrane integrity was occurring 1 h after incubation with PDTC plus IR. Reduction in the glutathione (GSH)/glutathione disulfide (GSSG) ratio and GSH demonstrated that both IR (8.5 Gy) and PDTC acted as pro-oxidants, but their mechanisms of action differed: In contrast to IR, which promoted p53 activation and caspase 3/7-mediated apoptosis, PDTC inhibited IR-induced p53 and caspase 3/7 activity. However, PDTC increased H(2)O(2) formation and necrosis, resulting in an overall increase in IR-induced cell death. Catalase prevented the PDTC-induced increase in IR cytotoxicity implicating the generation of H(2)O(2) as a major factor in this mechanism. These results demonstrate that in NMSC PDTC acts as pro-oxidant and enhances IR-induced cell cytotoxicity by increasing H(2)O(2)formation and thiol oxidation. As such, they strongly suggest that the use of PDTC as an adjunct to reduce radiation toxicity should be avoided.

  1. Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia-reperfusion injury in rats.

    PubMed

    Yucel, Mehmet; Kucuk, Aysegul; Bayraktar, Aslihan Cavunt; Tosun, Murat; Yalcinkaya, Soner; Hatipoglu, Namik Kemal; Erkasap, Nilufer; Kavutcu, Mustafa

    2013-10-01

    The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia-reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p < 0.05). The TBARS levels were significantly decreased in group III compared with the group II (p < 0.05). CAT, SOD and GST activities were decreased in group II, but these enzymes levels were significantly increased in group III according to the group II (p < 0.05). Under microscopic evaluation NF-кB expression increased significantly in group II compared to the group I (p < 0.05) and then decreased in group III (p < 0.05). HSP60 and p53 expression in group II was increased significantly compared with group I. Under microscopic evaluation we detected that HSP60 and p53 expression was increased significantly in group II compared with group I. In group III PDTC administration was decreased the HSP60 and p53 expression, this difference was statistically significant (p < 0.05). The results of the present study have demonstrated that NF-кB inhibition with PDTC protects and provides beneficial effects on ischemia/reperfusion stress related bladder tissue destruction.

  2. Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB.

    PubMed

    Zhang, J; Jiang, W; Zuo, Z

    2014-03-07

    Surgery induces learning and memory impairment. Neuroinflammation may contribute to this impairment. Nuclear factor κB (NF-κB) is an important transcription factor to regulate the expression of inflammatory cytokines. We hypothesize that inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC) reduces neuroinflammation and the impairment of learning and memory. To test this hypothesis, four-month-old male Fischer 344 rats were subjected to right carotid exploration under propofol and buprenorphine anesthesia. Some rats received two doses of 50mg/kg PDTC given intraperitoneally 30min before and 6h after the surgery. Rats were tested in the Barnes maze and fear conditioning paradigm begun 6days after the surgery. Expression of various proteins related to inflammation was examined in the hippocampus at 24h or 21days after the surgery. Here, surgery, but not anesthesia alone, had a significant effect on prolonging the time needed to identify the target hole during the training sessions of the Barnes maze. Surgery also increased the time for identifying the target hole in the long-term memory test and decreased context-related learning and memory in fear conditioning test. Also, surgery increased nuclear expression of p65, a NF-κB component, decreased cytoplasmic amount of inhibitor of NF-κB, and increased the expression of interleukin-1β, interleukin-6, ionized calcium binding adaptor molecule 1 and active matrix metalloproteinase 9 (MMP-9). Finally, surgery enhanced IgG extravasation in the hippocampus. These surgical effects were attenuated by PDTC. These results suggest that surgery, but not propofol-based anesthesia, induces neuroinflammation and impairment of learning and memory. PDTC attenuates these effects possibly by inhibiting NF-κB activation and the downstream MMP-9 activity.

  3. Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu(2+) and Zn(2+).

    PubMed

    Erl, W; Weber, C; Hansson, G K

    2000-06-01

    Pyrrolidine dithiocarbamate (PDTC) has been found to induce or inhibit apoptosis in different cell types. Here we show that PDTC dose-dependently reduced the viability of rat smooth muscle cells (rSMC), human fibroblasts, and endothelial cells at low but not at high cell density. Endothelial cells were least sensitive, fibroblasts showed a medium sensitivity, and rSMC showed a high sensitivity to PDTC-mediated cell death. An early reduction in the mitochondrial membrane potential indicated a rapid onset of apoptosis in rSMC. Apoptosis was further confirmed by annexin V staining and DNA fragmentation analysis. Gel shift analysis demonstrated increased nuclear factor (NF)-kappaB activity in high-density rSMC compared with low-density cells. NF-kappaB has recently been shown to regulate the induction of anti-apoptotic proteins. Although PDTC is widely used as an inhibitor for NF-kappaB and a radical scavenger, our data show that PDTC rather enhanced NF-kappaB activity and, alone or in combination with menadione, induced oxygen radical generation. Notably, PDTC failed to reduce rSMC viability in medium without Cu(2+) or Zn(2+), and addition of Cu(2+) or Zn(2+) resulted in a dose-dependent increase in PDTC-induced cell death. Addition of both Cu(2+) and Zn(2+) showed synergistic effects. Our results indicate that the induction of apoptosis by PDTC requires Cu(2+) and Zn(2+) and is dependent on cell type and density. Such differential effects may have implications for studies of PDTC as an anti-atherosclerotic or immunomodulatory drug.

  4. Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension

    PubMed Central

    Cau, SBA; Guimaraes, DA; Rizzi, E; Ceron, CS; Souza, LL; Tirapelli, CR; Gerlach, RF; Tanus-Santos, JE

    2011-01-01

    BACKGROUND AND PURPOSE Mounting evidence implicates matrix metalloproteinase (MMP) in the vascular dysfunction and remodelling associated with hypertension. We tested the hypothesis that treatment with pyrrolidine dithiocarbamate (PDTC), which interferes with NF-κB-induced MMPs gene transcription, could exert antihypertensive effects, prevent MMP-2 and MMP-9 up-regulation, and protect against the functional alterations and vascular remodelling of two-kidney, one clip (2K1C) hypertension. EXPERIMENTAL APPROACH Sham-operated or hypertensive rats were treated with vehicle or PDTC (100 mg·Kg−1·day−1) by gavage for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic rings were isolated to assess endothelium-dependent relaxations. Quantitative morphometry of structural alterations of the aortic wall was carried out in haematoxylin/eosin sections. Formation of vascular reactive oxygen species (ROS), and inducible (i) NOS and phosphorylated-p65 NF-κB subunit expression were measured in the aortas. MMP-2 and MMP-9 aortic levels and gelatinolytic activity were determined by gelatin and in situ zymography and by immunofluorescence. KEY RESULTS Treatment with PDTC attenuated the increases in SBP and prevented the endothelial dysfunction associated with 2K1C hypertension. Moreover, PDTC reversed the vascular aortic remodelling, the increases in aortic ROS levels and in iNOS and phosphorylated-p65 NF-κB expression found in 2K1C rats. These effects were associated with attenuation of 2K1C up-regulation of aortic MMP-2 and MMP-9 levels and gelatinolytic activity. CONCLUSION AND IMPLICATIONS These findings suggest that PDTC down-regulates vascular MMPs and ameliorates vascular dysfunction and remodelling in renovascular hypertension, thus providing evidence supporting the suggestion that PDTC is probably a good candidate to be used to treat hypertension. PMID:21434884

  5. In vitro antitumour and antibacterial studies of some Pt(IV) dithiocarbamate complexes

    NASA Astrophysics Data System (ADS)

    Manav, N.; Mishra, A. K.; Kaushik, N. K.

    2006-09-01

    A few Pt(IV) complexes of the type [Pt(L) 2Cl 2] [where L = morpholine dithiocarbamate (L 1), aniline dithiocarbamate (L 2), N-(methyl, cyclohexyl) dithiocarbamate (L 3) and N-(ethyl, cyclohexyl) dithiocarbamate (L 4)] were synthesized. The complexes have been characterized by elemental analysis, molar conductance, IR, electronic, 1H and 13C NMR spectroscopic studies. The ligands found to act in monobasic bidentate fashion. Cyclicvoltammetric studies, antibacterial and in vitro antitumour studies were also carried out.

  6. New mono-organotin (IV) dithiocarbamate complexes

    NASA Astrophysics Data System (ADS)

    Muthalib, Amirah Faizah Abdul; Baba, Ibrahim

    2014-09-01

    Eighteen new mono-organotin dithiocarbamate compounds derived each nine from methyltin(IV) and phenyltin(IV) reacted using in-situ method with various type of N-dialkylamine together with carbon disulphide with the ratio of 1:3:3. Elemental and gravimetric analysis showed that the general formula of these compounds were RSnCl[S2CNR'R″]2 (R= Ph, CH3, R' = CH3, C2H5, C7H7 and R″ = C2H5, C6H11, iC3H7, C7H7). These compounds had been characterized by infrared spectroscopy, ultraviolet spectroscopy, 1H, 13C NMR spectroscopy and single crystal X-ray crystallography. The infrared spectra of these compounds showed three important peaks indicating the formation of dithiocarbamate compounds, ν(CN), ν(CS) and ν(Sn-S) band which present in the region of 1444-1519, 954-1098 and 318-349 cm-1 respectively. The ultraviolet-visible spectra showed an absorption band for the π - π* transition of NCS group in the range of 253 - 259 nm due to the intramolecular charge transfer of the ligand. The 13C NMR spectra showed an important shift for δ(N13CS2) in the range of 196.8 - 201.9 ppm.. Single crystal X-ray diffraction studies showed three new structures with the general formula of PhSnCl[S2CN(Et)(i-Pr)]2, MeSnCl[S2CN(Me)(Cy)]2 and MeSnCl[S2CN(i-Pr)(CH2Ph)]2. All structures having a distorted octahedral geometry set by CClS4 donor atom from the two chelating dithiocarbamate ligands.

  7. New mono-organotin (IV) dithiocarbamate complexes

    SciTech Connect

    Muthalib, Amirah Faizah Abdul; Baba, Ibrahim

    2014-09-03

    Eighteen new mono-organotin dithiocarbamate compounds derived each nine from methyltin(IV) and phenyltin(IV) reacted using in-situ method with various type of N-dialkylamine together with carbon disulphide with the ratio of 1:3:3. Elemental and gravimetric analysis showed that the general formula of these compounds were RSnCl[S{sub 2}CNR′R″]{sub 2} (R= Ph, CH{sub 3}, R′ = CH{sub 3}, C{sub 2}H{sub 5}, C{sub 7}H{sub 7} and R″ = C{sub 2}H{sub 5}, C{sub 6}H{sub 11}, iC{sub 3}H{sub 7}, C{sub 7}H{sub 7}). These compounds had been characterized by infrared spectroscopy, ultraviolet spectroscopy, {sup 1}H, {sup 13}C NMR spectroscopy and single crystal X-ray crystallography. The infrared spectra of these compounds showed three important peaks indicating the formation of dithiocarbamate compounds, ν(CN), ν(CS) and ν(Sn-S) band which present in the region of 1444–1519, 954–1098 and 318–349 cm{sup −1} respectively. The ultraviolet-visible spectra showed an absorption band for the π - π* transition of NCS group in the range of 253 – 259 nm due to the intramolecular charge transfer of the ligand. The {sup 13}C NMR spectra showed an important shift for δ(N{sup 13}CS{sub 2}) in the range of 196.8 – 201.9 ppm.. Single crystal X-ray diffraction studies showed three new structures with the general formula of PhSnCl[S{sub 2}CN(Et)(i−Pr)]{sub 2}, MeSnCl[S{sub 2}CN(Me)(Cy)]{sub 2} and MeSnCl[S{sub 2}CN(i−Pr)(CH{sub 2}Ph)]{sub 2}. All structures having a distorted octahedral geometry set by CClS{sub 4} donor atom from the two chelating dithiocarbamate ligands.

  8. Pyrrolidine Dithiocarbamate Inhibits Herpes Simplex Virus 1 and 2 Replication, and Its Activity May Be Mediated through Dysregulation of the Ubiquitin-Proteasome System

    PubMed Central

    Qiu, Min; Chen, Yu; Cheng, Lin; Chu, Ying; Song, Hong-Yong

    2013-01-01

    Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF-κB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus, and influenza virus. In this paper, we report that PDTC could inhibit the replication of herpes simplex virus 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediate early (IE) and late (membrane protein gD) genes and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn2+. Although PDTC could potently block reactive oxygen species (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting the mitogen-activated protein kinase (MAPK) pathway activation induced by viral infection that was vital for the virus's propagation. We found that PDTC modulated cellular ubiquitination and, furthermore, influenced HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced PML stability in the nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of the cellular ubiquitin-proteasome system (UPS). PMID:23740985

  9. Metabonomic potential plasma biomarkers in abnormal fast buoyancy ascent escape-induced decompression sickness model and the protective effects of pyrrolidine dithiocarbamic acid.

    PubMed

    Yiqun, Fan; Pu, You; Haitao, Wang; Xiaochen, Bao; Jun, Ma; Shi, Zhang; Yinghui, Fan

    2017-01-01

    Decompression sickness (DCS) induced by fast buoyancy ascent escape (FBAE) is a special DCS, characterized with cardiopulmonary injuries. Serum metabonomics of this type of DCS has not yet been studied. We proposed a metabonomics approach for assessing serum metabonomics changes and evaluating the preventive effect of pyrrolidine dithiocarbamic acid (PDTC) in FBAE-induced DCS rats. Sixty-five (65) rats were divided into three groups, including the Control, DCS and PDTC groups. After receiving physiological saline or PDTC pretreatment, rats in the DCS and PDTC groups received the same protocol of simulated FBAE. Following this, a metabonomics approach - combined with pattern recognition methods including PCA and PLS-DA - was used to characterize the global serum metabolic profile on survival rats (five rats per group) associated with abnormal FBAE-induced DCS. As the VIP-value threshold cutoff of the metabolites was set to 2, metabolites above this threshold were filtered out as potential target biomarkers. Sixteen (16) distinct potential biomarkers in rat plasma were identified. PDTC significantly lowered DSC mortality from 60% to 10%, and alleviated ultrastructural alteration of the left ventricular apex compared to the DCS group. It was found that abnormal FBAE-induced DCS was closely related to disturbed fatty acid metabolism, glycerophospholipid metabolism, sterol lipid metabolism, and bile acid metabolism. With the presented metabonomic method, we systematically analyzed the protective effects of PDTC. The results demonstrated that PDTC administration could provide satisfactory effects on abnormal FBAE-induced DCS through partially regulating the perturbed metabolic pathways.

  10. Determination of lead in blood by chelation with ammonium pyrrolidine dithio-carbamate followed by tungsten-coil atomic absorption spectrometry

    NASA Astrophysics Data System (ADS)

    Salido, Arthur; Sanford, Caryn L.; Jones, Bradley T.

    1999-08-01

    An inexpensive, bench-top blood Pb analyzer has been developed. The system is based on tungsten-coil atomic absorption spectrometry. Pb atomization occurs on W-coils extracted from commercially available slide projector bulbs. The system has minimal power requirements: 120 ACV and 15 A. A small, computer-controlled CCD spectrometer is used as the detector. A Pb hollow cathode lamp is used as the source. Blood Pb is chelated with ammonium pyrrolidine dithio-carbamate and extracted into methyl iso-butyl ketone (4-methyl 2-pentanone). Twenty-microliter volumes of the organic phase are deposited on the W-coil, dried at 1.4 A, charred at 2.3 A and atomized at 6.0 A. Graphite furnace atomic absorption spectrometry is used as a comparison for W-coil results. Levels 1-4 of a NIST standard reference material 955b ‘lead in bovine blood’ are used to test accuracy and precision. The analytical figures of merit for the system are: 12-pg instrument detection limit, 24-pg blood detection limit and a characteristic mass of 28 pg.

  11. Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate.

    PubMed

    Kitamei, Hirokuni; Iwabuchi, Kazuya; Namba, Kenichi; Yoshida, Kazuhiko; Yanagawa, Yoshiki; Kitaichi, Nobuyoshi; Kitamura, Mizuki; Ohno, Shigeaki; Onoé, Kazunori

    2006-06-01

    Experimental autoimmune uveoretinitis (EAU) is a T helper type 1 cell-mediated autoimmune disease, which serves as a model of human chronic uveitis. In this model, cells of a monocyte/macrophage lineage and retinal antigen (Ag)-specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory cytokines and various stimuli activate a transcriptional factor, nuclear factor-kappaB (NF-kappaB), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), was examined in a murine EAU model. It was shown that PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice. mRNA expressions of tumor necrosis factor alpha and interleukin-1beta were suppressed in eyes of PDTC-treated EAU mice. However, when T cells from PDTC-treated EAU mice, Ag-presenting cells (APC), and the retinal Ag peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell-proliferative response and cytokine production. Pretreatment of Ag-primed T cells or APC with PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of PDTC is attributed mainly to the suppression of effector-phase responses including inflammation but not to the inhibition of T cell priming. Regulation of NF-kappaB pathway in the lesion could be a novel target for the successful control of uveoretinitis.

  12. Activation of heat shock factor 1 plays a role in pyrrolidine dithiocarbamate-mediated expression of the co-chaperone BAG3.

    PubMed

    Song, Shaoming; Kole, Sutapa; Precht, Patricia; Pazin, Michael J; Bernier, Michel

    2010-11-01

    Adaptive responses to physical and inflammatory stressors are mediated by transcription factors and molecular chaperones. The transcription factor heat shock factor 1 (HSF1) has been implicated in extending lifespan in part by increasing expression of heat shock response genes. Pyrrolidine dithiocarbamate (PDTC) is a small thiol compound that exerts in vivo and in vitro anti-inflammatory properties through mechanisms that remain unclear. Here we report that PDTC induced the release of monomeric HSF1 from the molecular chaperone heat shock protein 90 (Hsp90), with concomitant increase in HSF1 trimer formation, translocation to the nucleus, and binding to promoter of target genes in human HepG2 cells. siRNA-mediated silencing of HSF1 blocked BAG3 gene expression by PDTC. The protein levels of the co-chaperone BAG3 and its interaction partner Hsp72 were stimulated by PDTC in a dose-dependent fashion, peaking at 6h. Inhibition of Hsp90 function by geldanamycin derivatives and novobiocin elicited a pattern of HSF1 activation and BAG3 expression that was similar to PDTC. Chromatin immunoprecipitation studies showed that PDTC and the inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhanced the binding of HSF1 to the promoter of several target genes, including BAG3, HSPA1A, HSPA1B, FKBP4, STIP1 and UBB. Cell treatment with PDTC increased significantly the level of Hsp90α thiol oxidation, a posttranslational modification known to inhibit its chaperone function. These results unravel a previously unrecognized mechanism by which PDTC and related compounds could confer cellular protection against inflammation through HSF1-induced expression of heat shock response genes. Published by Elsevier Ltd.

  13. Pyrrolidine Dithiocarbamate Inhibits Nuclear Factor κB and Toll-Like Receptor 4 Expression in Rats with Acute Necrotizing Pancreatitis

    PubMed Central

    Xu, Min; Wang, Kun-Ning; Wu, Kai; Wang, Xing-Peng

    2015-01-01

    Background/Aims To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor κB (NF-κB), as well as to determine the relationship between TLR4 and NF-κB in ANP pathogenesis. Methods A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-κB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor α, interleukin (IL)-1β, and IL-6 were measured by reverse transcription polymerase chain reaction. Results The expressions of TLR4, NF-κB, and cytokine (NF-κB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-κB, and cytokine genes in the pancreatic tissue. Conclusions The expressions of TLR4 and NF-κB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-κB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes. PMID:25287011

  14. Pyrrolidine dithiocarbamate attenuates paraquat-induced acute pulmonary poisoning in vivo via transforming growth factor β1 and nuclear factor κB pathway interaction.

    PubMed

    Huang, M; Lou, D; Li, H-H; Cai, Q; Wang, Y-P; Yang, H-F

    2016-12-01

    Paraquat (PQ) exposure could cause pulmonary fibrosis. The aim of this study was to investigate the protective effect of pyrrolidine dithiocarbamate (PDTC) in an acute PQ poison model. One hundred and forty-four Sprague Dawley rats were equally divided into three experimental groups: control group, PQ group, and PQ + PDTC group. At days 1, 3, 7, 14, 28, and 56 of treatment, the serum levels of transforming growth factor β1 (TGF-β1), the levels of hydroxyproline, the protein expression of nuclear factor κB (NF-κB) pathway, and histopathological change in lung tissue were assessed. The survival rate of rats treated with PQ + PDTC was increased compared with that of rats treated only with PQ (p < 0.05), and the occurrence of pathological changes was dramatically attenuated in the PQ + PDTC group. The serum levels of TGF-β1 and the hydroxyproline levels in the PQ group were significantly increased in a time-dependent manner compared with those in the control and PQ + PDTC groups on days 7, 14, 28, and 56 (p < 0.05). Additionally, the protein levels of NF-κB proteins p65, inhibitor of κB (IκB) kinase (IKKβ, and IκB-α were significantly downregulated in the PQ + PDTC group as determined by array analysis. The present findings suggest that overexpression of TGF-β1 may play an important role in PQ-induced lung injury and that PDTC, a strong NF-κB inhibitor, can rescue PQ-induced pulmonary fibrosis by influencing the protein expression of NF-κB pathway. © The Author(s) 2016.

  15. Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia

    PubMed Central

    Francioli, Cyril; Wang, Xingyu; Parapanov, Roumen; Abdelnour, Etienne; Lugrin, Jérôme; Gronchi, Fabrizio; Perentes, Jean; Eckert, Philippe; Ris, Hans-Beat; Piquilloud, Lise

    2017-01-01

    Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation. PMID:28323904

  16. The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase-2 Up-Regulation in Renovascular Hypertension.

    PubMed

    Cau, Stefany B A; Guimaraes, Danielle A; Rizzi, Elen; Ceron, Carla S; Gerlach, Raquel F; Tanus-Santos, Jose E

    2015-10-01

    Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  17. Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.

    PubMed

    Francioli, Cyril; Wang, Xingyu; Parapanov, Roumen; Abdelnour, Etienne; Lugrin, Jérôme; Gronchi, Fabrizio; Perentes, Jean; Eckert, Philippe; Ris, Hans-Beat; Piquilloud, Lise; Krueger, Thorsten; Liaudet, Lucas

    2017-01-01

    Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation.

  18. Polynuclear transition metal complexes with thiocarbohydrazide and dithiocarbamates

    NASA Astrophysics Data System (ADS)

    Siddiqi, K. S.; Khan, Sadaf; Nami, Shahab A. A.; El-ajaily, M. M.

    2007-07-01

    Sn(tch) 2{MCl 2} 2 was prepared from the precursor Sn(tch) 2 and MCl 2. It was subsequently allowed to react with diethyldithiocarbamate which yielded the trinuclear complexes of the type Sn(tch) 2{M 2(dtc) 4}, where tch = thiocarbohydrazide, M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and dtc = diethyldithiocarbamate. They were characterized on the basis of microanalytical, thermal (TGA/DSC), spectral (IR, UV-vis, EPR, 1H NMR) studies, conductivity measurement and magnetic moment data. On the basis of spectral data a tetrahedral geometry has been proposed for the halide complexes, Sn(tch) 2{MCl 2} 2 except for Cu(II) which exhibits a square planar coordination although the transition metal ion in Sn(tch) 2{M 2(dtc) 4} achieves an octahedral geometry where the dithiocarbamato moiety acts as a symmetrical bidentate ligand. The bidentate nature has been established by the appearance of a sharp single ν(C-S) around 1000 cm -1. A downfield shift observed in NH a and NH b protons on moving from Sn(tch) 2 to Sn(tch) 2{MCl 2} 2 is due to the drift of electrons toward metal atoms. A two-step pyrolysis has been observed in the Sn(tch) 2{MCl 2} 2 complexes while their dithiocarbamato derivatives exhibit a three-stage degradation pattern. Finally, the in vitro antibacterial activity of Sn(tch) 2{M 2(dtc) 4} and the mononuclear Sn(tch) 2 has been carried out on bacterial strains Escherichia coli and Salmonella typhi. The compounds were found to be active against the test organisms. The activity of the complexes is enhanced with increasing concentration. The maximum activity in both the strains was achieved by cobalt(II) dithiocarbamate complex. Minimum activity was found for Sn(tch) 2 which generally increases with the introduction of transition metal ion in the complex.

  19. Triphenyl phosphine adducts of platinum(IV) and palladium(II) dithiocarbamates complexes: a spectral and in vitro study

    NASA Astrophysics Data System (ADS)

    Manav, N.; Mishra, A. K.; Kaushik, N. K.

    2004-11-01

    Triphenyl phosphine adducts of dithiocarbamate complexes of platinum(IV) and palladium(II) of the type [Pt(L) 2PPh 3Cl 2] and [Pd(L) 2PPh 3] [L: morpholine dithiocarbamate (L 1), aniline dithiocarbamate (L 2) and N-(methyl, cyclohexyl) dithiocarbamate (L 3)] were prepared and characterized by elemental analysis, electronic, IR, 1H NMR and 13C NMR spectral studies. Thermal studies of the complexes were carried out. In vitro antitumor activity has been screened towards human adenocarcinoma cell lines and showed significant inhibition even at very low concentration.

  20. Synthesis, NMR spectral and structural studies on mixed ligand complexes of Pd(II) dithiocarbamates: First structural report on palladium(II) dithiocarbamate with SCN-ligand

    NASA Astrophysics Data System (ADS)

    Prakasam, Balasubramaniam Arul; Lahtinen, Manu; Peuronen, Anssi; Muruganandham, Manickavachagam; Kolehmainen, Erkki; Haapaniemi, Esa; Sillanpää, Mika

    2016-03-01

    Three new mixed ligand complexes of palladium(II) dithiocarbamates; [Pd(4-dpmpzdtc)(PPh3)(SCN)] (1), [Pd(4-dpmpzdtc)(PPh3)Cl] (2) and [Pd(bzbudtc)(PPh3)Cl] (3), (where, 4-dpmpzdtc = 4-(diphenylmethyl)piperazinecarbodithioato anion, bzbudtc = N-benzyl-N-butyldithiocarbamato anion and PPh3 = triphenylphosphine) have been synthesized from their respective parent dithiocarbamates by ligand exchange reactions and characterized by IR and NMR (1H, 13C and 31P) spectroscopy. IR and NMR spectral data support the isobidentate coordination of the dithiocarbamate ligands in all complexes (1-3) in solid and in solution, respectively. Single crystal diffraction analysis of complexes 1-3 evidences that all three complexes are exhibiting distorted square planar geometry. The Pd-S distances in 1-3 vary in accordance with the differences in trans influences of PPh3, SCN- and Cl- and it is in the order of PPh3 > SCN- > and Cl-. Interchange of the anionic auxiliary ligand (SCN- to Cl-) induces asymmetry to the dithiocarbamate-metal bonds. Thioureide C-N bond distances are short in 1-3, supporting a contribution of thioureide form to the structures. The observed distortions in the square planar geometry for 1-3, are in the order of 1 > 2 > 3.

  1. Spectral, thermal and in vitro antimicrobial studies of cyclohexylamine- N-dithiocarbamate transition metal complexes

    NASA Astrophysics Data System (ADS)

    Mamba, Saul M.; Mishra, Ajay K.; Mamba, Bhekie B.; Njobeh, Patrik B.; Dutton, Mike F.; Fosso-Kankeu, Elvis

    2010-10-01

    Transition metal complexes of the type [M(L) 2] and those containing monodentate phosphines of the type [M(L) 2(PPh 3)] {M = Ni, Co, Cu and Zn; L = cyclohexylamine- N-dithiocarbamate; PPh 3 = triphenylphosphine} have been synthesized. The complexes were characterized using IR, UV-vis, NMR spectroscopy, and thermal analysis (TGA). The 1H NMR, 13C NMR and 31P NMR showed the expected signals for the dithiocarbamate and triphenylphosphine moieties. The spectral studies in all compounds revealed that the coordination of metals occurs via the sulphur atom of the dithiocarbamate ligand in a bidentate fashion. Thermal behavior of the complexes showed that the complexes were more stable than their parent ligands. The ligand moiety is lost in the first step and the rest of the organic moiety decomposes in the subsequent steps. Furthermore, the ligand and their metal complexes were screened in vitro for their antibacterial activity against Escherichia coli, Staphylococcus aureus, Salmonella typhi, Enterococcus faecalis, Pseudomonas aeruginosa and Bacillus cereus and antifungal activities against Aspergillus flavus, Aspergillus carbonarius, Aspergillus niger and Aspergillus fumigatus. The metal complexes exhibited higher antimicrobial activity than the parent ligands. Generally, the zinc complexes were effective against the growth of bacteria with Zn(L) 2 displaying broad spectrum bacteriocidal activity at concentrations of 50 μg/mL; and Ni(L) 2 was more effective against the growth of fungi at concentrations of 100-400 μg/mL under laboratory conditions.

  2. Synthesis and structural characterization of new dithiocarbamate complexes from Sb(III) and Bi(III)

    SciTech Connect

    Jamaluddin, Nur Amirah; Baba, Ibrahim

    2013-11-27

    Twenty new antimony and bismuth dithiocarbamate complexes which employed ten different type of amines have been successfully synthesized. The synthesized complexes with metal to dithiocarbamate ratio at 1:3. Elemental analysis of the complexes gave the general formula of MCl[S{sub 2}CNR’R”]{sub 2} where M = Sb(III), Bi(III); R’ = methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, benzyl; R” = ethanol, methyl, ethyl, propyl, isopropyl, cyclohexyl, benzyl. The complexes were analysed by IR and NMR spectroscopy. The crystal structure of five-coordinated antimony (III) complex have been determined by X-ray single crystal diffraction. Single crystal X-ray diffraction studies on SbCl[S{sub 2}CN(C{sub 4}H{sub 9})(C{sub 2}H{sub 5})]{sub 2} adopted a triclinic system with a space group P1 with a = 10.0141(8) Å, b = 10.1394(7) Å, c = 11.8665(9) Å, α = 67.960°, β =87.616°, γ = 80.172°.

  3. Nickel(II) Dithiocarbamate Complexes Containing Sulforhodamine B as Fluorescent Probes for Selective Detection of Nitrogen Dioxide

    PubMed Central

    Yan, Yan; Krishnakumar, Saarangan; Yu, Huan; Ramishetti, Srinivas; Deng, Lih Wen; Wang, Suhua; Huang, Leaf; Huang, Dejian

    2013-01-01

    We synthesized the Ni(II) complexes with dithiocarbamate ligand derived from ortho and para isomers sulforhodamine B fluorophores and demonstrated they are highly selective in reaction with nitrogen dioxide (NO2). Comparing to the para isomer, the ortho isomer showed much greater fluorescence increase upon reaction with nitrogen dioxide, which led to oxidation and de-complexation of dithiocarbamate ligand from Ni(II). We applied this probe for visual detection of 1 ppm nitrogen dioxide in gas phase and fluorescence imaging of NO2 in macrophage cells treated with nitrogen oxide donor. PMID:23530626

  4. An analytical method for hydrogeochemical surveys: Inductively coupled plasma-atomic emission spectrometry after using enrichment coprecipitation with cobalt and ammonium pyrrolidine dithiocarbamate

    USGS Publications Warehouse

    Hopkins, D.M.

    1991-01-01

    Trace metals that are commonly associated with mineralization were concentrated and separated from natural water by coprecipitation with ammonium pyrollidine dithiocarbamate (APDC) and cobalt and determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The method is useful in hydrogeochemical surveys because it permits preconcentration near the sample sites, and selected metals are preserved shortly after the samples are collected. The procedure is relatively simple: (1) a liter of water is filtered; (2) the pH is adjusted; (3) Co chloride and APDC are added to coprecipitate the trace metals; and (4) later, the precipitate is filtered, dissolved, and diluted to 10 ml for a 100-fold concentration enrichment of the separated metals. Sb(III), As(III), Cd, Cr, Cu, Fe, Pb, Mo, Ni, Ag, V, and Zn can then be determined simultaneously by ICP-AES. In an experiment designed to measure the coprecipitation efficiency, Sb(III), Cd and Ag were recovered at 70 to 75% of their original concentration. The remaining metals were recovered at 85 to 100% of their original concentrations, however. The range for the lower limits of determination for the metals after preconcentration is 0.1 to 3.0 ??g/l. The precision of the method was evaluated by replicate analyses of a Colorado creek water and two simulated water samples. The accuracy of the method was estimated using a water reference standard (SRM 1643a) certified by the U.S. National Bureau of Standards. In addition, the method was evaluated by analyzing groundwater samples collected near a porphyry copper deposit in Arizona and by analyzing meltwater from glacier-covered areas favorable for mineralization in south-central Alaska. The results for the ICP-AES analyses compared favorably with those obtained using the sequential technique of GFAAS on the acidified but unconcentrated water samples. ICP-AES analysis of trace-metal preconcentrates for hydrogeochemical surveys is more efficient than GFAAS because a

  5. Multimetallic complexes based on a diphosphine-dithiocarbamate "Janus" ligand.

    PubMed

    Sherwood, Rebecca; Gonzàlez de Rivera, Ferran; Wan, Jane Hui; Zhang, Qi; White, Andrew J P; Rossell, Oriol; Hogarth, Graeme; Wilton-Ely, James D E T

    2015-05-04

    The HCl salt of the aminodiphosphine ligand HN(CH2CH2PPh2)2 reacts with [M(CO)4(pip)2] (M = Mo, W; pip = piperidine) to yield [M{κ(2)-HN(CH2CH2PPh2)2}(CO)4]. The molybdenum analogue readily loses a carbonyl ligand to form [Mo{κ(3)-HN(CH2CH2PPh2)2}(CO)3], which was structurally characterized. The same ligand backbone is used to form the new bifunctional ligand, KS2CN(CH2CH2PPh2)2, which reacts with nickel and cobalt precursors to yield [Ni{S2CN(CH2CH2PPh2)2}2] and [Co{S2CN(CH2CH2PPh2)2}3]. Addition of [AuCl(tht)] (tht = tetrahydrothiophene) to [Ni{S2CN(CH2CH2PPh2)2}2] leads to formation of the pentametallic complex, [Ni{S2CN(CH2CH2PPh2AuCl)2}2]. In contrast, addition of [PdCl2(py)2] (py = pyridine) to [Ni{S2CN(CH2CH2PPh2)2}2] does not lead to a trimetallic complex but instead yields the transmetalated cyclic compound [Pd{S2CN(CH2CH2PPh2)2}]2, which was structurally characterized. The same product is obtained directly from [PdCl2(py)2] and KS2CN(CH2CH2PPh2)2. In contrast, the same reaction with [PtCl2(NCPh)2] yields the oligomer, [Pt{S2CN(CH2CH2PPh2)2}]n. Reaction of KS2CN(CH2CH2PPh2)2 with cis-[RuCl2(dppm)2] provides [Ru{S2CN(CH2CH2PPh2)2}(dppm)2](+), which reacts with [AuCl(tht)] to yield [Ru{S2CN(CH2CH2PPh2AuCl)2}(dppm)2](+). Addition of [M(CO)4(pip)2] (M = Mo, W) to the same precursor leads to formation of the bimetallic compounds [(dppm)2Ru{S2CN(CH2CH2PPh2)2}M(CO)4](+), while treatment with [ReCl(CO)5] yields [(dppm)2Ru{S2CN(CH2CH2PPh2)2}ReCl(CO)3](+). Reaction of KS2CN(CH2CH2PPh2)2 with [Os(CH═CHC6H4Me-4)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-benzothiadiazole) provides [Os(CH═CHC6H4Me-4){S2CN(CH2CH2PPh2)2}(CO)(PPh3)2], but reaction with the analogous ruthenium precursor fails to yield a clean product.

  6. Multiple nitrene insertions into metal-sulfur bonds of dithiocarbamate complexes: synthesis of sulfido-amido and zwitterionic tetraamido complexes.

    PubMed

    Hogarth, Graeme; Holman, K Travis; Pateman, Andrew; Sella, Andrea; Steed, Jonathan W; Richards, Idris

    2005-08-21

    The iodine(III) reagent, PhI[double bond, length as m-dash]NTs, acts as a source of the nitrene fragment NTs, which undergoes facile insertion into the metal-sulfur bonds of a range of dithiocarbamate complexes. Addition of two equivalents of PhI=NTs to [M(S(2)CNR2)2] affords sulfido-amido complexes [M{SC(NR2)SNTs}2](M=Ni, Cu), which insert two further nitrene fragments to afford zwitterionic tetraamido complexes [M{TsNSC(NR2)SNTs}2](M=Co, Ni, Cu). Crystallographic studies have been carried out on both types of complex allowing possible resonance hydrids of the new ligand types to be assessed.

  7. Phosphinogold(I) Dithiocarbamate Complexes: Effect of the Nature of Phosphine Ligand on Anticancer Properties

    PubMed Central

    2015-01-01

    The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1–3), [Au2L2(dppe)] (4–6), [(Au2L2)(dppp)] (7–9), and [Au2(L)2(dpph)] (10–12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4–6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1–3 and 7–12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 μM and 0.14 μM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers. PMID:24476103

  8. Group 12 dithiocarbamate complexes: synthesis, spectral studies and their use as precursors for metal sulfides nanoparticles and nanocomposites.

    PubMed

    Ajibade, Peter A; Ejelonu, Benjamin C

    2013-09-01

    Zn(II), Cd(II) and Hg(II) dithiocarbamate complexes have been synthesized and characterized by elemental analysis, thermogravimetric analysis, UV-Vis, FTIR, (1)H- and (13)C NMR spectroscopy. The complexes were thermolysed at 180 °C and used as single molecule precursors for the synthesis of HDA capped ZnS, CdS and HgS nanoparticles and polymethylmethacrylate (PMMA) nanocomposites. The optical and structural properties of the nanoparticles and nanocomposites were studied by UV-Vis, PL, XRD and SEM. The crystallites sizes of the nanoparticles varied between 3.03 and 23.45 nm. SEM and EDX analyses of the nanocomposites confirmed the presence of the nanoparticles in the polymer matrix. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Mixed Ligand Complexes of N-Methyl-N-phenyl Dithiocarbamate: Synthesis, Characterisation, Antifungal Activity, and Solvent Extraction Studies of the Ligand

    PubMed Central

    Ekennia, Anthony C.; Onwudiwe, Damian C.; Ume, Cyril; Ebenso, Eno E.

    2015-01-01

    A series of mixed ligand dithiocarbamate complexes with a general formula [ML2(py)2], where M = Mn(II), Co(II), Ni(II), and Cu(II), py = pyridine, and L = N-methyl-N-phenyl dithiocarbamate have been prepared and characterised by elemental analysis, FTIR and Uv spectroscopy, magnetic moment, and thermogravimetric and conductance analysis. The infrared spectra showed that symmetrical bidentate coordination occurred with the dithiocarbamate moiety through the sulfur atoms, while neutral monodentate coordination occurred through the nitrogen atom for the pyridine molecule in the complexes. The electronic spectra, elemental analysis, and magnetic moment results proved that the complexes adopted octahedral geometry. The conductance measurement showed that the complexes are nonelectrolytes proving their nonionic nature. The compounds were screened for three human pathogenic fungi: Aspergillus flavus, Aspergillus niger, and Candida albicans. The cobalt complex showed the best antifungal activity among the test compounds. Liquid-liquid extractive abilities of the ligand towards copper and nickel ions in different solvent media were investigated. The ligand showed a strong binding affinity towards the metals ions with an extractive efficiency of about 99%. PMID:26543441

  10. Tris dithiocarbamate of Co(III) complexes: Synthesis, characterization, thermal decomposition studies and experimental and theoretical studies on their crystal structures

    NASA Astrophysics Data System (ADS)

    Sonia, Ayyavoo Sait; Bhaskaran, Ramalingam

    2017-04-01

    New homoleptic complexes of the form [Co(L1)3] & [Co(L2)3] where L1 = (ethylaminoethanol dithiocarbamate) 1 and L2 = (methylaminoethanol dithiocarbamate) 2 have been prepared and characterized by elemental analysis, IR, UV-visible absorption spectra, Cyclic voltammetry,1H and C13 NMR. The thermal properties were studied using a simultaneous thermal analyzer, and showed two main steps of decomposition. In addition, structures for 1 and 2 have been elucidated by X-ray crystallography. The single-crystal X-ray analysis for both the complexes showed distorted octahedral geometry. The optimized molecular structure, natural bond orbital analysis, electrostatic potential map, HOMO-LUMO energies, molecular properties, and atomic charges of these molecules have been studied by performing DFT/B3LYP/6-31G(d,p) level of theory in gas phase.

  11. Technetium-99m nitrido dithiocarbamate complex with lateral ester groups: A potential agent for cerebral perfusion. Direct labeling and kinetic results in baboons

    SciTech Connect

    Bottlaender, M.; Bourguignon, M.; Maziere, M.

    1994-05-01

    Previous studies have shown that technetium-99m-nitrido (TcN) complexes of ester derivatives of dithiocarbamate cross the brain-blood barrier and one term of this class, namely the complex formed with sarcosine methyl ester dithiocarbamate (TcN-PR13) is retained in the brain of Cynomolgus monkeys. However these compounds were obtained through an in situ esterification of preformed TcN dicarboxylic derivative. We have been able to synthesize one term of this class of ligands, the sarcosine methylester dithiocarbamate, by reacting sarcosine with thionyl chloride in methanol to give the sarcosine methyl ester, which was reacted with carbon disulfide and NaOH in methanol to give the sodium salt of the dithiocarbamate derivative which was isolated as an oil. The corresponding TcN complex was obtained with a radiochemical purity greater than 96% by a kit method. The complex was injected in baboons and its radioactive distribution compared to that obtained with Tc-HMPAO. Blood and plasma kinetics were calculated from arterial sampling whereas tissue kinetics (brain, lungs) were obtained by ROI`s analysis. The values of the half-life in the blood were comparable for the two tracers, although the absolute activity was about 20% lower for TcN-PR13. The brain uptake of TcN-PR13 was 10% lower than that observed for Tc-HMPAO, and remained stable during 2 hours. TcN-PR13 displayed lower lung uptake and faster clearance from this organ than Tc-HMPAO. Brain/Lung ratios were 1.11 and 1.65 at 30 and 60 min for TcN-PR13 compared to 0.93 and 0.99 at the same time for Tc-HMPAO.

  12. Phase-transformation-induced twinning of an iron(III) calix[4]pyrrolidine complex.

    PubMed

    Journot, Guillaume; Neier, Reinhard; Stoeckli-Evans, Helen

    2014-07-01

    The title compound, tetrachlorido-1κCl;2κ(3)Cl-(2,2,7,7,12,12,17,17-octamethyl-21,22,23,24-tetraazapentacyclo[16.2.1.1(3,6).1(8,11).1(13,16)]tetracosane-1κ(4)N,N',N'',N''')-μ2-oxido-diiron(III), [Fe2Cl4O(C28H52N4)], undergoes a slow phase transformation at ca 173 K from monoclinic space group P2(1)/n, denoted form (I), to the maximal non-isomorphic subgroup, triclinic space group P1, denoted form (II), which is accompanied by nonmerohedral twinning [twin fractions of 0.693 (4) and 0.307 (4)]. The transformation was found to be reversible, as on raising the temperature the crystal reverted to monoclinic form (I). In the asymmetric unit of form (I), Z' = 1, while in form (II), Z' = 2, with a very small reduction (ca 1.8%) in the unit-cell volume. The two independent molecules (A and B) in form (II) are related by a pseudo-twofold screw axis along the b axis. The molecular overlay of molecule A on molecule B has an r.m.s. deviation of 0.353 Å, with the largest distance between two equivalent atoms being 1.202 Å. The reaction of calix[4]pyrrolidine, the fully reduced form of meso-octamethylporphyrinogen, with FeCl3 gave a red-brown solid that was recrystallized from ethanol in air, resulting in the formation of the title compound. In both forms, (I) and (II), the Fe(III) atoms are coordinated to the macrocyclic ligand and have distorted octahedral FeN4OCl coordination spheres. These Fe(III) atoms lie out of the mean plane of the four N atoms, displaced towards the O atom of the [OFeCl3] unit by 0.2265 (5) Å in form (I), and by 0.2210 (14) and 0.2089 (14) Å, respectively, in the two independent molecules (A and B) of form (II). The geometry of the [OFeCl3] units are similar, with each Fe(III) atom having a tetrahedral coordination sphere. The NH H atoms are directed below the planes of the macrocycles and are hydrogen bonded to the coordinated Cl(-) ions. There are also intramolecular C-H···Cl hydrogen bonds present in both (I) and (II

  13. Thermal Studies of Zn(II), Cd(II) and Hg(II) Complexes of Some N-Alkyl-N-Phenyl-Dithiocarbamates

    PubMed Central

    Onwudiwe, Damian C.; Ajibade, Peter A.

    2012-01-01

    The thermal decomposition of Zn(II), Cd(II) and Hg(II) complexes of N-ethyl-N-phenyl and N-butyl-N-phenyl dithiocarbamates have been studied using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The products of the decomposition, at two different temperatures, were further characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The results show that while the zinc and cadmium complexes undergo decomposition to form metal sulphides, and further undergo oxidation forming metal oxides as final products, the mercury complexes gave unstable volatiles as the final product. PMID:22949811

  14. Nitric oxide donors or nitrite counteract copper-[dithiocarbamate](2)-mediated tumor cell death and inducible nitric oxide synthase down-regulation: possible role of a nitrosyl-copper [dithiocarbamate](2) complex.

    PubMed

    Rhenals, Maricela Viola; Strasberg-Rieber, Mary; Rieber, Manuel

    2010-02-25

    In contrast to other metal-dithiocarbamate [DEDTC] complexes, the copper-DEDTC complex is highly cytotoxic, inducing oxidative stress, preferentially in tumor cells. Because nitric oxide (NO) forms adducts with Cu[DEDTC](2), we investigated whether NO donors like S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP), and nitrite, a NO decomposition product, modulate Cu[DEDTC](2) cytotoxicity against human tumor cells. We show that apoptosis-associated PARP cleavage and inducible nitric oxide synthase (iNOS) down-regulation induced by nanomolar Cu[DEDTC](2), are counteracted by 50 muM SNAP, SNP, or CoCl(2), an inducer of hypoxia and NO signaling. Nitrite was stochiometrically effective in antagonizing Cu[DEDTC](2) cytotoxicity and inducing shifts in the absorption spectrum of the binary complex in the 280 and 450 nm regions. Subtoxic concentrations of Cu[DEDTC](2) became lethal when tumor cells were pretreated with c-PTIO, a membrane-impermeable scavenger for extracellular NO. Our results suggest that: (a) reactive oxygen species induced by Cu[DEDTC](2) are scavenged by nitrite released from NO, (b) the extent of lethality of Cu[DEDTC](2) is dependent on the reciprocal formation of an inactive ternary Cu[DEDTC](2)NO copper-nitrosyl complex.

  15. DNA Binding and Antitumor Activity of α-Diimineplatinum(II) and Palladium(II) Dithiocarbamate Complexes

    PubMed Central

    Mansouri-Torshizi, Hassan; Saeidifar, Maryam; Khosravi, Fatemeh; Divsalar, Adeleh; Saboury, Ali Akbar; Hassani, Fatemeh

    2011-01-01

    The two water-soluble designed platinum(II) complex, [Pt(Oct-dtc)(bpy)]NO3 (Oct-dtc = Octyldithiocarbamate and bpy = 2,2′ -bipyridine) and palladium(II) complex, [Pd(Oct-dtc)(bpy)]NO3, have been synthesized and characterized by elemental analyses, molar conductivity measurements, IR, 1H NMR, and electronic spectra studies. Studies of antitumor activity of these complexes against human cell tumor lines (K562) have been carried out. They show Ic50 values lower than that of cisplatin. The complexes have been investigated for their interaction with calf thymus DNA (CT-DNA) by utilizing the electronic absorption spectroscopy, fluorescence spectra, and ethidium bromide displacement and gel filtration techniques. Both of these water-soluble complexes bound cooperatively and intercalatively to the CT-DNA at very low concentrations. Several binding and thermodynamic parameters are also described. PMID:22110410

  16. Spectrophotometric determination of ferbam [iron(III) dimethyl dithiocarbamate] in commercial sample and wheat grains after extraction of its bathophenanthroline tetraphenylborate complex into molten naphthalene.

    PubMed

    Malik, A K; Rao, A L

    2000-09-01

    A procedure has been developed for the determination of iron(III) dimethyldithiocarbamate by converting it into a iron(III)-bathophenanthroline-tetraphenylborate complex, which was then extracted into molten naphthalene, and the absorbance was measured at 534 nm against a reagent blank. Beer's law is obeyed over the concentration range 0.4-20 microg mL(-)(1) in final solution. The method is sensitive and highly selective and is applied for the determination of ferbam in a commercial sample, in mixtures with various dithiocarbamates (ziram, zineb, maneb, etc.), and from wheat grains.

  17. Synthesis and spectral studies on Pb(II) dithiocarbamate complexes containing benzyl and furfuryl groups and their use as precursors for PbS nanoparticles.

    PubMed

    Sathiyaraj, Ethiraj; Thirumaran, Subbiah

    2012-11-01

    Nine lead bis(dithiocarbamate) complexes based on benzyl and furfuryl groups have been prepared. The complexes were characterized using IR and NMR spectroscopy. All the complexes showed the expected signals in (1)H and (13)C NMR spectra associated with the dithiocarbamate ligands. IR and (13)C NMR spectral studies indicate that the S(2)CN double bond character increases with increase in length of alkyl chain bonded to nitrogen atom. Bis(N-benzyl-N-(2-phenylethyl)dithiocarbamato-S,S')lead(II) (3) and bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')lead(II) (4) have been used as single source precursors for the synthesis of ethylenediamine capped PbS nanoparticles. Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), FTIR, UV-vis and fluorescence spectroscopy have been used to characterize the as-prepared lead sulfide nanoparticles. The PXRD measurements suggest that PbS nanoparticles are single phase with face-centered-cubic structure.

  18. Synthesis and spectral studies on Pb(II) dithiocarbamate complexes containing benzyl and furfuryl groups and their use as precursors for PbS nanoparticles

    NASA Astrophysics Data System (ADS)

    Sathiyaraj, Ethiraj; Thirumaran, Subbiah

    2012-11-01

    Nine lead bis(dithiocarbamate) complexes based on benzyl and furfuryl groups have been prepared. The complexes were characterized using IR and NMR spectroscopy. All the complexes showed the expected signals in 1H and 13C NMR spectra associated with the dithiocarbamate ligands. IR and 13C NMR spectral studies indicate that the S2Cpdbdtd N double bond character increases with increase in length of alkyl chain bonded to nitrogen atom. Bis(N-benzyl-N-(2-phenylethyl)dithiocarbamato-S,S')lead(II) (3) and bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')lead(II) (4) have been used as single source precursors for the synthesis of ethylenediamine capped PbS nanoparticles. Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), FTIR, UV-vis and fluorescence spectroscopy have been used to characterize the as-prepared lead sulfide nanoparticles. The PXRD measurements suggest that PbS nanoparticles are single phase with face-centered-cubic structure.

  19. Synthesis, characterization and antibacterial study of cyclometalated rhodium(III) complex containing dithiocarbamate

    NASA Astrophysics Data System (ADS)

    Mansouri, Ghobad; Heidarizadi, Fateme; Naghipour, Ali; Notash, Behrouz

    2016-10-01

    The novel cyclometalated Rh(III) complex, [Rh(phpy)2(SˆS)], Where phpy is 2-phenylpyridine and (SˆS) is diethyldithiocarbamate, has been prepared and characterized by elemental analysis, IR, 13C and 1H NMR, electronic absorption and Fluorescence spectroscopies, cyclic voltammetry, and X-ray crystallography. The crystal structure of [Rh(phpy)2(SˆS)] shows that the coordination geometry around the Rh(III) is a distorted octahedron, with bite angles of 71.19-81.04° for all three bidentate ligands. Electrochemical analysis by cyclic voltammetry reveals irreversible redox behavior of the rhodium centre. Antibacterial activity of the complex has also been studied by agar disc diffusion method against three Gram-negative bacteria (Pseudomonas aeroginosa, Salmonella typhi and Escherichia coli) and two Gram-positive bacteria (Staphylococcus aureus and Corynebacterium renale).

  20. Decomposition of water-soluble mononitrosyl iron complexes with dithiocarbamates and of dinitrosyl iron complexes with thiol ligands in animal organisms.

    PubMed

    Serezhenkov, Vladimir A; Timoshin, Alexander A; Orlova, Tsvetina R; Mikoyan, Vasak D; Kubrina, Lioudmila N; Poltorakov, Alexander P; Ruuge, Enno K; Sanina, Natalia A; Vanin, Anatoly F

    2008-05-01

    EPR studies have shown that water-soluble mononitrosyl iron complexes with N-methyl-d-glucamine dithiocarbamate (MNIC-MGD) (3 micromol) injected to intact mice were decomposed virtually completely within 1h. The total content of MNIC-MGD in animal urine did not exceed 30 nmol/ml. In the liver, a small amount of MNIC-MGD were converted into dinitrosyl iron complexes (30 nmol/g of liver tissue). The same was observed in intact rabbits in which MNIC-MGD formation was induced by endogenous or exogenous NO binding to NO traps, viz., iron complexes with MGD. In mice, the content of MNIC-MGD in urine samples did not change after bacterial lipopolysaccharide-induced expression of iNOS. It was supposed that MNIC-MGD decomposition in intact animals was largely due to the release of NO from the complexes and its further transfer to other specific acceptors. In mice with iNOS expression, the main contribution to MNIC-MGD decomposition was made by superoxide ions whose destructive effect is mediated by an oxidative mechanism. This effect could fully compensate the augmented synthesis of MNIC-MGD involving endogenous NO whose production was supported by iNOS. Water-soluble dinitrosyl iron complexes (DNIC) with various thiol-containing ligands and thiosulfate injected to intact mice were also decomposed; however, in this case the effect was less pronounced than in the case of MNIC-MGD. It was concluded that DNIC decomposition was largely due to the oxidative effect of superoxide ions on these complexes.

  1. Dithiocarbamate toxicity - An appraisal

    USDA-ARS?s Scientific Manuscript database

    Dithiocarbamates are used as agricultural pesticides and general biocides in a variety of applications. However, acute or chronic exposure to these chemicals can produce neurotoxicity, developmental deformities, endocrine disruption, hypersensitivity, and metabolic dysfunctions in animals and human...

  2. DFT calculations in the assignment of solid-state NMR and crystal structure elucidation of a lanthanum(iii) complex with dithiocarbamate and phenanthroline.

    PubMed

    Gowda, Vasantha; Laitinen, Risto S; Telkki, Ville-Veikko; Larsson, Anna-Carin; Antzutkin, Oleg N; Lantto, Perttu

    2016-12-06

    The molecular, crystal, and electronic structures as well as spectroscopic properties of a mononuclear heteroleptic lanthanum(iii) complex with diethyldithiocarbamate and 1,10-phenanthroline ligands (3 : 1) were studied by solid-state (13)C and (15)N cross-polarisation (CP) magic-angle-spinning (MAS) NMR, X-ray diffraction (XRD), and first principles density functional theory (DFT) calculations. A substantially different powder XRD pattern and (13)C and (15)N CP-MAS NMR spectra indicated that the title compound is not isostructural to the previously reported analogous rare earth complexes with the space group P21/n. Both (13)C and (15)N CP-MAS NMR revealed the presence of six structurally different dithiocarbamate groups in the asymmetric unit cell, implying a non-centrosymmetric packing arrangement of molecules. This was supported by single-crystal X-ray crystallography showing that the title compound crystallised in the triclinic space group P1[combining macron]. In addition, the crystal structure also revealed that one of the dithiocarbamate ligands has a conformational disorder. NMR chemical shift calculations employing the periodic gauge including projector augmented wave (GIPAW) approach supported the assignment of the experimental (13)C and (15)N NMR spectra. However, the best correspondences were obtained with the structure where the atomic positions in the X-ray unit cell were optimised at the DFT level. The roles of the scalar and spin-orbit relativistic effects on NMR shielding were investigated using the zeroth-order regular approximation (ZORA) method with the outcome that already the scalar relativistic level qualitatively reproduces the experimental chemical shifts. The electronic properties of the complex were evaluated based on the results of the natural bond orbital (NBO) and topology of the electron density analyses. Overall, we apply a multidisciplinary approach acquiring comprehensive information about the solid-state structure and the

  3. Zirconium and hafnium complexes bearing pyrrolidine derived salalen-type {ONNO} ligands and their application for ring-opening polymerization of lactides.

    PubMed

    Duan, Yu-Lai; Hu, Zhi-Jian; Yang, Bo-Qun; Ding, Fei-Fei; Wang, Wei; Huang, Yong; Yang, Ying

    2017-08-29

    The reactions of pyrrolidine derived salalen-type {ONNO} ligands (S)-L(1-3)-H2 with 1 equiv. M(O(i)Pr)4(HO(i)Pr) (M = Zr or Hf) in diethyl ether yielded complexes [L(1-3)M(O(i)Pr)2] (L = L(1), M = Zr (1); L = L(2), M = Zr (2), Hf (3); L = L(3), M = Zr (4), Hf (5)). All of these complexes were well characterized by NMR spectroscopy, elemental analyses and single-crystal X-ray analysis in the case of complexes 1 and 3-5. X-ray structural determination revealed that these complexes were analogous mononuclear species and had a similar structure in which the metal centers were six-coordinated to two oxygen atoms and two nitrogen atoms of one ligand and two oxygen atoms of two isopropoxy groups. All of these complexes efficiently initialized the ring-opening polymerization of lactides to afford polymers with controlled molecular weight and narrow polydispersity. Furthermore, the ring-opening polymerization of rac-lactide catalyzed by complexes 1-5 afforded isotactic-enriched polymers in solution (Pm = 0.74-0.80) and under melt conditions (Pm = 0.63-0.72).

  4. Synthesis and biodistribution of a novel (⁹⁹m)TcN complex of norfloxacin dithiocarbamate as a potential agent for bacterial infection imaging.

    PubMed

    Zhang, Shijian; Zhang, Weifang; Wang, Yue; Jin, Zhonghui; Wang, Xuebin; Zhang, Junbo; Zhang, Yanyan

    2011-03-16

    Achieving a (⁹⁹m)Tc-labeled fluoroquinolone derivative as a single photon emission computed tomography (SPECT) tracer is considered to be of great interest. The norfloxacin dithiocarbamate (NFXDTC) was synthesized and radiolabeled with a [(⁹⁹m)TcN]²(+) intermediate to form the (⁹⁹m)TcN-NFXDTC complex in high yield. The radiochemical purity of (⁹⁹m)TcN-NFXDTC was over 90%, as measured by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), without any notable decomposition at room temperature over a period of 6 h. The partition coefficient and electrophoresis results indicated that (⁹⁹m)TcN-NFXDTC was lipophilic and neutral. The bacterial binding assay studies showed tht (⁹⁹m)TcN-NFXDTC had a good binding affinity. Biodistribution results in bacterial infected mice showed that (⁹⁹m)TcN-NFXDTC had a higher uptake at the sites of infection and better abscess/blood and abscess/muscle ratios than those of (⁹⁹m)Tc-ciprofloxacin and (⁹⁹m)TcN-CPFXDTC (CPFXDTC = ciprofloxacin dithiocarbamate). The biodistribution results of (⁹⁹m)TcN-NFXDTC in bacterially infected mice and in mice with turpentine-induced abscesses indicated that (⁹⁹m)TcN-NFXDTC was suited to be a bacteria-specific infection imaging agent. Single photon emission computed tomography (SPECT) image studies showed there was a visible accumulation in infection sites, suggesting that it would be a promising candidate for bacterial infection imaging.

  5. Theoretical investigations of the structures and electronic spectra of Zn(II) and Ni(II) complexes with cyclohexylamine-N-dithiocarbamate

    NASA Astrophysics Data System (ADS)

    Yu, Xiaohan; Wang, Na; He, Hongqing; Wang, Li

    2014-03-01

    The ground-state structures of two ligands cyclohexylamine-N-dithiocarbamate (L) and PPh3 and four complexes [Zn(L)2] (A), [Ni(L)2] (B), [Zn(L)2PPh3] (C), and [Ni(L)2PPh3] (D) are optimized by M06, B3LYP, and B3PW91 methods with the same mixed basis set. As compared with the experimental data of other complexes containing the Ni-P bond, the result obtained by M06/6-31+G(d)-LANL2DZ method is finally regarded as accurate and reliable for this project. Based on the optimized geometries, the compositions of molecular orbitals are analyzed and the absorption spectra are simulated. When one more ligand PPh3 is coordinated, the lowest-lying transition energy presents red-shift; while it shows blue-shift when the metal coordination center change from Ni to Zn with the same ligands. The detailed transition characters related with the absorption spectrum are assigned. In all the key transitions, it is hard to find the contribution from Zn atom. On the contrary, the d orbital of Ni atom contributes a lot for the HOMO and LUMO of complexes B and D. Consequently, the transition characters of Zn(II) and Ni(II) complexes are different.

  6. Separation of heavy metal from water samples--The study of the synthesis of complex compounds of heavy metal with dithiocarbamates.

    PubMed

    Kane, Sonila; Lazo, Pranvera; Ylli, Fatos; Stafilov, Trajce; Qarri, Flora; Marku, Elda

    2016-01-01

    The toxicity and persistence of heavy metal (HM) ions may cause several problems to marine organisms and human beings. For this reason, it is growing the interest in the chemistry of sulphur donor ligands such as dithiocarbamates (DDTC), due to their applications particularly in analytical chemistry sciences. The aim of this work has been the study of heavy metal complexes with DDTC and their application in separation techniques for the preconcentration and/or removing of heavy metals from the water solutions or the water ecosystems prior to their analysis. The HM-DDTC complexes were prepared and characterized by elemental analysis, FTIR and UV-Vis spectroscopic methods. The elemental analysis and the yield of the synthesis (97.5-99.9%) revealed a good purity of the complexes. High values of complex formation yields of HM-DDTC complexes is an important parameter for quantitatively removing/and or preconcentration of heavy metal ions from water solution even at low concentration of heavy metals. Significant differences founded between the characteristic parameters of UV/Vis (λmax and ϵmax) and FTIR absorption spectra of the parent DDTC and HM-DDTC complexes revealed the complex formation. The presence of the peaks at the visible spectral zone is important to M(nd(10-m))-L electron charge transfer of the new complexes. The (C=N) (1450-1500 cm(-1)) and the un-splitting (C-S) band (950-1002 cm(-1)) in HM-DDTC FTIR spectra are important to the identification of their bidentate mode (HM[S2CNC4H10]2). The total CHCl3 extraction of trace level heavy metals from water samples after their complex formation with DDTC is reported in this article.

  7. New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

    PubMed Central

    Altaf, Muhammad; Monim-ul-Mehboob, Muhammad; Kawde, Abdel-Nasser; Corona, Giuseppe; Larcher, Roberto; Ogasawara, Marcia; Casagrande, Naike; Celegato, Marta; Borghese, Cinzia; Siddik, Zahid H.; Aldinucci, Donatella; Isab, Anvarhusein A.

    2017-01-01

    We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes. PMID:27888799

  8. New antimony(III) halide complexes with dithiocarbamate ligands derived from thiuram degradation: The effect of the molecule's close contacts on in vitro cytotoxic activity.

    PubMed

    Urgut, O S; Ozturk, I I; Banti, C N; Kourkoumelis, N; Manoli, M; Tasiopoulos, A J; Hadjikakou, S K

    2016-01-01

    Antimony(III) halide complexes of the formulae {[SbBr(Me2DTC)2]n} (1), {[SbI(Me2DTC)2]n} (2) and {[(Me2DTC)2Sb(μ2-I)Sb(Me2DTC)2](+).I3(-)} (3) (Me2DTC = dimethyldithiocarbomate) were synthesized from SbX3, (X = Br or I) and tetramethylthiuram monosulfide (Me4tms) or tetramethylthiuram disulfide (Me4tds). The complexes were characterized by melting point (m.p.), elemental analysis (e.a.), Fourier-transform Infra-Red (FT-IR), Fourier-transform Raman (FT-Raman), Nuclear Magnetic Resonance ((1)H,(13)C-NMR) spectroscopy and Thermogravimetric-Differential Thermal Analysis (TG-DTA). Crystal structures of complexes 1-3 were determined with single crystal X-ray diffraction analysis. Complexes 1 and 2 are polymers with distorted square pyramidal (SP) geometry in each monomeric unit, whereas complex 3 is ionic, containing an iodonium linkage Sb-I(+)-Sb and an I3(-) counter anion; to the best of our knowledge, this is the first ionic antimony(III) iodide complex. The in vitro cytotoxic activity of 1-3 against human adenocarcinoma cells: breast (MCF-7) and cervix (HeLa) cells and non-cancerous cells: MRC-5 (normal human fetal lung fibroblast cells) was evaluated with trypan blue (TB) and sulforhodamine B (SRB) assays. Among antimony(III) compounds with sulfur containing ligand, those of dithiocarbamates exhibit significant cytotoxic activity. Hirshfeld surface volumes were analyzed to clarify the nature of the intermolecular interactions by the 2D fingerprint plot. Molecules with lower H-all atoms inter-molecular interactions exhibit the higher activity against MCF-7 cells. The in vivo genotoxicity of 1-3 was evaluated by the mean of Allium cepa test. Alterations in the mitotic index values due to the chromosomal aberrations were observed in the case of complexes 2 and 3. Since, no such alteration is caused by 1, it makes this compound candidate for further study as potential drug.

  9. New comprehensive studies of a gold(III) Dithiocarbamate complex with proven anticancer properties: Aqueous dissolution with cyclodextrins, pharmacokinetics and upstream inhibition of the ubiquitin-proteasome pathway.

    PubMed

    Tomasello, Marianna F; Nardon, Chiara; Lanza, Valeria; Di Natale, Giuseppe; Pettenuzzo, Nicolò; Salmaso, Stefano; Milardi, Danilo; Caliceti, Paolo; Pappalardo, Giuseppe; Fregona, Dolores

    2017-09-29

    The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy-kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of α-cyclodextrins (CDs), namely β-CD, Me-β-CD and HP-β-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-β-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a tβ1/2 of few minutes and a slow escretion (tα1/2 of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP-β-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin-proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury.

    PubMed

    Valentine, Holly L; Viquez, Olga M; Amarnath, Kalyani; Amarnath, Venkataraman; Zyskowski, Justin; Kassa, Endalkachew N; Valentine, William M

    2009-01-01

    Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate's nitrogen substituents influences the lipophilicity of the copper complexes that it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generated dithiocarbamate-copper complexes that were lipid- and water-soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord, and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined, and the quantity of protein carbonyls was measured to assess levels of oxidative stress and injury. The data provided evidence that dithiocarbamate-copper complexes are redox active and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid-soluble copper complex, significant increases in copper accumulation, oxidative

  11. Asymmetric Synthesis of Polyfunctionalized Pyrrolidines from Sulfinimine-Derived Pyrrolidine 2-Phosphonates. Synthesis of Pyrrolidine 225C

    PubMed Central

    Xu, He; Wu, Yongzhong; Zhang, Junyi

    2008-01-01

    The Horner-Wadsworth-Emmons reaction of aldehydes with sulfinimine-derived 3-oxo pyrrolidine phosphonates represents a new method for the asymmetric synthesis of ring-functionalized cis-2,5-disubstituted 3-oxo pyrrolidines. PMID:16706504

  12. Nitrogen Substituent Polarity Influences Dithiocarbamate-Mediated Lipid Oxidation, Nerve Copper Accumulation, and Myelin Injury

    PubMed Central

    Valentine, Holly L.; Viquez, Olga M.; Amarnath, Kalyani; Amarnath, Venkataraman; Zyskowski, Justin; Kassa, Endalkachew N.; Valentine, William M.

    2009-01-01

    Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate’s nitrogen substituents influences the lipophilicity of the copper complexes it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generate dithiocarbamate-copper complexes that are lipid and water soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined and the quantity of protein carbonyls measured to assess levels of oxidative stress and injury. The data provide evidence that dithiocarbamate-copper complexes are redox active; and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid soluble copper complex, significant increases in copper accumulation, oxidative stress and myelin

  13. Synthesis Characterization and Biological Activities of Coordination Compounds of 4-Hydroxy-3-nitro-2H-chromen-2-one and Its Aminoethanoic Acid and Pyrrolidine-2-carboxylic Acid Mixed Ligand Complexes

    PubMed Central

    Akinkunmi, Ezekiel; Obuotor, Efere; Olawuni, Idowu; Isabirye, David; Jordaan, Johan

    2017-01-01

    Coordination compounds of 4-hydroxy-3-nitro-2H-chromen-2-one and their mixed ligand complexes with aminoethanoic acid and pyrrolidine-2-carboxylic acid were synthesized by the reaction of Cu(II) and Zn(II) salts in molar ratio 1 : 2 for the coumarin complexes and 1 : 1 : 1 for the mixed ligand complexes, in basic media. The compounds formed were characterized using infrared, Uv-vis spectrophotometric analyses, mass spectrometry, magnetic susceptibility measurements, and EDX analyses. It was concluded that 4-hydroxy-3-nitro-2H-chromen-2-one coordinated as a monobasic ligand for all the complexes; it also coordinated via the carbonyl moiety in the case of the Cu(II) mixed ligand complexes. Similarly it was proposed that the amino acids also coordinated in a bidentate fashion via their amino nitrogen and carboxylate oxygen atoms. The synthesized compounds were screened for their antimicrobial and cytotoxic activities. The complexes exhibited marginal antimicrobial activity but good cytotoxic activity. PMID:28270743

  14. Synthesis, characterisation and biological aspects of copper(II) dithiocarbamate complexes, [Cu{S2CNR(CH2CH2OH)}2], (R = Me, Et, Pr and CH2CH2OH)

    NASA Astrophysics Data System (ADS)

    de Lima, Geraldo M.; Menezes, Daniele C.; Cavalcanti, Camila A.; dos Santos, Jaqueline A. F.; Ferreira, Isabella P.; Paniago, Eucler B.; Wardell, James L.; Wardell, Solange M. S. V.; Krambrock, Klaus; Mendes, Isolda C.; Beraldo, Heloisa

    2011-03-01

    Cu(II) dithiocarbamates, [Cu{S2CNR(CH2CH2OH)}2], R = Me (1), Et (2), Pr (3) and CH2CH2OH (4), have been prepared from HNR(CH2CH2OH) (R = Me, Et, Pr and CH2CH2OH), CS2 and Cu(OAc)2. Characterisation of the complexes were generally achieved by infrared and EPR spectroscopies and, in addition, for (2) and (3), by X-ray crystallography at 120 K. Complex (2) crystallises as a Cu-S linked dimer, in which the CH2CH2OH groups have a cis arrangement in each monomer but are trans to those in the other monomer partner. On the other hand complex (3) exists in the solid state in the form of two similar and independent centrosymmetric monomers. The weak antiferromagnetic coupling, present in similar complexes, was absent in complexes (1)-(3). The in vitro activity of (1)-(4) was investigated against colonies of Candida albicans, Sthaphyloccocus aureus and Pseudomonas aeruginosa. They all displayed MIC (minimal inhibitory concentration) values against C. albicans close to those found for Fluconazole. All complexes were inert towards Gram-negative or Gram-positive bacteria, S. aureus and P. auruginosa, respectively.

  15. One-step synthesis of dithiocarbamates from metal powders

    NASA Technical Reports Server (NTRS)

    Hepp, Aloysius F.; Hehemann, David G.; Duraj, Stan A.; Clark, Eric B.; Eckles, William E.; Fanwick, Phillip E.

    1994-01-01

    Neutral metal dithiocarbamate complexes (M(NR2CS2)X) are well-known precursors to metal sulfides, a class of materials with numerous technological applications. We are involved in a research effort to prepare new precursors to metal sulfides using simple, reproducible synthetic procedures. We describe the results of our synthetic and characterization studies for M = Fe, Co, Ni, Cu. and In. For example, treatment of metallic indium with tetramethylthiuram disulfide (tmtd) in 4-methylpyridine (4-Mepy) at 25 deg C produces a new homoleptic indium (III) dithiocarbamate, In(N(CH3)2CS2)3(I), in yields of over 60 percent. The indium (III) dithiocarbamate was characterized by X-ray crystallography; (I) exists in the solid state as discrete distorted-octahedral molecules. Compound (I) crystallizes in the P1bar (No. 2) space group with lattice parameters: a = 9.282(1) A, b = 10.081(1) A, c = 12.502 A, alpha = 73.91(1) deg, beta = 70.21(1) deg, gamma = 85.8(1)deg, and Z = 2. X-ray diffraction and mass spectral data were used to characterize the products of the analogous reactions with Fe, Co, Ni, and Cu. We discuss both use of dithiocarbamates as precursors and our approach to their preparation.

  16. Synthesis, characterization and anticancer activity of a Cd(II) complex with in situ formation of (E)-1-(5-chloro-2-hydroxy-benzylideneamino)-pyrrolidin-2-one ligand

    NASA Astrophysics Data System (ADS)

    Huang, Qiu-Ying; Zheng, Ze-Bao; Diao, Yun-Peng

    2015-05-01

    A new complex of Cd(II) with (E)-1-(5-chloro-2-hydroxybenzylideneamino)-pyrrolidin-2-one [Cd(L)2ṡ2DMF] was synthesized and characterized by elemental analysis, IR, TG and single-crystal X-ray diffraction. Where the HL ligand is formed in situ by the intramolecular nucleophilic substitution of (E)-N‧-(5-chloro-2-hydroxybenzyli-dene)-4-(quinolin-8-yloxy)butanehydrazide (H2L‧). The cadmium(II) ion is hexacoordinated by two tridentate L- ligands and giving a distorted octahedral coordination geometry. A cytotoxicity of [Cd(L)2ṡ2DMF] against liver (SMMC-7721) and cervical (HeLa) cancer cells have been studied. The results revealed that this cadmium(II) complex exhibited an effective and selective anticancer activity against HeLa over SMMC-7721 cell line with IC50 of 1.54 ± 0.25 and 31.02 ± 3.76 μmol/dm-3.

  17. Lanthanum(III) and praseodymium(III) derivatives with dithiocarbamates derived from alpha-amino acids.

    PubMed

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

    2006-06-01

    Lanthanum(III) and praseodymium(III) complexes with dithiocarbamates have been synthesized by the reactions of lanthanum(III) and praseodymium(III) chloride with barium dithiocarbamate and complexes of type [LnCl(L)H2O]n have been obtained (where Ln=La(III) or Pr(III); L=barium salt of dithiocarbamate derived from glycine, L-leucine, L-valine, DL-alanine). The complexes have been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H NMR spectral studies. The presence of coordinated water molecule is inferred from thermogravimetric analysis which indicates the loss of one water molecule at 150-170 degrees C. The oscillator strength, Judd-Ofelt intensity parameter, stimulated emission cross-section, etc. have been obtained for different transitions of Pr3+.

  18. Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

    PubMed Central

    Martínez-Martínez, S; Gómez del Arco, P; Armesilla, A L; Aramburu, J; Luo, C; Rao, A; Redondo, J M

    1997-01-01

    Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants. PMID:9343406

  19. PRACTICAL SYNTHESIS OF AROMATIC DITHIOCARBAMATES

    PubMed Central

    Padungros, Panuwat; Wei, Alexander

    2015-01-01

    GRAPHICAL ABSTRACT Oxidation-sensitive N,N-diaryl dithiocarbamates (DTCs) are synthesized in good yields by the generation of metal amide salts from N-benzoyl precursors, followed by addition of CS2. para-Substituted diphenylamines are prepared by electrophilic aromatic substitution of diphenylbenzamide and saponification. Deacylation of electron-rich species such as bis(p-dimethylaminophenyl)benzamide is challenging because of the oxidative sensitivity of the anionic intermediate but could be achieved in good yield by using n-BuLi to generate a hemiaminal adduct, prior to acidification. The N,N-diaryl DTCs are stable as alkali salts and can be used to produce densely packed monolayers on gold surfaces. PMID:25999616

  20. Synthesis, DFT Calculation, and Antimicrobial Studies of Novel Zn(II), Co(II), Cu(II), and Mn(II) Heteroleptic Complexes Containing Benzoylacetone and Dithiocarbamate

    PubMed Central

    Ekennia, Anthony C.; Onwudiwe, Damian C.; Olasunkanmi, Lukman O.; Osowole, Aderoju A.; Ebenso, Eno E.

    2015-01-01

    Heteroleptic complexes of zinc(II), copper(II), manganese(II), and cobalt(II) of the types [MLL′(H2O)2]·nH2O and [MLL′]·nH2O have been synthesized using sodium N-methyl-N-phenyldithiocarbamate (L) and benzoylacetone (L′). The metal complexes were characterized by elemental analysis, electrical conductance, magnetic susceptibility, infrared (IR), and UV-visible spectroscopic studies. The electrical conductance measurements revealed the nonelectrolytic nature of the synthesized complexes. The results of the elemental analyses, magnetic susceptibility measurements, and electronic spectra inferred that the Zn(II) complex adopted a four-coordinate geometry while the Co(II), Cu(II), and Mn(II) complexes assumed octahedral geometries. The IR spectra showed that the metal ions coordinated with the ligands via the S- and O-donor atoms. The geometry, electronic, and thermodynamic parameters of the complexes were obtained from density functional theory (DFT) calculations. The spin density distributions, relative strength of H–bonds, and thermodynamic parameters revealed that the order of stability of the metal complexes is Mn < Co < Cu > Zn. The agar diffusion methods were used to study the antimicrobial activity of the complexes against two Gram positive bacteria (S. aureus and S. pneumoniae), one Gram negative bacterium (E. coli), and two fungi organisms (A. niger and A. candida) and the complexes showed a broad spectrum of activities against the microbes. PMID:26681931

  1. Synthesis and spectroscopic characterization of Ni(II) complexes involving functionalised dithiocarbamates and triphenylphosphine: Anagostic interaction in (N-cyclopropyl-N-(4-fluorobenzyl)dithiocarbamato-S,S‧) (thiocyanato-N)(triphenylphosphine)nickel(II)

    NASA Astrophysics Data System (ADS)

    Sathiyaraj, E.; Srinivasan, T.; Thirumaran, S.; Velmurugan, D.

    2015-12-01

    Twelve new nickel(II) complexes namely [Ni(S2CNRR‧)2](1-6) and [Ni(S2CNRR‧)(NCS)(PPh3)](7-12) [where R = cyclopropyl (cPr); R‧ = 2HO-C6H4-CH2- (1,7), 3HO-C6H4-CH2- (2,8), 4HO-C6H4-CH2- (3,9), 4CH3O-C6H4-CH2- (4,10), 4F-C6H4-CH2- (5,11), 4Cl-C6H4-CH2- (6,12)] have been prepared and characterized by elemental analysis, IR, UV-Vis and NMR (1H and 13C) spectroscopy. A single crystal X-ray structural analysis was carried out for (N-cyclopropyl-N-(4-fluorobenzyl)dithiocarbamato-S,S‧)(thiocyanato-N)- (triphenylphosphine)nickel(II). The increase in wavenumber of νC-N thioureide and decrease in chemical shift values of heteroleptic complexes 7-12 compared to that of homoleptic complexes 1-6 are due to the mesomeric drift of electron density from the dithiocarbamate moiety towards the metal centre, increasing the carbon-nitrogen double bond character. The increased strength of C-N bond is due to the presence of the π-accepting triphenylphosphine. Electronic spectral studies indicated square planar geometry around the nickel(II) central atom for all the complexes. Single crystal X-ray structural analysis of 11 confirms that the coordination geometry about the Ni is distorted square planar. The C-H…F interactions lead to a polymeric structure and a rare intramolecular anagostic interaction [M…H = 2.929 Å] is observed. The molecular geometry, HOMO-LUMO in the ground state and MEP have been calculated for 11 using the Hartree-Fock (HF) method with the LANL2DZ basic set. The optimized bond lengths and bond angles agree well with the experimental results. The asymmetry in the Ni-S bonds reveal the greater trans influence of triphenylphosphine compared to that of the isothiocyanate ion.

  2. 40 CFR 721.10314 - Dialkyl dithiocarbamate esters (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Dialkyl dithiocarbamate esters... Specific Chemical Substances § 721.10314 Dialkyl dithiocarbamate esters (generic). (a) Chemical substance... dialkyl dithiocarbamate esters (PMNs P-02-778, P-02-779, and P-02-780) are subject to reporting under...

  3. 40 CFR 721.10314 - Dialkyl dithiocarbamate esters (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Dialkyl dithiocarbamate esters... Specific Chemical Substances § 721.10314 Dialkyl dithiocarbamate esters (generic). (a) Chemical substance... dialkyl dithiocarbamate esters (PMNs P-02-778, P-02-779, and P-02-780) are subject to reporting under...

  4. 40 CFR 721.10314 - Dialkyl dithiocarbamate esters (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Dialkyl dithiocarbamate esters... Specific Chemical Substances § 721.10314 Dialkyl dithiocarbamate esters (generic). (a) Chemical substance... dialkyl dithiocarbamate esters (PMNs P-02-778, P-02-779, and P-02-780) are subject to reporting under...

  5. Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes.

    PubMed

    Otero-Fraga, Jorge; Suárez-Pantiga, Samuel; Montesinos-Magraner, Marc; Rhein, Dennis; Mendoza, Abraham

    2017-08-17

    Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first-row transition-metal catalysts inspired a new method to access complex poly-heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron-rich olefins in intermolecular [3+2] cycloadditions. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. ZnS, CdS and HgS Nanoparticles via Alkyl-Phenyl Dithiocarbamate Complexes as Single Source Precursors

    PubMed Central

    Onwudiwe, Damian C.; Ajibade, Peter A.

    2011-01-01

    The synthesis of II-VI semiconductor nanoparticles obtained by the thermolysis of certain group 12 metal complexes as precursors is reported. Thermogravimetric analysis of the single source precursors showed sharp decomposition leading to their respective metal sulfides. The structural and optical properties of the prepared nanoparticles were characterized by means of X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM) UV-Vis and photoluminescence spectroscopy. The X-ray diffraction pattern showed that the prepared ZnS nanoparticles have a cubic sphalerite structure; the CdS indicates a hexagonal phase and the HgS show the presence of metacinnabar phase. The TEM image demonstrates that the ZnS nanoparticles are dot-shaped, the CdS and the HgS clearly showed a rice and spherical morphology respectively. The UV-Vis spectra exhibited a blue-shift with respect to that of the bulk samples which is attributed to the quantum size effect. The band gap of the samples have been calculated from absorption spectra and werefound to be about 4.33 eV (286 nm), 2.91 eV (426 nm) and 4.27 eV (290 nm) for the ZnS, CdS and HgS samples respectively. PMID:22016607

  7. Novel pyrrolidine heterocycles as CCR1 antagonists.

    PubMed

    Merritt, J Robert; James, Ray; Paradkar, Vidyadhar M; Zhang, Chongwu; Liu, Ruiyan; Liu, Jinqi; Jacob, Biji; Chiriac, Camelia; Ohlmeyer, Michael J; Quadros, Elizabeth; Wines, Pamela; Postelnek, Jennifer; Hicks, Catherine M; Chen, Weiqing; Kimble, Earl F; O'Brien, Linda; White, Nicole; Desai, Hema; Appell, Kenneth C; Webb, Maria L

    2010-09-15

    A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  8. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  9. Cytotoxicity Profiles for a Series of Triorganophosphinegold(I) Dithiocarbamates and Triorganophosphinegold(I) Xanthates

    PubMed Central

    de Vos, Dick; Ho, Soo Yei

    2004-01-01

    A series of triorganophosphinegold(1) dithiocarbamate (R3PAuS2CNR'2) and xanthate (R3PAuS2COR') complexes have been prepared and characterised spectroscopically. Based on crystallographic evidence, the molecules feature linear gold(1) geometries defined by sulphur and phosphorus donors. The complexes, along with a series of known anti-cancer agents, have been screened against a panel of seven human cancer cell lines. Uniformly, the dithiocarbamate derivatives are more active than their xanthate counterparts, with the most active complex being Et3PAu(S2CNEt2), and are more active than cisplatin in all cell lines screened but, not as potent as taxol. PMID:18365074

  10. Synthesis, Structure, Characterization, and Decomposition of Nickel Dithiocarbamates: Effect of Precursor Structure and Processing Conditions on Solid-State Products

    NASA Technical Reports Server (NTRS)

    Hepp, Aloysius F.; Kulis, Michael J.; McNatt, Jeremiah S.; Duffy, Norman V.; Hoops, Michael D.; Gorse, Elizabeth; Fanwick, Philip E.; Masnovi, John; Cowen, Jonathan E.; Dominey, Raymond N.

    2016-01-01

    Single-crystal X-ray structures of four nickel dithiocarbamate complexes, the homoleptic mixed-organic bis-dithiocarbamates Ni[S2CN(isopropyl)(benzyl)]2, Ni[S2CN(ethyl)(n-butyl)]2, and Ni[S2CN(phenyl)(benzyl)]2, as well as the heteroleptic mixed-ligand complex NiCl[P(phenyl)3][(S2CN(phenyl)(benzyl)], were determined. Synthetic, spectroscopic, structural, thermal, and sulfide materials studies are discussed in light of prior literature. The spectroscopic results are routine. A slightly distorted square-planar nickel coordination environment was observed for all four complexes. The organic residues adopt conformations to minimize steric interactions. Steric effects also may determine puckering, if any, about the nickel and nitrogen atoms, both of which are planar or nearly so. A trans-influence affects the Ni-S bond distances. Nitrogen atoms interact with the CS2 carbons with a bond order of about 1.5, and the other substituents on nitrogen display transoid conformations. There are no strong intermolecular interactions, consistent with prior observations of the volatility of nickel dithiocarbamate complexes. Thermogravimetric analysis of the homoleptic species under inert atmosphere is consistent with production of 1:1 nickel sulfide phases. Thermolysis of nickel dithiocarbamates under flowing nitrogen produced hexagonal or -NiS as the major phase; thermolysis under flowing forming gas produced millerite (-NiS) at 300 C, godlevskite (Ni9S8) at 325 and 350 C, and heazlewoodite (Ni3S2) at 400 and 450 C. Failure to exclude oxygen results in production of nickel oxide. Nickel sulfide phases produced seem to be primarily influenced by processing conditions, in agreement with prior literature. Nickel dithiocarbamate complexes demonstrate significant promise to serve as single-source precursors to nickel sulfides, a quite interesting family of materials with numerous potential applications.

  11. Self assembled homodinuclear dithiocarbamates: One pot synthesis and spectral characterization

    NASA Astrophysics Data System (ADS)

    Nami, Shahab A. A.; Husain, Ahmad; Ullah, Irfan

    2014-01-01

    Several self assembled homodinuclear complexes of the type [M2(Ldtc)2·4H2O] derived from quadridentate ligand (Ldtc), where Ldtc = 2-aminobenzoylhydrazidebis(dithiocarbamate) and M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II) have been reported. The in situ procedure gives high yield with the formation of single product as evident by TLC and various other physicochemical techniques. Elemental analysis, TGA, 1H NMR, 13C NMR, ESI mass spectrometry, EPR, UV-vis. and IR spectroscopy were used to characterize the homodinuclear complexes. The spectroscopic evidences and room temperature magnetic moment values suggest that all the complexes have octahedral geometry around the transition metal atom. A symmetrical bidentate coordination of the dithiocarbamato moiety has been observed in all the complexes. The energy-minimized structure of the molecule also showed that each metal atom acquires a distorted octahedral geometry. The complexes exhibit a three-step thermolytic pattern and are non-electrolyte in nature.

  12. Preparation of 1,5-disubstituted pyrrolidin-2-ones.

    PubMed

    Katritzky, A R; Mehta, S; He, H Y; Cui, X

    2000-07-14

    1,5-Disubstituted pyrrolidin-2-ones 18a-g, 19a-h, and 20a-f were synthesized in good to excellent yields via the nucleophilic substitution of 5-(benzotriazol-1-yl)-1-substituted-pyrrolidin-2-ones 9 with allylsilanes, organozinc reagents, and phosphorus compounds. Compounds 9 and 5-(benzotriazol-2-yl)-1-substituted-pyrrolidin-2-one isomers 10 are readily prepared in total 70-84% yields from 2, 5-dimethoxy-2,5-dihydrofuran (7), primary amines 8, and benzotriazole; 9 and 10 react identically with nucleophiles.

  13. Measurements of the solubility of metal dithiocarbamates in supercritical carbon dioxide

    SciTech Connect

    Bartle, K.D.; Cowey, C.M.; Burford, M.D.; Clifford, A.A.

    1996-10-01

    Heavy metal contamination of the environmental has been traditionally analyzed by acid digestion and organic solvent extraction methods. However, recently supercritical fluids such as carbon dioxide have been investigated as a potentially more rapid and environmentally friendly extraction procedure for metal recovery. Direct extraction of metal ions by pure supercritical carbon dioxide has previously proved ineffective as charge neutralization of the ion using a ligand is required to significantly enhance the solute solvent interactions. Commercial chelating agents such as dithiocarbamates have been extensively used in both conventional and supercritical extractions for the recovery of a wide range of heavy metal. Initial studies using diethldithiocarbamate metal complexes at low supercritical temperatures (50 {degrees}C) and pressure (100 atm.) Showed poor solubility (1x10{sup {minus}6}mol dm{sup 3}) in supercritical carbon dioxide. In this study, the solubility of Pb, Cd, Fe, Zn, and Cu dithiocarbamates were measures at both high and low supercritical fluid temperatures and pressures and a significant increase in the solubility of the metal complexes (e.g. two orders of magnitude) was achieved using 100 {degrees}C, 350 atm supercritical carbon dioxide. Increasing the alkyl chain length of the dithiocarbamate ligand was also investigated and it was shown that as the hydrocarbon content of the ligand increased and became more non-polar in nature the solubility of the corresponding metal complex increased. The results from the solubility study will be subsequently used to assists in the optimization of methods used for the extraction of metals in environmental samples.

  14. Transition metal ferrocenyl dithiocarbamates functionalized dye-sensitized solar cells with hydroxy as an anchoring group

    NASA Astrophysics Data System (ADS)

    Yadav, Reena; Waghadkar, Yogesh; Kociok-Köhn, Gabriele; Kumar, Abhinav; Rane, Sunit B.; Chauhan, Ratna

    2016-12-01

    Three new transition-metal dithiocarbamates involving ferrocene (Fc), namely [Co(FcCH2EtOHdtc)3] (Co), [M(FcCH2EtOHdtc)2] M = Ni (Ni), Cu (Cu) (EtOHdtc = N-ethanol dithiocarbamate), have been synthesized and characterized by microanalyses, FTIR, 1H and 13C NMR spectroscopies and single crystal X-ray diffraction technique. The peak broadening in the 1H spectrum of the copper complex indicates the paramagnetic behavior of this compound. The observed single quasi-reversible cyclic voltammograms for the complexes indicate the stabilization of a metal center (except copper) other than Fe in their characteristic oxidation state. These complexes have been used as photo-sensitizer in dye-sensitized solar cells which indicates that Co displays the best photosensitization property with an overall conversion efficiency of 3.25 ± 0.04%. The low cell efficiency of Ni and Cu complexes may be due to slow regeneration of the dye by iodine/iodide redox couple followed by charge injection into TiO2.

  15. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors

    SciTech Connect

    Iserloh, U.; Wu, Y.; Cumming, J.N.; Pan, J.; Wang, L.Y.; Stamford, A.W.; Kennedy, M.E.; Kuvelkar, R.; Chen, X.; Parker, E.M.; Strickland, C.; Voigt, J.

    2008-08-18

    Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date. The discovery and development of novel BACE-1 inhibitors incorporating a cyclic amine scaffold is described.

  16. INHIBITORY ACTION OF DITHIOCARBAMATES ON ENZYMES OF ANIMAL TISSUES

    DTIC Science & Technology

    these compounds on the oxidative phase of intermediary carbohydrate metabolism. All of the compounds were effective inhibitors of the tricarboxylic...oxidase, and succinic dehydrogenase. The salts of dithiocarbamic acid were effective inhibitors of these enzymatic reactions in vivo but the disulfide...cytochrome c and inhibited tyrosinase activity in vitro. The results of this investigation suggest that the acute mammalian toxicity of the

  17. Sediment washing by EDTA and its reclamation by sodium polyamidoamine-multi dithiocarbamate.

    PubMed

    Deng, Tianlin; Zhang, Bingru; Li, Fengting; Jin, Luyao

    2017-02-01

    Sodium polyamidoamine-multi dithiocarbamate (PAMAM-DTC) is a kind of heavy metals capturing agent, containing functional groups of dithiocarbamate that could strongly chelate heavy metals. In this paper, it was applied to precipitate heavy metal ions from meal-EDTA and reclaim EDTA during sediment washing process. The extracting performance of fresh EDTA was studied as a function of EDTA concentration, liquid/sediment (L/S), pH, and extraction time. Then the EDTA effluents were treated with PAMAM-DTC, Na2S and sodium diethyldithiocarbamate (DDTC) to compare their effectiveness on capturing metals from metal-EDTA complexes. Four divalent heavy metals were investigated (Pb, Cd, Cu, Zn). PAMAM-DTC shows much better performance. Pb, Cd and Cu could almost be precipitated completely by PAMAM-DTC under the dosage of 350 mg L(-1), while Zn could be only partly precipitated which may due to its failure in competition with the other three metal ions on chelation with PAMAM-DTC. The reclaimed EDTA was reused in three cycles of sediment washing, and the amount of heavy metals extracted just slightly decreased in each cycle. Copyright © 2016. Published by Elsevier Ltd.

  18. The ethylene bis-dithiocarbamate fungicide Mancozeb activates voltage-gated KCNQ2 potassium channel.

    PubMed

    Li, Ping; Zhu, Jin; Kong, Qingya; Jiang, Baifeng; Wan, Xia; Yue, Jinfeng; Li, Min; Jiang, Hualiang; Li, Jian; Gao, Zhaobing

    2013-06-07

    Mancozeb (manganese/zinc ethylene bis-dithiocarbamate) is an organometallic fungicide that has been associated with human neurotoxicity and neurodegeneration. In a high-throughput screen for modulators of KCNQ2 channel, a fundamental player modulating neuronal excitability, Mancozeb, was found to significantly potentiate KCNQ2 activity. Mancozeb was validated electrophysiologically as a KCNQ2 activator with an EC50 value of 0.92±0.23μM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe(3+)) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specific complex rather than two separate additive or synergistic components. Our study suggests that potentiation on KCNQ2 potassium channels might be the possible mechanism of Mancozeb toxicity in the nervous system.

  19. Low-energy electron-induced dissociation in gas-phase nicotine, pyridine, and methyl-pyrrolidine

    NASA Astrophysics Data System (ADS)

    Ryszka, Michal; Alizadeh, Elahe; Li, Zhou; Ptasińska, Sylwia

    2017-09-01

    Dissociative electron attachment to nicotine, pyridine, and N-methyl-pyrrolidine was studied in the gas phase in order to assess their stability with respect to low-energy electron interactions. Anion yield curves for different products at electron energies ranging from zero to 15 eV were measured, and the molecular fragmentation pathways were proposed. Nicotine does not form a stable parent anion or a dehydrogenated anion, contrary to other biological systems. However, we have observed complex dissociation pathways involving fragmentation at the pyrrolidine side accompanied by isomerization mechanisms. Combining structure optimization and enthalpy calculations, performed with the Gaussian09 package, with the comparison with a deuterium-labeled N-methyl-d3-pyrrolidine allowed for the determination of the fragmentation pathways. In contrast to nicotine and N-methylpyrrolidine, the dominant pathway in dissociative electron attachment to pyridine is the loss of hydrogen, leading to the formation of an [M—H]- anion. The presented results provide important new information about the stability of nicotine and its constituent parts and contribute to a better understanding of the fragmentation mechanisms and their effects on the biological environment.

  20. Low-energy electron-induced dissociation in gas-phase nicotine, pyridine, and methyl-pyrrolidine.

    PubMed

    Ryszka, Michal; Alizadeh, Elahe; Li, Zhou; Ptasińska, Sylwia

    2017-09-07

    Dissociative electron attachment to nicotine, pyridine, and N-methyl-pyrrolidine was studied in the gas phase in order to assess their stability with respect to low-energy electron interactions. Anion yield curves for different products at electron energies ranging from zero to 15 eV were measured, and the molecular fragmentation pathways were proposed. Nicotine does not form a stable parent anion or a dehydrogenated anion, contrary to other biological systems. However, we have observed complex dissociation pathways involving fragmentation at the pyrrolidine side accompanied by isomerization mechanisms. Combining structure optimization and enthalpy calculations, performed with the Gaussian09 package, with the comparison with a deuterium-labeled N-methyl-d3-pyrrolidine allowed for the determination of the fragmentation pathways. In contrast to nicotine and N-methylpyrrolidine, the dominant pathway in dissociative electron attachment to pyridine is the loss of hydrogen, leading to the formation of an [M-H](-) anion. The presented results provide important new information about the stability of nicotine and its constituent parts and contribute to a better understanding of the fragmentation mechanisms and their effects on the biological environment.

  1. [Effects of dithiocarbamates on the mitotic activity of thymocytes].

    PubMed

    Hennighausen, G; Kröning, G

    1988-01-01

    The effects of dithiocarbamates on the mitotic activity of thymocytes were studied in vitro and in vivo. The mitotic activity was determined by counting of the metaphases blocked by colchicine. Using thymocytes of mice the mitotic activity in short-time cultures was inhibited (50%) by the following concentrations of the substances under study (EC50-values in mol/l): tetraethylthiuramdisulfide; (1; disulfiram) 4.2.10(-9); diethyldithiocarbamate (2) 3.2.10(-8), Cu-2, 2.6.10(-8), Zn-dimethyldithiocarbamate (3; Ziram) 1.9.10(-8), Zn-ethylene-bis-dithiocarbamate (4; Zineb) 2.3.10(-6). Using rat and guinea-pig thymocytes the ED50- values for 1 and 2 were found in the same concentration range as compared with thymocytes of mice. There was no impact on the vitality of cells by the mitosis inhibiting concentrations. In vivo the mitotic activity of thymocytes in mice was decreased only after application of high doses (500 mg/kg i.p.) of 2. After depletion of reduced glutathione (GSH) by the pretreatment of mice with diethylmaleate the effects of 2 were increased in vivo. In vitro GSH (10(-4) mol/l) decreased the mitosis inhibiting activity of 2 in mice thymocytes and the inhibition of the SH-enzyme ecto-ATPase in rat thymocytes. It is supposed that the inhibition of mitosis is due to the reaction of dithiocarbamates with SH-groups of microtubules and other functionally important proteines. The formation of tiyl radicals from dithiocarbamates may play a certain role in redox processes which can be influenced by GSH.

  2. Gold nanoparticles assembled with dithiocarbamate-anchored molecular wires

    PubMed Central

    Reeler, Nini E. A.; Lerstrup, Knud A.; Somerville, Walter; Speder, Jozsef; Petersen, Søren V.; Laursen, Bo W.; Arenz, Matthias; Qiu, Xiaohui; Vosch, Tom; Nørgaard, Kasper

    2015-01-01

    A protocol for the bottom-up self-assembly of nanogaps is developed through molecular linking of gold nanoparticles (AuNPs). Two π-conjugated oligo(phenylene ethynylene) molecules (OPE) with dithiocarbamate anchoring groups are used as ligands for the AuNPs. OPE-4S with a dithiocarbamate in each end of the molecule and a reference molecule OPE-2S with only a single dithiocarbamate end group. The linking mechanism of OPE-4S is investigated by using a combination of TEM, UV-Vis absorption and surface enhanced Raman spectroscopy (SERS) as well as studying the effect of varying the OPE-4S to AuNP concentration ratio. UV-Vis absorption confirms the formation of AuNP aggregates by the appearance of an extended plasmon band (EPB) for which the red shift and intensity depend on the OPE-4S:AuNP ratio. SERS confirms the presence of OPE-4S and shows a gradual increase of the signal intensity with increasing OPE-4S:AuNP ratios up to a ratio of about 4000, after which the SERS intensity does not increase significantly. For OPE-2S, no linking is observed below full coverage of the AuNPs indicating that the observed aggregate formation at high OPE-2S:AuNP ratios, above full AuNP coverage, is most likely of a physical nature (van der Waals forces or π-π interactions). PMID:26471461

  3. Anti-inflammatory effect of thalidomide dithiocarbamate and dithioate analogs.

    PubMed

    Talaat, Roba; El-Sayed, Waheba; Agwa, Hussein S; Gamal-Eldeen, Amira M; Moawia, Shaden; Zahran, Magdy A H

    2015-08-05

    Thalidomide has anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It has been used to treat a variety of cancers and autoimmune diseases. This study aimed to characterize anti-inflammatory activities of novel thalidomide analogs by exploring their effects on splenocytes proliferation and macrophage functions and their antioxidant activity. MTT assay was used to assess the cytotoxic effect of thalidomide analogs against splenocytes. Tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB-P65) were determined by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was estimated by colorimetric assay. Antioxidant activity was examined by ORAC assay. Our results demonstrated that thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 produced a slight increase in splenocyte proliferation compared with thalidomide. Thalidomide dithiocarbamate analog 1 is a potent inhibitor of TNF-α production, whereas thalidomide dithiocarbamate analog 5 is a potent inhibitor of both TNF-α and NO. Analog 2 has a pronounced inhibitory effect on NF-κB-P65 production level. All thalidomide analogs showed prooxidant activity against hydroxyl (OH) radical. Analog 1 and thalidomide dithioate analog 3 have prooxidant activity against peroxyl (ROO) radical in relation to thalidomide. On the other hand, analog 4 has a potent scavenging capacity against peroxyl (ROO) radical compared with thalidomide. Taken together, the results of this study suggest that thalidomide analogs might have valuable anti-inflammatory activities with more pronounced effect than thalidomide itself.

  4. Effects of mancozeb and other dithiocarbamate fungicides on Saccharomyces cerevisiae: the role of mitochondrial petite mutants in dithiocarbamate tolerance.

    PubMed

    Casalone, E; Bonelli, E; Polsinelli, M

    2010-11-01

    Saccharomyces cerevisiae as model system was used to evaluate the occurrence of resistant mutants and adaptation mechanism to mancozeb (MZ), a widespread fungicide of the dithiocarbamate class with a broad spectrum of action and multiple cell targets. We were unable to isolate mutants resistant to inhibitory concentration of MZ but found an unusually large number of mitochondrial defective petite mutants among cells incubated in the presence of subinhibitory MZ concentration. Similar results were obtained with two other dithiocarbamate fungicides. Comparison of wild type and petite mutants showed that the latter were more resistant to toxic effects of MZ, highlighting the role of mitochondria in MZ-tolerance. The data suggest that petite cells, arising by exposure to sub-inhibitory MZ concentration, are not induced by fungicides but are spontaneous mutants already present in the population before the contact with the fungicide.

  5. Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile.

    PubMed

    Lall, Manjinder S; Hoge, Garrett; Tran, Tuan P; Kissel, William; Murphy, Sean T; Taylor, Clarke; Hutchings, Kim; Samas, Brian; Ellsworth, Edmund L; Curran, Timothy; Showalter, H D Hollis

    2012-05-18

    (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.

  6. Dithiocarbamate Self-Assembled Monolayers as Efficient Surface Modifiers for Low Work Function Noble Metals

    SciTech Connect

    Meyer, Dominik; Schäfer, Tobias; Schulz, Philip; Jung, Sebastian; Rittich, Julia; Mokros, Daniel; Segger, Ingolf; Maercks, Franziska; Effertz, Christian; Mazzarello, Riccardo; Wuttig, Matthias

    2016-09-06

    Tuning the work function of the electrode is one of the crucial steps to improve charge extraction in organic electronic devices. Here, we show that N,N-dialkyl dithiocarbamates (DTC) can be effectively employed to produce low work function noble metal electrodes. Work functions between 3.1 and 3.5 eV are observed for all metals investigated (Cu, Ag, and Au). Ultraviolet photoemission spectroscopy (UPS) reveals a maximum decrease in work function by 2.1 eV as compared to the bare metal surface. Electronic structure calculations elucidate how the complex interplay between intrinsic dipoles and dipoles induced by bond formation generates such large work function shifts. Subsequently, we quantify the improvement in contact resistance of organic thin film transistor devices with DTC coated source and drain electrodes. These findings demonstrate that DTC molecules can be employed as universal surface modifiers to produce stable electrodes for electron injection in high performance hybrid organic optoelectronics.

  7. Dithiocarbamate Self-Assembled Monolayers as Efficient Surface Modifiers for Low Work Function Noble Metals.

    PubMed

    Meyer, Dominik; Schäfer, Tobias; Schulz, Philip; Jung, Sebastian; Rittich, Julia; Mokros, Daniel; Segger, Ingolf; Maercks, Franziska; Effertz, Christian; Mazzarello, Riccardo; Wuttig, Matthias

    2016-09-06

    Tuning the work function of the electrode is one of the crucial steps to improve charge extraction in organic electronic devices. Here, we show that N,N-dialkyl dithiocarbamates (DTC) can be effectively employed to produce low work function noble metal electrodes. Work functions between 3.1 and 3.5 eV are observed for all metals investigated (Cu, Ag, and Au). Ultraviolet photoemission spectroscopy (UPS) reveals a maximum decrease in work function by 2.1 eV as compared to the bare metal surface. Electronic structure calculations elucidate how the complex interplay between intrinsic dipoles and dipoles induced by bond formation generates such large work function shifts. Subsequently, we quantify the improvement in contact resistance of organic thin film transistor devices with DTC coated source and drain electrodes. These findings demonstrate that DTC molecules can be employed as universal surface modifiers to produce stable electrodes for electron injection in high performance hybrid organic optoelectronics.

  8. A modular synthesis of dithiocarbamate pendant unnatural α-amino acids

    EPA Science Inventory

    Unnatural α-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in-situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to...

  9. A modular synthesis of dithiocarbamate pendant unnatural α-amino acids

    EPA Science Inventory

    Unnatural α-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in-situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to...

  10. Asymmetric Synthesis of α-Trifluoromethyl Pyrrolidines through Organocatalyzed 1,3-Dipolar Cycloaddition Reaction.

    PubMed

    Dong, Zhenghao; Zhu, Yuanyuan; Li, Boyu; Wang, Cui; Yan, Wenjin; Wang, Kairong; Wang, Rui

    2017-02-28

    The optically active α-trifluoromethyl pyrrolidines have been achieved through organocatalyzed 1, 3-dipolar cycloaddition reaction firstly. With diphenyl- prolinol trimethylsilyl ether as catalyst and in the presence of 3, 5-dinitrobenzoic acid, the reaction of trifluoroethylamine-derived ketimine with 2-enals gave α-trifluoro-methyl pyrrolidines bearing three contiguous stereogenic centers in excellent diastereoselectivies, stereoselectivities and yields.

  11. Synthesis of Enantioenriched Pyrrolidines via Gold-Catalyzed Tandem Cycloisomerization/Hydrogenation of Chiral Homopropargyl Sulfonamides.

    PubMed

    Yu, Yong-Fei; Shu, Chao; Tan, Tong-De; Li, Long; Rafique, Shahid; Ye, Long-Wu

    2016-10-07

    A novel gold-catalyzed tandem cycloisomerization/hydrogenation of chiral homopropargyl sulfonamides has been developed. Various enantioenriched pyrrolidines can be obtained in excellent yields and excellent enantioselectivities by combination of chiral tert-butylsulfinimine chemistry with gold catalysis. Importantly, this represents the first example of a pyrrolidine synthesis from homopropargyl sulfonamide.

  12. Method of removing nitrogen monoxide from a nitrogen monoxide-containing gas using a water-soluble iron ion-dithiocarbamate, xanthate or thioxanthate

    DOEpatents

    Liu, D. Kwok-Keung; Chang, Shih-Ger

    1987-08-25

    The present invention relates to a method of removing of nitrogen monoxide from a nitrogen monoxide-containing gas which method comprises contacting a nitrogen oxide-containing gas with an aqueous solution of water soluble organic compound-iron ion chelate complex. The NO absorption efficiency of ferrous urea-dithiocarbamate and ferrous diethanolamine-xanthate as a function of time, oxygen content and solution ph is presented. 3 figs., 1 tab.

  13. Pyrrolidine synthesis via palladium-catalyzed trimethylenemethane cycloaddition and related studies

    SciTech Connect

    Marrs, C.M.

    1992-01-01

    The palladium catalyzed trimethylenemethane cycloaddition has been extended to the synthesis of pyrrolidines and azepines. In contrast to previous attempts with N-alkyl and N-aryl imine, successful cycloadditions were recorded with several aromatic and aliphatic electron-deficient imines. Sulfonimines were found to be excellent acceptors, yielding pyrrolidine cycloadducts in excellent yields. Aromatic sulfonimines were observed to undergo cycloaddition very rapidly at or below room temperature. Some aliphatic nitrimine and N-phenyl, C-carbalkoxy imines were also found to be useful acceptors. Azepines were obtained from the cycloaddition of cisoid lockeed [alpha],[beta] unsaturated sulfonimines. In order to support the cycloaddition studies, a novel synthetic method was developed for the synthesis of sulfonimines. bis(Toluene-sulfonylimido)tellurium, Te(=N-Ts)[sub 2], generated from tellurium metal and anhydrous chloramine-t, was found to convert both aromatic and aliphatic aldehydes into the corresponding sulfonimines. Chiral ligands were examined in this cyclization and an enantiomeric excess of 35% was achieved with Hayashi's bidentate ferrocenyl ligand (BPFA). In support of this effort, the total synthesis of [+-] nicotine was accomplished in seven steps starting from pyridine 3-carboxaldehyde using these methodologies in order to verify the enantiomeric excess. Finally, the trimethylenemethane cycloaddition was examined with tropone irontricarbonyl complex. A novel [5+3] cycloaddition was observed to proceed in good yield, which upon decomplexation from the iron tricarbonyl moiety yielded the tricyclo[3.2.0] system. The scope and generality were briefly examined. Extended Huekel calculations were performed in order to help rationalize the unexpected regiochemistry.

  14. μ-η2:η2-Peroxido-bis­[nitratodioxido­bis(pyrrolidin-2-one)uranium(VI)

    PubMed Central

    Takao, Koichiro; Ikeda, Yasuhisa

    2010-01-01

    In the crystal structure of the title compound, [U2(NO3)2O4(O2)(C4H7NO)4], two UO2 2+ ions are connected by a μ-η2:η2-O2 unit. The O2 unit shows ‘side-on’ coordination to both U atoms. An inversion center is located at the midpoint of the O—O bond in the O2 unit, affording a centrosymmetrically expanded dimeric structure. The U—O(axial) bond lengths are 1.777 (4) Å and 1.784 (4) Å, indicating that the oxidation state of U is exclusively 6+, i.e., UO2 2+. Furthermore, the O—O distance is 1.492 (8) Å, which is typical of peroxide, O2 2–. The U atom is eight-coordinated in a hexa­gonal-bipyramidal geometry. The coordinating atoms of the nitrate and pyrrolidine-2-one ligands and the μ-η2:η2-O2 2– unit are located in the equatorial plane and form an irregular hexa­gon. An inter­molecular hydrogen bond is found between N—H of the pyrrolidine-2-one ligand and the coordinating O of the same ligand in a neighboring complex. A second inter­molecular hydrogen bond is found between the N—H of the other pyrrolidine-2-one ligand and one of the uranyl oxido atoms. PMID:21579030

  15. Comparative effects of N,N-disubstituted dithiocarbamates and dimercaptosuccinate on mobilization of methylmercury in mice

    SciTech Connect

    Gale, G.R.; Atkins, L.M.; Smith, A.B.; Walker, E.M. Jr.; Jones, M.M.

    1984-07-01

    Diethyldithiocarbamate (DDTC) and five of its N,N-disubstituted analogs were compared with dimercaptosuccinate (DMSA) for effectiveness in mobilizing and promoting excretion of methylmercury (MeHg) following administration of a sublethal dose of MeHg labeled with Me203Hg. The previously reported effectiveness of DMSA was confirmed. Of the dithiocarbamates assessed, only di(carboxymethyl)-dithiocarbamate (DCDC) was active in mobilizing MeHg, and its activity on a molar dose basis was less than that of DMSA. The disparate structural requirements of dithiocarbamates as antagonists of MeHg and of cadmium were discussed.

  16. Human umbilical vein endothelial cells accelerate oxalate-induced apoptosis of human renal proximal tubule epithelial cells in co-culture system which is prevented by pyrrolidine dithiocarbamate.

    PubMed

    Sarıca, Kemal; Aydin, Hasan; Yencilek, Faruk; Telci, Dilek; Yilmaz, Bayram

    2012-10-01

    Oxalate is the most common component of kidney stones and elevated urinary levels induce renal tubular cell toxicity and death which is essential for crystal attachment. Endothelial cells, in some studies have been shown to regulate certain functions of renal proximal tubule cells. The aim of this study was to evaluate the effect of endothelial cells on tubular cell apoptosis in a co-culture system mimicking the in vivo renal physiological settings. The human umbilical vein endothelial cells (HUVEC) and human renal proximal tubule epithelial cells (RPTEC) were exposed to increasing concentrations (0-1.0 mM) of oxalate with or without 10 μM PDTC pretreatment for 24 h. In HUVEC, RPTEC and HUVEC-RPTEC co-cultures, the cell viability was measured using the WST-1 assay and cell death with the TUNEL analysis using the flow cytometry. The treatment of RPTECs with oxalate lead to 8.9-26.2% cell death which was reduced to 0-1.6% with the PDTC pretreatment. The death rate of RPTECs was significantly increased by 15-19% at different oxalate concentrations when co-cultured with HUVECs. In contrast, cell viability was not substantially altered in PDTC pretreated RPTECs that were co-cultured with HUVECs. Apoptosis was the way of cell death as similar rate of apoptosis was observed in cell culture systems. Although cell viability of RPTECs was further reduced when co-cultured with HUVECs, it was restored with the pretreatment of PDTC. This is the first study focusing on the role of endothelial cells on RPTEC apoptosis following hyperoxaluria.

  17. Iron- and cobalt-catalyzed arylation of azetidines, pyrrolidines, and piperidines with Grignard reagents.

    PubMed

    Barré, Baptiste; Gonnard, Laurine; Campagne, Rémy; Reymond, Sébastien; Marin, Julien; Ciapetti, Paola; Brellier, Marie; Guérinot, Amandine; Cossy, Janine

    2014-12-05

    Iron- and cobalt-catalyzed cross-couplings between iodo-azetidines, -pyrrolidines, -piperidines, and Grignard reagents are disclosed. The reaction is efficient, cheap, chemoselective and tolerates a large variety of (hetero)aryl Grignard reagents.

  18. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo.

    PubMed

    Carta, Fabrizio; Aggarwal, Mayank; Maresca, Alfonso; Scozzafava, Andrea; McKenna, Robert; Masini, Emanuela; Supuran, Claudiu T

    2012-02-23

    A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glucoma.

  19. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo#

    PubMed Central

    Carta, Fabrizio; Aggarwal, Mayank; Maresca, Alfonso; Scozzafava, Andrea; McKenna, Robert; Masini, Emanuela; Supuran, Claudiu T.

    2012-01-01

    A series of dithiocarbamates was prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of 4 human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. X-ray crystal structure of hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed effective intraocular pressure lowering activity in an animal model of glucoma. PMID:22276570

  20. Detection and quantification of dithiocarbamate pesticides by Surface Enhanced Raman Spectroscopy (SERS)

    NASA Astrophysics Data System (ADS)

    Saute, Benjamin Calvin

    Dithiocarbamates are a subclass of carbamate pesticides that are widely used as insecticidal agents on food crops in the US and abroad. Quantitative determination of trace quantities of dithiocarbamates is necessary in order to mitigate potential human exposure via pesticide residues left on inadequately washed food items as well as groundwater contamination from agricultural runoff. The focus of this research is on the development and optimization of a Surface Enhanced Raman Spectroscopy (SERS) based analytical technique for the quantitative determination of trace amounts of dithiocarbamate pesticides in different matrices. Gold nanoparticles of different shapes and sizes will be investigated to determine the suitability of these materials as SERS active substrates for the trace analysis of dithiocarbamate pesticides. Analytical sensitivity will be evaluated by determining the limits of detection using established statistical methods.

  1. Punigratane, a novel pyrrolidine alkaloid from Punica granatum rind with putative efflux inhibition activity.

    PubMed

    Rafiq, Zumaana; Narasimhan, Sreevidya; Vennila, Rosy; Vaidyanathan, Rama

    2016-02-25

    A new pyrrolidine alkaloid named Punigratane was isolated from the rind of Punica granatum. This is the first report of a pyrrolidine-like structure from the rind. The activity of this compound was tested in a representative MDR Klebsiella pneumoniae strain which exhibited high efflux pump activity. At a concentration of 6 mg, this compound Punigratane was found to have efflux inhibition activity.

  2. Interactions of nitric oxide with copper(II) dithiocarbamates in aqueous solution.

    PubMed

    Díaz, Alicia; Ortiz, Mayreli; Sánchez, Ileana; Cao, Roberto; Mederos, Alfredo; Sanchiz, Joaquin; Brito, Felipe

    2003-07-01

    This is the first report on the formation of air-stable copper nitrosyl complexes. The interaction of nitric oxide, NO, with Cu(DTC)(2).3H(2)O (DTC: dithiocarbamate) and was studied in aqueous solution at pH 7.4 and 293 K. The stability constants were determined from UV-Vis data, using LETAGROP program. The high values obtained, log beta(1)=9.743(5) and log beta(2)=15.44(2) for Cu(ProDTC)(2)-NO, (ProDTC=L-prolinedithiocarbamate) and log beta(1)=8.723(5) and log beta(2)=11.45(2) for Cu(MorDTC)(2)-NO system, (MorDTC=morpholyldithiocarbamate), indicate the formation of two stable nitrosyl complexes, Cu(DTC)(2)NO and Cu(DTC)(2)(NO)(2). Coordinated NO is neither affected by the presence of air nor when the solution is purged with Ar. Cu(MorDTC)(2)NO.3H(2)O was isolated in the solid state and its nuNO (IR) band at 1682 cm(-1), but affected by temperature variations over 333 K.

  3. Synthesis, characterization, structural and biological aspects of copper(II) dithiocarbamate complexes - Part II, [Cu{S2CN(Me)(R1)}2], [Cu{S2CN(Me)(R2)}2] and [Cu{S2CN(R3)(R4)}2] {R1 = CH2CH(OMe)2, R2 = 2-methyl-1,3-dioxolane, R3 = CH2(CH2)2NCHPhOCH2Ph and R4 = CH2CH2OH}

    NASA Astrophysics Data System (ADS)

    Ferreira, Isabella P.; de Lima, Geraldo M.; Paniago, Eucler B.; Takahashi, Jacqueline A.; Krambrock, Klaus; Pinheiro, Carlos B.; Wardell, James L.; Visentin, Lorenzo C.

    2013-09-01

    Three new copper(II) dithiocarbamates (DTC), [Cu{S2CN(Me)(R1)}2] (1), [Cu{S2CN(Me)(R2)}2] (2) and [Cu{S2CN(R3)(R4)}2] (3) with R1 = CH2CH(OMe)2, R2 = 2-methyl-1,3-dioxolane, R3 = CH2(CH2)2NCHPhOCH2Ph and R4 = CH2CH2OH, have been synthesized and characterized by different spectroscopic techniques. Complexes (1) and (2) display typical EPR spectra for separated Cu(II) centers, and the spectrum of (3) is characteristic of two magnetically coupled Cu(II) ions with S = 1. The X-ray crystallographic determination has shown that complexes (1) and (2) crystallise in the triclinic and monoclinic systems. In addition both complexes are monomers in which the geometry at each Cu(II) is square planar. The in vitro antimicrobial activity of the sodium salts of ligands, and of the Cu(II)-DTC complexes have been screened against Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus, Penicillium citrinum and Curvularia senegalensis, as well as Gram positive and Gram negative bacteria. Finally, the toxic effects of complexes (1)-(3) were performed using Chlorella vulgaris.

  4. Antitumor effect of sonodynamically activated pyrrolidine tris-acid fullerene

    NASA Astrophysics Data System (ADS)

    Iwase, Yumiko; Nishi, Koji; Fujimori, Junya; Fukai, Toshio; Yumita, Nagahiko; Ikeda, Toshihiko; Chen, Fu-shin; Momose, Yasunori; Umemura, Shin-ichiro

    2016-07-01

    In this study, the sonodynamically induced antitumor effect of pyrrolidine tris-acid fullerene (PTF) was investigated. Sonodynamically induced antitumor effects of PTF by focused ultrasound were investigated using isolated sarcoma-180 cells and mice bearing ectopically-implanted colon 26 carcinoma. Cell damage induced by ultrasonic exposure was enhanced by 5-fold in the presence of 80 µM PTF. The combined treatment of ultrasound and PTF suppressed the growth of the implanted colon 26 carcinoma. Ultrasonically induced 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (4oxoTEMPO) production in the presence and absence of PTF was assessed, and it was shown that 80 µM PTF enhanced 4oxoTEMPO production as measured by ESR spectroscopy. Histidine, a reactive oxygen scavenger, significantly reduced cell damage and 4oxoTEMPO generation caused by ultrasonic exposure in the presence of PTF. These results suggest that singlet oxygen is likely to be involved in the ultrasonically induced cell damage enhanced by PTF.

  5. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis.

    PubMed

    He, Xin; Alian, Akram; Stroud, Robert; Ortiz de Montellano, Paul R

    2006-10-19

    In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.

  6. Pyrrolidine Carboxamides as a Novel Class of Inhibitors of Enoyl Acyl Carrier Protein Reductase (InhA) from Mycobacterium tuberculosis

    PubMed Central

    He, Xin; Alian, Akram; Stroud, Robert; de Montellano, Paul R. Ortiz

    2008-01-01

    In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here discovery through high throughput screening of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA. PMID:17034137

  7. Regulation of p53 by metal ions and by antioxidants: dithiocarbamate down-regulates p53 DNA-binding activity by increasing the intracellular level of copper.

    PubMed Central

    Verhaegh, G W; Richard, M J; Hainaut, P

    1997-01-01

    Mutations in the p53 tumor suppressor gene frequently fall within the specific DNA-binding domain and prevent the molecule from transactivating normal targets. DNA-binding activity is regulated in vitro by metal ions and by redox conditions, but whether these factors also regulate p53 in vivo is unclear. To address this question, we have analyzed the effect of pyrrolidine dithiocarbamate (PDTC) on p53 DNA-binding activity in cell lines expressing wild-type p53. PDTC is commonly regarded as an antioxidant, but it can also bind and transport external copper ions into cells and thus exert either pro- or antioxidant effects in different situations. We report that PDTC, but not N-acetyl-L-cysteine, down-regulated the specific DNA-binding activity of p53. Loss of DNA binding correlated with disruption of the immunologically "wild-type" p53 conformation. Using different chelators to interfere with copper transport by PDTC, we found that bathocuproinedisulfonic acid (BCS), a non-cell-permeable chelator of Cu1+, prevented both copper import and p53 down-regulation. In contrast, 1,10-orthophenanthroline, a cell-permeable chelator of Cu2+, promoted the redox activity of copper and up-regulated p53 DNA-binding activity through a DNA damage-dependent pathway. We have previously reported that p53 protein binds copper in vitro in the form of Cu1+ (P. Hainaut, N. Rolley, M. Davies, and J. Milner, Oncogene 10:27-32, 1995). The data reported here indicate that intracellular levels and redox activity of copper are critical for p53 protein conformation and DNA-binding activity and suggest that copper ions may participate in the physiological control of p53 function. PMID:9315628

  8. Dual platinum and pyrrolidine catalysis in the direct alkylation of allylic alcohols: selective synthesis of monoallylation products.

    PubMed

    Shibuya, Ryozo; Lin, Lu; Nakahara, Yasuhito; Mashima, Kazushi; Ohshima, Takashi

    2014-04-22

    A dual platinum- and pyrrolidine-catalyzed direct allylic alkylation of allylic alcohols with various active methylene compounds to produce products with high monoallylation selectivity was developed. The use of pyrrolidine and acetic acid was essential, not only for preventing undesirable side reactions, but also for obtaining high monoallylation selectivity.

  9. Prediction on the inhibition ratio of pyrrolidine derivatives on matrix metalloproteinase based on gene expression programming.

    PubMed

    Li, Yuqin; You, Guirong; Jia, Baoxiu; Si, Hongzong; Yao, Xiaojun

    2014-01-01

    Quantitative structure-activity relationships (QSAR) were developed to predict the inhibition ratio of pyrrolidine derivatives on matrix metalloproteinase via heuristic method (HM) and gene expression programming (GEP). The descriptors of 33 pyrrolidine derivatives were calculated by the software CODESSA, which can calculate quantum chemical, topological, geometrical, constitutional, and electrostatic descriptors. HM was also used for the preselection of 5 appropriate molecular descriptors. Linear and nonlinear QSAR models were developed based on the HM and GEP separately and two prediction models lead to a good correlation coefficient (R (2)) of 0.93 and 0.94. The two QSAR models are useful in predicting the inhibition ratio of pyrrolidine derivatives on matrix metalloproteinase during the discovery of new anticancer drugs and providing theory information for studying the new drugs.

  10. Effects of substituted dithiocarbamates on distribution and excretion of inorganic mercury in mice

    SciTech Connect

    Gale, G.R.; Atkins, L.M.; Smith, A.B.; Jones, M.M.

    1985-02-01

    Diethyldithiocarbamate (DDTC) and six of its N,N-disubstituted congeners were evaluated for their relative efficacies in mobilizing and promoting excretion of mercury (Hg/sup + +/) using mice which had been given /sup 203/Hg/sup + +/; D-penicillamine (PEN) was used as a positive control compound. While none was as effective as PEN when compared on a molar dose basis, significant activity as assessed by reduction of whole body /sup 203/Hg burden, was observed following treatment with three of the analogs. The order of effectiveness was PEN greater than N-methyl-N-dithiocarboxyglucamine (MDCG) greater than di(carboxymethyl)dithiocarbamate (DCDC) greater than di(hydroxyethyl)dithiocarbamate (DHDC).

  11. Toxic Epidermal Necrolysis After Exposure to Dithiocarbamate Fungicide Mancozeb.

    PubMed

    Zakharov, Sergey; Csomor, Jan; Urbanek, Petr; Pelclova, Daniela

    2016-01-01

    Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality. Dithiocarbamates (DTC) are organosulphur compounds widely used in agriculture, industry and households. We report a case of TEN after exposure to mancozeb in fungicide. A 48-year-old 75 kg b.w. man was admitted with fever and generalized skin/mucous lesions after application of fungicide in a home garden. The patient had necrotic desquamation of gastrointestinal/respiratory tract mucosa, ocular lesion and skin epidermolysis of 90% of body surface. The laboratory findings included elevation of inflammatory parameters, hyperglycaemia, increased urea, creatinine, liver enzymes, hypoalbuminemia and electrolyte disturbances. The treatment included supportive care, management of fluid/electrolyte requirements, analgesics and enteral nutrition. Skin lesions were treated with occlusive non-adhesive biological wound dressings. Due to the proof of Acinetobacter, Escherichia coli and Escherichia faecalis from skin swabs, a combination of meropenem with amikacin was administered. During the next 2 weeks, complete re-epithelialization of skin lesions occurred, mucosal lesions healed and the laboratory parameters returned to normal. The patient was discharged on day 42. TEN is a rare condition that is generally caused by medications. Nevertheless, high attention should be paid to the cases of occupational or household exposure to DTC fungicides widely used in agriculture and home gardens because of their ability to cause TEN after skin and inhalation exposure. Greater emphasis on the hazardous properties of these products is necessary to ensure non-professional users are aware of the necessity of protective clothing during mixing, loading, application and early re-entry into treated fields.

  12. Stereoselective access to heteroarylmethylene-substituted pyrrolidines: fully organocatalytic Mannich-hydroamination reactions.

    PubMed

    Jean, Alexandre; Blanchet, Jérôme; Rouden, Jacques; Maddaluno, Jacques; De Paolis, Michaël

    2013-02-25

    A one-pot sequence of organocatalytic transformations delivers heteroarylmethylene-substituted pyrrolidines with high stereo- and enantioselectivity. A Mannich coupling of N-heteroarylalkyne aldehydes with aldimine and an original metal-free hydroamination of the resulting adducts are the key transformations of the process delivering highly functionalized molecules with high potential for synthetic applications.

  13. Microglia activation and cell death in response to diethyl-dithiocarbamate acute administration.

    PubMed

    Zucconi, Gigliola Grassi; Laurenzi, Maria Assunta; Semprevivo, Massimo; Torni, Federica; Lindgren, Jan Ake; Marinucci, Eva

    2002-04-29

    An increasing body of evidence suggests a role for activated microglia in the pathogenesis of neurodegenerative disorders. Hence, it would be useful to have a better understanding of the significance of microglial activation for neuronal damage. Unfortunately, most models of microglial activation use invasive or long-lasting insults, which make it difficult to evaluate the role played by microglia. We have instead developed a model for microglial activation by using brief exposure to the widely available neurotoxin diethyl-dithiocarbamate (DDTC). Despite evidence for the neurotoxic nature of this substance, microglia involvement has not been hitherto investigated. After acute i.p. administration of DDTC at two different doses, microglia were already activated in selected areas of the rat brain (hippocampal dentate gyrus, entorhinal-pyriform cortex and hypothalamus) after 1 hour, reaching a peak at 3-6 hours and subsided within 6-48 hours, depending on the brain region. Microglia activation was associated with interleukin-1 beta immunopositivity between 3 and 6 hours and with up-regulation of major histocompatibility complex class II expression between 24 and 48 hours. No significant changes in astrocyte immunostaining were detected between 6 hours and 6 days. The TUNEL procedure revealed the death of a limited number of cells in the above-mentioned structures that peaked at 6h and then declined rapidly. Cell death was detected in sites with major, minor, or no microglial activation, indicating that these two events can occur concomitantly or independently. The study shows that the administration of DDTC provides a useful model for studying the implications of region-specific reactivity of microglia and its differential interaction with neuronal damage.

  14. Synthesis, Characterization, and Processing of Copper, Indium, and Gallium Dithiocarbamates for Energy Conversion Applications

    NASA Technical Reports Server (NTRS)

    Duraj, S. A.; Duffy, N. V.; Hepp, A. F.; Cowen, J. E.; Hoops, M. D.; Brothrs, S. M.; Baird, M. J.; Fanwick, P. E.; Harris, J. D.; Jin, M. H.-C.

    2009-01-01

    Ten dithiocarbamate complexes of indium(III) and gallium(III) have been prepared and characterized by elemental analysis, infrared spectra and melting point. Each complex was decomposed thermally and its decomposition products separated and identified with the combination of gas chromatography/mass spectrometry. Their potential utility as photovoltaic materials precursors was assessed. Bis(dibenzyldithiocarbamato)- and bis(diethyldithiocarbamato)copper(II), Cu(S2CN(CH2C6H5)2)2 and Cu(S2CN(C2H5)2)2 respectively, have also been examined for their suitability as precursors for copper sulfides for the fabrication of photovoltaic materials. Each complex was decomposed thermally and the products analyzed by GC/MS, TGA and FTIR. The dibenzyl derivative complex decomposed at a lower temperature (225-320 C) to yield CuS as the product. The diethyl derivative complex decomposed at a higher temperature (260-325 C) to yield Cu2S. No Cu containing fragments were noted in the mass spectra. Unusual recombination fragments were observed in the mass spectra of the diethyl derivative. Tris(bis(phenylmethyl)carbamodithioato-S,S'), commonly referred to as tris(N,N-dibenzyldithiocarbamato)indium(III), In(S2CNBz2)3, was synthesized and characterized by single crystal X-ray crystallography. The compound crystallizes in the triclinic space group P1(bar) with two molecules per unit cell. The material was further characterized using a novel analytical system employing the combined powers of thermogravimetric analysis, gas chromatography/mass spectrometry, and Fourier transform infrared (FT-IR) spectroscopy to investigate its potential use as a precursor for the chemical vapor deposition (CVD) of thin film materials for photovoltaic applications. Upon heating, the material thermally decomposes to release CS2 and benzyl moieties in to the gas phase, resulting in bulk In2S3. Preliminary spray CVD experiments indicate that In(S2CNBz2)3 decomposed on a Cu substrate reacts to produce

  15. Asymmetric synthesis of functionalized trifluoromethyl-substituted pyrrolidines via an organocatalytic domino Michael/Mannich [3+2] cycloaddition.

    PubMed

    Zhi, Ying; Zhao, Kun; Liu, Qiang; Wang, Ai; Enders, Dieter

    2016-11-29

    The asymmetric synthesis of highly functionalized pyrrolidine derivatives with three contiguous stereogenic centers and bearing a trifluoromethyl group has been developed through an organocatalytic domino Michael/Mannich [3+2] cycloaddition sequence. Employing a commercially available secondary amine as the catalyst, the scalable one-pot protocol occurs with high yields and excellent stereoselectivities, providing a short entry into a series of trifluoromethylated pyrrolidines with potential medical value.

  16. Expanding The Scope Of Oligo-pyrrolinone-pyrrolidines As Protein-protein Interface Mimics

    PubMed Central

    Raghuraman, Arjun; Xin, Dongyue; Perez, Lisa M.; Burgess, Kevin

    2013-01-01

    Oligo-pyrrolinone-pyrrolidines (generic structure 1) have the potential to interfere with protein-protein interactions (PPIs), but to reduce this to practice it is necessary to be able to synthesize these structures with a variety of different side-chains corresponding to genetically encoded proteins. This paper describes expansion of the synthetic scope of 1, the difficulties encountered in this process, particularly issues with epimerization and slow coupling rates, and methods to overcome them. Finally, spectroscopic and physicochemical properties as well as proteolytic stabilities of molecules in this series were measured; these data highlight the suitability of oligo-pyrrolinone-pyrrolidines for the development of pharmacological probes or pharmaceutical leads. PMID:23654284

  17. Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

    PubMed

    Kaminski, Krzysztof

    2017-01-01

    The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors.

    PubMed

    Bannwart, Linda M; Carter, David S; Cai, Hai-Ying; Choy, Jason C; Greenhouse, Robert; Jaime-Figueroa, Saul; Iyer, Pravin S; Lin, Clara J; Lee, Eun Kyung; Lucas, Matthew C; Lynch, Stephen M; Madera, Ann Marie; Moore, Amy; Ozboya, Kerem; Raptova, Lubica; Roetz, Ralf; Schoenfeld, Ryan C; Stein, Karin Ann; Steiner, Sandra; Villa, Marzia; Weikert, Robert J; Zhai, Yansheng

    2008-12-01

    A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.

  19. Facile access to unnatural dipeptide-alcohols based on cis-2,5-disubstituted pyrrolidines.

    PubMed

    Jia, Yan-Yan; Li, Xiao-Ye; Wang, Ping-An; Wen, Ai-Dong

    2015-02-11

    Well-defined unnatural dipeptide-alcohols based on a cis-2,5-disubstitued pyrrolidine backbone were synthesized from commercially available starting materials meso-diethyl-2,5-dibromoadipate, (S)-(-)-1-phenylethylamine, and phenylalaninol. The structures of these unnatural dipeptide-alcohols are supported by HRMS, 1H- and 13C-NMR spectroscopy. These unnatural dipeptide-alcohols can act as building blocks for peptidomimetics.

  20. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  1. Pyrrolidin-2-one derivatives may reduce body weight in rats with diet-induced obesity.

    PubMed

    Dudek, Magdalena; Knutelska, Joanna; Bednarski, Marek; Nowiński, Leszek; Zygmunt, Małgorzata; Kazek, Grzegorz; Mordyl, Barbara; Głuch-Lutwin, Monika; Zaręba, Paula; Kulig, Katarzyna; Sapa, Jacek

    2016-04-05

    Obesity affects an increasing number of individuals in the human population and significant importance is attached to research leading to the discovery of drug which would effectively reduce weight. The search for new drugs with anorectic activity and acting within the adrenergic system has attracted the interest of researchers. This study concerns the experimental effects on body weight of α2-adrenoceptor antagonists from the group of pyrrolidin-2-one derivatives in rats with diet-induced obesity. The intrinsic activity of the test compounds at the α-adrenoreceptors was tested. Obesity in rats was obtained by the use of fatty diet and then the influence of the test compounds on body weight, food and water intakes, lipid and glucose profiles and glycerol and cortisol levels were determinated. The effects of the compounds on locomotor activity, body temperature, blood pressure and heart rate were tested. One of the test compounds (1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one) reduces the animal's body weight and the amount of peritoneal adipose tissue during chronic administration, at the same time it does not cause significant adverse effects on the cardiovascular system. This compound decreases temperature and elevates glycerol levels and does not change the locomotor activity and cortisol level at anti-obese dose. Some derivatives of pyrrolidin-2-one that act as antagonists of the α2-adrenoreceptor may reduce body weight. Reducing body weight for 1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one can be associated with decrease in food intake, body fat reduction, reduction of blood glucose, and increased thermogenesis and lipolysis. This effect cannot be the result of changes in spontaneous activity or stress. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Total reflection X-ray fluorescence trace mercury determination by trapping complexation: Application in advanced oxidation technologies

    NASA Astrophysics Data System (ADS)

    Custo, Graciela; Litter, Marta I.; Rodríguez, Diana; Vázquez, Cristina

    2006-11-01

    It is well known that Hg species cause high noxious effects on the health of living organisms even at very low levels (5 μg/L). Quantification of this element is an analytical challenge due to the peculiar physicochemical properties of all Hg species. The regulation of the maximal allowable Hg concentration led to search for sensitive methods for its determination. Total reflection X-ray fluorescence is a proved instrumental analytical tool for the determination of trace elements. In this work, the use of total reflection X-ray fluorescence for Hg quantification is investigated. However, experimental determination by total reflection X-ray fluorescence requires depositing a small volume of sample on the reflector and evaporation of the solvent until dryness to form a thin film. Because of volatilization of several Hg forms, a procedure to capture these volatile species in liquid samples by using complexing agents is proposed. Acetate, oxalic acid, ethylenediaminetetracetic acid and ammonium pyrrolidine-dithiocarbamate were assayed for trapping the analytes into the solution during the preparation of the sample and onto the reflector during total reflection X-ray fluorescence measurements. The proposed method was applied to evaluate Hg concentration during TiO 2-heterogeneous photocatalysis, one of the most known advanced oxidation technologies. Advanced oxidation technologies are processes for the treatment of effluents in waters and air that involve the generation of very active oxidative and reductive species. In heterogeneous photocatalysis, Hg is transformed to several species under ultraviolet illumination in the presence of titanium dioxide. Total reflection X-ray fluorescence was demonstrated to be applicable in following the extent of the heterogeneous photocatalysis reaction by determining non-transformed Hg in the remaining solution.

  3. Development of new portable miniaturize solid phase microextraction of silver-APDC complex using micropipette tip in-syringe system couple with electrothermal atomic absorption spectrometry

    NASA Astrophysics Data System (ADS)

    Naeemullah; Kazi, Tasneem Gul; Afridi, Hassan Imran; Shah, Faheem; Arain, Sadaf Sadia; Arain, Salma Aslam; Panhwar, Abdul Haleem; Arain, Mariam Shahzadi; Samoon, Muhammad Kashif

    2016-02-01

    An innovative and simple miniaturized solid phase microextraction (M-SPME) method, was developed for preconcentration and determination of silver(I) in the fresh and waste water samples. For M-SPME, a micropipette tip packed with activated carbon cloth (ACC) as sorbent, in a syringe system. The size, morphology and elemental composition of ACC before and after adsorption of analyte have been characterized by scanning electron microscopy and energy dispersive spectroscopy. The sample solution treated with a complexing reagent, ammonium pyrrolidine dithiocarbamate (APDC), was drawn into the syringe filled with ACC and dispensed manually for 2 to 10 aspirating/dispensing cycle. Then the Ag- complex sorbed on the ACC in micropipette was quantitatively eluted by drawing and dispensing of different concentrations of acids for 2 to 5 aspirating/dispensing cycles. The extracted Ag ions with modifier were injected directly into the electrothermal atomic absorption spectrometry for analysis. The influence of different variables on the extraction efficiency, including the concentration of ligand, pH, sample volume, eluent type, concentration and volume was investigated. Validity and accuracy of the developed method was checked by the standard addition method. Reliability of the proposed methodology was checked by the relative standard deviation (%RSD), which was found to be < 5%. Under the optimized experimental variables, the limits of detection (LOD) and enhancement factors (EF), were obtained to be 0.86 ng L- 1 and 120, respectively. The proposed method was successfully applied for the determination of trace levels of silver ions in fresh and waste water samples.

  4. Development of new portable miniaturize solid phase microextraction of silver-APDC complex using micropipette tip in-syringe system couple with electrothermal atomic absorption spectrometry.

    PubMed

    Naeemullah; Kazi, Tasneem Gul; Afridi, Hassan Imran; Shah, Faheem; Arain, Sadaf Sadia; Arain, Salma Aslam; Panhwar, Abdul Haleem; Arain, Mariam Shahzadi; Samoon, Muhammad Kashif

    2016-02-05

    An innovative and simple miniaturized solid phase microextraction (M-SPME) method, was developed for preconcentration and determination of silver(I) in the fresh and waste water samples. For M-SPME, a micropipette tip packed with activated carbon cloth (ACC) as sorbent, in a syringe system. The size, morphology and elemental composition of ACC before and after adsorption of analyte have been characterized by scanning electron microscopy and energy dispersive spectroscopy. The sample solution treated with a complexing reagent, ammonium pyrrolidine dithiocarbamate (APDC), was drawn into the syringe filled with ACC and dispensed manually for 2 to 10 aspirating/dispensing cycle. Then the Ag- complex sorbed on the ACC in micropipette was quantitatively eluted by drawing and dispensing of different concentrations of acids for 2 to 5 aspirating/dispensing cycles. The extracted Ag ions with modifier were injected directly into the electrothermal atomic absorption spectrometry for analysis. The influence of different variables on the extraction efficiency, including the concentration of ligand, pH, sample volume, eluent type, concentration and volume was investigated. Validity and accuracy of the developed method was checked by the standard addition method. Reliability of the proposed methodology was checked by the relative standard deviation (%RSD), which was found to be <5%. Under the optimized experimental variables, the limits of detection (LOD) and enhancement factors (EF), were obtained to be 0.86 ng L(-1) and 120, respectively. The proposed method was successfully applied for the determination of trace levels of silver ions in fresh and waste water samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Dithiocarbamate fungicides increase intracellular Zn(2+) levels by increasing influx of Zn(2+) in rat thymic lymphocytes.

    PubMed

    Kanemoto-Kataoka, Yumiko; Oyama, Tomohiro M; Ishibashi, Hitoshi; Oyama, Yasuo

    2015-07-25

    Dithiocarbamate fungicides are used as alternative antifouling agents to highly toxic organotin antifouling agents, such as tri-n-butyltin and triphenyltin. There are some concerns regarding their environmental and health risks. It has been shown that tri-n-butyltin increases intracellular Zn(2+) levels of mammalian lymphocytes. Therefore, we examined the effects of dithiocarbamate fungicides (Ziram, Thiram, and Zineb) on rat thymic lymphocytes using a flow-cytometric technique to elucidate how these fungicides affect intracellular Zn(2+) levels. We further determined whether the agents increase intracellular Zn(2+) and/or Ca(2+), because both Zn(2+) and Ca(2+) are intracellular signals in lymphocytes, and excessive increases in their intracellular concentrations can have adverse effects. Dithiocarbamate fungicides increased intracellular Zn(2+) levels, without affecting intracellular Ca(2+) levels. Ziram was the most potent compound, increasing intracellular Zn(2+) levels via Zn(2+) influx. Ziram (1μM) greatly decreased the cellular nonprotein thiol content, and Zn(2+) chelators attenuated the Ziram-induced decrease. Ziram increased the population of annexin V-positive cells in a Zn(2+)-dependent manner. Therefore, we propose that dithiocarbamate fungicides induce Zn(2+) influx, resulting in an excessive elevation of intracellular Zn(2+) levels, leading to the induction of apoptosis. This study gives a basic insight into the mechanisms of dithiocarbamate fungicide-induced adverse events.

  6. ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents.

    PubMed

    Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled A M; Abou El Ella, Dalal A; Ismail, Nasser S M

    2009-05-15

    A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.

  7. Assessment of Dithiocarbamate Residues on Tomatoes Conventionally Grown in Uganda and the Effect of Simple Washing to Reduce Exposure Risk to Consumers.

    PubMed

    Atuhaire, Aggrey; Kaye, Emmanuel; Mutambuze, Innocent Louis; Matthews, Graham; Friedrich, Theodor; Jørs, Erik

    2017-01-01

    Pesticide misuse by farmers poses health risks to consumers. This study assessed the level of dithiocarbamate residues in tomatoes acquired from 20 farmers and 25 market vendors in Wakiso District, how simple washing affects these residues, and the potential chronic health risk for Ugandans eating such tomatoes. Results revealed that mancozeb was the only reported dithiocarbamate, and 47.4% and 14% of farm and market samples, respectively, had dithiocarbamate residues exceeding the Codex alimentarius maximum residue limit of 2 mgCS2/kg. Mixing concentration had a positive significant effect on dithiocarbamate residue levels (P = 0.004). Washing reduced dithiocarbamate residues by a factor of 0.3. Dietary risk assessment revealed no chronic health risk to both children and general population when a national daily per capita consumption of 1.0 g is considered. This study recommends comprehensive research into Uganda's food production and consumption patterns and establishment of a national pesticide residue surveillance program.

  8. Importance of the nature of α-substituents in pyrrolidine organocatalysts in asymmetric Michael additions.

    PubMed

    Patil, Mahendra P; Sharma, Akhilesh K; Sunoj, Raghavan B

    2010-11-05

    The fundamental factors contributing toward the stereoselectivity in organocatalyzed asymmetric Michael reaction between aldehydes (propanal and 3-phenyl propanal) and methyl vinyl ketone (MVK) are established by using density functional theory methods. Three of the most commonly employed α-substituted pyrrolidine organocatalysts are examined. Several key stereochemical modes of addition between (i) a model enamine or (ii) pyrrolidine enamines derived from aldehydes and secondary amine to MVK are examined. Among these possibilities, the addition of (E)-enamine to cis-MVK is found to have a lower activation barrier. The stereochemical outcome of the reaction is reported on the basis of the relative energies between pertinent diastereomeric transition states. Moderate selectivity is predicted for the reaction involving pyrrolidine catalysts I and II, which carry relatively less bulky α-substituents dimethylmethoxymethyl and diphenylmethyl, respectively. On the other hand, high selectivity is computed in the case of catalyst III having a sufficiently large α-substituent (diarylmethoxymethyl or diphenylprolinol methyl ether). The enantiomeric excess in the case of 3-phenyl propanal is found to be much higher as compared to that with unsubstituted propanal, suggesting potential for improvement in stereoselectivity by substrate modifications. The computed enantiomeric excess is found to be in reasonable agreement with the reported experimental stereoselectivities. A detailed investigation on the geometries of the crucial transition states reveals that apart from steric interactions between the α-substituent and MVK, various other factors such as orbital interactions and weak stabilizing hydrogen-bonding interactions play a vital role in stereoselectivity. The results serve to establish the importance of cumulative effects of various stabilizing and destabilizing interactions at the transition state as responsible for the stereochemical outcome of the reaction. The

  9. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

    SciTech Connect

    Ammirati, Mark J.; Andrews, Kim M.; Boyer, David D.; Brodeur, Anne M.; Danley, Dennis E.; Doran, Shawn D.; Hulin, Bernard; Liu, Shenping; McPherson, R. Kirk; Orena, Stephen J.; Parker, Janice C.; Polivkova, Jana; Qiu, Xiayang; Soglia, Carolyn B.; Treadway, Judith L.; VanVolkenburg, Maria A.; Wilder, Donald C.; Piotrowski, David W.; Pfizer

    2010-10-01

    A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC{sub 50} = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

  10. Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

    PubMed Central

    Bini, Davide; Cardona, Francesca; Forcella, Matilde; Parmeggiani, Camilla; Parenti, Paolo; Nicotra, Francesco

    2012-01-01

    Summary A small set of nojirimycin- and pyrrolidine-based iminosugar derivatives has been synthesized and evaluated as potential inhibitors of porcine and insect trehalases. Compounds 12, 13 and 20 proved to be active against both insect and porcine trehalases with selectivity towards the insect glycosidase, while compounds 10, 14 and 16 behaved as inhibitors only of insect trehalase. Despite the fact that the activity was found in the micromolar range, these findings may help in elucidating the structural features of this class of enzymes of different origin, which are still scarcely characterised. PMID:22509223

  11. Removal of mercury species with dithiocarbamate-anchored polymer/organosmectite composites.

    PubMed

    Say, Ridvan; Birlik, Ebru; Erdemgil, Zerrin; Denizli, Adil; Ersöz, Arzu

    2008-02-11

    Mercury is one of the most toxic heavy metals found in solid and liquid waste disposed by chloro-alkali, paint, paper/pulp, battery, pharmaceutical, oil refinery and mining companies. Any form of mercury introduced to nature through any means is converted into a more toxic form such as methylmercury chloride (as produced by aquatic organisms) which usually accumulates in the tissue of fish and birds. The primary aim of this study was to investigate performance of dithiocarbamate-anchored polymer/organosmectite composites as sorbents for removal of mercury from aqueous solution. The modified smectite nanocomposites then were reacted with carbondisulfide to incorporate dithiocarbamate functional groups into the nanolayer of the organoclay. These dithiocarbamate-anchored composites were used for the removal of mercury species [Hg(II), CH(3)Hg(I) and C(6)H(5)Hg(I)]. Mercury adsorption was found to be dependent on the solution pH, mercury concentration and the type of mercury species to be adsorbed. The maximum adsorption capacities were equal to 157.3 mg g(-1) (782.5 micromol g(-1)) for Hg(II); 214.6 mg g(-1) (993.9 micromol g(-1)) for CH(3)Hg(I); 90.3 mg g(-1) (325 micromol g(-1)) for C(6)H(5)Hg(I). The competitive adsorption capacities (i.e. adsorption capacities based on solutions containing all three mercuric ions) are 7.7 mg g(-l) (38.3 micromol g(-1)), 9.2 mg g(-l) (42.6 micromol g(-1)) and 12.7 mg g(-1) (45.7 micromol g(-1)) for Hg(II), CH(3)Hg(I) and C(6)H(5)Hg(I), respectively, at 10 ppm initial concentration. The adsorption capacities on molar basis were in order of C(6)H(5)Hg(I)>CH(3)Hg(I)>Hg(II).

  12. Feasible Management of Southern Corn Leaf Blight via Induction of Systemic Resistance by Bacillus cereus C1L in Combination with Reduced Use of Dithiocarbamate Fungicides

    PubMed Central

    Lai, Yi-Ru; Lin, Pei-Yu; Chen, Chao-Ying; Huang, Chien-Jui

    2016-01-01

    Dithiocarbamate fungicides such as maneb and mancozeb are widely used nonsystemic protectant fungicides to control various plant fungal diseases. Dithiocarbamate fungicides should be frequently applied to achieve optimal efficacy of disease control and avoid either decline in effectiveness or wash-off from leaf surface. Dithiocarbamates are of low resistance risk but have the potential to cause human neurological diseases. The objective of this study was to develop a strategy to effectively control plant disease with reduced use of dithiocarbamtes. Southern corn leaf blight was the model pathosystem for the investigation. When corn plants were drench-treated with Bacillus cereus C1L, a rhizobacterium able to induce systemic resistance in corn plants against southern leaf blight, frequency of spraying dithiocarbamate fungicides could be decreased. The treatment of B. cereus C1L was able to protect maize from southern leaf blight while residues of dithiocarbamates on leaf surface were too low to provide sufficient protection. On the other hand, frequent sprays of mancozeb slightly but significantly reduced growth of corn plants under natural conditions. In contrast, application of B. cereus C1L can significantly promote growth of corn plants whether sprayed with mancozeb or not. Our results provide the information that plant disease can be well controlled by rhizobacteria-mediated induced systemic resistance in combination with reduced but appropriate application of dithiocarbamate fungicides just before a heavy infection period. An appropriate use of rhizobacteria can enhance plant growth and help plants overcome negative effects caused by dithiocarbamates. PMID:27721698

  13. Feasible Management of Southern Corn Leaf Blight via Induction of Systemic Resistance by Bacillus cereus C1L in Combination with Reduced Use of Dithiocarbamate Fungicides.

    PubMed

    Lai, Yi-Ru; Lin, Pei-Yu; Chen, Chao-Ying; Huang, Chien-Jui

    2016-10-01

    Dithiocarbamate fungicides such as maneb and mancozeb are widely used nonsystemic protectant fungicides to control various plant fungal diseases. Dithiocarbamate fungicides should be frequently applied to achieve optimal efficacy of disease control and avoid either decline in effectiveness or wash-off from leaf surface. Dithiocarbamates are of low resistance risk but have the potential to cause human neurological diseases. The objective of this study was to develop a strategy to effectively control plant disease with reduced use of dithiocarbamtes. Southern corn leaf blight was the model pathosystem for the investigation. When corn plants were drench-treated with Bacillus cereus C1L, a rhizobacterium able to induce systemic resistance in corn plants against southern leaf blight, frequency of spraying dithiocarbamate fungicides could be decreased. The treatment of B. cereus C1L was able to protect maize from southern leaf blight while residues of dithiocarbamates on leaf surface were too low to provide sufficient protection. On the other hand, frequent sprays of mancozeb slightly but significantly reduced growth of corn plants under natural conditions. In contrast, application of B. cereus C1L can significantly promote growth of corn plants whether sprayed with mancozeb or not. Our results provide the information that plant disease can be well controlled by rhizobacteria-mediated induced systemic resistance in combination with reduced but appropriate application of dithiocarbamate fungicides just before a heavy infection period. An appropriate use of rhizobacteria can enhance plant growth and help plants overcome negative effects caused by dithiocarbamates.

  14. Speciation of AsIII and AsV in fruit juices by dispersive liquid–liquid microextraction and hydride generation-atomic fluorescence spectrometry

    USDA-ARS?s Scientific Manuscript database

    A new procedure was developed to speciate and quantify As(III) and As(V) in fruit juices. At pH 3.0, As(III) and ammonium pyrrolidine dithiocarbamate (APDC) formed a complex, which was extracted into carbon tetrachloride by dispersive liquid–liquid microextraction (DLLME) and subsequently quantified...

  15. Masked thiol sugars: chemical behavior and synthetic applications of S-glycopyranosyl-N-monoalkyl dithiocarbamates.

    PubMed

    Megia-Fernandez, Alicia; de la Torre-Gonzalez, Diego; Parada-Aliste, Jose; Lopez-Jaramillo, Francisco Javier; Hernandez-Mateo, Fernando; Santoyo-Gonzalez, Francisco

    2014-02-01

    The chemical behavior of S-glycopyranosyl-N-monoalkyl dithiocarbamates (DTCs) as masked 1-glycosyl thiols, easily prepared by the nucleophilic displacement of 1-halo sugars with dithiocarbamate salts of primary amines, has been studied and synthetically exploited. This behavior relies on the abstraction of the proton of the carbamate functionality that allows controlled access to thiolate sugar intermediates. The basic character of the DTC salts used as reagents leads to thiolates that evolve in situ to symmetrical diglycosyldisulfides (DGDSs) when long reaction times are allowed. Alternatively, controlled unmasking of the thiolate function can be efficiently attained by treatment with an external base of isolated anomeric glycosyl DTCs, the formation of which is prevalent when using short reaction times. In this manner, a second methodology for the preparation of symmetrical DGDSs and a chemical protocol for the S-glycosylation of any electrophilic substrate are established. The applications of this last strategy for the preparation of thioglycosyl vinyl sulfones, thiodisaccharides, and S-linked homo- and heterodivalent neoglycoconjugates are described as a proof-of-concept of the great potential of the sugar DTCs in any chemical scenario in which the covalent attachment of a thiol sugar is required. The evaluation of the biological functionality of some divalent sulfurated sugar systems is also described.

  16. Toxicity of the dithiocarbamate fungicide mancozeb to the nontarget soil nematode, Caenorhabditis elegans.

    PubMed

    Easton, A; Guven, K; de Pomerai, D I

    2001-01-01

    We have previously shown that the dithiocarbamate fungicide, Mancozeb, strongly induces lacZ reporter expression from an endogenous heat-shock promoter (hsp16) in the PC72 transgenic strain of the nematode Caenorhabditis elegans. Such evidence of organismal stress, in a nontarget species at subapplication concentrations, was much less apparent for the related fungicide, Maneb, which only weakly induced reporter expression. We now show that reporter induction by Mancozeb is marginal (<60%) after a few hours' exposure, but increases substantially (to almost 10-fold) after overnight exposure. In conjunction with our previous results using intermediate exposure periods, this suggests that the factor limiting reporter responses is likely to be a slow rate of uptake and/or metabolism of the fungicide. We confirm that a potentially toxic metabolite of dithiocarbamate fungicides, namely ethylenethiourea (ETU), has minimal toxicity toward C. elegans, even after prolonged exposure at high concentrations. We demonstrate that exposure to Mancozeb (but not ETU) significantly inhibits larval growth in C. elegans, although this parameter is not markedly more sensitive than reporter induction as a toxicological endpoint. Finally, we have used two-dimensional electrophoresis to show that high concentrations of both Maneb and Mancozeb drastically simplify the protein spot profile compared with controls. However, only in the latter case is there evidence of novel proteins being induced. Both fungicides appear toxic to C. elegans, but only Mancozeb induces a strong heat-shock response.

  17. Quantum chemical study of a derivative of 3-substituted dithiocarbamic flavanone

    NASA Astrophysics Data System (ADS)

    Gosav, Steluta; Paduraru, Nicoleta; Maftei, Dan; Birsa, Mihail Lucian; Praisler, Mirela

    2017-02-01

    The aim of this work is to characterize a quite novel 3-dithiocarbamic flavonoid by vibrational spectroscopy in conjunction with Density Functional Theory (DFT) calculations. Quantum mechanics calculations of energies, geometries and vibrational wavenumbers in the ground state were carried out by using hybrid functional B3LYP with 6-311G(d,p) as basis set. The results indicate a remarkable agreement between the calculated molecular geometries, as well as vibrational frequencies, and the corresponding experimental data. In addition, a complete assignment of all the absorption bands present in the vibrational spectrum has been performed. In order to assess its chemical potential, quantum molecular descriptors characterizing the interactions between the 3-dithiocarbamic flavonoid and its biological receptors have been computed. The frontier molecular orbitals and the HOMO-LUMO energy gap have been used in order to explain the way in which the new molecule can interact with other species and to characterize its molecular chemical stability/reactivity. The molecular electrostatic potential (MEP) map, computed in order to identify the sites of the studied flavonoid that are most likely to interact with electrophilic and nucleophilic species, is discussed.

  18. In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

    PubMed

    El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

    2014-08-01

    Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents.

  19. Synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics via one-pot sequential lactam reduction/Joullié-Ugi reaction.

    PubMed

    Szcześniak, Piotr; Maziarz, Elżbieta; Stecko, Sebastian; Furman, Bartłomiej

    2015-04-03

    A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartz's reagent followed by a multicomponent Ugi-Joullié reaction.

  20. Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones.

    PubMed

    Yin, Feng; Garifullina, Ainash; Tanaka, Fujie

    2017-08-07

    To concisely synthesize highly enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-carboxylic acids, organocatalytic enantioselective Michael addition reactions of 4-alkyl-substituted 4-oxo-2-enoates with nitroalkanes have been developed. Using the developed reaction method, 5-methylpyrrolidine-3-carboxylic acid with 97% ee was obtained in two steps.

  1. Design, synthesis, molecular docking and biological evaluation of new dithiocarbamates substituted benzimidazole and chalcones as possible chemotherapeutic agents.

    PubMed

    Bacharaju, Keerthana; Jambula, Swathi Reddy; Sivan, Sreekanth; Jyostnatangeda, Saritha; Manga, Vijjulatha

    2012-05-01

    A series of novel dithiocarbamates with benzimidazole and chalcone scaffold have been designed synthesised and evaluated for their antimitotic activity. Compounds 4c and 9d display the most promising antimitotic activity with IC(50) of 1.66 μM and 1.52 μM respectively. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids.

    PubMed

    Steffan, Tobias; Renukappa-Gutke, Thejavathi; Höfner, Georg; Wanner, Klaus T

    2015-03-15

    In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114.

  3. Nucleophilic phosphine-catalyzed intramolecular Michael reactions of N-allylic substituted α-amino nitriles: construction of functionalized pyrrolidine rings via 5-endo-trig cyclizations.

    PubMed

    En, Da; Zou, Gong-Feng; Guo, Yuan; Liao, Wei-Wei

    2014-05-16

    Pyrrolidine rings are common moieties for pharmaceutical candidates and natural compounds, and the construction of these skeletons has received much attention. α-Amino nitriles are versatile intermediates in synthetic chemistry and have been widely used in the generation of multiple polyfunctional structures. Herein, a novel nucleophilic phosphine-catalyzed intramolecular Michael reaction of N-allylic substituted α-amino nitriles has been developed for the efficient construction of functionalized 2,4-disubstituted pyrrolidines (N-heterocyclic α-amino nitriles) via 5-endo-trig cyclization. Furthermore, the one-pot sequence of the synthesis of pyrrolidine and the subsequent transformations of the functionalized products have also been demonstrated.

  4. Mechanistic Insight into the Binding of Multivalent Pyrrolidines to α-Mannosidases.

    PubMed

    Mirabella, Stefania; D'Adamio, Giampiero; Matassini, Camilla; Goti, Andrea; Delgado, Sandra; Gimeno, Ana; Robina, Inmaculada; Moreno-Vargas, Antonio J; Šesták, Sergej; Jiménez-Barbero, Jesús; Cardona, Francesca

    2017-08-07

    Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean α-mannosidase and a Golgi α-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal α-mannosidase, which is important for anticancer applications. STD NMR and molecular modeling studies supported a multivalent mechanism with specific interactions of the bioactive iminosugars with Jack bean α-mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular cross-linked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. The effects of a pyrrolidine functional group on the magnetic properties of N@C 60

    NASA Astrophysics Data System (ADS)

    Zhang, Jinying; Morton, John J. L.; Sambrook, Mark R.; Porfyrakis, Kyriakos; Ardavan, Arzhang; Briggs, G. Andrew D.

    2006-12-01

    A new stable pyrrolidine functionalized fullerene derivative, C 69H 10N 2O 2, has been synthesized, purified by high performance liquid chromatography, and characterized by MALDI mass spectrometry, UV-vis spectroscopy, Fourier transform infrared, 1H and 13C nuclear magnetic resonance. The magnetic properties of the analogous endohedral species have been studied by both continuous wave (CW) and pulsed EPR. CW-EPR spectra indicated an anisotropic hyperfine interaction and a permanent zero-field-splitting (ZFS). Both CW and pulsed EPR showed the ZFS parameter Deff to be around 17 MHz. Pulsed EPR revealed a biexponential decay in both T 1 and T 2, yielding a molecular tumbling correlation time τc of 31.4 ± 2.5 ps.

  6. Dithiocarbamates have a common toxic effect on zebrafish body axis formation

    SciTech Connect

    Tilton, Fred; La Du, Jane K.; Vue, Meng; Alzarban, Noor; Tanguay, Robert L. . E-mail: Robert.Tanguay@oregonstate.edu

    2006-10-01

    We previously determined that the dithiocarbamate pesticide sodium metam (NaM) and its active ingredient methylisothiocyanate (MITC) were developmentally toxic causing notochord distortions in the zebrafish. In this study, developing zebrafish were exposed to isothiocyanates (ITCs), dithiocarbamates (DTCs) and several degradation products to determine the teratogenic relationship of these chemical classes at the molecular level. All dithiocarbamates tested elicited notochord distortions with notochord NOELs from <4 to 40 ppb, while none of the ITCs caused notochord distortions with the exception of MITC. Carbon disulfide (CS{sub 2}), a common DTC degradate, also caused distortions at concentrations >200 times the DTCs. Whole mount in situ hybridization of developmental markers for collagen (collagen2a1), muscle (myoD), and body axis formation (no tail) was perturbed well after cessation of treatment with pyrolidine-DTC (PDTC), dimethyl-DTC (DMDTC), NaM, MITC, and CS{sub 2}. Therefore, distinct albeit related chemical classes share a common toxic effect on zebrafish notochord development. To test the responsiveness of the distortion to metal perturbation, five metal chelators and 2 metals were studied. The membrane permeable copper chelator neocuproine (NCu) was found to cause notochord distortions similar to DTC-related molecules. DMDTC and NCu treated animals were protected with copper, and collagen 2a1 and no tail gene expression patterns were identical to controls in these animals. PDTC, NaM, MITC, and CS{sub 2} were not responsive to copper indicating that the chelation of metals is not the primary means by which these molecules elicit their developmental toxicity. Embryos treated with DMDTC, NaM, and NCu were rescued by adding triciaine (MS-222) which abolishes the spontaneous muscle contractions that begin at 18 hpf. In these animals, only collagen 2a1 expression showed a similar pattern to the other notochord distorting molecules. This indicates that the

  7. Mechanism of action of some acrylophenones, quinolines and dithiocarbamate as potent, non-detergent spermicidal agents.

    PubMed

    Maikhuri, J P; Dwivedi, A K; Dhar, J D; Setty, B S; Gupta, G

    2003-05-01

    Some suitably substituted acrylophenones, quinolines and dithiocarbamate were synthesized as new generation, non-detergent spermicides and were studied for their mechanism of action in comparison with various known spermicides belonging to several different classes of chemical compound. Nonoxynol-9, benzalkonium chloride, Sapindus saponins, verapamil, emetine and tartaric acid were used as reference molecules to study the effect of new spermicides on human sperm motility parameters (using computer-assisted semen analyzer), plasma membrane integrity, lipid peroxidation and defense system against reactive oxygen species (ROS). Results have indicated that sperm plasma membrane remains the primary site of action of most of the spermicides, though the effect may be predominantly on the physiological integrity rather than the structural integrity in case of the new compounds. Lipid peroxidation may play an important role in disrupting sperm membrane physiology that may or may not be accompanied with a detrimental effect on the defense system of the human spermatozoa against the ROS.

  8. Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles.

    PubMed

    Elías-Rodríguez, Pilar; Moreno-Clavijo, Elena; Carmona, Ana T; Moreno-Vargas, Antonio J; Robina, Inmaculada

    2014-08-21

    The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).

  9. Synthesis and biological evaluation of a series of dithiocarbamates as new cholinesterase inhibitors.

    PubMed

    Altıntop, Mehlika D; Gurkan-Alp, A Selen; Ozkay, Yusuf; Kaplancıklı, Zafer A

    2013-08-01

    In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4-(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by (1) H NMR, mass spectral data, and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The most potent AChE inhibitor was found as compound 2g (IC50  = 0.53 ± 0.001 µM) followed by compounds 2f (IC50  = 0.74 ± 0.001 µM) and 2j (IC50  = 0.89 ± 0.002 µM) when compared with donepezil (IC50  = 0.048 ± 0.001 µM). Compounds 2f and 2g were more effective than donepezil (IC50  = 7.88 ± 0.52 µM) on BuChE inhibition. Compounds 2f and 2g exhibited the inhibitory effect on BuChE with IC50 values of 1.39 ± 0.041 and 3.64 ± 0.072 µM, respectively. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Design and synthesis of 2-(3-alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones as potent antitumor agents.

    PubMed

    Huang, Shih-Ming; Cheng, Yung-Yi; Chen, Ming-Hua; Huang, Chi-Hung; Huang, Li-Jiau; Hsu, Mei-Hua; Kuo, Sheng-Chu; Lee, Kuo-Hsiung

    2013-02-01

    2-(3-Alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones 1-3 were synthesized and screened for anti-proliferative activity against three human cancer cell lines, as well as the normal cell line Detroit 551. All of the synthesized target compounds 1-3 demonstrated potent cytotoxic activity against the cancer cell lines, but weak inhibitory activity toward the normal cell line. 2-(3-Methyl aminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (1), one of the potent compounds in vitro, was also tested in an in vivo Hep3B xenograft nude mice model, and its significant anticancer activity was reconfirmed. Therefore, compound 1 merits further investigation as an antitumor clinical trial candidate and potential anticancer agent.

  11. Ionic liquid-supported (ILS) (S)-pyrrolidine sulfonamide, a recyclable organocatalyst for the highly enantioselective Michael addition to nitroolefins.

    PubMed

    Ni, Bukuo; Zhang, Qianying; Dhungana, Kritanjali; Headley, Allan D

    2009-02-19

    A new class of ionic liquid supported (ILS) (S)-pyrrolidine sulfonamide organocatalyst has been developed and shown to be a very effective catalyst for the asymmetric Michael addition reactions of ketones and aldehyde to nitroolefins with high enantio- and diastereoselectivities. This ILS organocatalyst is also easily recycled and could be reused at least five times without significant loss of its ability to affect the outcome of the asymmetric reactions.

  12. Analgesic activity of (+)-1-(3-methyl-4-morpholino-2:2-diphenylbutyryl)pyrrolidine (r.875) in student volunteers

    PubMed Central

    Cahal, D. A.

    1958-01-01

    (+)-1-(3-Methyl-4-morpholino-2:2-diphenylbutyryl)pyrrolidine (R.875) raised the threshold to ischaemic pain in healthy human volunteers. The peak effect for all doses was reached after about 2 hr. The drug frequently caused nausea and vomiting but no euphoria. Muscular weakness was experienced by many subjects and was sometimes followed 1 to 2 hr. later by hiccup and muscle twitching, suggesting that R.875 may have an effect on striped muscle. PMID:13523131

  13. Highly enantioselective Michael addition of cyclohexanone to nitroolefins catalyzed by pyrrolidine-based bifunctional benzoylthiourea in water.

    PubMed

    Wang, Zhen-Yu; Ban, Shu-Rong; Yang, Meng-Chen; Li, Qing-Shan

    2016-11-01

    Organocatalysis and aqueous reactions are identified as the focus of the greening of chemistry. Combining these two strategies effectively remains an interesting challenge in organic synthesis. Herein, we used pyrrolidine-based benzoylthiourea 1c to catalyze the asymmetric Michael addition of cyclohexanone to various nitroolefins in water to afford the corresponding compounds in moderate to good yields, and with excellent diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 99% ee).

  14. Stereospecific synthesis of pyrrolidines with varied configurations via 1,3-dipolar cycloadditions to sugar-derived enones.

    PubMed

    Oliveira Udry, Guillermo A; Repetto, Evangelina; Varela, Oscar

    2014-06-06

    Enantiomerically pure pyrrolidines have been obtained by 1,3-dipolar cycloaddition of stabilized azomethine ylides and sugar enones (dihydropyranones) derived from pentoses. Thus, the S-enone (menthyl 3,4-dideoxy-(1S)-pent-3-enopyranosid-2-ulose) was prepared from D-xylose, while the R analogue was obtained from L-arabinose. The dipoles were generated in situ from α-arylimino esters of common amino acids (glycine, alanine, or phenylalanine) and aromatic aldehydes (benzaldehyde, 3-formylpyridine and 4-methoxybenzaldehyde). Under optimized conditions, the cycloaddition reactions were highly diastereo- and regioselective to yield, in most of the cases, a very major adduct of the 16 theoretically possible. The diastereoselectivity relies on the strict stereocontrol exerted by the stereogenic center of the pyranone. Thus, the (S)-enone, derived from D-xylose, gave tetrasubstituted pyrrolidines having a defined stereochemistry for the four stereocenters of the ring, while they had the opposite configuration when starting from the (R)-dihydropyranone. Furthermore, some endo-cycloadducts underwent isomerization of the carbons vicinal to the nitrogen atom to afford pyrrolidines with a rather unusual stereochemistry for the direct dipolar cycloadditions.

  15. Trace analysis of dithiocarbamate fungicide residues on fruits and vegetables by hydrophilic interaction liquid chromatography/tandem mass spectrometry.

    PubMed

    Crnogorac, Goranka; Schmauder, Sabrina; Schwack, Wolfgang

    2008-08-01

    The simultaneous determination of dithiocarbamate (DTC) fungicide residues on fruits and vegetables was performed by liquid chromatography (LC) on a ZIC-pHILIC column coupled to tandem mass spectrometry (MS/MS). For each DTC subclass, i.e. dimethyldithiocarbamates (DMDs), ethylenebis(dithiocarbamates) (EBDs), and propylenebis(dithiocarbamates) (PBDs), the limits of detection and quantification were approximately 0.001 and 0.005 mg kg(-1), respectively. Recoveries from tomatoes, spiked in the range of 0.05-1 mg kg(-1), averaged between 97 and 101%. Several fruits and vegetables from a local market and different countries of origin (apples, pears, grapes, cherry tomatoes, cocktail tomatoes, cucumbers, tomatoes, tamarillos, papaya, and broccoli) were analyzed by LC/MS/MS, LC/MS, and by the routine CS(2) method. In general, the results obtained by both LC/MS and LC/MS/MS were in good agreement with those obtained by the CS(2) method except for the false positive CS(2) results for broccoli and papaya. The results demonstrate that both LC/MS and LC/MS/MS can be used for routine analyses of DTC residues, whereas LC/MS/MS is more sensitive and selective than LC/MS. Copyright (c) 2008 John Wiley & Sons, Ltd.

  16. Supercritical Fluid Extraction of Pyrrolidine Alkaloid from Leaves of Piper amalago L.

    PubMed Central

    Filho, L. C.; Faiões, V. S.; Cunha-Júnior, E. F.; Torres-Santos, E. C.; Cortez, D. A. G.

    2017-01-01

    Supercritical fluid extraction was used to extract the alkaloid N-[7-(3′,4′-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl]pyrrolidine from leaves of Piper amalago L. A three-level orthogonal array design matrix, OAD OA9(34), was used for optimization of the parameters of supercritical extraction of the alkaloid, employing supercritical carbon dioxide: extraction time (20, 40, and 60 min), temperature (40, 50, and 60°C), pressure (150, 200, and 250 bar), and the use of cosolvents (ethanol, methanol, and propyleneglycol). All parameters had significant effect on the alkaloid yield. The alkaloid yield after 60 min of extraction without cosolvents at 9 different conditions (32) in terms of temperature (40, 50, and 60°C) and pressure (150, 200, and 250 bar) was also evaluated. The optimal yield (≈3.8 mg g−1) was obtained with supercritical CO2 + methanol (5% v : v) at 40°C and 200 bar for 60 min of extraction. PMID:28539966

  17. Tunable diastereoselection of biased rigid systems by Lewis acid induced conformational effects: a rationalization of the vinylation of cyclic nitrones en route to polyhydroxylated pyrrolidines.

    PubMed

    Delso, Ignacio; Marca, Eduardo; Mannucci, Vanni; Tejero, Tomás; Goti, Andrea; Merino, Pedro

    2010-08-23

    The diastereofacial selection in addition reactions to biased rigid systems can be modulated by the action of Lewis acids. As an example, the stereoselectivity of the nucleophilic addition of vinyl magnesium bromide (VMB) to cyclic nitrones in the presence of diethylaluminum chloride (DEAC) shows a strong dependence on the temperature and the carbon substituent adjacent at the reaction center; it is remarkable that whereas a high selectivity is obtained at higher temperatures, in the presence of DEAC, a trend to invert the stereochemical course of the reaction is observed at lower temperatures, provided the substituent at C3 of the pyrrolidine ring allows delivery of the vinyl moiety. This behavior and difference in selectivity is to be attributed to the high conformational barriers of the intermediate nitrone-DEAC-VMB complex. A clear inversion of the selectivity is observed at -78 degrees C for the reaction of the nitrone protected as an O-methyl derivative. The present study provides a rationalization for the stereocontrolled addition of nucleophiles to rigid systems (cyclic nitrones).

  18. Assessment of Dithiocarbamate Residues on Tomatoes Conventionally Grown in Uganda and the Effect of Simple Washing to Reduce Exposure Risk to Consumers

    PubMed Central

    Atuhaire, Aggrey; Kaye, Emmanuel; Mutambuze, Innocent Louis; Matthews, Graham; Friedrich, Theodor; Jørs, Erik

    2017-01-01

    Pesticide misuse by farmers poses health risks to consumers. This study assessed the level of dithiocarbamate residues in tomatoes acquired from 20 farmers and 25 market vendors in Wakiso District, how simple washing affects these residues, and the potential chronic health risk for Ugandans eating such tomatoes. Results revealed that mancozeb was the only reported dithiocarbamate, and 47.4% and 14% of farm and market samples, respectively, had dithiocarbamate residues exceeding the Codex alimentarius maximum residue limit of 2 mgCS2/kg. Mixing concentration had a positive significant effect on dithiocarbamate residue levels (P = 0.004). Washing reduced dithiocarbamate residues by a factor of 0.3. Dietary risk assessment revealed no chronic health risk to both children and general population when a national daily per capita consumption of 1.0 g is considered. This study recommends comprehensive research into Uganda’s food production and consumption patterns and establishment of a national pesticide residue surveillance program. PMID:28615952

  19. Oxidation of dithiocarbamates to yield N-nitrosamines by water disinfection oxidants.

    PubMed

    Padhye, Lokesh P; Kim, Jae-Hong; Huang, Ching-Hua

    2013-02-01

    Two most commonly used dithiocarbamate (DTC) pesticides, dimethyldithiocarbamate (DMDTC) and diethyldithiocarbamate (DEDTC), were examined in this study to evaluate their potential to form nitrosamines when in contact with various water disinfection oxidants. Results show that DTCs can serve as nitrosamine precursors, by release of secondary amines through hydrolysis or through reactions with oxidants. The reactions of DTCs with monochloramine and ozone were found to be particularly problematic in the risk of generating nitrosamines, though all four tested oxidants, including free chlorine and chlorine dioxide, formed nitrosamines. NDEA yield from DEDTC was lower, by different degrees, than NDMA yield from DMDTC for all four oxidants, which was attributed to the steric hindrance associated with bulkier reaction intermediate that are more difficult to be further oxidized to form nitrosamine. The yield of nitrosamines increased with the oxidant dosage for both monochloramination and ozonation of DTCs. Results for nitrosamine formation from DTCs at varying pH were found to be consistent with the pH trend of nitrosamine formation from ozonation and monochloramination of secondary amines. Kinetic study results and identification and quantification of reaction products suggest that the DTCs were not significant direct precursors of nitrosamines during monochloramination or ozonation, but rather nitrosamines formed were primarily from reaction of oxidants with the amine which may be generated either through hydrolysis or through oxidation of DTCs.

  20. Dithiocarbamates are teratogenic to developing zebrafish through inhibition of lysyl oxidase activity

    SciTech Connect

    Boxtel, Antonius L. van; Kamstra, Jorke H.; Fluitsma, Donna M.; Legler, Juliette

    2010-04-15

    Dithiocarbamates (DTCs) are a class of compounds that are extensively used in agriculture as pesticides. As such, humans and wildlife are undoubtedly exposed to these chemicals. Although DTCs are thought to be relatively safe due to their short half lives, it is well established that they are teratogenic to vertebrates, especially to fish. In zebrafish, these teratogenic effects are characterized by distorted notochord development and shortened anterior to posterior axis. DTCs are known copper (Cu) chelators but this does not fully explain the observed teratogenic effects. We show here that DTCs cause malformations in zebrafish that highly resemble teratogenic effects observed by direct inhibition of a group of cuproenzymes termed lysyl oxidases (LOX). Additionally, we demonstrate that partial knockdown of three LOX genes, lox, loxl1 and loxl5b, sensitizes the developing embryo to DTC exposure. Finally, we show that DTCs directly inhibit zebrafish LOX activity in an ex vivo amine oxidase assay. Taken together, these results provide the first evidence that DTC induced teratogenic effects are, at least in part, caused by direct inhibition of LOX activity.

  1. Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate moiety as new cholinesterase inhibitors.

    PubMed

    Altintop, Mehlika D; Özdemir, Ahmet; Kaplancikli, Zafer A; Turan-Zitouni, Gülhan; Temel, Halide E; Çiftçi, Gülşen A

    2013-03-01

    In the present study, new pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl)-5-aryl-2-pyrazolines with sodium salts of N,N-disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17, when compared with eserine. Compounds effective on AChE carry the 2-dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2-dimethylaminoethyl and 3,4-methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Triazole-dithiocarbamate based, selective LSD1 inactivators inhibit gastric cancer cell growth, invasion and migration

    PubMed Central

    Ma, Jin-Lian; Xu, Rui-Min; Zi, Xiaolin; Lv, Wen-Lei; Wang, Meng-Meng; Ye, Xian-Wei; Zhu, Shun; Mobley, David; Zhu, Yan-Yan; Wang, Jun-Wei; Li, Jin-Feng; Wang, Zhi-Ru; Zhao, Wen; Liu, Hong-Min

    2013-01-01

    Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1, 2, 3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer. PMID:24131029

  3. Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents.

    PubMed

    Tan, Yee Seng; Ooi, Kah Kooi; Ang, Kok Pian; Akim, Abdah Md; Cheah, Yoke-Kqueen; Halim, Siti Nadiah Abdul; Seng, Hoi-Ling; Tiekink, Edward R T

    2015-09-01

    In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.

  4. Functionalized dithiocarbamate chelating resin for the removal of Co2+ from simulated wastewater

    NASA Astrophysics Data System (ADS)

    Shi, Xuewei; Fu, Linwei; Wu, Yanyang; Zhao, Huiling; Zhao, Shuangliang; Xu, Shouhong

    2017-06-01

    Industrial wastewater that contains trace amounts of heavy metal ions is often seen in petrochemical industry. While this wastewater can not be directly discharged, it is difficult to treat due to the low concentration of metal ions. Introducing chelating reagents into this wastewater for selective ion adsorption, followed by a mechanical separation process, provides an appealing solution. Toward the success of this technology, the development of effective chelating resins is of key importance. In the present work, a chelating resin containing amino and dithiocarbamate groups was reported for the removal of Co(II) metal ions in trace concentrations from simulated wastewater. By investigating the adsorption performance of the chelating resin at different solution pH values, adsorbent dosages, contact time, initial ion concentrations, and adsorption temperatures, the maximum adsorption capacity of the resin for Co(II) was identified to be 24.89 mg g-1 for a 2 g L-1 adsorbent dosage and a pH value of 5. After four adsorption-desorption cycles, 97% of the adsorption capacity of the resin was maintained. The adsorption kinetics and thermodynamics were analyzed and discussed as well.

  5. Method validation and analysis of nine dithiocarbamates in fruits and vegetables by LC-MS/MS.

    PubMed

    Schmidt, B; Christensen, H B; Petersen, A; Sloth, J J; Poulsen, M E

    2013-01-01

    An analytical method for separation and quantitative determination of nine dithiocarbamates (DTCs) in fruits and vegetables by using LC-MS/MS was developed, validated and applied to samples purchased in local supermarkets. The nine DTCs were ziram, ferbam, thiram, maneb, zineb, nabam, metiram, mancozeb and propineb. Validation parameters of mean recovery for two matrices at two concentration levels, relative repeatability (RSDr), relative within-laboratory reproducibility (RSDR) and LOD were obtained for the nine DTCs. The results from the analysis of fruits and vegetables served as the basis for an exposure assessment within the given commodities and a risk assessment by comparing the calculated exposure to the acceptable daily intake and acute reference dose for various exposure groups. The analysis indicated positive findings of DTCs in apples, pears, plums, table grapes, papaya and broccoli at concentrations ranging from 0.03 mg/kg to 2.69 mg/kg expressed as the equivalent amount of CS2. None of the values exceeded the Maximum residue level (MRL) set by the European Union, and furthermore, it was not possible to state whether illegal use had taken place or not, because a clear differentiation between the various DTCs in the LC-MS/MS analysis was lacking. The exposure and risk assessment showed that only for maneb in the case of apples and apple juice, the acute reference dose was exceeded for infants in the United Kingdom and for children in Germany, respectively.

  6. Dithiocarbamates effectively inhibit the β-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa.

    PubMed

    Vullo, Daniela; Del Prete, Sonia; Nocentini, Alessio; Osman, Sameh M; AlOthman, Zeid; Capasso, Clemente; Bozdag, Murat; Carta, Fabrizio; Gratteri, Paola; Supuran, Claudiu T

    2017-02-01

    A series of dithiocarbamates (DTCs) was investigated for the inhibition of the β-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa, MgCA, a validated anti-dandruff drug target. These DTCs incorporate various scaffold, among which those of N,N-dimethylaminoethylenediamine, the aminoalcohols with 3-5 carbon atoms in their molecule, 3-amino-quinuclidine, piperidine, morpholine and piperazine derivatives, as well as phenethylamine and its 4-sulfamoylated derivative. Several DTCs resulted more effective in inhibiting MgCA compared to the standard sulfonamide drug acetazolamide (KI of 74μM), with KIs ranging between 383 and 6235nM. A computational approach, involving a homology modeling of the enzyme and docking inhibitors within its active site, helped us rationalize the results. This study may contribute to better understand the inhibition profile of MgCA, and offer new ideas for the design of modulators of activity which belong to less investigated chemical classes, thus potentially useful to combat dandruff and other fungal infections. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Dithiocarbamate-modified starch derivatives with high heavy metal adsorption performance.

    PubMed

    Xiang, Bo; Fan, Wen; Yi, Xiaowei; Wang, Zuohua; Gao, Feng; Li, Yijiu; Gu, Hongbo

    2016-01-20

    In this work, three types of dithiocarbamate (DTC)-modified starch derivatives including DTC starch (DTCS), DTC enzymolysis starch (DTCES) and DTC mesoporous starch (DTCMS) were developed, which showed the significant heavy metal adsorption performance. The adsorption ability of these three DTC modified starch derivatives followed the sequences: DTCMS>DTCES>DTCS. In single metal aqueous solutions, the uptake amount of heavy metal ions onto the modified starches obeyed the orders: Cu(II)>Ni(II)>Cr(VI)>Zn(II)>Pb(II). The adsorption mechanism was proved by the chelating between DTC groups and heavy metal ions through the pH effect measurements. A monolayer adsorption of Langmuir isotherm model for the adsorption of Cu(II) onto DTCMS was well fitted rather than the multilayer adsorption of Freundlich isotherm model. The adsorption kinetics of Cu(II) onto starch derivatives was found to be fit well with the pseudo-second-order model. Additionally, in the presence of EDTA, the adsorption ability and uptake amount of heavy metal ions onto these three DTC modified starch derivatives is identical with the results obtained in the absence of EDTA.

  8. The effects of the endocrine disruptors dithiocarbamates on the mammalian ovary with particular regard to mancozeb.

    PubMed

    Cecconi, Sandra; Paro, Rita; Rossi, Gianna; Macchiarelli, Guido

    2007-01-01

    Many human-made chemicals are called endocrine disruptors (EDs) because they have the potential to disrupt endocrine functions in exposed organisms. Many EDs can disrupt hormonal homeostasis by interfering with hormone receptor recognition, binding and activation, while others act by still unknown mechanisms. Among the EDs specifically affecting the female reproductive system, those with steroidogenic/antisteroidogenic effects have been extensively studied and the mechanisms of toxicity clarified also at molecular level. For many others, information is restricted to few epidemiological data and in vivo/in vitro experiments with animal models. This is the case of the dithiocarbamates, and in particular of the fungicide mancozeb, an ethylenedithiocarbamate widely used to protect fruit and vegetables, ginseng included, because of its low acute toxicity in humans. Although the mechanism(s) by which mancozeb may specifically act on female reproductive organs are largely unknown, data on experimental animals in vivo have demonstrated that the fungicide can induce several disturbances on estrus cycle. When used in vitro at concentrations considered too low to cause human health injuries, the fungicide impairs mouse embryo development and meiotic spindle assembly. The possibility that the female germ cell (the oocyte) could be a specific target of mancozeb suggests a role for this fungicide as probable inductor of infertility also in exposed human populations.

  9. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles.

    PubMed

    Kouassi, Affiba Florance; Kone, Mawa; Keita, Melalie; Esmel, Akori; Megnassan, Eugene; N'Guessan, Yao Thomas; Frecer, Vladimir; Miertus, Stanislav

    2015-12-12

    We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50(exp)). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50(exp). Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50(exp) (pIC50(exp) = -0.1552·ΔΔGcom + 5.0448, R² = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50(pre) reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.

  10. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles

    PubMed Central

    Kouassi, Affiba Florance; Kone, Mawa; Keita, Melalie; Esmel, Akori; Megnassan, Eugene; N’Guessan, Yao Thomas; Frecer, Vladimir; Miertus, Stanislav

    2015-01-01

    We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles. PMID:26703572

  11. Validation of a GC-MS method for the estimation of dithiocarbamate fungicide residues and safety evaluation of mancozeb in fruits and vegetables.

    PubMed

    Mujawar, Sumaiyya; Utture, Sagar C; Fonseca, Eddie; Matarrita, Jessie; Banerjee, Kaushik

    2014-05-01

    A sensitive and rugged residue analysis method was validated for the estimation of dithiocarbamate fungicides in a variety of fruit and vegetable matrices. The sample preparation method involved reaction of dithiocarbamates with Tin(II) chloride in aqueous HCl. The CS2 produced was absorbed into an isooctane layer and estimated by GC-MS selected ion monitoring. Limit of quantification (LOQ) was ⩽40μgkg(-1) for grape, green chilli, tomato, potato, brinjal, pineapple and chayote and the recoveries were within 75-104% (RSD<15% at LOQ). The method could be satisfactorily applied for analysis of real world samples. Dissipation of mancozeb, the most-used dithiocarbamate fungicide, in field followed first+first order kinetics with pre-harvest intervals of 2 and 4days in brinjal, 7 and 10days in grapes and 0day in chilli at single and double dose of agricultural applications. Cooking practices were effective for removal of mancozeb residues from vegetables.

  12. Enantio- and diastereoselective Michael addition reactions of unmodified aldehydes and ketones with nitroolefins catalyzed by a pyrrolidine sulfonamide.

    PubMed

    Wang, Jian; Li, Hao; Lou, Bihshow; Zu, Liansuo; Guo, Hua; Wang, Wei

    2006-05-24

    Chiral (S)-pyrrolidine trifluoromethanesulfonamide has been shown to serve as an effective catalyst for direct Michael addition reactions of aldehydes and ketones with nitroolefins. A wide range of aldehydes and ketones as Michael donors and nitroolefins as acceptors participate in the process, which proceeds with high levels of enantioselectivity (up to 99 % ee) and diastereoselectivity (up to 50:1 d.r.). The methodology has been employed successfully in an efficient synthesis of the potent H(3) agonist Sch 50917. In addition, a practical three-step procedure for the preparation of (S)-pyrrolidine trifluoromethanesulfonamide has been developed. The high levels of stereochemical control attending Michael addition reactions catalyzed by this pyrrolidine sulfonamide, have been investigated by using ab initio and density functional methods. Transition state structures for the rate-limiting C--C bond-forming step, corresponding to re- and si-face addition to the reactive conformation of the key enamine intermediates have been calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for si-face attack in reactions of aldehydes to form 2R,3S products is lower than that for the re-face attack leading to 2S,3R products. In contrast, the energy barrier for re-face addition is lower than that for si-face addition in reactions of ketones. The computational results, which are in good agreement with the experimental observations, are discussed in the context of the stereochemical course of these Michael addition reactions.

  13. Preparation and characterization of the 'research chemical' diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers.

    PubMed

    Wallach, Jason; Kavanagh, Pierce V; McLaughlin, Gavin; Morris, Noreen; Power, John D; Elliott, Simon P; Mercier, Marion S; Lodge, David; Morris, Hamilton; Dempster, Nicola M; Brandt, Simon D

    2015-05-01

    Substances with the diphenylethylamine nucleus represent a recent addition to the product catalog of dissociative agents sold as 'research chemicals' on the Internet. Diphenidine, i.e. 1-(1,2-diphenylethyl)piperidine (1,2-DEP), is such an example but detailed analytical data are less abundant. The present study describes the synthesis of diphenidine and its most obvious isomer, 1-(2,2-diphenylethyl)piperidine (2,2-DEP), in order to assess the ability to differentiate between them. Preparation and characterization were also extended to the two corresponding pyrrolidine analogues 1-(1,2-diphenylethyl)- and 1-(2,2-diphenylethyl)pyrrolidine, respectively. Analytical characterizations included high-resolution electrospray mass spectrometry (HR-ESI-MS), liquid chromatography ESI-MS/MS, gas chromatography ion trap electron and chemical ionization MS, nuclear magnetic resonance spectroscopy (NMR) and infrared spectroscopy. Differentiation between the two isomeric pairs was possible under GC-(EI/CI)-MS conditions and included the formation of distinct iminium ions, such as m/z 174 for 1,2-DEP and m/z 98 for 2,2-DEP, respectively. The pyrrolidine counterparts demonstrated similar phenomena including the expected mass difference of 14 Da due to the lack of one methylene unit in the ring. Two samples obtained from an Internet vendor provided confirmation that diphenidine was present in both samples, concurring with the product label. Finally, it was confirmed that diphenidine (30 μM) reduced N-methyl-D-aspartate-mediated field excitatory postsynaptic potentials (NMDA-fEPSPs) to a similar extent to that of ketamine (30 μM) when using rat hippocampal slices. The appearance of 1,2- diphenylethylamines appears to reflect the exploration of alternatives to arylcyclohexylamine-type substances, such as methoxetamine, PCP and PCPy-based analogues that also show NMDA receptor activity as demonstrated here for diphenidine. Copyright © 2014 John Wiley & Sons, Ltd.

  14. Enantioselective Formal [3 + 1 + 1] Cycloaddition Reaction by Ru(II)/Iminium Cocatalysis for Construction of Multisubstituted Pyrrolidines.

    PubMed

    Li, Mingfeng; Chu, Rui; Chen, Jianghui; Wu, Xiang; Zhao, Yun; Liu, Shunying; Hu, Wenhao

    2017-03-01

    A Ru(II)/iminium cocatalyzed asymmetric formal [3 + 1 + 1] cycloaddition reaction of diazoacetophenones, anilines, and enals is disclosed to construct multisubstituted pyrrolidines in one step with excellent diastereoselectivity and enantioselectivity. The reaction mechanism was postulated as a successful trapping of Ru(II)-associated ammonium ylides via a selective 1,4-addition to chiral amine activated enals followed by a tandem aza-aldol process. The control experiments and theoretical density functional theory investigation revealed that the reversible NaOAc-facilitated aza-aldol process led to the diastereomeric conversion to provide a stable product.

  15. Substituted 6-(1-pyrrolidine)quinolin-2(1H)-ones as novel selective androgen receptor modulators.

    PubMed

    Martinborough, Esther; Shen, Yixing; Oeveren, Arjan van; Long, Yun Oliver; Lau, Thomas L S; Marschke, Keith B; Chang, William Y; López, Francisco J; Vajda, Eric G; Rix, Peter J; Viveros, O Humberto; Negro-Vilar, Andrés; Zhi, Lin

    2007-10-18

    The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.

  16. Metal-free oxysulfenylation of alkenes with 1-(arylthio)pyrrolidine-2,5-diones and alcohols.

    PubMed

    Yu, Jipan; Gao, Chang; Song, Zhixuan; Yang, Haijun; Fu, Hua

    2015-05-07

    β-Alkoxy sulfides are widely used as versatile building blocks in organic synthesis. Therefore, it is highly desirable to develop a convenient and efficient method for oxysulfenylation of alkenes. In this communication, an easy and efficient metal-free approach to β-alkoxy sulfides has been developed. The protocol uses readily available 1-(arylthio)pyrrolidine-2,5-diones and alcohols as the oxysulfenylating agents, chloroform as the solvent, and no ligand, additive and exclusion of air were required. Therefore, the present method provides a useful strategy for synthesis of β-alkoxy sulfides.

  17. Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.

    PubMed

    Stachel, Shawn J; Steele, Thomas G; Petrocchi, Alessia; Haugabook, Sharie J; McGaughey, Georgia; Katharine Holloway, M; Allison, Timothy; Munshi, Sanjeev; Zuck, Paul; Colussi, Dennis; Tugasheva, Katherine; Wolfe, Abigail; Graham, Samuel L; Vacca, Joseph P

    2012-01-01

    We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

  18. Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.

    PubMed

    Van Huis, Chad A; Bigge, Christopher F; Casimiro-Garcia, Agustin; Cody, Wayne L; Dudley, Danette A; Filipski, Kevin J; Heemstra, Ronald J; Kohrt, Jeffrey T; Narasimhan, Lakshmi S; Schaum, Robert P; Zhang, Erli; Bryant, John W; Haarer, Staci; Janiczek, Nancy; Leadley, Robert J; McClanahan, Thomas; Thomas Peterson, J; Welch, Kathleen M; Edmunds, Jeremy J

    2007-06-01

    A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

  19. 3-[(2-Hy-droxy-1-naphth-yl)(pyrrolidin-1-yl)meth-yl]benzonitrile.

    PubMed

    Xue, Meng Wei

    2010-07-14

    The title compound, C(22)H(20)N(2)O, was obtained from the condensation reaction of 3-formyl-benzonitrile, 2-naphthol and pyrrolidine. There are two mol-ecules in the asymmetric unit, having similar conformations. Intra-molecular O-H⋯N and C-H⋯O hydrogen bonds occur, with only van der Waals forces between mol-ecules. The dihedral angles between the naphthalene ring system and the phenyl ring in the two molecules are 75.28 (10) and 76.07 (11)°. The five-membered rings adopt half-chair conformations.

  20. Crystal structure of 1-{4-hy-droxy-3-[(pyrrolidin-1-yl)meth-yl]phen-yl}-3-phenyl-prop-2-en-1-one.

    PubMed

    Aydın, Abdullah; Akkurt, Mehmet; Gul, Halise Inci; Yerdelen, Kadir Ozden; Celik, Raziye Catak

    2016-05-01

    In the title compound, C20H21NO2, the pyrrolidine ring adopts an envelope conformation with the N atom at the flap position. The central benzene ring makes dihedral angles of 21.39 (10) and 80.10 (15)° with the phenyl ring and the mean plane of the pyrrolidine ring, respectively. The mol-ecular conformation is stabilized by an intra-molecular O-H⋯N hydrogen bond, which closes an S(6) ring. A weak C-H⋯π inter-action is observed in the crystal.

  1. Pyrrolidine analogs of lobelane: Relationship of affinity for the dihydrotetrabenazine binding site with function of the vesicular monoamine transporter 2 (VMAT2)

    PubMed Central

    Vartak, Ashish P.; Nickell, Justin R.; Chagkutip, Jaturaporn; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Ring size reduction of the central piperidine ring of lobelane yielded pyrrolidine analogs that showed marked inconsistencies in their ability to bind to the dihydrotetrabenazine (DTBZ) binding site on the vesicular monoamine transporter-2 (VMAT2) and their ability to inhibit VMAT2 function. The structure activity relationships indicate that structural modification within the pyrrolidine series resulted in analogs that interact with two different sites, i.e., the DTBZ binding site and an alternative site on VMAT2 to inhibit transporter function. PMID:19691331

  2. Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.

    PubMed

    Backes, Bradley J; Longenecker, Kenton; Hamilton, Gregory L; Stewart, Kent; Lai, Chunqiu; Kopecka, Hana; von Geldern, Thomas W; Madar, David J; Pei, Zhonghua; Lubben, Thomas H; Zinker, Bradley A; Tian, Zhenping; Ballaron, Stephen J; Stashko, Michael A; Mika, Amanda K; Beno, David W A; Kempf-Grote, Anita J; Black-Schaefer, Candace; Sham, Hing L; Trevillyan, James M

    2007-04-01

    A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.

  3. Study of sulfur adlayers on Au(1 1 1) from basic hydrolysis of piperazine bis(dithiocarbamate) sodium salt

    NASA Astrophysics Data System (ADS)

    Martínez, Javier A.; Valenzuela, José; Hernandez-Tamargo, Carlos E.; Cao-Milán, Roberto; Herrera, José A.; Díaz, Jesús A.; Farías, Mario H.; Mikosch, Hans; Hernández, Mayra P.

    2015-08-01

    Sulfur adlayers on Au(1 1 1) were obtained after the interaction of a gold substrate with an alkaline solution of piperazine bis(dithiocarbamate) sodium salt. Characterization of the sulfur modified gold surface was performed by means of X-Ray Photoelectron Spectroscopy (XPS), Scanning Tunneling Microscopy (STM) and Density Functional Theory (DFT) calculations. XPS signals indicated the presence of S-Au bonds, monomeric and polymeric sulfur, and absence of nitrogen and sodium. Images from STM showed the formation of quasi-rectangular octomers in coexistence with another phase. A DFT model using the arrangement of sulfur dimers on the Au(1 1 1) surface effectively reproduced the experimental STM images.

  4. Extraction of haptens from solid products and their delivery to the skin, exemplified by dithiocarbamates from rubber gloves.

    PubMed

    Bergendorff, O; Persson, C; Hansson, C

    2005-07-01

    Allergic contact dermatitis is often caused by solid products such as rubber gloves. Patch testing with the product as is often gives negative results. Extraction of the haptens into an organic solvent is commonly performed to achieve a more correct investigation. The technique used for extraction of haptens from solid materials is only sporadically described. In this study, we investigated and optimized the yields of dithiocarbamates obtained by extraction from rubber gloves. The influence of solvent, extraction time and the procedures for extraction are evaluated. The delivery of zinc dibutyldithiocarbamate from the patch test preparation to the skin is determined.

  5. Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.

    PubMed

    Mathieu, Cécile; Bui, Linh-Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joelle; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2017-02-03

    Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.

  6. Pyrrolidine and Piperidine Formation Via Copper(II) Carboxylate Promoted Intramolecular Carboamination of Unactivated Olefins: Diastereoselectivity and Mechanism

    PubMed Central

    Sherman, Eric S.; Fuller, Peter H.; Kasi, Dhanalakshmi; Chemler, Sherry R.

    2008-01-01

    An expanded substrate scope and in depth analysis of the reaction mechanism of the copper(II) carboxylate promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic γ- and δ-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring. PMID:17428100

  7. Pharmacokinetics and metabolism of N-(2-hydroxyethyl)-2,5-[14C]-pyrrolidine (HEP, Epolamine) in male healthy volunteers.

    PubMed

    Giachetti, C; Assandri, A; Mautone, G; Tajana, E; Palumbo, B; Palumbo, R

    1996-01-01

    N-(2-hydroxyethyl)-pyrrolidine (HEP, Epolamine) is a strong base used to salify organic acids of pharmaceutical interest in order to improve their solubility in water. Diclofenac-HEP (Flector) is the first example of an epolamine salt of a drug. In this study, [14C]-HEP was administered by oral route (300 mg, about 50 microCi/subject) to 3 volunteers with the aim to investigate its plasma profile and to calculate the relevant pharmacokinetic parameters. The experimental data correlated with a two-compartment pharmacokinetic model. Total radioactivity in urine and faeces was also measured. The radioactivity was excreted preferentially by the faecal route (about 65% of the dose administered in the 0-72 h collection interval). Urinary excretion accounted for about 30% of the dose and occurred very rapidly (about 22% of the dose was in the 0-8 h collection interval). Metabolic investigations were carried out on urine samples. TLC analysis with radioscan detector indicated a main radioactive zone, accounting for about 98% of the radioactivity in the plate. After scraping off and purification of the radioactive areas, the compound isolated (Met I) was analysed by gas chromatography-mass spectrometry with electron-impact ionization process. The structure of the metabolite was postulated to be pyrrolidine N-oxide.

  8. Pyrrolidine and piperidine formation via copper(II) carboxylate-promoted intramolecular carboamination of unactivated olefins: diastereoselectivity and mechanism.

    PubMed

    Sherman, Eric S; Fuller, Peter H; Kasi, Dhanalakshmi; Chemler, Sherry R

    2007-05-11

    An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic gamma- and delta-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

  9. 1-(5-Bromo-4-phenyl-1,3-thia­zol-2-yl)pyrrolidin-2-one

    PubMed Central

    Ghabbour, Hazem A.; Kadi, Adnan A.; El-Subbagh, Hussein I.; Chia, Tze Shyang; Fun, Hoong-Kun

    2012-01-01

    The asymmetric unit of the title compound, C13H11BrN2OS, consists of two crystallographically independent mol­ecules (A and B). In each mol­ecule, the pyrrolidine ring adopts an envelope conformation with a methyl­ene C atom as the flap atom. In mol­ecule A, the central thia­zole ring makes a dihedral angle of 36.69 (11)° with the adjacent phenyl ring, whereas the corresponding angle is 36.85 (12)° in mol­ecule B. The pyrrolidine ring is slightly twisted from the thia­zole ring, with C—N—C—N torsion angles of 4.8 (3) and 3.0 (4)° in mol­ecules A and B, respectively. In the crystal, C—H⋯π and π–π [centroid-to-centroid distance = 3.7539 (14) Å] inter­actions are observed. The crystal studied was a pseudo-merohedral twin with twin law (-100 0-10 101) and a refined component ratio of 0.7188 (5):0.2812 (5). PMID:22719524

  10. Biomimetic synthesis of highly biocompatible gold nanoparticles with amino acid-dithiocarbamate as a precursor for SERS imaging

    NASA Astrophysics Data System (ADS)

    Li, Li; Liu, Jianbo; Yang, Xiaohai; Huang, Jin; He, Dinggeng; Guo, Xi; Wan, Lan; He, Xiaoxiao; Wang, Kemin

    2016-03-01

    Amino acid-dithiocarbamate (amino acid-DTC) was developed as both the reductant and ligand stabilizer for biomimetic synthesis of gold nanoparticles (AuNPs), which served as an excellent surface-enhanced Raman scattering (SERS) contrast nanoprobe for cell imaging. Glycine (Gly), glutamic acid (Glu), and histidine (His) with different isoelectric points were chosen as representative amino acid candidates to synthesize corresponding amino acid-DTC compounds through mixing with carbon disulfide (CS2), respectively. The pyrogenic decomposition of amino acid-DTC initiated the reduction synthesis of AuNPs, and the strong coordinating dithiocarbamate group of amino acid-DTC served as a stabilizer that grafted onto the surface of the AuNPs, which rendered the as-prepared nanoparticles a negative surface charge and high colloidal stability. MTT cell viability assay demonstrated that the biomimetic AuNPs possessed neglectful toxicity to the human hepatoma cell, which guaranteed them good biocompatibility for biomedical application. Meanwhile, the biomimetic AuNPs showed a strong SERS effect with an enhancement factor of 9.8 × 105 for the sensing of Rhodamine 6G, and two distinct Raman peaks located at 1363 and 1509 cm-1 could be clearly observed in the cell-imaging experiments. Therefore, biomimetic AuNPs can be explored as an excellent SERS contrast nanoprobe for biomedical imaging, and the amino acid-DTC mediated synthesis of the AuNPs has a great potential in bio-engineering and biomedical imaging applications.

  11. Synthesis of a novel silica-supported dithiocarbamate adsorbent and its properties for the removal of heavy metal ions.

    PubMed

    Bai, Lan; Hu, Huiping; Fu, Weng; Wan, Jia; Cheng, Xiliang; Zhuge, Lei; Xiong, Lei; Chen, Qiyuan

    2011-11-15

    Silica-supported dithiocarbamate adsorbent (Si-DTC) was synthesized by anchoring the chelating agent of macromolecular dithiocarbamate (MDTC) to the chloro-functionalized silica matrix (SiCl), as a new adsorbent for adsorption of Pb(II), Cd(II), Cu(II) and Hg(II) from aqueous solution. The surface characterization was performed by FT-IR, XPS, SEM and elemental analysis indicating that the modification of the silica surface was successfully performed. The effects of media pH, adsorption time, initial metal ion concentration and adsorption temperature on adsorption capacity of the adsorbent had been investigated. Experimental data were exploited for kinetic and thermodynamic evaluations related to the adsorption processes. The characteristics of the adsorption process were evaluated by using the Langmuir, Freundlich and Dubinin-Radushkevich (D-R) adsorption isotherms and adsorption capacities were found to be 0.34 mmol g(-1), 0.36 mmol g(-1), 0.32 mmol g(-1) and 0.40 mmol g(-1) for Pb(II), Cd(II), Cu(II) and Hg(II), respectively. The adsorption mechanism of Hg(II) onto Si-DTC is quite different from that of Pb(II), Cd(II) or Cu(II) onto Si-DTC, which is demonstrated by the XPS and FT-IR results.

  12. Dietary exposure assessment of Danish consumers to dithiocarbamate residues in food: a comparison of the deterministic and probabilistic approach.

    PubMed

    Jensen, B H; Andersen, J H; Petersen, A; Christensen, T

    2008-06-01

    Probabilistic and deterministic estimates of the acute and chronic exposure of the Danish populations to dithiocarbamate residues were performed. The Monte Carlo Risk Assessment programme (MCRA 4.0) was used for the probabilistic risk assessment. Food consumption data were obtained from the nationwide dietary survey conducted in 2000--02. Residue data for 5721 samples from the monitoring programme conducted in the period 1998--2003 were used for dithiocarbamates, which had been determined as carbon disulphide. Contributions from 26 commodities were included in the calculations. Using the probabilistic approach, the daily acute intakes at the 99.9% percentile for adults and children were 11.2 and 28.2 microg kg(-1) body weight day(-1), representing 5.6% and 14.1% of the ARfD for maneb, respectively. When comparing the point estimate approach with the probabilistic approach, the outcome of the point estimate calculations was generally higher or comparable with the outcome of the probabilistic approach at the 99.9 percentile (consumers only). The chronic exposures for adults and children were 0.35 and 0.76 microg kg(-1) body weight day(-1) at the 99.9 percentile, representing 0.7% and 1.5%, respectively, of the acceptable daily intake for mancozeb and maneb at 50 microg kg(-1) body weight.

  13. Stereoselective Synthesis of cis-2,5-Disubstituted Pyrrolidines via Wacker-Type Aerobic Oxidative Cyclization of Alkenes with tBu-Sulfinamide Nucleophiles

    PubMed Central

    Redford, Joanne E.; McDonald, Richard I.; Rigsby, Matthew L.; Wiensch, Joshua D.

    2012-01-01

    Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes. PMID:22352383

  14. Synthesis of functionalized β-lactams and pyrrolidine-2,5-diones through a metal-free sequential Ugi-4CR/cyclization reaction.

    PubMed

    Ghabraie, Elmira; Balalaie, Saeed; Mehrparvar, Saber; Rominger, Frank

    2014-09-05

    An efficient approach for the synthesis of functionalized β-lactams and pyrrolidine-2,5-diones was achieved through a sequential Ugi-4CR/cyclization reaction. Diversity-oriented synthesis, good to high yields, easy workup, and short reaction times are advantages of this procedure.

  15. 1'-Methyl-4'-[4-(trifluoro-meth-yl)phen-yl]dispiro-[indan-2,2'-pyrrolidine-3',2''-indan]-1,3,1''-trione.

    PubMed

    Wei, Ang Chee; Ali, Mohamed Ashraf; Choon, Tan Soo; Hemamalini, Madhukar; Fun, Hoong-Kun

    2011-11-01

    In the title compound, C(28)H(20)F(3)NO(3), the pyrrolidine ring adopts a half-chair conformation. The other five-membered rings adopt envelope conformations with the spiro and methylene C atoms as the flap atoms. In the crystal, mol-ecules are connected via weak C-H⋯O hydrogen bonds, forming sheets parallel to the bc plane.

  16. Phosphine-Catalyzed Enantioselective [2+4] Cycloaddition to Synthesize Pyrrolidin-2-one Fused Dihydropyrans Using α-Substituted Allenoates as C2 Synthons.

    PubMed

    Wang, Chang; Jia, Hao; Zhang, Cheng; Gao, Zhenzhen; Zhou, Leijie; Yuan, Chunhao; Xiao, Yumei; Guo, Hongchao

    2017-01-06

    A bifunctional phosphine-catalyzed highly enantioselective [2+4] cycloaddition of α-substituted allenoates with (E)-1-benzyl-4-olefinicpyrrolidine-2,3-diones has been achieved, giving pyrrolidin-2-one fused dihydropyran derivatives in moderate to good yields with excellent enantioselectivities (up to 98% ee). This reaction provides a useful catalytic asymmetric access to dihydropyran structural motifs.

  17. The Novel Pyrrolidine Nor-Lobelane Analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] Inhibits VMAT2 Function, Methamphetamine-Evoked Dopamine Release, and Methamphetamine Self-Administration in RatsS⃞

    PubMed Central

    Beckmann, Joshua S.; Siripurapu, Kiran B.; Nickell, Justin R.; Horton, David B.; Denehy, Emily D.; Vartak, Ashish; Crooks, Peter A.; Bardo, Michael T.

    2010-01-01

    Both lobeline and lobelane attenuate methamphetamine self-administration in rats by decreasing methamphetamine-induced dopamine release via interaction with vesicular monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane, cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and its trans-isomers, (2R,5R)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-111) and (2S,5S)-trans-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-112), were evaluated for inhibition of [3H]dihydrotetrabenazine binding and [3H]dopamine uptake by using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were evaluated for inhibition of [3H]nicotine and [3H]methyllycaconitine binding to assess interaction with the major nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of methamphetamine-evoked endogenous dopamine release by using striatal slices. The most promising compound, UKCP-110, was evaluated for its ability to decrease methamphetamine self-administration and methamphetamine discriminative stimulus cues and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and UKCP-112 inhibited [3H]dihydrotetrabenazine binding (Ki = 2.66 ± 0.37, 1.05 ± 0.10, and 3.80 ± 0.31 μM, respectively) and had high potency inhibiting [3H]dopamine uptake (Ki = 0.028 ± 0.001, 0.046 ± 0.008, 0.043 ± 0.004 μM, respectively), but lacked affinity at nicotinic receptors. Although the trans-isomers did not alter methamphetamine-evoked dopamine release, UKCP-110 inhibited (IC50 = 1.8 ± 0.2 μM; Imax = 67.18 ± 6.11 μM) methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110 decreased the number of methamphetamine self-infusions, while having no effect on food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110 represents a new lead in the development of novel pharmacotherapies for

  18. Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione.

    PubMed

    Rybka, Sabina; Obniska, Jolanta; Rapacz, Anna; Filipek, Barbara; Żmudzki, Paweł

    2016-12-01

    Synthesis and anticonvulsant properties of 26 new N-Mannich bases of 3-benzhydryl-(5-17) and 3-isopropyl-pyrrolidine-2,5-diones (18-30) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2,5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2,5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (9) with ED5 0 value =42.71 mg/kg (MES), ED5 0 value >150 mg/kg (scPTZ), and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (13) with ED5 0 value =101.46 mg/kg (MES) and ED5 0 value =72.59 mg/kg (scPTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and 13), their influence on Nav1.2 and l-type calcium channel was evaluated in vitro.

  19. Structure sensitive normal coordinate analysis of metal-diethyldithiocarbamate - complexes

    NASA Astrophysics Data System (ADS)

    Mikosch, H.; Bauer, G.; Kellner, R.; Trendafilova, N. S.; St. Nikolov, G.

    1986-03-01

    Symmetry changes in the course of dissolution are assumed to produce frequency shifts in molecular spectra of N, N-Disubstituted Dithiocarbamates. Using (mass-weighted) cartesian coordinates it is possible to calculate eigenvalues both for the site- and the molecular symmetry. Calculated shifts for Cu- and Zn- complexes are of the same order of magnitude as experimental results and calculation of frequencies even for assumed structures is possible.

  20. Methyl 1-ethyl-3'-[hy-droxy(naphthalen-1-yl)meth-yl]-1'-methyl-2-oxo-spiro-[indo-line-3,2'-pyrrolidine]-3'-carboxyl-ate.

    PubMed

    Vijayakumar, Vinodhkumar; Peters, Gunther H; Suresh, M; Raghavachary, Raghunathan; Jagadeesan, G

    2014-05-01

    In the title compound, C27H28N2O4, the pyrrolidine ring adopts a twist conformation. The plane of the indole ring is almost perpendicular to that of the pyrrolidine ring, making a dihedral angle of 88.50 (6)°. The planes of the naphthyl ring system and the pyrrolidine ring are tilted by an angle of 55.86 (5)°. The mol-ecular conformation is stabilized by intra-molecular O-H⋯O and O-H⋯N hydrogen bonds.

  1. Hydrido copper clusters supported by dithiocarbamates: oxidative hydride removal and neutron diffraction analysis of [Cu7(H){S2C(aza-15-crown-5)}6].

    PubMed

    Liao, Ping-Kuei; Fang, Ching-Shiang; Edwards, Alison J; Kahlal, Samia; Saillard, Jean-Yves; Liu, C W

    2012-06-18

    Reactions of Cu(I) salts with Na(S(2)CR) (R = N(n)Pr(2), NEt(2), aza-15-crown-5), and (Bu(4)N)(BH(4)) in an 8:6:1 ratio in CH(3)CN solution at room temperature yield the monocationic hydride-centered octanuclear Cu(I) clusters, [Cu(8)(H){S(2)CR}(6)](PF(6)) (R = N(n)Pr(2), 1(H); NEt(2), 2(H); aza-15-crown-5, 3(H)). Further reactions of [Cu(8)(H){S(2)CR}(6)](PF(6)) with 1 equiv of (Bu(4)N)(BH(4)) produced neutral heptanuclear copper clusters, [Cu(7)(H){S(2)CR}(6)] (R = N(n)Pr(2), 4(H); NEt(2), 5(H); aza-15-crown-5, 6(H)) and clusters 4-6 can also be generated from the reaction of Cu(BF(4))(2), Na(S(2)CR), and (Bu(4)N)(BH(4)) in a 7:6:8 molar ratio in CH(3)CN. Reformation of cationic Cu(I)(8) clusters by adding 1 equiv of Cu(I) salt to the neutral Cu(7) clusters in solution is observed. Intriguingly, the central hydride in [Cu(8)(H){S(2)CN(n)Pr(2)}(6)](PF(6)) can be oxidatively removed as H(2) by Ce(NO(3))(6)(2-) to yield [Cu(II)(S(2)CN(n)Pr(2))(2)] exploiting the redox-tolerant nature of dithiocarbamates. Regeneration of hydride-centered octanuclear copper clusters from the [Cu(II)(S(2)CN(n)Pr(2))(2)] can be achieved by reaction with Cu(I) ions and borohydride. The hydride release and regeneration of Cu(I)(8) was monitored by UV-visible titration experiments. To our knowledge, this is the first time that hydride encapsulated within a copper cluster can be released as H(2) via chemical means. All complexes have been fully characterized by (1)H NMR, FT-IR, UV-vis, and elemental analysis, and molecular structures of 1(H), 2(H), and 6(H) were clearly established by single-crystal X-ray diffraction. Both 1(H) and 2(H) exhibit a tetracapped tetrahedral Cu(8) skeleton, which is inscribed within a S(12) icosahedron constituted by six dialkyl dithiocarbamate ligands in a tetrametallic-tetraconnective (μ(2), μ(2)) bonding mode. The copper framework of 6(H) is a tricapped distorted tetrahedron in which the four-coordinate hydride is demonstrated to occupy the central site by

  2. Complexity.

    PubMed

    Gómez-Hernández, J Jaime

    2006-01-01

    It is difficult to define complexity in modeling. Complexity is often associated with uncertainty since modeling uncertainty is an intrinsically difficult task. However, modeling uncertainty does not require, necessarily, complex models, in the sense of a model requiring an unmanageable number of degrees of freedom to characterize the aquifer. The relationship between complexity, uncertainty, heterogeneity, and stochastic modeling is not simple. Aquifer models should be able to quantify the uncertainty of their predictions, which can be done using stochastic models that produce heterogeneous realizations of aquifer parameters. This is the type of complexity addressed in this article.

  3. Enantiodivergent Synthesis of (+)- and (-)-Pyrrolidine 197B: Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular Hydroamination.

    PubMed

    Pérez, Sixto J; Purino, Martín A; Cruz, Daniel A; López-Soria, Juan M; Carballo, Rubén M; Ramírez, Miguel A; Fernández, Israel; Martín, Víctor S; Padrón, Juan I

    2016-10-17

    A highly efficient, diastereoselective, iron(III)-catalyzed intramolecular hydroamination/cyclization reaction involving α-substituted amino alkenes is described. Thus, enantiopure trans-2,5-disubstituted pyrrolidines and trans-5-substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l-α-amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)- and (-)-pyrrolidine 197B alkaloids from l-glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Enantioselective Construction of Pyrrolidines by Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of Trimethylenemethane with Imines

    PubMed Central

    Trost, Barry M.; Silverman, Steven M.

    2012-01-01

    A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complimentary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters. PMID:22309214

  5. Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1.

    PubMed

    Mould, Daniel P; Bremberg, Ulf; Jordan, Allan M; Geitmann, Matthis; McGonagle, Alison E; Somervaille, Tim C P; Spencer, Gary J; Ogilvie, Donald J

    2017-08-24

    As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Variation of the Molecular Conformation, Shape, and Cavity Size in Dinuclear Metalla-Macrocycles Containing Hetero-Ditopic Dithiocarbamate-Carboxylate Ligands from a Homologous Series of N-Substituted Amino Acids.

    PubMed

    Torres-Huerta, Aaron; Cruz-Huerta, Jorge; Höpfl, Herbert; Hernández-Vázquez, Luis G; Escalante-García, Jaime; Jiménez-Sánchez, Arturo; Santillan, Rosa; Hernández-Ahuactzi, Irán F; Sánchez, Mario

    2016-12-05

    A homologous series of dithiocarbamate ligands derived from N-substituted amino acids was reacted with different diorganotin dichlorides to give 18 diorganotin complexes. Spectroscopic and mass spectrometric analysis evidenced the formation of assemblies with six-coordinate tin atoms embedded in skewed-trapezoidal bipyramidal coordination environments of composition C2SnS2O2. Single-crystal X-ray diffraction analysis for three of the compounds revealed a one-dimensional polymeric structure for the complex with the ligand derived from 5-aminopentanoic acid, which through further intermolecular Sn···O interactions generated an overall two-dimensional coordination polymer containing 40-membered hexanuclear tin macrocycles. On the contrary, the ligands derived from 6-aminohexanoic and 8-aminooctanoic acid provided the expected 22- and 26-membered dinuclear macrocyclic structures. Density functional theory calculations for a representative series of macrocyclic complexes of composition [Me2SnLx]2 with Lx = ¯S2CN(Me)-(CH2)x-COO¯ (x = 3-12) enabled a detailed analysis of the variations in the molecular conformation, shape, and cavity size of the macrocycles in dependence of the aliphatic spacer. Because of odd-even effects, the difunctional ligands can adopt either a curved or a twisted-pincer shape, while the SnSxO4-x (x = 0-4) moieties can act either as linear or angular tectons with varying connectivity angles.

  7. Visual Identification of Light-Driven Breakage of the Silver-Dithiocarbamate Bond by Single Plasmonic Nanoprobes

    PubMed Central

    Gao, Peng Fei; Yuan, Bin Fang; Gao, Ming Xuan; Li, Rong Sheng; Ma, Jun; Zou, Hong Yan; Li, Yuan Fang; Li, Ming; Huang, Cheng Zhi

    2015-01-01

    Insight into the nature of metal-sulfur bond, a meaningful one in life science, interface chemistry and organometallic chemistry, is interesting but challenging. By utilizing the localized surface plasmon resonance properties of silver nanoparticles, herein we visually identified the photosensitivity of silver-dithiocarbamate (Ag-DTC) bond by using dark field microscopic imaging (iDFM) technique at single nanoparticle level. It was found that the breakage of Ag-DTC bond could be accelerated effectively by light irradiation, followed by a pH-dependent horizontal or vertical degradation of the DTC molecules, in which an indispensable preoxidation process of the silver was at first disclosed. These findings suggest a visualization strategy at single plasmonic nanoparticle level which can be excellently applied to explore new stimulus-triggered reactions, and might also open a new way to understand traditional organic reaction mechanisms. PMID:26493773

  8. Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole-dithiocarbamate-urea hybrids.

    PubMed

    Duan, Ying-Chao; Zheng, Yi-Chao; Li, Xiao-Chen; Wang, Meng-Meng; Ye, Xian-Wei; Guan, Yuan-Yuan; Liu, Gai-Zhi; Zheng, Jia-Xin; Liu, Hong-Min

    2013-06-01

    A series of novel 1,2,3-triazole-dithiocarbamate-urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 μM and 0.76 to 13.55 μM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 μM and 70 μM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques.

  9. CS(2) blinds in Brassica crops: false positive results in the dithiocarbamate residue analysis by the acid digestion method.

    PubMed

    Perz, R C; van Lishaut, H; Schwack, W

    2000-03-01

    Various members of the Brassicaceae family (cauliflower, savoy cabbage, red cabbage, turnip-rooted cabbage) grown without any application of pesticides were analyzed according to the acid digestion method commonly used for the determination of dithiocarbamate fungicide residues. Depending on postharvest treatments, high non-anthropogenic CS(2) values up to 4 mg/kg were found in some cases, especially in frozen raw cabbage samples, exceeding maximum residue limits. To explore phytogenic CS(2) occurrences, two model substances (phenylisothiocyanate and methyl tryptaminedithiocarbamate) representing natural mustard oils and brassinines, respectively, were analyzed for their acid hydrolysis decomposition products. In both cases, COS was found generally, but CS(2) was readily formed during acid digestion, too, when sulfides were present. The results obtained clearly demonstrate that CS(2) values determined by using the acid digestion method of crops rich in secondary metabolism sulfur compounds have to be interpreted carefully.

  10. Biomimetic synthesis of highly biocompatible gold nanoparticles with amino acid-dithiocarbamate as a precursor for SERS imaging.

    PubMed

    Li, Li; Liu, Jianbo; Yang, Xiaohai; Huang, Jin; He, Dinggeng; Guo, Xi; Wan, Lan; He, Xiaoxiao; Wang, Kemin

    2016-03-11

    Amino acid-dithiocarbamate (amino acid-DTC) was developed as both the reductant and ligand stabilizer for biomimetic synthesis of gold nanoparticles (AuNPs), which served as an excellent surface-enhanced Raman scattering (SERS) contrast nanoprobe for cell imaging. Glycine (Gly), glutamic acid (Glu), and histidine (His) with different isoelectric points were chosen as representative amino acid candidates to synthesize corresponding amino acid-DTC compounds through mixing with carbon disulfide (CS2), respectively. The pyrogenic decomposition of amino acid-DTC initiated the reduction synthesis of AuNPs, and the strong coordinating dithiocarbamate group of amino acid-DTC served as a stabilizer that grafted onto the surface of the AuNPs, which rendered the as-prepared nanoparticles a negative surface charge and high colloidal stability. MTT cell viability assay demonstrated that the biomimetic AuNPs possessed neglectful toxicity to the human hepatoma cell, which guaranteed them good biocompatibility for biomedical application. Meanwhile, the biomimetic AuNPs showed a strong SERS effect with an enhancement factor of 9.8 × 10(5) for the sensing of Rhodamine 6G, and two distinct Raman peaks located at 1363 and 1509 cm(-1) could be clearly observed in the cell-imaging experiments. Therefore, biomimetic AuNPs can be explored as an excellent SERS contrast nanoprobe for biomedical imaging, and the amino acid-DTC mediated synthesis of the AuNPs has a great potential in bio-engineering and biomedical imaging applications.

  11. Effect of additives on Hg2+ reduction and precipitation inhibited by sodium dithiocarbamate in simulated flue gas desulfurization solutions.

    PubMed

    Lu, Rongjie; Hou, Jiaai; Xu, Jiang; Tang, Tingmei; Xu, Xinhua

    2011-11-30

    Mercury (II) (Hg(2+)) ion can be reduced by aqueous S(IV) (sulfite and/or bisulfite) species, which leads to elemental mercury (Hg(0)) emissions in wet flue gas desulfurization (FGD) systems. Numerous reports have demonstrated the high trapping efficiency of sodium dithiocarbamate over heavy metals. In this paper, a novel sodium dithiocarbamate, DTCR, was utilized as a precipitator to control Hg(2+) reduction and Hg(0) emission against S(IV) in FGD solutions. Results indicated that Hg(2+) reduction efficiency decreased dramatically while precipitation rate peaked at around 91.0% in consistence with the increment of DTCR dosage. Initial pH and temperature had great inhibitory effects on Hg(2+) reduction: the Hg(2+) removal rate gradually increased and reached a plateau along with the increment of temperature and initial pH value. Chloride played a key role in Hg(2+) reduction and precipitation reactions. When Cl(-) concentration increased from 0 to 150 mM, Hg(2+) removal rate dropped from 93.84% to 86.05%, and the Hg(2+) reduction rate remained at a low level (<7.8%). SO(4)(2-), NO(3)(-) and other common metal ions would affect the efficiency of Hg(2+) reduction and precipitation reactions in the simulated desulfurization solutions: Hg(2+) removal rate could always be above 90%, while Hg(2+) reduction rate was maintained at below 10%. The predominance of DTCR over aqueous S(IV), indicated by the results above, has wide industrial applications in FGD systems.

  12. Crystal structure of methyl 3'-benzamido-4'-(4-meth-oxy-phen-yl)-1'-methyl-spiro-[indeno-[1,2-b]quinoxaline-11,2'-pyrrolidine]-3'-carboxyl-ate.

    PubMed

    Chandralekha, Kuppan; Sureshbabu, Adukamparai Rajukrishnan; Gavaskar, Deivasigamani; Lakshmi, Srinivasakannan

    2016-09-01

    In the title compound, C35H30N4O3, the spiro C atom connects the five-membered pyrrolidine ring and the indeno-quinoxaline ring system. The pyrrolidine ring adopts a twist conformation. An intra-molecular N-H⋯N inter-action between the amino group and the pyrazine ring is observed. In the crystal, mol-ecules are linked by a pairs of C-H⋯O hydrogen bonds, forming inversion dimers.

  13. Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

    PubMed Central

    Hati, Santanu; Tripathy, Sayantan; Dutta, Pratip Kumar; Agarwal, Rahul; Srinivasan, Ramprasad; Singh, Ashutosh; Singh, Shailja; Sen, Subhabrata

    2016-01-01

    The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions. PMID:27573798

  14. Stereoselective behavior of the functional diltiazem analogue 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a new L-type calcium channel blocker.

    PubMed

    Carosati, Emanuele; Budriesi, Roberta; Ioan, Pierfranco; Cruciani, Gabriele; Fusi, Fabio; Frosini, Maria; Saponara, Simona; Gasparrini, Francesco; Ciogli, Alessia; Villani, Claudio; Stephens, Philip J; Devlin, Frank J; Spinelli, Domenico; Chiarini, Alberto

    2009-11-12

    We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(+)/S-(-). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity.

  15. Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

    NASA Astrophysics Data System (ADS)

    Hati, Santanu; Tripathy, Sayantan; Dutta, Pratip Kumar; Agarwal, Rahul; Srinivasan, Ramprasad; Singh, Ashutosh; Singh, Shailja; Sen, Subhabrata

    2016-08-01

    The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

  16. Design and synthesis of formononetin-dithiocarbamate hybrids that inhibit growth and migration of PC-3 cells via MAPK/Wnt signaling pathways.

    PubMed

    Fu, Dong-Jun; Zhang, Li; Song, Jian; Mao, Ruo-Wang; Zhao, Ruo-Han; Liu, Ying-Chao; Hou, Yu-Hui; Li, Jia-Huan; Yang, Jia-Jia; Jin, Cheng-Yun; Li, Ping; Zi, Xiao-Lin; Liu, Hong-Min; Zhang, Sai-Yang; Zhang, Yan-Bing

    2017-02-15

    A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC50 = 1.97 μM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.

  17. ToF-SIMS analysis of anti-fretting films generated on the surface of ball bearings containing dithiocarbamate and dithiophosphate grease additives

    NASA Astrophysics Data System (ADS)

    Duque, Ricardo G.; Wang, Zhiyu; Duell, Dave; Fowler, David E.

    2004-06-01

    During transport of hard drives from the factory to the end customer, vibrations can induce small repetitive displacements of the ball bearings giving rise to fretting corrosion at the metal surfaces. On the other hand, it has been found that some particular types of grease additives can form thin layers on steel surfaces and thus protect against fretting corrosion. ToF-SIMS has been used to study the chemical nature of layers formed on bearing surfaces containing greases with dithiocarbamates, dithiophosphates, and metal sulfonate additives. In cases where fretting was prevented, the presence of MoS 2-, FeS - and ion fragments containing Mo-Fe-S - were observed, whereas none of these ions were detected on the surfaces of fretted bearings. Finally, it is inferred that the action of metal sulfonates may have an antagonist effect on the anti-fretting activity of the dithiocarbamate and dithiophosphate compounds studied.

  18. Synthesis of Pyrrolidines and Pyrrolizidines with α-Pseudoquaternary Centers by Copper-Catalyzed Condensation of α-Diazodicarbonyl Compounds and Aryl γ-Lactams.

    PubMed

    Goudedranche, Sébastien; Besnard, Céline; Egger, Léo; Lacour, Jérôme

    2016-10-24

    N-aryl γ-lactams react intermolecularly with acceptor-acceptor diazo reagents, usually dicarbonyl compounds, in a copper-catalyzed process to yield functionalized pyrrolidines with α-pseudoquaternary centers. As 1,2-acyl or -phosphoryl migration is preferred, single regioisomers are obtained. Furthermore, in the presence of a Lewis acid, subsequent Friedel-Crafts reactions yield tricyclic pyrrolizidines in excellent yields (90-96 %) and diastereoselectivities (up to >20:1).

  19. Synthesis and characterization of the novel fluorescent prolyl oligopeptidase inhibitor 4-fluoresceinthiocarbamoyl-6-aminocaproyl-L-prolyl-2(S)-(hydroxyacetyl)pyrrolidine.

    PubMed

    Venäläinen, Jarkko I; Wallén, Erik A A; Poso, Antti; García-Horsman, J Arturo; Männistö, Pekka T

    2005-11-17

    The synthesis and characterization of the first fluorescent prolyl oligopeptidase inhibitor 4-fluoresceinthiocarbamoyl-6-aminocaproyl-L-prolyl-2(S)-(hydroxyacetyl)pyrrolidine is described. This compound has an IC50 value of 0.83 nM and a dissociation half-life of 160 min, and its fluorescence signal is detectable using standard filters for fluorescein. These properties make this compound a suitable probe for visualizing prolyl oligopeptidase in various applications.

  20. Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability.

    PubMed

    Kamal, Ahmed; Sathish, Manda; Nayak, V Lakshma; Srinivasulu, Vunnam; Kavitha, Botla; Tangella, Yellaiah; Thummuri, Dinesh; Bagul, Chandrakant; Shankaraiah, Nagula; Nagesh, Narayana

    2015-09-01

    A series of new β-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a-l and 13a-l and their starting precursors (7 a-d and 12 a-d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7 c, 12 c, 8 a, 8 d, 8 i, 8 j, 8 k, 8l and 13 d-l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC50<10μM). Interestingly, most of the derivatives (8 a-l and 13a-l) exhibited enhanced activity than their precursors (7 a-d and 12 a-d), which indicates that the combination of dithiocarbamate with β-carboline enhances the cytotoxicity of 8 a-l and 13 a-l. Moreover, the derivatives 8 j and 13 g exhibited significant cytotoxic activity with IC50 values of 1.34 μM and 0.79 μM on DU-145 cancer cells, respectively. Further, the induction of apoptosis by these derivatives was confirmed by Annexin V-FITC and Hoechst staining assays. However, both biophysical as well as molecular docking studies suggested a combilexin-type of interaction between these derivatives and DNA, unlike simple β-carbolines. With a view to understand their mechanism of action, DNA topoisomerase II (topo II) inhibition assay was also performed. Overall, the present study emphasizes the importance of linking a dithiocarbamate moiety to the β-carboline scaffold for exhibiting profound activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Determination of dithiocarbamate pesticides in occupational hygiene sampling devices using the isooctane method and comparison with an automatic thermal desorption (ATD) method.

    PubMed

    Coldwell, Matthew R; Pengelly, Ian; Rimmer, Duncan A

    2003-01-10

    Two new methods for the determination of dithiocarbamate pesticides in occupational hygiene sampling devices are described. Dithiocarbamate spiked occupational hygiene sampling devices, consisting of glass fibre (GF/A) filters, cotton pads, cotton gloves and disposable overalls, were reduced under acidic conditions and the CS2 evolved as a decomposition product was extracted into isooctane. The isooctane was then analysed using gas chromatography with mass spectrometry, for CS2, which provided a quantitative result for dithiocarbamates. Recoveries obtained were generally within a 70-110% range and reproducibilities better than 15% RSD were typically achieved. The method has been successfully applied to samples collected during occupational exposure surveys. A second method employing automatic thermal desorption-gas chromatography-mass spectrometry (ATD-GC-MS) has also been developed and applied to the direct analysis of GF/A (airborne) samples. The method relies on the thermal degradation of dithiocarbamates to release CS2, which is used to quantify the analytes. Thiram spiked GF/A filters gave an average recovery of 107% with an RSD of 4%. The performance of the two analytical methods were directly compared by analysing sub-portions of GF/A filters collected during a survey to evaluate occupational exposures to thiram during seed treatment operations. Both methods performed well for the analysis of airborne (GF/A) samples and produced results in good agreement. ATD-GC-MS is the preferred method for studies involving GF/A (airborne) samples only. Because of the wider applicability of the isooctane method for other sampling devices, it is the preferred choice when carrying out surveys which require a dermal as well as respirable exposure assessment.

  2. Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734 821 Pyrrolidine Bis-piperazines

    PubMed Central

    2015-01-01

    The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17 340 to 4 879 681 compounds) for analgesia directly in the mouse tail withdrawal model. The “all X” mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738 192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28 392 compounds each (26 × 26 × 42) and 42 functionalities at the fourth made up of 19 915 compounds each (26 × 26 × 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 °C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant

  3. Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734,821 Pyrrolidine Bis-piperazines.

    PubMed

    Houghten, Richard A; Ganno, Michelle L; McLaughlin, Jay P; Dooley, Colette T; Eans, Shainnel O; Santos, Radleigh G; LaVoi, Travis; Nefzi, Adel; Welmaker, Greg; Giulianotti, Marc A; Toll, Lawrence

    2016-01-11

    The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17,340 to 4,879,681 compounds) for analgesia directly in the mouse tail withdrawal model. The "all X" mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738,192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28,392 compounds each (26 × 26 × 42) and 42 functionalities at the fourth made up of 19,915 compounds each (26 × 26 × 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 °C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant respiratory

  4. β-CA-specific inhibitor dithiocarbamate Fc14-584B: a novel antimycobacterial agent with potential to treat drug-resistant tuberculosis.

    PubMed

    Aspatwar, Ashok; Hammarén, Milka; Koskinen, Sanni; Luukinen, Bruno; Barker, Harlan; Carta, Fabrizio; Supuran, Claudiu T; Parikka, Mataleena; Parkkila, Seppo

    2017-12-01

    Inhibition of novel biological pathways in Mycobacterium tuberculosis (Mtb) creates the potential for alternative approaches for treating drug-resistant tuberculosis. In vitro studies have shown that dithiocarbamate-derived β-carbonic anhydrase (β-CA) inhibitors Fc14-594 A and Fc14-584B effectively inhibit the activity of Mtb β-CA enzymes. We screened the dithiocarbamates for toxicity, and studied the in vivo inhibitory effect of the least toxic inhibitor on M. marinum in a zebrafish model. In our toxicity screening, Fc14-584B emerged as the least toxic and showed minimal toxicity in 5-day-old larvae at 300 µM concentration. In vitro inhibition of M. marinum showed that both compounds inhibited growth at a concentration of 75 µM. In vivo inhibition studies using 300 µM Fc14-584B showed significant (p > .05) impairment of bacterial growth in zebrafish larvae at 6 days post infection. Our studies highlight the therapeutic potential of Fc14-584B as a β-CA inhibitor against Mtb, and that dithiocarbamate compounds may be developed into potent anti-tuberculosis drugs.

  5. RECOVERY OF URANIUM BY CYCLOALKYLDITHIO-CARBAMATE COMPLEXING

    DOEpatents

    Neville, O.K.

    1959-06-30

    The separation of uranium-233 from an aqueous nitric acid solution of neutron irradiated thorium by selectively complexing the uranium is described. The separation is carried out by contacting the thorium solution with a non- aromatic organic dithiocarbamate selected from the group which consists of alkali and alkaline earth cycloalkyldithiocarbamates and recovering the resulting uranyl cycloalkyldithiocarbamate complex by organic solvent extraction such as with methyl ethyl ketone. The complexed uranium may be stripped from the separated organic phase by scrubbing with one normal nitric acid solution.

  6. Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1.

    PubMed

    Wróbel, Martyna Z; Chodkowski, Andrzej; Herold, Franciszek; Gomółka, Anna; Kleps, Jerzy; Mazurek, Aleksander P; Pluciński, Franciszek; Mazurek, Andrzej; Nowak, Gabriel; Siwek, Agata; Stachowicz, Katarzyna; Sławińska, Anna; Wolak, Małgorzata; Szewczyk, Bernadeta; Satała, Grzegorz; Bojarski, Andrzej J; Turło, Jadwiga

    2013-05-01

    A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.

  7. Low polydispersity (N-ethyl pyrrolidine methacrylamide-co-1-vinylimidazole) linear oligomers for gene therapy applications.

    PubMed

    Velasco, D; Réthoré, G; Newland, B; Parra, J; Elvira, C; Pandit, A; Rojo, L; San Román, J

    2012-11-01

    Nonviral methods for gene delivery are becoming ever more prevalent along with the need to design new vectors that are highly effective, stable in biological fluids, inexpensive, and facile to produce. Here, we synthesize our previously reported monomer N-ethyl pyrrolidine methacrylamide (EPA) and evaluate its effectiveness in gene vector applications when copolymerized with 1-vinylimidazole (VI). A range of these novel linear cationic copolymers were synthesized via free radical polymerization with low molecular weights (oligomers) and low polydispersities showing two pK(a) values as the two co-monomers are cationic. DNA-polymer polyplexes had average sizes between 100 and 250nm and zeta-potentials between 10 and 25mV, and a strong dependence of composition on the size on the zeta-potential was observed. The cytotoxicity of the homopolymers, oligomers, and polyplexes toward human fibroblasts and 3T3 mouse fibroblasts was evaluated using the MTT and AlamarBlue™ assays, proving that formulations could be made with toxicity as low as low molecular weight linear poly (dimethylaminoethyl methacrylate) (PDMAEMA). The transfection capability of the polyplexes measured using the G-luciferase marker gene far superseded PDMAEMA when evaluated in biological conditions. Furthermore, blood compatibility studies showed that these new oligomers exhibit no significant hemolysis or platelet activation above PBS controls. These new EPA based oligomers with low toxicity and ease of scalability show high transfection abilities in serum conditions, and blood compatibility showing its potential for systemic gene delivery applications.

  8. Synthesis of first ever 4-quinolone-3-carboxylic acid-appended spirooxindole-pyrrolidine derivatives and their biological applications.

    PubMed

    Arasakumar, Thangaraj; Mathusalini, Sadasivam; Ata, Athar; Shankar, Ramasamy; Gopalan, Subashini; Lakshmi, Krishnasamy; Sakthivel, Pandiyarajan; Mohan, Palathurai Subramaniam

    2017-02-01

    A series of 4-quinolone-3-carboxylic acid-containing spirooxindole-pyrrolidine derivatives was synthesized via multicomponent 1,3-dipolar cycloaddition reactions of azomethine ylides with new (E)-4-oxo-6-(3-phenyl-acryloyl)-1,4-dihydroquinoline-3-carboxylic acids in good yields with high regioselectivity. The cycloadducts were characterized by analytical and spectral data including [Formula: see text], [Formula: see text], 2D NMR and mass spectroscopy. The structure of one of the compounds (8a) was investigated theoretically by computational techniques. DFT studies support the proposed mechanism for this cycloaddition reaction. Furthermore, antibacterial activities of the new compounds were evaluated against Gram-positive and Gram-negative bacterial strains. Compounds 8f, 8m and 8p showed potent inhibition activities against selected bacteria. The in vitro cytotoxicity of spirooxindole derivatives (8a-r) was evaluated against MCF-7 breast cancer cell line. Among the various compounds tested, compound 8f [Formula: see text] showed significant cytotoxic activity compared to the standard drug doxorubicin [Formula: see text].

  9. Results of long-term experimental studies on the carcinogenicity of ethylene-bis-dithiocarbamate (Mancozeb) in rats.

    PubMed

    Belpoggi, Fiorella; Soffritti, Morando; Guarino, Marina; Lambertini, Luca; Cevolani, Daniela; Maltoni, Cesare

    2002-12-01

    Mancozeb, an ethylene-bis-dithiocarbamate (EBDC), has been one of the most commonly used fungicides in commercial use for several decades. Nevertheless, up to now, no adequate published experimental studies on the carcinogenicity of Mancozeb have been published. Because of the importance of the compound and of the number of people potentially exposed (workers engaged in the production and use of the fungicide, people living in agricultural areas where the compound is sprayed, and people consuming polluted products), a long-term experimental study of Mancozeb was begun at the Cancer Research Center of the Ramazzini Foundation. Groups of 150 male and female Sprague-Dawley rats, 8 weeks old at the start of the treatment, were administered Mancozeb at the concentration of 1000, 500, 100, 10, and 0 ppm in feed supplied ad libitum for 104 weeks. At the end of the treatment, animals were kept under controlled conditions until spontaneous death. Mancozeb caused an increase in (1) total malignant tumors, (2) malignant mammary tumors, (3) Zymbal gland and ear duct carcinomas, (4) hepatocarcinomas, (5) malignant tumors of the pancreas, (6) malignant tumors of the thyroid gland, (7) osteosarcomas of the bones of the head, and (8) hemolymphoreticular neoplasias. On the basis of these data, Mancozeb must be considered a multipotent carcinogenic agent.

  10. Primary risk assessment of dimethyldithiocarbamate, a dithiocarbamate fungicide metabolite, based on their probabilistic concentrations in a coastal environment.

    PubMed

    Hano, Takeshi; Ito, Katsutoshi; Mochida, Kazuhiko; Ohkubo, Nobuyuki; Kono, Kumiko; Onduka, Toshimitsu; Ito, Mana; Ichihashi, Hideki; Fujii, Kazunori; Tanaka, Hiroyuki

    2015-07-01

    The primary ecological risk of dimethyldithiocarbamate (DMDC), a dithiocarbamate fungicide (DTC) metabolite, was evaluated based on their probabilistic environmental concentration distributions (ECDs) in the coastal environment, Hiroshima Bay, Japan. And their behavior and temporal trends was further considered. This is the first report of the identification of DMDC from environmental seawater and sediment samples. DMDC concentrations in bottom seawater were substantially higher than those in surface seawater, which are associated with the leachability from sediments in bottom seawaters, and with photodegradation in surface seawaters. Furthermore, seasonal risks are dominated by higher concentrations from April to June, indicating temporal variation in the risk to exposed species. Hierarchical Bayesian analysis offered DMDC ECD medians and range (5th to 95th percentiles) of 0.85 ng L(-1) (0.029, 22), 12 ng L(-1) (3.2, 48) and 110 ng kg dry(-1) (9.5, 1200) in surface seawater, bottom seawater and sediment, respectively. Considering that DMDC and DTCs have similar toxicological potential to aquatic organisms, the occurrence of the compound in water is likely to be of biological relevance. In summary, this work provides the first demonstration that the ecological risk of DMDC and its derived DTCs in Hiroshima Bay is relatively high, and that DTCs should be a high priority for future research on marine contamination, especially in bottom seawaters.

  11. Exposure to Mn/Zn ethylene-bis-dithiocarbamate and glyphosate pesticides leads to neurodegeneration in Caenorhabditis elegans.

    PubMed

    Negga, Rekek; Rudd, David A; Davis, Nathan S; Justice, Amanda N; Hatfield, Holly E; Valente, Ana L; Fields, Anthony S; Fitsanakis, Vanessa A

    2011-06-01

    Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24h (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC(50)=8.0% (r(2)=0.6890), while the chronic LC(50)=5.7% (r(2)=0.9433). Acute MZ exposure led to an LC(50)=0.22% (r(2)=0.5093), and chronic LC(50)=0.50% (r(2)=0.9733). The combined treatment for TD+MZ yielded an LC(50)=12.5% (r(2)=0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p<0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally relevant concentrations of TD or MZ.

  12. 4′-(4-Methoxy­phen­yl)-1,1′,1′′-trimethyl­dispiro­[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidine]-2,2′′,5′′-trione

    PubMed Central

    Nirmala, S.; Karthikeyan, K.; Kamala, E. Theboral Sugi; Sudha, L.; Perumal, P. T.

    2009-01-01

    In the title compound, C24H25N3O4, the pyrrolidine ring adopts an envelope conformation while the pyrrolidine-2′′,5′′-dione ring adopts a twist conformation. The indoline unit is planar [maximum deviation of −0.050 (9) Å] and forms a dihedral angle of 40.36 (4)° with the methoxy­phenyl ring. Intra­molecular C—H⋯O hydrogen bonds are observed. In the crystal, mol­ecules are linked into a two-dimensional network parallel to the ab plane by inter­molecular C—H⋯O hydrogen bonds and C—H⋯π inter­actions. PMID:21582918

  13. Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease.

    PubMed

    Andrews, David M; Barnes, Michael C; Dowle, Mike D; Hind, S Lucy; Johnson, Martin R; Jones, Paul S; Mills, Gail; Patikis, Angela; Pateman, Tony J; Redfern, Tracy J; Robinson, J Ed; Slater, Martin J; Trivedi, Naimisha

    2003-11-27

    [reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.

  14. Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction.

    PubMed

    Leiva, Rosana; Griñan-Ferré, Christian; Seira, Constantí; Valverde, Elena; McBride, Andrew; Binnie, Margaret; Pérez, Belén; Luque, F Javier; Pallàs, Mercè; Bidon-Chanal, Axel; Webster, Scott P; Vázquez, Santiago

    2017-10-20

    Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. 2-Amino-4-(4-chloro­phen­yl)-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile

    PubMed Central

    Inglebert, S. Antony; Kamalraja, Jayabal; Sethusankar, K.; Vasuki, Gnanasambandam

    2012-01-01

    In the title compound, C17H14ClN5, two C atoms and their attached H atoms of the pyrrolidine ring are disordered over two sets of sites with an occupancy ratio of 0.638 (10):0.362 (10). The benzene and pyridine rings are inclined to one another by 60.57 (8)°. In the crystal, the amino group forms an N—H⋯N hydrogen bond with one of the cyano groups, linking the mol­ecules into chains along [010]. PMID:22589876

  16. Construction of Fused Pyrrolidines and β-Lactones by Carbene-Catalyzed C-N, C-C, and C-O Bond Formations.

    PubMed

    Wu, Xingxing; Hao, Lin; Zhang, Yuexia; Rakesh, Maiti; Reddi, Rambabu N; Yang, Song; Song, Bao-An; Chi, Yonggui Robin

    2017-03-15

    A carbene-catalyzed intermolecular C-N bond formation, which initiates a highly selective cascade reaction for the synthesis of pyrrolidine fused β-lactones, is disclosed. The nitrogen-containing bicyclic β-lactone products are obtained with good yields and excellent stereoselectivities. Synthetic transformations of the reaction products into useful functional molecules, such as amino catalysts, can be efficiently realized under mild reaction conditions. Mechanistically, this study provides insights into modulating the reactivities of heteroatoms, such as nitrogen atoms, in challenging carbene-catalyzed asymmetric carbon-heteroatom bond-forming reactions.

  17. Efficient iodine catalyzed three components domino reaction for the synthesis of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives possessing anticancer activities.

    PubMed

    Ramachandran, Gunasekar; Karthikeyan, Natesan S; Giridharan, Periyasamy; Sathiyanarayanan, Kulathu I

    2012-07-28

    A simple and efficient three components domino reaction of γ-butyrolactam (2-pyrrolidinone), aromatic aldehyde and substituted thiophenol catalyzed by elemental iodine resulted in the formation of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives. The stability of the synthesized analogues was evaluated in stimulated gastric fluid (SGF) and bovine serum albumin (BSA). In vitro anticancer activity was investigated in the low micromolar range and a few analogues were found to possess good activity. This current protocol provides several advantages like shorter reaction time, excellent yield and convenient work-up.

  18. A review of methods for the analysis of orphan and difficult pesticides: glyphosate, glufosinate, quaternary ammonium and phenoxy acid herbicides, and dithiocarbamate and phthalimide fungicides.

    PubMed

    Raina-Fulton, Renata

    2014-01-01

    This article reviews the chromatography/MS methodologies for analysis of pesticide residues of orphan and difficult chemical classes in a variety of sample matrixes including water, urine, blood, and food. The review focuses on pesticide classes that are not commonly included in multiresidue analysis methods such as highly polar or ionic herbicides including glyphosate, glufosinate, quaternary ammonium, and phenoxy acid herbicides, and some of their major degradation or metabolite products. In addition, dithiocarbamate and phthalimide fungicides, which are thermally unstable and have stability issues in some solvents or sample matrixes, are also examined due to their special needs in residue analysis.

  19. 2-Trimethylsilylethanesulfonyl (SES) versus tosyl (Ts) protecting group in the preparation of nitrogen-containing five-membered rings. A novel route for the synthesis of substituted pyrrolines and pyrrolidines.

    PubMed

    Declerck, Valérie; Allouchi, Hassan; Martinez, Jean; Lamaty, Frédéric

    2007-02-16

    The 2-trimethylsilylethanesulfonyl (or SES) protecting group was compared to the tosyl (Ts) group in the preparation of a nitrogen-containing five-membered ring obtained by the aza-Baylis-Hillman/alkylation/RCM route. While deprotection of Ts-protected pyrrolines gave only pyrroles, deprotection of the same SES-protected compounds gave either pyrroles or free amine pyrrolines depending on the deprotection conditions. The SES-protected pyrrolines were hydrogenated to yield pyrrolidines with an excellent diastereoselectivity. Free amine pyrrolidines were obtained by HF-mediated deprotection of the SES group.

  20. Crystal structure of 1-{4-hy­droxy-3-[(pyrrolidin-1-yl)meth­yl]phen­yl}-3-phenyl­prop-2-en-1-one

    PubMed Central

    Aydın, Abdullah; Akkurt, Mehmet; Gul, Halise Inci; Yerdelen, Kadir Ozden; Celik, Raziye Catak

    2016-01-01

    In the title compound, C20H21NO2, the pyrrolidine ring adopts an envelope conformation with the N atom at the flap position. The central benzene ring makes dihedral angles of 21.39 (10) and 80.10 (15)° with the phenyl ring and the mean plane of the pyrrolidine ring, respectively. The mol­ecular conformation is stabilized by an intra­molecular O—H⋯N hydrogen bond, which closes an S(6) ring. A weak C—H⋯π inter­action is observed in the crystal. PMID:27308021

  1. 1-[(2-Hy­droxy­phen­yl)(pyrrolidin-1-yl)­meth­yl]naphthalen-2-ol N,N-dimethyl­formamide monosolvate

    PubMed Central

    Wang, Wen-xiang

    2012-01-01

    The title compound, C21H21NO2·C3H7NO, was synthesized by solvent-free one-pot three-component reaction of naphthalen-2-ol, 2-hy­droxy­benzaldehyde and pyrrolidine. The dihedral angle between the naphthalene ring system and the benzene ring is 77.74 (6)°. The pyrrolidine ring assumes an envelope conformation. An intra­molecular O—H⋯N and an inter­molecular O—H⋯O hydrogen bond are observed. PMID:22412735

  2. A hepatic metabolomics-based diagnostic approach to assess lethal toxicity of dithiocarbamate fungicide polycarbamate in three marine fish species.

    PubMed

    Hano, Takeshi; Ohkubo, Nobuyuki; Mochida, Kazuhiko

    2017-04-01

    The present study was performed to evaluate the toxic effect of the dithiocarbamate fungicide polycarbamate (PC) on the hepatic metabolic profiles of three marine fish species, red sea bream (Pagrus major), spotted halibut (Verasper variegatus), and marbled flounder (Pleuronectes yokohamae). First, juvenile fish were exposed to graded concentrations of PC for 96h; the 96-h LC50 values obtained were 22-29, 239-553, and 301-364µgL(-1) for red sea bream, spotted halibut, and marbled flounder, respectively, indicating that red sea bream possessed higher sensitivity to PC than the two benthic species. Second, the fish were exposed to lethal-equivalent concentration (H group) or sub-lethal (one-tenth of the H group concentrations; L group) for 24 and 96h and gas-chromatography based metabolomics approach was employed to explore the crucial biomarker metabolite associated with lethal toxicity. Of the 53 metabolites identified, only reduced glutathione (GSH) was consistently elevated in the H group for the three fish species at 96h. The calculated cut-off value of GSH (mM) based on receiver operating curve analysis between H group and the other treatment groups (control, solvent control, and L group) was obtained at 0.56mM, which allowed to distinguish between the groups with high confidence for the three fish species. These results are the first to demonstrate the potential of using GSH as a possible biomarker metabolite and its usefulness of threshold cut-off value for diagnosing life-threatening health conditions of fish. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. The neonicotinoid pesticide imidacloprid and the dithiocarbamate fungicide mancozeb disrupt the pituitary-thyroid axis of a wildlife bird.

    PubMed

    Pandey, Surya Prakash; Mohanty, Banalata

    2015-03-01

    Thyroid is an important homeostatic regulator of metabolic activities as well as endocrine mechanisms including those of reproduction. Present investigation elucidated the thyroid disrupting potential of a neonicotinoid imidacloprid and a dithiocarbamate mancozeb in a seasonally breeding wildlife bird, Red Munia (Amandava amandava) who is vulnerable to these two pesticides through diet (seed grains and small insects). Adult male birds were exposed to 0.5% LD50 mgkg(-1)bwd(-1) of both the pesticides through food for 30days during the preparatory and breeding phases. Weight, volume and histopathology of thyroid gland were distinctly altered. Disruption of thyroid follicles reflected in nucleus-to-cytoplasm ratio (N/C) in epithelial and stromal cells, epithelial cell hypertrophy and altered colloid volume. Impairment of thyroid axis was pesticide and phase specific as evident from the plasma levels of thyroid (T4 and T3) and pituitary (TSH) hormones. In preparatory phase, plasma TSH was increased in response to decrease of T4 on mancozeb exposure showing responsiveness of the hypothalamic-pituitary-thyroid (HPT) axis to feedback regulation. On imidacloprid exposure, however, plasma levels of both T4 and TSH were decreased indicating non-functioning of negative feedback mechanism. Increased plasma T3 in response to both the pesticides exposure might be due to synthesis from non-thyroidal source(s) in a compensatory response to decrease level of T4. In breeding phase, impairment of HPT axis was more pronounced as plasma T4, T3 and TSH were significantly decreased in response to both mancozeb and imidacloprid. Thus, low dose pesticide exposure could affect the thyroid homeostasis and reproduction.

  4. Exposure to Mn/Zn Ethylene-bis-Dithiocarbamate and Glyphosate Pesticides Leads to Neurodegeneration in Caenorhabditis elegans

    PubMed Central

    Negga, Rekek; Rudd, David A.; Davis, Nathan S.; Justice, Amanda N.; Hatfield, Holly E.; Valente, Ana L.; Fields, Anthony S.; Fitsanakis, Vanessa A.

    2011-01-01

    Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24 hours (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC50 = 8.0% (r2: = 0.6890), while the chronic LC50 = 5.7% (r2 = 0.9433). Acute MZ exposure led to an LC50 = 0.22% (r2 = 0.5093), and chronic LC50 = 0.50% (r2 = 0.9733). The combined treatment for TD + MZ yielded an LC50 = 12.5% (r2 = 0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p < 0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally-relevant concentrations of TD or MZ. PMID:21376751

  5. Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from 3-(1-phenylethyl)- and 3-benzyl-pyrrolidine-2,5-dione.

    PubMed

    Rybka, Sabina; Obniska, Jolanta; Rapacz, Anna; Furgała, Anna; Filipek, Barbara; Żmudzki, Paweł

    2016-05-01

    Two series of new derivatives of pyrrolidine-2,5-dione were synthesized and evaluated for their anticonvulsant properties. Initial screening for their anticonvulsant properties was performed in mice after intraperitoneal administration, using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6-Hz seizure tests. Quantitative pharmacological research revealed that the highest level of protection was demonstrated by compound N-[{4-methylpiperazin-1-yl}-methyl]-3-(1-phenylethyl)-pyrrolidine-2,5-dione monohydrochloride (22) which was effective both in the scPTZ test (ED50=39 mg/kg) and in the 6-Hz test (ED50=36 mg/kg). This molecule showed higher potency than reference antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. With the aim of explaining the possible mechanism of action of the selected molecule, its influence on sodium and calcium channels as well as NMDA and GABAA receptors binding properties were evaluated in vitro. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione.

    PubMed

    Rapacz, Anna; Rybka, Sabina; Obniska, Jolanta; Sałat, Kinga; Powroźnik, Beata; Pękala, Elżbieta; Filipek, Barbara

    2016-03-01

    The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.

  7. Evaluation of the influence of proline, hydroxyproline or pyrrolidine in the presence of sodium nitrite on N-nitrosamine formation when heating cured meat.

    PubMed

    Drabik-Markiewicz, G; Dejaegher, B; De Mey, E; Impens, S; Kowalska, T; Paelinck, H; Vander Heyden, Y

    2010-01-11

    N-nitrosamines are meant to be probable or possible carcinogenic components, possibly formed out of a reaction between nitrite and N-containing substances such as amino acids and secondary amines. Nitrite is often used for processing meat products because of its colouring and antimicrobial properties. During this experimental setup, the influence of proline, hydroxyproline or pyrrolidine on N-nitrosamine formation in meat samples was evaluated. The N-nitrosamines concentrations were measured with gas chromatography-thermal energy analyzer. Only the concentrations of N-nitrosodimethylamine and N-nitrosopyrrolidine were found above the limit of detection in a number of tested experimental conditions. The concentration of these two N-nitrosamines was modelled as a function of temperature and nitrite concentration for different situations (presence or absence of added natural N-containing meat components). It could be concluded that proline and pyrrolidine promoted the formation of N-nitrosopyrrolidine. It could also be confirmed that the higher the temperature of the meat processing procedure and the higher the sodium nitrite amounts added, the higher were the yields of the respective N-nitrosamines.

  8. Molecular Aggregation in Binary Mixtures of Pyrrolidine, N-Methylpyrrolidine, Piperidine, and N-Methylpiperidine with Water: Thermodynamic, SANS and Theoretical Studies.

    PubMed

    Marczak, Wojciech; Varfolomeev, Mikhail A; Rakipov, Ilnaz T; Lodowski, Piotr; Kowalska-Szojda, Katarzyna; Łężniak, Marta; Almasy, Laszlo; Len, Adél

    2017-03-21

    Piperidine and N-methylpiperidine hydrates aggregate in liquid aqueous solutions due to hydrogen bonds between hydration water molecules. No such effects occur in the mixtures of the amines with methanol, that supports the idea of active role of water solvent in the aggregation. However, the question of contributions in thermodynamic functions due to specific interactions, van der Waals forces, and the size and shape of the molecules remains open. In the present study, limiting partial molar enthalpies of solution of pyrrolidine, N-methylpyrrolidine, piperidine and N-methylpiperidine in water and methanol and vice versa were measured and compared with those assessed from theoretically calculated molecular interaction energies using a simple "chemical reaction" model. Nearly quantitative agreement of the enthalpies was achieved for the systems studied, except the amines in water. The latter required an empirical hydrophobic hydration term to be considered. The hydrogen bonds formation and breaking which accompany the mixtures formation leads to considerable excess volumes, while the size of the solute molecules is manifested rather in the compressibility of aqueous solutions. SANS evidenced that aqueous solutions are microheterogeneous on the nanometer-order length scale. The propensity to promote phase separation increases in the order: N-methylpiperidine < N-methylpyrrolidine < piperidine < pyrrolidine.

  9. 2-[1′-(Benz­yloxy)spiro­[indane-1,2′-pyrrolidine]-5′-yl]aceto­nitrile

    PubMed Central

    Moreno-Fuquen, Rodolfo; Soto, Diana M.; Jaramillo-Gómez, Luz M.; Ellena, Javier; Tenorio, Juan C.

    2013-01-01

    In the title compound, C21H22N2O, the planes of the two six-membered rings make a dihedral angle of 89.51 (7)°. The pyrrolidine ring has a puckering amplitude q 2 = 0.418 (3) and a pseudo-rotation phase angle ϕ2 = −166.8 (5), adopting a twist conformation (T). The other five-membered ring has a puckering amplitude q 2 = 0.247 (2) and a pseudo-rotation phase angle ϕ2 = −173.7 (5), adopting an envelope conformation with the CH2 atom adjacent to the C atom common with the pyrrolidine ring as the flap. In the crystal, mol­ecules are linked via C—H⋯N, enclosing R 2 2(20) rings, forming chains propagating along [100]. The aceto­nitrile group is disordered over two positions and was refined with a fixed occupancy ratio of 0.56:0.44. PMID:24109293

  10. Crystal structure of poly[bis-(ammonium) [bis-(μ4-benzene-1,3,5-tri-carboxyl-ato)dizincate] 1-methyl-pyrrolidin-2-one disolvate].

    PubMed

    Ordonez, Carlos; Fonari, Marina S; Wei, Qiang; Timofeeva, Tatiana V

    2016-05-01

    The title three-dimensional metal-organic framework (MOF) compound, {(NH4)2[Zn2(C9H3O6)2]·2C5H9NO} n , features an anionic framework constructed from Zn(2+) cations and benzene-1,3,5-tri-carboxyl-ate (BTC) organic anions. Charge balance is achieved by outer sphere ammonium cations formed by degradation of di-n-butyl-amine in the solvothermal synthesis of the compound. Binuclear {Zn2(COO)2} entities act as the framework's secondary building units. Each Zn(II) atom has a tetrahedral coordination environment with an O4 set of donor atoms. The three-dimensional framework adopts a rutile-type topology and channels are filled in an alternating fashion with ordered and disordered 1-methyl-pyrrolidin-2-one solvent mol-ecules and ammonium cations. The latter are held in the channels via four N-H⋯O hydrogen bonds, including three with the benzene-1,3,5-tri-carboxyl-ate ligands of the anionic framework and one with a 1-methyl-pyrrolidin-2-one solvent mol-ecule.

  11. Antioxidant properties of thio-caffeine derivatives: Identification of the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine as antioxidant and highly potent cytoprotective agent.

    PubMed

    Jasiewicz, Beata; Sierakowska, Arleta; Wandyszewska, Natalia; Warżajtis, Beata; Rychlewska, Urszula; Wawrzyniak, Rafał; Mrówczyńska, Lucyna

    2016-08-15

    A series of nine thio-caffeine analogues were synthesized and characterised by NMR, FT-IR and MS spectroscopic methods. Molecular structures of four of them were determined using single crystal X-ray diffraction methods. The antioxidant properties of all compounds, at concentration ranges from 0.025 to 0.1mg/mL, were evaluated by various chemical- and cell-based antioxidant assays. Human erythrocytes were used to examine in vitro haemolytic activity of all compounds and their protective effect against oxidative haemolysis induced by AAPH, one of the commonly used free radical generator. All compounds studied showed no effect on the human erythrocytes membrane structure and permeability with the exception of 8-(phenylsulfanyl)caffeine. Among the nine caffeine thio-analogues tested, the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine possessed exceptionally high antioxidant properties. Moreover, it protects human erythrocytes against AAPH-induced oxidative damage as efficiently as the standard antioxidant Trolox. Therefore, 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine may have a significant cytoprotective potential caused by its antioxidant activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. The synthesis of N,O-ferrocenyl pyrrolidine-containing ligands and their application in the diethyl- and diphenylzinc addition to aromatic aldehydes.

    PubMed

    Ahern, Theresa; Müller-Bunz, Helge; Guiry, Patrick J

    2006-09-29

    A facile route to a series of planar chiral N,O-ferrocenyl pyrrolidine-containing ligands with varying substituents at the nitrogen and oxygen donor atoms is described. The oxygen donor atom was introduced via a diastereoselective ortho-metalation of N-methylpyrrolidinyl and N-allylpyrrolidinyl ferrocene intermediates and was quenched with various ketones. The nitrogen substituent was varied through deallylation and subsequent derivatization of a secondary pyrrolidine. The efficacy of these novel ligands was investigated in the enantioselective addition of diethylzinc and diphenylzinc to aromatic aldehydes. The ligands proved highly effective in the diethylzinc addition to benzaldehyde that resulted in high yields of up to 99% and enantioselectivities (ee's) of up to 95%. The role of planar chirality was explored and the results indicated that the planar chirality, and not the central chirality, of the ferrocenyl ligands was the dominant stereo-controlling element. Employment of a mixed ethyl-phenylzinc reagent in the phenylation of aromatic aldehydes led to a mixture of the two additional products, and the phenylated product was obtained in up to 37% ee.

  13. Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2, 5-dione derivatives as anticonvulsants.

    PubMed

    Malik, Sachin; Ahuja, Priya; Sahu, Kapendra; Khan, Suroor Ahmad

    2014-09-12

    A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a-7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs.

  14. Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.

    PubMed

    Noronha, Glenn; Barrett, Kathy; Boccia, Antonio; Brodhag, Tessa; Cao, Jianguo; Chow, Chun P; Dneprovskaia, Elena; Doukas, John; Fine, Richard; Gong, Xianchang; Gritzen, Colleen; Gu, Hong; Hanna, Ehab; Hood, John D; Hu, Steven; Kang, Xinshan; Key, Jann; Klebansky, Boris; Kousba, Ahmed; Li, Ge; Lohse, Dan; Mak, Chi Ching; McPherson, Andrew; Palanki, Moorthy S S; Pathak, Ved P; Renick, Joel; Shi, Feng; Soll, Richard; Splittgerber, Ute; Stoughton, Silva; Tang, Suhan; Yee, Shiyin; Zeng, Binqi; Zhao, Ningning; Zhu, Hong

    2007-02-01

    We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth.

  15. Ligand-free gold nanoparticles as colorimetric probes for the non-destructive determination of total dithiocarbamate pesticides after solid phase extraction.

    PubMed

    Giannoulis, Kyriakos M; Giokas, Dimosthenis L; Tsogas, George Z; Vlessidis, Athanasios G

    2014-02-01

    In this work, we describe a simple and sensitive non-destructive method for the determination of the total concentration of dithiocarbamate fungicides (DTCs) in real samples. The proposed method combines for the first time the benefits of an extraction method for sample clean-up and preconcentration with a sensitive colorimetric assay based on gold nanoparticle probes. In this two-step procedure, the target DTCs are isolated from the matrix and preconcentrated by solid phase extraction onto commercially available C18 sorbents. Following elution, the extract containing the target dithiocarbamates, free from most interferences and matrix components, is delivered into an aqueous dispersion of plain citrate-capped gold nanoparticles (AuNPs) which aggregate in response to DTCs coordination on AuNPs surface through multiple gold thiolate bonds. This aggregation is evidenced by changes in the spectral properties of the solution involving a decrease in the original absorbance of Au nanoparticles at 522 nm and the appearance of a new absorption band above 700 nm. An ensuing chromatic shift of the solution from wine-red to purple-blue is observed which is visual by naked eye at concentrations as low as 50 μg L(-1). Further improvement in the detection limits can be accomplished by scaling-down the method to micro-volume conditions alleviating the need to preconcentrate larger sample volumes. Overall, by combining sample clean-up and preconcentration with the strong affinity of DTC thiol group for the gold surface, the total concentration of dithiocarbamate pesticides was successfully determined in various water samples at the low and ultra-low μg L(-1) levels without resorting to destructive techniques, sophisticated instrumentation or post-synthetic modification of gold nanoparticles. Method application in real samples showed good analytical features in terms of recoveries (81.0-94.0%), precision (5.6-8.9%) and reproducibility (~9%) rendering the method as an attractive

  16. Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease.

    PubMed

    Cheng, Wei-Chieh; Wang, Jen-Hon; Yun, Wen-Yi; Li, Huang-Yi; Hu, Jia-Ming

    2017-01-27

    The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Theoretical elucidation on the functional role of pyrrolidine-type ionic liquids in inducing stereoselectivity of the Michael addition of cyclohexanone with trans-β-nitrostyrene.

    PubMed

    Sun, Hui; Zhang, Dongju

    2011-03-01

    Density functional theory calculations have been carried out to elucidate the stereoselectivity of the Michael addition of cyclohexanone with trans-β-nitrostyrene, induced by a chiral ionic liquid (CIL) pyrrolidine-imidazolium bromide. By comparison of the C-C bond forming processes in the absence and presence of Br(-) anion, we found that intermolecular H-bonds between the imidazolium cation and the nitro group of trans-β-nitrostyrene and the steric hindrance of the imidazolium cation moiety on the Si-face of enamine dominate the stereoselectivity of the Michael addition. The presence of Br(-) anion obviously reduces the barrier by increasing the polarity of the C4=C5 bond of enamine. The theoretical results rationalize well the early experimental finding, and reveal a valuable clue for the further CIL design with high catalytic efficiency.

  18. 4,5-Bis(4-fluoro-phen-yl)-5-hy-droxy-3-(2-methyl-propano-yl)-1-phenyl-pyrrolidin-2-one.

    PubMed

    Huang, Jian-Ying; Zhou, Fengyan

    2011-04-01

    The title compound, C(26)H(23)F(2)NO(3), was synthesized by the reaction of 2-(4-fluoro-benzyl-idene)-4-methyl-3-oxo-N-phenyl-penta-namide and 4-fluoro-benzaldehyde. The dihedral angles between the mean plane through the pyrrolidine ring (nearly planar; maximum deviation of 0.145 Å for the C atom bearing the hydroxy group) with the phenyl and benzene rings are 37.22 (7), 51.88 (7) and 87.64 (9)°, respectively. The pyyolidine ring is near coplaner, with max offset of 0.145 A for C19 atom.\\uff09 In the crystal, mol-ecules are linked by pairs of O-H⋯O hydrogen bonds into inversion dimers, which are further assembled into chains parallel to the b axis by weak C-H⋯O hydrogen bonds.

  19. Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.

    PubMed

    Asano, Moriteru; Hitaka, Takenori; Imada, Takashi; Yamada, Masami; Morimoto, Megumi; Shinohara, Hiromi; Hara, Takahito; Yamaoka, Masuo; Santou, Takashi; Nakayama, Masaharu; Imai, Yumi; Habuka, Noriyuki; Yano, Jason; Wilson, Keith; Fujita, Hisashi; Hasuoka, Atsushi

    2017-05-01

    We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Synthesis and Anticonvulsant Properties of New 3,3-Diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides and 3,3-Diphenyl-propionamides.

    PubMed

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Żmudzki, Paweł; Kamiński, Krzysztof

    2017-04-01

    The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test. Additionally, several compounds were studied also in the 6-Hz seizures recognized as the animal model of human pharmacoresistant epilepsy. In this series, compound 3q displayed a broad spectrum of activity across the preclinical seizure models (ED50 MES = 31.64 mg/kg; ED50 scPTZ = 75.41 mg/kg, ED50 6-Hz (32 mA) = 38.15 mg/kg). Consequently, compound 3q revealed a wider spectrum of protection, higher activity or/and a better safety profile than the commonly used antiepileptic drugs such as phenytoin, ethosuximide, valproic acid, or/and levetiracetam. Notably, the in vitro studies showed that the most possible mechanism of action of 3q may be connected to the interaction with neuronal voltage-sensitive sodium channels (site 2). Other substances were active predominantly in the chemically induced seizures. The results of the current studies indicate that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable for anticonvulsant activity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Gold nanorods as surface enhanced Raman spectroscopy substrates for sensitive and selective detection of ultra-low levels of dithiocarbamate pesticides.

    PubMed

    Saute, Benjamin; Premasiri, Ranjith; Ziegler, Lawrence; Narayanan, Radha

    2012-11-07

    We report the use of gold nanorods as solution-based SERS substrates for the detection of ultralow-levels of three different dithiocarbamate fungicides: thiram, ferbam and ziram. Gold nanorods are attractive to use as SERS substrates due to the ability to tune the surface plasmon resonance of the nanoparticles to the laser excitation wavelength of the Raman spectrometer equipped with a 785 nm diode laser. The gold nanorods are synthesized using a seed-mediated growth method and characterized using UV-Visible spectroscopy, zeta potential, and TEM. The gold nanorods have an aspect ratio of 2.19 ± 0.21 and have an average length of 37.81 ± 4.83 nm. SERS spectra are acquired at different concentrations of each fungicide and calibration curves are obtained by monitoring the intensity of the band arising from the ν(C-N) stretching mode coupled to the symmetric δ(CH(3)) motion. The limits of detection and limits of quantitation are obtained for each fungicide. The limits of detection are 11.00 ± 0.95 nM, 8.00 ± 1.01 nM, and 4.20 ± 1.22 nM for thiram, ferbam, and ziram respectively. The limits of quantitation are 34.43 ± 0.95 nM, 25.61 ± 1.01 nM, and 12.94 ± 1.22 nM for thiram, ferbam, and ziram respectively. It can be seen that the three different dithiocarbamates can be detected in the low nM range based on the limits of detection that are achieved.

  2. (3RS,4SR)-Methyl 4-(2-chloro-5,8-di­methoxy­quinolin-3-yl)-1-phenyl­pyrrolidine-3-carboxyl­ate

    PubMed Central

    Benzerka, Saida; Bouraiou, Abdelmalek; Bouacida, Sofiane; Rhouati, Salah; Belfaitah, Ali

    2008-01-01

    The mol­ecule of the title compound, C23H23ClN2O4, contains a quinolyl unit linked to a functionalized pyrrolidine system with a 3,4-trans arrangement of the substituents. The unit cell contains two stereoisomers that have the absolute stereochemistry 3S,4R and 3R,4S. The pyrrolidine ring adopts a twist conformation with pseudo-rotation parameters P = 258.2 (3)° and τ(M) = 35.3 (1)°. The packing is stabilized by C—H⋯π inter­actions and offset π–π stacking (centroid-to-centroid distance = 3.849 Å, inter­planar distance = 3.293 Å and slippage = 1.994 Å) between phenyl rings, leading to a two-dimensional network. PMID:21580954

  3. [Effect of hydrocinnamoyl-L-valyl pyrrolidine on healing quality of deep partial-thickness scald wound in mice].

    PubMed

    Yang, M L; Li, Y H; Tan, Q; Li, J T; Que, L L

    2016-11-20

    Objective: To observe the effect of Toll interleukin-1 recptor homology/BB-loop mimetic hydrocinnamoyl-L-valyl pyrrolidine (AS-1) on the healing quality of deep partial-thickness scald wound in mice. Methods: Forty-two adult C57BL/6 mice were divided into sham injury group (SI), scald group (S), early AS-1 treatment group (EAT), early dimethyl sulfoxide (DMSO) control group (EDC), late AS-1 treatment group (LAT), late DMSO control group (LDC) according to the random number table, with 7 mice in each group. Mice in group SI were sham injured without other treatment. Deep partial-thickness scald model with 10% total body surface area was reproduced on the back of the other mice, and the wound was treated by daily wound cleaning with saline and dressing changing with vaseline gauze after injury. Mice in group EAT and those in group LAT were intraperitoneally injected with 20 mg/mL AS-1 50 mg/kg each day respectively from post scald hour (PSH) 8 and post scald day (PSD) 15 on. Mice in group EDC and those in group LDC were intraperitoneally injected with 20 mg/mL DMSO 50 mg/kg each day respectively from PSH 8 and PSD 15 on. On PSD 21, the gross condition of wound healing of mice with scald was observed, and the wound healing rate was calculated. Tissue samples of healed wound were collected and stained with HE and Masson respectively to observe the histomorphological change and fibrosis of collagen, and the percentage of fibrosis of collagen was calculated. The mRNA expressions of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), matrix metalloproteinase-1 (MMP-1), tissue inhibitors of metalloproteinase 1 (TIMP-1), connective tissue growth factor (CTGF), type Ⅰ collagen and type Ⅲ collagen in healed wound tissue were detected by real time fluorescent quantitive reverse transcription polymerase chain reaction. The protein expressions of type Ⅰ collagen and type Ⅲ collagen in healed wound tissue were detected by

  4. Crystal structure of 4'-(2-meth-oxy-quinolin-3-yl)-1'-methyl-dispiro-[indan-2,2'-pyrrolidine-3',3''-indoline]-1,3,2''-trione.

    PubMed

    Mathusalini, Sadasivam; Viswanathan, Vijayan; Mohan, Palathurai Subramaniam; Lin, Chia-Her; Velmurugan, Devadasan

    2015-12-01

    In the title compound, C30H23N3O4, the central 1-methyl-pyrrolidine ring adopts a twist conformation on the N-CH2 bond. The pyrrolidin-2-one ring of the indolin-2-one ring system also has a twist conformation on the C-C bond involving the spiro C atom and the carbonyl C atom. The five-membered ring of the indene-1,3-dione moiety has an envelope conformation with the spiro C atom as the flap. The quinoline ring system adopts an almost planar conformation (r.m.s. deviation = 0.04 Å). The mean planes of the indolin-2-one ring system, the indene-1,3-dione ring system and the the quinoline ring system are inclined to the mean plane of the central 1-methyl-pyrrolidine ring by 77.97 (7), 86.98 (7) and 46.58 (6)°, respectively. In the crystal, mol-ecules are linked via N-H⋯N hydrogen bonds, forming chains along the b axis. The chains are linked via a number of C-H⋯O hydrogen bonds, and C-H⋯π and π-π inter-actions [inter-centroid distance = 3.7404 (9) Å], forming a three-dimensional network.

  5. A triclinic polymorph of methyl (3R,3'S)-1',1''-dimethyl-2,2''-dioxodispiro-[indoline-3,2'-pyrrolidine-3',3''-indoline]-4'-carboxyl-ate.

    PubMed

    Ganesh, G; Yuvaraj, Panneer Selvam; Divakara, Chinthalapuri; Reddy, Boreddy S R; Subbiahpandi, A

    2012-12-01

    In the title compound, C22H21N3O4, the central pyrrolidine ring adopts a C-envelope conformation with a C atom 0.6593 (13) Å displaced from the mean plane formed by the remaining ring atoms. The indoline ring systems (r.m.s. devisations of 0.0356 and 0.0547 Å) are almost perpendicular to the mean plane of the pyrrolidine ring, making dihedral angles of 89.7 (6) and 82.5 (6)°. The acetate group attached to the pyrrolidine ring assumes an extended conformation. In the crystal,N-H⋯O and C-H⋯O hydrogen bonds connect adjacent molecules, forming an infinite tape extending along [1-1-1]. The crystal packing is further consolidated by strong π-π inter-actions with a centroid-centroid distance of 3.2585 (8) Å. The title compound is a polymorph of previously reported monoclinic structure [Ganesh et al. (2012 ▶). Acta Cryst. E68, o2902-o2903].

  6. A new type of polymeric heavy metal complexing precipitant used as fishery disinfectant and antiparasitic drug

    NASA Astrophysics Data System (ADS)

    Liu, Y. C.; Zhang, A. N.; Wang, X. B.; Xu, J.; Zeng, X. H.; Wang, H. M.

    2017-08-01

    This paper presents a technique to produce a new kind of fishery drug that is water emulsion suspending agent containing polymeric calcium-iron-dithiocarbamate with heavy metal complexing precipitate ability, good disinfection and auxiliary insecticidal efficacy. The product has good dispersion, high efficiency and low toxicity, as well as no pollution and no harmful residues. It not only can be used in the pond waters and ornamental waters, but also can meet the high requirements of the aquaculture waters. There is non-pollutant emission in the production, which is a green environment-friendly technique without three waste discharges. This technology belongs to the ecological and environmental protection.

  7. 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1, 2-c]quinolin-11-one (BPIQ), A Quinoline Derivative Inhibits Human Hepatocellular Carcinoma Cells by Inducing ER Stress and Apoptosis.

    PubMed

    Chang, Wen-Tsan; Fong, Yao; Chuang, Shih-Chang; Chou, Chon-Kit; Chou, Han-Lin; Yang, Chun-Feng; Tseng, Chih-Hua; Chen, Yeh-Long; Chiu, Chien-Chih

    2017-01-01

    Hepatocellular carcinoma (HCC) is one of the leading cancers in the world, including Taiwan. The chemoresistance of advanced HCC frequently results in the poor prognosis of patients. Previous studies demonstrated the quinoline derivative, 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11Hindeno[ 1,2-c]quinolin-11-one (BPIQ) exerts the inhibitory potential against several cancer cells, including liver cancer cells. We further investigated the anti-HCC effects of BPIQ, including apoptosis and the modulation of ER stress. Both trypan blue exclusion assay and colony formation assay were performed to examine whether BPIQ affects the growth of HCC cell lines Ha22T and Huh7. Flow cytometry-based assay was performed for determining the cell cycle distribution and apoptosis. Western blot assay was conducted for detecting the changes in apoptosis- and endoplasmic reticulum (ER) stress-associated proteins. BPIQ inhibits cell growth and induces the apoptosis of both Ha22T and Huh7 cell lines significantly. The level of γH2AX, an endogenous DNA damage biomarker was dramatically increased suggesting the involvement of DNA damage pathway in BPIQ-induced apoptosis. Further, BPIQ down-regulates the pro-survival proteins, survivin, XIAP and cyclin D1. BPIQ also may regulate ER stress response through modulating the levels of ER stress-related proteins Glucose-regulated protein of 78 kD (GRP78), Inositol-requiring kinase-1α (IREα), C/EBP homologous protein (Chop) and calnexin. The anti-HCC effect of BPIQ may occur through down-regulating pro-survival proteins, and the modulation of ER stress may contribute to the BPIQ-induced apoptosis of HCC cells. The chemotherapeutic or chemopreventive applications of BPIQ for HCC treatment will be worthy of further investigation in future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

    PubMed

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

    2016-04-15

    This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Copyright © 2016. Published by Elsevier Ltd.

  9. A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities.

    PubMed

    Bharkavi, Chelliah; Vivek Kumar, Sundaravel; Ashraf Ali, Mohamed; Osman, Hasnah; Muthusubramanian, Shanmugam; Perumal, Subbu

    2016-11-15

    A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC50 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC50 <1.56μM) and 6l (IC50=2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC50 values of 1.10 and 1.16μmol/L respectively.

  10. Molybdenum-containing nicotine hydroxylase genes in a nicotine degradation pathway that is a variant of the pyridine and pyrrolidine pathways.

    PubMed

    Yu, Hao; Tang, Hongzhi; Li, Yangyang; Xu, Ping

    2015-12-01

    Ochrobactrum sp. strain SJY1 utilizes nicotine as a sole source of carbon, nitrogen, and energy via a variant of the pyridine and pyrrolidine pathways (the VPP pathway). Several strains and genes involved in the VPP pathway have recently been reported; however, the first catalyzing step for enzymatic turnover of nicotine is still unclear. In this study, a nicotine hydroxylase for the initial hydroxylation step of nicotine degradation was identified and characterized. The nicotine hydroxylase (VppA), which converts nicotine to 6-hydroxynicotine in the strain SJY1, is encoded by two open reading frames (vppAS and vppAL [subunits S and L, respectively]). The vppA genes were heterologously expressed in the non-nicotine-degrading strains Escherichia coli DH5α and Pseudomonas putida KT2440; only the Pseudomonas strain acquired the ability to degrade nicotine. The small subunit of VppA contained a [2Fe-2S] cluster-binding domain, and the large subunit of VppA contained a molybdenum cofactor-binding domain; however, an FAD-binding domain was not found in VppA. Resting cells cultivated in a molybdenum-deficient medium had low nicotine transformation activity, and excess molybdenum was detected in the purified VppA by inductively coupled plasma-mass spectrometry analysis. Thus, it is demonstrated that VppA is a two-component molybdenum-containing hydroxylase.

  11. Molybdenum-Containing Nicotine Hydroxylase Genes in a Nicotine Degradation Pathway That Is a Variant of the Pyridine and Pyrrolidine Pathways

    PubMed Central

    Yu, Hao; Li, Yangyang

    2015-01-01

    Ochrobactrum sp. strain SJY1 utilizes nicotine as a sole source of carbon, nitrogen, and energy via a variant of the pyridine and pyrrolidine pathways (the VPP pathway). Several strains and genes involved in the VPP pathway have recently been reported; however, the first catalyzing step for enzymatic turnover of nicotine is still unclear. In this study, a nicotine hydroxylase for the initial hydroxylation step of nicotine degradation was identified and characterized. The nicotine hydroxylase (VppA), which converts nicotine to 6-hydroxynicotine in the strain SJY1, is encoded by two open reading frames (vppAS and vppAL [subunits S and L, respectively]). The vppA genes were heterologously expressed in the non-nicotine-degrading strains Escherichia coli DH5α and Pseudomonas putida KT2440; only the Pseudomonas strain acquired the ability to degrade nicotine. The small subunit of VppA contained a [2Fe-2S] cluster-binding domain, and the large subunit of VppA contained a molybdenum cofactor-binding domain; however, an FAD-binding domain was not found in VppA. Resting cells cultivated in a molybdenum-deficient medium had low nicotine transformation activity, and excess molybdenum was detected in the purified VppA by inductively coupled plasma-mass spectrometry analysis. Thus, it is demonstrated that VppA is a two-component molybdenum-containing hydroxylase. PMID:26407884

  12. Anticonvulsant and antinociceptive activity of new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in mice.

    PubMed

    Rapacz, Anna; Obniska, Jolanta; Wiklik-Poudel, Beata; Rybka, Sabina; Sałat, Kinga; Filipek, Barbara

    2016-06-15

    The aim of the present experiments was to examine the anticonvulsant and antinociceptive activity of five new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in animal models of seizures and pain. The antiseizure activity was investigated in three acute models of seizures, namely, the maximal electroshock (MES), the subcutaneous pentylenetetrazole (scPTZ), and 6Hz psychomotor seizure tests in mice. The antinociceptive properties were estimated in the formalin model of tonic pain, and in the oxaliplatin-induced neuropathic pain model in mice. Considering drug safety evaluation, acute neurological toxicity was determined in the rotarod test. Three tested compounds (3, 4, and 7) displayed a broad spectrum of anticonvulsant activity and showed better protective indices than those obtained for MES/scPTZ/6Hz active reference drug - valproic acid. Furthermore, three compounds (3, 4, and 6) demonstrated a significant antinociceptive effect in the formalin test, as well as antiallodynic activity in the oxaliplatin-induced neuropathic pain model. Among the tested agents, compounds 3 and 4 displayed not only antiseizure properties, but also collateral prominent analgesic properties. The in vitro binding study indicated that the plausible mechanism of action of chosen compound (4) was the influence on neuronal voltage-sensitive sodium (site 2) and L-type calcium channels.

  13. Tuning of β-glucosidase and α-galactosidase inhibition by generation and in situ screening of a library of pyrrolidine-triazole hybrid molecules.

    PubMed

    Martínez-Bailén, Macarena; Carmona, Ana T; Moreno-Clavijo, Elena; Robina, Inmaculada; Ide, Daisuke; Kato, Atsushi; Moreno-Vargas, Antonio J

    2017-09-29

    The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two β-glucosidase (almond) inhibitors (14b,f) in the low μM range. The additional biological analysis of 14b,f towards β-glucocerebrosidase (human lysosomal β-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards β-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver β-glucosidase as neutral hydrolase. In contrast to what was observed for β-glucosidase inhibition, the coffee bean α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Core-shell magnetite-silica dithiocarbamate-derivatised particles achieve the Water Framework Directive quality criteria for mercury in surface waters.

    PubMed

    Lopes, C B; Figueira, P; Tavares, D S; Lin, Z; Daniel-da-Silva, A L; Duarte, A C; Rocha, J; Trindade, T; Pereira, E

    2013-09-01

    The sorption capacity of nanoporous titanosilicate Engelhard titanosilicate number 4 (ETS-4) and silica-coated magnetite particles derivatised with dithiocarbamate groups towards Hg(II) was evaluated and compared in spiked ultra-pure and spiked surface-river water, for different batch factors. In the former, and using a batch factor of 100 m(3)/kg and an initial Hg(II) concentrations matching the maximum allowed concentration in an effluent discharge, both materials achieve Hg(II) uptake efficiencies in excess of 99 % and a residual metal concentration lower than the guideline value for drinking water quality. For the surface-river water and the same initial concentration, the Hg(II) uptake efficiency of magnetite particles is outstanding, achieving the quality criteria established by the Water Framework Directive (concerning Hg concentration in surface waters) using a batch factor of 50 m(3)/kg, while the efficiency of ETS-4 is significantly inferior. The dissimilar sorbents' Hg(II) removal efficiency is attributed to different uptake mechanisms. This study also highlights the importance of assessing the effective capacity of the sorbents under realistic conditions in order to achieve trustable results.

  15. Cyclen dithiocarbamate-functionalized silver nanoparticles as a probe for colorimetric sensing of thiram and paraquat pesticides via host-guest chemistry

    NASA Astrophysics Data System (ADS)

    Rohit, Jigneshkumar V.; Kailasa, Suresh Kumar

    2014-11-01

    We have developed a simple and rapid colorimetric method for on-site analysis of thiram and paraquat using cyclen dithiocarbamate-functionalized silver nanoparticles (CN-DTC-Ag NPs) as a colorimetric probe. The synthesized CN-DTC-Ag NPs were characterized by UV-Visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy, dynamic light scattering, and transmission electron microscopic techniques. The CN-DTC molecules provide good supramolecular self assembly on the surfaces of Ag NPs to encapsulate thiram and paraquat selectively via "host-guest" chemistry, resulting in red-shift in surface plasmon resonance peak of CN-DTC-Ag NPs from 396 to 530 nm and 510 nm and color change from yellow to pink for thiram and to orange for paraquat, which can be naked-eye detected. The present method shows good linearity in the range of 10.0-20.0 µM and of 50.0-250 µM with limits of detection 2.81 × 10-6 M and 7.21 × 10-6 M for thiram and paraquat, respectively. This method was proved as a promising tool for on-site and real-time monitoring of thiram and paraquat in environmental water, potato, and wheat samples.

  16. C-Jun N-terminal Kinase and Apoptotic Signaling in Prostate Cancer

    DTIC Science & Technology

    2002-01-01

    hydrogen peroxide (H20 2) to induce JNK activation varied in different cell types. Pyrrolidine dithiocarbamate (PDTC), a presumed antioxidant (13,14...Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate...and Tan, T.-H. (2001) Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine

  17. Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues.

    PubMed

    Wallach, Jason; De Paoli, Giorgia; Adejare, Adeboye; Brandt, Simon D

    2014-01-01

    Classic examples of psychoactive arylcycloalkylamines include ketamine and 1-(1-phenylcyclohexyl)piperidine (PCP) and many others serve as important structural templates for neuropharmacological research. The recent emergence of PCP analogues that can be obtained from internet retailers requires the implementation of appropriate monitoring strategies for harm reduction purposes. Access to analytical data plays a key part when encountering these substances, especially if reference material is not available. The present study describes the synthesis of three substituted 1-(1-phenylcyclohexyl)piperidines, (3-MeO-, 4-MeO- and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO- and 3-Me-PCPy). Analytical characterizations of all six arylcyclohexylamines and their primary 1-phenylcyclohexanamine intermediates included gas chromatography ion trap electron- and chemical ionization and high resolution mass spectrometry, liquid chromatography electrospray hybrid triple-quadrupole linear ion trap tandem mass spectrometry, infrared, diode array detection and (1) H and (13) C nuclear magnetic resonance (NMR) spectroscopy. Solvent (CDCl3 vs. d6 -DMSO) and protonation effects (free bases vs hydrochloride salts) were studied in order to investigate the impact on shifts and splitting patterns, for example, when attempting to assign separate axial and equatorial proton chemical shifts of NMR spectra. Differentiation between the isomeric 3-MeO-/4-MeO-PCP and PCPy analogues was feasible under mass spectral conditions. Gas chromatography analysis appeared to induce notable degradation of the 4-MeO-substituted analytes, especially when dealing with the HCl salts which led to the detection of the substituted 1-phenylcyclohex-1-ene nucleus. This phenomenon was observed to be less pronounced with the 3-MeO isomers, possibly due to the resonance properties of the para-methoxy group followed by more facile elimination of the amine. Copyright © 2013

  18. Antinociceptive properties of N-Mannich bases derived from 3-substituted pyrrolidine-2,5-dione in the formalin model of persistent pain in mice.

    PubMed

    Obniska, Jolanta; Sałat, Kinga; Librowski, Tadeusz; Kamiński, Krzysztof; Lipkowska, Anna; Wiklik, Beata; Rybka, Sabina; Rapacz, Anna

    2015-02-01

    Accumulated data indicate that anticonvulsants possess antinociceptive properties in rodent pain models. In view of the anticonvulsant activity demonstrated previously among N-Mannich bases derived from 3-mono- (1-6) and 3,3-disubstituted pyrrolidine-2,5-diones (7-14) their analgesic activity has been investigated in the formalin model of tonic pain in mice. The compounds 1-14 were tested at doses equal to the respective ED50 values obtained earlier in the MES test. 0.5% formalin solution was given as intraplantar injections into the hind paw of the mouse and the duration of the nocifensive response was counted in drug-treated and vehicle-treated animals in the acute and the late phases of the test. A significant antinociceptive activity was observed for majority of the compounds. In the first phase of the test all the active compounds, except for 9-11, reduced the duration of the licking response up to 88% (compounds 2 and 6; p<0.001). In the late phase the 1-3, 5, 6, 9 and 14 were the most effective agents and their analgesic activities ranged from 92 to 100%. The results of the research indicate that some of the investigated compounds reduced effectively either both phases of the test or were able to attenuate pain during only the acute or late phase of the formalin test. These properties, which are particularly strong in case of the compounds 1-3, 5, 6, 9 and 14, might be relevant for the development of novel analgesic-active compounds and their possible use in neuropathic pain syndromes. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Comment on "Structural and vibrational studies on 1-(5-Methyl- [1,3,4] thiadiazol-2-yl)-pyrolidin-2-ol" [Spectrochimica Acta Part A, 152 (2016) 252-261]. The importance of intramolecular OH ⋯ N hydrogen bonding in the conformational properties of thiadiazol-pyrrolidin-2-ol bearing species

    NASA Astrophysics Data System (ADS)

    Laurella, Sergio L.; Erben, Mauricio F.

    2016-07-01

    The title paper [1] reports a study on the spectroscopic and physicochemical properties of 1-(5-methyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (MTPN) based on experimental and theoretical data. The latter ones are based on the computed molecular structure for a rather unusual conformer. Here, after a careful analysis of the conformational space of MTPN, the most stable conformation was determined for the molecule isolated in a vacuum, which results to be 21.9 kJ/mol more stable than the conformer reported previously. Our study also includes the closely related species 1-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (FMTPN). An intramolecular OH ⋯ N hydrogen bond determines the conformational behavior of the [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol group as demonstrated by Natural Bond Orbital population analysis.

  20. Comment on "Structural and vibrational studies on 1-(5-Methyl- [1,3,4] thiadiazol-2-yl)-pyrolidin-2-ol" [Spectrochimica Acta Part A, 152 (2016) 252-261]. The importance of intramolecular OH⋯N hydrogen bonding in the conformational properties of thiadiazol-pyrrolidin-2-ol bearing species.

    PubMed

    Laurella, Sergio L; Erben, Mauricio F

    2016-07-05

    The title paper [1] reports a study on the spectroscopic and physicochemical properties of 1-(5-methyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (MTPN) based on experimental and theoretical data. The latter ones are based on the computed molecular structure for a rather unusual conformer. Here, after a careful analysis of the conformational space of MTPN, the most stable conformation was determined for the molecule isolated in a vacuum, which results to be 21.9kJ/mol more stable than the conformer reported previously. Our study also includes the closely related species 1-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (FMTPN). An intramolecular OH⋯N hydrogen bond determines the conformational behavior of the [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol group as demonstrated by Natural Bond Orbital population analysis.

  1. beta-2,2-Amino Acid N-Carboxy Anhydrides Relying on Sequential Enantioselective C(4)-Functionalization of Pyrrolidin-2,3-diones and Regioselective Baeyer-Villiger Oxidation.

    PubMed

    Palomo, Claudio; Mielgo, Antonia; Olaizola, Iurre; Vázquez, Ana; Badiola, Eider; Vera, Silvia

    2017-02-28

    A catalytic enantioselective entry to beta-2,2-amino acids enabling their direct coupling with nucleophiles is described. The approach is based upon an effective bifunctional Brønsted base catalyzed construction of a quaternary carbon stereocenter at C4 position of pyrrolidin-2,3-diones. Subsequent regioselective Baeyer-Villiger oxidation of the resultant adducts gives beta-2,2-amino acid N-carboxy anhydrides as the reactive species, which can further react with nucleophiles. Following this strategy both, 2,2-amino acid derivatives with different functionalities at the newly created stereocenter, and spirocyclic structures can be efficiently prepared.

  2. Exposure to Glyphosate- and/or Mn/Zn-Ethylene-bis-Dithiocarbamate-Containing Pesticides Leads to Degeneration of γ-Aminobutyric Acid and Dopamine Neurons in Caenorhabditis elegans

    PubMed Central

    Negga, Rekek; Stuart, J Andrew; Machen, Morgan L; Salva, Joel; Lizek, Amanda J; Richardson, S Jayne; Osborne, Amanda S; Mirallas, Oriol; McVey, Kenneth A; Fitsanakis, Vanessa A

    2011-01-01

    Previous studies demonstrate a positive correlation between pesticide usage and Parkinson’s disease (PD), which preferentially targets dopaminergic (DAergic) neurons. In order to examine the potential relationship between two common pesticides and specific neurodegeneration, we chronically (24 hours) or acutely (30 min) exposed two Caenorhabditis elegans (C. elegans) strains to varying concentrations (LC25, LC50 or LC75) of TouchDown® (TD) as per cent active ingredient (glyphosate), or Mancozeb® (MZ) as per cent active ingredient (manganese/zinc ethylene-bis-dithiocarbamate). Furthermore, to more precisely model environmental exposure, worms were also exposed to TD for 30 min, followed by 30-min incubation with varying MZ concentrations. Previous data from out lab suggested general neuronal degeneration using the worm strain NW1229 (pan-neuronal::green fluorescent protein (GFP) construct). To determine whether distinct neuronal groups were preferentially affected, we specifically used EG1285 (GABAergic neurons::GFP construct) and BZ555 (DAergic neurons::GFP construct) worms to verify GABAergic and DAergic neurodegeneration, respectively. Results indicated a statistically significant decrease, when compared to controls (CN), in number of green pixels associated with GABAergic neurons in both chronic (*p < 0.05) and acute (*p < 0.05) treatment paradigms. Analysis of the BZ555 worms indicated a statistically significant decrease (*p < 0.05) in number of green pixels associated with DAergic neurons in both treatment paradigms (chronic and acute) when compared to CN. Taken together, our data suggest that exposure to TD and/or MZ promotes neurodegeneration in both GABAergic and DAergic neurons in the model organism C. elegans. PMID:21922334

  3. Exposure to glyphosate- and/or Mn/Zn-ethylene-bis-dithiocarbamate-containing pesticides leads to degeneration of γ-aminobutyric acid and dopamine neurons in Caenorhabditis elegans.

    PubMed

    Negga, Rekek; Stuart, J Andrew; Machen, Morgan L; Salva, Joel; Lizek, Amanda J; Richardson, S Jayne; Osborne, Amanda S; Mirallas, Oriol; McVey, Kenneth A; Fitsanakis, Vanessa A

    2012-04-01

    Previous studies demonstrate a positive correlation between pesticide usage and Parkinson's disease (PD), which preferentially targets dopaminergic (DAergic) neurons. In order to examine the potential relationship between two common pesticides and specific neurodegeneration, we chronically (24 h) or acutely (30 min) exposed two Caenorhabditis elegans (C. elegans) strains to varying concentrations (LC(25), LC(50) or LC(75)) of TouchDown(®) (TD) as percent active ingredient (glyphosate), or Mancozeb(®) (MZ) as percent active ingredient (manganese/zinc ethylene-bis-dithiocarbamate). Furthermore, to more precisely model environmental exposure, worms were also exposed to TD for 30 min, followed by 30-min incubation with varying MZ concentrations. Previous data from out lab suggested general neuronal degeneration using the worm strain NW1229 (pan-neuronal//green fluorescent protein (GFP) construct). To determine whether distinct neuronal groups were preferentially affected, we specifically used EG1285 (GABAergic neurons//GFP construct) and BZ555 (DAergic neurons//GFP construct) worms to verify GABAergic and DAergic neurodegeneration, respectively. Results indicated a statistically significant decrease, when compared to controls (CN), in number of green pixels associated with GABAergic neurons in both chronic (*P < 0.05) and acute (*P < 0.05) treatment paradigms. Analysis of the BZ555 worms indicated a statistically significant decrease (*P < 0.05) in number of green pixels associated with DAergic neurons in both treatment paradigms (chronic and acute) when compared to CN. Taken together, our data suggest that exposure to TD and/or MZ promotes neurodegeneration in both GABAergic and DAergic neurons in the model organism C. elegans.

  4. Disruption of the hypothalamic-pituitary-thyroid axis on co-exposures to dithiocarbamate and neonicotinoid pesticides: Study in a wildlife bird, Amandava amandava.

    PubMed

    Pandey, Surya Prakash; Mohanty, Banalata

    2017-05-01

    Non-target organisms, including human and wildlife, are susceptible to deleterious effects of pesticide mixtures in their environment. Present study demonstrated the disruption of the hypothalamic-pituitary-thyroid (HPT) axis in a seasonally breeding wildlife bird Amandava amandava on co-exposure to dithiocarbamate mancozeb/MCZ and neonicotinoid imidacloprid/IMI, at concentrations even lower than respective environmentally realistic exposure level of each of the pesticide. Adult male birds (n=8/group) were exposed individually to 0.25% LD50 of each of MCZ (0.14mg) and IMI (2.75μl) followed by co-exposure to their equimixture as MIX-I (0.25% LD50 of each) and MIX-II (0.5% LD50 of each) through food for 30d in preparatory phase of reproductive cycle. Disruptions of thyroid gland and pituitary-thyroid axis were evident. Altered thyroid weight and volume, follicles with inactive colloids and lesions, decrease of height and nucleus-to-cytoplasm ratio of follicular epithelial cells were noted. Plasma levels of T4 and T3 were decreased, more significant in mixture groups than in individually exposed groups. Within co-exposed groups, comparatively high plasma T4 and T3 levels in MIX-II than MIX-I indicated dose non-responsiveness of the pesticides in mixtures; a characteristic displayed by endocrine disrupters. Plasma TSH level was increased in MCZ- and IMI- but decreased in MIX-I and MIX-II suggesting the disruption of the negative feedback and impairment of the HPT axis in co-exposed groups. Effects were more prominent in co-exposed groups due to combinatorial action and cumulative toxicity of pesticides. Considering the role of thyroid hormones in reproductive development, pesticides even in low dose could affect the thyroid homeostasis and reproductive axis. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Technetium-99m and rhenium-188 complexes with one and two pendant bisphosphonate groups for imaging arterial calcification.

    PubMed

    Bordoloi, Jayanta Kumar; Berry, David; Khan, Irfan Ullah; Sunassee, Kavitha; de Rosales, Rafael Torres Martin; Shanahan, Catherine; Blower, Philip J

    2015-03-21

    The first (99m)Tc and (188)Re complexes containing two pendant bisphosphonate groups have been synthesised, based on the mononuclear M(v) nitride core with two dithiocarbamate ligands each with a pendant bisphosphonate. The structural identity of the (99)Tc and stable rhenium analogues as uncharged, mononuclear nitridobis(dithiocarbamate) complexes was determined by electrospray mass spectrometry. The (99m)Tc complex showed greater affinity for synthetic and biological hydroxyapatite, and greater stability in biological media, than the well-known but poorly-characterised and inhomogeneous bone imaging agent (99m)Tc-MDP. It gave excellent SPECT images of both bone calcification (mice and rats) and vascular calcification (rat model), but the improved stability and the availability of two pendant bisphosphonate groups conferred no dramatic advantage in imaging over the conventional (99m)Tc-MDP agent in which the bisphosphonate group is bound directly to Tc. The (188)Re complex also showed preferential uptake in bone. These tracers and the biological model of vascular calcification offer the opportunity to study the biological interpretation and clinical potential of radionuclide imaging of vascular calcification and to deliver radionuclide therapy to bone metastases.

  6. Crystal structure of methyl 3′-benzamido-4′-(4-meth­oxy­phen­yl)-1′-methyl­spiro­[indeno­[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carboxyl­ate

    PubMed Central

    Chandralekha, Kuppan; Sureshbabu, Adukamparai Rajukrishnan; Gavaskar, Deivasigamani; Lakshmi, Srinivasakannan

    2016-01-01

    In the title compound, C35H30N4O3, the spiro C atom connects the five-membered pyrrolidine ring and the indeno­quinoxaline ring system. The pyrrolidine ring adopts a twist conformation. An intra­molecular N—H⋯N inter­action between the amino group and the pyrazine ring is observed. In the crystal, mol­ecules are linked by a pairs of C—H⋯O hydrogen bonds, forming inversion dimers. PMID:27920911

  7. Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and its 3-methyl-, 3-isopropyl, and 3-benzhydryl analogs.

    PubMed

    Rybka, Sabina; Obniska, Jolanta; Rapacz, Anna; Filipek, Barbara; Żmudzki, Paweł

    2017-03-15

    The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-[{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED50=41.0mg/kg), scPTZ (ED50=101.6kg/mg), and 6Hz (ED50=45.42mg/kg) tests. This compound displayed more beneficial protection index (PI) than antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. In vitro studies for compound 15 were conducted and provided information that its possible mechanism of action is related to blocking of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. A DFT study on PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles for the formation of functionalized pyrrolidines: mechanisms, selectivities, and the role of catalysts.

    PubMed

    Zheng, Linjie; Tang, Mingsheng; Wang, Yang; Guo, Xiaokang; Wei, Donghui; Qiao, Yan

    2016-03-21

    The mechanisms and chemo- and stereo-selectivities of PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles leading to functionalized pyrrolidines (5-endo-trig cyclization, Mechanism A) and their competing reaction leading to another kind of pyrrolidine (5-exo-trig cyclization, Mechanism B) have been investigated using density functional theory (DFT). Multiple possible reaction pathways associated with four different isomers (RR, SR, RS, and SS) for Mechanism A, and two isomers (R and S) for Mechanism B have been studied. The calculated results indicate that the Gibbs free energy barriers of Mechanism A are remarkably lower than those of Mechanism B, and the reaction pathway leading to the RS-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experiments. A C-H···π interaction has been identified to be responsible for the favorability of RS isomers by non-covalent interaction (NCI) analysis. Moreover, global reaction indexes (GRIs) and NBO analyses confirm that PBu3 acts as a Lewis base to strengthen the nucleophilicity of the reaction active site. The mechanistic insights gained in the present study should be valuable for the rational design of effective organocatalysts for this kind of reaction with high chemo- and stereo-selectivities.

  9. Larvicidal activity of isolated compound 5-(2,4-dimethylbenzyl) pyrrolidin-2-one from marine Streptomyces VITSVK5 sp. against Rhipicephalus (Boophilus) microplus, Anopheles stephensi, and Culex tritaeniorhynchus.

    PubMed

    Saurav, Kumar; Rajakumar, Govindasamy; Kannabiran, Krishnan; Rahuman, Abdul Abdul; Velayutham, Kanayairam; Elango, Gandhi; Kamaraj, Chinnaperumal; Zahir, Abdul Abduz

    2013-01-01

    The aim of the present study was to assess the larvicidal property of marine actinobacterial compound 5-(2,4-dimethylbenzyl) pyrrolidin-2-one (DMBPO) extracted and isolated from Streptomyces VITSVK5 sp. tested against the larvae of Rhipicephalus (Boophilus) microplus Canestrini (Acari: Ixodidae), Anopheles stephensi Liston, and Culex tritaeniorhynchus Giles (Diptera: Culicidae). The isolate bacteria was taxonomically characterized, identified, and designated as Streptomyces VITSVK5 sp. The crude extract was loaded on silica gel column and eluted with chloroform:methanol. The isolated pure compound was analyzed by thin layer chromatography using chloroform and methanol as the solvent system and confirmed by high-performance liquid chromatography. The structure of the purified compound was established from infrared, ultraviolet, (1)H-nuclear magnetic resonance (NMR), (13)C-NMR, and mass spectral data. The chemical shift assignments obtained for the aliphatic compound from (1)H-NMR corresponding to the molecular formula C(13)H(17)NO. Bioassay-guided fractionation led to the isolation of compound which was identified as DMBPO. In the present study, Streptomyces VITSVK5 sp. crude extract and different fractions were tested against the larvae of parasites at the concentration of 1,000 ppm. Those fractions showing 100% mortality in 24 h alone was selected for further column chromatographic separation. The purified compound, C(13)H(17)NO, was tested in the concentrations of 500, 250, 125, 62.5, and 31.25 ppm and observed the percent larval mortality of 100, 70, 64, 40, and 28 against R. microplus; 100, 79, 63, 36, and 22 against A. stephensi; and 100, 84, 67, 42, and 27 against C. tritaeniorhynchus, respectively. The crude extract showed parasitic effects after 24 h of exposure at 1,000 ppm, and parasite mortality was observed against the larvae of R. microplus (LC(50) = 210.39 ppm, r (2) = 0.873); A. stephensi (LC(50) = 169.38 ppm, r (2) = 0

  10. Selective Nuclear Factor Kappa b (NFkB) Inhibitor, Pyrrolidium Dithiocarbamate Prevents, Long-Term Histologic Damage in Ischemia-Reperfusion Injuries after Delayed Testicular Torsion.

    PubMed

    Ozcan, Levent; Otunctemur, Alper; Polat, Emre Can; Ozbek, Emin; Kirecci, Sinan Levent; Somay, Adnan

    2016-06-28

    Nuclear factor kapa b (NFKB) is a transcription factor that is required for cytokine-mediated induction of the human inducible nitric oxide synthase (iNOS) gene. Recent studies have shown that in the pathophysiology of ischemia-reperfusion (IR) injuries NFKB is involved. In our study we aimed to determine the efficacy of the selective NFKB inhibitor, pyrrolidium dithiocarbamate (PDTC), on long-term histological damage in testicular IR injuries. Twenty-one adult male Wistar albino rats were divided into 3 equal groups. In groups 1-2, the left testes in rats underwent 4 hours of 720° experimental torsion. In group 2, PDTC (100 mg/kg) was administered intraperitoneally in the last 1 hour before detorsion; and group 3 underwent a sham operation. All rats underwent bilateral orchiectomy 45 days after the experiment. The testes weights were measured and compared to the other groups and their contralateral values. Testes samples were fixed with Bouin solution for histological (Johnsen score) and immunohistochemical examination. Immunohistochemically iNOS and an active subunit of NFKB, p65 were evaluated using mouse primary monoclonal antibodies and were evaluated semi quantitatively. Testicular weights and Johnsen scores in ipsilateral testes were 0.67 ± 0.85, 1.54 ± 0.11, 1.84 ± 0.64 and 1.63 (1-4), 6.94 (4-10), 5.29 (1-9) in the torsion, sham and PDTC groups, respectively. In contralateral testes the same values were 1.74 ± 0.84, 1.59 ± 0.13, 1.50 ± 0.54 and 5.38 (2-8), 7.17 (5-10), 6.30 (4-9). Testicular weights and Johnsen scores were significantly different in the ipsilateral torsion group (P < .05). In the PDTC group testicular weights and Johnsen scores were similar with the control group (P > .05). Immunohistochemically there was marked staining in the iNOS and p65 expressions in the torsion group compared with group 2 and 3. In rats administered PDTC, iNOS and p65 expressions were significantly reduced compared

  11. Speciation of inorganic arsenic in drinking water by wavelength-dispersive X-ray fluorescence spectrometry after in situ preconcentration with miniature solid-phase extraction disks.

    PubMed

    Hagiwara, Kenta; Inui, Tetsuo; Koike, Yuya; Aizawa, Mamoru; Nakamura, Toshihiro

    2015-03-01

    A rapid and simple method using wavelength-dispersive X-ray fluorescence (WDXRF) spectrometry after in situ solid-phase extraction (SPE) was developed for the speciation and evaluation of the concentration of inorganic arsenic (As) in drinking water. The method involves the simultaneous collection of As(III) and As(V) using 13 mm ϕ SPE miniature disks. The removal of Pb(2+) from the sample water was first conducted to avoid the overlapping PbLα and AsKα spectra on the XRF spectrum. To this end, a 50 mL aqueous sample (pH 5-9) was passed through an iminodiacetate chelating disk. The filtrate was adjusted to pH 2-3 with HCl, and then ammonium pyrrolidine dithiocarbamate solution was added. The solution was passed through a hydrophilic polytetrafluoroethylene filter placed on a Zr and Ca loaded cation-exchange disk at a flow rate of 12.5 mL min(-1) to separate As(III)-pyrrolidine dithiocarbamate complex and As(V). Each SPE disk was affixed to an acrylic plate using adhesive cellophane tape, and then examined by WDXRF spectrometry. The detection limits of As(III) and As(V) were 0.8 and 0.6 μg L(-1), respectively. The proposed method was successfully applied to screening for As speciation and concentration evaluation in spring water and well water.

  12. Optimization of Phenyl-Substituted Benzimidazole Carboxamide Poly(ADP-Ribose) Polymerase Inhibitors: Identification of (S)-2-(2-Fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a Highly Potent and Efficacious Inhibitor

    SciTech Connect

    Penning, Thomas D.; Zhu, Gui-Dong; Gong, Jianchun; Thomas, Sheela; Gandhi, Viraj B.; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Johnson, Eric F.; Park, Chang H.; Fry, Elizabeth H.; Donawho, Cherrie K.; Frost, David J.; Buchanan, Fritz G.; Bukofzer, Gail T.; Rodriguez, Luis E.; Bontcheva-Diaz, Velitchka; Bouska, Jennifer J.; Osterling, Donald J.; Olson, Amanda M.; Marsh, Kennan C.; Luo, Yan; Giranda, Vincent L.

    2010-06-21

    We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K{sub i} of 1 nM and an EC{sub 50} of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

  13. DFT calculations of the tautomerization and NLO properties of 5-amino-7-(pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8-carbonitrile (APNC)

    NASA Astrophysics Data System (ADS)

    Wazzan, Nuha; Safi, Zaki

    2017-09-01

    Amine-imine tautomerization in 5-amino-7-(pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8-carbonitrile (APNC) has been studied using the B3LYP, CAM-B3LYP and ωB97XD with 6-311++G(d,p) basis set. Optimum molecular geometries, electronic properties, energetics and electronic densities of these systems have been discussed and compared with the available experimental data. Investigation reveals that one tautomer (the amine tautomer) dominates the gas phase. The photochromic properties of APNC and its two imine tautomers have been studied at the elected DFT-functionals and basis set. The interconversion A1 to I2/I3 is predicted to occur photochemically. The NLO properties were also evaluated and discussed.

  14. Crystal structure of N-(7-di­bromo­methyl-5-methyl-1,8-naphthyridin-2-yl)benzamide–pyrrolidine-2,5-dione (1/1)

    PubMed Central

    Wang, Bang Zhong; Zhou, Jun Ping; Zhou, Yong; Luo, Jian Song; Yang, Jun Jie; Chi, Shao M.ing

    2017-01-01

    The title compound, C17H13Br2N3O·C4H5NO2, is a co-crystal of N-(7-di­bromo­methyl-5-methyl-1,8-naphthyridin-2-yl)benzamide and pyrrolidine-2,5-dione (succinimide). The benzamide mol­ecule exhibits pseudo-mirror symmetry, with an r.m.s. deviation of the non-H atoms of 0.09 Å (except for the two Br atoms). The angle between the least-squares planes of the two mol­ecules is 26.2 (2)°. In the crystal, the two mol­ecules are mutually linked by N—H⋯O and N—H⋯N hydrogen bonds. The packing is consolidated by C—H⋯(O,N) hydrogen bonds and π–π stacking inter­actions. PMID:28083121

  15. 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

    2013-08-05

    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.

  16. (1R*,3′S*,4′R*)-4′-(4-Chloro­phen­yl)-3′-[(4-hy­droxy-2-oxo-1,2-dihydro­quinolin-3-yl)carbon­yl]-1′-methyl­spiro­[ace­naphthyl­ene-1,2′-pyrrolidin]-2-one

    PubMed Central

    Vennila, K. N.; Sankaran, M.; Mohan, P. S.; Velmurugan, D.

    2011-01-01

    The title compound, C32H23ClN2O4, has a quinoline, a chloro­phenyl and an acenaphthalene ring system attached to a central pyrrolidine ring, which has three stereogenic centers. Nevertheless, the compound crystallizes as a racemate with two mol­ecules of identical chirality in the asymmetric unit. They differ in the conformation of the five-membered pyrrolidine ring; in one molecule it has an envelope conformation, while in the other molecule it has a twisted conformation. In each molecule there is an intra­molecular O—H⋯O hydrogen bond making an S(6) ring motif. In the crystal, pairs of N—H⋯O hydrogen bonds produce inversion dimers with R 2 2(8) motifs. There are also C—H⋯O interactions present. The crystal structure contains voids (60 Å3) within which there is no evidence of solvent mol­ecules. PMID:22199868

  17. Discovery of a factor Xa inhibitor (3R,4R)-1-(2,2-difluoro-ethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloro-pyridin-2-yl)-amide] 4-[[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide] as a clinical candidate.

    PubMed

    Anselm, Lilli; Banner, David W; Benz, Jörg; Zbinden, Katrin Groebke; Himber, Jacques; Hilpert, Hans; Huber, Walter; Kuhn, Bernd; Mary, Jean-Luc; Otteneder, Michael B; Panday, Narendra; Ricklin, Fabienne; Stahl, Martin; Thomi, Stefan; Haap, Wolfgang

    2010-09-01

    A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized. Copyright 2010 Elsevier Ltd. All rights reserved.

  18. Crystal structure of 4′-(2-meth­oxy­quinolin-3-yl)-1′-methyl­dispiro­[indan-2,2′-pyrrolidine-3′,3′′-indoline]-1,3,2′′-trione

    PubMed Central

    Mathusalini, Sadasivam; Viswanathan, Vijayan; Mohan, Palathurai Subramaniam; Lin, Chia-Her; Velmurugan, Devadasan

    2015-01-01

    In the title compound, C30H23N3O4, the central 1-methyl­pyrrolidine ring adopts a twist conformation on the N—CH2 bond. The pyrrolidin-2-one ring of the indolin-2-one ring system also has a twist conformation on the C—C bond involving the spiro C atom and the carbonyl C atom. The five-membered ring of the indene-1,3-dione moiety has an envelope conformation with the spiro C atom as the flap. The quinoline ring system adopts an almost planar conformation (r.m.s. deviation = 0.04 Å). The mean planes of the indolin-2-one ring system, the indene-1,3-dione ring system and the the quinoline ring system are inclined to the mean plane of the central 1-methyl­pyrrolidine ring by 77.97 (7), 86.98 (7) and 46.58 (6)°, respectively. In the crystal, mol­ecules are linked via N—H⋯N hydrogen bonds, forming chains along the b axis. The chains are linked via a number of C—H⋯O hydrogen bonds, and C—H⋯π and π–π inter­actions [inter-centroid distance = 3.7404 (9) Å], forming a three-dimensional network. PMID:26870486

  19. 4′-(1H-Imidazol-2-yl)-3′-[(1H-indol-3-yl)carbon­yl]-1′-methyl-2-oxo­spiro­[indoline-3,2′-pyrrolidine]-3′-carbo­nitrile 0.15-hydrate

    PubMed Central

    Inglebert, S. Antony; Arun, Yuvaraj; Sethusankar, K.; Perumal, Paramasivam T.

    2013-01-01

    In the title compound, C25H20N6O2·0.15H2O, the dihedral angles between the least-squares planes of the indole and pyrrolidine rings and between the oxindole and imidazole rings are 77.66 (7) and 45.31 (7)°, respectively. The pyrrolidine ring and the fused five-membered pyrrolidine ring of the oxindole moiety exhibit twisted conformations. The amide N atom is involved in both intra- and inter­molecular hydrogen bonding, having a bifurcated character. The mol­ecular structure is characterized by an intra­molecular N—H⋯O hydrogen bond, which generates an S(7) ring motif while an inter­molecular N—H⋯O hydrogen bond links the organic and solvent water mol­ecules. In the crystal, N—H⋯N hydrogen bonds generate a zigzag chain running parallel to c-axis direction. The H atoms of the solvent water mol­ecule were not located. PMID:24427102

  20. Formation of mono(dithiolene)-thiocarboxamido complexes in reactions of thio(dithiocarbamato)-Mo/W complexes and dimethyl acetylenedicarboxylate.

    PubMed

    Lim, Patrick J; Slizys, Damian A; Tiekink, Edward R T; Young, Charles G

    2005-01-10

    Reactions of TpMS(S(2)CNEt(2)) with dimethyl acetylenedicarboxylate in dichloromethane produce olive green/black TpM{S(2)C(2)(CO(2)Me)(2)}(SCNEt(2)-kappa(2)S,C) (M = Mo (1), W (2); Tp = hydrotris(3,5-dimethylpyrazol-1-yl)borate). The seven-coordinate complexes exhibit pseudo-octahedral (1) and distorted pentagonal bipyramidal (2) coordination spheres comprised of tridentate fac-Tp, bidentate dithiolene, and thiocarboxamido-kappa(2)S,C ligands. In the solid state, molecules of 1 exhibit pseudo-C(s)() symmetry, with the thiocarboxamide NEt(2) group in a cleft in the Tp ligand. Molecules of 2 have C(1) symmetry in the solid state; here, the thiocarboxamide unit is orientated along one of the W-S(dithiolene) bonds with its NEt(2) group projecting away from the Tp ligand. Both complexes possess effective C(s)() symmetry in solution. Reaction of TpMoI(CO)(3) with AgS(2)CNEt(2) affords olive green TpMo(S(2)CNEt(2))(CO)(2) (3), which reacts with propylene sulfide in a new synthesis for TpMoS(S(2)CNEt(2)), the starting material for 1. Complex 3 exhibits a distorted pentagonal bipyramidal structure, the axial sites being defined by a Tp nitrogen atom and a carbonyl ligand, the pentagonal plane by the remaining nitrogen and carbonyl donors and the two sulfur atoms of the bidentate dithiocarbamate ligand.

  1. 5-(4-Chloro­phen­yl)-7-(4-methyl­phen­yl)-4-(pyrrolidin-1-yl)-7H-pyrrolo­[2,3-d]pyrimidine

    PubMed Central

    Patel, Urmila H.; Modh, Rajesh D.; Shah, Dhaval A.

    2013-01-01

    The title compound, C23H21ClN4, contains two molecules (A and B) in the asymmetric unit, which are related to one another by a pseudo-inversion center. The non-aromatic pyrrolidine ring in each independent mol­ecule adopts a half-chair conformation; the ring puckering parameters are θ = 0.407 (3) Å and ϕ = 270.5 (4)°, and the pseudo-rotation parameters are ρ = 72.5 (3)° and τ = 42.2 (2)° for an N—C bond of molecule A, and the corresponding values are 0.415 (3) Å, 271.6 (4)°, 73.6 (3)° and 42.6 (2)° for molecule B. The dihedral angles between the central fused-ring system and the substituted chlorophenyl and methylphenyl rings are 66.35 and 45.59°, respectively, for molecule A, and 64.51 and 41.89° for molecule B. The geometry of all four intramolecular C—H⋯π interactions are of type III. π–π interactions involving the centroids of symmetry-related pyrrole rings of molecule B are 4.390 Å, contributing further to the stability of the molecule. PMID:24109367

  2. Synthesis and evaluation of new dithiocarbamic acid 6,11-dioxo-6,11-dihydro-1H-anthra[1,2-d]-imidazol-2-yl methyl esters.

    PubMed

    Onder, Nur İpek; İncesu, Zerrin; Özkay, Yusuf

    2015-07-01

    A novel series of dithiocarbamic acid 6,11-dioxo-6,11-dihydro-1H-anthra[1,2-d]imidazol-2-yl methyl esters were synthesized and their cytotoxic and apoptotic activities were evaluated on HeLa cells. Some of these compounds showed potent cytotoxic activities and are able to induce the apoptosis mechanism in this cell line. Especially, 2c, 2d, and 2f had a high cytotoxic activity with an IC50 value of 8 or 10 μM at 24 h. These three compounds also induced HeLa cell apoptosis as compared to mitoxantrone. Particularly, 3 μM of 2f induced a high rate of early apoptotic cells (12.9%) at 6 h whereas mitoxantrone induced early apoptosis (5.5%) at 24 h. Compound 2c demonstrated a high ADP/ATP ratio (9.31) in HeLa cells at 12 h compared to mitoxantrone or other compounds, suggesting that 2c might induce HeLa cell apoptosis through the mitochondrial pathway. Caspase-3 activity started to increase after treatment with 6 μM of 2c for 6 h, and the maximal peak of activity was obtained at 12 h of incubation time. All three compounds were found to be potent apoptotic inducers compared to mitoxantrone. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Synthesis, characterization and biocidal activities of heterobimetallic complexes having tin(IV) as a padlock

    NASA Astrophysics Data System (ADS)

    Husain, Ahmad; Nami, Shahab A. A.; Siddiqi, K. S.

    2010-04-01

    A mononuclear precursor complex, [(CH 3) 2Sn(tpdtc)] and several of its heterobimetallic derivatives of the type, [(CH 3) 2Sn(tpdtc)]MCl 2 have been synthesized by the simple addition reaction of transition metal chlorides, MCl 2· nH 2O where tpdtc = tetraethylenepentamine bis(dithiocarbamate) anion, M = Fe(II), Co(II), Ni(II), Cu(II) and Zn(II). The synthesized complexes have been systematically characterized by the physicochemical and spectroscopic techniques. A square-pyramidal geometry has been proposed for all the transition metal atoms with chloride ions occupying the axial while the three nitrogen atoms occupying the equatorial positions. A symmetrical bidentate coordination has been observed for the dithiocarbamato moiety leading to the formation of 18 member cavity. The thermal studies reveal that the mononuclear complex decomposes in three stages while its heterobimetallic analog exhibits a simple two-stage profile. The conductivity measurement data (1 mmol solution) implies a non-electrolytic behavior for all the complexes as evident by their low conductivity values obtained at room temperature. The heterobimetallic complexes have also been tested against the bacterial ( Escherichia coli and Pseudomonas aeruginosa) and antifungal strains ( Aspergillus niger and Fusarium oxysporum). All the complexes were found to be active against the test organisms and maximum activity was found for [(CH 3) 2Sn(tpdtc)]CuCl 2 complex.

  4. Investigation of the inhibiting action of O-, S- and N-dithiocarbamato(1,4,8,11-tetraazacyclotetradecane)cobalt(III) complexes on the corrosion of iron in HClO 4 acid

    NASA Astrophysics Data System (ADS)

    Babić-Samardžija, K.; Khaled, K. F.; Hackerman, N.

    2005-02-01

    The inhibiting properties of four macrocyclic cobalt(III) complexes of the general formula [Co III(Rdtc)cyclam](ClO 4) 2, where cyclam and Rdtc- refer to 1,4,8,11-tetraazacyclotetradecane and morpholine-, thiomorpholine-, piperazine-, N-methylpiperazine-dithiocarbamates, respectively, has been studied on the corrosion of iron in aerated 0.1 M HClO 4 solutions by potentiodynamic polarization (dc) technique and electrochemical impedance spectroscopy (ac). Inhibitor efficiency for the corrosion of iron is found to be better for cobalt complexes then for related amino-ligands. The impedance increases with inhibitor concentration. Polarization curves indicate that the inhibitors are predominantly mixed-type. Better protection by the complex inhibitors was obtained with longer immersion time. The best fit for inhibitors adsorption is obtained using the Langmuir isotherm model. Molecular modeling calculations were used to correlate structural properties of the complex species and their inhibition efficiency.

  5. Asymmetric epoxidation of unsaturated ketones catalyzed by heterobimetallic rare earth-lithium complexes bearing phenoxy-functionalized chiral diphenylprolinolate ligand.

    PubMed

    Qian, Qinqin; Tan, Yufang; Zhao, Bei; Feng, Tao; Shen, Qi; Yao, Yingming

    2014-09-05

    Four novel heterobimetallic complexes [REL2]{[(THF)3Li]2(μ-Cl)} stabilized by chiral phenoxy-functionalized prolinolate (RE = Yb (1), Y (2), Sm (3), Nd (4), H2L = (S)-2,4-di-tert-butyl-6-[[2-(hydroxydiphenylmethyl)pyrrolidin-1-yl]methyl]phenol have been synthesized and characterized. These readily available complexes are highly active in catalyzing the epoxidation of α,β-unsaturated ketones, while the enantioselectivity varies according to the ionic radii of the rare earth center. A series of chalcone derivatives were converted to chiral epoxides in 80 → 99% ee at 0 °C using TBHP as the oxidant in the presence of 10 mol % of 1.

  6. Redox reactivity of mononuclear and binuclear rhenium complexes

    SciTech Connect

    Holder, G.N.

    1988-01-01

    Six different classes of monomeric and dimeric rhenium complexes containing substituted nitriles, substituted pyridines, dithiocarbamates, and substituted phosphines as ligands were synthesized. Monomers had the general formula ReCl{sub 3} (NCR) (PPh{sub 3}){sub 2}, ReCl{sub 3}-(NCCH{sub 3})(P-(aryl-R){sub 3}){sub 2}, and ReOCl{sub 3} (P-(aryl-R){sub 3}){sub 2}. Dimers had the general formula Re{sub 2}Cl{sub 4} (dppm){sub 2} (NCR) and (Re{sub 2}Cl{sub 3}(dppm){sub 2}-(NCR){sub 2}){sup +} (dppm = bis(diphenylphosphino)methane) and Re{sub 2}O{sub 3}Cl{sub 4}-(py){sub 4}, where R was an alkyl or halogenated substituent chosen to systematically vary the donor-acceptor properties of the nitrile, pyridine, or phosphine ligand. The effects of this structural change on the function of the molecule was monitored both spectrally and electrochemically. Rate constants for addition of nitriles to the metal-metal bridged dimeric complex were found to vary linearly with the identity of the substitutent. Spectroscopic data followed these trends as well. The structure-function relationships derived from this work will aid in the design of future Technetium and Rhenium-based organ selective radioimaging agents.

  7. π donation and its effects on the excited-state lifetimes of luminescent platinum(II) terpyridine complexes in solution.

    PubMed

    Hight, Lauren M; McGuire, Meaghan C; Zhang, Yu; Bork, Matthew A; Fanwick, Phillip E; Wasserman, Adam; McMillin, David R

    2013-08-05

    Introducing electron-donating groups extends the excited-state lifetimes of platinum(II)-terpyridine complexes in fluid solution. Such systems are of interest for a variety of applications, viz., as DNA-binding agents or as components in luminescence-based devices, especially sensors. The complexes investigated here are of the form [Pt(4'-X-T)Y](+), where 4'-X-T denotes a 4'-substituted 2,2':6',2″-terpyridine ligand and Y denotes the coligand. The π-donating abilities of -X and -Y increase systematically in the orders -NHMe < -NMe2 < -(pyrrolidin-1-yl) and -CN < -Cl < -CCPh, respectively. The results presented include crystal structures of two new 4'-NHMe-T complexes of platinum, as well as absorption, emission, and excited-state lifetime data for nine complexes. Excited-state lifetimes obtained in deoxygenated dichloromethane vary by a factor of 100, ranging from 24 μs for [Pt(4'-pyrr-T)CN](+) to 0.24 μs for [Pt(4'-ma-T)Cl](+), where ma-T denotes 4'-(methylamino)-2,2':6',2″-terpyridine and pyrr-T denotes 4'-(pyrrolidin-1-yl)-2,2':6',2″-terpyridine. Analysis of experimental and computational results shows that introducing a simple amine group on the terpyridine and/or a π-donating coligand engenders the emitting state with intraligand charge-transfer (ILCT) and/or ligand-ligand charge-transfer (LLCT) character. The excited-state lifetime increases when the change in orbital parentage lowers the emission energy, suppresses quenching via d-d states, and encourages delocalization of the excitation onto the ligand(s). At some point, however, the energy is low enough that direct vibronic coupling to the ground-state surface becomes important, and the lifetime begins to decrease again.

  8. Comparison between 3-Nitrooxyphenyl acetylsalicylate (NO-ASA) and O2-(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA) as safe anti-inflammatory, analgesic, antipyretic, antioxidant prodrugs.

    PubMed

    Chattopadhyay, Mitali; Velazquez, Carlos A; Pruski, April; Nia, Kamran V; Abdellatif, Khaled R; Keefer, Larry K; Kashfi, Khosrow

    2010-11-01

    Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O(2)- (acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE(2) in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N

  9. Iodine catalyzed three component synthesis of 1-((2-hydroxy naphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives: Rationale as potent PI3K inhibitors and anticancer agents.

    PubMed

    Muralidharan, Vivek Panyam; Alagumuthu, Manikandan; Iyer, Sathiyanarayanan Kulathu

    2017-06-01

    A series of 1-((2-hydroxynaphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives by an efficient iodine catalyzed domino reaction involving various aromatic aldehydes, 2-pyrrolidinone and β-naphthol was achieved and the structures were elucidated by FTIR (1)H NMR, (13)C NMR, and HRMS. Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7), colon cancer (HCT116) cell lines. In the cytotoxicity, the relative inhibition activity was remarkably found to be high in MCF-7 cell lines as 79% (4c), 83% (4f) and the IC50values were 1.03µM (4c), 0.98µM (4f). Compounds 4a, 4e, 4k-m, and 4q were found to be inactive and rest showed a moderate activity. In order to get more insight into the binding mode and inhibitor binding affinity, compounds (4a-q) were docked into the active site phosphoinositide 3-kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results suggested that the hydrophobic interactions in the binding pockets of PI3K exploited affinity of the most favourable binding ligands (4c and 4f: inhibitory constant (ki)=66.22nM and 107.39nM). The SAR studies demonstrated that the most potent compounds are 4c and 4f and can be developed into precise PI3K inhibitors with the capability to treat various cancers. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Synthesis and biological evaluation of conformationally restricted 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenediam ines as sigma receptor ligands. 1. Pyrrolidine, piperidine, homopiperidine, and tetrahydroisoquinoline classes.

    PubMed

    de Costa, B R; Dominguez, C; He, X S; Williams, W; Radesca, L; Bowen, W

    1992-11-13

    The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using [3H](+)-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.

  11. Synthesis, spectral, single crystal X-ray structural, CShM and BVS characterization of iron(III) cyclohexyl dithiocarbamates and their solvothermal decomposition to nano iron(II) sulphide

    NASA Astrophysics Data System (ADS)

    Ramalingam, K.; Srinivasan, S.

    2015-11-01

    [Fe(chmdtc)3] (1), [Fe(chedtc)3] (2), [Fe(achdtc)3] (3) and [Fe(chpdtc)3] (4) (where chmdtc = cyclohexylmethylcarbodithioate, chedtc = cyclohexylethylcarbodithioate, achdtc = allylcyclohexylcarbodithioate and chpdtc = cyclohexylpiperazinecarbodithioate) have been prepared and characterisized by elemental analysis, electronic, IR spectral, magnetic susceptibility, thermogravimetric analysis. The single crystal X-ray crystal structures of [Fe(chedtc)3] (2)and [Fe(chpdtc)3] (4) have been determined. Characteristic thioureide IR bands occur at 1483, 1477, 1454 and 1479 cm-1 for (1), (2), (3) and (4) respectively. Electronic spectral bands at 514,512,510 and 510 nm for (1), (2), (3) and (4) respectively are due to dxy → dx2 - y2 transition. One electron quasi reversible reductions due to Fe(III)/Fe(II) redox process are observed in CV. Magnetic susceptibility measurements exhibit a temperature dependent variation. Final residue obtained in thermal processes is FeS, which indicates the reduction of Fe(III) → Fe(II). Single crystal X-ray structures of [Fe(chedtc)3] (2)and [Fe(chpdtc)3] (4) show that the central atom is in a distorted octahedral environment. The CShM values have been calculated from the structural data as 2.5807 and 3.2329 for (2) and (4) respectively in a scale of zero to hundred. The observed values show that compound (4) is relatively more distorted than (2) in its octahedral coordination due to the steric demands of the cyclohexyl ring attached to piperazine. Both of them prefer octahedral coordination environment over trigonal prism. Bond Valence Sum (BVS) calculations confirmed the oxidation state of iron as +3. A non conventional solvothermal formation of FeS nano particles is reported with iron dithiocarbamates as single source precursors. Morphology and composition of the nano product have been characterized by PXRD and EDX analysis.

  12. Intramolecular alkene aminopalladation reactions of (dppf)Pd(Ar)[N(Ar(1))(CH(2))(3)CH=CH(2)] complexes. insertion of unactivated alkenes into Pd-N bonds.

    PubMed

    Neukom, Joshua D; Perch, Nicholas S; Wolfe, John P

    2010-05-12

    The synthesis of (dppf)Pd(C(6)H(4)-p-F)[N(Ar(1))(CH(2))(3)CH horizontal lineCH(2)] complexes (3), which are thought to be intermediates in Pd-catalyzed alkene carboamination reactions, is described. These complexes undergo syn-migratory insertion of the alkene into the Pd-N bond to yield observable (dppf)palladium(aryl)(pyrrolidin-2-yl-methyl) complexes 6. Reductive elimination from 6 provides 2-benzylpyrrolidine derivatives 4. The rates of conversion of 3 to 6 (k(1)) and 6 to 4 (k(2)) were measured and are within 1 order of magnitude of each other. The syn-migratory insertion stereochemistry was confirmed through a deuterium labeling experiment. These are the first examples of syn-migratory insertions of unactivated alkenes into Pd-N bonds of well-defined complexes.

  13. Synthesis and biodistribution of a new 99mTc nitrido complex as a potential myocardial and cerebral imaging agent.

    PubMed

    Zhang, JunBo; Wang, XueBin; Li, ChunYun

    2002-06-01

    The bis(N-methyl, N-cyclohexyl dithiocarbamato) nitrido technetium-99m complex [99mTcN(MECHDTC)2] (MECHDTC: N-methyl, N-cyclohexyl dithiocarbamato) has been synthesized through a ligand-exchange reaction. The two-step procedure consisted of an initial reaction of 99mTcO4- with succinic dihydrazide in the presence of stannous chloride as reducing agent and propylenediamine tetraacetic acid as complexant, and successive addition of sodium salt of N-methyl, N-cyclohexyl dithiocarbamate. The radiochemical purity of the complex was over 90%, as measured by thin layer chromatography. No decomposition of the complex at room temperature was observed over a period of 6 h. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was neutral. Biodistribution in mice showed that the complex accumulated in the heart and brain with high uptake. The heart/blood, heart/lung and brain/blood ratios were 5.55, 2.11 and 1.10, respectively, at 30 min post-injection, suggesting that this compound is a potential myocardial and cerebral imaging agent.

  14. Uptake of dissolved organic carbon-complexed ⁶⁵Cu by the green mussel Perna viridis.

    PubMed

    Zhong, Huan; Evans, Douglas; Wang, Wen-Xiong

    2012-02-21

    Stable Cu isotope ((65)Cu) was complexed with various representative dissolved organic carbon (DOC) types, including coastal seawater DOC, fulvic acid (FA), cyanobacteria spirulina (SP) DOC, histidine (His), cysteine (Cys), and lipophilic diethyl dithiocarbamate (DDC) at different concentrations. The uptake of these dissolved Cu species by the coastal green mussel Perna viridis was quantified for the first time. Copper complexed with different DOC types were taken up in some measure by mussels, depending on the DOC types. However, complexation generally reduced Cu uptake as compared to that of inorganic Cu species, and DOC type-specific negative relationships were found between DOC levels and Cu uptake. Strong Cu binding sites (including His and organic sulfur functional groups) within DOC appeared to control the inhibitory effects of DOC on Cu uptake, possibly due to the competitive binding of Cu between the dissolved phase and biological membranes. Therefore, differences in strong Cu binding site levels may explain the differences in bioavailability of Cu complexed with different types of DOC. At the same time, the variations in Cu-DOC uptake may also be partly attributed to the absorption of Cu-DOC complexes, especially for the small Cu-DOC complexes (e.g., Cu-Cys, Cu-His, or Cu-DDC). Our study highlights the importance of considering the specificity of Cu-DOC complexes when assessing biological exposure to dissolved Cu in natural waters, especially during events, such as phytoplankton bloom periods, that could modify DOC composition and concentrations.

  15. Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis.

    PubMed

    Laskar, Sujay; Sánchez-Sánchez, Luis; López-Ortiz, Manuel; López-Muñoz, Hugo; Escobar-Sánchez, María L; Sánchez, Arturo T; Regla, Ignacio

    2017-12-01

    Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.

  16. Nicotine Dehydrogenase Complexed with 6-Hydroxypseudooxynicotine Oxidase Involved in the Hybrid Nicotine-Degrading Pathway in Agrobacterium tumefaciens S33.

    PubMed

    Li, Huili; Xie, Kebo; Yu, Wenjun; Hu, Liejie; Huang, Haiyan; Xie, Huijun; Wang, Shuning

    2016-01-04

    Nicotine, a major toxic alkaloid in tobacco wastes, is degraded by bacteria, mainly via pyridine and pyrrolidine pathways. Previously, we discovered a new hybrid of the pyridine and pyrrolidine pathways in Agrobacterium tumefaciens S33 and characterized its key enzyme 6-hydroxy-3-succinoylpyridine (HSP) hydroxylase. Here, we purified the nicotine dehydrogenase initializing the nicotine degradation from the strain and found that it forms a complex with a novel 6-hydroxypseudooxynicotine oxidase. The purified complex is composed of three different subunits encoded by ndhAB and pno, where ndhA and ndhB overlap by 4 bp and are ∼26 kb away from pno. As predicted from the gene sequences and from chemical analyses, NdhA (82.4 kDa) and NdhB (17.1 kDa) harbor a molybdopterin cofactor and two [2Fe-2S] clusters, respectively, whereas Pno (73.3 kDa) harbors an flavin mononucleotide and a [4Fe-4S] cluster. Mutants with disrupted ndhA or ndhB genes did not grow on nicotine but grew well on 6-hydroxynicotine and HSP, whereas the pno mutant did not grow on nicotine or 6-hydroxynicotine but grew well on HSP, indicating that NdhA and NdhB are responsible for initialization of nicotine oxidation. We successfully expressed pno in Escherichia coli and found that the recombinant Pno presented 2,6-dichlorophenolindophenol reduction activity when it was coupled with 6-hydroxynicotine oxidation. The determination of reaction products catalyzed by the purified enzymes or mutants indicated that NdhAB catalyzed nicotine oxidation to 6-hydroxynicotine, whereas Pno oxidized 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoylsemialdehyde pyridine. These results provide new insights into this novel hybrid pathway of nicotine degradation in A. tumefaciens S33.

  17. Nicotine Dehydrogenase Complexed with 6-Hydroxypseudooxynicotine Oxidase Involved in the Hybrid Nicotine-Degrading Pathway in Agrobacterium tumefaciens S33

    PubMed Central

    Li, Huili; Xie, Kebo; Yu, Wenjun; Hu, Liejie; Huang, Haiyan; Xie, Huijun

    2016-01-01

    Nicotine, a major toxic alkaloid in tobacco wastes, is degraded by bacteria, mainly via pyridine and pyrrolidine pathways. Previously, we discovered a new hybrid of the pyridine and pyrrolidine pathways in Agrobacterium tumefaciens S33 and characterized its key enzyme 6-hydroxy-3-succinoylpyridine (HSP) hydroxylase. Here, we purified the nicotine dehydrogenase initializing the nicotine degradation from the strain and found that it forms a complex with a novel 6-hydroxypseudooxynicotine oxidase. The purified complex is composed of three different subunits encoded by ndhAB and pno, where ndhA and ndhB overlap by 4 bp and are ∼26 kb away from pno. As predicted from the gene sequences and from chemical analyses, NdhA (82.4 kDa) and NdhB (17.1 kDa) harbor a molybdopterin cofactor and two [2Fe-2S] clusters, respectively, whereas Pno (73.3 kDa) harbors an flavin mononucleotide and a [4Fe-4S] cluster. Mutants with disrupted ndhA or ndhB genes did not grow on nicotine but grew well on 6-hydroxynicotine and HSP, whereas the pno mutant did not grow on nicotine or 6-hydroxynicotine but grew well on HSP, indicating that NdhA and NdhB are responsible for initialization of nicotine oxidation. We successfully expressed pno in Escherichia coli and found that the recombinant Pno presented 2,6-dichlorophenolindophenol reduction activity when it was coupled with 6-hydroxynicotine oxidation. The determination of reaction products catalyzed by the purified enzymes or mutants indicated that NdhAB catalyzed nicotine oxidation to 6-hydroxynicotine, whereas Pno oxidized 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoylsemialdehyde pyridine. These results provide new insights into this novel hybrid pathway of nicotine degradation in A. tumefaciens S33. PMID:26729714

  18. Vibrational Overtone Spectroscopy of Pyrrole and Pyrrolidine

    DTIC Science & Technology

    1991-05-23

    general pattern is a strong peak accompanied by two or three weaker peaks to lower energy. For instance, the 13,305 cm-I band in pyrrole has three weaker...Orza, J.M. Anales de Quimica 1984, 80, 59. 29. Navarro, R.; Orza, J.M. Anales de Quimica 1982, 79, 557. 30. Xie, Y; Fan, K.; Boggs,J., Molec. Phys

  19. One-pot synthesis of novel (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl) pyrrolidine-2-carboxamides via [Formula: see text]-NPs and [Formula: see text] catalysts and investigation of their biological activities.

    PubMed

    Darehkordi, Ali; Ramezani, Mahin

    2017-05-01

    A new class of (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide compounds was synthesized by a facile one-pot reaction of trans-4-hydroxy proline and trifluoroacetimidoyl chlorides in the presence of [Formula: see text]-nanoparticles as a catalyst and sodium bicarbonate as a base. Synthesized compounds showed cytotoxicity with [Formula: see text] values of 15.3-70.3 [Formula: see text] against K562 (Homo sapiens, human) cells. The results of the study provide a valuable method for one-pot synthesis of trans-4-hydroxy proline-based N-(2,2,2-trifluoroacetylated) compounds. Also, these compounds show significant pharmaceutical activities as antibacterial and antifungal reagents.

  20. The Fe(III) and Ga(III) coordination chemistry of 3-(1-hydroxymethylidene) and 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione: novel tetramic acid degradation products of homoserine lactone bacterial quorum sensing molecules.

    PubMed

    Romano, Ariel A; Hahn, Tobias; Davis, Nicole; Lowery, Colin A; Struss, Anjali K; Janda, Kim D; Böttger, Lars H; Matzanke, Berthold F; Carrano, Carl J

    2012-02-01

    Bacteria use small diffusible molecules to exchange information in a process called quorum sensing (QS). An important class of quorum sensing molecules used by Gram-negative bacteria is the family of N-acylhomoserine lactones (HSL). It was recently discovered that a degradation product of the QS molecule 3-oxo-C(12)-homoserine lactone, the tetramic acid 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione, is a potent antibacterial agent, thus implying roles for QS outside of simply communication. Because these tetramic acids also appear to bind iron with appreciable affinity it was suggested that metal binding might contribute to their biological activity. Here, using a variety of spectroscopic tools, we describe the coordination chemistry of both the methylidene and decylidene tetramic acid derivatives with Fe(III) and Ga(III) and discuss the potential biological significance of such metal binding.

  1. The Fe(III) and Ga(III) coordination chemistry of 3-(1-hydroxymethylidene) and 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione: Novel tetramic acid degradation products of homoserine lactone bacterial quorum sensing molecules

    PubMed Central

    Romano, Ariel A.; Hahn, Tobias; Davis, Nicole; Lowery, Colin A.; Struss, Anjali K.; Janda, Kim D.; Böttger, Lars H.; Matzanke, Berthold F.; Carrano, Carl J.

    2011-01-01

    Bacteria use small diffusible molecules to exchange information in a process called quorum sensing (QS). An important class of quorum sensing molecules used by Gram-negative bacteria is the family of N-acylhomoserine lactones (HSL). It was recently discovered that a degradation product of the QS molecule 3-oxo-C12-homoserine lactone, the tetramic acid 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione, is a potent antibacterial agent, thus implying roles for QS outside of simply communication. Because these tetramic acids also appear to bind iron with appreciable affinity it was suggested that metal binding might contribute to their biological activity. Here, using a variety of spectroscopic tools, we describe the coordination chemistry of both the methylidene and decylidene tetramic acid derivatives with Fe(III) and Ga(III) and discuss the potential biological significance of such metal binding. PMID:22178671

  2. Complexity Survey.

    ERIC Educational Resources Information Center

    Gordon, Sandra L.; Anderson, Beth C.

    To determine whether consensus existed among teachers about the complexity of common classroom materials, a survey was administered to 66 pre-service and in-service kindergarten and prekindergarten teachers. Participants were asked to rate 14 common classroom materials as simple, complex, or super-complex. Simple materials have one obvious part,…

  3. Complexity Survey.

    ERIC Educational Resources Information Center

    Gordon, Sandra L.; Anderson, Beth C.

    To determine whether consensus existed among teachers about the complexity of common classroom materials, a survey was administered to 66 pre-service and in-service kindergarten and prekindergarten teachers. Participants were asked to rate 14 common classroom materials as simple, complex, or super-complex. Simple materials have one obvious part,…

  4. Communication complexity and information complexity

    NASA Astrophysics Data System (ADS)

    Pankratov, Denis

    Information complexity enables the use of information-theoretic tools in communication complexity theory. Prior to the results presented in this thesis, information complexity was mainly used for proving lower bounds and direct-sum theorems in the setting of communication complexity. We present three results that demonstrate new connections between information complexity and communication complexity. In the first contribution we thoroughly study the information complexity of the smallest nontrivial two-party function: the AND function. While computing the communication complexity of AND is trivial, computing its exact information complexity presents a major technical challenge. In overcoming this challenge, we reveal that information complexity gives rise to rich geometrical structures. Our analysis of information complexity relies on new analytic techniques and new characterizations of communication protocols. We also uncover a connection of information complexity to the theory of elliptic partial differential equations. Once we compute the exact information complexity of AND, we can compute exact communication complexity of several related functions on n-bit inputs with some additional technical work. Previous combinatorial and algebraic techniques could only prove bounds of the form theta( n). Interestingly, this level of precision is typical in the area of information theory, so our result demonstrates that this meta-property of precise bounds carries over to information complexity and in certain cases even to communication complexity. Our result does not only strengthen the lower bound on communication complexity of disjointness by making it more exact, but it also shows that information complexity provides the exact upper bound on communication complexity. In fact, this result is more general and applies to a whole class of communication problems. In the second contribution, we use self-reduction methods to prove strong lower bounds on the information

  5. Synthesis and biodistribution of a novel [99mTcN(PNP5)(DMCHDTC)]+ complex as a potential myocardial perfusion imaging agent.

    PubMed

    Zhang, JunBo; Song, ZhiXin; Jinfeng, Chu; Wang, XueBin

    2009-09-01

    The [(99m)TcN(PNP5)(DMCHDTC)](+)(DMCHDTC: 2,3-dimethyl cyclohexyl dithiocarbamate, PNP5:bis(dimethoxypropylphosphinoethyl)ethoxyethylamine) complex was synthesized through a ligand-exchange reaction. The two-step procedure involved the initial reaction of (99m)TcO(4)(-) with succinic dihydrazide (SDH) as a donor of nitride nitrogen atom (N(3-)) in the presence of stannous chloride dihydrate as reducing agent and propylenediamine tetraacetic acid (PDTA) as complexant, followed by the addition of the PNP5 ligand and the DMCHDTC ligand. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 h. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was cationic. The biodistribution results in mice indicated that [(99m)TcN(PNP5)(DMCHDTC)](+) was significantly retained into the heart. The heart uptake (ID%/g) was 14.47, 12.23 and 8.76 at 5, 30 and 60 min post-injection, respectively. The heart/liver, heart/lung and heart/blood ratios of the complex were 1.24, 3.62 and 23.05 at 60 min post-injection, suggesting it will be a potential myocardial imaging agent.

  6. Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.

    PubMed

    Aguilar, Angelo; Lu, Jianfeng; Liu, Liu; Du, Ding; Bernard, Denzil; McEachern, Donna; Przybranowski, Sally; Li, Xiaoqin; Luo, Ruijuan; Wen, Bo; Sun, Duxin; Wang, Hengbang; Wen, Jianfeng; Wang, Guangfeng; Zhai, Yifan; Guo, Ming; Yang, Dajun; Wang, Shaomeng

    2017-04-13

    We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.

  7. Complexation of the vulcanization accelerator tetramethylthiuram disulfide and related molecules with zinc compounds including zinc oxide clusters (Zn4O4).

    PubMed

    Steudel, Ralf; Steudel, Yana; Wong, Ming Wah

    2008-01-01

    Zinc chemicals are used as activators in the vulcanization of organic polymers with sulfur to produce elastic rubbers. In this work, the reactions of Zn(2+), ZnMe(2), Zn(OMe)(2), Zn(OOCMe)(2), and the heterocubane cluster Zn(4)O(4) with the vulcanization accelerator tetramethylthiuram disulfide (TMTD) and with the related radicals and anions Me(2)NCS(2)(*), Me(2)NCS(3)(*), Me(2)NCS(2)(-), and Me(2)NCS(3)(-) have been studied by quantum chemical methods at the MP2/6-31+G(2df,p)//B3LYP/6-31+G* level of theory. More than 35 zinc complexes have been structurally characterized and the energies of formation from their components calculated for the first time. The binding energy of TMTD as a bidendate ligand increases in the order ZnMe(2)complexes with the radicals Me(2)NCS(2)(*) and Me(2)NCS(3)(*). Dissociation of the TMTD molecule at the S-S bond on reaction with the Zn(4)O(4) cluster is predicted to be strongly exothermic, in sharp contrast to the endothermic S-S bond dissociation of the free molecule. The same holds for tetramethylthiuram trisulfide (TMTT). Surprisingly, the resulting complexes contain Zn-S as well as S-O bonds. The Zn(4)O(4) nanocluster serves here as a model for bulk zinc oxide used as an activator in rubber vulcanization by sulfur. The further uptake of sulfur atoms by the various complexes from S(8) or TMTD with formation of species derived from the radical Me(2)NCS(3)(*) or the trithiocarbamate anion Me(2)NCS(3)(-) is endothermic for mono- and dinuclear zinc dithiocarbamate (dtc) complexes such as [Zn(dtc)(2)] and [Zn(2)(dtc)(4)], but exothermic in the case of polynuclear zinc oxide species containing bridging ligands as in [Zn(4)O(4)(mu-S(2)CNMe(2))] and [Zn(4)O(4)(mu-dtc)]. Therefore, zinc oxide as a polynuclear species is predicted to promote the formation of trisulfido complexes, which are generally assumed to serve as catalysts for the transfer of

  8. Complex odontoma.

    PubMed

    Preetha, A; Balikai, Bharati S; Sujatha, D; Pai, Anuradha; Ganapathy, K S

    2010-01-01

    Odontomas are hamartomatous lesions or malformations composed of mature enamel, dentin, and pulp. They may be compound or complex, depending on the extent of morphodifferentiation or their resemblance to normal teeth. The etiology of odontoma is unknown, although several theories have been proposed. This article describes a case of a large infected complex odontoma in the residual mandibular ridge, resulting in considerable mandibular expansion.

  9. Designing Complexity

    ERIC Educational Resources Information Center

    Glanville, Ranulph

    2007-01-01

    This article considers the nature of complexity and design, as well as relationships between the two, and suggests that design may have much potential as an approach to improving human performance in situations seen as complex. It is developed against two backgrounds. The first is a world view that derives from second order cybernetics and radical…

  10. Complex derivatives

    NASA Astrophysics Data System (ADS)

    Battiston, Stefano; Caldarelli, Guido; Georg, Co-Pierre; May, Robert; Stiglitz, Joseph

    2013-03-01

    The intrinsic complexity of the financial derivatives market has emerged as both an incentive to engage in it, and a key source of its inherent instability. Regulators now faced with the challenge of taming this beast may find inspiration in the budding science of complex systems.

  11. Newer mixed ligand Schiff base complexes from aquo-N-(2‧-hydroxy acetophenone) glycinatocopper(II) as synthon: DFT, antimicrobial activity and molecular docking study

    NASA Astrophysics Data System (ADS)

    Pramanik, Harun A. R.; Das, Dharitri; Paul, Pradip C.; Mondal, Paritosh; Bhattacharjee, Chira R.

    2014-02-01

    Synthesis of a series of newer mixed ligand copper(II) complexes of aminoacid Schiff base of the type [CuL(X)] (L = N-(2‧-hydroxy acetophenone) glycinate, X = imidazole (im) 2, benzimidazole (benz) 3, pyridine (py) 4, hydrazine (hz) 5,8-hydroxyquinoline (8-hq) 6, pyrrolidine (pyrr) 7, piperidine (pip) 8, and nicotinamide (nic) 9) have been accomplished from the interaction of an aquated Schiff base complex, [CuL(H2O)]·H2O, 1 with some selected neutral nitrogen-donor ligands. The copper(II) Schiff base complex, [CuL(H2O)]·H2O, L = N-(2‧-hydroxy acetophenone) glycinate was synthesized from the reaction of glycine and 2‧ hydroxy acetophenone and copper(II) acetate. The compounds were characterised by elemental analysis, spectral, magnetic and thermal studies. The density functional theory calculations were performed using LANL2DZ and 6-311 G(d, p) basis sets with B3LYP correlation functional to ascertain the stable electronic structure, HOMO-LUMO energy gap, chemical hardness and dipole moment of the mixed ligand complexes. A distorted square planar geometry has been conjectured for the complexes. Antibacterial activities of the ligand and its metal complexes have been tested against selected gram-positive and gram-negative strains and correlated with computational docking scores.

  12. Complex Clouds

    Atmospheric Science Data Center

    2013-04-16

    ...     View Larger Image The complex structure and beauty of polar clouds are highlighted by these images acquired ... MD. The MISR data were obtained from the NASA Langley Research Center Atmospheric Science Data Center in Hampton, VA. Image ...

  13. Softball Complex

    ERIC Educational Resources Information Center

    Ellis, Jim

    1977-01-01

    The Parks and Recreation Department of Montgomery, Alabama, has developed a five-field softball complex as part of a growing community park with facilities for camping, golf, aquatics, tennis, and picnicking. (MJB)

  14. An unprecedented binuclear cadmium di-thio-carbamate adduct: bis-[μ2-N-(2-hydroxy-eth-yl)-N-iso-propyl-carbamodi-thio-ato-κ(3)S:S,S']bis-{[N-(2-hydroxy-eth-yl)-N-iso-propyl-carbamodi-thio-ato-κ(2)S,S'](3-{(1E)-[(E)-2-(pyridin-3-yl-methyl-idene)hydrazin-1-yl-idene]meth-yl}pyridine-κN)cadmium]} dihydrate.

    PubMed

    Arman, Hadi D; Poplaukhin, Pavel; Tiekink, Edward R T

    2016-09-01

    The asymmetric unit in the title binuclear compound, [Cd(C6H12NOS2)2(C12H10N4)]2·2H2O, comprises a Cd(II) atom, two di-thio-carbamate (dtc) anions, a monodentate 3-pyridine-aldazine ligand and a lattice water mol-ecule. The binuclear mol-ecule is constructed by the application of inversion symmetry. One dtc ligand simultaneously chelates one cadmium atom and bridges the centrosymmetric mate, while the other dtc ligand is chelating only. This leads to a centrosymmetric [Cd(dtc)2]2 core to which are appended two 3-pyridine-aldazine ligands. The resulting NS5 donor set is based on an octa-hedron. The three-dimensional mol-ecular packing is sustained by hydroxyl-O-H(hydrox-yl) and water-O-H⋯O(hydrox-yl) hydrogen bonding, leading to supra-molecular layers parallel to (101) which are connected by water-O-H⋯N(pyrid-yl) hydrogen bonding; additional C-H⋯O, S π(chelate ring) inter-actions are also evident. The retention of the central [Cd(dtc)2]2 core upon adduct formation is unprecedented in the structural chemistry of the zinc-triad di-thio-carbamates.

  15. In vitro antifilarial activity of organometallic complexes against infective larvae of Molinema dessetae and adult females of Brugia pahangi.

    PubMed

    Loiseau, P M; Jaffe, J J; Craciunescu, D G

    1998-08-01

    New organometallic complexes having protozoocidal properties were evaluated for their in vitro antifilarial activity using two models: infective larvae of Molinema dessetae and adult females of Brugia pahangi. The compound most active on the M. dessetae model was Ir(I)-COD-pentamidine tetraphenylborate with an EC50 = 6 +/- 1 microM after 7-day-incubation. In the 2-aminobenzothiazole series, Ruthenium was more potent than Iridium for antifilarial activity. A dithiocarbamate function significantly enhanced the antifilarial activity. The compounds derived from benzimidazole were inactive whatever the metal (Iridium or Rhodium). The other compounds exhibited EC50 ranging from 10 to 31 microM. On adult female Brugia pahangi in vitro, Pt-DDH-N-acetylleucine, Pt-diminazene and Pd-Cl4-piperazine at 20 microM began to kill both microfilariae and the developing embryos within the mothers on day 2. The compounds, except for Pd-Cl4-piperazine, killed the adults after 5 days. Rh-Cl-2-chloropyridine caused obvious slowing of the adults from day 3 onward but did not affect the viability of adults, microfilariae or developing embryos. In vivo antifilarial investigations are necessary to appreciate the real advantage of heavy metal complexes in the experimental treatment of filariasis.

  16. Complex chimerism

    PubMed Central

    Ma, Kimberly K.; Petroff, Margaret G.; Coscia, Lisa A.; Armenti, Vincent T.; Adams Waldorf, Kristina M.

    2013-01-01

    Thousands of women with organ transplantation have undergone successful pregnancies, however little is known about how the profound immunologic changes associated with pregnancy might influence tolerance or rejection of the allograft. Pregnant women with a solid organ transplant are complex chimeras with multiple foreign cell populations from the donor organ, fetus, and mother of the pregnant woman. We consider the impact of complex chimerism and pregnancy-associated immunologic changes on tolerance of the allograft both during pregnancy and the postpartum period. Mechanisms of allograft tolerance are likely dynamic during pregnancy and affected by the influx of fetal microchimeric cells, HLA relationships (between the fetus, pregnant woman and/or donor), peripheral T cell tolerance to fetal cells, and fetal minor histocompatibility antigens. Further research is necessary to understand the complex immunology during pregnancy and the postpartum period of women with a solid organ transplant. PMID:23974274

  17. Multimetallic complexes and functionalized gold nanoparticles based on a combination of d- and f-elements.

    PubMed

    Sung, Simon; Holmes, Holly; Wainwright, Luke; Toscani, Anita; Stasiuk, Graeme J; White, Andrew J P; Bell, Jimmy D; Wilton-Ely, James D E T

    2014-02-17

    The new DO3A-derived dithiocarbamate ligand, DO3A-(t)Bu-CS2K, is formed by treatment of the ammonium salt [DO3A-(t)Bu]HBr with K2CO3 and carbon disulfide. DO3A-(t)Bu-CS2K reacts with the ruthenium complexes cis-[RuCl2(dppm)2] and [Ru(CH═CHC6H4Me-4)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-benzothiadiazole) to yield [Ru(S2C-DO3A-(t)Bu)(dppm)2](+) and [Ru(CH═CHC6H4Me-4)(S2C-DO3A-(t)Bu)(CO)(PPh3)2], respectively. Similarly, the group 10 metal complexes [Pd(C,N-C6H4CH2NMe2)Cl]2 and [PtCl2(PPh3)2] form the dithiocarbamate compounds, [Pd(C,N-C6H4CH2NMe2)(S2C-DO3A-(t)Bu)] and [Pt(S2C-DO3A-(t)Bu)(PPh3)2](+), under the same conditions. The linear gold complexes [Au(S2C-DO3A-(t)Bu)(PR3)] are formed by reaction of [AuCl(PR3)] (R = Ph, Cy) with DO3A-(t)Bu-CS2K. However, on reaction with [AuCl(tht)] (tht = tetrahydrothiophene), the homoleptic digold complex [Au(S2C-DO3A-(t)Bu)]2 is formed. Further homoleptic examples, [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3], are formed from treatment of NiCl2·6H2O, Cu(OAc)2, or Co(OAc)2, respectively, with DO3A-(t)Bu-CS2K. The molecular structure of [Ni(S2C-DO3A-(t)Bu)2] was determined crystallographically. The tert-butyl ester protecting groups of [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3] are cleaved by trifluoroacetic acid to afford the carboxylic acid products, [M(S2C-DO3A)2] (M = Ni, Cu) and [Co(S2C-DO3A)3]. Complexation with Gd(III) salts yields trimetallic [M(S2C-DO3A-Gd)2] (M = Ni, Cu) and tetrametallic [Co(S2C-DO3A-Gd)3], with r(1) values of 11.5 (Co) and 11.0 (Cu) mM(-1) s(-1) per Gd center. DO3A-(t)Bu-CS2K can also be used to prepare gold nanoparticles, Au@S2C-DO3A-(t)Bu, by displacement of the surface units from citrate-stabilized nanoparticles. This material can be transformed into the carboxylic acid derivative Au@S2C-DO3A by treatment with trifluoroacetic acid. Complexation with Gd(OTf)3 or GdCl3 affords Au@S2C-DO3A-Gd with an r(1) value of 4.7 mM(-1) s(-1) per chelate and 1500 mM(-1) s(-1) per

  18. Complex interactions

    NASA Astrophysics Data System (ADS)

    de Régules, Sergio

    2016-04-01

    Complexity science - which describes phenomena such as collective and emergent behaviour - is the focus of a new centre where researchers are examining everything from the spread of influenza to what a healthy heartbeat looks like. Sergio de Régules reports.

  19. Amorphic complexity

    NASA Astrophysics Data System (ADS)

    Fuhrmann, G.; Gröger, M.; Jäger, T.

    2016-02-01

    We introduce amorphic complexity as a new topological invariant that measures the complexity of dynamical systems in the regime of zero entropy. Its main purpose is to detect the very onset of disorder in the asymptotic behaviour. For instance, it gives positive value to Denjoy examples on the circle and Sturmian subshifts, while being zero for all isometries and Morse-Smale systems. After discussing basic properties and examples, we show that amorphic complexity and the underlying asymptotic separation numbers can be used to distinguish almost automorphic minimal systems from equicontinuous ones. For symbolic systems, amorphic complexity equals the box dimension of the associated Besicovitch space. In this context, we concentrate on regular Toeplitz flows and give a detailed description of the relation to the scaling behaviour of the densities of the p-skeletons. Finally, we take a look at strange non-chaotic attractors appearing in so-called pinched skew product systems. Continuous-time systems, more general group actions and the application to cut and project quasicrystals will be treated in subsequent work.

  20. Researching Complexity.

    ERIC Educational Resources Information Center

    Sumara, Dennis J.

    2000-01-01

    Discusses what Complexity Theory (presented as a rubric that collects theoretical understandings from a number of domains such as ecology, biology, neurology, and education) suggests about mind, selfhood, intelligence, and practices of reading, and the import of these reconceptualizations to reader-response researchers. Concludes that developing…

  1. Researching Complexity.

    ERIC Educational Resources Information Center

    Sumara, Dennis J.

    2000-01-01

    Discusses what Complexity Theory (presented as a rubric that collects theoretical understandings from a number of domains such as ecology, biology, neurology, and education) suggests about mind, selfhood, intelligence, and practices of reading, and the import of these reconceptualizations to reader-response researchers. Concludes that developing…

  2. Complex chemistry with complex compounds

    NASA Astrophysics Data System (ADS)

    Eichler, Robert; Asai, M.; Brand, H.; Chiera, N. M.; Di Nitto, A.; Dressler, R.; Düllmann, Ch. E.; Even, J.; Fangli, F.; Goetz, M.; Haba, H.; Hartmann, W.; Jäger, E.; Kaji, D.; Kanaya, J.; Kaneya, Y.; Khuyagbaatar, J.; Kindler, B.; Komori, Y.; Kraus, B.; Kratz, J. V.; Krier, J.; Kudou, Y.; Kurz, N.; Miyashita, S.; Morimoto, K.; Morita, K.; Murakami, M.; Nagame, Y.; Ooe, K.; Piguet, D.; Sato, N.; Sato, T. K.; Steiner, J.; Steinegger, P.; Sumita, T.; Takeyama, M.; Tanaka, K.; Tomitsuka, T.; Toyoshima, A.; Tsukada, K.; Türler, A.; Usoltsev, I.; Wakabayashi, Y.; Wang, Y.; Wiehl, N.; Wittwer, Y.; Yakushev, A.; Yamaki, S.; Yano, S.; Yamaki, S.; Qin, Z.

    2016-12-01

    In recent years gas-phase chemical studies assisted by physical pre-separation allowed for the investigation of fragile single molecular species by gas-phase chromatography. The latest success with the heaviest group 6 transactinide seaborgium is highlighted. The formation of a very volatile hexacarbonyl compound Sg(CO)6 was observed similarly to its lighter homologues molybdenum and tungsten. The interactions of these gaseous carbonyl complex compounds with quartz surfaces were investigated by thermochromatography. Second-generation experiments are under way to investigate the intramolecular bond between the central metal atom of the complexes and the ligands addressing the influence of relativistic effects in the heaviest compounds. Our contribution comprises some aspects of the ongoing challenging experiments as well as an outlook towards other interesting compounds related to volatile complex compounds in the gas phase.

  3. Synthesis, crystal structure and photoconductivity of the first [60]fullerene complex with metal diethyldithiocarbamate: {CuII(dedtc)2}2.C60.

    PubMed

    Konarev, Dmitri V; Kovalevsky, Andrey Y; Lopatin, Dmitri V; Umrikhin, Alexey V; Yudanova, Evgeniya I; Coppens, Philip; Lyubovskaya, Rimma N; Saito, Gunzi

    2005-05-21

    The first molecular complex of fullerene C60 with metal dithiocarbamate, namely, {CuII(dedtc)2}2.C60(dedtc: diethyldithiocarbamate) (1) was obtained as single crystals. Butterfly-shaped CuII(dedtc)2 molecules efficiently co-crystallized with spherical fullerene molecules to form a layered structure, in which closely packed hexagonal C60 layers alternate with the layers composed of CuII(dedtc)2 dimers. The formation of the complex with C60 changes geometry and the EPR spectrum of starting CuII(dedtc)2. Magnetic susceptibility of 1 follows the Curie-Weiss law in the 300-1.9 K range with the negative Weiss constant of -2.5 K showing a weak antiferromagnetic interaction between CuII centers in the dimers. The crystals of 1 have low dark conductivity of 10(-11) S cm-1, which is consistent with a neutral ground state of the complex. Illumination of the crystals by white light increases the photocurrent by 20-50 times. The photoconductivity spectrum of 1 has a maximum at 470 nm showing that both intermolecular charge transfer between neighboring C60 molecules and photoexcitation of CuII(dedtc)2 can contribute to photogeneration of free charge carriers. The effect of a weak magnetic field with Bo<0.5 T on the photoconductivity of 1 has been found.

  4. Transition metal complexes of oxazolinylboranes and cyclopentadienyl-bis(oxazolinyl)borates: Catalysts for asymmetric olefin hydroamination and acceptorless alcohol decarbonylation

    SciTech Connect

    Manna, Kuntal

    2012-12-17

    The research presented and discussed in this dissertation involves the synthesis of transition metal complexes of oxazolinylboranes and cyclopentadienyl-bis(oxazolinyl)borates, and their application in catalytic enantioselective olefin hydroamination and acceptorless alcohol decarbonylation. Neutral oxazolinylboranes are excellent synthetic intermediates for preparing new borate ligands and also developing organometallic complexes. Achiral and optically active bis(oxazolinyl)phenylboranes are synthesized by reaction of 2-lithio-2-oxazolide and 0.50 equiv of dichlorophenylborane. These bis(oxazolinyl)phenylboranes are oligomeric species in solid state resulting from the coordination of an oxazoline to the boron center of another borane monomer. The treatment of chiral bis(oxazolinyl)phenylboranes with sodium cyclopentadienide provide optically active cyclopentadienyl-bis(oxazolinyl)borates H[PhB(C5H5)(OxR)2] [OxR = Ox4S-iPr,Me2, Ox4R-iPr,Me2, Ox4S-tBu]. These optically active proligands react with an equivalent of M(NMe2)4 (M = Ti, Zr, Hf) to afford corresponding cyclopentadienyl-bis(oxazolinyl)borato group 4 complexes {PhB(C5H4)(OxR)2}M(NMe2)2 in high yields. These group 4 compounds catalyze cyclization of aminoalkenes at room temperature or below, providing pyrrolidine, piperidine, and azepane with enantiomeric excesses up to 99%. Our mechanistic investigations suggest a non-insertive mechanism involving concerted C-N/C-H bond formation in the turnover limiting step of the catalytic cycle. Among cyclopentadienyl-bis(oxazolinyl)borato group 4 catalysts, the zirconium complex {PhB(C5H4)(Ox4S-iPr,Me2)2}Zr(NMe2)2 ({S-2}Zr(NMe2)2) displays highest activity and enantioselectivity. Interestingly, S-2

  5. Crystal structure of ethyl (2S,2′R)-1′-benzyl-3-oxo-3H-di­spiro­[1-benzo­thio­phene-2,3′-pyrrolidine-2′,11′′-indeno[1,2-b]quinoxaline]-4′-carboxyl­ate

    PubMed Central

    Govindaraj, J.; Raja, R.; Suresh, M.; Raghunathan, R.; SubbiahPandi, A.

    2015-01-01

    In the title compound, C35H27N3O3S, the spiro-linked five-membered rings both adopt twisted conformations. The pyrrolidine ring makes dihedral angles of 80.5 (1) and 77.4 (9)° with the benzo­thio­phene ring system and the quinoxaline ring system, respectively. The S atom and C=O unit of the benzo­thio­phene ring system are disordered over two opposite orientations in a 0.768 (4):0.232 (4) ratio. The atoms of the ethyl side chain are disordered over two sets of sites in a 0.680 (16):0.320 (16) ratio. In the crystal, mol­ecules are linked by C—H⋯O, C—H⋯N and π–π inter­actions [shortest centroid–centroid distance = 3.4145 (19) Å], resulting in a three-dimensional network. PMID:25844245

  6. Conformation of the nootropic agents 1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) and 4-hydroxymethyl-1-benzyl-pyrrolidin-2-one (WEB-1868): X-ray crystal structures, theoretical MO calculations (AM-1) and 600 MHZ 1H NMR spectra

    NASA Astrophysics Data System (ADS)

    Amato, Maria E.; Bandoli, Giuliano; Djedaïni, Florence; Dolmella, Alessandro; Grassi, Antonio; Pappalardo, Giuseppe C.

    1990-05-01

    The crystal and molecular structures of the cognition activators 1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) ( 1) and 4-hydroxymethyl-1-benzyl-pyrrolidin-2-one (WEB-1868) ( 2) have been determined by X-ray analysis. The conformations of the isolated molecules 1 and 2 have been deduced from AM1-type theoretical calculations. Whilst in 1 there are no hydrogen bonds, in 2 stabilization of the crystal occurs through effective inter- and intramolecular ? bonds. The five-membered ring in both 1 and 2 adopts an envelope conformation in the solid with C(3) at the flap displaced from the C(1), C(2), C(4), N(5) mean plane. Bond distances and angles are normal and comparable with previously known similar structures. In the crystal, the torsion angles C(1)-N(5)-C(6)-C(7) and N(5)-C(6)-C(7)-C(8) in 1 are 43.1° and 44.8°, respectively; the same torsion angles in 2 are -101° and 42°, respectively. Results of theoretical calculations correlate well with the conformation of 1 in the solid, whilst in the case of 2 these indicate that the conformation in the crystal should not be retained by the isolated molecule. The complete analysis of the very high field (600 MHz) 1H NMR spectra of both compounds in CDCl 3, gives results well in line with the above established conformational features.

  7. Complex Questions Promote Complex Thinking

    ERIC Educational Resources Information Center

    Degener, Sophie; Berne, Jennifer

    2017-01-01

    Intermediate-grade teachers often express concerns about meeting the Common Core State Standards for Reading, primarily because of the emphasis on deep understanding of complex texts. No matter how difficult the text, if teachers demand little of the reading, student meaning making is not challenged. This article offers a tool for teachers to…

  8. Managing Complexity

    SciTech Connect

    Chassin, David P.; Posse, Christian; Malard, Joel M.

    2004-08-01

    Physical analogs have shown considerable promise for understanding the behavior of complex adaptive systems, including macroeconomics, biological systems, social networks, and electric power markets. Many of today’s most challenging technical and policy questions can be reduced to a distributed economic control problem. Indeed, economically-based control of large-scale systems is founded on the conjecture that the price-based regulation (e.g., auctions, markets) results in an optimal allocation of resources and emergent optimal system control. This paper explores the state of the art in the use physical analogs for understanding the behavior of some econophysical systems and to deriving stable and robust control strategies for them. In particular we review and discussion applications of some analytic methods based on the thermodynamic metaphor according to which the interplay between system entropy and conservation laws gives rise to intuitive and governing global properties of complex systems that cannot be otherwise understood.

  9. Complex Systems

    PubMed Central

    Goldberger, Ary L.

    2006-01-01

    Physiologic systems in health and disease display an extraordinary range of temporal behaviors and structural patterns that defy understanding based on linear constructs, reductionist strategies, and classical homeostasis. Application of concepts and computational tools derived from the contemporary study of complex systems, including nonlinear dynamics, fractals and “chaos theory,” is having an increasing impact on biology and medicine. This presentation provides a brief overview of an emerging area of biomedical research, including recent applications to cardiopulmonary medicine and chronic obstructive lung disease. PMID:16921107

  10. Research on magnetic separation for complex nickel deep removal and magnetic seed recycling.

    PubMed

    Qiu, Yiqin; Xiao, Xiao; Ye, Ziwei; Guan, Zhijie; Sun, Shuiyu; Ren, Jie; Yan, Pingfan

    2017-04-01

    This study investigated the deep removal of complex nickel from simulated wastewater using magnetic separation and magnetic seed recycling. Nano-magnetite (Fe3O4) was used as the magnetic seed. The flocculant applied was N,N-bis-(dithiocarboxy) ethanediamine (EDTC), a highly efficient heavy metal chelating agent included in dithiocarbamate (DTC). Important investigated parameters included hydraulic retention time, magnetic seed dosage, and magnetic field strength. The study also explored the magnetic flocculation mechanism involved in the reaction. The result indicated that the residual Ni concentration was reduced to less than 0.1 mg/L from the initial concentration of 50 mg/L under optimal conditions. Magnetic seed recovery reached 76.42% after a 3-h stirring period; recycled magnetic seeds were analyzed using scanning electron microscope (SEM) and X-ray diffraction (XRD). The zeta potential results illustrated that magnetic seeds firmly combined with flocs when the pH ranged from 6.5 to 7.5 due to the electrostatic attraction. When the pH was less than 7, magnetic seeds and EDTC were also combined due to electrostatic attraction. Particle size did affect microfloc size; it decreased microfloc size and increased floc volume through magnetic seed loading. The effective binding sites between flocs and magnetic seeds increased when adding the magnetic seeds. This led the majority of magnetic flocs to be integrated with the magnetic seeds, which served as a nucleus to enhance the flocculation property and ultimately improve the nickel complex removal rate.

  11. Cosmic Complexity

    NASA Technical Reports Server (NTRS)

    Mather, John C.

    2012-01-01

    What explains the extraordinary complexity of the observed universe, on all scales from quarks to the accelerating universe? My favorite explanation (which I certainty did not invent) ls that the fundamental laws of physics produce natural instability, energy flows, and chaos. Some call the result the Life Force, some note that the Earth is a living system itself (Gaia, a "tough bitch" according to Margulis), and some conclude that the observed complexity requires a supernatural explanation (of which we have many). But my dad was a statistician (of dairy cows) and he told me about cells and genes and evolution and chance when I was very small. So a scientist must look for me explanation of how nature's laws and statistics brought us into conscious existence. And how is that seemll"!gly Improbable events are actually happening a!1 the time? Well, the physicists have countless examples of natural instability, in which energy is released to power change from simplicity to complexity. One of the most common to see is that cooling water vapor below the freezing point produces snowflakes, no two alike, and all complex and beautiful. We see it often so we are not amazed. But physlc!sts have observed so many kinds of these changes from one structure to another (we call them phase transitions) that the Nobel Prize in 1992 could be awarded for understanding the mathematics of their common features. Now for a few examples of how the laws of nature produce the instabilities that lead to our own existence. First, the Big Bang (what an insufficient name!) apparently came from an instability, in which the "false vacuum" eventually decayed into the ordinary vacuum we have today, plus the most fundamental particles we know, the quarks and leptons. So the universe as a whole started with an instability. Then, a great expansion and cooling happened, and the loose quarks, finding themselves unstable too, bound themselves together into today's less elementary particles like protons and

  12. Cosmic Complexity

    NASA Technical Reports Server (NTRS)

    Mather, John C.

    2012-01-01

    What explains the extraordinary complexity of the observed universe, on all scales from quarks to the accelerating universe? My favorite explanation (which I certainty did not invent) ls that the fundamental laws of physics produce natural instability, energy flows, and chaos. Some call the result the Life Force, some note that the Earth is a living system itself (Gaia, a "tough bitch" according to Margulis), and some conclude that the observed complexity requires a supernatural explanation (of which we have many). But my dad was a statistician (of dairy cows) and he told me about cells and genes and evolution and chance when I was very small. So a scientist must look for me explanation of how nature's laws and statistics brought us into conscious existence. And how is that seemll"!gly Improbable events are actually happening a!1 the time? Well, the physicists have countless examples of natural instability, in which energy is released to power change from simplicity to complexity. One of the most common to see is that cooling water vapor below the freezing point produces snowflakes, no two alike, and all complex and beautiful. We see it often so we are not amazed. But physlc!sts have observed so many kinds of these changes from one structure to another (we call them phase transitions) that the Nobel Prize in 1992 could be awarded for understanding the mathematics of their common features. Now for a few examples of how the laws of nature produce the instabilities that lead to our own existence. First, the Big Bang (what an insufficient name!) apparently came from an instability, in which the "false vacuum" eventually decayed into the ordinary vacuum we have today, plus the most fundamental particles we know, the quarks and leptons. So the universe as a whole started with an instability. Then, a great expansion and cooling happened, and the loose quarks, finding themselves unstable too, bound themselves together into today's less elementary particles like protons and

  13. Cosmic Complexity

    NASA Technical Reports Server (NTRS)

    Mather, John C.

    2012-01-01

    What explains the extraordinary complexity of the observed universe, on all scales from quarks to the accelerating universe? My favorite explanation (which I certainty did not invent) ls that the fundamental laws of physics produce natural instability, energy flows, and chaos. Some call the result the Life Force, some note that the Earth is a living system itself (Gaia, a "tough bitch" according to Margulis), and some conclude that the observed complexity requires a supernatural explanation (of which we have many). But my dad was a statistician (of dairy cows) and he told me about cells and genes and evolution and chance when I was very small. So a scientist must look for me explanation of how nature's laws and statistics brought us into conscious existence. And how is that seemll"!gly Improbable events are actually happening a!1 the time? Well, the physicists have countless examples of natural instability, in which energy is released to power change from simplicity to complexity. One of the most common to see is that cooling water vapor below the freezing point produces snowflakes, no two alike, and all complex and beautiful. We see it often so we are not amazed. But physlc!sts have observed so many kinds of these changes from one structure to another (we call them phase transitions) that the Nobel Prize in 1992 could be awarded for understanding the mathematics of their common features. Now for a few examples of how the laws of nature produce the instabilities that lead to our own existence. First, the Big Bang (what an insufficient name!) apparently came from an instability, in which the "false vacuum" eventually decayed into the ordinary vacuum we have today, plus the most fundamental particles we know, the quarks and leptons. So the universe as a whole started with an instability. Then, a great expansion and cooling happened, and the loose quarks, finding themselves unstable too, bound themselves together into today's less elementary particles like protons and

  14. Dispersive liquid-liquid microextraction combined with graphite furnace atomic absorption spectrometry: ultra trace determination of cadmium in water samples.

    PubMed

    Zeini Jahromi, Elham; Bidari, Araz; Assadi, Yaghoub; Milani Hosseini, Mohammad Reza; Jamali, Mohammad Reza

    2007-03-07

    Dispersive liquid-liquid microextraction (DLLME) technique was successfully used as a sample preparation method for graphite furnace atomic absorption spectrometry (GF AAS). In this extraction method, 500 microL methanol (disperser solvent) containing 34 microL carbon tetrachloride (extraction solvent) and 0.00010 g ammonium pyrrolidine dithiocarbamate (chelating agent) was rapidly injected by syringe into the water sample containing cadmium ions (interest analyte). Thereby, a cloudy solution formed. The cloudy state resulted from the formation of fine droplets of carbon tetrachloride, which have been dispersed, in bulk aqueous sample. At this stage, cadmium reacts with ammonium pyrrolidine dithiocarbamate, and therefore, hydrophobic complex forms which is extracted into the fine droplets of carbon tetrachloride. After centrifugation (2 min at 5000 rpm), these droplets were sedimented at the bottom of the conical test tube (25+/-1 microL). Then a 20 microL of sedimented phase containing enriched analyte was determined by GF AAS. Some effective parameters on extraction and complex formation, such as extraction and disperser solvent type and their volume, extraction time, salt effect, pH and concentration of the chelating agent have been optimized. Under the optimum conditions, the enrichment factor 125 was obtained from only 5.00 mL of water sample. The calibration graph was linear in the rage of 2-20 ng L(-1) with detection limit of 0.6 ng L(-1). The relative standard deviation (R.S.D.s) for ten replicate measurements of 20 ng L(-1) of cadmium was 3.5%. The relative recoveries of cadmium in tap, sea and rivers water samples at spiking level of 5 and 10 ng L(-1) are 108, 95, 87 and 98%, respectively. The characteristics of the proposed method have been compared with cloud point extraction (CPE), on-line liquid-liquid extraction, single drop microextraction (SDME), on-line solid phase extraction (SPE) and co-precipitation based on bibliographic data. Therefore, DLLME

  15. In vitro bioactivation of a selective estrogen receptor modulator (2S,3R)-(+)-3-(3-hydroxyphenyl)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol (I) in liver microsomes: formation of adenine adducts.

    PubMed

    Li, Ying; Doss, George A; Li, Yan; Chen, Qing; Tang, Wei; Zhang, Zhoupeng

    2012-11-19

    As part of our efforts to develop safer selective estrogen receptor modulators (SERMs), compound I {(2S,3R)-(+)-3-(3-hydroxyphenyl)-2-[4-(2-pyrrolidin-1-ylethoxy)-phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol} was previously identified as a lead for further development. Subsequent studies showed that compound I is genotoxic in both in vitro Chinese hamster ovary (CHO) cells and in vivo mouse studies. To better understand the possible mechanisms for the observed genetoxicity effects, in vitro incubations of I with liver microsomes of human, monkey, and mouse in the presence of adenine were performed, which led to the detection of five adenine adducts. The formation of these adducts was NADPH-dependent, suggesting the involvement of oxidative bioactivation catalyzed by cytochrome P450 enzymes. The mechanism for the formation of the major adenine adduct (A1) involves the formation of a reactive ring-opened para-quinone intermediate. The formation of four other adenine adducts may involve the formation of a reactive epoxide or ortho-quinone intermediate. Furthermore, incubations of compound I with human hepatocytes showed dose-dependent DNA damages in Comet assays. All of the above suggest that some reactive metabolites of compound I, formed through bioactivation mechanisms, have a potential to interact with DNA molecules in vitro and in vivo. This may be one of the causes of the genotoxicity observed preclinically both in vitro and in vivo. This case study demonstrated an approach using in vitro DNA trapping assays for assessing the genotoxicity potential of drug candidates.

  16. (SP-4-4)-[Hydrogen N-({2-[(2S)-1-benzyl­pyrrolidine-2-carboxamido]phen­yl}(phen­yl)methyl­ene)-l-glutamato(2−)]nickel(II)

    PubMed Central

    Zhou, Jia-Dong; Cao, Fei; Ying, Han-Jie; Wei, Ping

    2009-01-01

    In the mol­ecule of the title complex, [Ni(C30H29N3O5)], the Ni atom is coordinated in a distorted square-planar geometry by three N and one O atoms. The aromatic rings are oriented at dihedral angles of 29.01 (3), 79.73 (3) and 83.37 (3)°. The remaining rings adopt envelope conformations with the C and N atoms at the flap positions. In the crystal structure, inter­molecular O—H⋯O hydrogen bonds link the mol­ecules into chains along the b axis. There is also a weak C—H⋯π inter­action. PMID:21582389

  17. (SP-4-4)-[Hydrogen N-({2-[(2S)-1-benzyl-pyrrolidine-2-carboxamido]phen-yl}(phen-yl)methyl-ene)-l-glutamato(2-)]nickel(II).

    PubMed

    Zhou, Jia-Dong; Cao, Fei; Ying, Han-Jie; Wei, Ping

    2009-03-28

    In the mol-ecule of the title complex, [Ni(C(30)H(29)N(3)O(5))], the Ni atom is coordinated in a distorted square-planar geometry by three N and one O atoms. The aromatic rings are oriented at dihedral angles of 29.01 (3), 79.73 (3) and 83.37 (3)°. The remaining rings adopt envelope conformations with the C and N atoms at the flap positions. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into chains along the b axis. There is also a weak C-H⋯π inter-action.

  18. Photophysical investigations on determination of molecular structure and binding strength of supramolecular complexation between fulleropyrrolidine and a designed bisporphyrin in solution

    NASA Astrophysics Data System (ADS)

    Mukherjee, Sibayan; Bauri, Ajoy K.; Bhattacharya, Sumanta

    2013-05-01

    The present article reports, for the first time, the photophysical aspects of non-covalent interaction of a fullerene derivative, namely, C60 pyrrolidine tris-acid ethyl ester (PyC60) with a designed bisporphyrin (1) (having carbazole spacer unit) in toluene. Absorption spectrophotometric studies reveal that decrease in the absorption intensity of the Soret absorption band of 1 takes in presence of PyC60 in the solvent studied. Steady state fluorescence studies reveal efficient quenching of fluorescence intensity of 1 in presence of PyC60. Static quenching model explores a binding constant (KS) value of 2,910 dm3 mol-1 in toluene. Time resolved emission study establishes static quenching mechanism for the investigated supramolecule in non-polar solvent. Molecular mechanics calculations in vacuo evoke the single projection structure of the PyC60-1 complex and interpret the geometrical arrangement of both PyC60 and 1 during non-covalent complexation.

  19. A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules.

    PubMed

    Kim, Young-Seung; He, Zhengjie; Hsieh, Wen-Yuan; Liu, Shuang

    2006-01-01

    This report describes a novel ternary ligand system composed of a phenylhydrazine, a crown ether-containing dithiocarbamate (DTC), and a PNP-type bisphosphine (PNP). The combination of three different ligands with (99m)Tc results in cationic (99m)Tc-diazenido complexes, [(99m)Tc(NNAr)(DTC)(PNP)]+, with potential radiopharmaceuticals for heart imaging. Synthesis of cationic (99m)Tc-diazenido complexes can be accomplished in two steps. For example, the reaction of phenylhydrazine with (99m)TcO4- at 100 degrees C in the presence of excess stannous chloride and 1,2-diaminopropane-N,N,N',N'-tetraacetic acid (PDTA) results in the [(99m)Tc(NNPh)(PDTA)n] intermediate, which then reacts with sodium N-(dithiocarbamato)-2-aminomethyl-15-Crown-5 (L4) and N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]ethoxyethylamine (PNP6) at 100 degrees C for 15 min to give the complex, [(99m)Tc(NNPh)(L4)(PNP6)]+ in high yield (>90%). Cationic complexes [(99m)Tc(NNPh)(DTC)(PNP)]+ are stable for > or = 6 h. Their composition was determined to be 1:1:1:1 for Tc:NNPh:DTC:PNP using the mixed-ligand experiments on the tracer ((99m)Tc) level and was further confirmed by the ESI-MS spectral data of a model compound [Re(NNPh)(L4)(L6)]+. It was found that both DTCs and bisphosphines have a significant impact on the lipophilicity of their cationic (99m)Tc-diazenido complexes. Results from a (99m)Tc-labeling efficiency experiment showed that 4-hydrazinobenzoic acid (HYBA) might be useful as a bifunctional coupling agent for (99m)Tc-labeling of small biomolecules. However, the (99m)Tc-labeling efficiency of HYBA is much lower than that of 6-hydrazinonicotinic acid (HYNIC) with tricine and trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands.

  20. Cloud point extraction combined with electrothermal atomic absorption spectrometry for the speciation of antimony(III) and antimony(V) in food packaging materials.

    PubMed

    Jiang, Xiuming; Wen, Shengping; Xiang, Guoqiang

    2010-03-15

    A simple, sensitive method for the speciation of inorganic antimony by cloud point extraction combined with electrothermal atomic absorption spectrometry (ETAAS) is presented and evaluated. The method based on the fact that formation of a hydrophobic complex of antimony(III) with ammonium pyrrolidine dithiocarbamate (APDC) at pH 5.0 and subsequently the hydrophobic complex enter into surfactant-rich phase, whereas antimony(V) remained in aqueous solutions. Antimony(III) in surfactant-rich phase was analyzed by ETAAS after dilution by 0.2 mL nitric acid in methanol (0.1M), and antimony(V) was calculated by subtracting antimony(III) from the total antimony after reducing antimony(V) to antimony(III) by l-cysteine. The main factors affecting the cloud point extraction, such as pH, concentration of APDC and Triton X-114, equilibrium temperature and incubation time, sample volume were investigated in detail. Under the optimum conditions, the detection limit (3 sigma) of the proposed method was 0.02 ng mL(-1) for antimony(III), and the relative standard deviation was 7.8% (c=1.0 ng mL(-1), n=7). The proposed method was successfully applied to speciation of inorganic antimony in the leaching solutions of different food packaging materials with satisfactory results. (c) 2009 Elsevier B.V. All rights reserved.

  1. Separation-preconcentration of nickel and lead in food samples by a combination of solid-liquid-solid dispersive extraction using SiO2 nanoparticles, ionic liquid-based dispersive liquid-liquid micro-extraction.

    PubMed

    Jalbani, Nusrat; Soylak, Mustafa

    2015-01-01

    A microextraction method for the determination of nickel and lead using solid-liquid-solid dispersive extraction followed by ionic liquid-based dispersive liquid-liquid microextraction (SLSDE-ILDLLME) was presented. It was applied to the extraction of nickel and lead from food samples. Ammonium pyrrolidine dithiocarbamate (APDC) as complexing agent, [C4MIM][PF6] as ionic liquid, SiO2 as nanoparticles and 2 mol L(-1) HNO3 as eluent were used. Several important parameters such as amount of IL, extraction time, pH and volume of the complexing agent were investigated. The quantitative recoveries were obtained at pH 7.0 for analytes. Under the optimum conditions, the limits of detection (LODs) calculated using 3(Sd)blank/m were 0.17 for Ni(II) and 0.79 µg L(-1) for Pb(II) for aqueous solutions with 125 enrichment factor (EF). The limit of detections of the analyte ions (3(Sd)blank/m) for solid samples were 0.09 µg g(-1) (Ni) and 0.40 µg g(-1) (Pb). The accuracy of the proposed method was confirmed by the analysis of standard reference material (1577c bovine liver) and spiked recovery test. The proposed method was applied to determine nickel and lead levels in chicken, fish and meat samples.

  2. Ionic liquid-linked dual magnetic microextraction of lead(II) from environmental samples prior to its micro-sampling flame atomic absorption spectrometric determination.

    PubMed

    Yilmaz, Erkan; Soylak, Mustafa

    2013-11-15

    A novel and rapid microextraction approach termed as ionic liquid-linked dual magnetic microextraction (IL-DMME), was developed for the atomic absorption spectrometric determination of lead. The developed method based on a combination of dispersive liquid-liquid microextraction (DLLME) and dispersive micro solid-phase extraction (D-μ-SPE). In the first DLLME step, 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6], was selected to extract the lead-pyrrolidine-dithiocarbamate (Pb-PDC) complex from sample solution by the assistance of vortex agitator. After the first step, fifty milligrams of Fe3O4 magnetic nanoparticles (MNPs) were added to extraction of the ionic liquid and Pb-PDC complex in aqueous solution. The effective factors in proposed IL-DMME procedure, including volume of 1-butyl-3-methylimidazolium hexafluorophosphate, amount of Fe3O4 magnetic nanoparticles, vortex time, amount of ammonium pyrrolidinedithiocarbamate, sample volume and matrix effect were optimized in details. Under the optimal conditions, the method present has low detection limit (0.57 μg L(-1)), high preconcentration factor (160) and good repeatability (<7.5%, n=10). The accuracy of the developed method was evaluated by the analysis of the certified reference materials and addition-recovery tests. The method was successfully applied to the determination of lead in water, plant and hair samples. © 2013 Elsevier B.V. All rights reserved.

  3. Inorganic selenium speciation analysis in Allium and Brassica vegetables by ionic liquid assisted liquid-liquid microextraction with multivariate optimization.

    PubMed

    Castro Grijalba, Alexander; Martinis, Estefanía M; Wuilloud, Rodolfo G

    2017-03-15

    A highly sensitive vortex assisted liquid-liquid microextraction (VA-LLME) method was developed for inorganic Se [Se(IV) and Se(VI)] speciation analysis in Allium and Brassica vegetables. Trihexyl(tetradecyl)phosphonium decanoate phosphonium ionic liquid (IL) was applied for the extraction of Se(IV)-ammonium pyrrolidine dithiocarbamate (APDC) complex followed by Se determination with electrothermal atomic absorption spectrometry. A complete optimization of the graphite furnace temperature program was developed for accurate determination of Se in the IL-enriched extracts and multivariate statistical optimization was performed to define the conditions for the highest extraction efficiency. Significant factors of IL-VA-LLME method were sample volume, extraction pH, extraction time and APDC concentration. High extraction efficiency (90%), a 100-fold preconcentration factor and a detection limit of 5.0ng/L were achieved. The high sensitivity obtained with preconcentration and the non-chromatographic separation of inorganic Se species in complex matrix samples such as garlic, onion, leek, broccoli and cauliflower, are the main advantages of IL-VA-LLME. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Determination of arsenic in chicken feed by hydride generation atomic absorption spectrometry after pre-concentration with polyurethane foam.

    PubMed

    Dos Passos, A S; Néri, T S; Maciel, M V; da Silva Romão, I L; Lemos, V A

    2012-01-01

    A pre-concentration procedure with solid-phase extraction was developed for the determination of arsenic (As) in chicken feed using hydride generation atomic absorption spectrometry (HG-AAS). The procedure was based on the sorption of As(III) ions as complexes with ammonium pyrrolidine dithiocarbamate onto a mini-column packed with polyurethane foam. After pre-concentration, the As was removed from the mini-column by acid solution, and the analyte content in the eluate was measured by HG-AAS. The following main experimental conditions were established: adjustment of the As solution pH with 0.05 mol l⁻¹ HCl, 2.88 × 10⁻³ mol l⁻¹ complexing agent concentration and 6.0 mol l⁻¹ eluting hydrochloric acid concentration. The proposed method produced an enrichment factor of 67, with 0.050 and 0.165 µg g⁻¹ limits of detection and quantification, respectively. The procedure was applied to the determination of As content in two types of chicken feed using the proposed procedure and atomic absorption spectrometry with electrothermal atomisation (ETAAS). The t-test indicated that the results were not significantly different at a confidence level of 95%.

  5. Towards the chiral metabolomics: Liquid chromatography-mass spectrometry based DL-amino acid analysis after labeling with a new chiral reagent, (S)-2,5-dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidine-2-carboxylate, and the application to saliva of healthy volunteers.

    PubMed

    Mochizuki, Toshiki; Takayama, Takahiro; Todoroki, Kenichiro; Inoue, Koichi; Min, Jun Zhe; Toyo'oka, Toshimasa

    2015-05-22

    A novel triazine-type chiral derivatization reagent, i.e., (S)-2,5-dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl) pyrrolidine-2-carboxylate (DMT-(S)-Pro-OSu), was developed for the highly sensitive and selective detection of chiral amines and amino acids by UPLC-MS/MS analysis. The enantiomers of amino acids were easily labeled with the reagents at room temperature within 40 min in an alkaline medium containing triethylamine. The diastereomers derived from proteolytic amino acids, except serine, were well separated under isocratic elution conditions by reversed-phase chromatography using an ODS column (Rs=1.2-9.0). DL-Serine was separated by use of an ADME column which has relatively higher polar surface than the conventional ODS column. The characteristic product ions, i.e., m/z 195.3 and m/z 209.3, were detected from all the diastereomers by the collision-induced dissociation of the protonated molecule. A highly sensitive detection on the amol-fmol level was obtained from the selected reaction monitoring (SRM) chromatogram. The chiral amines (e.g., adrenaline and noradrenaline) labeled with DMT-(S)-Pro-OSu were also well separated and sensitively detected by the present procedure. The method using DMT-(S)-Pro-OSu was used for the determination of DL-amino acids in the human saliva from healthy volunteers. Various L-amino acids were identified in the saliva. Furthermore, D-alanine (D-Ala) and D-proline (D-Pro) were also detected in relatively high concentrations (>5%). The ratio was higher in male saliva than in female saliva. However, the difference in the ratio of D-Ala for one day was not very high and the effect of foods and beverage seemed to be negligible. Based on the results using L-Ala-d3, the D-Ala in saliva seemed to be produced due to the racemization with some enzymes such as racemase. The racemization reaction was reversible, i.e., D-Ala-d3 was also racemized to L-Ala-d3 in saliva. Thus, care should be taken during the analysis of DL

  6. Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-D-Aspartate 2B (GluN2B) Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

    PubMed

    Bristow, Linda J; Gulia, Jyoti; Weed, Michael R; Srikumar, Bettadapura N; Li, Yu-Wen; Graef, John D; Naidu, Pattipati S; Sanmathi, Charulatha; Aher, Jayant; Bastia, Tanmaya; Paschapur, Mahesh; Kalidindi, Narasimharaju; Kumar, Kuchibholta Vijaya; Molski, Thaddeus; Pieschl, Rick; Fernandes, Alda; Brown, Jeffrey M; Sivarao, Digavalli V; Newberry, Kimberly; Bookbinder, Mark; Polino, Joseph; Keavy, Deborah; Newton, Amy; Shields, Eric; Simmermacher, Jean; Kempson, James; Li, Jianqing; Zhang, Huiping; Mathur, Arvind; Kallem, Raja Reddy; Sinha, Meenakshee; Ramarao, Manjunath; Vikramadithyan, Reeba K; Thangathirupathy, Srinivasan; Warrier, Jayakumar; Bronson, Joanne J; Olson, Richard E; Macor, John E; Albright, Charlie F; King, Dalton; Thompson, Lorin A; Marcin, Lawrence R; Sinz, Michael

    2017-09-27

    (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), and the phosphate prodrug (BMS-986163), were identified from a drug discovery effort focused on the development of novel, intravenous, glutamate N-methyl-D-aspartate 2B receptor (GluN2B) negative allosteric modulators for treatment resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-D-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human Ether-a-go-go-related gene (hERG) channel activity (IC50 = 28.4 micromolar) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163, dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H]MK-801 binding confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency and increased ex vivo hippocampal long term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD. The American Society for Pharmacology and Experimental Therapeutics.

  7. Differential effects of the substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC) and the non-substrate inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA) of glutamate transporters on neuronal damage and extracellular amino acid levels in rat brain in vivo.

    PubMed

    Montiel, T; Camacho, A; Estrada-Sánchez, A M; Massieu, L

    2005-01-01

    The extracellular concentration of glutamate is highly regulated by transporter proteins, due to its neurotoxic properties. Dysfunction or reverse activation of these transporters is related to the extracellular accumulation of excitatory amino acids and neuronal damage associated with ischemia and hypoglycemia. We have investigated by microdialysis the effects of the substrate and the non-substrate inhibitors of glutamate transporters, l-trans-2,4-pyrrolidine dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA), respectively, on the extracellular levels of amino acids in the rat hippocampus in vivo. In addition, we have studied the effect of both inhibitors on neuronal damage after direct administration into the hippocampus and striatum. Electroencephalographic activity was recorded after the intrahippocampal infusion of DL-TBOA or PDC. Microdialysis administration of 500 microM DL-TBOA into the hippocampus increased 3.4- and nine-fold the extracellular levels of aspartate and glutamate, respectively. Upon stereotaxic administration it induced neuronal damage dose-dependently in CA1 and dentate gyrus, and convulsive behavior. Electroencephalographic recording showed the appearance of limbic seizures in the hippocampus after DL-TBOA infusion. In the striatum it also induced dose-dependent neuronal damage. These effects were prevented by the i.p. administration of the glutamate receptor antagonists (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-iminemaleate and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline. In contrast to dl-TBOA, PDC (500 microM) induced a more discrete elevation of excitatory amino acids levels (2.6- and three-fold in aspartate and glutamate, respectively), no neuronal damage or behavioral changes, and no alterations in electroencephalographic activity. The differential results obtained with DL-TBOA and PDC might be attributed to their distinct effects on the extracellular concentration of amino acids. Results

  8. On the nature of a compound formed from dinitrosyl-iron complexes with cysteine and responsible for a long-lasting vasorelaxation.

    PubMed

    Mokh, Vladimir P; Poltorakov, Alexander P; Serezhenkov, Vladimir A; Vanin, Anatoly F

    2010-05-15

    The nature of a compound able to induce long-lasting (> or =20 min) relaxation of rat abdominal aorta rings after addition of rapidly (within several minutes) disappeared mono- and binuclear dinitrosyl iron complexes with cysteine (M- and B-DNICs, respectively) (10 micromol) to the Krebs medium has been investigated. It has been found that long-lasting vasorelaxation is not induced either by S-nitrosocysteine formed upon decomposition of DNICs or by accumulation of free nitric oxide molecules or nitrite remaining in the incubation medium. Long-term air bubbling of the Krebs medium initially containing M-DNIC is accompanied by conversion of the complex first into B-DNIC, which represents a Roussin's red salt cysteine ester and then into a more stable diamagnetic compound X, which displays an intense absorption band at 278 nm. Compound X is decomposed after treatment with the strong bivalent iron chelator bathophenanthroline disulfonate (BPDS) and N-methyl-D-glucamine dithiocarbamate (MGD). The MGD-induced decomposition of compound X is concomitant with the formation of EPR-detectable mononitrosyl iron complexes with MGD. Treatment of compound X with cysteine results in its decomposition and the appearance of optical absorption bands characteristic of M- and B-DNICs. Evidently, compound X, has an iron-nitrosyl origin similar to that of M- and B-DNICs and its formation in oxygenated DNIC solutions is determined by the lowering cysteine content in them. It is hypothesized that compound X represents a cysteine ester of nitrosyl iron complexes, namely, a black Roussin's salt cysteine ester responsible for long-lasting vasorelaxation initiated by addition of M- and B-DNICs that are rapidly decomposed to compound X to the incubation medium.

  9. On State Complexes and Special Cube Complexes

    ERIC Educational Resources Information Center

    Peterson, Valerie J.

    2009-01-01

    This thesis presents the first steps toward a classification of non-positively curved cube complexes called state complexes. A "state complex" is a configuration space for a "reconfigurable system," i.e., an abstract system in which local movements occur in some discrete manner. Reconfigurable systems can be used to describe, for example,…

  10. On State Complexes and Special Cube Complexes

    ERIC Educational Resources Information Center

    Peterson, Valerie J.

    2009-01-01

    This thesis presents the first steps toward a classification of non-positively curved cube complexes called state complexes. A "state complex" is a configuration space for a "reconfigurable system," i.e., an abstract system in which local movements occur in some discrete manner. Reconfigurable systems can be used to describe, for example,…

  11. STRUCTURES OF THE CLASS D CARBAPENEMASE OXA-24 FROM ACINETOBACTER BAUMANNII IN COMPLEX WITH DORIPENEM

    PubMed Central

    Schneider, Kyle D.; Ortega, Caleb J.; Renck, Nicholas A.; Bonomo, Robert A.; Powers, Rachel A.; Leonard, David A.

    2011-01-01

    The emergence of class D β-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram negative pathogens such as Acinetobacter baumanii. Unfortunately, class D β-lactamases with carbapenemase activity are resistant to β-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6α hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and may be useful for the design of novel inhibitors. PMID:21215758

  12. Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem

    SciTech Connect

    Schneider, Kyle D.; Ortega, Caleb J.; Renck, Nicholas A.; Bonomo, Robert A.; Powers, Rachel A.; Leonard, David A.

    2012-02-08

    The emergence of class D {beta}-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D {beta}-lactamases with carbapenemase activity are resistant to {beta}-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6a hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors.

  13. Nuclear Factor-Kappa B Activity Regulates Brain Expression of P-Glycoprotein in the Kainic Acid-Induced Seizure Rats

    PubMed Central

    Yu, Nian; Di, Qing; Liu, Hao; Hu, Yong; Jiang, Ying; Yan, Yu-kui; Zhang, Yan-fang; Zhang, Ying-dong

    2011-01-01

    This study was aimed to investigate the effect of NF-κB activity on the seizure susceptibility, brain damage, and P-gp expression in kainic acid- (KA-) induced seizure rats. Male SD rats were divided into saline control group (NS group), KA induced epilepsy group (EP group), and epilepsy group intervened with NF-κB inhibitor-pyrrolidine dithiocarbamate salt (PDTC group) or with dexamethasone (DEX group). No seizures were observed in the rats of NS group. Compared with NS group, increased P-gp expression and NF-κB activation in the rat brain of the EP group were observed after KA micro-injection. Both PDTC and DEX pre-treatment significantly increased the latency to grade III or V seizure onset compared to EP group but failed to show neuron-protective effect as the number of survival neurons didn't significantly differ from that in EP group. Furthermore, PDTC pre-treatment significantly decreased P-gp expression along with NF-κB activation in the hippocampus CA3 area and amygdala complex of rats compared with the EP group, implying that NF-κB activation involved in the seizure susceptibility and seizure induced brain P-gp over-expression. Additionally, DEX pre-treatment only decreased P-gp expression level without inhibition of NF-κB activation, suggesting NF-κB independent pathway may also participate in regulating seizure induced P-gp over-expression. PMID:21403895

  14. Determination of inorganic selenium species in water and garlic samples with on-line ionic liquid dispersive microextraction and electrothermal atomic absorption spectrometry.

    PubMed

    Martinis, Estefanía M; Escudero, Leticia B; Berton, Paula; Monasterio, Romina P; Filippini, María F; Wuilloud, Rodolfo G

    2011-09-30

    A non-chromatographic separation and preconcentration method for Se species determination based on the use of an on-line ionic liquid (IL) dispersive microextraction system coupled to electrothermal atomic absorption spectrometry (ETAAS) is proposed. Retention and separation of the IL phase was achieved with a Florisil(®)-packed microcolumn after dispersive liquid-liquid microextraction (DLLME) with tetradecyl(trihexyl)phosphonium chloride IL (CYPHOS(®) IL 101). Selenite [Se(IV)] species was selectively separated by forming Se-ammonium pyrrolidine dithiocarbamate (Se-APDC) complex followed by extraction with CYPHOS(®) IL 101. The methodology was highly selective towards Se(IV), while selenate [Se(VI)] was reduced and then indirectly determined. Several factors influencing the efficiency of the preconcentration technique, such as APDC concentration, sample volume, extractant phase volume, type of eluent, elution flow rate, etc., have been investigated in detail. The limit of detection (LOD) was 15 ng L(-1) and the relative standard deviation (RSD) for 10 replicates at 0.5 μg L(-1) Se concentration was 5.1%, calculated with peak heights. The calibration graph was linear and a correlation coefficient of 0.9993 was achieved. The method was successfully employed for Se speciation studies in garlic extracts and water samples. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Nuclear factor-kappa B activity regulates brain expression of P-glycoprotein in the kainic acid-induced seizure rats.

    PubMed

    Yu, Nian; Di, Qing; Liu, Hao; Hu, Yong; Jiang, Ying; Yan, Yu-kui; Zhang, Yan-fang; Zhang, Ying-dong

    2011-01-01

    This study was aimed to investigate the effect of NF-κB activity on the seizure susceptibility, brain damage, and P-gp expression in kainic acid- (KA-) induced seizure rats. Male SD rats were divided into saline control group (NS group), KA induced epilepsy group (EP group), and epilepsy group intervened with NF-κB inhibitor-pyrrolidine dithiocarbamate salt (PDTC group) or with dexamethasone (DEX group). No seizures were observed in the rats of NS group. Compared with NS group, increased P-gp expression and NF-κB activation in the rat brain of the EP group were observed after KA micro-injection. Both PDTC and DEX pre-treatment significantly increased the latency to grade III or V seizure onset compared to EP group but failed to show neuron-protective effect as the number of survival neurons didn't significantly differ from that in EP group. Furthermore, PDTC pre-treatment significantly decreased P-gp expression along with NF-κB activation in the hippocampus CA3 area and amygdala complex of rats compared with the EP group, implying that NF-κB activation involved in the seizure susceptibility and seizure induced brain P-gp over-expression. Additionally, DEX pre-treatment only decreased P-gp expression level without inhibition of NF-κB activation, suggesting NF-κB independent pathway may also participate in regulating seizure induced P-gp over-expression.

  16. Natural complexity, computational complexity and depth.

    PubMed

    Machta, J

    2011-09-01

    Depth is a complexity measure for natural systems of the kind studied in statistical physics and is defined in terms of computational complexity. Depth quantifies the length of the shortest parallel computation required to construct a typical system state or history starting from simple initial conditions. The properties of depth are discussed and it is compared with other complexity measures. Depth can only be large for systems with embedded computation.

  17. [Complexity of land ecosystem].

    PubMed

    Wu, Cifang; Chen, Meiqiu

    2002-06-01

    In recent years, complexity studies has become a new research region and been widely applied in engineering, biology, economy, management, military, police and sociology. In this paper, from the view of complex science, the main complexity characteristics of land ecosystem were described, furthermore, the application of fractal, chaos, and artificial neural network on the complexity of land ecosystem were also discussed.

  18. Protein Complexes in Bacteria

    PubMed Central

    Caufield, J. Harry; Abreu, Marco; Wimble, Christopher; Uetz, Peter

    2015-01-01

    Large-scale analyses of protein complexes have recently become available for Escherichia coli and Mycoplasma pneumoniae, yielding 443 and 116 heteromultimeric soluble protein complexes, respectively. We have coupled the results of these mass spectrometry-characterized protein complexes with the 285 “gold standard” protein complexes identified by EcoCyc. A comparison with databases of gene orthology, conservation, and essentiality identified proteins conserved or lost in complexes of other species. For instance, of 285 “gold standard” protein complexes in E. coli, less than 10% are fully conserved among a set of 7 distantly-related bacterial “model” species. Complex conservation follows one of three models: well-conserved complexes, complexes with a conserved core, and complexes with partial conservation but no conserved core. Expanding the comparison to 894 distinct bacterial genomes illustrates fractional conservation and the limits of co-conservation among components of protein complexes: just 14 out of 285 model protein complexes are perfectly conserved across 95% of the genomes used, yet we predict more than 180 may be partially conserved across at least half of the genomes. No clear relationship between gene essentiality and protein complex conservation is observed, as even poorly conserved complexes contain a significant number of essential proteins. Finally, we identify 183 complexes containing well-conserved components and uncharacterized proteins which will be interesting targets for future experimental studies. PMID:25723151

  19. Complex networks analysis of language complexity

    NASA Astrophysics Data System (ADS)

    Amancio, Diego R.; Aluisio, Sandra M.; Oliveira, Osvaldo N., Jr.; Costa, Luciano da F.

    2012-12-01

    Methods from statistical physics, such as those involving complex networks, have been increasingly used in the quantitative analysis of linguistic phenomena. In this paper, we represented pieces of text with different levels of simplification in co-occurrence networks and found that topological regularity correlated negatively with textual complexity. Furthermore, in less complex texts the distance between concepts, represented as nodes, tended to decrease. The complex networks metrics were treated with multivariate pattern recognition techniques, which allowed us to distinguish between original texts and their simplified versions. For each original text, two simplified versions were generated manually with increasing number of simplification operations. As expected, distinction was easier for the strongly simplified versions, where the most relevant metrics were node strength, shortest paths and diversity. Also, the discrimination of complex texts was improved with higher hierarchical network metrics, thus pointing to the usefulness of considering wider contexts around the concepts. Though the accuracy rate in the distinction was not as high as in methods using deep linguistic knowledge, the complex network approach is still useful for a rapid screening of texts whenever assessing complexity is essential to guarantee accessibility to readers with limited reading ability.

  20. Evolution of biological complexity.

    PubMed

    Adami, C; Ofria, C; Collier, T C

    2000-04-25

    To make a case for or against a trend in the evolution of complexity in biological evolution, complexity needs to be both rigorously defined and measurable. A recent information-theoretic (but intuitively evident) definition identifies genomic complexity with the amount of information a sequence stores about its environment. We investigate the evolution of genomic complexity in populations of digital organisms and monitor in detail the evolutionary transitions that increase complexity. We show that, because natural selection forces genomes to behave as a natural "Maxwell Demon," within a fixed environment, genomic complexity is forced to increase.

  1. Evolution of biological complexity

    PubMed Central

    Adami, Christoph; Ofria, Charles; Collier, Travis C.

    2000-01-01

    To make a case for or against a trend in the evolution of complexity in biological evolution, complexity needs to be both rigorously defined and measurable. A recent information-theoretic (but intuitively evident) definition identifies genomic complexity with the amount of information a sequence stores about its environment. We investigate the evolution of genomic complexity in populations of digital organisms and monitor in detail the evolutionary transitions that increase complexity. We show that, because natural selection forces genomes to behave as a natural “Maxwell Demon,” within a fixed environment, genomic complexity is forced to increase. PMID:10781045

  2. Radioisotope trithiol complexes

    DOEpatents

    Jurisson, Silvia S.; Cutler, Cathy S.; Degraffenreid, Anthony J.

    2016-08-30

    The present invention is directed to a series of stable radioisotope trithiol complexes that provide a simplified route for the direct complexation of radioisotopes present in low concentrations. In certain embodiments, the complex contains a linking domain configured to conjugate the radioisotope trithiol complex to a targeting vector. The invention is also directed to a novel method of linking the radioisotope to a trithiol compound to form the radioisotope trithiol complex. The inventive radioisotope trithiol complexes may be utilized for a variety of applications, including diagnostics and/or treatment in nuclear medicine.

  3. Cyanobacterial NADPH dehydrogenase complexes

    SciTech Connect

    Ogawa, Teruo; Mi, Hualing

    2007-07-01

    Cyanobacteria possess functionally distinct multiple NADPH dehydrogenase (NDH-1) complexes that are essential to CO2 uptake, photosystem-1 cyclic electron transport and respiration. The unique nature of cyanobacterial NDH-1 complexes is the presence of subunits involved in CO2 uptake. Other than CO2 uptake, chloroplastic NDH-1 complex has similar role as cyanobacterial NDH-1 complexes in photosystem-1 cyclic electron transport and respiration (chlororespiration). In this mini-review we focus on the structure and function of cyanobacterial NDH-1 complexes and their phylogeny. The function of chloroplastic NDH-1 complex and characteristics of plants defective in NDH-1 are also described forcomparison.

  4. Bonding analyses, formation energies, and vibrational properties of M-R2dtc complexes (M=Ag(I), Ni(II), Cu(II), or Zn(II)).

    PubMed

    Georgieva, I; Trendafilova, N

    2007-12-20

    Detailed theoretical studies based on density functional theory (DFT)/B3LYP calculations of dimethyl- and diethyldithiocarbamate complexes of Ni(II), Cu(II), Zn(II), and Ag(I) are performed to characterize the metal-ligand bonding type as well as the metal-ligand bonding strength depending on the metal and the dialkyl substituent. The metal-ligand interactions in the studied complexes are investigated by means of charge decomposition analysis, energy partitioning analysis (EPA), and natural bond orbital analysis. According to the EPA calculations, the electrostatic attraction is the dominant contribution to the M-S2(R2dtc) (dtc=dithiocarbamate) bonding. The electrostatic and the orbital energies follow the order of the total binding energy, and hence both contributions are responsible for the binding energy order of M(R2dtc)2 complexes. The stability of the M(R2dtc)2 complexes is estimated by means of calculated formation reaction energies in the gas phase and solution, and it decreases in the order Ni(R2dtc)2>Cu(R2dtc)2>Zn(R2dtc)2. Larger formation reaction energies are found for M(Et2dtc)2 than for M(Me2dtc)2 complexes. The calculations predict stabilization of M(II)(R2dtc)2 complexes going from the gas phase to a polar solvent and destabilization of the bidentate AgR2dtc complex in a polar solvent. Gas-phase frequency calculations of all possible bonding types, symmetrical, asymmetrical, and uni- and bidentate, predict one band due to the nu(CS) IR absorption, and therefore the number of the bands in the 1060-920 cm(-1) region could not be used to discern the metal-ligand bonding type. Periodic DFT frequency calculations for Cu(Et2dtc)2 reveal that the splitting observed in the solid-state spectra of the complexes arises from the nonplanar MS4 fragment and intermolecular contacts but not from asymmetrical bonding. The calculations suggest that the important vibrational characteristic that can be used to discern uni- and bidentate bonding is the Raman activity of

  5. Adaptive Leadership: Fighting Complexity with Complexity

    DTIC Science & Technology

    2014-06-01

    Leader’s Framework for Decision Making,” 71. 24 Melanie Mitchell, Complexity: A Guided Tour (Oxford, UK: Oxford University Press, 2009), 12. 25...2011), 377. 29 Mitchell, Complexity: A Guided Tour. 30 Douglas Hofstadter, Gödel, Escher, Bach: An Eternal Golden Braid (New York: Penguin Books...A Guided Tour, 10. 34 Barabasi, Linked: How Everything is Connected to Everything Else and what it Means, 145. 13

  6. Oligocyclopentadienyl transition metal complexes

    SciTech Connect

    de Azevedo, Cristina G.; Vollhardt, K. Peter C.

    2002-01-18

    Synthesis, characterization, and reactivity studies of oligocyclopentadienyl transition metal complexes, namely those of fulvalene, tercyclopentadienyl, quatercyclopentadienyl, and pentacyclopentadienyl(cyclopentadienyl) are the subject of this account. Thermal-, photo-, and redox chemistries of homo- and heteropolynuclear complexes are described.

  7. Irinotecan Lipid Complex Injection

    MedlinePlus

    Irinotecan lipid complex is used in combination with other medications to treat pancreatic cancer that has spread to other ... worsened after treatment with other chemotherapy medications. Irinotecan lipid complex is in a class of antineoplastic medications ...

  8. Vincristine Lipid Complex Injection

    MedlinePlus

    Vincristine lipid complex is used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer ... least two different treatments with other medications. Vincristine lipid complex is in a class of medications called ...

  9. Daunorubicin Lipid Complex Injection

    MedlinePlus

    Daunorubicin lipid complex is used to treat advanced Kaposi's sarcoma (a type of cancer that causes abnormal tissue to ... body) related to acquired immunodeficiency syndrome (AIDS). Daunorubicin lipid complex is in a class of medications called ...

  10. Weighted growing simplicial complexes

    NASA Astrophysics Data System (ADS)

    Courtney, Owen T.; Bianconi, Ginestra

    2017-06-01

    Simplicial complexes describe collaboration networks, protein interaction networks, and brain networks and in general network structures in which the interactions can include more than two nodes. In real applications, often simplicial complexes are weighted. Here we propose a nonequilibrium model for weighted growing simplicial complexes. The proposed dynamics is able to generate weighted simplicial complexes with a rich interplay between weights and topology emerging not just at the level of nodes and links, but also at the level of faces of higher dimension.

  11. The nuclear pore complex

    PubMed Central

    Adam, Stephen A

    2001-01-01

    Nuclear pore complexes, the conduits for information exchange between the nucleus and cytoplasm, appear broadly similar in eukaryotes from yeast to human. Precisely how nuclear pore complexes regulate macromolecular and ionic traffic remains unknown, but recent advances in the identification and characterization of components of the complex by proteomics and genomics have provided new insights. PMID:11574060

  12. Crystallization of macromolecular complexes: combinatorial complex crystallization

    NASA Astrophysics Data System (ADS)

    Stura, Enrico A.; Graille, Marc; Charbonnier, Jean-Baptiste

    2001-11-01

    The usefulness of antibody complexation, as a way of increasing the chances of crystallization needs to be re-evaluated after many antibody complexes have been crystallized and their structure determined. It is somewhat striking that among these, only a small number is a complex with a large protein antigen. The problem is that the effort of raising, cleaving and purifying an Fab is rewarded only by an extra chance of getting crystals; depending on the relative likelihood of crystallization of the complexed and uncomplexed protein. The example of the complex between HIV gp120, CD4 and an Fab fragment from a neutralizing antibody suggests that further complexation of an antigen-antibody complex with a third protein could, by increasing the number of possible combinations, improve the likelihood of crystallization. We propose the use of Ig-binding proteins as a way of extending the method from HIV gp120 to all proteins for which there are monoclonal antibodies. We discuss this technique, combinatorial complex crystallization (CCC), as part of a multi-component system for the enhancement of crystallization of macromolecular complexes. The method makes use of single Ig-binding domains from Staphylococcus aureus protein A (SpA), Peptostreptococcus magnus protein L (PpL) and the streptococcal protein G (SpG). The generality of the method depends on the ability of these domains to interact with a large repertoire of antibodies without affecting antigen binding. There is strong evidence to suggest that these Ig-binding domains bind outside the antigen-combining site of the antibody without perturbing antigen binding. It is clear from the crystal structure of the single SpG domain complexed with an Fab that the interaction involves mainly the immunoglobulin CH1 domain, a region not involved in antigen recognition. We have recently determined the structure of the complex between a human Fab and the domain D from SpA and found that steric hindrance is unlikely even for large

  13. DNA damage in Wistar rats exposed to dithiocarbamate pesticide mancozeb.

    PubMed

    Goldoni, A; Klauck, C R; Da Silva, S T; Da Silva, M D; Ardenghi, P G; Da Silva, L B

    2014-01-01

    Pesticides are used in large amounts in agriculture and the evaluation of their toxic effects is of major concern to public and environmental health. The aim of the present study was to investigate the genotoxic potential of a commercial formulation of the fungicide mancozeb by the micronucleus test in bone marrow and the comet assay in total blood of Wistar rats. Adult male Wistar rats were treated with a solution of mancozeb at a concentration of 40 mg/kg/day, administered intraperitoneally for 18 consecutive days, and compared to a control group. The results indicate that mancozeb induced significantly higher DNA damage as detected by the comet assay and increased the frequency of micronuclei. The results show that mancozeb is genotoxic and may adversely affect the DNA integrity of exposed organisms.

  14. Complex Correspondence Principle

    SciTech Connect

    Bender, Carl M.; Meisinger, Peter N.; Hook, Daniel W.; Wang Qinghai

    2010-02-12

    Quantum mechanics and classical mechanics are distinctly different theories, but the correspondence principle states that quantum particles behave classically in the limit of high quantum number. In recent years much research has been done on extending both quantum and classical mechanics into the complex domain. These complex extensions continue to exhibit a correspondence, and this correspondence becomes more pronounced in the complex domain. The association between complex quantum mechanics and complex classical mechanics is subtle and demonstrating this relationship requires the use of asymptotics beyond all orders.

  15. The Oriented Graph Complexes

    NASA Astrophysics Data System (ADS)

    Willwacher, Thomas

    2015-03-01

    The oriented graph complexes are complexes of directed graphs without directed cycles. They govern, for example, the quantization of Lie bialgebras and infinite dimensional deformation quantization. Similar to the ordinary graph complexes GC n introduced by Kontsevich they come in two essentially different versions, depending on the parity of n. It is shown that, surprisingly, the oriented graph complex is quasi-isomorphic to the ordinary commutative graph complex of opposite parity GC n-1, up to some known classes. This yields in particular a combinatorial description of the action of on Lie bialgebras, and shows that a cycle-free formality morphism in the sense of Shoikhet can be constructed rationally without reference to configuration space integrals. Curiously, the obstruction class in the oriented graph complex found by Shoikhet corresponds to the well known theta graph in the ordinary graph complex.

  16. Complex virial theorem and complex scaling

    SciTech Connect

    Junker, B.R.

    1983-06-01

    We present the simple generalization to complex energies of the normal global real scaling used for bound-state calculations to produce a variational energy which satisfies the virial theorem. We show that in two limiting cases, one or the other of which is almost always p satisfied in all calculations, the virially stabilized complex energy is sensitive to only the real part or the imaginary part of the complex virial expression. We then compute the virial expression for a number of wave functions for the 1s2s/sup 2/ /sup 2/S He/sup -/, 1s2s2p /sup 2/P/sup o/ He/sup -/, and 1s/sup 2/2s/sup 2/kp /sup 2/P/sup o/ Be/sup -/ resonances and the corresponding virially stabilized resonance energies. In all calculations one of the limiting cases was applicable.

  17. Assessing physiological complexity.

    PubMed

    Burggren, W W; Monticino, M G

    2005-09-01

    Physiologists both admire and fear complexity, but we have made relatively few attempts to understand it. Inherently complex systems are more difficult to study and less predictable. However, a deeper understanding of physiological systems can be achieved by modifying experimental design and analysis to account for complexity. We begin this essay with a tour of some mathematical views of complexity. After briefly exploring chaotic systems, information theory and emergent behavior, we reluctantly conclude that, while a mathematical view of complexity provides useful perspectives and some narrowly focused tools, there are too few generally practical take-home messages for physiologists studying complex systems. Consequently, we attempt to provide guidelines as to how complex systems might be best approached by physiologists. After describing complexity based on the sum of a physiological system's structures and processes, we highlight increasingly refined approaches based on the pattern of interactions between structures and processes. We then provide a series of examples illustrating how appreciating physiological complexity can improve physiological research, including choosing experimental models, guiding data collection, improving data interpretations and constructing more rigorous system models. Finally, we conclude with an invitation for physiologists, applied mathematicians and physicists to collaborate on describing, studying and learning from studies of physiological complexity.

  18. Hypergraph coloring complexes.

    PubMed

    Breuer, Felix; Dall, Aaron; Kubitzke, Martina

    2012-08-28

    The aim of this paper is to generalize the notion of the coloring complex of a graph to hypergraphs. We present three different interpretations of those complexes-a purely combinatorial one and two geometric ones. It is shown, that most of the properties, which are known to be true for coloring complexes of graphs, break down in this more general setting, e.g., Cohen-Macaulayness and partitionability. Nevertheless, we are able to provide bounds for the [Formula: see text]- and [Formula: see text]-vectors of those complexes which yield new bounds on chromatic polynomials of hypergraphs. Moreover, though it is proven that the coloring complex of a hypergraph has a wedge decomposition, we provide an example showing that in general this decomposition is not homotopy equivalent to a wedge of spheres. In addition, we can completely characterize those hypergraphs whose coloring complex is connected.

  19. Complexation of Optoelectronic Systems

    NASA Astrophysics Data System (ADS)

    Boreisho, A. S.; Il‧in, M. Yu.; Konyaev, M. A.; Mikhailenko, A. S.; Morozov, A. V.; Strakhov, S. Yu.

    2016-05-01

    Problems of increasing the efficiency and the functionality of complex optoelectronic systems for monitoring real atmospheric conditions and of their use are discussed. It is shown by the example of a meteorological complex comprising an infrared wind-sensing lidar and an X-range Doppler radar that the complexation of probing systems working in different electromagnetic-radiation ranges opens up new opportunities for determining the meteorological parameters of a turbulent atmosphere and investigating the interaction of radiation with it.

  20. An electrochemical study of the speciation of copper, zinc and iron in two estuaries in England

    NASA Astrophysics Data System (ADS)

    van den Berg, Constant M. G.; Buckley, Philip J. M.; Huang, Zi Qiang; Nimmo, M.

    1986-04-01

    The organic speciation of copper, iron and zinc in estuarine waters is studied using electrochemical techniques. Complexing capacities for copper and zinc were determined by cathodic stripping voltammetry (CSV) of their complexes with respectively catechol and amino pyrrolidine dithiocarbamate (APDC). Iron speciation was studied by CSV measurements of dissolved iron before ('free iron') and after acidification and UV-irradiation ('total iron') of the filtered samples. Complexing capacities of copper were found to vary between 1·4 and 5 × 10 -7M with conditional stability constants, log K' CuL, between 9·2 and 10·3 in the Tamar estuary. Complexing capacities of zinc were less at between 0·4 and 1·6 × 10 -7M with values for log K' ZnL between 8·1 and 9·4. Copper complexing capacities generally decreased with increasing salinity, and variations in the results were related to high concentrations of suspended material. Similar variations in the dissolved vanadium concentrations suggested that part of this element was associated with colloidal material. The total dissolved iron concentration in samples from the River Ribble decreased from 10 -6M at low salinity to 10 -7M at high salinity, but the free iron concentration was found to decrease from 8 to 3 × 10 -8M over the same salinity range, which may be compared with the calculated solubility of iron in seawater of 2 × 10 -8M. Comparative experiments showed that on average about 24% of the non-labile iron fraction was stabilized by organic material, the rest being composed of inorganic colloidal material.

  1. Visual complexity: a review.

    PubMed

    Donderi, Don C

    2006-01-01

    The idea of visual complexity, the history of its measurement, and its implications for behavior are reviewed, starting with structuralism and Gestalt psychology at the beginning of the 20th century and ending with visual complexity theory, perceptual learning theory, and neural circuit theory at the beginning of the 21st. Evidence is drawn from research on single forms, form and texture arrays and visual displays. Form complexity and form probability are shown to be linked through their reciprocal relationship in complexity theory, which is in turn shown to be consistent with recent developments in perceptual learning and neural circuit theory. Directions for further research are suggested.

  2. Complexity and schizophrenia.

    PubMed

    Fernández, Alberto; Gómez, Carlos; Hornero, Roberto; López-Ibor, Juan José

    2013-08-01

    Complexity estimators have been broadly utilized in schizophrenia investigation. Early studies reported increased complexity in schizophrenia patients, associated with a higher variability or "irregularity" of their brain signals. However, further investigations showed reduced complexities, thus introducing a clear divergence. Nowadays, both increased and reduced complexity values are reported. The explanation of such divergence is a critical issue to understand the role of complexity measures in schizophrenia research. Considering previous arguments a complementary hypothesis is advanced: if the increased irregularity of schizophrenia patients' neurophysiological activity is assumed, a "natural" tendency to increased complexity in EEG and MEG scans should be expected, probably reflecting an abnormal neuronal firing pattern in some critical regions such as the frontal lobes. This "natural" tendency to increased complexity might be modulated by the interaction of three main factors: medication effects, symptomatology, and age effects. Therefore, young, medication-naïve, and highly symptomatic (positive symptoms) patients are expected to exhibit increased complexities. More importantly, the investigation of these interacting factors by means of complexity estimators might help to elucidate some of the neuropathological processes involved in schizophrenia.

  3. Bacterial formate hydrogenlyase complex

    PubMed Central

    McDowall, Jennifer S.; Murphy, Bonnie J.; Haumann, Michael; Palmer, Tracy; Armstrong, Fraser A.; Sargent, Frank

    2014-01-01

    Under anaerobic conditions, Escherichia coli can carry out a mixed-acid fermentation that ultimately produces molecular hydrogen. The enzyme directly responsible for hydrogen production is the membrane-bound formate hydrogenlyase (FHL) complex, which links formate oxidation to proton reduction and has evolutionary links to Complex I, the NADH:quinone oxidoreductase. Although the genetics, maturation, and some biochemistry of FHL are understood, the protein complex has never been isolated in an intact form to allow biochemical analysis. In this work, genetic tools are reported that allow the facile isolation of FHL in a single chromatographic step. The core complex is shown to comprise HycE (a [NiFe] hydrogenase component termed Hyd-3), FdhF (the molybdenum-dependent formate dehydrogenase-H), and three iron-sulfur proteins: HycB, HycF, and HycG. A proportion of this core complex remains associated with HycC and HycD, which are polytopic integral membrane proteins believed to anchor the core complex to the cytoplasmic side of the membrane. As isolated, the FHL complex retains formate hydrogenlyase activity in vitro. Protein film electrochemistry experiments on Hyd-3 demonstrate that it has a unique ability among [NiFe] hydrogenases to catalyze production of H2 even at high partial pressures of H2. Understanding and harnessing the activity of the FHL complex is critical to advancing future biohydrogen research efforts. PMID:25157147

  4. U1A Complex

    SciTech Connect

    2014-10-28

    Some of the most sophisticated experiments in the stockpile stewardship program are conducted in an environmentally safe manner, nearly 1000 feet below the ground at the site. The U1a complex a sprawling underground laboratory and tunnel complex is home to a number of unique capabilities.

  5. The Tom Core Complex

    PubMed Central

    Ahting, Uwe; Thun, Clemens; Hegerl, Reiner; Typke, Dieter; Nargang, Frank E.; Neupert, Walter; Nussberger, Stephan

    1999-01-01

    Translocation of nuclear-encoded preproteins across the outer membrane of mitochondria is mediated by the multicomponent transmembrane TOM complex. We have isolated the TOM core complex of Neurospora crassa by removing the receptors Tom70 and Tom20 from the isolated TOM holo complex by treatment with the detergent dodecyl maltoside. It consists of Tom40, Tom22, and the small Tom components, Tom6 and Tom7. This core complex was also purified directly from mitochondria after solubilization with dodecyl maltoside. The TOM core complex has the characteristics of the general insertion pore; it contains high-conductance channels and binds preprotein in a targeting sequence-dependent manner. It forms a double ring structure that, in contrast to the holo complex, lacks the third density seen in the latter particles. Three-dimensional reconstruction by electron tomography exhibits two open pores traversing the complex with a diameter of ∼2.1 nm and a height of ∼7 nm. Tom40 is the key structural element of the TOM core complex. PMID:10579717

  6. COMPLEXITY IN ECOLOGICAL SYSTEMS

    EPA Science Inventory

    The enormous complexity of ecosystems is generally obvious under even the most cursory examination. In the modern world, this complexity is further augmented by the linkage of ecosystems to economic and social systems through the human use of the environment for technological pu...

  7. Performance Improvement Assuming Complexity

    ERIC Educational Resources Information Center

    Rowland, Gordon

    2007-01-01

    Individual performers, work teams, and organizations may be considered complex adaptive systems, while most current human performance technologies appear to assume simple determinism. This article explores the apparent mismatch and speculates on future efforts to enhance performance if complexity rather than simplicity is assumed. Included are…

  8. Complexity and Relations

    ERIC Educational Resources Information Center

    Lancaster, Jeanette Elizabeth

    2013-01-01

    A central feature of complexity is that it is based on non-linear, recursive relations. However, in most current accounts of complexity such relations, while non-linear, are based on the reductive relations of a Newtonian onto-epistemological framework. This means that the systems that are emergent from the workings of such relations are a…

  9. Visual Complexity: A Review

    ERIC Educational Resources Information Center

    Donderi, Don C.

    2006-01-01

    The idea of visual complexity, the history of its measurement, and its implications for behavior are reviewed, starting with structuralism and Gestalt psychology at the beginning of the 20th century and ending with visual complexity theory, perceptual learning theory, and neural circuit theory at the beginning of the 21st. Evidence is drawn from…

  10. Visual Complexity: A Review

    ERIC Educational Resources Information Center

    Donderi, Don C.

    2006-01-01

    The idea of visual complexity, the history of its measurement, and its implications for behavior are reviewed, starting with structuralism and Gestalt psychology at the beginning of the 20th century and ending with visual complexity theory, perceptual learning theory, and neural circuit theory at the beginning of the 21st. Evidence is drawn from…

  11. U1A Complex

    ScienceCinema

    None

    2016-07-12

    Some of the most sophisticated experiments in the stockpile stewardship program are conducted in an environmentally safe manner, nearly 1000 feet below the ground at the site. The U1a complex a sprawling underground laboratory and tunnel complex is home to a number of unique capabilities.

  12. Complexity and valued landscapes

    Treesearch

    Michael M. McCarthy

    1979-01-01

    The variable "complexity," or "diversity," has received a great deal of attention in recent research efforts concerned with visual resource management, including the identification of complexity as one of the primary evaluation measures. This paper describes research efforts that support the hypothesis that the landscapes we value are those with...

  13. Complexity and Relations

    ERIC Educational Resources Information Center

    Lancaster, Jeanette Elizabeth

    2013-01-01

    A central feature of complexity is that it is based on non-linear, recursive relations. However, in most current accounts of complexity such relations, while non-linear, are based on the reductive relations of a Newtonian onto-epistemological framework. This means that the systems that are emergent from the workings of such relations are a…

  14. COMPLEXITY IN ECOLOGICAL SYSTEMS

    EPA Science Inventory

    The enormous complexity of ecosystems is generally obvious under even the most cursory examination. In the modern world, this complexity is further augmented by the linkage of ecosystems to economic and social systems through the human use of the environment for technological pu...

  15. Complexity in Picture Books

    ERIC Educational Resources Information Center

    Sierschynski, Jarek; Louie, Belinda; Pughe, Bronwyn

    2015-01-01

    One of the key requirements of Common Core State Standards (CCSS) in English Language Arts is that students are able to read and access complex texts across all grade levels. The CCSS authors emphasize both the limitations and lack of accuracy in the current CCSS model of text complexity, calling for the development of new frameworks. In response…

  16. Performance Improvement Assuming Complexity

    ERIC Educational Resources Information Center

    Rowland, Gordon

    2007-01-01

    Individual performers, work teams, and organizations may be considered complex adaptive systems, while most current human performance technologies appear to assume simple determinism. This article explores the apparent mismatch and speculates on future efforts to enhance performance if complexity rather than simplicity is assumed. Included are…

  17. Complexity and emergent phenomena.

    PubMed

    Suki, Béla; Bates, Jason H T; Frey, Urs

    2011-04-01

    Complex biological systems operate under non-equilibrium conditions and exhibit emergent properties associated with correlated spatial and temporal structures. These properties may be individually unpredictable, but tend to be governed by power-law probability distributions and/or correlation. This article reviews the concepts that are invoked in the treatment of complex systems through a wide range of respiratory-related examples. Following a brief historical overview, some of the tools to characterize structural variabilities and temporal fluctuations associated with complex systems are introduced. By invoking the concept of percolation, the notion of multiscale behavior and related modeling issues are discussed. Spatial complexity is then examined in the airway and parenchymal structures with implications for gas exchange followed by a short glimpse of complexity at the cellular and subcellular network levels. Variability and complexity in the time domain are then reviewed in relation to temporal fluctuations in airway function. Next, an attempt is given to link spatial and temporal complexities through examples of airway opening and lung tissue viscoelasticity. Specific examples of possible and more direct clinical implications are also offered through examples of optimal future treatment of fibrosis, exacerbation risk prediction in asthma, and a novel method in mechanical ventilation. Finally, the potential role of the science of complexity in the future of physiology, biology, and medicine is discussed.

  18. Complexity: against systems.

    PubMed

    Chu, Dominique

    2011-09-01

    This article assumes a specific intuitive notion of complexity as a difficulty to generate and/or assess the plausibility of models. Based on this intuitive understanding of complexity, it identifies two main causes of complexity, namely, radical openness and contextuality. The former is the idea that there are no natural systems. The modeler always needs to draw artificial boundaries around phenomena to generate feasible models. Contextuality is intimately connected to the requirement to simplify models and to leave out most aspects. Complexity occurs when contextuality and radical openness cannot be contained that is when it is not clear where the boundaries of the system are and which abstractions are the correct ones. This concept of complexity is illustrated using a number of example from evolution.

  19. Hypergraph coloring complexes

    PubMed Central

    Breuer, Felix; Dall, Aaron; Kubitzke, Martina

    2012-01-01

    The aim of this paper is to generalize the notion of the coloring complex of a graph to hypergraphs. We present three different interpretations of those complexes–a purely combinatorial one and two geometric ones. It is shown, that most of the properties, which are known to be true for coloring complexes of graphs, break down in this more general setting, e.g., Cohen–Macaulayness and partitionability. Nevertheless, we are able to provide bounds for the f- and h-vectors of those complexes which yield new bounds on chromatic polynomials of hypergraphs. Moreover, though it is proven that the coloring complex of a hypergraph has a wedge decomposition, we provide an example showing that in general this decomposition is not homotopy equivalent to a wedge of spheres. In addition, we can completely characterize those hypergraphs whose coloring complex is connected. PMID:23483700

  20. Complexity and behavioral economics.

    PubMed

    Rosser, J Barkley; Rosser, Marina V

    2015-04-01

    This paper will consider the relationship between complexity economics and behavioral economics. A crucial key to this is to understand that Herbert Simon was both the founder of explicitly modern behavioral economics as well as one of the early developers of complexity theory. Bounded rationality was essentially derived from Simon's view of the impossibility of full rationality on the part of economic agents. Modern complexity theory through such approaches as agent-based modeling offers an approach to understanding behavioral economics by allowing for specific behavioral responses to be assigned to agents who interact within this context, even without full rationality. Other parts of modern complexity theory are considered in terms of their relationships with behavioral economics. Fundamentally, complexity provides an ultimate foundation for bounded rationality and hence the need to use behavioral economics in a broader array of contexts than most economists have thought appropriate.

  1. A Novel Ternary Ligand System Useful for Preparation of Cationic 99mTc-Diazenido Complexes and 99mTc-Labeling of Small Biomolecules

    PubMed Central

    Kim, Young-Seung; He, Zhengjie; Hsieh, Wen-Yuan; Liu, Shuang

    2008-01-01

    This report describes a novel ternary ligand system composed of a phenylhydrazine, a crown ether-containing dithiocarbamate (DTC) and a PNP-type bisphosphine (PNP). The combination of three different ligands with 99mTc results in cationic 99mTc-diazenido complexes,[99mTc(NNAr)(DTC)(PNP)]+, with potential radiopharmaceuticals for heart imaging. Synthesis of cationic 99mTc-diazenido complexes can be accomplished in two steps with high yield. For example, the reaction of phenylhydrazine with 99mTcO4− at 100 °C in the presence of excess stannous chloride and 1,2-diaminopropane-N,N,N’,N’-tetraacetic acid (PDTA) results in the [99mTc(NNPh)(PDTA)n] intermediate, which then reacts with sodium N-(dithiocarbamato)-2-aminimethyl-15-Crown-5 (L4) and N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]ethoxy-ethylamine (PNP6) at 100 °C for 15 min to give the complex, [99mTc(NNPh)(L4)(PNP6)]+ in high yield (> 90%). Cationic complexes [99mTc(NNPh)(DTC)(PNP)]+ are stable for ≥6 h. Their composition was determined to be 1:1:1:1 for Tc:NNPh:DTC:PNP using the mixed-ligand experiments on the tracer (99mTc) level, and was further confirmed by the ESI-MS spectral data of a model compound [Re(NNPh)(L4)(L6)]+. It was found that both DTCs and bisphosphines have a significant impact on the lipophilicity of their cationic 99mTc-diazenido complexes. Results from a 99mTc-labeling efficiency experiment showed that 4-hydrazinobenzoic acid (HYBA) might be useful as a bifunctional coupling agent for 99mTc-labeling of small biomolecules. However, the 99mTc-labeling efficiency of HYBA is much lower than that of 6-hydrazinonicotinic acid (HYNIC) with tricine and trisodium triphenylphosphine-3,3’,3”-trisulfonate (TPPTS) as coligands. PMID:16536480

  2. Determination of traces of silver in waters by anion exchange and atomic absorption spectrophotometry

    USGS Publications Warehouse

    Chao, T.T.; Fishman, M. J.; Ball, J.W.

    1969-01-01

    A method has been developed for the accurate determination of 0.1-1 ??g of silver per liter of water. The method permits stabilization of silver in water without loss to container walls. Optimum conditions have been established for the complete recovery of silver from water with an anion-exchange column, for quantitative elution of silver from the resin, and for measurement of silver by atomic absorption spectrophotometry after chelation with ammonium pyrrolidine dithiocarbamate and extraction of the chelate with MIBK. Silver in the 1-10 ??g 1 range can be determined by extraction without pre-concentration on an ion-exchange resin. ?? 1969.

  3. Selenophene transition metal complexes

    SciTech Connect

    White, Carter James

    1994-07-27

    This research shows that selenophene transition metal complexes have a chemistry that is similar to their thiophene analogs. Selenophene coordination has been demonstrated and confirmed by molecular structure in both the η5- and the η1(Se)-coordination modes. The reaction chemistry of selenophene complexes closely resembles that of the analogous thiophene complexes. One major difference, however, is that selenophene is a better donor ligand than thiophene making the selenophene complexes more stable than the corresponding thiophene complexes. The 77Se NMR chemical shift values for selenophene complexes fall within distinct regions primarily depending on the coordination mode of the selenophene ligand. In the final paper, the C-H bond activation of η1(S)-bound thiophenes, η1(S)-benzothiophene and η1(Se)-bound selenophenes has been demonstrated. The deprotonation and rearrangement of the η1(E)-bound ligand to the carbon bound L-yl complex readily occurs in the presence of base. Reprotonation with a strong acid gives a carbene complex that is unreactive towards nucleophilic attack at the carbene carbon and is stable towards exposure to air. The molecular structure of [Cp(NO)(PPh3)Re(2-benzothioenylcarbene)]O3SCF3 was determined and contains a Re-C bond with substantial double bond character. Methyl substitution for the thienylcarbene or selenylcarbene gives a carbene that rearranges thermally to give back the η1(E)-bound complex. Based on these model reactions, a new mechanism for the H/D exchange of thiophene over the hydrodesulfurization catalyst has been proposed.

  4. Complexity and robustness

    PubMed Central

    Carlson, J. M.; Doyle, John

    2002-01-01

    Highly optimized tolerance (HOT) was recently introduced as a conceptual framework to study fundamental aspects of complexity. HOT is motivated primarily by systems from biology and engineering and emphasizes, (i) highly structured, nongeneric, self-dissimilar internal configurations, and (ii) robust yet fragile external behavior. HOT claims these are the most important features of complexity and not accidents of evolution or artifices of engineering design but are inevitably intertwined and mutually reinforcing. In the spirit of this collection, our paper contrasts HOT with alternative perspectives on complexity, drawing on real-world examples and also model systems, particularly those from self-organized criticality. PMID:11875207

  5. Afterglow Complex Plasma

    SciTech Connect

    Samarian, A. A.; Boufendi, L.; Mikikian, M.

    2008-09-07

    The review of the first detailed experimental and theoretical studies of complex plasma in RF discharge afterglow is presented. The studies have been done in a frame of FAST collaborative research project between Complex Plasma Laboratory of the University of Sydney and the GREMI laboratory of Universite d'Orleans. We examined the existing models of plasma decay, presents experimental observations of dust dynamics under different afterglow complex plasma conditions, presents the experimental data obtained (in particular the presence of positively charged particles in discharge afterglow), discusses the use of dust particles as a probe to study the diffusion losses in afterglow plasmas.

  6. Complexity and forensic pathology.

    PubMed

    Jones, Richard Martin

    2015-12-01

    It has become increasingly apparent that nonlinearity and complexity are the norm in human physiological systems, the relevance of which is informing an enhanced understanding of basic pathological processes such as inflammation, the host response to severe trauma, and critical illness. This article will explore how an understanding of nonlinear systems and complexity might inform the study of the pathophysiology of deaths of medicolegal interest, and how 'complexity thinking' might usefully be incorporated into modern forensic medicine and forensic pathology research, education and practice.

  7. Complex and unpredictable Cardano

    NASA Astrophysics Data System (ADS)

    Ekert, Artur

    2008-08-01

    This purely recreational paper is about one of the most colorful characters of the Italian Renaissance, Girolamo Cardano, and the discovery of two basic ingredients of quantum theory, probability and complex numbers.

  8. Complex Flow Workshop Report

    SciTech Connect

    none,

    2012-05-01

    This report documents findings from a workshop on the impacts of complex wind flows in and out of wind turbine environments, the research needs, and the challenges of meteorological and engineering modeling at regional, wind plant, and wind turbine scales.

  9. Reconstruction Using Witness Complexes

    PubMed Central

    Oudot, Steve Y.

    2010-01-01

    We present a novel reconstruction algorithm that, given an input point set sampled from an object S, builds a one-parameter family of complexes that approximate S at different scales. At a high level, our method is very similar in spirit to Chew’s surface meshing algorithm, with one notable difference though: the restricted Delaunay triangulation is replaced by the witness complex, which makes our algorithm applicable in any metric space. To prove its correctness on curves and surfaces, we highlight the relationship between the witness complex and the restricted Delaunay triangulation in 2d and in 3d. Specifically, we prove that both complexes are equal in 2d and closely related in 3d, under some mild sampling assumptions. PMID:21643440

  10. Complex Regional Pain Syndrome

    MedlinePlus

    Complex regional pain syndrome (CRPS) is a chronic pain condition. It causes intense pain, usually in the arms, hands, legs, or feet. ... in skin temperature, color, or texture Intense burning pain Extreme skin sensitivity Swelling and stiffness in affected ...

  11. Doxorubicin Lipid Complex Injection

    MedlinePlus

    ... in combination with another chemotherapy drug to treat multiple myeloma (a type of cancer of the bone marrow) ... When doxorubicin lipid complex is used to treat multiple myeloma, it is given on certain days every 3 ...

  12. A complex legacy

    NASA Astrophysics Data System (ADS)

    Moore, Cristopher

    2011-11-01

    In his tragically short life, Alan Turing helped define what computing machines are capable of, and where they reach inherent limits. His legacy is still felt every day, in areas ranging from computational complexity theory to cryptography and quantum computing.

  13. Pigment-protein complexes

    SciTech Connect

    Siegelman, H W

    1980-01-01

    The photosynthetically-active pigment protein complexes of procaryotes and eucaryotes include chlorophyll proteins, carotenochlorophyll proteins, and biliproteins. They are either integral components or attached to photosynthetic membranes. Detergents are frequently required to solubilize the pigment-protein complexes. The membrane localization and detergent solubilization strongly suggest that the pigment-protein complexes are bound to the membranes by hydrophobic interactions. Hydrophobic interactions of proteins are characterized by an increase in entropy. Their bonding energy is directly related to temperature and ionic strength. Hydrophobic-interaction chromatography, a relatively new separation procedure, can furnish an important method for the purification of pigment-protein complexes. Phycobilisome purification and properties provide an example of the need to maintain hydrophobic interactions to preserve structure and function.

  14. Indicators: Physical Habitat Complexity

    EPA Pesticide Factsheets

    Physical habitat complexity measures the amount and variety of all types of cove at the water’s edge in lakes. In general, dense and varied shoreline habitat is able to support more diverse communities of aquatic life.

  15. DNA complexes: Durable binders

    NASA Astrophysics Data System (ADS)

    Urbach, Adam R.

    2011-11-01

    A tetra-intercalator compound that threads through a DNA double-helix to form a remarkably stable complex exhibits an unusual combination of sequence specificity and rapid association yet slow dissociation.

  16. An erupted complex odontoma.

    PubMed

    Tozoglu, Sinan; Yildirim, Umran; Buyukkurt, M Cemil

    2010-01-01

    Odontomas are benign tumors of odontogenic origin. The cause of the odontoma is unknown, but it is believed to be hereditary or due to a disturbance in tooth development triggered by trauma or infection. Odontomas may be either compound or complex. Although these tumors are seen frequently, erupted odontomas are rare. The purpose of this study is to present a rare case of complex odontoma that erupted into the oral cavity.

  17. Inside the complexity labyrinth

    NASA Astrophysics Data System (ADS)

    Fraser, Gordon

    2010-02-01

    Although the world we live in is complex, complexity as a science does not have a long history. For generations, most physicists tried to understand everything in terms of interactions between pairs of idealized "test particles". Then, about a 100 years ago, Henri Poincaré pointed out that a fully interacting three-body system was not just the sum of its three component pairs. The famous "three-body problem" was born.

  18. Electrospun complexes - functionalised nanofibres

    NASA Astrophysics Data System (ADS)

    Meyer, T.; Wolf, M.; Dreyer, B.; Unruh, D.; Krüger, C.; Menze, M.; Sindelar, R.; Klingelhöfer, G.; Renz, F.

    2016-12-01

    Here we present a new approach of using iron-complexes in electro-spun fibres. We modify poly(methyl methacrylate) (PMMA) by replacing the methoxy group with Diaminopropane or Ethylenediamine. The complex is bound covalently via an imine-bridge or an amide. The resulting polymer can be used in the electrospinning process without any further modifications in method either as pure reagent or mixed with small amounts of not functionalised polymer resulting in fibres of different qualities (Fig. 1).

  19. Pulling complexes out of complex diseases

    PubMed Central

    Mohan, Ryan D; Abmayr, Susan M; Workman, Jerry L

    2014-01-01

    Spinocerebellar ataxia 7 (SCA7) is an incurable disease caused by expansion of CAG trinucleotide sequences within the Ataxin-7 gene. This elongated CAG tract results in an Ataxin-7 protein bearing an expanded polyglutamine (PolyQ) repeat. SCA7 disease is characterized by progressive neural and retinal degeneration leading to ataxia and blindness. Evidence gathered from investigating SCA7 and other PolyQ diseases strongly suggest that misregulation of gene expression contributes to neurodegeneration. In fact, Ataxin-7 is a subunit of the essential Spt-Ada-Gcn5-Acetltransferase (SAGA) chromatin modifying complex that regulates expression of a large number of genes. Here we discuss recent insights into Ataxin-7 function and, considering these findings, propose a model for how polyglutamine expansion of Ataxin-7 may affect Ataxin-7 function to alter chromatin modifications and gene expression. PMID:25054097

  20. Cell complexes through time

    NASA Astrophysics Data System (ADS)

    Klette, Reinhard

    2000-10-01

    The history of cell complexes is closely related to the birth and development of topology in general. Johann Benedict Listing (1802 - 1882) introduced the term 'topology' into mathematics in a paper published in 1847, and he also defined cell complexes for the first time in a paper published in 1862. Carl Friedrich Gauss (1777 - 1855) is often cited as the one who initiated these ideas, but he did not publish either on topology or on cell complexes. The pioneering work of Leonhard Euler (1707 - 1783) on graphs is also often cited as the birth of topology, and Euler's work was cited by Listing in 1862 as a stimulus for his research on cell complexes. There are different branches in topology which have little in common: point set topology, algebraic topology, differential topology etc. Confusion may arise if just 'topology' is specified, without clarifying the used concept. Topological subjects in mathematics are often related to continuous models, and therefore quite irrelevant to computer based solutions in image analysis. Compared to this, only a minority of topology publications in mathematics addresses discrete spaces which are appropriate for computer-based image analysis. In these cases, often the notion of a cell complex plays a crucial role. This paper briefly reports on a few of these publications. This paper is not intended to cover the very lively progress in cell complex studies within the context of image analysis during the last two decades. Basically it stops its historic review at the time when this subject in image analysis research gained speed in 1980 - 1990. As a general point of view, the paper indicates that image analysis contributes to a fusion of topological concepts, the geometric and the abstract cell structure approach and point set topology, which may lead towards new problems for the study of topologies defined on geometric or abstract cell complexes.

  1. Turbulent complex (dusty) plasma

    NASA Astrophysics Data System (ADS)

    Zhdanov, Sergey; Schwabe, Mierk

    2017-04-01

    As a paradigm of complex system dynamics, solid particles immersed into a weakly ionized plasma, so called complex (dusty) plasmas, were (and continue to be) a subject of many detailed studies. Special types of dynamical activity have been registered, in particular, spontaneous pairing, entanglement and cooperative action of a great number of particles resulting in formation of vortices, self-propelling, tunneling, and turbulent movements. In the size domain of 1-10 mkm normally used in experiments with complex plasmas, the characteristic dynamic time-scale is of the order of 0.01-0.1 s, and these particles can be visualized individually in real time, providing an atomistic (kinetic) level of investigations. The low-R turbulent flow induced either by the instability in a complex plasma cloud or formed behind a projectile passing through the cloud is a typical scenario. Our simulations showed formation of a fully developed system of vortices and demonstrated that the velocity structure functions scale very close to the theoretical predictions. As an important element of self-organization, cooperative and turbulent particle motions are present in many physical, astrophysical, and biological systems. Therefore, experiments with turbulent wakes and turbulent complex plasma oscillations are a promising mean to observe and study in detail the anomalous transport on the level of individual particles.

  2. Complexes and imagination.

    PubMed

    Kast, Verena

    2014-11-01

    Fantasies as imaginative activities are seen by Jung as expressions of psychic energy. In the various descriptions of active imagination the observation of the inner image and the dialogue with inner figures, if possible, are important. The model of symbol formation, as Jung describes it, can be experienced in doing active imagination. There is a correspondence between Jung's understanding of complexes and our imaginations: complexes develop a fantasy life. Complex episodes are narratives of difficult dysfunctional relationship episodes that have occurred repeatedly and are internalized with episodic memory. This means that the whole complex episode (the image for the child and the image for the aggressor, connected with emotions) is internalized and can get constellated in everyday relationship. Therefore inner dialogues do not necessarily qualify as active imaginations, often they are the expression of complex-episodes, very similar to fruitless soliloquies. If imaginations of this kind are repeated, new symbols and new possibilities of behaviour are not found. On the contrary, old patterns of behaviour and fantasies are perpetuated and become cemented. Imaginations of this kind need an intervention by the analyst. In clinical examples different kinds of imaginations are discussed. © 2014, The Society of Analytical Psychology.

  3. Hydridomethyl iridium complex

    DOEpatents

    Bergman, Robert G.; Buchanan, J. Michael; Stryker, Jeffrey M.; Wax, Michael J.

    1989-01-01

    A process for functionalizing methane comprising: (a) reacting methane with a hydridoalkyl metal complex of the formula: CpIr[P(R.sub.1).sub.3 ]H(R.sub.2) wherein Cp represents a cyclopentadienyl or alkylcyclopentadienyl radical having from 1 to 5 carbon atoms; Ir represents an iridium atom; P represents a phosphorus atom; R.sub.1 represents an alkyl group; R.sub.2 represents an alkyl group having at least two carbon atoms; and H represents a hydrogen atom, in the presence of a liquid alkane R.sub.3 H having at least three carbon atoms to form a hydridomethyl complex of the formula: CpIr[P(R.sub.1).sub.3 ]HMe where Me represents a methyl radical. (b) reacting said hydridomethyl complex with an organic halogenating agent such as a tetrahalomethane or a haloform of the formulas: CX'X"X'"X"" or CHX'X"X'"; wherein X', X", X"', and X"" represent halogens selected from bromine, iodine and chlorine, to halomethyl complex of step (a) having the formula: CpIr[P(R.sub.1).sub.3 ]MeX: (c) reacting said halomethyl complex with a mercuric halide of the formula HgX.sub.2 to form a methyl mercuric halide of the formula HgMeX; and (d) reacting said methyl mercuric halide with a molecular halogen of the formula X.sub.2 to form methyl halide.

  4. Quantum Complexity in Graphene

    NASA Astrophysics Data System (ADS)

    Baskaran, G.

    Carbon has a unique position among elements in the periodic table. It produces an allotrope, graphene, a mechanically robust two dimensional semimetal. The multifarious properties that graphene exhibits has few parallels among elemental metals. From simplicity, namely carbon atoms connected by pure sp2 bonds, a wealth of novel quantum properties emerge. In classical complex systems such as a spin glass or a finance market, several competing agents or elements are responsible for unanticipated and difficult to predict emergent properties. The complex (sic) structure of quantum mechanics is responsbile for an unanticipated set of emergent properties in graphene. We call this quantum complexity. In fact, most quantum systems, phenomena and modern quantum field theory could be viewed as examples of quantum complexity. After giving a brief introduction to the quantum complexity we focus on our own work, which indicates the breadth in the type of quantum phenomena that graphene could support. We review our theoretical suggestions of, (i) spin-1 collective mode in netural graphene, (ii) relativistic type of phenomena in crossed electric and magnetic fields, (iii) room temperature superconductivity in doped graphene and (iv) composite Fermi sea in neutral graphene in uniform magnetic field and (v) two-channel Kondo effect. Except for the relativistic type of phenomena, the rest depend in a fundamental way on a weak electron correlation that exists in the broad two-dimensional band of graphene.

  5. Quantum Complexity in Graphene

    NASA Astrophysics Data System (ADS)

    Baskaran, G.

    Carbon has a unique position among elements in the periodic table. It produces an allotrope, graphene, a mechanically robust two dimensional semimetal. The multifarious properties that graphene exhibits has few parallels among elemental metals. From simplicity, namely carbon atoms connected by pure sp2 bonds, a wealth of novel quantum properties emerge. In classical complex systems such as a spin glass or a finance market, several competing agents or elements are responsible for unanticipated and difficult to predict emergent properties. The complex (sic) structure of quantum mechanics is responsbile for an unanticipated set of emergent properties in graphene. We call this quantum complexity. Infact, most quantum systems, phenomena and modern quantum field theory could be viewed as examples of quantum complexity. After giving a brief introduction to the quantum complexity we focus on our own work, which indicates the breadth in the type of quantum phenomena that graphene could support. We review our theoretical suggestions of, (i) spin-1 collective mode in netural graphene, (ii) relativistic type of phenomena in crossed electric and magnetic fields, (iii) room temperature superconductivity in doped graphene and (iv) composite Fermi sea in neutral graphene in uniform magnetic field and (v) 2-channel Kondo effect. Except for the relativistic type of phenomena and Kondo effect, the rest depend in a fundamental way on a weak electron correlations that exist in graphene.

  6. Engineering complex tissues.

    PubMed

    Atala, Anthony; Kasper, F Kurtis; Mikos, Antonios G

    2012-11-14

    Tissue engineering has emerged at the intersection of numerous disciplines to meet a global clinical need for technologies to promote the regeneration of functional living tissues and organs. The complexity of many tissues and organs, coupled with confounding factors that may be associated with the injury or disease underlying the need for repair, is a challenge to traditional engineering approaches. Biomaterials, cells, and other factors are needed to design these constructs, but not all tissues are created equal. Flat tissues (skin); tubular structures (urethra); hollow, nontubular, viscus organs (vagina); and complex solid organs (liver) all present unique challenges in tissue engineering. This review highlights advances in tissue engineering technologies to enable regeneration of complex tissues and organs and to discuss how such innovative, engineered tissues can affect the clinic.

  7. Viral quasispecies complexity measures.

    PubMed

    Gregori, Josep; Perales, Celia; Rodriguez-Frias, Francisco; Esteban, Juan I; Quer, Josep; Domingo, Esteban

    2016-06-01

    Mutant spectrum dynamics (changes in the related mutants that compose viral populations) has a decisive impact on virus behavior. The several platforms of next generation sequencing (NGS) to study viral quasispecies offer a magnifying glass to study viral quasispecies complexity. Several parameters are available to quantify the complexity of mutant spectra, but they have limitations. Here we critically evaluate the information provided by several population diversity indices, and we propose the introduction of some new ones used in ecology. In particular we make a distinction between incidence, abundance and function measures of viral quasispecies composition. We suggest a multidimensional approach (complementary information contributed by adequately chosen indices), propose some guidelines, and illustrate the use of indices with a simple example. We apply the indices to three clinical samples of hepatitis C virus that display different population heterogeneity. Areas of virus biology in which population complexity plays a role are discussed.

  8. The complex pendulum

    NASA Astrophysics Data System (ADS)

    Bender, Carl M.

    1998-12-01

    In this talk we propose to broaden the conventional notion of quantum mechanics. In conventional quantum mechanics one imposes the condition H†=H, where † represents complex conjugation and matrix transpose, to ensure that the Hamiltonian has a real spectrum. Replacing this mathematical condition by the weaker and more physical requirement H‡=H, where ‡=PT represents combined parity reflection and time reversal, one obtains new infinite classes of complex Hamiltonians whose spectra are also real and positive. These PT-symmetric theories may be viewed as analytic continuations of conventional theories from real to complex phase space. This talk describes the unusual classical and quantum properties of PT-symmetric quantum mechanical and quantum field theoretic models.

  9. The complex pendulum

    NASA Astrophysics Data System (ADS)

    Bender, Carl M.

    1999-07-01

    This talk proposes a generalization of conventional quantum mechanics. In conventional quantum mechanics one imposes the condition H †=H , where † represents complex conjugation and matrix transpose, to ensure that the Hamiltonian has a real spectrum. By replacing this mathematical condition with the weaker and more physical requirement H ‡=H , where ‡= PT represents combined parity reflection and time reversal, one obtains new infinite classes of complex Hamiltonians whose spectra are also real and positive. These PT-symmetric theories may be viewed as analytic continuations of conventional theories from real to complex-phase space. This talk describes the unusual classical and quantum properties of PT-symmetric quantum-mechanical and quantum-field-theoretic models.

  10. Nonergodic complexity management

    NASA Astrophysics Data System (ADS)

    Piccinini, Nicola; Lambert, David; West, Bruce J.; Bologna, Mauro; Grigolini, Paolo

    2016-06-01

    Linear response theory, the backbone of nonequilibrium statistical physics, has recently been extended to explain how and why nonergodic renewal processes are insensitive to simple perturbations, such as in habituation. It was established that a permanent correlation results between an external stimulus and the response of a complex system generating nonergodic renewal processes, when the stimulus is a similar nonergodic process. This is the principle of complexity management, whose proof relies on ensemble distribution functions. Herein we extend the proof to the nonergodic case using time averages and a single time series, hence making it usable in real life situations where ensemble averages cannot be performed because of the very nature of the complex systems being studied.

  11. Alanine water complexes.

    PubMed

    Vaquero, Vanesa; Sanz, M Eugenia; Peña, Isabel; Mata, Santiago; Cabezas, Carlos; López, Juan C; Alonso, José L

    2014-04-10

    Two complexes of alanine with water, alanine-(H2O)n (n = 1,2), have been generated by laser ablation of the amino acid in a supersonic jet containing water vapor and characterized using Fourier transform microwave spectroscopy. In the observed complexes, water molecules bind to the carboxylic group of alanine acting as both proton donors and acceptors. In alanine-H2O, the water molecule establishes two intermolecular hydrogen bonds forming a six-membered cycle, while in alanine-(H2O)2 the two water molecules establish three hydrogen bonds forming an eight-membered ring. In both complexes, the amino acid moiety is in its neutral form and shows the conformation observed to be the most stable for the bare molecule. The microsolvation study of alanine-(H2O)n (n = 1,2) can be taken as a first step toward understanding bulk properties at a microscopic level.

  12. Synchronization in complex networks

    SciTech Connect

    Arenas, A.; Diaz-Guilera, A.; Moreno, Y.; Zhou, C.; Kurths, J.

    2007-12-12

    Synchronization processes in populations of locally interacting elements are in the focus of intense research in physical, biological, chemical, technological and social systems. The many efforts devoted to understand synchronization phenomena in natural systems take now advantage of the recent theory of complex networks. In this review, we report the advances in the comprehension of synchronization phenomena when oscillating elements are constrained to interact in a complex network topology. We also overview the new emergent features coming out from the interplay between the structure and the function of the underlying pattern of connections. Extensive numerical work as well as analytical approaches to the problem are presented. Finally, we review several applications of synchronization in complex networks to different disciplines: biological systems and neuroscience, engineering and computer science, and economy and social sciences.

  13. 21 CFR 181.30 - Substances used in the manufacture of paper and paperboard products used in food packaging.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... diamine and potassium N-methyl dithiocarbamate and/or sodium 2-mercaptobenzothiazole (slimicides).* Ethyl....* Myristo chromic chloride complex. Nitrocellulose. Polyethylene glycol 400. Polyvinyl acetate. Potassium... and low viscosity polyvinyl alcohol for fatty foods only. Rubber hydrochloride. Sodium...

  14. Universality classes of complexity

    NASA Astrophysics Data System (ADS)

    Saakian, David B.

    We give several criteria of complexity and define different universality classes. According to our classification, at the lowest class of complexity are random graph, Markov Models and Hidden Markov Models. At the next level is Sherrington-Kirkpatrick spin glass, connected with neuron-network models. On a higher level are critical theories, spin glass phase of Random Energy Model, percolation, self organized criticality (SOC). The top level class involves HOT design, error threshold in optimal coding, language, and, maybe, financial market. Alive systems are also related with the last class.

  15. Complexity and Fly Swarms

    NASA Astrophysics Data System (ADS)

    Cates, Grant; Murray, Joelle

    Complexity is the study of phenomena that emerge from a collection of interacting objects and arises in many systems throughout physics, biology, finance, economics and more. Certain kinds of complex systems can be described by self-organized criticality (SOC). An SOC system is one that is internally driven towards some critical state. Recent experimental work suggests scaling behavior of fly swarms-one of the hallmarks of an SOC system. Our goal is to look for SOC behavior in computational models of fly swarms.

  16. Luminescent macrocyclic lanthanide complexes

    DOEpatents

    Raymond, Kenneth N; Corneillie, Todd M; Xu, Jide

    2014-05-20

    The present invention provides a novel class of macrocyclic compounds as well as complexes formed between a metal (e.g., lanthanide) ion and the compounds of the invention. Preferred complexes exhibit high stability as well as high quantum yields of lanthanide ion luminescence in aqueous media without the need for secondary activating agents. Preferred compounds incorporate hydroxy-isophthalamide moieties within their macrocyclic structure and are characterized by surprisingly low, non-specific binding to a variety of polypeptides such as antibodies and proteins as well as high kinetic stability. These characteristics distinguish them from known, open-structured ligands.

  17. Luminescent macrocyclic lanthanide complexes

    DOEpatents

    Raymond, Kenneth N [Berkeley, CA; Corneillie, Todd M [Campbell, CA; Xu, Jide [Berkeley, CA

    2012-05-08

    The present invention provides a novel class of macrocyclic compounds as well as complexes formed between a metal (e.g., lanthanide) ion and the compounds of the invention. Preferred complexes exhibit high stability as well as high quantum yields of lanthanide ion luminescence in aqueous media without the need for secondary activating agents. Preferred compounds incorporate hydroxy-isophthalamide moieties within their macrocyclic structure and are characterized by surprisingly low, non-specific binding to a variety of polypeptides such as antibodies and proteins as well as high kinetic stability. These characteristics distinguish them from known, open-structured ligands.

  18. Electrostatically driven complexation

    NASA Astrophysics Data System (ADS)

    Netz, Roland

    2004-03-01

    Many biological and synthetic systems are electrically charged, which makes them soluble in aqueous environments. Often, electrostatic interactions are dominant, and lead to complexation (i.e. tight aggregation) of oppositely charged objects. As an example, charged polymers such as DNA exhibit a number of different complexation modes when mixed with other charged objects such as spheres or cylinders. A simple model for the complexation of semiflexible polyelectrolytes with oppositely charged spheres is considered, which can exhibit tightly wrapped polymer structures. Using the appropriate parameters for DNA-histone complexes, one finds complete wrapping for intermediate salt concentrations only, in agreement with experiments. The forces needed to pull the DNA off from histones show a plateau at 10-40 pN (depending on salt concentration). We also consider the interaction between such complexes, which have been measured using osmometry, and found to be attractive for intermediate salt concentration (suggesting precipitation) and repulsive elsewhere. Chain fluctuations can be treated within a normal-mode analysis and distinguish associated-unwrapped from dissociated structures. Since some time it is known that also similarly charged objects attract each other for sufficiently large surface-charge densities and/or in the presence of multivalent ions, a phenomenon not explicable within standard (Poisson-Boltzmann) approaches. The so-called strong-coupling theory, valid in the limit of large surface charge densities and for multi-valent ions, yields attraction between similarly charged walls, cylinders, and spheres in quantitative agreement with Monte-Carlo simulations. Charged complexes can be destroyed by applying an electric field, which is an important factor in understanding their electrophoresis. By performing dynamic simulations, the relation between the electrophoretic mobility and the non-equilibrium perturbation of the complex structure is investigated. 1

  19. The ESCRT Complexes

    PubMed Central

    Hurley, James H.

    2010-01-01

    The ESCRT machinery consists of the peripheral membrane protein complexes, ESCRT-0, -I, -II, -III, and Vps4-Vta1, and the ALIX homodimer. The ESCRT system is required for degradation of unneeded or dangerous plasma membrane proteins; biogenesis of the lysosome and the yeast vacuole; the budding of most membrane enveloped viruses; the membrane abscission step in cytokinesis; macroautophagy; and several other processes. From their initial discovery in 2001-2002, the literature on ESCRTs has grown exponentially. This review will describe the structure and function of the six complexes noted above and summarizes current knowledge of their mechanistic roles in cellular pathways and in disease. PMID:20653365

  20. The Corona Australis Complex.

    NASA Astrophysics Data System (ADS)

    Vaile, Roberta Anne

    What began as a HI study of the CrA star formation region has grown to incorporate the following: (1) a detailed investigation of the HI content of the CrA dark cloud; (2) an extensive molecular survey of the CrA dark cloud, from which the CrA molecular abundances were determined and compared to those of other Galactic environments; (3) an extensive HI survey of the CrA complex, which was compared to the established Galactic distributions in and near the region; (4) an examination of the extent and nature of the CrA IVCs, components of gas at intermediate, anomalous velocities; (5) an investigation of the correlations which may exist between the features of the CrA region; and (6) an evaluation of where the CrA complex fits within the framework of our understanding of the Galaxy. A review of our perceptions of the Galactic structure is contained in Chapter I. The established state of knowledge of the CrA dark cloud region--chiefly, that of a region of young and on-going star formation--is given in Chapter II. The observational studies of the CrA dark cloud region specifically are presented in Chapter III. The HI survey of the CrA complex is presented in Chapter IV, with the CrA IVCs results presented in Chapter V. A comparison of the CrA HI structure with nearby Galactic features suggests that the CrA complex--exemplified by the T_ {rm A} morphology given as a frontispiece and in Figure 4.1--is a coherently -moving HI structure falling subject to the Rayleigh-Taylor, Kelvin-Helmholtz, flute and Parker hydrodynamic and magnetohydrodynamic instabilities under the Galactic gravitational and differential rotation forces. As the distance to the CrA IVCs still remains speculative, no definitive identity for the CrA IVCs was established. Considering the whole, the CrA complex was interpreted as a feature triggered by the Sco-Cen association, possibly a late-comer to the Lindblad Ring and possibly a result of the Tau-Gem events. The similarities with the Oph northern

  1. Planning Complex Projects Automatically

    NASA Technical Reports Server (NTRS)

    Henke, Andrea L.; Stottler, Richard H.; Maher, Timothy P.

    1995-01-01

    Automated Manifest Planner (AMP) computer program applies combination of artificial-intelligence techniques to assist both expert and novice planners, reducing planning time by orders of magnitude. Gives planners flexibility to modify plans and constraints easily, without need for programming expertise. Developed specifically for planning space shuttle missions 5 to 10 years ahead, with modifications, applicable in general to planning other complex projects requiring scheduling of activities depending on other activities and/or timely allocation of resources. Adaptable to variety of complex scheduling problems in manufacturing, transportation, business, architecture, and construction.

  2. Tuberous sclerosis complex.

    PubMed

    DiMario, Francis J; Sahin, Mustafa; Ebrahimi-Fakhari, Darius

    2015-06-01

    Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The genetic cause is mutations in the TSC1 gene, found on chromosome 9q34, and TSC2 gene, found on chromosome 16p13. The clinical phenotypes resulting from mutations in either of the 2 genes are variable in each individual. Herein, advances in the understanding of molecular mechanisms in tuberous sclerosis complex are reviewed, and current guidelines for diagnosis, treatment, follow-up, and management are summarized. Published by Elsevier Inc.

  3. Humic acid protein complexation

    NASA Astrophysics Data System (ADS)

    Tan, W. F.; Koopal, L. K.; Weng, L. P.; van Riemsdijk, W. H.; Norde, W.

    2008-04-01

    Interactions of purified Aldrich humic acid (PAHA) with lysozyme (LSZ) are investigated. In solution LSZ is moderately positively and PAHA negatively charged at the investigated pH values. The proton binding of PAHA and of LSZ is determined by potentiometric proton titrations at various KCl concentrations. It is also measured for two mixtures of PAHA-LSZ and compared with theoretically calculated proton binding assuming no mutual interaction. The charge adaptation due to PAHA-LSZ interaction is relatively small and only significant at low and high pH. Next to the proton binding, the mass ratio PAHA/LSZ at the iso-electric point (IEP) of the complex at given solution conditions is measured together with the pH using the Mütek particle charge detector. From the pH changes the charge adaptation due to the interaction can be found. Also these measurements show that the net charge adaptation is weak for PAHA-LSZ complexes at their IEP. PAHA/LSZ mass ratios in the complexes at the IEP are measured at pH 5 and 7. At pH 5 and 50 mmol/L KCl the charge of the complex is compensated for 30-40% by K +; at pH 7, where LSZ has a rather low positive charge, this is 45-55%. At pH 5 and 5 mmol/L KCl the PAHA/LSZ mass ratio at the IEP of the complex depends on the order of addition. When LSZ is added to PAHA about 25% K + is included in the complex, but no K + is incorporated when PAHA is added to LSZ. The flocculation behavior of the complexes is also different. After LSZ addition to PAHA slow precipitation occurs (6-24 h) in the IEP, but after addition of PAHA to LSZ no precipitation can be seen after 12 h. Clearly, PAHA/LSZ complexation and the colloidal stability of PAHA-LSZ aggregates depend on the order of addition. Some implications of the observed behavior are discussed.

  4. Cytoplasmic Viral Replication Complexes

    PubMed Central

    den Boon, Johan A.; Diaz, Arturo; Ahlquist, Paul

    2010-01-01

    Many viruses that replicate in the cytoplasm compartmentalize their genome replication and transcription in organelle-like structures that enhance replication efficiency and protection from host defenses. In particular, recent studies with diverse positive-strand RNA viruses have further elucidated the ultrastructure of membrane-bounded RNA replication complexes and their close coordination with virion assembly and budding. The structure, function and assembly of some positive-strand RNA virus replication complexes have parallels and potential evolutionary links with the replicative cores of double-strand RNA virus and retrovirus virions, and more general similarities with the replication factories of cytoplasmic DNA viruses. PMID:20638644

  5. Graphical Representation of Complex Functions.

    ERIC Educational Resources Information Center

    Renka, Robert J.

    1988-01-01

    Describes methods and software for graphing representation of a complex function of a complex variable. Includes an application of a graphical interpretation of the complex zeros of the cubic and their properties. (PK)

  6. Salen complexes with dianionic counterions

    DOEpatents

    Job, Gabriel E.; Farmer, Jay J.; Cherian, Anna E.

    2016-08-02

    The present invention describes metal salen complexes having dianionic counterions. Such complexes can be readily precipitated and provide an economical method for the purification and isolation of the complexes, and are useful to prepare novel polymer compositions.

  7. Nature, computation and complexity

    NASA Astrophysics Data System (ADS)

    Binder, P.-M.; Ellis, G. F. R.

    2016-06-01

    The issue of whether the unfolding of events in the world can be considered a computation is explored in this paper. We come to different conclusions for inert and for living systems (‘no’ and ‘qualified yes’, respectively). We suggest that physical computation as we know it exists only as a tool of complex biological systems: us.

  8. Launching Complex Tasks

    ERIC Educational Resources Information Center

    Jackson, Kara J.; Shahan, Emily C.; Gibbons, Lynsey K.; Cobb, Paul A.

    2012-01-01

    Mathematics lessons can take a variety of formats. In this article, the authors discuss lessons organized around complex mathematical tasks. These lessons usually unfold in three phases. First, the task is introduced to students. Second, students work on solving the task. Third, the teacher "orchestrates" a concluding whole-class discussion in…

  9. Managing Complex Dynamical Systems

    ERIC Educational Resources Information Center

    Cox, John C.; Webster, Robert L.; Curry, Jeanie A.; Hammond, Kevin L.

    2011-01-01

    Management commonly engages in a variety of research designed to provide insight into the motivation and relationships of individuals, departments, organizations, etc. This paper demonstrates how the application of concepts associated with the analysis of complex systems applied to such data sets can yield enhanced insights for managerial action.

  10. Complex Planar Splines.

    DTIC Science & Technology

    1981-05-01

    try todefine a complex planar spline by holomorphic elements like polynomials, then by the well known identity theorem (e.g. Diederich- Remmert [9, p...R. Remmert : Funktionentheorie I, Springer, Berlin, Heidelberg, New York, 1972, 246 p. 10 0. Lehto - K.I. Virtanen: Quasikonforme AbbildunQen, Springer

  11. Accessibility in complex networks

    NASA Astrophysics Data System (ADS)

    Travençolo, B. A. N.; da F. Costa, L.

    2008-12-01

    This Letter describes a method for the quantification of the diversity of non-linear dynamics in complex networks as a consequence of self-avoiding random walks. The methodology is analyzed in the context of theoretical models and illustrated with respect to the characterization of the accessibility in urban streets.

  12. Subelliptic Estimates for Complexes

    PubMed Central

    Guillemin, Victor; Sternberg, Shlomo

    1970-01-01

    New results are announced linking properties of the symbol module and characteristic variety of a differential complex with test estimates near the characteristic variety of the type considered by Hörmander (½-estimate). The first result is the invariance of the test estimates under pseudo-differential change of coordinates, and this leads to the introduction of a normal form for the complex in the neighborhood of a Cohen-MacCauley point of the symbol module. If the characteristic variety V is a manifold near the Cohen-MacCauley point (x0,ζ0) with parametrizing functions p1,...,pq, where q is the codimension of the characteristic variety in the complexified contangent bundle, the matrix [Formula: see text] of Poisson brackets defines invariantly a Hermitian form Q on the normal space to V at (x0,ζ0) when the dpζ(x0,ζ0) are used as basis, and the test estimates are satisfied at the ith stage of the complex if sig. Q (signature of Q) is ≥ n - i + 1 (n the dimension of the base manifold) or rank Q - sig. Q ≥ i + 1. Finally, conditions are given in order that, on a manifold with smooth boundary, the associated boundary complexes satisfy the ½-estimate. PMID:16591855

  13. Complexity in Cultural Identity

    ERIC Educational Resources Information Center

    Holliday, Adrian

    2010-01-01

    Despite their diverse national backgrounds, 28 interviewees speak similarly about the complexity of the cultural realities with which they live, and refuse to be pinned down to specific cultural types. While nation is of great importance, unless personally inspiring, it tends to be an external force which is in conflict with a wide variety of…

  14. E Complex groundbreaking

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Representatives from NASA, Orbital Sciences Corp. and Aerojet participate in a ribbon-cutting ceremony for construction of a flame deflector trench at Stennis Space Center's E Test Complex. Participants included Orbital CEO J.R. Thompson (center, left) and Stennis Space Center Director Gene Goldman (center, right).

  15. Complexity, Systems, and Software

    DTIC Science & Technology

    2014-08-14

    2014 Carnegie Mellon University Complexity, Systems, and Software Software Engineering Institute Carnegie Mellon University Pittsburgh, PA...NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Software Engineering Institute Carnegie Mellon University Pittsburgh, PA 15213 8...for the operation of the Software Engineering Institute, a federally funded research and development center sponsored by the United States

  16. Coordination Complexes of Cobalt.

    ERIC Educational Resources Information Center

    Williams, Gregory M.; And Others

    1989-01-01

    Described is an experiment involving the synthesis and spectral studies of cobalt complexes that not only give general chemistry students an introduction to inorganic synthesis but allows them to conduct a systematic study on the effect of different ligands on absorption spectra. Background information, procedures, and experimental results are…

  17. Cytarabine Lipid Complex Injection

    MedlinePlus

    ... used to treat lymphomatous meningitis (a type of cancer in the covering of the spinal cord and brain). Cytarabine lipid complex is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in your body.

  18. Restricting Grammatical Complexity

    ERIC Educational Resources Information Center

    Frank, Robert

    2004-01-01

    Theories of natural language syntax often characterize grammatical knowledge as a form of abstract computation. This paper argues that such a characterization is correct, and that fundamental properties of grammar can and should be understood in terms of restrictions on the complexity of possible grammatical computation, when defined in terms of…

  19. Analyzing Complex Survey Data.

    ERIC Educational Resources Information Center

    Rodgers-Farmer, Antoinette Y.; Davis, Diane

    2001-01-01

    Uses data from the 1994 AIDS Knowledge and Attitudes Supplement to the National Health Interview Survey (NHIS) to illustrate that biased point estimates, inappropriate standard errors, and misleading tests of significance can result from using traditional software packages, such as SPSS or SAS, for complex survey analysis. (BF)

  20. Complex Digital Visual Systems

    ERIC Educational Resources Information Center

    Sweeny, Robert W.

    2013-01-01

    This article identifies possibilities for data visualization as art educational research practice. The author presents an analysis of the relationship between works of art and digital visual culture, employing aspects of network analysis drawn from the work of Barabási, Newman, and Watts (2006) and Castells (1994). Describing complex network…