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Sample records for bifunctional chelator alternative

  1. Macrocyclic bifunctional chelating agents

    DOEpatents

    Meares, Claude F.; DeNardo, Sally J.; Cole, William C.; Mol, Min K.

    1987-01-01

    A copper chelate conjugate which is stable in human serum. The conjugate includes the copper chelate of a cyclic tetraaza di-, tri-, or tetra-acetic acid, a linker attached at one linker end to a ring carbon of the chelate, and a biomolecule joined at the other end of the linker. The conjugate, or the linker-copper chelate compound used in forming the conjugate, are designed for use in diagnostic and therapeutic applications which involve Cu(II) localization via the systemic route.

  2. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    2000-02-08

    Bicyclo[2.2.2]octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo[2.2.1]heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  3. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    1998-07-21

    Bicyclo›2.2.2! octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo›2.2.1! heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  4. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, M.P.; Mease, R.C.; Srivastava, S.C.

    1998-07-21

    Bicyclo[2.2.2] octane-2,3 diamine-N,N,N`,N`-tetraacetic acids (BODTA) and bicyclo[2.2.1] heptane-2,3 diamine-N,N,N`,N`-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  5. Bifunctional Gallium-68 Chelators: Past, Present, and Future.

    PubMed

    Spang, Philipp; Herrmann, Christian; Roesch, Frank

    2016-09-01

    This article reviews the development of bifunctional chelates for synthesising (68)Ga radiopharmaceuticals. It structures the chelates into groups of macrocycles, nonmacrocycles, and chimeric derivatives. The most relevant bifunctional chelates are discussed in chelate structure, parameters of (68)Ga-labeling, and stability of the (68)Ga-chelate complexes. Furthermore those derivatives are included, where (67)Ga was applied instead of (68)Ga. A particular feature discussed is the ability of certain bifunctional chelate structures to function in kit-type preparation of the (68)Ga radiopharmaceuticals. Currently, nonmacrocyclic and chimeric derivates attract particular attention such as THP-derivates and DATA-derivates. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Synthesis, conjugation, and radiolabeling of a novel bifunctional chelating agent for (225)Ac radioimmunotherapy applications.

    PubMed

    Chappell, L L; Deal, K A; Dadachova, E; Brechbiel, M W

    2000-01-01

    225Ac (t(1/2) = 10 days) is an alternative alpha-emitter that has been proposed for radioimmunotherapy (RIT) due to its many favorable properties, such as half-life and mode of decay. The factor limiting use of (225)Ac in RIT is the lack of an acceptably stable chelate for in vivo applications. Herein is described the first reported bifunctional chelate for (225)Ac that has been evaluated for stability for in vivo applications. The detailed synthesis of a bifunctional chelating agent 2-(4-isothiocyanatobenzyl)-1,4,7,10,13, 16-hexaazacyclohexadecane- 1,4,7,10,13,16-hexaacetic acid (HEHA-NCS) is reported. This ligand was conjugated to three monoclonal antibodies, CC49, T101, and BL-3 with chelate-to-protein ratios between 1.4 and 2. The three conjugates were radiolabeled with (225)Ac, and serum stability study of the [(225)Ac]BL-3-HEHA conjugate was performed.

  7. (Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents)

    SciTech Connect

    Not Available

    1991-01-01

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  8. [Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

    SciTech Connect

    Not Available

    1991-12-31

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  9. Bifunctional chelates of RH-105 and AU199 as potential radiotherapeutic agents

    SciTech Connect

    Droege, P.

    1997-03-01

    Research is presented on new bifunctional chelating ligand systems with stability on the macroscopic and radiochemical levels. The synthesis of the following complexes are described: rhodium 105, palladium 109, and gold 198.

  10. Efficient bifunctional gallium-68 chelators for positron emission tomography: tris(hydroxypyridinone) ligands

    PubMed Central

    Berry, David J.; Ma, Yongmin; Ballinger, James R.; Tavaré, Richard; Koers, Alexander; Sunassee, Kavitha; Zhou, Tao; Nawaz, Saima; Mullen, Gregory E. D.; Hider, Robert C.; Blower, Philip J.

    2014-01-01

    A new tripodal tris(hydroxypyridinone) bifunctional chelator for gallium allows easy production of 68Ga-labelled proteins rapidly under mild conditions in high yields at exceptionally high specific activity and low concentration. PMID:21623436

  11. Bifunctional chelating agent for the design and development of site specific radiopharmaceuticals and biomolecule conjugation strategy

    DOEpatents

    Katti, Kattesh V.; Prabhu, Kandikere R.; Gali, Hariprasad; Pillarsetty, Nagavara Kishore; Volkert, Wynn A.

    2003-10-21

    There is provided a method of labeling a biomolecule with a transition metal or radiometal in a site specific manner to produce a diagnostic or therapeutic pharmaceutical compound by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radio metal or a transition metal, and covalently linking the resulting metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. Also provided is a method of synthesizing the --PR.sub.2 containing biomolecules by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radiometal or a transition metal, and covalently linking the resulting radio metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. There is provided a therapeutic or diagnostic agent comprising a --PR.sub.2 containing biomolecule.

  12. Liposomal Cu-64 labeling method using bifunctional chelators: poly(ethylene glycol) spacer and chelator effects.

    PubMed

    Seo, Jai Woong; Mahakian, Lisa M; Kheirolomoom, Azadeh; Zhang, Hua; Meares, Claude F; Ferdani, Riccardo; Anderson, Carolyn J; Ferrara, Katherine W

    2010-07-21

    Two bifunctional Cu-64 chelators (BFCs), (6-(6-(3-(2-pyridyldithio)propionamido)hexanamido)benzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA-PDP) and 4-(2-(2-pyridyldithioethyl)ethanamido)-11-carboxymethyl-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A-PDEA), were synthesized and conjugated to long-circulating liposomes (LCLs) via attachment to a maleimide lipid. An in vitro stability assay of (64)Cu-TETA, (64)Cu-TETA-PEG2k, and (64)Cu-CB-TE2A-PEG2k liposomes showed that more than 86% of the radioactivity remains associated with the liposomal fraction after 48 h of incubation with mouse serum. The in vivo time activity curves (TAC) for the three liposomal formulations showed that approximately 50% of the radioactivity cleared from the blood pool in 16-18 h. As expected, the in vivo biodistribution and TAC data obtained at 48 h demonstrate that the clearance of radioactivity from the liver slows with the incorporation of a poly(ethylene glycol)-2k (PEG2k) brush. Our data suggest that (64)Cu-TETA and (64)Cu-CB-TE2A are similarly stable in the blood pool and accumulation of radioactivity in the liver and spleen is not related to the stability of Cu-64 chelator complex; however, clearance of Cu-64 from the liver and spleen are faster when injected as (64)Cu-TETA-chelated liposomes rather than (64)Cu-CB-TE2A-chelated liposomes.

  13. Liposomal Cu-64 labeling method using bifunctional chelators: polyethylene glycol spacer and chelator effects

    PubMed Central

    Seo, Jai Woong; Mahakian, Lisa M.; Kheirolomoom, Azadeh; Zhang, Hua; Meares, Claude F.; Ferdani, Riccardo; Anderson, Carolyn J.; Ferrara, Katherine W.

    2010-01-01

    Two bifunctional Cu-64 chelators (BFCs), (6-(6-(3-(2-pyridyldithio)propionamido)hexanamido)benzyl)-1,4,8,11-tetraazacyclotetradecane- 1,4,8,11-tetraacetic acid (TETA-PDP) and 4-(2-(2-pyridyldithioethyl)ethanamido)-11-carboxymethyl-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A-PDEA), were synthesized and conjugated to long circulating liposomes (LCLs) via attachment to a maleimide lipid. An in vitro stability assay of 64Cu-TETA, 64Cu-TETA-PEG2k, and 64Cu-CB-TE2A-PEG2k liposomes showed that more than 86% of the radioactivity remains associated with the liposomal fraction after 48 hours of incubation with mouse serum. The in vivo time activity curves (TAC) for the three liposomal formulations showed that ~50% of the radioactivity cleared from the blood pool in 16 - 18 hours. As expected, the in vivo biodistribution and TAC data obtained at 48 hours demonstrate that the clearance of radioactivity from the liver slows with the incorporation of a polyethylene glycol-2k (PEG2k) brush. Our data suggest that 64Cu-TETA and 64Cu-CB-TE2A are similarly stable in the blood pool and accumulation of radioactivity in the liver and spleen is not related to the stability of Cu-64 chelator complex; however clearance of Cu-64 from the liver and spleen are faster when injected as 64Cu-TETA-chelated liposomes rather than 64Cu-CB-TE2A-chelated liposomes. PMID:20568726

  14. Development of a Tetrathioether (S4) Bifunctional Chelate System for Rh-105

    DTIC Science & Technology

    2012-07-01

    bombesin (BBN) targeting vector. Bombesin targets gastrin releasing peptide (GRP) receptors, which have been shown to be over-expressed on the surface of...prostate cancer cells. Here we report the successful synthesis and characterization of a bombesin agonist coupled tetrathioether (S4) bifunctional...1: Synthesis of bombesin (7-14) coupled tetrathioether bifunctional chelate 1a: Synthesize dicarboxylic acid functionalized ligand 3,3,3-S4-(COOH)2

  15. Efficient bifunctional gallium-68 chelators for positron emission tomography: tris(hydroxypyridinone) ligands.

    PubMed

    Berry, David J; Ma, Yongmin; Ballinger, James R; Tavaré, Richard; Koers, Alexander; Sunassee, Kavitha; Zhou, Tao; Nawaz, Saima; Mullen, Gregory E D; Hider, Robert C; Blower, Philip J

    2011-07-07

    A new tripodal tris(hydroxypyridinone) bifunctional chelator for gallium allows easy production of (68)Ga-labelled proteins rapidly under mild conditions in high yields at exceptionally high specific activity and low concentration. This journal is © The Royal Society of Chemistry 2011

  16. Novel Bifunctional Cyclic Chelator for 89Zr Labeling–Radiolabeling and Targeting Properties of RGD Conjugates

    PubMed Central

    2015-01-01

    Within the last years 89Zr has attracted considerable attention as long-lived radionuclide for positron emission tomography (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αvß3 integrins were synthesized using different conjugation strategies and labeled with 89Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [89Zr]FSC-RGD conjugates or [89Zr]triacetylfusarinine C (TAFC). Quantitative 89Zr labeling was achieved within 90 min at room temperature. The distribution coefficients of the different radioligands indicate hydrophilic character. Compared to [89Zr]DFO, [89Zr]FSC derivatives showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging experiments showed efficient receptor-specific targeting of [89Zr]FSC-RGD conjugates. No bone uptake was observed analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of 89Zr-based PET imaging agents. PMID:25941834

  17. Maleimido-functionalized NOTA derivatives as bifunctional chelators for site-specific radiolabeling.

    PubMed

    Förster, Christian; Schubert, Maik; Pietzsch, Hans-Jürgen; Steinbach, Jörg

    2011-06-22

    Two basic and simple synthetic routes for mono- and bis-maleimide bearing 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) chelators as new bifunctional chelators are described. The syntheses are characterized by their simplicity and short reaction times, as well as practical purification methods and acceptable to very good chemical yields. The usefulness of these two synthetic pathways is demonstrated by the preparation of a set of mono- and bis-maleimide functionalized NOTA derivatives. In conclusion, these two methods can easily be expanded to the syntheses of further tailored maleimide-NOTA chelators for diverse applications.

  18. Bifunctional chelators in the design and application of radiopharmaceuticals for oncological diseases.

    PubMed

    Sarko, D; Eisenhut, M; Haberkorn, U; Mier, W

    2012-01-01

    Radiopharmaceuticals constitute diagnostic and therapeutic tools for both clinical and preclinical applications. They are a blend of a tracer moiety that mediates a site specific accumulation and an effector: a radioisotope whose decay enables either molecular imaging or exhibits cytotoxic effects. Radioactive halogens and lanthanides are the most commonly used isotopes for radiopharmaceuticals. Due to their ready availability and the facile labeling metallic radionuclides offer ideal characteristics for applications in nuclear medicine. A stable link between the radionuclide and the carrier molecule is the primary prerequisite for in vivo applications. The radionuclide is selected according to its physical and chemical properties i.e. half-life, the type of decay, the energy emitted and its availability. Bifunctional chelating agents are used to stably link the radiometal to the carrier moiety of the radiopharmaceutical. The design of the bifunctional chelator has to consider the impact of the radiometal chelate on the biological properties of the target-specific pharmaceutical. Here, with an emphasis on oncology, we review applications of radiopharmaceuticals that contain bifunctional chelators, while highlighting successes and identifying the key challenges that need to be addressed for the successful translation of target binding molecules into tracers for molecular imaging and endoradiotherapy.

  19. Labeling Biomolecules with Radiorhenium - a Review of the Bifunctional Chelators

    PubMed Central

    Liu, Guozheng; Hnatowich, Donald J.

    2007-01-01

    For radiotherapy, biomolecules such as intact antibodies, antibody fragments, peptides, DNAs and other oligomers have all been labeled with radiorhenium (186Re and 188Re). Three different approaches have been employed that may be referred to as direct, indirect and integral labeling. Direct labeling applies to proteins and involves the initial reduction of endogenous disulfide bridges to provide chelation sites. Indirect labeling can apply to most biomolecules and involves the initial attachment of an exogenous chelator. Finally, integral labeling is a special case applying only to small molecules in which the metallic radionuclide serves to link two parts of a biomolecule together in forming the labeled complex. While the number of varieties for the direct and integral radiolabeling approaches is rather limited, a fairly large and diverse number of chelators have been reported in the case of indirect labeling. Our objective herein is to provide an overview of the various chelators that have been used in the indirect labeling of biomolecules with radiorhenium, including details on the labeling procedures, the stability of the radiolabel and, where possible, the influence of the label on biological properties. PMID:17504162

  20. Labeling biomolecules with radiorhenium: a review of the bifunctional chelators.

    PubMed

    Liu, Guozheng; Hnatowich, Donald J

    2007-05-01

    For radiotherapy, biomolecules such as intact antibodies, antibody fragments, peptides, DNAs and other oligomers have all been labeled with radiorhenium ((186)Re and (188)Re). Three different approaches have been employed that may be referred to as direct, indirect and integral labeling. Direct labeling applies to proteins and involves the initial reduction of endogenous disulfide bridges to provide chelation sites. Indirect labeling can apply to most biomolecules and involves the initial attachment of an exogenous chelator. Finally, integral labeling is a special case applying only to small molecules in which the metallic radionuclide serves to link two parts of a biomolecule together in forming the labeled complex. While the number of varieties for the direct and integral radiolabeling approaches is rather limited, a fairly large and diverse number of chelators have been reported in the case of indirect labeling. Our objective herein is to provide an overview of the various chelators that have been used in the indirect labeling of biomolecules with radiorhenium, including details on the labeling procedures, the stability of the radiolabel and, where possible, the influence of the label on biological properties.

  1. Chemistry and bifunctional chelating agents for binding (177)Lu.

    PubMed

    Parus, Józef L; Pawlak, Dariusz; Mikolajczak, Renata; Duatti, Adriano

    2015-01-01

    A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu(3+) ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands.

  2. Synthesis and Evaluation of New Generation Cross-Bridged Bifunctional Chelator for (64)Cu Radiotracers.

    PubMed

    Dale, Ajit V; An, Gwang Il; Pandya, Darpan N; Ha, Yeong Su; Bhatt, Nikunj; Soni, Nisarg; Lee, Hochun; Ahn, Heesu; Sarkar, Swarbhanu; Lee, Woonghee; Huynh, Phuong Tu; Kim, Jung Young; Gwon, Mi-Ri; Kim, Sung Hong; Park, Jae Gyu; Yoon, Young-Ran; Yoo, Jeongsoo

    2015-09-08

    Bifunctional chelators have been successfully used to construct (64)Cu-labeled radiopharmaceuticals. Previously reported chelators with cross-bridged cyclam backbones have various essential features such as high stability of the copper(II) complex, high efficiency of radiolabeling at room temperature, and good biological inertness of the radiolabeled complex, along with rapid body clearance. Here, we report a new generation propylene-cross-bridged chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) developed with the aim of combining these key properties in a single chelator. The PCB-TE1A1P was synthesized from cyclam with good overall yield. The Cu(II) complex of our chelator showed good robustness in kinetic stability evaluation experiments, such as acidic decomplexation and cyclic voltammetry studies. The Cu(II) complex of PCB-TE1A1P remained intact under highly acidic conditions (12 M HCl, 90 °C) for 8 d and showed quasi-reversible reduction/oxidation peaks at -0.77 V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled with (64)Cu ions in an acetate buffer at 60 °C within 60 min. The electrophoresis study revealed that the (64)Cu-PCB-TE1A1P complex has net negative charge in aqueous solution. The biodistribution and in vivo stability study profiles of (64)Cu-PCB-TE1A1P indicated that the radioactive complex was stable under physiological conditions and cleared rapidly from the body. A whole body positron emission tomography (PET) imaging study further confirmed high in vivo stability and fast clearance of the complex in mouse models. In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator for (64)Cu-based radiopharmaceuticals, especially those involving peptides.

  3. Isomerism in benzyl-DOTA derived bifunctional chelators: implications for molecular imaging.

    PubMed

    Payne, Katherine M; Woods, Mark

    2015-02-18

    The bifunctional chelator IB-DOTA has found use in a range of biomedical applications given its ability to chelate many metal ions, but in particular the lanthanide(III) ions. Gd(3+) in particular is of interest in the development of new molecular imaging agents for MRI and is highly suitable for chelation by IB-DOTA. Given the long-term instability of the aryl isothiocyanate functional group we have used the more stable nitro derivative (NB-DOTA) to conduct a follow-up study of some of our previous work on the coordination chemistry of chelates of these BFCs. Using a combination of NMR and HPLC to study the Eu(3+) and Yb(3+) chelates of NB-DOTA, we have demonstrated that this ligand will produce two discrete regioisomeric chelates at the point at which the metal ion is introduced into the BFC. These regioisomers are defined by the position of the benzylic substituent on the macrocyclic ring: adopting an equatorial position either at the corner or the side of the [3333] ring conformation. These regioisomers are incapable of interconversion and are distinct, separate structures with different SAP/TSAP ratios. The side isomer exhibits an increased population of the TSAP isomer, pointing to more rapid water exchange kinetics in this regioisomer. This has potential ramifications for the use of these two regioisomers of Gd(3+)-BFC chelates in MRI applications. We have also found that, remarkably, there is little or no freedom of rotation about the first single bond extending from the macrocyclic ring to the benzylic substituent. Since this is the linkage through which the chelate is conjugated to the remainder of the molecular imaging probe, this result implies that there may be reduced local rotation of the Gd(3+) chelate within a molecular imaging probe. This implies that this type of BFC could exhibit higher relaxivities than other types of BFC.

  4. Preparation and protein conjugation of a divinyl sulphone derivatized bifunctional chelating agent.

    PubMed

    Somayaji, V V; Naicker, S S; Sykes, T R; Guay, V; Noujaim, A A

    1996-12-01

    A new bifunctional chelating agent with a novel linking arm, 2-[p-¿N-benzyl-N-(2-vinylsulfoethyl)¿- (aminobenzyl)¿-1,3-propane-diamine-N,N,N',N'-tetraacetic acid (VS-PDTA) was synthesized and was conjugated to protein for the purpose of attaching radiometals to monoclonal antibodies (MAbs). The effect of various parameters such as ligand concentration, protein concentration, pH, temperature and reaction period on the conjugation have been examined using chromatographic (SE and TLC) analysis after labeling with 111In. The parameters and chemical variables studied have significant effects on the efficiency and rate of protein conjugation.

  5. Synthesis and evaluation of analogues of HYNIC as bifunctional chelators for technetium.

    PubMed

    Meszaros, Levente K; Dose, Anica; Biagini, Stefano C G; Blower, Philip J

    2011-06-21

    6-Hydrazinonicotinic acid (HYNIC, 1) is a well-established bifunctional technetium-binding ligand often used to synthesise bioconjugates for radiolabelling with Tc-99m. It is capable of efficient capture of technetium at extremely low concentrations, but the structure of the labelled complexes is heterogeneous and incompletely understood. In particular, it is of interest to determine whether, at the no-carrier-added level, it acts in a chelating or non-chelating mode. Here we report two new isomers of HYNIC: 2-hydrazinonicotinic acid (2-HYNIC, 2), which (like 1) is capable of chelation through the mutually ortho hydrazine and pyridine nitrogens and 4-hydrazinonicotinic acid (4-HYNIC, 3), which is not (due to the para-relationship of the hydrazine and pyridine nitrogens). LC-MS shows that the coordination chemistry of 2 with technetium closely parallels that of conventional 1, and no advantages of one over the other in terms of potential labelling efficiency or isomerism were discernable. Both 1 and 2 formed complexes with the loss of 5 protons from the ligand set, whether the co-ligand was tricine or EDDA. Ligand 3, however, failed to complex technetium except at very high ligand concentration: the marked contrast with 1 and 2 suggests that chelation, rather than nonchelating coordination, is a key feature of technetium coordination by HYNIC. Two further new HYNIC analogues, 2-chloro-6-hydrazinonicotinic acid (2-chloro-HYNIC, 4a) and 2,6-dihydrazinonicotinic acid (diHYNIC, 5) were also synthesised. The coordination chemistry of 4a with technetium was broadly parallel to that of 1 and 2 although it was a less efficient chelator, while 5 also behaved as an efficient chelator of technetium, but its coordination chemistry remains poorly defined and requires further investigation before it can sensibly be adopted for (99m)Tc-labelling. The new analogues 4a and 5 present an opportunity to develop trifunctional HYNIC analogues for more complex bioconjugate synthesis.

  6. Density Functional Theory Study on the Complexation of NOTA as a Bifunctional Chelator with Radiometal Ions.

    PubMed

    Adeowo, F Y; Honarparvar, B; Skelton, A A

    2017-08-17

    1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a key bifunctional chelator utilized for the complexation of metal ions in radiopharmaceutical applications; the ability of these chelators depends on the strength of their binding with ions. The focus of the present work is to evaluate the complexation of Cu(2+), Ga(3+), Sc(3+), and In(3+) radiometal ions with NOTA using density functional theory (B3LYP functional) and 6-311+G(2d,2p)/DGDZVP basis sets. The significant role of ion-water interactions in the chelation interaction energies in solution reflects the competition between ion-water and NOTA-ion interaction in the chelation process. There is reasonable agreement between experimental and theoretical binding constants, geometries, and (1)H NMR chemical shifts. Chelation interaction energies, Gibbs free energies, and entropies in solution show that the NOTA-Ga(3+) and NOTA-Cu(2+) are the most and least stable complexes, respectively. The natural atomic charges and second order perturbation analysis reveal charge transfer between NOTA and radiometal ions. The theoretical (1)H NMR chemical shifts of NOTA are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. Global scalar properties such as EHOMO/ELUMO, ΔELUMO-HOMO, and chemical hardness/softness confirm that the NOTA-Cu(2+) complex, which has a singly occupied molecular orbital, has the lowest ΔELUMO-HOMO value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and ΔELUMO-HOMO values of the complexes can be attributed to the different positions of the metal ions on the periodic table. This study affirms that, among the radiometal ions, Ga(3+) can be used to effectively radiolabel NOTA chelator for radiopharmaceutical usage as it binds most stably with NOTA.

  7. MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET.

    PubMed

    Moreau, M; Poty, S; Vrigneaud, J-M; Walker, P; Guillemin, M; Raguin, O; Oudot, A; Bernhard, C; Goze, C; Boschetti, F; Collin, B; Brunotte, F; Denat, F

    2017-09-01

    Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each (64)Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each (64)Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of (64)Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g(-1) 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling.

  8. p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr ImmunoPET.

    PubMed

    Deri, Melissa A; Ponnala, Shashikanth; Kozlowski, Paul; Burton-Pye, Benjamin P; Cicek, Huseyin T; Hu, Chunhua; Lewis, Jason S; Francesconi, Lynn C

    2015-12-16

    Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the (89)Zr(4+) cation is being released in vivo. Therefore, a more robust chelator for (89)Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of (89)Zr(4+) and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with (89)Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the (89)Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for (89)Zr-DFO-trastuzumab while (89)Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for (89)Zr. In vivo studies demonstrate the successful use of (89)Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with (89)Zr-HOPO-trastuzumab suggests superior stability of the (89)Zr-HOPO complex.

  9. The determination of the rate of conjugation immunoglobuline with bifunctional chelator

    NASA Astrophysics Data System (ADS)

    Málek, Z.; Miler, V.; Budský, F.

    2006-01-01

    The work was performed under the GACR project: "Technology of preparation of radionuclides and their labelled compounds for nuclear medicine and pharmacy with the use of the reactor LVR-15" reg. no. 104/03/0499. Imaging of cell’s antigens with the use of labelled immunoglobulines allows imaging of specific receptors on cell membrane and specific tumours. It is necessary to carry out the labelling of the immunoglobulines with radionuclides of suitable physical properties, which form cations (e.g., 111In, 90Y, 177Lu) that form very strong chelates of sufficiently high stability constant preventing the dissociation of complexes or the radionuclide under “in-vivo” conditions. The immunoglobuline must be conjugated with the bifunctional chelator (BCH), which contains both chelating unit and reactive group for binding to the immunoglobuline. In our laboratory we have conjugated human IgG and monoclonal antibody CD20 with diethylenetriamine pentaacetic acid dianhydride (cDTPAA). Radionuclides 90Y and 177Lu prepared on the LVR-15 reactor in NRI Rez were used for labelling. After conjugation and labelling the yields in relation to the amount of isotopic carrier have been determined.

  10. Cage-like bifunctional chelators, copper-64 radiopharmaceuticals and PET imaging using the same

    DOEpatents

    Conti, Peter S.; Cai, Hancheng; Li, Zibo; Liu, Shuanglong

    2016-08-02

    Disclosed is a class of versatile Sarcophagine based bifunctional chelators (BFCs) containing a hexa-aza cage for labeling with metals having either imaging, therapeutic or contrast applications radiolabeling and one or more linkers (A) and (B). The compounds have the general formula ##STR00001## where A is a functional group selected from group consisting of an amine, a carboxylic acid, an ester, a carbonyl, a thiol, an azide and an alkene, and B is a functional group selected from the group consisting of hydrogen, an amine, a carboxylic acid, and ester, a carbonyl, a thiol, an azide and an alkene. Also disclosed are conjugate of the BFC and a targeting moiety, which may be a peptide or antibody. Also disclosed are metal complexes of the BFC/targeting moiety conjugates that are useful as radiopharmaceuticals, imaging agents or contrast agents.

  11. Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity

    PubMed Central

    2015-01-01

    Multifunctional metal chelators that can modulate the amyloid β (Aβ) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimer’s disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aβ42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers. Given their ability to reduce the toxicity of soluble Aβ42 and Cu-Aβ42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aβ42 species in AD. PMID:25333939

  12. H6phospa-Trastuzumab: Bifunctional Methylenephosphonate-based Chelator with 89Zr, 111In and 177Lu

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.

    2013-01-01

    The acyclic chelator H6phospa and the bifunctional derivative p-SCN-Bn-H6phospa have been synthesized using nosyl protection chemistry and evaluated with 89Zr, 111In, and 177Lu. The p-SCN-Bn-H6phospa derivative was successfully conjugated to trastuzumab with isotopic dilution assays indicating 3.3 ± 0.1 chelates per antibody and in vitro cellular binding assays indicating an immunoreactivity value of 97.9 ± 2.6%. Radiolabeling of the H6phospa-trastuzumab immunoconjugate was achieved with 111In in 70–90% yields at room temperature in 30 minutes, while 177Lu under the same conditions produced more inconsistent yields of 40–80%. Stability experiments in human serum revealed the 111In-phospa-trastuzumab complex to be 52.0 ± 5.3% intact after 5 days at 37 °C, while the 177Lu-phospa-trastuzumab to be only 2.0 ± 0.3% intact. Small animal SPECT/CT imaging using mice bearing subcutaneous SKOV-3 ovarian cancer xenografts was performed, and it was found that 111In-phospa-trastuzumab successfully identified and delineated small (~2 mm in diameter) tumors from surrounding tissues, despite visible uptake in the kidneys and bone due to moderate chelate instability. As predicted from stability assays in serum, the 177Lu-phospa-trastuzumab conjugate served as a negative control and displayed no tumor uptake, with high uptake in bones indicating rapid and complete radiometal dissociation and suggesting a potential application of H6phospa in transient lanthanide chelation for bone-delivery. Radiolabeling with 89Zr was attempted, but even with elevated temperatures of 37 °C, the maximum observed radiometal incorporation over 18 hours was 12%. It can be concluded from this work that H6phospa is not superior to the previously studied H4octapa for use with 111In and 177Lu, but improvements in 89Zr radiolabeling were observed over H4octapa, suggesting H6phospa to be an excellent starting point for elaboration of 89Zr-based radiopharmaceutical development. To our knowledge, H6

  13. Application of the Ugi four-component reaction to the synthesis of ditopic bifunctional chelating agents.

    PubMed

    Tei, Lorenzo; Gugliotta, Giuseppe; Avedano, Stefano; Giovenzana, Giovanni B; Botta, Mauro

    2009-11-07

    The Ugi four-component reaction (Ugi 4CR) was exploited for the first time to obtain in a single synthetic step bifunctional ditopic chelators by using DOTA monoamide (DOTAMA) derivatives as amino and acid components. A number of ditopic systems in which the two DOTAMA units are connected by a central alpha-acylaminoamide group were synthesized by reacting different aldehydes, isocyanides and two DOTAMA chelates containing amino and acid functionalities. Variation of the components allows the insertion of another functional group into the alpha-acylaminoamide skeleton for further conjugation to biomolecules. The optimal reaction conditions were found by using methanol as solvent and ultrasound irradiation at a power of 60 W (20 kHz) for 3 h. The Gd(III) complexes of the dimeric ligands L1 and L2 (bearing a cyclohexyl ring and an octadecyl chain on the central alpha-acylaminoamide moiety, respectively) were fully characterized in aqueous media by relaxometric techniques with varying temperature and magnetic field strength. The relaxivity of Gd(2)L1 and Gd(2)L2 (in the aggregated form), at 20 MHz and 310 K, are 5.6 and 20.0 mM(-1) s(-1), respectively. The enhanced value found for Gd(2)L2 indicates that this lipophilic complex forms micelles at concentrations <0.1 mM. Finally, the binding of Gd(2)L2 to human serum albumin (HSA) was investigated by proton relaxometry, and the affinity constant of the complex and the relaxivity of the macromolecular adduct (r(1p)(b) = 38.1 mM(-1) s(-1); 20 MHz and 310 K) derived.

  14. Fusarinine C, a novel siderophore-based bifunctional chelator for radiolabeling with Gallium-68.

    PubMed

    Zhai, Chuangyan; Summer, Dominik; Rangger, Christine; Haas, Hubertus; Haubner, Roland; Decristoforo, Clemens

    2015-05-15

    Fusarinine C (FSC), a siderophore-based chelator coupled with the model peptide c(RGDfK) (FSC(succ-RGD)3), revealed excellent targeting properties in vivo using positron emission tomography (PET). Here, we report the details of radiolabeling conditions and specific activity as well as selectivity for (68)Ga. (68)Ga labeling of FSC(succ-RGD)3 was optimized regarding peptide concentration, pH, temperature, reaction time, and buffer system. Specific activity (SA) of [(68)Ga]FSC(succ-RGD)3 was compared with (68)Ga-1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid RGD ([(68)Ga]NODAGA-RGD). Stability was evaluated in 1000-fold ethylenediaminetetraacetic acid (EDTA) solution (pH 7) and phosphate-buffered saline (PBS). Metal competition tests (Fe, Cu, Zn, Al, and Ni) were carried out using [(68)Ga]-triacetylfusarinine C. High radiochemical yield was achieved within 5 min at room temperature, in particular allowing labeling with (68)Ga up to pH 8 with excellent stability in 1000-fold EDTA solution and PBS. The 10-fold to 20-fold lower concentrations of FSC(succ-RGD)3 led to the same radiochemical yield compared with [(68)Ga]NODAGA-RGD with SA up to 1.8 TBq/µmol. Metal competition tests showed high selective binding of (68)Ga to FSC. FSC is a multivalent siderophore-based bifunctional chelator allowing fast and highly selective labeling with (68)Ga in a wide pH range and results in stable complexes with high SA. Thus it is exceptionally well suited for the development of new (68)Ga-tracers for in vivo molecular imaging with PET.

  15. Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

    PubMed Central

    2014-01-01

    The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-selective ligand, 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB256), which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker. PMID:24944744

  16. Monofunctionalization of Calix[4]arene Tetracarboxylic Acid at the Upper Rim with Isothiocyanate Group: First Bifunctional Chelating Agent for Alpha-Emitter Ac-225

    PubMed Central

    Chen, Xiaoyuan; Ji, Min; Fisher, Darrell R.

    2010-01-01

    A procedure is reported for synthesizing a novel, water-soluble bifunctional chelating agent derived from calix[4]arene. This chelate features tetracarboxylic acid groups at the lower rim as an actinium-225 ionophore, and an isothiocyanate functional group at the upper rim for labeling of the N-terminus of monoclonal antibodies through thiourea linkage. PMID:20651937

  17. Hexadentate bispidine derivatives as versatile bifunctional chelate agents for copper(II) radioisotopes.

    PubMed

    Juran, Stefanie; Walther, Martin; Stephan, Holger; Bergmann, Ralf; Steinbach, Jörg; Kraus, Werner; Emmerling, Franziska; Comba, Peter

    2009-02-01

    The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (64Cu) or therapy (67Cu) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand 1 with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue betahomo-Glu-betaAla-betaAla-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D(o/w) < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, 1 h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of 64Cu-6 in Wistar rats. Preliminary in vivo studies of 64Cu-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2

  18. Synthesis and Evaluation of a New Bifunctional NETA Chelate for Molecular Targeted Radiotherapy Using 90Y or 177Lu

    PubMed Central

    Kang, Chi Soo; Chen, Yunwei; Lee, Hyunbeom; Liu, Dijie; Sun, Xiang; Kweon, Junghun; Lewis, Michael R.; Chong, Hyun-Soon

    2015-01-01

    Introduction Therapeutic potential of β-emitting cytotoxic radionuclides 90Y and 177Lu have been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy 90Y and 177Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of 90Y and 177Lu. Methods 5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-CNETA-c(RGDyK). 177Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice. Result The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, 90Y or 177Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (>99%, RT, <1 min). 90Y- and 177Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with 90Y or 177Lu. 177Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile. Conclusion The results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of 90Y and 177Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals. PMID

  19. Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using(90)Y or(177)Lu.

    PubMed

    Kang, Chi Soo; Chen, Yunwei; Lee, Hyunbeom; Liu, Dijie; Sun, Xiang; Kweon, Junghun; Lewis, Michael R; Chong, Hyun-Soon

    2015-03-01

    Therapeutic potential of β-emitting cytotoxic radionuclides (90)Y and (177)Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy (90)Y and (177)Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of (90)Y and (177)Lu. 5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). (177)Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice. The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, (90)Y or (177)Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (>99%, RT, <1 min). (90)Y- and (177)Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with (90)Y or (177)Lu. (177)Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile. The results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of (90)Y and (177)Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals. Copyright © 2014

  20. (68)Ga labeled fatty acids for cardiac metabolic imaging: Influence of different bifunctional chelators.

    PubMed

    Jain, Akanksha; Mathur, Anupam; Pandey, Usha; Sarma, Haladhar Dev; Dash, Ashutosh

    2016-12-01

    Development of (68)Ga labeled fatty acids is of immense interest due to the availability of (68)Ga through a generator and its superiority over SPECT based tracers in carrying out dynamic imaging on a PET scanner. Our present work explores the influence of different chelators on the cardiac uptake and pharmacokinetics of the (68)Ga-labeled fatty acids. Two new (68)Ga labeled fatty acids were synthesized by conjugation of 11-aminoundecanoic acid with the bifunctional chelators (BFCs) viz. p-SCN-Bn-DTPA (S-2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid) and p-SCN-Bn-NODAGA (S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) and their comparison was carried out with the previously reported (68)Ga-NOTA-undecanoic acid. Both the conjugates were radiolabeled with (68)Ga in high yields and purities (>95%). Their formation was established by preparation and characterization of their inactive analogs with (nat)Ga at macroscopic levels. Biodistribution studies of the complexes in Swiss mice showed lower initial myocardial uptake for (68)Ga-NODAGA-undecanoic acid (3.8±0.6%ID/g) and (68)Ga-DTPA-undecanoic acid (1.3±0.5%ID/g) complexes in comparison to previously reported (68)Ga-NOTA-undecanoic acid complex (7.4±2.8%ID/g) at 2min p.i. However, significant retention of the tracer in the myocardium was observed in the case of (68)Ga-NODAGA-undecanoic complex, which led to improved heart/non-target ratios of the complex over time in comparison to the other (68)Ga complexes. Similarly, the DTPA complex exhibited increased washout from the liver in comparison to other (68)Ga derivatives. The β oxidation mechanism in myocytes was investigated by isolating the myocardial extract post intravenous injection of the respective (68)Ga complexes and analyzing them by radio-HPLC, which showed metabolic transformation of the parent fatty acid complex peak in all the three complexes. This study has provided an insight into the design

  1. Combining bifunctional chelator with (3 + 2)-cycloaddition approaches: synthesis of dual-function technetium complexes.

    PubMed

    Braband, Henrik; Imstepf, Sebastian; Benz, Michael; Spingler, Bernhard; Alberto, Roger

    2012-04-02

    A new concept for the synthesis of dual-functionalized technetium (Tc) compounds is presented, on the basis of the reactivity of fac-{Tc(VII)O(3)}(+) complexes. The concept combines the "classical" bifunctional chelator (BFC) approach with the new ligand centered labeling strategy of fac-{TcO(3)}(+) complexes with alkenes ((3 + 2)-cycloaddition approach). To evidence this concept, fac-{(99)TcO(3)}(+) model complexes containing functionalized 1,4,7-triazacyclononane (tacn) derivatives N-benzyl-2-(1,4,7-triazonan-1-yl)acetamide (tacn-ba) and 2,2',2″-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (nota·3H) were synthesized and characterized. Whereas [(99)TcO(3)(tacn-ba)](+) [2](+) can be synthesized following a established oxidation procedure starting from the Tc(V) complex [(99)TcO(glyc)(tacn-ba)](+) [1](+), a new synthetic pathway for the synthesis of [(99)TcO(3)(nota)](2-) [5](2-) had to be developed, starting from [(99)Tc(nota·3H)(CO)(3)](+) [4](+) and using sodium perborate tetrahydrate (NaBO(3)·4H(2)O) as oxidizing reagent. While [(99)TcO(3)(nota)](2-) [5](2-) is a very attractive candidate for the development of trisubstituted novel multifunctional radioprobes, (3 + 2)-cycloaddition reactions of [(99)TcO(3)(tacn-ba)](+) [2](+) with 4-vinylbenzenesulfonate (styrene-SO(3)(-)) demonstrated the suitability of monosubstituted tacn derivatives for the new mixed "BFC-(3 + 2)-cycloaddition" approach. Kinetic studies of this reaction lead to the conclusion that the alteration of the electronic structure of the nitrogen donors by, e.g., alkylation can be used to tune the rate of the (3 + 2)-cycloaddition.

  2. Radiochemical studies of 99mTc complexes of modified cysteine ligands and bifunctional chelating agents.

    PubMed

    Pillai, M R; Kothari, K; Banerjee, S; Samuel, G; Suresh, M; Sarma, H D; Jurisson, S

    1999-07-01

    The synthesis of four novel ligands using the amino-acid cysteine and its ethyl carboxylate derivative is described. The synthetic method involves a two-step procedure, wherein the intermediate Schiff base formed by the condensation of the amino group of the cysteine substrate and salicylaldehyde is reduced to give the target ligands. The intermediates and the final products were characterized by high resolution nuclear magnetic resonance spectroscopy. Complexation studies of the ligands with 99mTc were optimized using stannous tartrate as the reducing agent under varying reaction conditions. The complexes were characterized using standard quality control techniques such as thin layer chromatography, paper electrophoresis, and paper chromatography. Lipophilicities of the complexes were estimated by solvent extraction into chloroform. Substantial changes in net charge and lipophilicity of the 99mTc complexes were observed on substituting the carboxylic acid functionality in ligands I and II with the ethyl carboxylate groups (ligands II and IV). All the ligands formed 99mTc complexes in high yield. Whereas the complexes with ligands I and II were observed to be hydrophilic in nature and not extractable into CHCl3, ligands III and IV resulted in neutral and lipophilic 99mTc complexes. The 99mTc complex with ligand II was not stable and on storage formed a hydrophilic and nonextractable species. The biodistribution of the complexes of ligands I and II showed that they cleared predominantly through the kidneys, whereas the complexes with ligands III and IV were excreted primarily through the hepatobiliary system. No significant brain uptake was observed with the 99mTc complexes with ligands III and IV despite their favorable properties of neutrality, lipophilicity, and conversion into a hydrophilic species. These ligands offer potential for use as bifunctional chelating agents.

  3. Enantiopure bifunctional chelators for copper radiopharmaceuticals--does chirality matter in radiotracer design?

    PubMed

    Singh, Ajay N; Dakanali, Marianna; Hao, Guiyang; Ramezani, Saleh; Kumar, Amit; Sun, Xiankai

    2014-06-10

    It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.

  4. Evaluation of bifunctional chelates for the development of gallium-based radiopharmaceuticals.

    PubMed

    Ferreira, Cara L; Lamsa, Eric; Woods, Michael; Duan, Yin; Fernando, Pasan; Bensimon, Corinne; Kordos, Myra; Guenther, Katharina; Jurek, Paul; Kiefer, Garry E

    2010-03-17

    Ga radioisotopes, including the generator-produced positron-emitting isotope (68)Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs containing different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochemical yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concentrations of BFC, or heating to obtain equivalent radiochemical yields. Better stability was observed for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, especially with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that (68)Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of (68)Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, (68

  5. Isothiocyanate-functionalized bifunctional chelates and fac-[MI(CO)3]+ (M = Re, 99mTc) complexes for targeting uPAR in prostate cancer

    USDA-ARS?s Scientific Manuscript database

    Developing strategies to rapidly incorporate the fac-[MI(CO)3]+ (M = Re, 99mTc) core into biological targeting vectors is a growing realm in radiopharmaceutical development. This work presents the preparation of a novel isothiocyanate-functionalized bifunctional chelate based on 2,2´-dipicolylamine ...

  6. Preparation of bifunctional isocyanate hydroxamate linkers: Synthesis of carbamate and urea tethered polyhydroxamic acid chelators

    PubMed Central

    Fernando, Rasika; Shirley, Jonathan M.; Torres, Emilio; Jacobs, Hollie K.; Gopalan, Aravamudan S.

    2012-01-01

    Two novel bifunctional N-methylhydroxamate-isocyanate linkers 20 and 21 were prepared in good yield and high purity from the corresponding amine salts using a biphasic reaction with phosgene. The facile ring opening reaction of N-Boc lactams using the anion of O-benzylhydroxylamine gave the protected amino hydroxamates 6a and 6c in good yields. The selective methylation of the hydroxamate nitrogen in the presence of the N-Boc group in these intermediates could be readily accomplished. The utility of the linkers was clearly demonstrated by the synthesis of the carbamate-tethered trishydroxamic acid 27 and the urea-tethered 29 PMID:23162172

  7. Monooxorhenium(V) complexes with 222-N2S2 MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation.

    PubMed

    Demoin, Dustin Wayne; Dame, Ashley N; Minard, William D; Gallazzi, Fabio; Seickman, Gary L; Rold, Tammy L; Bernskoetter, Nicole; Fassbender, Michael E; Hoffman, Timothy J; Deakyne, Carol A; Jurisson, Silvia S

    2016-12-01

    Targeted radiotherapy using the bifunctional chelate approach with (186/188)Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7-14)NH2) were synthesized, complexed with rhenium, radiolabeled with (99m)Tc and (186)Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. An IC50 value of 2.0±0.7nM for (nat)ReO-222-MAMA(N-6-Ahx-BBN(7-14)NH2) compared to [(125)I]-Tyr(4)-BBN(NH2) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added (99m)Tc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normal mice. The (186)ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2 chelator is appropriate for chelating (186/188)Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The (99m)Tc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Detailed evaluation on the effect of metal ion impurities on complexation of generator eluted 68Ga with different bifunctional chelators.

    PubMed

    Chakravarty, Rubel; Chakraborty, Sudipta; Dash, Ashutosh; Pillai, M R A

    2013-02-01

    The introduction of (68)Ga-based positron emission tomography (PET) to clinical practice using (68)Ge/(68)Ga generator represents a developmental milestone in the field of molecular imaging. Herein, we report a systematic study on (68)Ga complexes with different bifunctional chelators (BFCs) and the effect of metal ion impurities on the radiochemical yields in order to identify the most suitable BFC to be used for the development of (68)Ga-based target specific radiopharmaceuticals. Radiolabeling of four commonly used BFCs namely p-isothiocyanato benzyl derivatives of diethylenetriaminepentacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) with (68)Ga was studied with respect to optimal radiolabeling conditions, effect of metal ion impurities on radiochemical yield, in vitro stability and in vivo clearance properties in biological system. Out of the four BFCs studied, p-isothiocyanato benzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-NCS) could be radiolabeled instantly with (68)Ga at room temperature with >98% yield, even in presence of up to 10 ppm of other metal ion impurities (such as Zn, Cu, Fe, Al, Sn and Ti ions). The (68)Ga-complex of NOTA-NCS demonstrated high in vitro stability even in the presence of 1000 times molar excess of metal ions (such as Fe, Cu, Zn and Ca ions). In contrast, other (68)Ga-labeled BFCs (DTPA-NCS, DOTA-NCS and PCTA-NCS) showed reduced radiochemical yields when incubated with the above concentration of metal ions. The biodistribution studies in Swiss mice revealed that (68)Ga-NOTA-NCS cleared rapidly through the kidneys with minimum retention in any major organ. The simple and rapid approach for preparation of (68)Ga-radiopharmaceuticals using NOTA based bifunctional chelators would render (68)Ga-radiopharmaceutical chemistry more convenient with

  9. Study of a Bifunctional Aβ Aggregation Inhibitor with the Abilities of Antiamyloid-β and Copper Chelation.

    PubMed

    Zhang, Qian; Hu, Xiaoyu; Wang, Wei; Yuan, Zhi

    2016-02-08

    In this study, a bifunctional Aβ aggregation inhibitor peptide, GGHRYYAAFFARR (GR), with the abilities to bind copper and antiamyloid was designed to inhibit the neurotoxicity of the Aβ-Cu(II) complex. The thioflavin T (ThT) assay, turbidimetric analysis, transmission electron microscopy (TEM), and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay were used to study its potential inhibitory effect on Aβ aggregation. Our findings indicate that GGH was the specific chelating sequence and that the RYYAAFFARR (RR) component acted as an aggregation inhibitor. More importantly, GR significantly decreased the cytotoxicity of the Aβ-Cu(II) complex. The cell viability improved to 88%, which was higher than with the single functional peptide GGH and RR by 39% and 20%, respectively. Moreover, the qualitative effect of Cu(II) on the Aβ-Cu(II) complex was also studied. Our results indicate that Cu(II) induces the formation of the β-sheet structure with a subequimolar Cu(II):Aβ molar ratio (0.25:1) but led to increased ROS production at a supra-equimolar ratio.

  10. Multivalent Bifunctional Chelator Scaffolds for Gallium-68 Based Positron Emission Tomography Imaging Probe Design: Signal Amplification via Multivalency

    PubMed Central

    Singh, Ajay N.; Liu, Wei; Hao, Guiyang; Kumar, Amit; Gupta, Anjali; Öz, Orhan K.; Hsieh, Jer-Tsong; Sun, Xiankai

    2011-01-01

    The role of the multivalent effect has been well recognized in the design of molecular imaging probes towards the desired imaging signal amplification. Recently we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds (tBu3-1-COOH, tBu3-2-(COOH)2 and tBu3-3-(COOH)3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via multivalent effect. For proof of principle, a known integrin αvβ3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H31, H32, and H33), which present 1 – 3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin αvβ3 binding affinities (IC50 values), the enhanced specific binding was observed for multivalent conjugates (H32: 43.9 ± 16.1 nM; H33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga3+ within 30 min at room temperature in high radiochemical yields (> 95%). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2 and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin αvβ3 positive PC-3 tumor xenografts (n = 3). All 68Ga -labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h post-injection (p.i.). The PET signal amplification in PC-3 tumor by multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates (68Ga-3: 2.55 ± 0.50%ID/g; 68Ga-2: 1.90 ± 0.10 %ID/g; 68Ga-1: 1.66 ± 0.15 %ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications

  11. New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with (68)Ga(3.).

    PubMed

    Ma, Michelle T; Cullinane, Carleen; Imberti, Cinzia; Baguña Torres, Julia; Terry, Samantha Y A; Roselt, Peter; Hicks, Rodney J; Blower, Philip J

    2016-02-17

    Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with (68)Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1). Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new (68)Ga(3+)-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1-2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.

  12. New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with 68Ga3+

    PubMed Central

    2015-01-01

    Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with 68Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced 68Ga3+ in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60–80 MBq nmol–1. Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new 68Ga3+-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1–2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of 68Ga biomolecules under mild conditions suitable for peptides and proteins. PMID:26286399

  13. Imaging Cancer Using PET – the Effect of the Bifunctional Chelator on the Biodistribution of a 64Cu-Labeled Antibody

    PubMed Central

    Dearling, Jason L.J.; Voss, Stephan D.; Dunning, Patricia; Snay, Erin; Fahey, Frederic; Smith, Suzanne V.; Huston, James S.; Meares, Claude F.; Treves, S. Ted; Packard, Alan B.

    2010-01-01

    Introduction Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the 64Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with 64Cu using these chelators in tumor-bearing mice. Methods The chelators (p-NH2-Bn-NOTA, BAT-6, p-NH2-Bn-DOTA, DOTA, and SarAr) were conjugated to the anti-GD2 antibody ch14.18, and the conjugated antibody was labeled with 64Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from PET images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out. Results The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [64Cu]ch14.18-p-NH2-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [64Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. Conclusions The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant differences in uptake of the tracer by the tumor. However, there were significant differences in tracer concentration in other tissues, including those involved in clearance of the radioimmunoconjugate (e.g., liver and spleen). PMID:21220127

  14. Evaluation of K(HYNIC)2 as A Bifunctional Chelator for 99mTc-Labeling of Small Biomolecules

    PubMed Central

    Ji, Shundong; Zhou, Yang; Shao, Guoqiang; Liu, Shuang

    2013-01-01

    This study sought to evaluate K(HYNIC)2 (K = lysine and HYNIC = 6-hydrazinonicotinyl) as a bifunctional chelator for 99mTc-labeling of biomolecule. In this study, four K(HYNIC)2–conjugated cyclic RGD peptides, K(HYNIC)2-RGD2 (RGD2 = E[c(RGDfK)]2), K(HYNIC)2-3G-RGD2 (3G-RGD2 = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)]2), K(HYNIC)2-2P-RGD2 (2P-RGD2 = E[PEG4-c(RGDfK)]2, and PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid), and K(HYNIC)2-3P-RGD2 (3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2) were prepared, and evaluated for their integrin αvβ3 binding affinity. IC50 values were determined to be 47 ± 2, 35 ± 2, 37 ± 2, 85 ± 2 and 422 ± 15 nM for K(HYNIC)2-2P-RGD2, K(HYNIC)2-3P-RGD2, K(HYNIC)2-3G-RGD2, K(HYNIC)2-RGD2 and c(RGDyK), respectively, against 125I-echistatin bound to U87MG cells. Macrocyclic complexes [99mTc(K(HYNIC)2-RGD2)(tricine)] (1), [99mTc(K(HYNIC)2-3G-RGD2)(tricine)] (2), [99mTc(K(HYNIC)2-2P-RGD2)(tricine)] (3), and [99mTc(K(HYNIC)2-3P-RGD2)(tricine)] (4) were prepared, and evaluated in athymic nude mice bearing U87MG glioma xenografts for their tumor targeting capability and biodistribution. It was found that 1 – 4 all had high solution stability and more than two isomers, as evidenced by the presence of multiple radiometric peaks in their radio-HPLC chromatograms. The tumor uptake of 1 – 4 was 3.78 ± 0.81, 7.46 ± 1.68, 9.74 ± 1.65 and 8.59 ± 1.52 %ID/g, respectively, which was completely consistent with trend of integrin αvβ3 binding affinity for cyclic RGD peptides. Replacing [99mTc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) with [99mTc(K(HYNIC)2)(tricine)] had little impact on radiotracer tumor uptake; but it had significant effect on the uptake of radiotracer in kidneys, lungs and spleen. The tumor was clearly visualized by SPECT/CT with excellent contrast in a glioma-bearing mouse administered with 4. K(HYNIC)2 would be particularly useful for 99mTc-labeling of small biomolecules with one or more

  15. A systematic study on the utility of CHX-A''-DTPA-NCS and NOTA-NCS as bifunctional chelators for (177)Lu radiopharmaceuticals.

    PubMed

    Pandey, Usha; Gamre, Naresh; Lohar, Sharad Pandurang; Dash, Ashutosh

    2017-09-01

    This paper describes the evaluation of [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA-NCS) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-NCS) as bifunctional chelators for (177)Lu. While (177)Lu-CHX-A''-DTPA-NCS could be obtained in high yields at equimolar ratios of lutetium to CHX-A''-DTPA-NCS, >95% yield of (177)Lu-NOTA-NCS could be achieved at 1:2M ratio of lutetium to NOTA-NCS. Trace metals reduced the yields of (177)Lu-NOTA-NCS significantly as compared to (177)Lu-CHX-A''-DTPA-NCS. In vitro stability of (177)Lu-CHX-A''-DTPA-NCS was also superior to (177)Lu-NOTA-NCS. It could be concluded from this study that among the two chelators evaluated, CHX-A''-DTPA-NCS is more appropriate for preparation of (177)Lu radiopharmaceuticals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. New cross-bridged cyclam derivative CB-TE1K1P, an improved bifunctional chelator for copper radionuclides.

    PubMed

    Zeng, Dexing; Ouyang, Qin; Cai, Zhengxin; Xie, Xiang-Qun; Anderson, Carolyn J

    2014-01-04

    A new cross-bridged cyclam chelator, CB-TE1K1P, was developed for copper-based radiopharmaceuticals, and this chelator can be labelled with (64)Cu under mild conditions in high specific activity. DBCO-PEG4-CB-TE1K1P was synthesized for conjugation to proteins, while Dde-CB-TE1K1P((t)Bu2)-OH was synthesized for solid-phase peptide synthesis. Examples of the conjugation chemistry, radiolabelling and serum stability of each are presented.

  17. Phytic acid: an alternative root canal chelating agent.

    PubMed

    Nassar, Mohannad; Hiraishi, Noriko; Tamura, Yukihiko; Otsuki, Masayuki; Aoki, Kazuhiro; Tagami, Junji

    2015-02-01

    The objectives of this study were to investigate the effect of phytic acid, inositol hexakisphosphate (IP6), as a final rinse on the surface of instrumented root canals and smear-layered flat dentin surfaces treated with sodium hypochlorite (NaOCl) and to evaluate its effect on the viability and alkaline phosphatase activity of osteoblast-like cells (MC3T3-E1). The universally accepted chelating agent EDTA was used as the control in all conducted experiments. Root canals of human canines were instrumented with rotary files and irrigated with 5% NaOCl, followed by a final rinse of 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. NaOCl-treated flat coronal dentin surfaces were also treated with 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. The presence or absence of smear layer was evaluated with scanning electron microscopy. Cell viability and alkaline phosphatase assays were performed to evaluate the effect of IP6 and EDTA on cultured MC3T3-E1 cells. The results demonstrated the ability of IP6 to remove the smear layer from instrumented root canals and flat coronal dentin surfaces. When compared with EDTA, IP6 was less cytotoxic and did not affect the differentiation of MC3T3-E1 cells. IP6 shows the potential to be an effective and biocompatible chelating agent. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  18. Deferasirox-TAT(47-57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine.

    PubMed

    Goswami, Dibakar; Vitorino, Hector A; Alta, Roxana Y P; Silvestre, Daniel M; Nomura, Cassiana S; Machini, M Teresa; Espósito, Breno P

    2015-10-01

    Deferasirox (DFX), an orally active and clinically approved iron chelator, is being used extensively for the treatment of iron overload. However, its water insolubility makes it cumbersome for practical use. In addition to this, the low efficacy of DFX to remove brain iron prompted us to synthesize and evaluate a DFX-TAT(47-57) peptide conjugate for its iron chelation properties and permeability across RBE4 cell line, an in vitro model of the blood-brain barrier. The water-soluble conjugate was able to remove labile iron from buffered solution as well as from iron overloaded sera, and the permeability of DFX-TAT(47-57) conjugate into RBE4 cells was not affected compared to parent deferasirox. The iron bound conjugate was also able to translocate through the cell membrane.

  19. Investigation of a potential macromolecular MRI contrast agent prepared from PPI (G = 2, polypropyleneimine, generation 2) dendrimer bifunctional chelates

    NASA Astrophysics Data System (ADS)

    Wang, Jianxin Steven

    The long-term objective is to develop magnetic resonance (MR) contrast agents that actively and passively target tumors for diagnosis and therapy. Many diagnostic imaging techniques for cancer lack specificity. A dendrimer based magnetic resonance imaging contrast agent has been developed with large proton relaxation enhancements and high molecular relaxivities. A new type of linear dendrimer based MRI contrast agent that is built from the polypropyleneimine and polyamidoamine dendrimers in which free amines have been conjugated to the chelate DTPA, which further formed the complex with Gadolinium (Gd) was studied. The specific research goals were to test the hypothesis that a linear chelate with macromolecular agents can be used in vitro and in vivo. This work successfully examined the adequacy and viability of the application for this agent in vitro and in vivo. A small animal whole body counter was designed and constructed to allow us to monitor biodistribution and kinetic mechanisms using a radioisotope labeled complex. The procedures of metal labeling, separation and purification have been established from this work. A biodistribution study has been performed using radioisotope induced organ/tissue counting and gamma camera imaging. The ratio of percentage of injected dose per gram organ/tissue for kidney and liver is 3.71 from whole body counter and 3.77 from the gamma camera. The results suggested that retention of Gd (III) is too high and a more kinetically stable chelate should be developed. The pharmacokinetic was evaluated in the whole animal model with the whole body clearance, and a kinetics model was developed. The pharmacokinetic results showed a bi-exponential decay in the animal model with two component excretion constants 1.43e(-5) and 0.0038511, which give half-lives of 3 hours and 33.6 days, respectively. Magnetic resonance imaging of this complex resulted in a 52% contrast enhancement in the rat kidney following the agents' administration in

  20. Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases.

    PubMed

    Youdim, Moussa B H; Fridkin, Mati; Zheng, Hailin

    2005-02-01

    and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.

  1. p-NO2-Bn-H4neunpa and H4neunpa-Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and (111)In Immuno-Single Photon Emission Computed Tomography Imaging.

    PubMed

    Spreckelmeyer, Sarah; Ramogida, Caterina F; Rousseau, Julie; Arane, Karen; Bratanovic, Ivica; Colpo, Nadine; Jermilova, Una; Dias, Gemma M; Dude, Iulia; Jaraquemada-Peláez, Maria de Guadalupe; Bénard, François; Schaffer, Paul; Orvig, Chris

    2017-08-16

    Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H4neunpa and its immunoconjugate H4neunpa-trastuzumab for (111)In radiolabeling are synthesized. The ability of p-SCN-Bn-H4neunpa and H4neunpa-trastuzumab to quantitatively radiolabel (111)InCl3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In(3+), Bi(3+), and La(3+) resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both (111)In complexes to have high stability over 5 days. Mouse biodistribution of [(111)In][In(p-NO2-Bn-neunpa)](-), compared to that of [(111)In][In(p-NH2-Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))](2-), at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates (111)In-neunpa-trastuzumab and (111)In-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of (111)In-neunpa-trastuzumab compared to that of (111)In-CHX-A″-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H4neunpa to be a promising chelator for (111)In (and other radiometals) with high in vitro stability and also show H4neunpa-trastuzumab to be an excellent (111)In chelator with promising biodistribution in mice.

  2. Chemistry of bifunctional photoprobes. 3 -- Correlation between the efficiency of CH insertion by photolabile chelating agents and lifetimes of singlet nitrenes by flash photolysis: First example of photochemical attachment of {sup 99m}Tc-complex with human serum albumin

    SciTech Connect

    Pandurangi, R.S.; Lusiak, P.; Kuntz, R.R.; Volkert, W.A.; Rogowski, J.; Platz, M.S.

    1998-11-27

    Systematic functionalization of perfluoroaryl azides with chelating agents capable of complexing transition metals produces a new class of bifunctional photolabile chelating agents (BFPCAs). The strategy is shield the azide functionality from the electronic and steric influence of the electron-rich metal Pd through ester and amide bridges raised CH insertion efficiency to unprecedented levels (>92%) in a model solvent (cyclohexane). In contrast, perfluoroaryl azides attached to chelating agents via hydrazones show no significant CH insertion in cyclohexane upon photolysis. Measurements of the lifetimes of the singlet nitrenes derived from these agents by flash photolysis techniques correlate well with the efficiency of CH insertion by demonstrating longer lifetimes (10--50 times) for singlet nitrenes derived from azidotetrafluorinated esters and amides compared with the related hydrazones, which failed to yield significant CH insertion. A representative BFPCA 12 is chelated to diagnostic radionuclide {sup 99m}Tc and covalently attached to human serum albumin via photochemical activation extending the favorable bimolecular insertion characteristics of BFPCA to tracer level concentrations in buffer conditions. Flash photolysis experiments correlate singlet nitrene lifetimes with the efficiency of intermolecular insertion reactions. This work provides new photo-cross-linking technology, useful in radiodiagnostics and radiotherapy in nuclear medicine.

  3. Bifunctional CYP81AA proteins catalyse identical hydroxylations but alternative regioselective phenol couplings in plant xanthone biosynthesis

    PubMed Central

    El-Awaad, Islam; Bocola, Marco; Beuerle, Till; Liu, Benye; Beerhues, Ludger

    2016-01-01

    Xanthones are natural products present in plants and microorganisms. In plants, their biosynthesis starts with regioselective cyclization of 2,3′,4,6-tetrahydroxybenzophenone to either 1,3,5- or 1,3,7-trihydroxyxanthones, catalysed by cytochrome P450 (CYP) enzymes. Here we isolate and express CYP81AA-coding sequences from Hypericum calycinum and H. perforatum in yeast. Microsomes catalyse two consecutive reactions, that is, 3′-hydroxylation of 2,4,6-trihydroxybenzophenone and C–O phenol coupling of the resulting 2,3′,4,6-tetrahydroxybenzophenone. Relative to the inserted 3′-hydroxyl, the orthologues Hc/HpCYP81AA1 cyclize via the para position to form 1,3,7-trihydroxyxanthone, whereas the paralogue HpCYP81AA2 directs cyclization to the ortho position, yielding the isomeric 1,3,5-trihydroxyxanthone. Homology modelling and reciprocal mutagenesis reveal the impact of S375, L378 and A483 on controlling the regioselectivity of HpCYP81AA2, which is converted into HpCYP81AA1 by sextuple mutation. However, the reciprocal mutations in HpCYP81AA1 barely affect its regiospecificity. Product docking rationalizes the alternative C–O phenol coupling reactions. Our results help understand the machinery of bifunctional CYPs. PMID:27145837

  4. Alternative Chelator for 89Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)

    PubMed Central

    2015-01-01

    Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of mice suggests that 89Zr4+ is released from DFO in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of 89Zr-HOPO matched or surpassed that of 89Zr-DFO in every experiment. In healthy mice, 89Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for 89Zr-based PET imaging agents. PMID:24814511

  5. Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK

    PubMed Central

    2017-01-01

    This research aimed to develop new tumor targeted theranostic agents taking advantage of the similarities in coordination chemistry between technetium and rhenium. A γ-emitting radioactive isotope of technetium is commonly used in diagnostic imaging, and there are two β– emitting radioactive isotopes of rhenium that have the potential to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide (HYNIC) bifunctional ligands have been prepared by appending thioamide functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide ligands (SHYNIC). The new bidentate ligands were conjugated to the tumor targeting peptides Tyr3-octreotate and cyclic-RGD. The new ligands and conjugates were used to prepare well-defined {M=O}3+ complexes (where M = 99mTc or natRe or 188Re) that feature two targeting peptides attached to the single metal ion. These new SHYNIC ligands are capable of forming well-defined rhenium and technetium complexes and offer the possibility of using the 99mTc imaging and 188/186Re therapeutic matched pairs. PMID:28766938

  6. New bifunctional ligands for radioimmunoimaging and radioimmunotherapy

    SciTech Connect

    Brechbiel, M.W.

    1988-01-01

    The bifunctional EDTA ligand and two bifunctional DTPA ligands were synthesized by direct aminolysis of an amino acid ester followed by reduction, alkylation, and functional group modification to introduced bifunctionality. The reactive substituent chosen for protein conjugation was the isothiocyanate group. The generality of this approach was demonstrated with 9 different amino acids to produce the respective substituted diethylenetriamines. The remaining three bifunctional DTPA ligands were synthesized via classical peptide methodology producing a dipeptide amide which, after deprotection, was reduced to the triamine and alkylated to produce the ligand. Biodistribution studies of the ligands conjugated to monoclonal antibody B72.3 and labelled with In-111 revealed that superior retention of In-111 was attained and the dose to the liver was minimized when a full intact octadentate bifunctional DTPA chelate was used, e.g. DTPA > EDTA > DTTA (diethylenetritetraacetic acid from use of DTPA dianhydride (CA-DTPA)). The best scintigraphic images were obtained after 72 hours when a DTPA ligand was used to complex the In-111. Biodistribution studies using Yttrium-88 revealed that the disubstituted bifunctional DTPA was necessary to minimize the bone dose from the Yttrium while maintaining a high dose to the tumor.

  7. Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging.

    PubMed

    Boehm-Sturm, Philipp; Haeckel, Akvile; Hauptmann, Ralf; Mueller, Susanne; Kuhl, Christiane K; Schellenberger, Eyk A

    2017-01-07

    Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol(-1) · sec(-1), r2 = 2.5 mmol(-1) · sec(-1)) and Fe-DTPA (r1 = 0.9 mmol(-1) · sec(-1), r2 = 0.9 mmol(-1) · sec(-1)) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol(-1) · sec(-1), r2 = 4.8 mmol(-1) · sec(-1)). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe-DTPA Pearson R, 0

  8. Hyperaccumulator oilcake manure as an alternative for chelate-induced phytoremediation of heavy metals contaminated alluvial soils.

    PubMed

    Mani, Dinesh; Kumar, Chitranjan; Patel, Niraj Kumar

    2015-01-01

    The ability of hyperaccumulator oilcake manure as compared to chelates was investigated by growing Calendula officinalis L for phytoremediation of cadmium and lead contaminated alluvial soil. The combinatorial treatment T6 [2.5 g kg(-1) oilcake manure+5 mmol kg(-1) EDDS] caused maximum cadmium accumulation in root, shoot and flower up to 5.46, 4.74 and 1.37 mg kg(-1) and lead accumulation up to 16.11, 13.44 and 3.17 mg kg(-1), respectively at Naini dump site, Allahabad (S3). The treatment showed maximum remediation efficiency for Cd (RR=0.676%) and Pb (RR=0.202%) at Mumfordganj contaminated site (S2). However, the above parameters were also observed at par with the treatment T5 [2.5 g kg(-1) oilcake manure +2 g kg(-1) humic acid]. Applied EDDS altered chlorophyll-a, chlorophyll-b, and carotene contents of plants while application of oilcake manure enhanced their contents in plant by 3.73-8.65%, 5.81-17.65%, and 7.04-17.19%, respectively. The authors conclude that Calendula officinalis L has potential to be safely grown in moderately Cd and Pb-contaminated soils and application of hyperaccumulator oilcake manure boosts the photosynthetic pigments of the plant, leading to enhanced clean-up of the cadmium and lead-contaminated soils. Hence, the hyperaccumulator oilcake manure should be preferred over chelates for sustainable phytoremediation through soil-plant rhizospheric process.

  9. Iron Chelation

    MedlinePlus

    ... iron overload and need treatment. What is iron overload? Iron chelation therapy is used when you have ... may want to perform: How quickly does iron overload happen? This is different for each person. It ...

  10. Determination of alternative and conventional chelating agents as copper(II) complexes by capillary zone electrophoresis--the first use of didecyldimethylammonium bromide as a flow reversal reagent.

    PubMed

    Laamanen, Pirkko-Leena; Matilainen, Rose

    2007-02-12

    A capillary zone electrophoresis (CZE) method for analyzing 11 chelating agents [beta-alaninediacetic acid (beta-ADA), trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid (HEDTA), N-(2-hydroxyethyl)iminodiacetic acid (HEIDA), iminodiacetic acid (IDA), methylglycinediacetic acid (MGDA), nitrilotriacetic acid (NTA), 1,3-diaminopropane-N,N,N',N'-tetraacetic acid (PDTA) and triethylenetetraaminehexaacetic acid (TTHA)] as negatively charged copper(II) complexes has been established. Both conventional and alternative chelating agents were included in this study, because they are used side by side in industrial applications. In this study, didecyldimethylammonium bromide (DMDDAB) was successfully used as a flow reversal reagent for the first time in an aqueous CZE method based on phosphate BGE with UV spectrophotometric detection. In addition this new flow modifier was compared to common TTAB. Method development was done using a fused silica capillary (61 cm x 50 microm i.d.). The optimized BGE was a 105 mmol L(-1) phosphate buffer with TTAB or DMDDAB in the concentration 0.5 mmol L(-1) at pH 7.1. The measurements were done with -20 kV voltage using direct UV detection at 254 nm. In both CZE methods all 11 analyte zones were properly separated (resolutions > or =2.4), and the calibrations gave excellent correlation coefficients (> or =0.998; linear range tested 0.5-2.0 mmol L(-1)). The limits of detection were < or =34 and < or =49 micromol L(-1) with the method of DMDDAB and TTAB, respectively. A clear benefit of both methods was the short analysis time; all 11 complexes were detected in less than 6 and 5.5 min with the methods of TTAB and DMDDAB, respectively. The two methods were tested with dishwashing detergents and paper mill wastewater samples and proved to be suitable for practical use.

  11. Bifunctional alkaline oxygen electrodes

    NASA Technical Reports Server (NTRS)

    Swette, L.; Kackley, N.; Mccatty, S. A.

    1991-01-01

    The authors describe the identification and testing of electrocatalysts and supports for the positive electrode of moderate-temperature, single-unit, rechargeable alkaline fuel cells. Recent work on Na(x)Pt3O4, a potential bifunctional catalyst, is described, as well as the application of novel approaches to the development of more efficient bifunctional electrode structures. The three dual-character electrodes considered here showed similar superior performance; the Pt/RhO2 and Rh/RhO2 electrodes showed slightly better performance than the Pt/IrO2 electrode. It is concluded that Na(x)Pt3O4 continues to be a promising bifunctional oxygen electrode catalyst but requires further investigation and development.

  12. Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89

    SciTech Connect

    Pandya, Darpan N.; Pailloux, Sylvie; Tatum, David; Magda, Darren; Wadas, Thaddeus J.

    2014-12-18

    The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. Lastly, they represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr.

  13. Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89

    DOE PAGES

    Pandya, Darpan N.; Pailloux, Sylvie; Tatum, David; ...

    2014-12-18

    The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. Lastly, they represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr.

  14. Peroxisomal bifunctional enzyme deficiency.

    PubMed Central

    Watkins, P A; Chen, W W; Harris, C J; Hoefler, G; Hoefler, S; Blake, D C; Balfe, A; Kelley, R I; Moser, A B; Beard, M E

    1989-01-01

    Peroxisomal function was evaluated in a male infant with clinical features of neonatal adrenoleukodystrophy. Very long chain fatty acid levels were elevated in both plasma and fibroblasts, and beta-oxidation of very long chain fatty acids in cultured fibroblasts was significantly impaired. Although the level of the bile acid intermediate trihydroxycoprostanoic acid was slightly elevated in plasma, phytanic acid and L-pipecolic acid levels were normal, as was plasmalogen synthesis in cultured fibroblasts. The latter three parameters distinguish this case from classical neonatal adrenoleukodystrophy. In addition, electron microscopy and catalase subcellular distribution studies revealed that, in contrast to neonatal adrenoleukodystrophy, peroxisomes were present in the patient's tissues. Immunoblot studies of peroxisomal beta-oxidation enzymes revealed that the bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase) was deficient in postmortem liver samples, whereas acyl-CoA oxidase and the mature form of beta-ketothiolase were present. Density gradient centrifugation of fibroblast homogenates confirmed that intact peroxisomes were present. Immunoblots of fibroblasts peroxisomal fractions showed that they contained acyl-CoA oxidase and beta-ketothiolase, but bifunctional enzyme was not detected. Northern analysis, however, revealed that mRNA coding for the bifunctional enzyme was present in the patient's fibroblasts. These results indicate that the primary biochemical defect in this patient is a deficiency of peroxisomal bifunctional enzyme. It is of interest that the phenotype of this patient resembled neonatal adrenoleukodystrophy and would not have been distinguished from this disorder by clinical study alone. Images PMID:2921319

  15. Nanoparticle Superlattices as Efficient Bifunctional Electrocatalysts for Water Splitting.

    PubMed

    Li, Jun; Wang, Yongcheng; Zhou, Tong; Zhang, Hui; Sun, Xuhui; Tang, Jing; Zhang, Lijuan; Al-Enizi, Abdullah M; Yang, Zhongqin; Zheng, Gengfeng

    2015-11-18

    The solar-driven water splitting process is highly attractive for alternative energy utilization, while developing efficient, earth-abundant, bifunctional catalysts for both oxygen evolution reaction and hydrogen evolution reaction has remained as a major challenge. Herein, we develop an ordered CoMnO@CN superlattice structure as an efficient bifunctional water-splitting electrocatalyst, in which uniform Co-Mn oxide (CoMnO) nanoparticles are coated with a thin, continuous nitrogen-doped carbon (CN) framework. The CoMnO nanoparticles enable optimized OER activity with effective electronic structure configuration, and the CN framework serves as an excellent HER catalyst. Importantly, the ordered superlattice structure is beneficial for enhanced reactive sites, efficient charge transfer, and structural stability. This bifunctional superlattice catalyst manifests optimized current densities and electrochemical stability in overall water splitting, outperforming most of the previously reported single- or bifunctional electrocatalysts. Combining with a silicon photovoltaic cell, this CoMnO@CN superlattice bifunctional catalyst enables unassisted solar water splitting continuously for ∼5 days with a solar-to-hydrogen conversion efficiency of ∼8.0%. Our discovery suggests that these transition metal oxide-based superlattices may serve as a unique structure modality for efficient bifunctional water splitting electrocatalysts with scale-up potentials.

  16. Triamines and their derivatives as bifunctional chelating agents

    DOEpatents

    Troutner, David E.; John, Christy S.; Pillai, Maroor R. A.

    1992-03-31

    A group of functionalized triamine chelants and their derivatives that form complexes with radioactive metal ions are disclosed. The complexes can be covalently attached to a protein or an antibody or antibody fragment and used for therapeutic and/or diagnostic purposes.

  17. Triamines and their derivatives as bifunctional chelating agents

    DOEpatents

    Troutner, D.E.; John, C.S.; Pillai, M.R.A.

    1992-03-31

    A group of functionalized triamine chelants and their derivatives that form complexes with radioactive metal ions are disclosed. The complexes can be covalently attached to a protein or an antibody or antibody fragment and used for therapeutic and/or diagnostic purposes. No Drawings

  18. Hydroxypyridonate chelating agents

    DOEpatents

    Raymond, Kenneth N.; Scarrow, Robert C.; White, David L.

    1987-01-01

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

  19. Phosphonated chelates for nuclear imaging.

    PubMed

    Abada, Sabah; Lecointre, Alexandre; Christine, Câline; Ehret-Sabatier, Laurence; Saupe, Falk; Orend, Gertraud; Brasse, David; Ouadi, Ali; Hussenet, Thomas; Laquerrière, Patrice; Elhabiri, Mourad; Charbonnière, Loïc J

    2014-12-21

    A series of bis-, tris- and tetra-phosphonated pyridine ligands is presented. In view of their potential use as chelates for radiopharmaceutical applications, the physico-chemical properties of the ligands and of their Co(II), Ni(II), Cu(II), and Zn(II) complexes were studied by means of potentiometry and UV-Vis absorption spectroscopy. The pKa values of the ligands and of the complexes, as well as the stability constants for the formation of the complexes, are presented. The kinetic aspects of the formation of Cu(II) complexes and of their dissociation in acidic media were studied by means of stopped flow experiments, and the stability of the Cu(II) complex toward reduction to Cu(I) was investigated by cyclic voltammetry and by titration with different reducing agents. The different thermodynamic and kinetic aspects of the polyphosphonated ligands were compared with regard to the impact of the number of phosphonic acid functions. Considering the very promising properties for complexation, preliminary SPECT/CT imaging experiments were carried out on mice with (99m)Tc using the bis- and tetra-phosphonated ligands L(2) and L(1). Finally, a bifunctional version of chelate L(1), L*, was used to label MTn12, a rat monoclonal antibody with both specificity and relatively high affinity for murine tenascin-C. The labeling was monitored by MALDI/MS spectrometry and the affinity of the labeled antibody was checked by immunostaining experiments. After chelation with (99m)Tc, the (99m)Tc-L*-MTn12 antibody was injected into a transgenic mouse with breast cancer and the biodistribution of the labeled antibody was followed by SPECT/CT imaging.

  20. Radiometals (non-Tc, non-Re) and Bifunctional Labeling Chemistry

    NASA Astrophysics Data System (ADS)

    Fani, M.; Good, S.; Maecke, H. R.

    Radiometals are of increased current interest because of the growing use of targeted radiotherapy for tumors and the development of generators that produce positron-emitting radiometals. In addition, biomedical cyclotrons allow the cheap production of some relevant radiometals. The design of the corresponding radiopharmaceuticals includes the synthesis of bifunctional chelators, which carry a functional unit for the immobilization of the radiometal and a functional group for the covalent attachment to a vector molecule. Radiometals of interest for therapeutic applications are some lanthanides, 67Cu, and 90Y. For diagnostic applications 61Cu, 62Cu, 64Cu, 89Zr, and 68Ga are currently used and corresponding radiopharmaceuticals are being designed. In this chapter, some properties and the synthesis of bifunctional chelators including metal ion selectivity and special aspects of coupling chemistry are being described.

  1. Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89.

    PubMed

    Bhatt, Nikunj B; Pandya, Darpan N; Xu, Jide; Tatum, David; Magda, Darren; Wadas, Thaddeus J

    2017-01-01

    The development of bifunctional chelators (BFCs) for zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. Differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimization is necessary to enhance 89Zr chelation.

  2. Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89

    DOE PAGES

    Bhatt, Nikunj B.; Pandya, Darpan N.; Xu, Jide; ...

    2017-06-02

    The development of bifunctional chelators (BFCs) for zirconium-89 immuno-PET applications is an area of active research. We report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as zirconium-89 chelators. And while both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. The differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimizationmore » is necessary to enhance 89Zr chelation.« less

  3. Chelation in Metal Intoxication

    PubMed Central

    Flora, Swaran J.S.; Pachauri, Vidhu

    2010-01-01

    Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications. PMID:20717537

  4. Bifunctional DTPA-type ligand

    SciTech Connect

    Gansow, O.A.; Brechbiel, M.W.

    1990-03-26

    The subject matter of the invention relates to bifunctional cyclohexyl DTPA ligands and methods of using these compounds. Specifically, such ligands are useful for radiolabeling proteins with radioactive metals, and can consequently be utilized with respect to radioimmunoimaging and/or radioimmunotherapy.

  5. Chelation in root canal therapy reconsidered.

    PubMed

    Zehnder, Matthias; Schmidlin, Patrick; Sener, Beatrice; Waltimo, Tuomas

    2005-11-01

    The aim of this study was to assess interactions of EDTA and citric acid (CA) with sodium hypochlorite (NaOCl), the indispensable endodontic irrigant. Other chelators were simultaneously evaluated as possible alternatives: sodium triphosphate (STP), amino tris methylenephosphonic acid (ATMA), and 1- hydroxyethylidene-1, 1-bisphosphonate (HEBP). Available chlorine was titrated in chelator-NaOCl solutions. All chelators other than HEBP and STP caused an almost complete, immediate loss of available chlorine in solution. Atomic absorbtion spectrometry and SEM evaluation of root canal walls of instrumented teeth indicated that NaOCl had no negative effect on calcium-complexing ability of chelators. STP was too weak a complexing agent to warrant further studies. Finally, CA-, EDTA-, and HEBP-NaOCl mixtures were evaluated for their antimicrobial capacity. Again, EDTA and CA negatively interfered with NaOCl, while HEBP did not.

  6. Bifunctional oxygen/air electrodes

    NASA Astrophysics Data System (ADS)

    Jörissen, Ludwig

    A selective review on the materials and construction principles used for bifunctional oxygen/air electrodes is given. The discussion emphasizes the catalytically active materials used for the construction of these electrodes, which are a key component in electrically rechargeable air breathing electrochemical systems. Whereas, in acid electrolytes normally noble metal catalysts must be used, there is a possibility to use less expensive transition metal oxides in alkaline electrolytes. Typical transition metal oxides have the perovskite, pyrochlore and spinel structure.

  7. (S)-5-(p-Nitrobenzyl)-PCTA, a Promising Bifunctional Ligand with Advantageous Metal Ion Complexation Kinetics

    PubMed Central

    Tircsó, Gyula; Benyó, Enikő Tircsóné; Suh, Eul Hyun; Jurek, Paul; Kiefer, Garry E.; Sherry, A. Dean; Kovács, Zoltán

    2009-01-01

    A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N, N′, N″-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO2-Bn-PCTA) (M = Mg2+, Ca2+, Cu2+, Zn2+) complexes was similar to that of the corresponding PCTA complexes while the stability of Ln3+ complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO2-Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid catalyzed decomplexation kinetic studies of the selected Ln(NO2-Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO2-Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications. PMID:19220012

  8. (S)-5-(p-nitrobenzyl)-PCTA, a promising bifunctional ligand with advantageous metal ion complexation kinetics.

    PubMed

    Tircsó, Gyula; Benyó, Eniko Tircsóné; Suh, Eul Hyun; Jurek, Paul; Kiefer, Garry E; Sherry, A Dean; Kovács, Zoltán

    2009-03-18

    A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N,N',N''-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO(2)-Bn-PCTA) (M = Mg(2+), Ca(2+), Cu(2+), Zn(2+)) complexes was similar to that of the corresponding PCTA complexes, while the stability of Ln(3+) complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO(2)-Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid-catalyzed decomplexation kinetic studies of the selected Ln(NO(2)-Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO(2)-Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications.

  9. Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules

    NASA Astrophysics Data System (ADS)

    Xu, Liang; Gao, Ke; Bao, Chunyu; Wang, Xicheng

    2012-08-01

    The pathogenesis of Alzheimer's disease (AD) has been suggested to be related with the aggregation of amyloid β (Aβ) peptides. Metal ions (e.g. Cu, Fe, and Zn) are supposed to induce the aggregation of Aβ. Recent development of bifunctional molecules that are capable of interacting with Aβ and chelating biometal ions provides promising therapeutics to AD. However, the molecular mechanism for how Aβ, metal ions, and bifunctional molecules interact with each other is still elusive. In this study, the binding mode of Zn2+-bound Aβ with bifunctional molecules was investigated by the combination of conformational sampling of full-length Aβ peptides using replica exchange molecular dynamics simulations (REMD) and conformational selection using molecular docking and classical MD simulations. We demonstrate that Zn2+-bound Aβ(1-40) and Aβ(1-42) exhibit different conformational ensemble. Both Aβ peptides can adopt various conformations to recognize typical bifunctional molecules with different binding affinities. The bifunctional molecules exhibit their dual functions by first preferentially interfering with hydrophobic residues 17-21 and/or 30-35 of Zn2+-bound Aβ. Additional interactions with residues surrounding Zn2+ could possibly disrupt interactions between Zn2+ and Aβ, which then facilitate these small molecules to chelate Zn2+. The binding free energy calculations further demonstrate that the association of Aβ with bifunctional molecules is driven by enthalpy. Our results provide a feasible approach to understand the recognition mechanism of disordered proteins with small molecules, which could be helpful to the design of novel AD drugs.

  10. Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

    PubMed

    Chong, Hyun-Soon; Sun, Xiang; Chen, Yunwei; Sin, Inseok; Kang, Chi Soo; Lewis, Michael R; Liu, Dijie; Ruthengael, Varyanna C; Zhong, Yongliang; Wu, Ningjie; Song, Hyun A

    2015-03-01

    Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ((90)Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides (90)Y and (177)Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with (90)Y and (177)Lu, and the corresponding (90)Y or (177)Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding (90)Y and (177)Lu, and the corresponding (90)Y- and (177)Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of (90)Y and (177)Lu. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Synthesis and Comparative Biological Evalution of Bifunctional Ligands for Radiotherapy Applications of 90Y and 177Lu

    PubMed Central

    Chong, Hyun-Soon; Sun, Xiang; Chen, Yunwei; Sin, Inseok; Kang, Chi Soo; Lewis, Michael R.; Liu, Dijie; Ruthengael, Varyanna C.; Zhong, Yongliang; Wu, Ningjie; Song, Hyun A

    2015-01-01

    Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope (90Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin’s lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides 90Y and 177Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with 90Y and 177Lu, and the corresponding 90Y or 177Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding 90Y and 177Lu, and the corresponding 90Y- and 177Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of 90Y and 177Lu. PMID:25648683

  12. Nanoscale intimacy in bifunctional catalysts for selective conversion of hydrocarbons

    NASA Astrophysics Data System (ADS)

    Zecevic, Jovana; Vanbutsele, Gina; de Jong, Krijn P.; Martens, Johan A.

    2015-12-01

    The ability to control nanoscale features precisely is increasingly being exploited to develop and improve monofunctional catalysts. Striking effects might also be expected in the case of bifunctional catalysts, which are important in the hydrocracking of fossil and renewable hydrocarbon sources to provide high-quality diesel fuel. Such bifunctional hydrocracking catalysts contain metal sites and acid sites, and for more than 50 years the so-called intimacy criterion has dictated the maximum distance between the two types of site, beyond which catalytic activity decreases. A lack of synthesis and material-characterization methods with nanometre precision has long prevented in-depth exploration of the intimacy criterion, which has often been interpreted simply as ‘the closer the better’ for positioning metal and acid sites. Here we show for a bifunctional catalyst—comprising an intimate mixture of zeolite Y and alumina binder, and with platinum metal controllably deposited on either the zeolite or the binder—that closest proximity between metal and zeolite acid sites can be detrimental. Specifically, the selectivity when cracking large hydrocarbon feedstock molecules for high-quality diesel production is optimized with the catalyst that contains platinum on the binder, that is, with a nanoscale rather than closest intimacy of the metal and acid sites. Thus, cracking of the large and complex hydrocarbon molecules that are typically derived from alternative sources, such as gas-to-liquid technology, vegetable oil or algal oil, should benefit especially from bifunctional catalysts that avoid locating platinum on the zeolite (the traditionally assumed optimal location). More generally, we anticipate that the ability demonstrated here to spatially organize different active sites at the nanoscale will benefit the further development and optimization of the emerging generation of multifunctional catalysts.

  13. Nanoscale intimacy in bifunctional catalysts for selective conversion of hydrocarbons

    PubMed Central

    Zečević, Jovana; Vanbutsele, Gina; de Jong, Krijn P.; Martens, Johan A.

    2016-01-01

    The ability to precisely control nanoscale features is increasingly exploited to develop and improve monofunctional catalysts1–4. Striking effects might also be expected in the case of bifunctional catalysts, which play an important role in hydrocracking of fossil and renewable hydrocarbon sources to provide high-quality diesel fuel5–7. Such bifunctional hydrocracking catalysts contain metal sites and acid sites, and for more than 50 years the so-called ‘intimacy criterion’8 has dictated the maximum distance between the two site types beyond which catalytic activity decreases. The lack of synthesis and material characterization methods with nanometer precision has long prevented in-depth exploration of the criterion, which has often been interpreted simply as ‘the closer the better’ for positioning metal and acid sites8–11. Here we show for a bifunctional catalyst, comprised of an intimate mixture of zeolite Y and alumina binder and with platinum (Pt) metal controllably deposited20,21 on either the zeolite or the binder, that close proximity between metal and zeolite acid sites can be detrimental: the selectivity when cracking large hydrocarbon feedstock molecules for high-quality diesel production is optimized with the catalyst that contains Pt on the binder, i.e. with a larger distance between metal and acid sites. Cracking of the large and complex hydrocarbon molecules typically derived from alternative sources such as gas-to-liquid technology, vegetable oil or algal oil6–7 should thus benefit especially from bifunctional catalysts that avoid locating Pt on the zeolite as the traditionally assumed optimal location. More generally, we anticipate that the ability to spatially organize different active sites at the nanoscale demonstrated here will benefit the further development and optimization of the newly emerging generation of multifunctional catalysts12–15. PMID:26659185

  14. Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

    PubMed Central

    N.Tinianow, Jeff; Pandya, Darpan N.; Pailloux, Sylvie L.; Ogasawara, Annie; Vanderbilt, Alexander N.; Gill, Herman S.; Williams, Simon-P.; Wadas, Thaddeus J.; Magda, Darren; Marik, Jan

    2016-01-01

    A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89Zr; subsequently, it was used as a bi-functional chelator for preparation of 89Zr-labeled antibodies. Quantitative chelation of 89Zr4+ with the octadentate ligand forming 89ZrL complex was achieved under mild conditions within 15 minutes. The 89Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89Zr4+ from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89Zr-labeled monoclonal antibodies for immunoPET studies. PMID:26941844

  15. Liposome encapsulation of chelating agents

    DOEpatents

    Rahman, Yueh Erh

    1976-01-13

    A method for transferring a chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes and carrying the liposome-encapsulated chelating agent to the cellular membrane where the liposomes containing the chelating agent will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. A chelating agent can be introduced into the interior of a cell of a living organism wherein the liposomes will be decomposed, releasing the chelating agent to the interior of the cell. The released chelating agent will complex intracellularly deposited toxic heavy metals, permitting the more soluble metal complex to transfer across the cellular membrane from the cell and subsequently be removed from the living organism.

  16. Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

    PubMed Central

    Bryant, Laura A; Fanelli, Rossana

    2016-01-01

    Summary Cinchona alkaloids with a free 6'-OH functionality are being increasingly used within asymmetric organocatalysis. This fascinating class of bifunctional catalyst offers a genuine alternative to the more commonly used thiourea systems and because of the different spacing between the functional groups, can control enantioselectivity where other organocatalysts have failed. In the main, this review covers the highlights from the last five years and attempts to show the diversity of reactions that these systems can control. It is hoped that chemists developing asymmetric methodologies will see the value in adding these easily accessible, but underused organocatalysts to their screens. PMID:27340439

  17. Structural basis for bifunctional peptide recognition at human δ-Opioid receptor

    PubMed Central

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C.H.; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J.; Gati, Cornelius; Yefanov, Oleksandr M.; White, Thomas A.; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N.; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W.; Roth, Bryan L.; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C.; Cherezov, Vadim

    2015-01-01

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt(1)-Tic(2)-Phe(3)-Phe(4)-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt(1) and Tic(2). The observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics. PMID:25686086

  18. Structural basis for bifunctional peptide recognition at human δ-opioid receptor

    DOE PAGES

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; ...

    2015-02-16

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. In summary, the observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics.

  19. Structural basis for bifunctional peptide recognition at human δ-opioid receptor

    SciTech Connect

    Fenalti, Gustavo; Zatsepin, Nadia A.; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C. H.; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J.; Gati, Cornelius; Yefanov, Oleksandr M.; White, Thomas A.; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N.; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E.; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W.; Roth, Bryan L.; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C.; Cherezov, Vadim

    2015-02-16

    Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. In summary, the observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics.

  20. Structural basis for bifunctional peptide recognition at human δ-opioid receptor.

    PubMed

    Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia; Giguere, Patrick; Han, Gye Won; Ishchenko, Andrii; Liu, Wei; Guillemyn, Karel; Zhang, Haitao; James, Daniel; Wang, Dingjie; Weierstall, Uwe; Spence, John C H; Boutet, Sébastien; Messerschmidt, Marc; Williams, Garth J; Gati, Cornelius; Yefanov, Oleksandr M; White, Thomas A; Oberthuer, Dominik; Metz, Markus; Yoon, Chun Hong; Barty, Anton; Chapman, Henry N; Basu, Shibom; Coe, Jesse; Conrad, Chelsie E; Fromme, Raimund; Fromme, Petra; Tourwé, Dirk; Schiller, Peter W; Roth, Bryan L; Ballet, Steven; Katritch, Vsevolod; Stevens, Raymond C; Cherezov, Vadim

    2015-03-01

    Bifunctional μ- and δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human δ-OR bound to the bifunctional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt and Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics.

  1. Bifunctional transfer-messenger RNA

    PubMed Central

    Ramadoss, Nitya S.

    2011-01-01

    Transfer-messenger RNA (tmRNA) is a bifunctional RNA that has properties of a tRNA and an mRNA. tmRNA uses these two functions to release ribosomes stalled during translation and target the nascent polypeptides for degradation. This concerted reaction, known as trans-translation, contributes to translational quality control and regulation of gene expression in bacteria. tmRNA is conserved throughout bacteria, and is one of the most abundant RNAs in the cell, suggesting that trans-translation is of fundamental importance for bacterial fitness. Mutants lacking tmRNA activity typically have severe phenotypes, including defects in viability, virulence, and responses to environmental stresses. PMID:21664408

  2. Tailored bifunctional polymer for plutonium monitoring.

    PubMed

    Paul, Sumana; Pandey, Ashok K; Kumar, Pranaw; Kaity, Santu; Aggarwal, Suresh K

    2014-07-01

    Monitoring of actinides with sophisticated conventional methods is affected by matrix interferences, spectral interferences, isobaric interferences, polyatomic interferences, and abundance sensitivity problems. To circumvent these limitations, a self-supported disk and membrane-supported bifunctional polymer were tailored in the present work for acidity-dependent selectivity toward Pu(IV). The bifunctional polymer was found to be better than the polymer containing either a phosphate group or a sulfonic acid group in terms of (i) higher Pu(IV) sorption efficiency at 3-4 mol L(-1) HNO3, (ii) selective preconcentration of Pu(IV) in the presence of a trivalent actinide such as Am(III), and (iii) preferential sorption of Pu(IV) in the presence of a large excess of U(VI). The bifunctional polymer was formed as a self-supported matrix by bulk polymerization and also as a 1-2 μm thin layer anchored on a microporous poly(ether sulfone) by surface grafting. The proportions of sulfonic acid and phosphate groups in both the self-supported disk and membrane-supported bifunctional polymer were found to be the same as expected from the mole proportions of monomers in polymerizing solutions used for syntheses. α radiography by a solid-state nuclear track detector indicated fairly homogeneous anchoring of the bifunctional polymer on the surface of the membrane. Pu(IV) preconcentrated on a single bifunctional bead was used for determination of the Pu isotopic composition by thermal ionization mass spectrometry. The membrane-supported bifunctional polymer was used for preconcentration and subsequent quantification of Pu(IV) by α spectrometry using the absolute efficiency at a fixed counting geometry. The analytical performance of the membrane-supported-bifunctional-polymer-based α spectrometry method was found to be highly reproducible for assay of Pu(IV) in a variety of complex samples.

  3. Chelating ligands for nanocrystals' surface functionalization.

    PubMed

    Querner, Claudia; Reiss, Peter; Bleuse, Joël; Pron, Adam

    2004-09-22

    A new family of ligands for the surface functionalization of CdSe nanocrystals is proposed, namely alkyl or aryl derivatives of carbodithioic acids (R-C(S)SH). The main advantages of these new ligands are as follows: they nearly quantitatively exchange the initial surface ligands (TOPO) in very mild conditions; they significantly improve the resistance of nanocrystals against photooxidation because of their ability of strong chelate-type binding to metal atoms; their relatively simple preparation via Grignard intermediates facilitates the development of new bifunctional ligands containing, in addition to the anchoring carbodithioate group, a second function, which enables the grafting of molecules or macromolecules of interest on the nanocrystal surface. To give an example of this approach, we report, for the first time, the grafting of an electroactive oligomer from the polyaniline family-aniline tetramer-on CdSe nanocrystals after their functionalization with 4-formyldithiobenzoic acid. The grafting proceeds via a condensation reaction between the aldehyde group of the ligand and the terminal primary amine group of the tetramer. The resulting organic/inorganic hybrid exhibits complete extinction of the fluorescence of its constituents, indicating efficient charge or energy transfer between the organic and the inorganic semiconductors.

  4. Objectives and Methods of Iron Chelation Therapy

    PubMed Central

    Hershko, C.; Abrahamov, A.; Konijn, A. M.; Breuer, W.; Cabantchik, I. Z.; Pootrakul, P.; Link, G.

    2003-01-01

    Recent developments in the understanding of the molecular control of iron homeostasis provided novel insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival. However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Within recent years more than one thousand candidate compounds have been screened in animal models. The most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and; bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance by decreasing the demand on tedious parenteral drug administration. Combined use of DFO

  5. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

    PubMed

    Lux, Jacques; Chan, Minnie; Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-12-14

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd(3+) within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd(3+). This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.

  6. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability

    PubMed Central

    Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-01-01

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy. PMID:24505553

  7. Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

    PubMed Central

    Liu, Shuang

    2008-01-01

    Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

  8. Chelation of cadmium.

    PubMed Central

    Andersen, O

    1984-01-01

    The toxicity of cadmium is determined by chelation reactions: in vivo, Cd2+ exists exclusively in coordination complexes with biological ligands, or with administered chelating agents. The Cd2+ ion has some soft character, but it is not a typical soft ion. It has a high degree of polarizability, and its complexes with soft ligands have predominantly covalent bond characteristics. Cd2+ forms the most stable complexes with soft donor atoms (S much greater than N greater than 0). The coordination stereochemistry of Cd2+ is unusually varied, including coordination numbers from 2 to 8. Even though the Cd2+ ion is a d10 ion, disturbed coordination geometries are often seen. Generally, the stability of complexes increases with the number of coordination groups contributed by the ligand; consequently, complexes of Cd2+ with polydentate ligands containing SH groups are very stable. Cd2+ in metallothionein (MT) is coordinated with 4 thiolate groups, and the log stability constant is estimated to 25.5. Complexes between Cd2+ and low molecular weight monodentate or bidentate ligands, e.g., free amino acids (LMW-Cd), seem to exist very briefly, and Cd2+ is rapidly bound to high molecular weight proteins, mainly serum albumin. These complexes (HMW-Cd) are rapidly scavenged from blood, mainly by the liver, and Cd2+ is redistributed to MT. After about 1 day the Cd-MT complex (MT-Cd) almost exclusively accounts for the total retained dose of Cd2+, independent of the route of exposure. MT-Cd is slowly transferred to and accumulated in kidney cortex. The acute toxicity and interorgan distribution of parenterally administered Cd2+ are strongly influenced by preceding MT induction, or decreased capacity for MT synthesis; however, the gastrointestinal (GI) uptake of Cd2+ seems unaffected by preceding MT induction resulting in considerable capacity for Cd2+ chelation in intestinal mucosa, and this finding indicates that endogenous MT is not involved in Cd2+ absorption. The toxicity of

  9. [Arteriosclerosis and chelate therapy].

    PubMed

    Nissel, H

    1986-11-30

    Based on a case history the therapeutic value of an iv-chelate therapy in arteriosclerosis is discussed. Ethylenediaminetetraacetate (EDTA) is used as a standard regime in the treatment of poisoning with heavy metals. The usefulness of EDTA in arteriosclerosis is doubtful: some authors suppose, that Ca-deposits are removed from arteriosclerotic lesions. This concept has not yet been proven by in-vivo experiments. Severe side effects such as hypocalcemia may cause the death of a patient under treatment. Therefore no real indications exist for treatment of arteriosclerosis with EDTA.

  10. Natural chelates for radionuclide decorporation

    DOEpatents

    Premuzic, E.T.

    1983-08-25

    This invention relates to the method and resulting chelates of desorbing a radionuclide selected from thorium, uranium, and plutonium containing cultures in a bioavailable form involving pseudomonas or other microorganisms. A preferred microorganism is Pseudomonas aeruginosa which forms multiple chelates with thorium in the range of molecular weight 1000 to 1000 and also forms chelates with uranium of molecular weight in the area of 100 to 1000 and 1000 to 2000.

  11. Solid phase synthesis of bifunctional antibodies.

    PubMed

    DeSilva, B S; Wilson, G S

    1995-12-15

    Bifunctional antibodies were prepared using the principle of solid-phase synthesis. The two Fab' fragments were chemically linked together via a bismaleimide crosslinking reagent. The F(ab')2 fragments from intact IgG were prepared using an immobilized pepsin column. Goat, mouse and human antibodies were digested completely within 4 h. The F(ab')2 fragments thus produced did not contain any IgG impurities. The Fab' fragments were produced by reducing the inter-heavy chain disulfide bonds using 2-mercaptoethylamine. The use of the solid-phase reactor in the preparation of the bifunctional antibodies eliminated many of the time-consuming separation steps between the fragmentation and conjugation steps. This procedure facilitates the automation of the bifunctional antibody preparation and the rapid optimization of reaction conditions.

  12. Synthesis of bifunctional antibodies for immunoassays.

    PubMed

    DeSilva, B S; Wilson, G S

    2000-09-01

    The synthesis of bifunctional antibodies using the principle of solid-phase synthesis is described. Two Fab' fragments were chemically linked together via a bismaleimide crosslinking reagent. The F(ab')(2) fragments from intact immunoglobulin G (IgG) were prepared using an immobilized pepsin column. Goat, mouse, and human antibodies were digested completely within 4 h. The F(ab')(2) fragments thus produced did not contain any IgG impurities. Fab' fragments were produced by reducing the heavy interchain disulfide bonds using 2-mercaptoethylamine. Use of the solid-phase reactor in the preparation of the bifunctional antibodies eliminated many of the time-consuming separation steps between the fragmentation and conjugation steps. This procedure facilitates the automation of bifunctional antibody preparation and the rapid optimization of reaction conditions.

  13. Chelate assisted phytoextraction of heavy metals from soil. Effect, mechanism, toxicity, and fate of chelating agents.

    PubMed

    Evangelou, Michael W H; Ebel, Mathias; Schaeffer, Andreas

    2007-06-01

    The low-cost, plant-based phytoextraction technique has often been described as a promising technique to remediate heavy metal contaminated agricultural land. The application of chelating agents has shown positive effects in increasing the solubility of heavy metals in soil and therefore in enhancing phytoextraction. This paper gives an overview of the chelating agents applied in recent studies. Various synthetic aminopolycarboxylic acids, such as ethylene diamine tetraacetic acid, and natural ones such as, ethylene diamine disuccinate and nitrilotriacetic acid, are described. Additionally, results of the application of natural low molecular weight organic acids, such as citric and tartaric acid are given. The effectiveness of these different chelating agents varies according to the plant and the heavy metals used. Furthermore, a focus is laid on the chelating agents fate after application and on its toxicity to plants and soil microorganisms, as well as it degradation. The rate of degradation is of great importance for the future of chelate assisted phytoextraction as it has a direct impact on the leaching probability. An effective prevention of leaching will be crucial for the acceptance and the economic breakthrough of enhanced phytoextraction, but a satisfactory solution to this key issue has so far not been found. Possibly further experiments in the field of enhanced phytoextraction will be able to solve this major problem, but over decades various greenhouse experiments and recently field experiments have resulted in different observations. Therefore, it is questionable if further research in this direction will lead to a promising solution. Phytoextraction has possibly reached a turning point in which it should distance itself from chelate assisted phytoextraction and focus on alternative options.

  14. Metal chelate process to remove pollutants from fluids

    DOEpatents

    Chang, S.G.T.

    1994-12-06

    The present invention relates to improved methods using an organic iron chelate to remove pollutants from fluids, such as flue gas. Specifically, the present invention relates to a process to remove NO[sub x] and optionally SO[sub 2] from a fluid using a metal ion (Fe[sup 2+]) chelate wherein the ligand is a dimercapto compound wherein the --SH groups are attached to adjacent carbon atoms (HS--C--C--SH) or (SH--C--CCSH) and contain a polar functional group so that the ligand of DMC chelate is water soluble. Alternatively, the DMC is covalently attached to a water insoluble substrate such as a polymer or resin, e.g., polystyrene. The chelate is regenerated using electroreduction or a chemical additive. The dimercapto compound bonded to a water insoluble substrate is also useful to lower the concentration or remove hazardous metal ions from an aqueous solution. 26 figures.

  15. Metal chelate process to remove pollutants from fluids

    DOEpatents

    Chang, Shih-Ger T.

    1994-01-01

    The present invention relates to improved methods using an organic iron chelate to remove pollutants from fluids, such as flue gas. Specifically, the present invention relates to a process to remove NO.sub.x and optionally SO.sub.2 from a fluid using a metal ion (Fe.sup.2+) chelate wherein the ligand is a dimercapto compound wherein the --SH groups are attached to adjacent carbon atoms (HS--C--C--SH) or (SH--C--CCSH) and contain a polar functional group so that the ligand of DMC chelate is water soluble. Alternatively, the DMC' is covalently attached to a water insoluble substrate such as a polymer or resin, e.g., polystyrene. The chelate is regenerated using electroreduction or a chemical additive. The dimercapto compound bonded to a water insoluble substrate is also useful to lower the concentration or remove hazardous metal ions from an aqueous solution.

  16. Macroreticular chelating ion-exchangers.

    PubMed

    Hirsch, R F; E Gancher, R; Russo, F R

    1970-06-01

    Two macroreticular chelating ion-exchangers have been prepared and characterized. One contains the iminodiacetate group and the second contains the arsonate group as the ion-exchanging site. The macroreticular resins show selectivities among metal ions similar to those of the commercially available naicroreticular chelating resins. Chromatographie separations on the new resins are rapid and sharp.

  17. Polycatecholamide chelating agents

    DOEpatents

    Weitl, F.L.; Raymond, K.N.

    1984-04-10

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. The compounds have the formula given in patent. Polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO[sub 3]H, SO[sub 3]M, NO[sub 2], CO[sub 2]H or CO[sub 2]M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr[sub 3] or BCl[sub 3] in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated. No Drawings

  18. Polycatecholamide chelating agents

    DOEpatents

    Weitl, Frederick L.; Raymond, Kenneth N.

    1984-01-01

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. The compounds have the formula ##STR1## Polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO.sub.3 H, SO.sub.3 M, NO.sub.2, CO.sub.2 H or CO.sub.2 M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr.sub.3 or BCl.sub.3 in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated.

  19. Novel polycatecholamide chelating agents

    DOEpatents

    Weitl, F.L.; Raymond, K.N.

    1981-08-24

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. Formulas of the compounds are given. To prepare them polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO/sub 3/H, SO/sub 3/M, NO/sub 2/, CO/sub 2/H or CO/sub 2/M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr/sub 3/ or BCl/sub 3/ in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated.

  20. The Bi-Functional Organization of Human Basement Membranes

    PubMed Central

    Halfter, Willi; Monnier, Christophe; Müller, David; Oertle, Philipp; Uechi, Guy; Balasubramani, Manimalha; Safi, Farhad; Lim, Roderick; Loparic, Marko; Henrich, Paul Bernhard

    2013-01-01

    The current basement membrane (BM) model proposes a single-layered extracellular matrix (ECM) sheet that is predominantly composed of laminins, collagen IVs and proteoglycans. The present data show that BM proteins and their domains are asymmetrically organized providing human BMs with side-specific properties: A) isolated human BMs roll up in a side-specific pattern, with the epithelial side facing outward and the stromal side inward. The rolling is independent of the curvature of the tissue from which the BMs were isolated. B) The epithelial side of BMs is twice as stiff as the stromal side, and C) epithelial cells adhere to the epithelial side of BMs only. Side-selective cell adhesion was also confirmed for BMs from mice and from chick embryos. We propose that the bi-functional organization of BMs is an inherent property of BMs and helps build the basic tissue architecture of metazoans with alternating epithelial and connective tissue layers. PMID:23844050

  1. Fluoride ion recognition by chelating and cationic boranes.

    PubMed

    Hudnall, Todd W; Chiu, Ching-Wen; Gabbaï, François P

    2009-02-17

    Because of the ubiquity of fluoride ions and their potential toxicity at high doses, researchers would like to design receptors that selectively detect this anion. Fluoride is found in drinking water, toothpaste, and osteoporosis drugs. In addition, fluoride ions also can be detected as an indicator of uranium enrichment (via hydrolysis of UF(6)) or of the chemical warfare agent sarin, which releases the ion upon hydrolysis. However, because of its high hydration enthalpy, the fluoride anion is one of the most challenging targets for anion recognition. Among the various recognition strategies that are available, researchers have focused a great deal of attention on Lewis acidic boron compounds. These molecules typically interact with fluoride anions to form the corresponding fluoroborate species. In the case of simple triarylboranes, the fluoroborates are formed in organic solvents but not in water. To overcome this limitation, this Account examines various methods we have pursued to increase the fluoride-binding properties of boron-based receptors. We first considered the use of bifunctional boranes, which chelate the fluoride anion, such as 1,8-diborylnaphthalenes or heteronuclear 1-boryl-8-mercurio-naphthalenes. In these molecules, the neighboring Lewis acidic atoms can cooperatively interact with the anionic guest. Although the fluoride binding constants of the bifunctional compounds exceed those of neutral monofunctional boranes by several orders of magnitude, the incompatibility of these systems with aqueous media limits their utility. More recently, we have examined simple triarylboranes whose ligands are decorated by cationic ammonium or phosphonium groups. These cationic groups increase the electrophilic character of these boranes, and unlike their neutral analogs, they are able to complex fluoride in aqueous media. We have also considered cationic boranes, which form chelate complexes with fluoride anions. Our work demonstrates that Coulombic and chelate

  2. Facile synthesis of metal-chelating magnetic nanoparticles by exploiting organophosphorus coupling.

    PubMed

    Yang, Kun; Su, Wei Wen

    2011-01-01

    A new method is described for facile synthesis of metal-chelating magnetic nanoparticles by simply mixing iron oxide nanoparticles with a bifunctional organophosphorus compound, N-(phosphonomethyl)iminodiacetic acid (PM-IDA), in aqueous solution. On charging with nickel ions, the PM-IDA functionalized iron oxide nanoparticles exhibited high His-tag protein binding capacity (0.21 and 0.58 mg/mg for His-tagged green fluorescent protein and chloramphenicol acetyltransferase, respectively) and were successfully used to purify these proteins from bacterial cell extracts to high purity in a single step. Although other synthetic schemes for metal-chelating magnetic nanoparticles have been reported, the method described here is markedly simpler and involves only low-cost reagents. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Recent advances in chelator design and labelling methodology for (68) Ga radiopharmaceuticals.

    PubMed

    Burke, Benjamin P; Clemente, Gonçalo S; Archibald, Stephen J

    2014-04-01

    Gallium-68 has the potential to become the technetium-99m of positron emission tomography with ideal decay characteristics and a long-lived parent isotope for generator production. The work in the area of (68) Ga is focused on two key areas: (1) synthesis of a library of bifunctional chelators, which can be quickly radiolabelled to form kinetically inert complexes under mild conditions compatible with biomolecules and (2) development of radiosynthetic methodologies for clinical use and to facilitate radiolabelling of a wide range of chelators under mild conditions. Recent advances in these areas, with particular focus on the past 3 years, are covered herein. Copyright © 2014 John Wiley & Sons, Ltd.

  4. Hydroxypyridonate chelating agents and synthesis thereof

    DOEpatents

    Raymond, K.N.; Scarrow, R.C.; White, D.L.

    1985-11-12

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided. 4 tabs.

  5. Development of a Tetrathioether (S4) Bifunctional Chelate System for Rh-105

    DTIC Science & Technology

    2013-07-01

    information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and...maintaining the data needed, and completing and reviewing this collection of information . Send comments regarding this burden estimate or any other aspect...of this collection of information , including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services

  6. Development of a Tetrathioether (S4) Bifunctional Chelate System for Rh-105

    DTIC Science & Technology

    2013-06-01

    only one m/z value as discussed above, and suggests the presence of a single molecule. As each S is chiral on coordination to the metal center, it...ester (Figure 16, b) is formed by acid catalyzed esterification in the presence of ethanol. In sample (4) under aqueous conditions with excess NaCl...more dominate single 105 RhX2-S4- (COOH)2 species. The pendant ethyl esters on species (b), (c) and (e) (Figure 16) are formed by acid catalyzed

  7. Optimization of pentadentate bispidines as bifunctional chelators for 64Cu positron emission tomography (PET).

    PubMed

    Comba, Peter; Hunoldt, Sebastian; Morgen, Michael; Pietzsch, Jens; Stephan, Holger; Wadepohl, Hubert

    2013-07-15

    Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

  8. [Re(III)Cl(3)] core complexes with bifunctional single amino acid chelates.

    PubMed

    Banerjee, Sangeeta Ray; Wei, Lihui; Levadala, Murali K; Lazarova, Neva; Golub, Vladimir O; O'Connor, Charles J; Stephenson, Karin A; Valliant, John F; Babich, John W; Zubieta, Jon

    2002-11-04

    The reactions of the Re(V) starting material [ReO(PPh(3))(2)Cl(3)] with ligands of the type XN(Y)Z [X = Y = 2-pyridylmethyl, Z = -CH(2)CO(2)Et (L(1)Et), -CH(2)CH(2)CO(2)Et (L(2)Et), -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)Bu(t))CO(2)H (L(3)H); X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl, Z = -CH(2)CO(2)Et (L(4)Et)] yielded the Re(III) trichloride complexes of the type [ReCl(3)(L(n)R)]. The complexes are mononuclear, paramagnetic species with a facial geometry of the chloride ligands. The nitrogen donors of the tridentate L(n)()R ligands complete the distorted octahedral coordination spheres of the complexes. Crystal data: [ReCl(3)(L(1)Et)] (1), monoclinic, C2/m, a = 16.088(3) A, b = 9.980(2) A, c = 12.829(2) A, beta = 91.384(3) degrees, Z = 4, D(calc) = 1.967 g/cm(-)(3); [ReCl(3)(L(4)Et)] (4), monoclinic, C2/c, a = 22.880(1) A, b = 7.4926(4) A, c = 22.560(1) A, beta = 94.186(1) degrees, Z = 8, D(calc) = 2.001 g/cm(-3).

  9. Design and synthesis of site directed maleimide bifunctional chelators for technetium and rhenium.

    PubMed

    Banerjee, Sangeeta Ray; Schaffer, Paul; Babich, John W; Valliant, John F; Zubieta, Jon

    2005-12-21

    A new family of heterobifunctional linkers (L1-L9) containing a terminus consisting of a tridentate donor set for coordination of the {M(CO)(3)}(+) core (M = Tc, Re), and a thiol reactive maleimide group has been prepared conveniently and in high yield under Mitsunobu reaction conditions by the coupling of an appropriate alcohol derivative with maleimide. The rhenium complexes [Re(CO)(3)(Lx)]Br (x= 1-9) were prepared in good yields from the reactions of the ligands and (NEt(4))(2)[Re(CO)(3)Br(3)] in refluxing methanol. The ligands and their Re complexes were characterized by (1)H and (13)C NMR, IR, and ESI-MS. Ligand L4 and [Re(CO)(3)(L5)]Br have been structurally characterized by X-ray crystallography. Photoexcitation of solutions of the complexes [Re(CO)(3)(Lx)]Br (x= 4-6) gives rise to intense and prolonged luminescence at room temperature (fluorescence lifetimes of ca. 16 micros). The ligands and their Re complexes react smoothly at the maleimide linker with sulfhydryl groups of peptides and proteins at room temperature in phosphate-buffered saline (PBS, pH 7.4) to form stable thioether bioconjugates. The photoluminescence properties of the labeled conjugates are similar to those of the parent complexes, but with even longer lifetimes. The ligands can also be labeled at room temperature with (99m)Tc to give chemically robust complexes. The corresponding hydrazinonicotinamide derivative N-[5-(6'-hydrazinopyridine-3'-carbonyl)aminopentyl]maleimide (L10) was also prepared. While coupling of L10 to cysteine ethylester and synthesis of the rhenium derivative [ReCl(3)(HYNIC-maleimide)(2)] were successfully accomplished, attempts to couple [ReCl(3)(HYNIC-maleimide)(2)] to glutathione or BSA yielded intractable mixtures.

  10. Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding

    PubMed Central

    2017-01-01

    Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting. PMID:28462989

  11. Bifunctional hydrogen bonds in monohydrated cycloether complexes.

    PubMed

    Vallejos, Margarita M; Angelina, Emilio L; Peruchena, Nélida M

    2010-03-04

    In this work, the cooperative effects implicated in bifunctional hydrogen bonds (H-bonds) were studied (in monohydrated six-membered cycloether) within the framework of the atoms in molecules (AIM) theory and of the natural bond orbitals (NBO) analysis. The study was carried out in complexes formed by six-membered cycloether compounds (tetrahydropyrane, 1,4-dioxane, and 1,3-dioxane) and a water molecule. These compounds were used as model systems instead of more complicated molecules of biological importance. All the results were obtained at the second-order Møller-Plesset (MP2) level theory using a 6-311++G(d,p) basis set. Attention was focused on the indicators of the cooperative effects that arise when a water molecule interacts simultaneously with a polar and a nonpolar portion of a six-membered cycloether (via bifunctional hydrogen bonds) and compared with conventional H-bonds where the water molecule only interacts with the polar portion of the cycloether. Different indicators of H-bonds strength, such as structural and spectroscopic data, electron charge density, population analysis, hyperconjugation energy and charge transference, consistently showed significant cooperative effects in bifunctional H-bonds. From the AIM, as well as from the NBO analysis, the obtained results allowed us to state that in the monohydrated six-membered cycloether, where the water molecule plays a dual role, as proton acceptor and proton donor, a mutual reinforcement of the two interactions occurs. Because of this feature, the complexes engaged by bifunctional hydrogen bonds are more stabilized than the complexes linked by conventional hydrogen bonds.

  12. Variational Convergence Of Bifunctions: Motivating Applications

    DTIC Science & Technology

    2011-01-01

    Research Office (ARO) W911NS1010246 and Fondap- Matematicas Aplicadas, Universidad de Chile 1 Variational convergence of bifunctions The analysis of...The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing...problems. 1 . REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE 13. SUPPLEMENTARY NOTES The views, opinions and/or findings contained in this report are those

  13. New bifunctional metalloproteinase inhibitors: an integrated approach towards biological improvements and cancer therapy.

    PubMed

    Marques, Sérgio M; Abate, Claudia C; Chaves, Sílvia; Marques, Fernanda; Santos, Isabel; Nuti, Elisa; Rossello, Armando; Santos, M Amélia

    2013-10-01

    The key role of some matrix metalloproteinases (MMPs) on several pathological processes, including carcinogenesis and tumor growth, makes the development of MMP inhibitors (MMPIs) an attractive approach for cancer therapy. We present herein an integrated approach for the development of a new series of inhibitors of MMP2 and MMP14, two enzymes over-expressed by human ovarian cancer. As a first step, a new series of single model compounds bearing different zinc-binding groups (ZBGs), such as carboxylic, hydroxamic acid, hydrazide and sulfonylhydrazide groups, were studied and revealed reasonably good capacity for the Zn(II) chelation in solution and for the MMP inhibition. Aimed at further reinforcing the biological activity of these MMPIs as anti-cancer agents, a selection of those models was extra-functionalized with benzothiazole (BTA), a group with recognized antitumor activity. Analysis of the results obtained for these bifunctional compounds, in particular the inhibitory activity against MMP2 and MMP14 as well as the anti-proliferative activity on the A2780 ovarian cancer cell line, allowed to understand the activity dependence on the type of ZBG, as well as the relevance of the BTA moiety. Overall, the evidenced BTA-associated activity improvements on enzyme inhibition and cell antiproliferactivity, combined with the hydrolytic stability revealed by the hydrazide group, suggest that these new bifunctional BTA-hydrazide derivatives should be taken in consideration for the development of new generations of MMPIs with anti-cancer activity.

  14. Rational Design and Generation of a Bimodal Bifunctional Ligand for Antibody-Targeted Radiation Cancer Therapy

    PubMed Central

    Chong, Hyun-Soon; Ma, Xiang; Le, Thien; Kwamena, Baidoo; Milenic, Diane E.; Brady, Erik D.; Song, Hyun A.; Brechbiel, Martin W.

    2008-01-01

    An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212Bi, 213Bi, and 177Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177Lu—C-NETA and 205/6Bi—C-NETA possess an excellent or acceptable in vivo biodistribution profile. PMID:18062661

  15. Chelation therapy in intoxications with mercury, lead and copper.

    PubMed

    Cao, Yang; Skaug, Marit Aralt; Andersen, Ole; Aaseth, Jan

    2015-01-01

    In the present review we provide an update of the appropriate use of chelating agents in the treatment of intoxications with compounds of mercury, lead and copper. The relatively new chelators meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propanesulphonate (DMPS) can effectively mobilize deposits of mercury as well as of lead into the urine. These drugs can be administered orally and have relatively low toxicity compared to the classical antidote dimercaptopropanol (BAL). d-Penicillamine has been widely used in copper overload, although 2,3-dimercaptosuccinic acid or tetrathiomolybdate may be more suitable alternatives today. In copper-toxicity, a free radical scavenger might be recommended as adjuvant to the chelator therapy. Copyright © 2014 Elsevier GmbH. All rights reserved.

  16. Opsonic activity in human serum chelated with ethylene glycoltetra-aectic acid

    PubMed Central

    Forsgren, A.; Quie, P. G.

    1974-01-01

    The influence of the alternative pathway of complement activation on opsonization of S. aureus, E. coli and Candida albicans for phagocytosis was selectively studied by chelating serum with 10 mM EGTA and 10 mM MgC12. Opsonic activity of the chelated serum depended on the alternative pathway of complement activation. The classical pathway was inhibited. There was no phagocytosis of S. aureus in chelated normal serum, suggesting that activation of complement activity by the classical pathway is necessary for opsonization of this micro-organism. In control experiments when opsonization of S. aureus was accomplished by IgG separated from hyperimmune serum, without the requirement of complement activity, there was no inhibition of phagocytosis by EGTA and magnesium chloride. E. coli and C. albicans were opsonized in chelated normal serum, indicating that the alternative pathway of complement activation is involved in opsonization of these micro-organisms. PMID:4604857

  17. Hydroxypyridonate and hydroxypyrimidinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Doble, Daniel M.; Sunderland, Christopher J.; Thompson, Marlon

    2005-01-25

    The present invention provides hydroxypyridinone and hydroxypyrimidone chelating agents. Also provides are Gd(III) complexes of these agents, which are useful as contrast enhancing agents for magnetic resonance imaging. The invention also provides methods of preparing the compounds of the invention, as well as methods of using the compounds in magnetic resonance imaging applications.

  18. The phylogenetic origin of the bifunctional tyrosine-pathway protein in the enteric lineage of bacteria.

    PubMed

    Ahmad, S; Jensen, R A

    1988-05-01

    Because bifunctional enzymes are distinctive and highly conserved products of relatively infrequent gene-fusion events, they are particularly useful markers to identify clusters of organisms at different hierarchical levels of a phylogenetic tree. Within the subdivision of gram-negative bacteria known as superfamily B, there are two distinctive types of tyrosine-pathway dehydrogenases: (1) a broad-specificity dehydrogenase (recently termed cyclohexadienyl dehydrogenase [CDH]) that can utilize either prephenate or L-arogenate as alternative substrates and (2) a bifunctional CDH that also posseses chorismate mutase activity. (T-proteins). The bifunctional T-protein, thought to be encoded by fused ancestral genes for chorismate mutase and CDH, was found to be present in enteric bacteria (Escherichia, Shigella, Salmonella, Citrobacter, Klebsiella, Erwinia, Serratia, Morganella, Cedecea, Kluyvera, Hafnia, Edwardsiella, Yersinia, and Proteus) and in Aeromonas and Alteromonas. Outside of the latter "enteric lineage," the T-protein is absent in other major superfamily-B genera, such as Pseudomonas (rRNA homology group I), Xanthomonas, Acinetobacter, and Oceanospirillum. Hence, the T-protein must have evolved after the divergence of the enteric and Oceanospirillum lineages. 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase-phe, an early-pathway isozyme sensitive to feedback inhibition by L-phenylalanine, has been found in each member of the enteric lineage examined. The absence of both the T-protein and DAHP synthase-phe elsewhere in superfamily B indicates the emergence of these character states at approximately the same evolutionary time.

  19. Development of Cobalt Hydroxide as a Bifunctional Catalyst for Oxygen Electrocatalysis in Alkaline Solution.

    PubMed

    Zhan, Yi; Du, Guojun; Yang, Shiliu; Xu, Chaohe; Lu, Meihua; Liu, Zhaolin; Lee, Jim Yang

    2015-06-17

    Co(OH)2 in the form of hexagonal nanoplates synthesized by a simple hydrothermal reaction has shown even greater activity than cobalt oxides (CoO and Co3O4) in oxygen reduction and oxygen evolution reactions (ORR and OER) under alkaline conditions. The bifunctionality for oxygen electrocatalysis as shown by the OER-ORR potential difference (ΔE) could be reduced to as low as 0.87 V, comparable to the state-of-the-art non-noble bifunctional catalysts, when the Co(OH)2 nanoplates were compounded with nitrogen-doped reduced graphene oxide (N-rGO). The good performance was attributed to the nanosizing of Co(OH)2 and the synergistic interaction between Co(OH)2 and N-rGO. A zinc-air cell assembled with a Co(OH)2-air electrode also showed a performance comparable to that of the state-of-the-art zinc-air cells. The combination of bifunctional activity and operational stability establishes Co(OH)2 as an effective low-cost alternative to the platinum group metal catalysts.

  20. A Processive Carbohydrate Polymerase That Mediates Bifunctional Catalysis Using a Single Active Site

    PubMed Central

    May, John F.; Levengood, Matthew R.; Splain, Rebecca A.; Brown, Christopher D.; Kiessling, Laura L.

    2012-01-01

    Even in the absence of a template, glycosyltransferases can catalyze the synthesis of carbohydrate polymers of specific sequence. The paradigm has been that one enzyme catalyzes the formation of one type of glycosidic linkage, yet certain glycosyltransferases generate polysaccharide sequences composed of two distinct linkage types. In principle, bifunctional glycosyltransferases can possess separate active sites for each catalytic activity or one active site with dual activities. We encountered the fundamental question of one or two distinct active sites in our investigation of the galactosyltransferase GlfT2. GlfT2 catalyzes the formation of mycobacterial galactan, a critical cell-wall polymer composed of galactofuranose residues connected with alternating, regioisomeric linkages. We found that GlfT2 mediates galactan polymerization using only one active site that manifests dual regioselectivity. Structural modeling of the bifunctional glycosyltransferases hyaluronan synthase and cellulose synthase suggests that these enzymes also generate multiple glycosidic linkages using a single active site. These results highlight the versatility of glycosyltransferases for generating polysaccharides of specific sequence. We postulate that a hallmark of processive elongation of a carbohydrate polymer by a bifunctional enzyme is that one active site can give rise to two separate types of glycosidic bonds. PMID:22217153

  1. Natural chelating agents for radionuclide decorporation

    DOEpatents

    Premuzic, Eugene T.

    1988-01-01

    This invention relates to the preparation of new, naturally produced chelating agents as well as to the method and resulting chelates of desorbing cultures in a bioavailable form involving Pseudomonas species or other microorganisms. A preferred microorganism is Pseudomonas aeruginosa which forms multiple chelates with thorium in the range of molecular weight 100-1,000 and also forms chelates with uranium of molecular weight in the area of 100-1,000 and 1,000-2,000.

  2. Iron chelation and multiple sclerosis

    PubMed Central

    Weigel, Kelsey J.; Lynch, Sharon G.; LeVine, Steven M.

    2014-01-01

    Histochemical and MRI studies have demonstrated that MS (multiple sclerosis) patients have abnormal deposition of iron in both gray and white matter structures. Data is emerging indicating that this iron could partake in pathogenesis by various mechanisms, e.g., promoting the production of reactive oxygen species and enhancing the production of proinflammatory cytokines. Iron chelation therapy could be a viable strategy to block iron-related pathological events or it can confer cellular protection by stabilizing hypoxia inducible factor 1α, a transcription factor that normally responds to hypoxic conditions. Iron chelation has been shown to protect against disease progression and/or limit iron accumulation in some neurological disorders or their experimental models. Data from studies that administered a chelator to animals with experimental autoimmune encephalomyelitis, a model of MS, support the rationale for examining this treatment approach in MS. Preliminary clinical studies have been performed in MS patients using deferoxamine. Although some side effects were observed, the large majority of patients were able to tolerate the arduous administration regimen, i.e., 6–8 h of subcutaneous infusion, and all side effects resolved upon discontinuation of treatment. Importantly, these preliminary studies did not identify a disqualifying event for this experimental approach. More recently developed chelators, deferasirox and deferiprone, are more desirable for possible use in MS given their oral administration, and importantly, deferiprone can cross the blood–brain barrier. However, experiences from other conditions indicate that the potential for adverse events during chelation therapy necessitates close patient monitoring and a carefully considered administration regimen. PMID:24397846

  3. EDTA chelation therapy for cardiovascular disease: a systematic review

    PubMed Central

    Seely, Dugald MR; Wu, Ping; Mills, Edward J

    2005-01-01

    Background Numerous practitioners of both conventional and complementary and alternative medicine throughout North America and Europe claim that chelation therapy with EDTA is an effective means to both control and treat cardiovascular disease. These claims are controversial, and several randomized controlled trials have been completed dealing with this topic. To address this issue we conducted a systematic review to evaluate the best available evidence for the use of EDTA chelation therapy in the treatment of cardiovascular disease. Methods We conducted a systematic review of 7 databases from inception to May 2005. Hand searches were conducted in review articles and in any of the trials found. Experts in the field were contacted and registries of clinical trials were searched for unpublished data. To be included in the final systematic review, the studies had to be randomized controlled clinical trials. Results A total of seven articles were found assessing EDTA chelation for the treatment of cardiovascular disease. Two of these articles were subgroup analyses of one RCT that looked at different clinical outcomes. Of the remaining five studies, two smaller studies found a beneficial effect whereas the other three exhibited no benefit for cardiovascular disease from the use of EDTA chelation therapy. Adverse effects were rare but those of note included a few cases of hypocalcemia and a single case of increased creatinine in a patient on the EDTA intervention. Conclusion The best available evidence does not support the therapeutic use of EDTA chelation therapy in the treatment of cardiovascular disease. Although not considered to be a highly invasive or harmful therapy, it is possible that the use of EDTA chelation therapy in lieu of proven therapy may result in causing indirect harm to the patient. PMID:16262904

  4. Luminescent lanthanide chelates and methods of use

    DOEpatents

    Selvin, Paul R.; Hearst, John

    1997-01-01

    The invention provides lanthanide chelates capable of intense luminescence. The celates comprise a lanthanide chelator covalently joined to a coumarin-like or quinolone-like sensitizer. Exemplary sensitzers include 2- or 4-quinolones, 2- or 4-coumarins, or derivatives thereof e.g. carbostyril 124 (7-amino-4-methyl-2-quinolone), coumarin 120 (7-amino-4-methyl-2-coumarin), coumarin 124 (7-amino-4-(trifluoromethyl)-2-coumarin), aminomethyltrimethylpsoralen, etc. The chelates form high affinity complexes with lanthanides, such as terbium or europium, through chelator groups, such as DTPA. The chelates may be coupled to a wide variety of compounds to create specific labels, probes, diagnostic and/or therapeutic reagents, etc. The chelates find particular use in resonance energy transfer between chelate-lanthanide complexes and another luminescent agent, often a fluorescent non-metal based resonance energy acceptor. The methods provide useful information about the structure, conformation, relative location and/or interactions of macromolecules.

  5. Bifunctional acoustic metamaterial lens designed with coordinate transformation

    NASA Astrophysics Data System (ADS)

    Zhu, Rongrong; Ma, Chu; Zheng, Bin; Musa, Muhyiddeen Yahya; Jing, Liqiao; Yang, Yihao; Wang, Huaping; Dehdashti, Shahram; Fang, Nicholas X.; Chen, Hongsheng

    2017-03-01

    We propose a method to design bifunctional acoustic lens using acoustic metamaterials that possess separate functions at different directions. The proposed bifunctional acoustic lens can be implemented in practice with subwavelength unit cells exhibiting effective anisotropic parameters. With this methodology, we experimentally demonstrate an acoustic Luneburg-fisheye lens at operational frequencies from 6300 Hz to 7300 Hz. Additionally, a bifunctional acoustic square lens is proposed with different focal lengths for multi directions. This method paves the way to manipulating acoustic energy flows with functional lenses.

  6. Acid-base bifunctional catalytic surfaces for nucleophilic addition reactions.

    PubMed

    Motokura, Ken; Tada, Mizuki; Iwasawa, Yasuhiro

    2008-09-01

    This article illustrates the modification of oxide surfaces with organic amine functional groups to create acid-base bifunctional catalysts, summarizing our previous reports and also presenting new data. Immobilization of organic amines as bases on inorganic solid-acid surfaces afforded highly active acid-base bifunctional catalysts, which enabled various organic transformations including C--C coupling reactions, though these reactions did not proceed with either the homogeneous amine precursors or the acidic supports alone. Spectroscopic characterization, such as by solid-state MAS NMR and FTIR, revealed not only the interactions between acidic and basic sites but also bifunctional catalytic reaction mechanisms.

  7. Chelating Polymers and Environmental Remediation

    DTIC Science & Technology

    2009-03-01

    the metal, stereochemistry , steric constraints as well as electrostatic interactions (6). As previously discussed, the chelating functionality...metal ions will preferentially interact. Based on this scale, noble metals such as copper (Cu), Hg, Pb, and Cd are defined as soft acceptors and...preferentially interaction with soft donors such as nitrogen. On the other hand, chromium (Cr) is defined as a hard species and is best ligated by

  8. Origin of asymmetric induction in bicyclic guanidine-catalyzed thio-Michael reaction: a bifunctional mode of Lewis acid-Brønsted acid activation.

    PubMed

    Cho, Bokun; Tan, Choon-Hong; Wong, Ming Wah

    2012-08-03

    In addition to a bifunctional Brønsted acid activation mode, an unconventional bifunctional mode of Lewis and Brønsted acid activations was revealed in a DFT study of bicyclic guanidine-catalyzed thio-Michael reaction. This activation mode provides an alternate reaction pathway for the C-S bond forming step and influences the final stereochemical outcome. The calculated turnover frequencies of the R- and S-products, based on the energetic span model, are in good accord with the observed high stereoselectivity toward the S-product.

  9. Synthesis and Thermodynamic Evaluation of Mixed Hexadentate Linear Iron Chelators Containing Hydroxypyridinone and Terephthalamide Units1

    PubMed Central

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-01-01

    A series of new linear iron chelators containing hydroxypyridinone and terephthalamide moieties has been prepared. All are hexadentate ligands composed of a systematically varied combination of me-3,2-hydroxypyridinone and 2,3-dihydroxyterephthalamide binding units; most are based on a spermidine scaffold but one incorporates the bifunctional 2,3-dihydroxyterephthalamide unit as an integral part of the backbone. Protonation and ferric iron complex formation constants have been determined from solution thermodynamic studies giving log ε110 values of 25.7, 30.7, 36.3, 43.8, and 45.0 respectively. The ferric complexes display reversible reduction potentials from −276 mV to −1032 mV (measured relative to the normal hydrogen electrode NHE) in alkaline solution. The incremental replacement of hydroxypyridinone units by terephthalamide binding groups progressively reduces the ligand acidity, markedly increases the iron-chelate stability, and improves the selectivity for ferric ion over ferrous ion. While the majority of iron chelators forming very stable ferric complexes are based on a tripodal backbone such as TREN, the ferric 5-LIO(TAMmeg)2(TAM) complex, despite its non-tripodal scaffold, is one of the most stable iron complexes yet reported. Moreover, the high affinity for ferric ion of the discussed linear ligands strongly correlates with their ability to remove iron in vivo. PMID:16634594

  10. Iron Group Hydrides in Noyori Bifunctional Catalysis.

    PubMed

    Morris, Robert H

    2016-12-01

    This is an overview of the hydride-containing catalysts prepared in the Morris group for the efficient hydrogenation of simple ketones, imines, nitriles and esters and the asymmetric hydrogenation and transfer hydrogenation of prochiral ketones and imines. The work was inspired by and makes use of Noyori metal-ligand bifunctional concepts involving the hydride-ruthenium amine-hydrogen HRuNH design. It describes the synthesis and some catalytic properties of hydridochloro, dihydride and amide complexes of ruthenium and in one case, osmium, with monodentate, bidentate and tetradentate phosphorus and nitrogen donor ligands. The iron hydride that has been identified in a very effective asymmetric transfer hydrogenation process is also mentioned. The link between the HMNH structure and the sense of enantioinduction is demonstrated by use of simple transition state models.

  11. Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

    DTIC Science & Technology

    2015-06-01

    Award Number: W81XWH-11-1-0692 TITLE: Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor PRINCIPAL INVESTIGATOR: Anna ...Bifunctional Modulators of the Sb. GRANT NUMBER Androgen Receptor W81XWH-11-1-0692 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Anna ... Carey , N.; Finn, P.; Collins, L.; Tumber, A.; Ritchie, J.; Jensen, P.; Lichenstein, H.; Sehested, M. Determination of the class and isoform

  12. A novel bifunctional metabolizable linker for the conjugation of antibodies with radionuclides

    SciTech Connect

    Arano, Y.; Matsushima, H.; Tagawa, M.; Koizumi, M.; Endo, K.; Konishi, J.; Yokoyama, A. )

    1991-03-01

    A novel heterogeneous bifunctional reagent containing an ester bond, N-((4-(2-maleimidoethoxy)-succinyl)oxy)succinimide (MESS), was designed and synthesized for the conjugation of antibodies with the gallium-67 (67Ga) chelate of succinyldeferoxamine (SDF) via the ester bond. MESS was synthesized by the acylation of N-(2-hydroxyethyl)maleimide with succinic anhydride, followed by the activation of the resulting carboxylic acid to a succinimido ester. MESS possesses a maleimide group for protein conjugation and an active ester group for deferoxamine (DFO) coupling, and the two functional groups are linked via ester bonding. Conjugation of 67Ga-SDF with nonspecific human IgG was performed by reacting freshly thiolated IgG with the reaction product of MESS and DFO, followed by 67Ga labeling of the resulting conjugate using GaCl3 (67Ga-DFO-MESS-IgG). For comparison, 67Ga-DFO conjugated nonspecific human IgG with a nonmetabolizable linkage was synthesized under the same conjugation conditions as those for 67Ga-DFO-MESS-IgG, using a nonmetabolizable heterogenous bifunctional reagent (N-((6-maleimidocaproyl)oxy)succinimide, EMCS) instead of MESS (67Ga-DFO-EMCS-IgG). HPLC size-exclusion chromatography of both preparations showed a single radioactivity and UV peak corresponding to the intact IgG. Generation of 67Ga-SDF from the 67Ga-DFO-MESS-IgG was demonstrated by reverse-phase HPLC analysis and cellulose acetate electrophoresis after the incubation of 67Ga-DFO-MESS-IgG in a buffered solution containing carboxyesterase. After injection of 67Ga-DFO-MESS-IgG into mice, faster radioactivity clearance from the blood and less radioactivity accumulation in the liver, kidney, and spleen was noted than when 67Ga-DFO-EMCS-IgG was injected.

  13. A new approach to wastewater remediation based on bifunctional electrodes.

    PubMed

    Asmussen, Robert Matthew; Tian, Min; Chen, Aicheng

    2009-07-01

    Here we report an a novel approach, the marriage of photocatalytic degradation and electrochemical oxidation, to wastewater remediation based on the use of bifunctional electrodes. To illustrate this innovative technique, TiO2/Ti/ Ta2O5-IrO2 bifunctional electrodes were prepared using a facile thermal decomposition technique and employed in this study. The TiO2 photocatalyst was coated on one side of the Ti substrate, while the Ta2O5-IrO2 electrocatalytic thin film was coated on the other side. The fabricated bifunctional electrodes were characterized by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). The performance of the bifunctional electrodes was tested using both 4-nitrophenol (4-NPh) and 2-nitrophenol (2-NPh) as model pollutants. Our study demonstrates that the prepared bifunctional electrodes exhibit high efficiency for both 4-NPh and 2-NPh degradation. In the degradation of 4-NPh a rate constant of 1.06 x 10(-2) min(-1) was created and a rate constant of 1.93 x 10(-2) min(-1) was produced for 2-NPh by the combination of the photochemical and electrochemical oxidation on the novel bifunctional electrodes, quadruple the rate constant created by the individual photochemical and photoelectrochemical methods. The innovative approach described in this study provides a very promising and energy efficient environmentally friendly technology for water purification and waste effluent treatment.

  14. Recent developments in chelate degradation.

    PubMed

    Sillanpää, M; Pirkanniemi, K

    2001-07-01

    Chelating agents are used in various industrial processes to inactivate transition metals by forming cyclic complexes. As nitrogen containing compounds, these substances increase the nitrogen load in wastewater. Also, they increase the heavy metal concentrations in the wastewater effluent. It has been long recognised that EDTA and DTPA are relatively recalcitrant compounds and thus pass through wastewater treatment without adequate removal. A number of interesting studies on the degradability of EDTA and DTPA--either by advanced oxidation processes or biological processes--have been carried out recently. This review focuses mainly on these two compounds.

  15. Soil washing: Chelation chemistry boosts metals recovery

    SciTech Connect

    1996-03-01

    Treatment options for soils contaminated by heavy metals range from extraction and recycling, to stabilization and long-term disposal. Tallon, Inc. (Princeton, N.J.) has developed a new technology that combines soil washing with metals-extraction processes used in the mining industry. The continuous process integrates three key stages -- physical removal of oversized materials, organics recovery and metals recovery. Metals are extracted using chelation chemistry. Solid-phase chelating agents -- dubbed chelating adsorbents -- are added to the soil, along with leaching acids. Once the metals have been leached, the chelating adsorbents bind them. The Tallon system can treat a range of metals, including copper zinc, cadmium, lead nickel and mercury.

  16. Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

    PubMed Central

    Cusnir, Ruslan; Imberti, Cinzia; Hider, Robert C.; Blower, Philip J.; Ma, Michelle T.

    2017-01-01

    Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images. PMID:28075350

  17. Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68.

    PubMed

    Cusnir, Ruslan; Imberti, Cinzia; Hider, Robert C; Blower, Philip J; Ma, Michelle T

    2017-01-08

    Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe(3+) sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe(3+) at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, (68)Ga(3+), which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex (68)Ga(3+) at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of (68)Ga PET radiopharmaceuticals. (68)Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.

  18. 68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals.

    PubMed

    Fani, Melpomeni; André, João P; Maecke, Helmut R

    2008-01-01

    PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.

  19. 68Ga-PET radiopharmacy: A generator-based alternative to 18F-radiopharmacy.

    PubMed

    Maecke, H R; André, J P

    2007-01-01

    Positron emission tomography (PET) is becoming a dominating method in the field of molecular imaging. Most commonly used radionuclides are accelerator produced 11C and 18F. An alternative method to label biomolecules is the use of metallic positron emitters; among them 68Ga is the most promising as it can be produced from a generator system consisting of an inorganic or organic matrix immobilizing the parent radionuclide 68Ge. Germanium-68 has a long half-life of 271 days which allows the production of long-lived, potentially very cost-effective generator systems. A commercial generator from Obninsk, Russia, is available which uses TiO2 as an inorganic matrix to immobilize 68Ge in the oxidation state IV+. 68Ge(IV) is chemically sufficiently different to allow efficient separation from 68Ga(III). Ga3+ is redox-inert; its coordination chemistry is dominated by its hard acid character. A variety of mono- and bifunctional chelators were developed which allow immobilization of 68Ga3+ and convenient coupling to biomolecules. Especially peptides targeting G-protein coupled receptors overexpressed on human tumour cells have been studied preclinically and in patient studies showing high and specific tumour uptake and specific localization. 68Ga-radiopharmacy may indeed be an alternative to 18F-based radiopharmacy. Freeze-dried, kit-formulated precursors along with the generator may be provided, similar to the 99Mo/99mTc-based radiopharmacy, still the mainstay of nuclear medicine.

  20. Phosphinic acid functionalized polyazacycloalkane chelators for radiodiagnostics and radiotherapeutics: unique characteristics and applications.

    PubMed

    Notni, Johannes; Šimeček, Jakub; Wester, Hans-Jürgen

    2014-06-01

    Given the wide application of positron emission tomography (PET), positron-emitting metal radionuclides have received much attention recently. Of these, gallium-68 has become particularly popular, as it is the only PET nuclide commercially available from radionuclide generators, therefore allowing local production of PET radiotracers independent of an on-site cyclotron. Hence, interest in optimized bifunctional chelators for the elaboration of (68) Ga-labeled bioconjugates has been rekindled as well, resulting in the development of improved triazacyclononane-triphosphinate (TRAP) ligand structures. The most remarkable features of these ligands are unparalleled selectivity for Ga(III) , rapid Ga(III) complexation kinetics, extraordinarily high thermodynamic stability, and kinetic inertness of the respective Ga(III) chelates. As a result, TRAP chelators exhibit very favorable (68) Ga-labeling properties. Based on the scaffolds NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) and TRAP-Pr, tailored for convenient preparation of (68) Ga-labeled monomeric and multimeric bioconjugates, a variety of novel (68) Ga radiopharmaceuticals have been synthesized. These include bisphosphonates, somatostatin receptor ligands, prostate-specific membrane antigen (PSMA)-targeting peptides, and cyclic RGD pentapeptides, for in vivo PET imaging of bone, neuroendocrine tumors, prostate cancer, and integrin expression, respectively. Furthermore, TRAP-based (68) Ga-labeled gadolinium(III) complexes have been proposed as bimodal probes for PET/MRI, and a cyclen-based analogue of TRAP-Pr has been suggested for the elaboration of targeted radiotherapeutics comprising radiolanthanide ions. Thus, polyazacycloalkane-based polyphosphinic acid chelators are a powerful toolbox for pharmaceutical research, particularly for the development of (68) Ga radiopharmaceuticals. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Beliefs about chelation among thalassemia patients

    PubMed Central

    2012-01-01

    Background Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy. Methods The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks. Results Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p<0.001). Self-reported adherence to chelation was not associated with views about necessity or concerns, but negatively correlated with perceived sensitivity to DFO (Sensitive Soma scale; r=−0.23, p=0.01) and side effects of oral chelation (r=−0.14, p=0.04). High ferritin iron levels, potentially indicating lower adherence, were found in 41% of patients reporting low necessity of oral chelation compared to 24% reporting high necessity (p=0.048). Concerns about treatment were associated with lower quality of life and more symptoms of anxiety and depression. Conclusions Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. Clinicaltrials.gov identifier NCT00661804 PMID:23216870

  2. Sorption and detoxification of toxic compounds by a bifunctional organoclay.

    PubMed

    Groisman, Ludmila; Rav-Acha, Chaim; Gerstl, Zev; Mingelgrin, Uri

    2004-01-01

    Organoclays are excellent sorbents for nonionic contaminants and therefore may have many environmental applications. A major limitation on the use of organoclays is that the contaminant merely changes its location from one environmental compartment to another while still remaining intact. In this study, a new type of organoclay, termed a bifunctional organoclay, has been prepared. It is able not only to sorb organophosphate pesticides, but also to catalyze their hydrolysis, and thereby detoxify them. The bifunctional organoclay prepared in this study is based on sodium montmorillonite, in which the inorganic counter ions are replaced by N-decyl-N,N-dimethyl-N-(2-aminoethyl) ammonium (DDMAEA). The detoxifying capacity of this organoclay for two organophosphate pesticides, methyl parathion [O,O-dimethyl O-(p-nitrophenyl) thionophosphate] and tetrachlorvinphos [2-chloro-1-(2,4,5-trichlorophenyl)ethenyl dimethyl phosphate], was demonstrated. It was shown that although the sorption of these pesticides on the bifunctional organoclay is very similar to that on N-decyl-N,N,N-trimethyl ammonium (DTMA) organoclay (the corresponding nonbifunctional organoclay), the hydrolysis of these pesticides is substantially enhanced only by the bifunctional organoclay. The half-life for the hydrolysis of the investigated pesticides in the presence of the bifunctional organoclay is about 12 times less than for their spontaneous hydrolysis, and the enhancement is even more pronounced relative to the hydrolysis of these pesticides in the presence of the DTMA organoclay (which actually inhibits their hydrolysis). Based on kinetic measurements, the pK(a) of the ethylamino group of the bifunctional organoclay was estimated to be around 9.0. It is postulated that the catalytic effect of the bifunctional organoclay can be attributed to a nucleophilic attack of the unprotonated ethylamino group of the organoclay on the organophosphate ester.

  3. Iron Chelation Therapy in Myelodysplastic Syndromes

    PubMed Central

    Messa, Emanuela; Cilloni, Daniela; Saglio, Giuseppe

    2010-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous disorder of the hematopoietic stem cells, frequently characterized by anemia and transfusion dependency. In low-risk patients, transfusion dependency can be long lasting, leading to iron overload. Iron chelation therapy may be a therapeutic option for these patients, especially since the approval of oral iron chelators, which are easier to use and better accepted by the patients. The usefulness of iron chelation in MDS patients is still under debate, mainly because of the lack of solid prospective clinical trials that should take place in the future. This review aims to summarize what is currently known about the incidence and clinical consequences of iron overload in MDS patients and the state-of the-art of iron chelation therapy in this setting. We also give an overview of clinical guidelines for chelation in MDS published to date and some perspectives for the future. PMID:20672005

  4. Exploring copper chelation in Alzheimer's disease protein

    NASA Astrophysics Data System (ADS)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2012-02-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of aging people in the U.S. alone. Clinical studies have indicated that metal chelation is a promising new approach in alleviating the symptoms of AD. Our study explores the as yet undetermined mechanism of copper chelation in amyloid-β, a protein implicated in AD. The structure of amyloid-β is derived from experimental results and incorporates a planar copper-ion-binding structure in a semi-solvated state. We investigate the chelation process using the nudged elastic band method implemented in our ab initio real-space multigrid code. We find that an optimal sequence of unbonding and rebonding events as well as proton transfers are required for a viable chelation process. These findings provide fundamental insight into the process of chelation that may lead to more effective AD therapies.

  5. Astaxanthin diferulate as a bifunctional antioxidant.

    PubMed

    Papa, T B R; Pinho, V D; do Nascimento, E S P; Santos, W G; Burtoloso, A C B; Skibsted, L H; Cardoso, D R

    2015-01-01

    Astaxanthin when esterified with ferulic acid is better singlet oxygen quencher with k2 = (1.58 ± 0.1) 10(10) L mol(-1)s(-1) in ethanol at 25°C compared with astaxanthin with k2 = (1.12 ± 0.01) 10(9) L mol(-1)s(-1). The ferulate moiety in the astaxanthin diester is a better radical scavenger than free ferulic acid as seen from the rate constant of scavenging of 1-hydroxyethyl radicals in ethanol at 25°C with a second-order rate constant of (1.68 ± 0.1) 10(8) L mol(-1)s(-1) compared with (1.60 ± 0.03) 10(7) L mol(-1)s(-1) for the astaxanthin:ferulic acid mixture, 1:2 equivalents. The mutual enhancement of antioxidant activity for the newly synthetized astaxanthin diferulate becoming a bifunctional antioxidant is rationalized according to a two-dimensional classification plot for electron donation and electron acceptance capability.

  6. Peroxisomal D-bifunctional protein deficiency

    PubMed Central

    Lines, Matthew A.; Jobling, Rebekah; Brady, Lauren; Marshall, Christian R.; Scherer, Stephen W.; Rodriguez, Amadeo R.; Lee, Liesly; Lang, Anthony E.; Mestre, Tiago A.; Wanders, Ronald J.A.; Ferdinandusse, Sacha

    2014-01-01

    Objective: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic. Methods: The patients’ initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively. Results: Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP’s enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced. Conclusion: Exome sequencing provides a powerful and elegant tool in the specific diagnosis of “mild” or “atypical” neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features. PMID:24553428

  7. Shadow enhancers enable Hunchback bifunctionality in the Drosophila embryo.

    PubMed

    Staller, Max V; Vincent, Ben J; Bragdon, Meghan D J; Lydiard-Martin, Tara; Wunderlich, Zeba; Estrada, Javier; DePace, Angela H

    2015-01-20

    Hunchback (Hb) is a bifunctional transcription factor that activates and represses distinct enhancers. Here, we investigate the hypothesis that Hb can activate and repress the same enhancer. Computational models predicted that Hb bifunctionally regulates the even-skipped (eve) stripe 3+7 enhancer (eve3+7) in Drosophila blastoderm embryos. We measured and modeled eve expression at cellular resolution under multiple genetic perturbations and found that the eve3+7 enhancer could not explain endogenous eve stripe 7 behavior. Instead, we found that eve stripe 7 is controlled by two enhancers: the canonical eve3+7 and a sequence encompassing the minimal eve stripe 2 enhancer (eve2+7). Hb bifunctionally regulates eve stripe 7, but it executes these two activities on different pieces of regulatory DNA--it activates the eve2+7 enhancer and represses the eve3+7 enhancer. These two "shadow enhancers" use different regulatory logic to create the same pattern.

  8. Antibacterial and antibiofilm effects of iron chelators against Prevotella intermedia.

    PubMed

    Moon, Ji-Hoi; Kim, Cheul; Lee, Hee-Su; Kim, Sung-Woon; Lee, Jin-Yong

    2013-09-01

    Prevotella intermedia, a major periodontopathogen, has been shown to be resistant to many antibiotics. In the present study, we examined the effect of the FDA-approved iron chelators deferoxamine (DFO) and deferasirox (DFRA) against planktonic and biofilm cells of P. intermedia in order to evaluate the possibility of using these iron chelators as alternative control agents against P. intermedia. DFRA showed strong antimicrobial activity (MIC and MBC values of 0.16 mg ml(-1)) against planktonic P. intermedia. At subMICs, DFRA partially inhibited the bacterial growth and considerably prolonged the bacterial doubling time. DFO was unable to completely inhibit the bacterial growth in the concentration range tested and was not bactericidal. Crystal violet binding assay for the assessment of biofilm formation by P. intermedia showed that DFRA significantly decreased the biofilm-forming activity as well as the biofilm formation, while DFO was less effective. DFRA was chosen for further study. In the ATP-bioluminescent assay, which reflects viable cell counts, subMICs of DFRA significantly decreased the bioactivity of biofilms in a concentration-dependent manner. Under the scanning electron microscope, P. intermedia cells in DFRA-treated biofilm were significantly elongated compared to those in untreated biofilm. Further experiments are necessary to show that iron chelators may be used as a therapeutic agent for periodontal disease.

  9. Natural chelating agents for radionuclide decorporation

    DOEpatents

    Premuzic, E.T.

    1985-06-11

    This invention relates to the production of metal-binding compounds useful for the therapy of heavy metal poisoning, for biological mining and for decorporation of radionuclides. The present invention deals with an orderly and effective method of producing new therapeutically effective chelating agents. This method uses challenge biosynthesis for the production of chelating agents that are specific for a particular metal. In this approach, the desired chelating agents are prepared from microorganisms challenged by the metal that the chelating agent is designed to detoxify. This challenge induces the formation of specific or highly selective chelating agents. The present invention involves the use of the challenge biosynthetic method to produce new complexing/chelating agents that are therapeutically useful to detoxify uranium, plutonium, thorium and other toxic metals. The Pseudomonas aeruginosa family of organisms is the referred family of microorganisms to be used in the present invention to produce the new chelating agent because this family is known to elaborate strains resistant to toxic metals.

  10. Bi-functional air electrodes for metal-air batteries. Final report, September 15, 1993--December 14, 1994

    SciTech Connect

    Swette, L.L.; Manoukian, M.; LaConti, A.B.

    1995-12-01

    The program was directed to the need for development of bifunctional air electrodes for Zn-Air batteries for the consumer market. The Zn-Air system, widely used as a primary cell for hearing-aid batteries and as a remote-site power source in industrial applications, has the advantage of high energy density, since it consumes oxygen from the ambient air utilizing a thin, efficient fuel-cell-type gas-diffusion electrode, and is comparatively low in cost. The disadvantages of the current technology are a relatively low rate capability, and the lack of simple reversibility. {open_quotes}Secondary{close_quotes} Zn-Air cells require a third electrode for oxygen evolution or mechanical replacement of the Zinc anodes; thus the development of a bifunctional air electrode (i.e., an electrode that can alternately consume and evolve oxygen) would be a significant advance in Zn-Air cell technology. Evaluations of two carbon-free non-noble metal perovskite-type catalyst systems, La{sub 1-x}CA{sub x}CoO{sub 3} as bifunctional catalysts for potential application in Zn-air batteries were carried out. The technical objectives were to develop higher-surface-area materials and to fabricate reversible electrodes by modifying the hydrophobic/hydrophilic balance of the catalyst-binder structures.

  11. Bifunctional Oxygen Reaction Catalysis of Quadruple Manganese Perovskites.

    PubMed

    Yamada, Ikuya; Fujii, Hiroshi; Takamatsu, Akihiko; Ikeno, Hidekazu; Wada, Kouhei; Tsukasaki, Hirofumi; Kawaguchi, Shogo; Mori, Shigeo; Yagi, Shunsuke

    2017-01-01

    Bifunctional electrocatalysts for oxygen evolution/reduction reaction (OER/ORR) are desirable for the development of energy conversion technologies. It is discovered that the manganese quadruple perovskites CaMn7 O12 and LaMn7 O12 show bifunctional catalysis in the OER/ORR. A possible origin of the high OER activity is the unique surface structure through corner-shared planar MnO4 and octahedral MnO6 units to promote direct OO bond formations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Novel bifunctional natriuretic peptides as potential therapeutics.

    PubMed

    Dickey, Deborah M; Burnett, John C; Potter, Lincoln R

    2008-12-12

    Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics.

  13. Electrocatalysts for bifunctional oxygen/air electrodes

    NASA Astrophysics Data System (ADS)

    Nikolova, V.; Iliev, P.; Petrov, K.; Vitanov, T.; Zhecheva, E.; Stoyanova, R.; Valov, I.; Stoychev, D.

    Oxygen reduction and evolution have been studied with respect to the development of bifunctional air/oxygen electrode (BFE). Three groups of catalysts have been prepared: (i) Cu xCo 3- xO 4 by thermal decomposition of mixed nitrate and carbonate precursors; (ii) thin films of Co-Ni-Te-O and Co-Te-O were deposited by vacuum co-evaporation of Co, Ni and TeO 2 and (iii) Co xO v/ZrO 2 films were obtained by electrochemical deposition. The electrochemical behavior of the chemically synthesized catalysts was studied on classical bilayered gas diffusion electrodes (GDEs), where the catalyst is in form of powder. The GDE catalyzed with vacuum deposited catalysts was prepared by direct deposition of the catalyst on gas-supplying layer, thus creating a ready-to-use gas diffusion electrode. Catalysts prepared electrochemically were first deposited on Ni foam and than pressed onto the gas-supplying layer. Different catalysts deposited on classical and originally designed GDEs were compared by their electrochemical performances. Cu 0.3Co 2.7O 4 deposited on a classical bilayered GDE with loading of 50 mg cm -2 exhibits stable current-voltage characteristics after 200 charge-discharge cycles in a real metal hydride-air battery. The electrochemically and vacuum deposited Co xO v/ZrO 2, Co-Ni-Te-O and Co-Te-O films exhibit much higher mass activity compared to Cu 0.2Co 2.8O 4 for both oxygen reduction and evolution reactions. The difference is that the loading of electrochemically and vacuum deposited films is 0.06 mg cm -2 only, which is a substantial advantage from a practical viewpoint.

  14. Bifunctional Homodimeric Triokinase/FMN Cyclase

    PubMed Central

    Rodrigues, Joaquim Rui; Couto, Ana; Cabezas, Alicia; Pinto, Rosa María; Ribeiro, João Meireles; Canales, José; Costas, María Jesús; Cameselle, José Carlos

    2014-01-01

    Mammalian triokinase, which phosphorylates exogenous dihydroxyacetone and fructose-derived glyceraldehyde, is neither molecularly identified nor firmly associated to an encoding gene. Human FMN cyclase, which splits FAD and other ribonucleoside diphosphate-X compounds to ribonucleoside monophosphate and cyclic X-phosphodiester, is identical to a DAK-encoded dihydroxyacetone kinase. This bifunctional protein was identified as triokinase. It was modeled as a homodimer of two-domain (K and L) subunits. Active centers lie between K1 and L2 or K2 and L1: dihydroxyacetone binds K and ATP binds L in different subunits too distant (≈14 Å) for phosphoryl transfer. FAD docked to the ATP site with ribityl 4′-OH in a possible near-attack conformation for cyclase activity. Reciprocal inhibition between kinase and cyclase reactants confirmed substrate site locations. The differential roles of protein domains were supported by their individual expression: K was inactive, and L displayed cyclase but not kinase activity. The importance of domain mobility for the kinase activity of dimeric triokinase was highlighted by molecular dynamics simulations: ATP approached dihydroxyacetone at distances below 5 Å in near-attack conformation. Based upon structure, docking, and molecular dynamics simulations, relevant residues were mutated to alanine, and kcat and Km were assayed whenever kinase and/or cyclase activity was conserved. The results supported the roles of Thr112 (hydrogen bonding of ATP adenine to K in the closed active center), His221 (covalent anchoring of dihydroxyacetone to K), Asp401 and Asp403 (metal coordination to L), and Asp556 (hydrogen bonding of ATP or FAD ribose to L domain). Interestingly, the His221 point mutant acted specifically as a cyclase without kinase activity. PMID:24569995

  15. Space-Confined Earth-Abundant Bifunctional Electrocatalyst for High-Efficiency Water Splitting.

    PubMed

    Tang, Yanqun; Fang, Xiaoyu; Zhang, Xin; Fernandes, Gina; Yan, Yong; Yan, Dongpeng; Xiang, Xu; He, Jing

    2017-10-12

    Hydrogen generation from water splitting could be an alternative way to meet increasing energy demands while also balancing the impact of energy being supplied by fossil-based fuels. The efficacy of water splitting strongly depends on the performance of electrocatalysts. Herein, we report a unique space-confined earth-abundant electrocatalyst having the bifunctionality of simultaneous hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), leading to high-efficiency water splitting. Outperforming Pt/C or RuO2 catalysts, this mesoscopic, space-confined, bifunctional configuration is constructed from a monolithic zeolitic imidazolate framework@layered double hydroxide (ZIF@LDH) precursor on Ni foam. Such a confinement leads to a high dispersion of ultrafine Co3O4 nanoparticles within the N-doped carbon matrix by temperature-dependent calcination of the ZIF@LDH. We demonstrate that the OER has an overpotential of 318 mV at a current density of 10 mA cm(-2), while that of HER is -106 mV @ -10 mA cm(-2). The voltage applied to a two-electrode cell for overall water splitting is 1.59 V to achieve a stable current density of 10 mA cm(-2) while using the monolithic catalyst as both the anode and the cathode. It is anticipated that our space-confined method, which focuses on earth-abundant elements with structural integrity, may provide a novel and economically sound strategy for practical energy conversion applications.

  16. Chelation Effects on Azotobacter Cells and Cysts

    PubMed Central

    Goldschmidt, Millicent C.; Wyss, Orville

    1966-01-01

    Goldschmidt, Millicent C. (University of Texas, Austin), and Orville Wyss. Chelation effects on Azotobacter cells and cysts. J. Bacteriol. 91:120–124. 1966.—Ethylenediaminetetraacetate (EDTA) is very toxic to Azotobacter in the presence of nitrogen compounds that form complexes with it. This appears to be due to stronger chelation of certain metal ions by the complex. When such complexes of EDTA and nitrogen compound are absent, Azotobacter cysts can be ruptured by chelation without being killed. The lethal action as well as the cyst rupture is modified by the presence of salts. PMID:4955245

  17. [Purification of Cu-67 and Macrocyclic chelates for targeted therapy]. DOE annual report, 1993--94

    SciTech Connect

    DeNardo, S.J.

    1994-12-31

    {sup 67}Cu produced at the Brookhaven Linac Isotope Producer (BLIP) is purified from zinc target material and coproduced radioisotopes of cobalt, chromium, nickel, and gallium by a multi-step extraction process. This procedure introduces applicable amounts of cold copper into the sample, lowering the specific activity of the {sup 67}Cu. Because of this, the {sup 67}Cu produced at BLIP is not of high enough activity for use in radioimmunotherapy procedures. It is their goal to develop a procedure with which to purify {sup 67}Cu from the other radioisotopes produced, while at the same time minimize the amount of cold copper introduced into the system. There are two different approaches that they devised for the purification of {sup 67}Cu. They are an extraction method similar to what is used at Brookhaven already, and a copper affinity column. Bifunctional macrocyclic chelates have been developed to conjugate metals to antibodies, and metal chelated antibodies have been shown to have slower clearance from the tumor than iodinated antibodies. This provides a mechanism for increasing tumor radiation dose and the therapeutic index. Conditions for {sup 67}Cu radiolabeling of TETA immunoconjugates have been optimized, leading to rapid, quantitative complexation of metal binding sites, further contributing to high radioactive yield and to the routine production of {sup 67}Cu radiolabed immunoconjugates of therapeutic quality.

  18. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions

    PubMed Central

    Neufeld, Ellis J.

    2006-01-01

    For nearly 30 years, patients with transfusional iron overload have depended on nightly deferoxamine infusions for iron chelation. Despite dramatic gains in life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, the leading cause of death for young adults with thalassemia major and related disorders has been cardiac disease from myocardial iron deposition. Strategies to reduce cardiac disease by improving chelation regimens have been of the highest priority. These strategies have included development of novel oral iron chelators to improve compliance, improved assessment of cardiac iron status, and careful epidemiologic assessment of European outcomes with deferiprone, an oral alternative chelator available for about a decade. Each of these strategies is now bearing fruit. The novel oral chelator deferasirox was recently approved by the Food and Drug Administration (FDA); a randomized clinical trial demonstrates that deferasirox at 20 to 30 mg/kg/d can maintain or improve hepatic iron in thalassemia as well as deferoxamine. A randomized trial based on cardiac T2* magnetic resonance imaging (MRI) suggests that deferiprone can unload myocardial iron faster than deferoxamine. Retrospective epidemiologic data suggest dramatic reductions in cardiac events and mortality in Italian subjects exposed to deferiprone compared with deferoxamine. These developments herald a new era for iron chelation, but many unanswered questions remain. PMID:16627763

  19. Removal of heavy metals from aqueous solution by chelating resin in a multistage adsorption process.

    PubMed

    Lin, S H; Lai, S L; Leu, H G

    2000-08-28

    Copper and zinc removal from aqueous solution by chelating resin was investigated theoretically and experimentally in the present study. A multistage process was proposed as an alternative for enhancement of the heavy removal of the single-stage process. Heavy metal mass balance equations with empirical Freundlich adsorption isotherm were developed to represent the multistage process and the theoretical model permits determination of the inter-stage heavy metal concentrations and the total amount of chelating resin required for achieving a desired level of heavy metal removal. Optimization of the linearized theoretical model shows that equal division of the total amount of chelating resin among all stages of the multistage process yields the best results in terms of saving of chelating resin for a given heavy metal removal or enhanced heavy metal removal for a given total amount of chelating resin. Experimental tests were also conducted to establish the equilibrium adsorption of heavy metal by the chelating resin and to empirically verify the advantages of the multistage adsorption process.

  20. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    PubMed Central

    Orcutt, Kelly Davis; Slusarczyk, Adrian L; Cieslewicz, Maryelise; Ruiz-Yi, Benjamin; Bhushan, Kumar R; Frangioni, John V; Wittrup, K Dane

    2014-01-01

    Introduction In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to DOTA chelates for use in PRIT applications. Methods We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), reformatted as a single chain variable fragment (scFv). Results Modeling predicts that for high antigen density and saturating bsAb dose, a hapten binding affinity of 100 picomolar (pM) is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nanomolar (nM) to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2 ± 1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen (CEA), pretargeted high-affinity scFv results in significantly higher tumor retention of a 111In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions We have engineered a versatile, high-affinity DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals. PMID:21315278

  1. Biochemical and Structural Characterization of the Arabidopsis Bifunctional Enzyme Dethiobiotin Synthetase–Diaminopelargonic Acid Aminotransferase: Evidence for Substrate Channeling in Biotin Synthesis[C][W

    PubMed Central

    Cobessi, David; Dumas, Renaud; Pautre, Virginie; Meinguet, Céline; Ferrer, Jean-Luc; Alban, Claude

    2012-01-01

    Diaminopelargonic acid aminotransferase (DAPA-AT) and dethiobiotin synthetase (DTBS) catalyze the antepenultimate and the penultimate steps, respectively, of biotin synthesis. Whereas DAPA-AT and DTBS are encoded by distinct genes in bacteria, in biotin-synthesizing eukaryotes (plants and most fungi), both activities are carried out by a single enzyme encoded by a bifunctional gene originating from the fusion of prokaryotic monofunctional ancestor genes. In few angiosperms, including Arabidopsis thaliana, this chimeric gene (named BIO3-BIO1) also produces a bicistronic transcript potentially encoding separate monofunctional proteins that can be produced following an alternative splicing mechanism. The functional significance of the occurrence of a bifunctional enzyme in biotin synthesis pathway in eukaryotes and the relative implication of each of the potential enzyme forms (bifunctional versus monofunctional) in the plant biotin pathway are unknown. In this study, we demonstrate that the BIO3-BIO1 fusion protein is the sole protein form produced by the BIO3-BIO1 locus in Arabidopsis. The enzyme catalyzes both DAPA-AT and DTBS reactions in vitro and is targeted to mitochondria in vivo. Our biochemical and kinetic characterizations of the pure recombinant enzyme show that in the course of the reaction, the DAPA intermediate is directly transferred from the DAPA-AT active site to the DTBS active site. Analysis of several structures of the enzyme crystallized in complex with and without its ligands reveals key structural elements involved for acquisition of bifunctionality and brings, together with mutagenesis experiments, additional evidences for substrate channeling. PMID:22547782

  2. Questions and Answers on Unapproved Chelation Products

    MedlinePlus

    ... involves the use of certain chemicals to remove heavy metals from the body. In medicine, chelation has been ... tests that claim to detect the presence of heavy metals in urine to falsely justify the need for ...

  3. Pediatric fatality secondary to EDTA chelation.

    PubMed

    Baxter, Arla J; Krenzelok, Edward P

    2008-12-01

    Chelation therapy has emerged as a popular treatment modality to remove heavy metals that are thought to cause autism. We report a fatality that occurred as a consequence of chelation therapy for autism when the incorrect form of EDTA was administered. A five-year-old autistic male was being chelated in a physician's office. While receiving his third treatment he went into cardiac arrest. It was not determined until after the child's death that he had been given edetate disodium rather than edetate calcium disodium, causing profound hypocalcemia and triggering the cardiac events that led to his death. In 1991, the CDC recommended using only edetate calcium disodium, not edetate disodium, to children because edetate disodium may induce tetany and possible hypocalcemia as illustrated in this case. The use of chelation therapy in autistic children has not been validated and can have tragic consequences.

  4. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

  5. Bifunctional mesoporous silicas with clearly distinguished localization of grafted groups

    NASA Astrophysics Data System (ADS)

    Roik, N. V.; Belyakova, L. A.

    2013-12-01

    Bifunctional mesoporous silicas with clearly distinguished localization of grafted groups on the surface of particles and inside their pores were obtained by means of sol-gel synthesis with postsynthetic vapor-phase treatment in vacuum. It was found that the synthesized materials have the hexagonally ordered porous structure typical of MCM-41 type silica.

  6. Fluid extraction using carbon dioxide and organophosphorus chelating agents

    DOEpatents

    Smart, Neil G.; Wai, Chien M.; Lin, Yuehe; Kwang, Yak Hwa

    1998-01-01

    Methods for extracting metalloid and metal species from a solid or liquid material by exposing the material to a fluid solvent, particularly supercritical CO.sub.2, and a chelating agent are described. The chelating agent forms a chelate with the species, the chelate being soluble in the fluid to allow removal of the species from the material. In preferred embodiments the extraction solvent is supercritical CO.sub.2 and the chelating agent comprises an organophosphorous chelating agent, particularly sulfur-containing organophosphorous chelating agents, including mixtures of chelating agents. Examples of chelating agents include monothiophosphinic acid, di-thiophosphinic acid, phosphine sulfite, phosphorothioic acid, and mixtures thereof. The method provides an environmentally benign process for removing metal and metalloids from industrial waste solutions, particularly acidic solutions. Both the chelate and the supercritical fluid can be regenerated and the contaminant species recovered to provide an economic, efficient process.

  7. Fluid extraction using carbon dioxide and organophosphorus chelating agents

    DOEpatents

    Smart, N.G.; Wai, C.M.; Lin, Y.; Kwang, Y.H.

    1998-11-24

    Methods for extracting metalloid and metal species from a solid or liquid material by exposing the material to a fluid solvent, particularly supercritical CO{sub 2}, and a chelating agent are described. The chelating agent forms a chelate with the species, the chelate being soluble in the fluid to allow removal of the species from the material. In preferred embodiments the extraction solvent is supercritical CO{sub 2} and the chelating agent comprises an organophosphorous chelating agent, particularly sulfur-containing organophosphorous chelating agents, including mixtures of chelating agents. Examples of chelating agents include monothiophosphinic acid, di-thiophosphinic acid, phosphine sulfite, phosphorothioic acid, and mixtures thereof. The method provides an environmentally benign process for removing metal and metalloids from industrial waste solutions, particularly acidic solutions. Both the chelate and the supercritical fluid can be regenerated and the contaminant species recovered to provide an economic, efficient process. 1 fig.

  8. Labeling anti-HER2/neu monoclonal antibodies with 111In and 90Y using a bifunctional DTPA chelating agent.

    PubMed

    Blend, Michael J; Stastny, Jerry J; Swanson, Steven M; Brechbiel, Martin W

    2003-06-01

    The goal of this investigation was to develop stable radioimmunoconjugates (RICs) of anti-HER2/neu monoclonal antibodies (MoAbs) for imaging and therapy in an animal model bearing human breast tumor xenografts that express normal (MCF-7 cells) and increased amounts of HER2/neu receptors (HCC-1954, BT-474, SKBR-3 cells) on their cell surface membranes. Pharmacy-grade Herceptin, a murine anti-HER2/neu MoAb, and nonspecific mouse IgG protein were conjugated with the recently developed DTPA linker known as CHX-A"-DTPA. These immunoconjugates were labeled with (111)InCl(3) and (90)YCl(3). Using a molar excess of 10:1 CHX-A"-DTPA to immunoglobulin, average specific activities of 1.87 microCi (111)In/microg RIC and 2.71 microCi (90)Y/microg RIC were obtained. The purity of RICs was 96%+ for (111)In and 99%+ for (90)Y. Stability in human plasma at 37 degrees C for both RICs ranged from 98% at 24 h to 85% at 96 h. Binding capacity of the RICs was tested with human cancer cell lines MCF-7, HCC-1954, BT-474, and SKBR-3. Using (111)In-labeled nonspecific IgG protein as a control, (111)In-Herceptin RIC was found to bind to MCF-7 cells with a ratio of 2.5:1 and to SKBR-3 cells with a ratio of 85:1 after 3 h of incubation. (111)In anti-HER2/neu RIC bound to MCF-7 cells with a ratio of 6:1 and to SKBR-3 cells with a ratio of 115:1 after 3 h of incubation. (90)Y-anti-HER2/neu RIC bound 10-times greater to BT-474 cells than to MCF-7 cells. Thus, these MoAbs can be labeled with (111)In and (90)Y using the CHX-A"-DTPA linker. The resulting RICs ((111)In- and (90)Y-anti HER2/neu antibodies) are stable and bind significantly to HER2 overexpressing tumor cell lines.

  9. Copper Chelation in Alzheimer's Disease Protein

    NASA Astrophysics Data System (ADS)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2013-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. AD is primarily characterized at the cellular level by densely tangled fibrils of amyloid- β protein. These protein clusters have been found in association with elevated levels of multiple transition metals, with copper being the most egregious. Interestingly, metal chelation has shown promise in attenuating the symptoms of AD in recent clinical studies. We investigate this process by constructing an atomistic model of the amyloid- β-copper complex and profile the energetic viability in each of its subsequent disassociation stages. Our results indicate that five energetic barriers must be overcome for full metal chelation. The energy barriers are biologically viable in the presence water mediated bond and proton transfer between the metal and the protein. We model the chelation reaction using a consecutive path nudged elastic band method implemented in our ab initio real-space multi-grid code to obtain a viable sequence. This reaction model details a physically consistent explanation of the chelation process that could lead to the discovery of more effective chelation agents in the treatment of AD.

  10. Recent progress in asymmetric bifunctional catalysis using multimetallic systems.

    PubMed

    Shibasaki, Masakatsu; Kanai, Motomu; Matsunaga, Shigeki; Kumagai, Naoya

    2009-08-18

    The concept of bifunctional catalysis, wherein both partners of a bimolecular reaction are simultaneously activated, is very powerful for designing efficient asymmetric catalysts. Catalytic asymmetric processes are indispensable for producing enantiomerically enriched compounds in modern organic synthesis, providing more economical and environmentally benign results than methods requiring stoichiometric amounts of chiral reagents. Extensive efforts in this field have produced many asymmetric catalysts, and now a number of reactions can be rendered asymmetric. We have focused on the development of asymmetric catalysts that exhibit high activity, selectivity, and broad substrate generality under mild reaction conditions. Asymmetric catalysts based on the concept of bifunctional catalysis have emerged as a particularly effective class, enabling simultaneous activation of multiple reaction components. Compared with conventional catalysts, bifunctional catalysts generally exhibit enhanced catalytic activity and higher levels of stereodifferentiation under milder reaction conditions, attracting much attention as next-generation catalysts for prospective practical applications. In this Account, we describe recent advances in enantioselective catalysis with bifunctional catalysts. Since our identification of heterobimetallic rare earth-alkali metal-BINOL (REMB) complexes, we have developed various types of bifunctional multimetallic catalysts. The REMB catalytic system is effective for catalytic asymmetric Corey-Chaykovsky epoxidation and cyclopropanation. A dinucleating Schiff base has emerged as a suitable multidentate ligand for bimetallic catalysts, promoting catalytic syn-selective nitro-Mannich, anti-selective nitroaldol, and Mannich-type reactions. The sugar-based ligand GluCAPO provides a suitable platform for polymetallic catalysts; structural elucidation revealed that their higher order polymetallic structures are a determining factor for their function in the

  11. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture.

    PubMed

    Rush, Travis; Hjelmhaug, Julie; Lobner, Doug

    2009-01-01

    Chelation therapy for the treatment of acute, high dose exposure to heavy metals is accepted medical practice. However, a much wider use of metal chelators is by alternative health practitioners for so called "chelation therapy". Given this widespread and largely unregulated use of metal chelators it is important to understand the actions of these compounds. We tested the effects of four commonly used metal chelators, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), D-penicillamine (DPA), 2,3 dimercaptopropane-1-sulfonate (DMPS), and dimercaptosuccinic acid (DMSA) for their effects on heavy metal neurotoxicity in primary cortical cultures. We studied the toxicity of three forms of mercury, inorganic mercury (HgCl2), methyl mercury (MeHg), and ethyl mercury (thimerosal), as well as lead (PbCl2) and iron (Fe-citrate). DPA had the worst profile of effects, providing no protection while potentiating HgCl2, thimerosal, and Fe-citrate toxicity. DMPS and DMSA both attenuated HgCl2 toxicity and potentiated thimerosal and Fe toxicity, while DMPS also potentiated PbCl2 toxicity. CaNa2EDTA attenuated HgCl2 toxicity, but caused a severe potentiation of Fe-citrate toxicity. The ability of these chelators to attenuate the toxicity of various metals is quite restricted, and potentiation of toxicity is a serious concern. Specifically, protection is provided only against inorganic mercury, while it is lacking against the common form of mercury found in food, MeHg, and the form found in vaccines, thimerosal. The potentiation of Fe-citrate toxicity is of concern because of iron's role in oxidative stress in the body. Potentiation of iron toxicity could have serious health consequences when using chelation therapy.

  12. Effect of chelating agents and solubility of cadmium complexes on uptake from soil by Brassica juncea.

    PubMed

    Van Engelen, Debra L; Sharpe-Pedler, Rachel C; Moorhead, Kevin K

    2007-06-01

    Brassica juncea, or Indian mustard, was grown in soil artificially contaminated with either a soluble salt, CdCl(2), at 186mg Cdkg(-1), or alternately an insoluble, basic salt, CdCO(3), at 90mg Cdkg(-1). These experiments study the range of Cd uptake by Indian mustard from conditions of very high Cd concentration in a soluble form to the other extreme with an insoluble Cd salt. After plants were established, four different chelating agents were applied. Chelating agents increased plant uptake of Cd from the CdCl(2) soil but did not significantly increase plant uptake of Cd from the CdCO(3) contaminated soil. Addition of ethylenediaminetetraacetic acid (EDTA) increased the plant concentration of Cd by almost 10-fold in soils contaminated with CdCl(2), with a concentration of 1283mg Cdkg(-1) in the dried EDTA-treated plants over a concentration of 131mg Cdkg(-1) in plants without added chelate. However, EDTA increased the aqueous solubility of Cd by 36 times over the soil matrix without added chelator, and thereby, increased the possibility of leaching. Other chelators used in both experiments were ethylenebis(oxyethylenenitrilo)tetraacetic acid, trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, and diethylenetriaminepentaacetic acid (DTPA) increasing Cd in plants to 1240, 962, and 437mg Cdkg(-1), respectively. The other chelating agents increased the solubility of Cd in the leachate but not to the extent of EDTA. Comparing all chelating agents studied, DTPA increased plant uptake in terms of Cd in dried plant concentration most relative to the solubility of complexed Cd in runoff water.

  13. Method and apparatus for back-extracting metal chelates

    DOEpatents

    Wai, C.M.; Smart, N.G.; Lin, Y.

    1998-08-11

    A method is described for extracting metal and metalloid species from a solid or liquid substrate using a supercritical fluid solvent containing one or more chelating agents followed by back-extracting the metal and metalloid species from the metal and metalloid chelates formed thereby. The back-extraction acidic solution is performed utilizing an acidic solution. Upon sufficient exposure of the metal and metalloid chelates to the acidic solution, the metal and metalloid species are released from the chelates into the acid solution, while the chelating agent remains in the supercritical fluid solvent. The chelating agent is thereby regenerated and the metal and metalloid species recovered. 3 figs.

  14. Method and apparatus for back-extracting metal chelates

    DOEpatents

    Wai, Chien M.; Smart, Neil G.; Lin, Yuehe

    1998-01-01

    A method of extracting metal and metalloid species from a solid or liquid substrate using a supercritical fluid solvent containing one or more chelating agents followed by back-extracting the metal and metalloid species from the metal and metalloid chelates formed thereby. The back-extraction acidic solution is performed utilizing an acidic solution. Upon sufficient exposure of the metal and metalloid chelates to the acidic solution, the metal and metalloid species are released from the chelates into the acid solution, while the chelating agent remains in the supercritical fluid solvent. The chelating agent is thereby regenerated and the metal and metalloid species recovered.

  15. Method of encapsulating polyaminopolycarboxylic acid chelating agents in liposomes

    DOEpatents

    Rahman, Yueh Erh

    1977-11-10

    A method is provided for transferring a polyaminopolycarboxylic acid chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes, which liposomes will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. The chelating agent is encapsulated within liposomes by drying a lipid mixture to form a thin film and wetting the lipid film with a solution containing the chelating agent. Mixing then results in the formation of a suspension of liposomes encapsulating the chelating agent, which liposomes can then be separated.

  16. Bifunctional electrocatalysis in pt-ru nanoparticle systems.

    PubMed

    Roth, C; Benker, N; Theissmann, R; Nichols, R J; Schiffrin, D J

    2008-03-04

    Pt-Ru alloys are prominent electrocatalysts in fuel cell anodes as they feature a very high activity for the oxidation of reformate and methanol. The improved CO tolerance of these alloys has been discussed in relation to the so-called ligand and bifunctional mechanisms. Although these effects have been known for many years, they are still not completely understood. A new approach that bridges the gap between single crystals and practical catalysts is presented in this paper. Nanoparticulate model systems attached to an oxidized glassy carbon electrode were prepared by combining both ligand-stabilized and spontaneously deposited Pt and Ru nanoparticles. These electrodes showed very different voltammetric responses for CO and methanol oxidation. The cyclic voltammograms were deconvoluted into contributions attributed to Pt, Ru, and Pt-Ru contact regions to quantify the contribution of the latter to the bifunctional mechanism. Scanning transmission electron microscopy confirmed the proximity of Pt and Ru nanoparticles in the different samples.

  17. Preparation of a Versatile Bifunctional Zeolite for Targeted Imaging Applications

    PubMed Central

    Ndiege, Nicholas; Raidoo, Renugan; Schultz, Michael K.; Larsen, Sarah

    2011-01-01

    Bifunctional zeolite Y was prepared for use in targeted in vivo molecular imaging applications. The strategy involved functionalization of the external surface of zeolite Y with chloropropyltriethoxysilane followed by reaction with sodium azide to form azide-functionalized NaY, which is amenable to copper(1) catalyzed click chemistry. In this study, a model alkyne (4-pentyn-1-ol) was attached to the azide-terminated surface via click chemistry to demonstrate feasibility for attachment of molecular targeting vectors (e.g., peptides, aptamers) to the zeolite surface. The modified particle efficiently incorporates the imaging radioisotope gallium-68 (68Ga) into the pores of the azide-functionalized NaY zeolite to form a stable bifunctional molecular targeting vector. The result is a versatile “clickable” zeolite platform that can be tailored for future in vivo molecular targeting and imaging modalities. PMID:21306141

  18. The aminoindanol core as a key scaffold in bifunctional organocatalysts.

    PubMed

    G Sonsona, Isaac; Marqués-López, Eugenia; Herrera, Raquel P

    2016-01-01

    The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel-Crafts alkylation, Michael addition, Diels-Alder and aza-Henry reactions. However, the 1,2-aminoindanol core incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts.

  19. Preparation of a versatile bifunctional zeolite for targeted imaging applications.

    PubMed

    Ndiege, Nicholas; Raidoo, Renugan; Schultz, Michael K; Larsen, Sarah

    2011-03-15

    Bifunctional zeolite Y was prepared for use in targeted in vivo molecular imaging applications. The strategy involved functionalization of the external surface of zeolite Y with chloropropyltriethoxysilane followed by reaction with sodium azide to form azide-functionalized NaY, which is amenable to copper(1)-catalyzed click chemistry. In this study, a model alkyne (4-pentyn-1-ol) was attached to the azide-terminated surface via click chemistry to demonstrate feasibility for attachment of molecular targeting vectors (e.g., peptides, aptamers) to the zeolite surface. The modified particle efficiently incorporates the imaging radioisotope gallium-68 ((68)Ga) into the pores of the azide-functionalized NaY zeolite to form a stable bifunctional molecular targeting vector. The result is a versatile "clickable" zeolite platform that can be tailored for future in vivo molecular targeting and imaging modalities.

  20. The aminoindanol core as a key scaffold in bifunctional organocatalysts

    PubMed Central

    G. Sonsona, Isaac

    2016-01-01

    Summary The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel–Crafts alkylation, Michael addition, Diels–Alder and aza-Henry reactions. However, the 1,2-aminoindanol core incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts. PMID:27340443

  1. A Manganese Alternative to Gadolinium for MRI Contrast.

    PubMed

    Gale, Eric M; Atanasova, Iliyana P; Blasi, Francesco; Ay, Ilknur; Caravan, Peter

    2015-12-16

    Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However, safety concerns limit the use of iodinated and gadolinium (Gd)-based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese(II) complex [Mn(PyC3A)(H2O)](-) as a Gd alternative. [Mn(PyC3A)(H2O)](-) is among the most stable Mn(II) complexes at pH 7.4 (log KML = 11.40). In the presence of 25 mol equiv of Zn at pH 6.0, 37 °C, [Mn(PyC3A)(H2O)](-) is 20-fold more resistant to dissociation than [Gd(DTPA)(H2O)](2-). Relaxivity of [Mn(PyC3A)(H2O)](-) in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn(PyC3A)(H2O)](-) clears via a mixed renal/hepatobiliary pathway with >99% elimination by 24 h. [Mn(PyC3A)(H2O)](-) was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD(E) with Kd = 110 nM. Per Mn relaxivity of Mn-FBP is 4-fold greater than [Mn(PyC3A)(H2O)](-) and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analogue, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 h. [Mn(PyC3A)(H2O)](-) is a lead development candidate for an imaging probe that is compatible with renally compromised patients.

  2. A Manganese Alternative to Gadolinium for MRI Contrast

    PubMed Central

    Gale, Eric M.; Atanasova, Iliyana P.; Blasi, Francesco; Ay, Ilknur; Caravan, Peter

    2016-01-01

    Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However safety concerns limit the use of iodinated and gadolinium- (Gd) based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese(II) complex [Mn(PyC3A)(H2O)]- as a Gd alternative. [Mn(PyC3A)(H2O)]- is amongst the most stable Mn(II) complexes at pH 7.4 (log KML = 11.40). In the presence of 25 mol equiv. Zn at pH 6.0, 37 °C, [Mn(PyC3A)(H2O)]- is 20-fold more resistant to dissociation than [Gd(DTPA)(H2O)]2-. Relaxivity of [Mn(PyC3A)(H2O)]- in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn(PyC3A)(H2O)]- clears via a mixed renal/ hepatobiliary pathway with >99% elimination by 24h. [Mn(PyC3A)(H2O)]- was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD(E) with Kd = 110 nM. Per Mn relaxivity of Mn-FBP is 4-fold greater than [Mn(PyC3A)(H2O)]- and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analog, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 hr. [Mn(PyC3A)(H2O)]- is a lead development candidate for an imaging probe that is compatible with renally compromised patients. PMID:26588204

  3. Stereoselective Glycosylation of 2-Nitrogalactals Catalyzed by a Bifunctional Organocatalyst

    PubMed Central

    2016-01-01

    The use of a bifunctional cinchona/thiourea organocatalyst for the direct and α-stereoselective glycosylation of 2-nitrogalactals is demonstrated for the first time. The conditions are mild, practical, and applicable to a wide range of glycoside acceptors with products being isolated in good to excellent yields. The method is exemplified in the synthesis of mucin type Core 6 and 7 glycopeptides. PMID:27529800

  4. Bifunctional air electrodes containing elemental iron powder charging additive

    DOEpatents

    Liu, Chia-tsun; Demczyk, Brian G.; Gongaware, Paul R.

    1982-01-01

    A bifunctional air electrode for use in electrochemical energy cells is made, comprising a hydrophilic layer and a hydrophobic layer, where the hydrophilic layer essentially comprises a hydrophilic composite which includes: (i) carbon; (ii) elemental iron particles having a particle size of between about 25 microns and about 700 microns diameter; (iii) an oxygen evolution material; (iv) a nonwetting agent; and (v) a catalyst, where at least one current collector is formed into said composite.

  5. Room Temperature Hydrosilylation of Silicon Nanocrystals with Bifunctional Terminal Alkenes

    PubMed Central

    Yu, Yixuan; Hessel, Colin M.; Bogart, Timothy; Panthani, Matthew G.; Rasch, Michael R.; Korgel, Brian A.

    2013-01-01

    H-terminated Si nanocrystals undergo room temperature hydrosilylation with bifunctional alkenes with distal polar moieties—ethyl-, methyl-ester or carboxylic acids—without the aid of light or added catalyst. The passivated Si nanocrystals exhibit bright photoluminescence (PL) and disperse in polar solvents, including water. We propose a reaction mechanism in which ester or carboxylic acid groups facilitate direct nucleophilic attack of the highly curved Si surface of the nanocrystals by the alkene. PMID:23312033

  6. Phosphine-boronates: efficient bifunctional organocatalysts for Michael addition.

    PubMed

    Baslé, Olivier; Porcel, Susana; Ladeira, Sonia; Bouhadir, Ghenwa; Bourissou, Didier

    2012-05-11

    Phosphine-boronates R(2)P(o-C(6)H(4))B(OR')(2) have been evaluated as bifunctional organocatalysts for the Michael addition of malonate pronucleophiles to methylvinylketone. The presence of the Lewis acidic boron center adjacent to phosphorus significantly improves catalytic performance. Isolation and complete characterization of a key intermediate, namely a β-phosphonium enolate, substantiate the role of the Lewis acidic moiety in the catalytic process.

  7. Why Does Alkylation of the N-H Functionality within M/NH Bifunctional Noyori-Type Catalysts Lead to Turnover?

    PubMed

    Dub, Pavel A; Scott, Brian L; Gordon, John C

    2017-01-25

    Molecular metal/NH bifunctional Noyori-type catalysts are remarkable in that they are among the most efficient artificial catalysts developed to date for the hydrogenation of carbonyl functionalities (loadings up to ∼10(-5) mol %). In addition, these catalysts typically exhibit high C═O/C═C chemo- and enantioselectivities. This unique set of properties is traditionally associated with the operation of an unconventional mechanism for homogeneous catalysts in which the chelating ligand plays a key role in facilitating the catalytic reaction and enabling the aforementioned selectivities by delivering/accepting a proton (H(+)) via its N-H bond cleavage/formation. A recently revised mechanism of the Noyori hydrogenation reaction (Dub, P. A. et al. J. Am. Chem. Soc. 2014, 136, 3505) suggests that the N-H bond is not cleaved but serves to stabilize the turnover-determining transition states (TDTSs) via strong N-H···O hydrogen-bonding interactions (HBIs). The present paper shows that this is consistent with the largely ignored experimental fact that alkylation of the N-H functionality within M/NH bifunctional Noyori-type catalysts leads to detrimental catalytic activity. The purpose of this work is to demonstrate that decreasing the strength of this HBI, ultimately to the limit of its complete absence, are conditions under which the same alkylation may lead to beneficial catalytic activity.

  8. Why Does Alkylation of the N–H Functionality within M/NH Bifunctional Noyori-Type Catalysts Lead to Turnover?

    DOE PAGES

    Dub, Pavel; Gordon, John Cameron; Scott, Brian Lindley

    2017-01-25

    Molecular metal/NH bifunctional Noyori-type catalysts are remarkable in that they are among the most efficient artificial catalysts developed to date for the hydrogenation of carbonyl functionalities (loadings up to ~10–5 mol %). In addition, these catalysts typically exhibit high C$=$O/C$=$C chemo- and enantioselectivities. This unique set of properties is traditionally associated with the operation of an unconventional mechanism for homogeneous catalysts in which the chelating ligand plays a key role in facilitating the catalytic reaction and enabling the aforementioned selectivities by delivering/accepting a proton (H+) via its N–H bond cleavage/formation. A recently revised mechanism of the Noyori hydrogenation reaction (Dub,more » P. A. et al. J. Am. Chem. Soc. 2014, 136, 3505) suggests that the N–H bond is not cleaved but serves to stabilize the turnover-determining transition states (TDTSs) via strong N–H···O hydrogen-bonding interactions (HBIs). Here, the present paper shows that this is consistent with the largely ignored experimental fact that alkylation of the N–H functionality within M/NH bifunctional Noyori-type catalysts leads to detrimental catalytic activity. Finally, the purpose of this work is to demonstrate that decreasing the strength of this HBI, ultimately to the limit of its complete absence, are conditions under which the same alkylation may lead to beneficial catalytic activity.« less

  9. Invariants reveal multiple forms of robustness in bifunctional enzyme systems.

    PubMed

    Dexter, Joseph P; Dasgupta, Tathagata; Gunawardena, Jeremy

    2015-08-01

    Experimental and theoretical studies have suggested that bifunctional enzymes catalyzing opposing modification and demodification reactions can confer steady-state concentration robustness to their substrates. However, the types of robustness and the biochemical basis for them have remained elusive. Here we report a systematic study of the most general biochemical reaction network for a bifunctional enzyme acting on a substrate with one modification site, along with eleven sub-networks with more specialized biochemical assumptions. We exploit ideas from computational algebraic geometry, introduced in previous work, to find a polynomial expression (an invariant) between the steady state concentrations of the modified and unmodified substrate for each network. We use these invariants to identify five classes of robust behavior: robust upper bounds on concentration, robust two-sided bounds on concentration ratio, hybrid robustness, absolute concentration robustness (ACR), and robust concentration ratio. This analysis demonstrates that robustness can take a variety of forms and that the type of robustness is sensitive to many biochemical details, with small changes in biochemistry leading to very different steady-state behaviors. In particular, we find that the widely-studied ACR requires highly specialized assumptions in addition to bifunctionality. An unexpected result is that the robust bounds derived from invariants are strictly tighter than those derived by ad hoc manipulation of the underlying differential equations, confirming the value of invariants as a tool to gain insight into biochemical reaction networks. Furthermore, invariants yield multiple experimentally testable predictions and illuminate new strategies for inferring enzymatic mechanisms from steady-state measurements.

  10. Shadow enhancers enable Hunchback bifunctionality in the Drosophila embryo

    PubMed Central

    Staller, Max V.; Vincent, Ben J.; Bragdon, Meghan D. J.; Lydiard-Martin, Tara; Wunderlich, Zeba; Estrada, Javier; DePace, Angela H.

    2015-01-01

    Hunchback (Hb) is a bifunctional transcription factor that activates and represses distinct enhancers. Here, we investigate the hypothesis that Hb can activate and repress the same enhancer. Computational models predicted that Hb bifunctionally regulates the even-skipped (eve) stripe 3+7 enhancer (eve3+7) in Drosophila blastoderm embryos. We measured and modeled eve expression at cellular resolution under multiple genetic perturbations and found that the eve3+7 enhancer could not explain endogenous eve stripe 7 behavior. Instead, we found that eve stripe 7 is controlled by two enhancers: the canonical eve3+7 and a sequence encompassing the minimal eve stripe 2 enhancer (eve2+7). Hb bifunctionally regulates eve stripe 7, but it executes these two activities on different pieces of regulatory DNA—it activates the eve2+7 enhancer and represses the eve3+7 enhancer. These two “shadow enhancers” use different regulatory logic to create the same pattern. PMID:25564665

  11. Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

    DOE PAGES

    Wilson, Justin J.; Ferrier, Maryline; Radchenko, Valery; ...

    2015-05-01

    The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope ²¹³Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi³⁺, however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (Lpy), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (Lpz), were prepared by a previously reported method and investigated here for their abilitiesmore » to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)- cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, ²⁰⁷Bi (t1/2 = 32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi³⁺ and the generator parent ion Ac³⁺.In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi³⁺ in the presence of the parent isotope Ac³⁺. Among the four tested, Lpy was found to exhibit optimal Bi³⁺-binding kinetics and complex stability. Lpy complexes Bi³⁺ more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT

  12. Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes.

    PubMed

    Wilson, Justin J; Ferrier, Maryline; Radchenko, Valery; Maassen, Joel R; Engle, Jonathan W; Batista, Enrique R; Martin, Richard L; Nortier, Francois M; Fassbender, Michael E; John, Kevin D; Birnbaum, Eva R

    2015-05-01

    The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope (213)Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi(3+), however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L(py)), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L(pyd)), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L(pyr)), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L(pz)), were prepared by a previously reported method and investigated here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)- cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, (207)Bi (t(1/2)=32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi(3+) and the generator parent ion Ac(3+). In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi(3+) in the presence of the parent isotope Ac(3+). Among the four tested, L(py) was found to exhibit optimal Bi(3+)-binding kinetics and complex stability. L(py) complexes Bi(3+) more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations

  13. Triphenylphosphonium-desferrioxamine as a candidate mitochondrial iron chelator.

    PubMed

    Alta, Roxana Y P; Vitorino, Hector A; Goswami, Dibakar; Terêsa Machini, M; Espósito, Breno P

    2017-08-02

    Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP-DFO as a mitochondrial iron chelator. TPP-DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO. TPP-DFO was less toxic than TPP alone to A2780 cells (IC50 = 135.60 ± 1.08 and 4.34 ± 1.06 μmol L(-1), respectively) and its native fluorescence was used to assess its mitochondrial localization (Rr = +0.56). These results suggest that TPP-DFO could be an interesting alternative for the treatment of mitochondrial iron overload e.g. in Friedreich's ataxia.

  14. High Performance Anion Chromatography of Gadolinium Chelates.

    PubMed

    Hajós, Peter; Lukács, Diana; Farsang, Evelin; Horváth, Krisztian

    2016-11-01

    High performance anion chromatography (HPIC) method to separate ionic Gd chelates, [Formula: see text], [Formula: see text], [Formula: see text] and free matrix anions was developed. At alkaline pHs, polydentate complexing agents such as ethylene-diamine-tetraacetate, diethylene-triamine pentaacetate and trans-1,2-diamine-cyclohexane-tetraacetate tend to form stable Gd chelate anions and can be separated by anion exchange. Separations were studied in the simple isocratic chromatographic run over the wide range of pH and concentration of carbonate eluent using suppressed conductivity detection. The ion exchange and complex forming equilibria were quantitatively described and demonstrated in order to understand major factors in the control of selectivity of Gd chelates. Parameters of optimized resolution between concurrent ions were presented on a 3D resolution surface. The applicability of the developed method is represented by the simultaneous analysis of Gd chelates and organic/inorganic anions. Inductively coupled plasma atomic emission spectroscopy  (ICP-AES) analysis was used for confirmation of HPIC results for Gd. Collection protocols for the heart-cutting procedure of chromatograms were applied. SPE procedures were also developed not only to extract traces of free gadolinium ions from samples, but also to remove the high level of interfering anions of the complex matrices. The limit of detection, the recoverability and the linearity of the method were also presented. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Thermal Stability of Chelated Indium Activable Tracers

    SciTech Connect

    Chrysikopoulos, Costas; Kruger, Paul

    1986-01-21

    The thermal stability of indium tracer chelated with organic ligands ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA) was measured for reservoir temperatures of 150, 200, and 240 C. Measurements of the soluble indium concentration was made as a function of time by neutron activation analysis. From the data, approximate thermal decomposition rates were estimated. At 150 C, both chelated tracers were stable over the experimental period of 20 days. At 200 C, the InEDTA concentration remained constant for 16 days, after which the thermal decomposition occurred at a measured rate constant of k = 0.09 d{sup -1}. The thermal decomposition of InNTA at 200 C showed a first order reaction with a measured rate constant of k = 0.16 d{sup -1}. At 240 C, both indium chelated tracers showed rapid decomposition with rate constants greater than 1.8 d{sup -1}. The data indicate that for geothermal reservoir with temperatures up to about 200 C, indium chelated tracers can be used effectively for transit times of at least 20 days. These experiments were run without reservoir rock media, and do not account for concomitant loss of indium tracer by adsorption processes.

  16. Iron-chelating compound from Mycobacterium avium.

    PubMed Central

    McCullough, W G; Merkal, R S

    1976-01-01

    A iron-chelating monohydroxamate was isolated from cultures of Mycobacterium avium grown on an iron-limiting medium. The hydroxyamate metabolite was characterized by chemical degradation and spectral measurements as L-alpha-asparaginyl-L-alpha-(N-hydroxy)-asparagine. PMID:185194

  17. Matching chelators to radiometals for radiopharmaceuticals.

    PubMed

    Price, Eric W; Orvig, Chris

    2014-01-07

    Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g.(67)Ga, (99m)Tc, (111)In, (177)Lu) and positron emission tomography (PET, e.g.(68)Ga, (64)Cu, (44)Sc, (86)Y, (89)Zr), as well as therapeutic applications (e.g.(47)Sc, (114m)In, (177)Lu, (90)Y, (212/213)Bi, (212)Pb, (225)Ac, (186/188)Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.

  18. Shortened forms of provocative lead chelation

    SciTech Connect

    Sokas, R.K.; Atleson, J.; Keogh, J.P.

    1988-05-01

    Shortened urinary lead collections following provocative chelation have been standardized for pediatric patients, but have not been considered adequate for adults. This study compared shortened urine collections for lead excretion post chelation with standard 24-hour collections. Thirty-five patients without known current lead exposure and with serum creatinine measurements less than 2 mg/dL were hospitalized and had provocative chelation performed as follows: One gram of CaNa2-ethylenediaminetetraacetic acid (EDTA) was administered in 250 mL of a 5% dextrose in water solution intravenously over one hour; the same dose was repeated 12 hours later. A 24-hour urine collection for lead excretion was begun at the time of initiation of the first dose. At three hours and six hours from start of first dose, each patient was instructed to void, total volume to that point was recorded, and a 10-mL aliquot was withdrawn for lead measurement. Both three-hour and six-hour urinary lead excretion following a single dose of EDTA correlated linearly with 24-hour lead excretion post chelation (r = .89 and .94, respectively). When a 24-hour level of 600 micrograms was defined as true positive the three-hour collection had a sensitivity of 76% and specificity of 95% and six-hour urinary lead excretion had 82% sensitivity and 100% specificity. Mild renal insufficiency (reflected by serum creatinine levels between 1.5 and 2.1 mg/dL) did not significantly alter the correlation between three-, six-, and 24-hour urinary post-chelation lead excretion.

  19. Chelation therapy after the trial to assess chelation therapy: results of a unique trial.

    PubMed

    Avila, Maria D; Escolar, Esteban; Lamas, Gervasio A

    2014-09-01

    EDTA chelation therapy has been in off-label use for the treatment of atherosclerosis. We review the results of the first large-scale randomized trial of this treatment. The trial to assess chelation therapy was a $30 million National Institutes of Health-funded study of the safety and efficacy of EDTA-based chelation infusions in 1708 post-myocardial infarction (MI) patients. The trial to assess chelation therapy demonstrated a significant (P=0.035) 18% reduction in a combined primary endpoint of death, MI, stroke, coronary revascularization, or hospitalization for angina. In diabetic patients the benefit was more extreme, with a 41% relative reduction in risk (P=0.0002) and a 43% reduction in total mortality (P=0.011). Safety data were favorable. A reduction of oxidative stress by chelation of toxic metals has been proposed as a possible mechanism of action. Recent research suggests that EDTA chelation may be a well-tolerated and effective treatment for post-MI patients. Future replication and mechanistic studies are important prior to implementation in all post-MI patients.

  20. Chelation therapy after the Trial to Assess Chelation Therapy: results of a unique trial

    PubMed Central

    Avila, Maria D.; Escolar, Esteban; Lamas, Gervasio A.

    2014-01-01

    Purpose of review EDTA chelation therapy has been in off-label use for the treatment of atherosclerosis. We review the results of the first large-scale randomized trial of this treatment. Recent findings The trial to assess chelation therapy was a $30 million National Institutes of Health-funded study of the safety and efficacy of EDTA-based chelation infusions in 1708 post-myocardial infarction (MI) patients. The trial to assess chelation therapy demonstrated a significant (P = 0.035) 18% reduction in a combined primary endpoint of death, MI, stroke, coronary revascularization, or hospitalization for angina. In diabetic patients the benefit was more extreme, with a 41% relative reduction in risk (P = 0.0002) and a 43% reduction in total mortality (P = 0.011). Safety data were favorable. A reduction of oxidative stress by chelation of toxic metals has been proposed as a possible mechanism of action. Summary Recent research suggests that EDTA chelation may be a well-tolerated and effective treatment for post-MI patients. Future replication and mechanistic studies are important prior to implementation in all post-MI patients. PMID:25023079

  1. Chelator-induced phytoextraction of zinc and copper by rice seedlings.

    PubMed

    Yu, Xiao-Zhang; Wang, Dun-Qiu; Zhang, Xue-Hong

    2014-05-01

    Solution culture was carried to investigate capacity of synthetic aminopolycarboxylic acids (ethylenediamine tetraacetate, N-hydroxyethylenediaminetriacetic acid, and diethylenetriamine-pentaacetate) for enhancing botanical removal and transport of heavy metals (Cu and Zn) by plants. Biodegradable organic acids (citric acid, malic acid, and oxalic acid) were also selected as alternatives to compare them with synthesized chelating agents for effectiveness. Young rice seedlings (Oryza sativa L. cv. XZX 45) were grown in nutrient solutions treated with single or combined metal solutions in presence or absence of chelating compounds. Calculation by chemical equilibrium program VISUAL MINTEQ showed that different chelating compounds had various complex potential with Cu(2+) and Zn(2+) ions, in which synthetic chelators exhibited higher complexed capability than biodegradable organic acids. All applied synthetic aminopolycarboxylic acids significantly decreased removal of metal from nutrient solution (p < 0.01), while more or less effects of organic acids supplied on biosorptive potential were observed with all treatments (p > 0.05), compared with the treatment without metal ligands. Synthetic aminopolycarboxylic acids significantly decreased metal concentrations in plant materials in all treatments (p < 0.01). However, biodegradable organic acids decreased metal concentrations in roots (p < 0.01), but enhanced them in shoots (p < 0.01). Results obtained indicated that synthetic aminopolycarboxylic acids decreased uptake of metals by rice seedlings, but translocation of metals complexed within plant materials was evident. Although exogenous biodegradable organic acids showed negligible effect on botanical removal of metals, metals complexed with organic acids was more mobile than those complexed with other chelating agents. These information collected here had important implication for the use of biodegradable metal chelators in transport of essential micronutrients in

  2. Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications

    SciTech Connect

    Nagai, Rhoji; Murray, David B.; Metz, Thomas O.; Baynes, John

    2012-03-01

    Advanced glycation or glycoxidation end-products (AGE) increase in tissue proteins with age, and their rate of accumulation is increased in diabetes, nephropathy and inflammatory diseases. AGE inhibitors include a range of compounds that are proposed to act by trapping carbonyl and dicarbonyl intermediates in AGE formation. However, some among the newer generation of AGE inhibitors lack reactive functional groups that would trap reaction intermediates, indicating an alternative mechanism of action. We propose that AGE inhibitors function primarily as chelators, inhibiting metal-catalyzed oxidation reactions. The AGE-inhibitory activity of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also consistent with their chelating activity. Finally, compounds described as AGE breakers, or their hydrolysis products, also have strong chelating activity, suggesting that these compounds also act through their chelating activity. We conclude that chelation is the common, and perhaps the primary, mechanism of action of AGE inhibitors and breakers, and that chronic, mild chelation therapy should prove useful in treatment of diabetes and age-related diseases characterized by oxidative stress, inflammation and increased chemical modification of tissue proteins by advanced glycoxidation and lipoxidation end-products.

  3. Relationship among Chelator Adherence, Change in Chelators, and Quality of Life in Thalassemia

    PubMed Central

    Trachtenberg, Felicia L.; Gerstenberger, Eric; Xu, Yan; Mednick, Lauren; Sobota, Amy; Ware, Hannah; Thompson, Alexis A.; Neufeld, Ellis J.; Yamashita, Robert

    2015-01-01

    Purpose Thalassemia, a chronic blood disease, necessitates life-long adherence to blood transfusions and chelation therapy to reduce iron overload. We examine stability of Health-Related Quality of Life (HRQOL) in thalassemia and adherence to chelation therapy over time, especially after changes in chelator choice. Methods Thalassemia Longitudinal Cohort participants in the US, UK, and Canada completed the SF-36v2 (ages 14+), and the PF-28 CHQ (parents of children<14 years). Chelation adherence was defined as self-reported percent of doses administered in the last 4 weeks. Results 258 adults/adolescents (mean 29.7 years) and 133 children (mean 8.5 years) completed a mean of 2.8 years follow-up. Children made few chelator changes, whereas a mean of 2.2 changes was observed among the 37% of adults/adolescents who made chelator changes, mainly, due to patient preference or medical necessity. Physical HRQOL improved among those with lower iron burden (better health status) at baseline who made a single change in chelator, but declined among participants with multiple changes and/or high iron burden (worse health status). Mental health improved among participants with lower iron burden, but iron overload was negatively associated with social functioning. Adherence did not significantly change over follow-up except for an increase after a change from DFO infusion to oral deferasirox (p=0.03). Predictors of lower adherence for adults/adolescents at follow-up included side effects, smoking, younger age, problems preparing DFO, increased number of days per week DFO prescribed, and lower physical QOL. Conclusions Strategies to balance medical needs with family, work, and personal life may assist in adherence. PMID:24682717

  4. Positron Emission Tomographic Imaging of Copper 64– and Gallium 68–Labeled Chelator Conjugates of the Somatostatin Agonist Tyr3-Octreotate

    PubMed Central

    Nedrow, Jessie R.; White, Alexander G.; Modi, Jalpa; Nguyen, Kim; Chang, Albert J.; Anderson, Carolyn J.

    2014-01-01

    The bifunctional chelator and radiometal have been shown to have a direct effect on the pharmacokinetics of somatostatin receptor (SSTR)-targeted imaging agents. We evaluated three Y3-TATE analogues conjugated to NOTA-based chelators for radiolabeling with 64Cu and 68Ga for small-animal positron emission tomographic/computed tomographic (PET/CT) imaging. Two commercially available NOTA analogues, p-SCN-Bn-NOTA and NODAGA, were evaluated. The p-SCN-Bn-NOTA analogues were conjugated to Y3-TATE through β-Ala and PEG8 linkages. The NODAGA chelator was directly conjugated to Y3-TATE. The analogues labeled with 64Cu or 68Ga were analyzed in vitro for binding affinity and internalization and in vivo by PET/CT imaging, biodistribution, and Cerenkov imaging (68Ga analogues). We evaluated the effects of the radiometals, chelators, and linkers on the performance of the SSTR subtype 2-–targeted imaging agents and also compared them to a previously reported agent, 64Cu-CB-TE2A-Y3-TATE. We found that the method of conjugation, particularly the length of the linkage between the chelator and the peptide, significantly impacted tumor and nontarget tissue uptake and clearance. Among the 64Cu- and 68Ga-labeled NOTA analogues, NODAGA-Y3-TATE had the most optimal in vivo behavior and was comparable to 64Cu-CB-TE2A-Y3-TATE. An advantage of NODAGA-Y3-TATE is that it allows labeling with 64Cu and 68Ga, providing a versatile PET probe for imaging SSTr subtype 2–positive tumors. PMID:25060207

  5. Pretargeting of human mammary carcinoma xenografts with bispecific anti-MUC1/anti-Ga chelate antibodies and immunoscintigraphy with PET.

    PubMed

    Schuhmacher, J; Klivényi, G; Kaul, S; Henze, M; Matys, R; Hauser, H; Clorius, J

    2001-10-01

    We recently demonstrated the feasibility of combining enhanced tumor-to-tissue contrast and PET imaging for immunoscintigraphic tumor localization in pancreas and colon carcinoma bearing nude mice. Contrast enhancement was obtained with a multistep targeting technique that consists of the sequential administration of an antitumor/antihapten bispecific antibody (BS-MAb), a blocker to saturate the antihapten binding sites of the BS-MAb that remains in circulation, and a low molecular weight Ga chelate, labeled with the positron emitter 68Ga, which serves as the hapten. To evaluate the efficacy of this pretargeting technique for breast cancer localization, we synthesized a BS-MAb from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12 which reacts with the vast majority of human breast carcinomas, and the F(ab') fragment of an anti-Ga chelate MAb using a bifunctional chemical linker. The BS-MAb was tested for its affinity and its biokinetics in nude mice bearing a human mammary carcinoma. Equilibrium binding of the BS-MAb for mammary carcinoma cells was low (1.2 x 10(7) M(-1)) while the binding capacity of cells was high (8.4 x 10(6) BS-MAbs per cell). Tumor uptake of the 67Ga labeled chelate in pretargeted animals was to 5.8 +/- 0.8% iD/g resulting in a tumor-to-blood ratio of 2.6 at 1h postinjection. This compares with a ratio of 0.65 and 0.85 obtained with 125I-labeled native 12H12 at 24h and 48h postinjection. No difference in the tumor uptake of both the 68Ga and 67Ga labeled chelate was observed. PET imaging of mice, started 1h postinjection of the 68Ga chelate, clearly visualized all tumors.

  6. Safety evaluation of zinc threoninate chelate.

    PubMed

    Hu, Xiao-bo; Gong, Yi; Li, Lei; Nie, Shao-ping; Wang, Yuan-xing; Xie, Ming-yong

    2010-07-01

    The acute toxicity of zinc threoninate chelate was assessed. The oral lethal dose 50% (LD(50)) was 2710 mg/kg in female rats and 3160 mg/kg in male rats. Genotoxicity was assessed by Ames test in Salmonella typhimurium strains TA97, TA98, TA100, and TA102, by bone marrow mouse micronucleus test and a sperm abnormality test with mice. Thirty-day repeat dose toxicity study was conducted at oral daily doses of 0, 42, 169, and 675 mg/kg in rats. Teratogenicity was assessed at the same daily dose in pregnant rats by gavage. No significant changes in body weight, food consumption, organ weight, relative organ weight, hematology, blood biochemistry, histopathology, behavior, mortality, sperm abnormality, mutagenicity, and micronucleus formation were observed and no clinical signs or adverse effects were detected. Zinc threoninate chelate had no significant teratogenic effect at a daily dose of 42 mg/kg.

  7. Obligatory Reduction of Ferric Chelates in Iron Uptake by Soybeans

    PubMed Central

    Chaney, Rufus L.; Brown, John C.; Tiffin, Lee O.

    1972-01-01

    The contrasting Fe2+ and Fe3+ chelating properties of the synthetic chelators ethylenediaminedi (o-hydroxyphenylacetate) (EDDHA) and 4,7-di(4-phenylsulfonate)-1, 10-phenanthroline (bathophenanthrolinedisulfonate) (BPDS) were used to determine the valence form of Fe absorbed by soybean roots supplied with Fe3+-chelates. EDDHA binds Fe3+ strongly, but Fe2+ weakly; BPDS binds Fe2+ strongly but Fe3+ weakly. Addition of an excess of BPDS to nutrient solutions containing Fe3+-chelates inhibited soybean Fe uptake-translocation by 99+%; [Fe(II) (BPDS)3]4− accumulated in the nutrient solution. The addition of EDDHA caused little or no inhibition. These results were observed with topped and intact soybeans. Thus, separation and absorption of Fe from Fe3+-chelates appear to require reduction of Fe3+-chelate to Fe2+-chelate at the root, with Fe2+ being the principal form of Fe absorbed by soybean. PMID:16658143

  8. Biomolecule conjugation strategy using novel water-soluble phosphine-based chelating agents

    DOEpatents

    Katti, Kattesh V.; Gali, Hariprasad; Volkert, Wynn A.

    2004-08-24

    This invention describes a novel strategy to produce phosphine-functionalized biomolecules (e.g. peptides or proteins) for potential use in the design and development of site-specific radiopharmaceuticals for diagnosis or therapy of specific cancers. Hydrophilic alkyl phosphines, in general, tend to be oxidatively unstable. Therefore, incorporation of such phosphine functionalities on peptide (and other biomolecule) backbones, without oxidizing the P.sup.III centers, is difficult. In this context this discovery reports on a new technology by which phosphines, in the form of bifunctional chelating agents, can be directly incorporated on biomolecular backbones using manual synthetic or solid phase peptide synthesis methodologies. The superior ligating abilities of phosphine ligands, with various diagnostically (e.g. TC-99m) or therapeutically (e.g. Re186/188, Rh-105, Au-199) useful radiometals, coupled with the findings that the resulting complexes demonstrate high in vivo stability makes this approach useful in the development of radiolabeled biomolecules for applications in the design of tumor-specific radiopharmaceuticals.

  9. Three-dimensional metal-organic framework derived porous CoP3 concave polyhedrons as superior bifunctional electrocatalysts for the evolution of hydrogen and oxygen.

    PubMed

    Wu, Tianli; Pi, Mingyu; Wang, Xiaodeng; Zhang, Dingke; Chen, Shijian

    2017-01-18

    Developing low-cost and highly-efficient non-precious metal bifunctional electrocatalysts towards the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is an attractively alternative strategy to solve the environmental pollution problems and energy demands. In this study, metal-organic framework (MOF) derived porous cobalt poly-phosphide (CoP3) concave polyhedrons are prepared and explored as superior bifunctional electrocatalysts for the HER and OER. The prepared MOF derived CoP3 concave polyhedrons show excellent electrocatalytic activity and stability towards the HER and OER in both acidic and alkaline media, with the Tafel slopes of 53 mV dec(-1) and 76 mV dec(-1) and a current density of 10 mA cm(-2) at the overpotentials of -78 and 343 mV for the HER and OER, respectively, which are remarkably superior to those of the transition metal phosphides (TMPs) and comparable to those of the commercial precious metal catalysts. In addition, they also offer efficient catalytic activities and durabilities under neutral and basic conditions for the HER. The results of our study may shed light on the direction towards highly efficient bifunctional TMP electrocatalysts with high phosphorous component.

  10. Chelation-assisted palladium-catalyzed direct cyanation of 2-arylpyridine C-H bonds.

    PubMed

    Jia, Xiaofei; Yang, Dongpeng; Zhang, Shouhui; Cheng, Jiang

    2009-10-15

    A chelation-assisted palladium-catalyzed ortho-cyanation of the sp2 C-H bond by CuCN provided aromatic nitriles in moderate to good yields. Notably, the reaction could be conducted on a 10 mmol scale. The key intermediate of the natural product of Menispermum dauricum DC was concisely synthesized by the procedure. This new approach represents an exceedingly practical method for the synthesis of aromatic nitriles and offers an attractive alternative to the traditional Sandmeyer reaction.

  11. Organosilylated complex [Eu(TTA)3(Bpy-Si)]: a bifunctional moiety for the engeneering of luminescent silica-based nanoparticles for bioimaging.

    PubMed

    Duarte, Adriana P; Mauline, Léïla; Gressier, Marie; Dexpert-Ghys, Jeannette; Roques, Christine; Caiut, José Maurício A; Deffune, Elenice; Maia, Danielle C G; Carlos, Iracilda Z; Ferreira, Antonio A P; Ribeiro, Sidney J L; Menu, Marie-Joëlle

    2013-05-14

    A new highly luminescent europium complex with the formula [Eu(TTA)3(Bpy-Si)], where TTA stands for the thenoyltrifluoroacetone, (C4H3S)COCH2COCF3, chelating ligand and Bpy-Si, Bpy-CH2NH(CH2)3Si(OEt)3, is an organosilyldipyridine ligand displaying a triethoxysilyl group as a grafting function has been synthesized and fully characterized. This bifunctional complex has been grafted onto the surface of dense silica nanoparticles (NPs) and on mesoporous silica microparticles as well. The covalent bonding of [Eu(TTA)3(Bpy-Si)] inside uniform Stöber silica nanoparticles was also achieved. The general methodology proposed could be applied to any silica matrix, allowed high grafting ratios that overcome chelate release and the tendency to agglomerate. Luminescent silica-based nanoparticles SiO2-[Eu(TTA)3(Bpy-Si)], with a diameter of 28 ± 2 nm, were successfully tested as a luminescent labels for the imaging of Pseudomonas aeruginosa biofilms. They were also functionalized by a specific monoclonal antibody and subsequently employed for the selective imaging of Escherichia coli bacteria.

  12. Extraction of uranium by macroporous bifunctional phosphinic acid resin

    SciTech Connect

    Sabharwal, K.N.; Rao, P.R.V.; Srinivasan, M.

    1995-05-01

    The extraction of U(VI), Th(IV) and a number of fission products from nitric acid medium by a newly synthesised macroporous bifunctional phosphinic acid resin has been studied. The extraction of uranium from sulphuric acid medium has also been studied. While the gel type phosphinic acid resins seems to pose a number of problems in practical applications, the macroporous type resins are shown to be suitable for a variety of applications where conventional ion exchange resins are of limited use. 12 refs., 5 figs., 3 tabs.

  13. Enantioselective Iodolactonization of Disubstituted Olefinic Acids Using a Bifunctional Catalyst

    PubMed Central

    Fang, Chao; Paull, Daniel H.; Hethcox, J. Caleb; Shugrue, Christopher R.; Martin, Stephen F.

    2012-01-01

    The enantioselective iodolactonizations of a series of diversely-substituted olefinic carboxylic acids are promoted by a BINOL-derived, bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the corresponding γ- and δ-lactones having stereogenic C–I bonds in excellent yields and >97:3 er. Significantly, this represents the first organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic resolutions of racemic unsaturated acids is also demonstrated. PMID:23199100

  14. Charge transfer to a semi-esterified bifunctional phenol

    NASA Astrophysics Data System (ADS)

    Brede, O.; Hermann, R.; Orthner, H.

    1996-03-01

    The charge transfer from solvent radical cations of n-butyl chloride and cyclohexane to 2-butyl-6(3'-t-butyl-2'-hydroxy-5'-methylbenzyl)-4-methyl-phenylacrylate (GM) yields in the first step phenoxyl radicals as well as acrylate radical cations of this semi-acrylated bifunctional phenol. Subsequently an intramolecular charge transfer from the acrylate radical cation to the phenol group takes place. Because of the instability of phenol radical cations, under our experimental conditions (nanosecond pulse radiolysis, non-polar solvents, room temperature) phenoxyl radicals are the only observable products of phenol ionization.

  15. Bifunctional activation of a direct methanol fuel cell

    NASA Astrophysics Data System (ADS)

    Kulikovsky, A. A.; Schmitz, H.; Wippermann, K.; Mergel, J.; Fricke, B.; Sanders, T.; Sauer, D. U.

    We report a novel method for performance recovery of direct methanol fuel cells. Lowering of air flow rate below a critical value turns the cell into bifunctional regime, when the oxygen-rich part of the cell generates current while the rest part works in electrolysis mode (electrolytic domain). Upon restoring the normal (super-critical) air flow rate, the galvanic performance of the electrolytic domain increases. This recovery effect is presumably attributed to Pt surface cleaning on the cathode with the simultaneous increase in catalyst utilization on the anode.

  16. Iron chelation therapy in thalassemia syndromes.

    PubMed

    Cianciulli, Paolo

    2009-12-29

    Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients.

  17. Iron Chelation Therapy in Thalassemia Syndromes

    PubMed Central

    Cianciulli, Paolo

    2009-01-01

    Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients. PMID:21415999

  18. Chromatographic methods for the separation of biocompatible iron chelators from their synthetic precursors and iron chelates.

    PubMed

    Kovaríková, Petra; Mokrý, Milan; Klime, Jirí; Vávrová, Katerina

    2004-12-01

    Chromatographic methods have been developed for the separation of the three novel biocompatible iron chelators pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and pyridoxal 2-chlorobenzoyl hydrazone (o-108) from their synthetic precursors and iron chelates. The chromatographic analyses were achieved using analytical columns packed with 5 microm Nucleosil 120-5 C18. For the evaluation of all chelators in the presence of the synthetic precursors, EDTA was added to the mobile phase at a concentration of 2 mM. The best separation of PIH and its synthetic precursors was achieved using a mixture of phosphate buffer (0.01 M NaH2PO4, 5 mM 1-heptanesulfonic acid sodium salt; pH 3.0) and methanol (55:45, v/v). For separation of SIH and its synthetic precursors, the mobile phase was composed of 0.01 M phosphate buffer (pH 6.0) and methanol (60:40, v/v). o-108 was analyzed employing a mixture of 0.01 M phosphate buffer (pH 7.0), methanol, and acetonitrile (60:20:20, v/v/v). These mobile phases were slightly modified to separate each chelator from its iron chelate. Furthermore, a RP-TLC method has also been developed for fast separation of all compounds. The chromatographic methods described herein could be applied in the evaluation of purity and stability of these drug candidates.

  19. Cu-free 1,3-dipolar cycloaddition click reactions to form isoxazole linkers in chelating ligands for fac-[M(I)(CO)3]+ centers (M = Re, 99mTc).

    PubMed

    Bottorff, Shalina C; Kasten, Benjamin B; Stojakovic, Jelena; Moore, Adam L; MacGillivray, Leonard R; Benny, Paul D

    2014-02-17

    Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to Cu(I)-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (click, then chelate and chelate, then click) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective fac-[M(I)(CO)3](+) complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. (99m)Tc experiments demonstrate efficient radiolabeling with click, then chelate; however, the chelate, then click approach led to faster product formation, but lower yields compared to the Re analogues.

  20. Biodegradable chelating agents for industrial, domestic, and agricultural applications--a review.

    PubMed

    Pinto, Isabel S S; Neto, Isabel F F; Soares, Helena M V M

    2014-10-01

    Aminopolycarboxylates, like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), are chelating agents widely used in several industrial, agricultural, and domestic applications. However, the fact that they are not biodegradable leads to the presence of considerable amounts in aquatic systems, with serious environmental consequences. The replacement of these compounds by biodegradable alternatives has been the object of study in the last three decades. This paper reviews the most relevant studies towards the use of environmentally friendly chelating agents in a large number of applications: oxidative bleaching, detergents and cleaning compositions, scale prevention and reduction, remediation of soils, agriculture, electroplating, waste treatment, and biocides. Nitrilotriacetic acid (NTA), ethylenediaminedisuccinic acid (EDDS), and iminodisuccinic acid (IDS) are the most commonly suggested to replace the nonbiodegradable chelating agents. Depending on the application, the requirements for metal complexation might differ. Metal chelation ability of the most promising compounds [NTA, EDDS, IDS, methylglycinediacetic acid (MGDA), L-glutamic acid N,N-diacetic acid (GLDA), ethylenediamine-N,N'-diglutaric acid (EDDG), ethylenediamine-N,N'-dimalonic acid (EDDM), 3-hydroxy-2,2-iminodisuccinic acid (HIDS), 2-hydroxyethyliminodiacetic acid (HEIDA), pyridine-2,6-dicarboxylic acid (PDA)] with Fe, Mn, Cu, Pb, Cd, Zn, Ca, and Mg was simulated by computer calculations. The advantages or disadvantages of each compound for the most important applications were discussed.

  1. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

    PubMed

    Stěrba, Martin; Popelová, Olga; Vávrová, Anna; Jirkovský, Eduard; Kovaříková, Petra; Geršl, Vladimír; Simůnek, Tomáš

    2013-03-10

    Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

  2. Spectroscopy, modeling and computation of metal chelate solubility in supercritical CO{sub 2}

    SciTech Connect

    J. F. Brennecke; M. A. Stadtherr

    1999-12-10

    The overall objectives of this project were to gain a fundamental understanding of the solubility and phase behavior of metal chelates in supercritical CO{sub 2}. Extraction with CO{sub 2} is an excellent way to remove organic compounds from soils, sludges and aqueous solutions, and recent research has demonstrated that, together with chelating agents, it is a viable way to remove metals, as well. In this project the authors sought to gain fundamental knowledge that is vital to computing phase behavior, and modeling and designing processes using CO{sub 2} to separate organics and metal compounds from DOE mixed wastes. The overall program was a comprehensive one to measure, model and compute the solubility of metal chelate complexes in supercritical CO{sub 2} and CO{sub 2}/cosolvent mixtures. Through a combination of phase behavior measurements, spectroscopy and the development of a new computational technique, the authors have achieved a completely reliable way to model metal chelate solubility in supercritical CO{sub 2} and CO{sub 2}/co-contaminant mixtures. Thus, they can now design and optimize processes to extract metals from solid matrices using supercritical CO{sub 2}, as an alternative to hazardous organic solvents that create their own environmental problems, even while helping in metals decontamination.

  3. A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal 90Y☆

    PubMed Central

    Price, Eric W.; Edwards, Kimberly J.; Carnazza, Kathryn E.; Carlin, Sean D.; Zeglis, Brian M.; Adam, Michael J.; Orvig, Chris; Lewis, Jason S.

    2016-01-01

    Objectives To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal 90Y. Methods The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with 90Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. Results High radiochemical yields (>95%) were obtained with 90Y-CHX-A′-DTPA-trastuzumab and 90Y-octapa-trastuzumab after 15 min at room temperature. Both 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3 ± 4.0%ID/g for 90Y-CHX-A″-DTPA-trastuzumab and 30.1 ± 7.4%ID/g for 90Y-octapa-trastuzumab at 72 h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, 90Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Conclusions Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring 90Y. PMID:27419360

  4. A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal (90)Y.

    PubMed

    Price, Eric W; Edwards, Kimberly J; Carnazza, Kathryn E; Carlin, Sean D; Zeglis, Brian M; Adam, Michael J; Orvig, Chris; Lewis, Jason S

    2016-09-01

    To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal (90)Y. The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with (90)Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. High radiochemical yields (>95%) were obtained with (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab after 15min at room temperature. Both (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for (90)Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for (90)Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, (90)Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring (90)Y. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Photovoltachromic device with a micropatterned bifunctional counter electrode.

    PubMed

    Cannavale, Alessandro; Manca, Michele; De Marco, Luisa; Grisorio, Roberto; Carallo, Sonia; Suranna, Gian Paolo; Gigli, Giuseppe

    2014-02-26

    A photovoltachromic window can potentially act as a smart glass skin which generates electric energy as a common dye-sensitized solar cell and, at the same time, control the incoming energy flux by reacting to even small modifications in the solar radiation intensity. We report here the successful implementation of a novel architecture of a photovoltachromic cell based on an engineered bifunctional counter electrode consisting of two physically separated platinum and tungsten oxide regions, which are arranged to form complementary comb-like patterns. Solar light is partially harvested by a dye-sensitized photoelectrode made on the front glass of the cell which fully overlaps a bifunctional counter electrode made on the back glass. When the cell is illuminated, the photovoltage drives electrons into the electrochromic stripes through the photoelectrochromic circuit and promotes the Li(+) diffusion towards the WO3 film, which thus turns into its colored state: a photocoloration efficiency of 17 cm(2) min(-1) W(-1) at a wavelength of 650 nm under 1.0 sun was reported along with fast response (coloration time <2 s and bleaching time <5 s). A fairly efficient photovoltaic functionality was also retained due to the copresence of the independently switchable micropatterned platinum electrode.

  6. Stability and kinetics of a bifunctional amylase/trypsin inhibitor.

    PubMed

    Alagiri, S; Singh, T P

    1993-11-10

    The stability of the bifunctional amylase/trypsin inhibitor from ragi (Indian finger millet, Eleusine coracana) has been studied by methods of circular dichroism, UV absorption and intrinsic fluorescence. The inhibitor is stable in 8 M urea and 6 M guanidine-HCl. In 150 mM NaCl, thermal denaturation does not occur up to 90 degrees C. However, it is irreversibly denatured in 5 mM NaCl if heated over 73 degrees C. The acidic denaturation is reversible in both high and low salt conditions, but it shows different behavior below pH 1.65 under similar salt conditions. The helical content is about 2-4% in the pH range of 7-9 at which the inhibitor is active maximally. The NaCl concentration does not have a significant effect on the secondary structure elements. The beta-strand form does not show much variation under various conditions. Arg34-Leu35 is the reactive peptide bond in the trypsin-binding site. Trp and Tyr are involved in the binding with amylase. The bifunctional inhibitor represents the sum of individual inhibitors of trypsin and amylase.

  7. Divergent evolution of a bifunctional de novo protein.

    PubMed

    Smith, Betsy A; Mularz, Ann E; Hecht, Michael H

    2015-02-01

    Primordial proteins, the evolutionary ancestors of modern sequences, are presumed to have been minimally active and nonspecific. Following eons of selective pressure, these early progenitors evolved into highly active and specific proteins. While evolutionary trajectories from poorly active and multifunctional generalists toward highly active specialists likely occurred many times in evolutionary history, such pathways are difficult to reconstruct in natural systems, where primordial sequences are lost to time. To test the hypothesis that selection for enhanced activity leads to a loss of promiscuity, we evolved a de novo designed bifunctional protein. The parental protein, denoted Syn-IF, was chosen from a library of binary patterned 4-helix bundles. Syn-IF was shown previously to rescue two different auxotrophic strains of E. coli: ΔilvA and Δfes. These two strains contain deletions for proteins with very different biochemical functions; IlvA is involved in isoleucine biosynthesis, while Fes is involved in iron assimilation. In two separate experiments, Syn-IF, was evolved for faster rescue of either ΔilvA or Δfes. Following multiple rounds of mutagenesis, two new proteins were selected, each capable of rescuing the selected function significantly faster than the parental protein. In each case, the evolved protein also lost the ability to rescue the unselected function. In both evolutionary trajectories, the original bifunctional generalist was evolved into a monofunctional specialist with enhanced activity. © 2014 The Protein Society.

  8. Divergent evolution of a bifunctional de novo protein

    PubMed Central

    Smith, Betsy A; Mularz, Ann E; Hecht, Michael H

    2015-01-01

    Primordial proteins, the evolutionary ancestors of modern sequences, are presumed to have been minimally active and nonspecific. Following eons of selective pressure, these early progenitors evolved into highly active and specific proteins. While evolutionary trajectories from poorly active and multifunctional generalists toward highly active specialists likely occurred many times in evolutionary history, such pathways are difficult to reconstruct in natural systems, where primordial sequences are lost to time. To test the hypothesis that selection for enhanced activity leads to a loss of promiscuity, we evolved a de novo designed bifunctional protein. The parental protein, denoted Syn-IF, was chosen from a library of binary patterned 4-helix bundles. Syn-IF was shown previously to rescue two different auxotrophic strains of E. coli: ΔilvA and Δfes. These two strains contain deletions for proteins with very different biochemical functions; IlvA is involved in isoleucine biosynthesis, while Fes is involved in iron assimilation. In two separate experiments, Syn-IF, was evolved for faster rescue of either ΔilvA or Δfes. Following multiple rounds of mutagenesis, two new proteins were selected, each capable of rescuing the selected function significantly faster than the parental protein. In each case, the evolved protein also lost the ability to rescue the unselected function. In both evolutionary trajectories, the original bifunctional generalist was evolved into a monofunctional specialist with enhanced activity. PMID:25420677

  9. [The biotin-thyroxin conjugate as a bifunctional ligand of binding proteins].

    PubMed

    Novakovskiĭ, M E; Vashkevich, I I; Sviridov, O V

    2009-01-01

    The conjugate of the residue of vitamin H (biotin, Bt) with the hormone of thyroid gland thyroxin (T4) was prepared by N-acylation of N-(3-aminopropyl) biotin amide with N-hydroxysuccinimide ester of N-acetyl thyroxin. The interactions of the Bt-T4 conjugate with one or simultaneously with two binding proteins with affinity to Bt or T4 in solution and on a solid phase were studied by electron spectroscopy, enzyme immunoassay, and computer modeling. Bt-T4 was specifically fixed in the Bt-binding site of the streptavidin molecule via a large number of hydrogen bonds and hydrophobic interactions. The maximum of the streptavidin fluorescence shifted to a long-wave area and its intensity decreased as a result of complex formation. The degree of quenching of the protein emission was significantly higher than that of the streptavidin-Bt complex. Additional fluorescence quenching resulted from interactions which were sensitive to pH, ionic strength, and detergents and stabilized the position of the thyroxin part of the conjugate near Trp120 of streptavidin in its complex with Bt-T4. The Bt-T4 conjugate also formed a specific equimolar complex with T4-binding human globulin (TBG) by the same mechanism as that for T4. The Bt residue did not participate in the interactions which changed characteristics of the TBG fluorophores. The Bt-T4 conjugate was bound to avidin on a solid phase in the solid phase enzyme immunoassay owing to its biotin function, whereas its thyroxin part was exposed to a solution and interacted with polyclonal antibodies to T4. The intact T4 competitively inhibited this interaction after its addition to the system. Bt-T4 also exhibited its bifunctional activity in other immune analytic system. The conjugate bound streptavidin was labeled with Eu(3+)-chelate and subsequently formed a three component complex with participation of a monoclonal antibody to T4 immobilized on a solid phase. Free T4 inhibited the thyroxin function of the conjugate bound to the

  10. Chelators whose affinity for calcium is decreased by illumination

    NASA Technical Reports Server (NTRS)

    Tsien, Roger Y. (Inventor); Grynkiewicz, Grzegorz (Inventor); Minta, Akwasi (Inventor)

    1987-01-01

    The present invention discloses a group of calcium chelating compounds which have a descreased affinity for calcium following illumination. These new compounds contain a photolabile nitrobenzyl derivative coupled to a tetracarboxylate Ca.sup.2+ chelating parent compound having the octacoordinate chelating groups characteristic of EGTA or BAPTA. In a first form, the new compounds are comprised of a BAPTA-like chelator coupled to a single 2-nitrobenzyl derivative, which in turn is a photochemical precursor of a 2-nitrosobenzophenone. In a second form, the new compounds are comprised of a BAPTA-like chelator coupled to two 2-nitrobenzyl derivatives, themselves photochemical prcursors of the related 2-nitrosobenzophenones. The present invention also discloses a novel method for preparing 1-hydroxy- or 1-alkoxy-1-(2-nitroaryl)-1-aryl methanes. Methanes of this type are critical to the preparation of, or actually constitute, the photolabile Ca.sup.2+ chelating compounds disclosed and claimed herein.

  11. Metal regeneration of iron chelates in nitric oxide scrubbing

    DOEpatents

    Chang, Shih-Ger; Littlejohn, David; Shi, Yao

    1997-08-19

    The present invention relates to a process of using metal particles to reduce NO to NH.sub.3. More specifically, the invention concerns an improved process to regenerate iron (II) (CHELATE) by reduction of iron (II) (CHELATE) (NO) complex, which process comprises: a) contacting an aqueous solution containing iron (II) (CHELATE) (NO) with metal particles at between about 20.degree. and 90.degree. C. to reduce NO present, produce ammonia or an ammonium ion, and produce free iron (II) (CHELATE) at a pH of between about 3 and 8. The process is useful to remove NO from flue gas and reduce pollution.

  12. Metal regeneration of iron chelates in nitric oxide scrubbing

    DOEpatents

    Chang, S.G.; Littlejohn, D.; Shi, Y.

    1997-08-19

    The present invention relates to a process of using metal particles to reduce NO to NH{sub 3}. More specifically, the invention concerns an improved process to regenerate iron (II) (CHELATE) by reduction of iron (II) (CHELATE) (NO) complex, which process comprises: (a) contacting an aqueous solution containing iron (II) (CHELATE) (NO) with metal particles at between about 20 and 90 C to reduce NO present, produce ammonia or an ammonium ion, and produce free iron (II) (CHELATE) at a pH of between about 3 and 8. The process is useful to remove NO from flue gas and reduce pollution. 34 figs.

  13. Chelators as antidotes of metal toxicity: therapeutic and experimental aspects.

    PubMed

    Blanusa, Maja; Varnai, Veda M; Piasek, Martina; Kostial, Krista

    2005-01-01

    The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.

  14. Myelodysplastic Syndromes and Iron Chelation Therapy

    PubMed Central

    Angelucci, Emanuele; Urru, Silvana Anna Maria; Pilo, Federica; Piperno, Alberto

    2017-01-01

    Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS) has resulted in a fragmented and uncoordinated clinical evidence base. We’re therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias) are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of ‘toxic’ damage inflicted through multiple cellular pathways. Damage from iron may, therefore, occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the scientific and clinical evidence for iron overload in MDS to better characterize the iron overload phenotype in these patients, which differs from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area. PMID:28293409

  15. A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation

    PubMed Central

    Shen, Yang; Zeng, Lin; Novosyadlyy, Ruslan; Forest, Amelie; Zhu, Aiping; Korytko, Andrew; Zhang, Haifan; Eastman, Scott W; Topper, Michael; Hindi, Sagit; Covino, Nicole; Persaud, Kris; Kang, Yun; Burtrum, Douglas; Surguladze, David; Prewett, Marie; Chintharlapalli, Sudhakar; Wroblewski, Victor J; Shen, Juqun; Balderes, Paul; Zhu, Zhenping; Snavely, Marshall; Ludwig, Dale L

    2015-01-01

    Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor – type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique “capture-for-degradation” mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions. PMID:26073904

  16. A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation.

    PubMed

    Shen, Yang; Zeng, Lin; Novosyadlyy, Ruslan; Forest, Amelie; Zhu, Aiping; Korytko, Andrew; Zhang, Haifan; Eastman, Scott W; Topper, Michael; Hindi, Sagit; Covino, Nicole; Persaud, Kris; Kang, Yun; Burtrum, Douglas; Surguladze, David; Prewett, Marie; Chintharlapalli, Sudhakar; Wroblewski, Victor J; Shen, Juqun; Balderes, Paul; Zhu, Zhenping; Snavely, Marshall; Ludwig, Dale L

    2015-01-01

    Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor - type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique "capture-for-degradation" mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions.

  17. BIFUNCTIONAL ALUMINUN: A PERMEABLE BARRIER MATERIAL FOR THE DEGRADATION OF MTBE

    EPA Science Inventory

    Bifunctional aluminum is an innovative remedial material for the treatment of gasoline oxygenates in permeable reactive barriers (PRBs). PRBs represent a promising environmental technology for remediation of groundwater contamination. Although zero-valent metals (ZVM) have been...

  18. BIFUNCTIONAL ALUMINUN: A PERMEABLE BARRIER MATERIAL FOR THE DEGRADATION OF MTBE

    EPA Science Inventory

    Bifunctional aluminum is an innovative remedial material for the treatment of gasoline oxygenates in permeable reactive barriers (PRBs). PRBs represent a promising environmental technology for remediation of groundwater contamination. Although zero-valent metals (ZVM) have been...

  19. Efficacy of a novel chelator BPCBG for removing uranium and protecting against uranium-induced renal cell damage in rats and HK-2 cells.

    PubMed

    Bao, Yizhong; Wang, Dan; Li, Zhiming; Hu, Yuxing; Xu, Aihong; Wang, Quanrui; Shao, Chunlin; Chen, Honghong

    2013-05-15

    Chelation therapy is a known effective method to increase the excretion of U(VI) from the body. Until now, no any uranium chelator has been approved for emergency medical use worldwide. The present study aimed to evaluate the efficacy of new ligand BPCBG containing two catechol groups and two aminocarboxylic acid groups in decorporation of U(VI) and protection against acute U(VI) nephrotoxicity in rats, and further explored the detoxification mechanism of BPCBG for U(VI)-induced nephrotoxicity in HK-2 cells with comparison to DTPA-CaNa₃. Chelating agents were administered at various times before or after injections of U(VI) in rats. The U(VI) levels in urine, kidneys and femurs were measured 24 h after U(VI) injections. Histopathological changes in the kidney and serum urea and creatinine and urine protein were examined. After treatment of U(VI)-exposed HK-2 cells with chelating agent, the intracellular U(VI) contents, formation of micronuclei, lactate dehydrogenase (LDH) activity and production of reactive oxygen species (ROS) were assessed. It was found that prompt, advanced or delayed injections of BPCBG effectively increased 24 h-urinary U(VI) excretion and decreased the levels of U(VI) in kidney and bone. Meanwhile, BPCBG injection obviously reduced the severity of the U(VI)-induced histological alterations in the kidney, which was in parallel with the amelioration noted in serum indicators, urea and creatinine, and urine protein of U(VI) nephrotoxicity. In U(VI)-exposed HK-2 cells, immediate and delayed treatment with BPCBG significantly decreased the formation of micronuclei and LDH release by inhibiting the cellular U(VI) intake, promoting the intracellular U(VI) release and inhibiting the production of intracellular ROS. Our data suggest that BPCBG is a novel bi-functional U(VI) decorporation agent with a better efficacy than DTPA-CaNa₃. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Detection and isolation of nucleic acid sequences using a bifunctional hybridization probe

    DOEpatents

    Lucas, Joe N.; Straume, Tore; Bogen, Kenneth T.

    2000-01-01

    A method for detecting and isolating a target sequence in a sample of nucleic acids is provided using a bifunctional hybridization probe capable of hybridizing to the target sequence that includes a detectable marker and a first complexing agent capable of forming a binding pair with a second complexing agent. A kit is also provided for detecting a target sequence in a sample of nucleic acids using a bifunctional hybridization probe according to this method.

  1. Protein micropatterning on bifunctional organic-inorganic sol-gel hybrid materials.

    PubMed

    Kim, Woo-Soo; Kim, Min-Gon; Ahn, Jun-Hyeong; Bae, Byeong-Soo; Park, Chan Beum

    2007-04-24

    Active protein micropatterns and microarrays made by selective localization are popular candidates for medical diagnostics, such as biosensors, bioMEMS, and basic protein studies. In this paper, we present a simple fabrication process of thick (approximately 20 microm) protein micropatterning using capillary force lithography with bifunctional sol-gel hybrid materials. Because bifunctional sol-gel hybrid material can have both an amine function for linking with protein and a methacryl function for photocuring, proteins such as streptavidin can be immobilized directly on thick bifunctional sol-gel hybrid micropatterns. Another advantage of the bifunctional sol-gel hybrid materials is the high selective stability of the amine group on bifunctional sol-gel hybrid patterns. Because amine function is regularly contained in each siloxane oligomers, immobilizing sites for streptavidin are widely distributed on the surface of thick hybrid micropatterns. The micropatterning processes of active proteins using efficient bifunctional sol-gel hybrid materials will be useful for the development of future bioengineered systems because they can save several processing steps and reduce costs.

  2. Chelation Treatment for Autism Spectrum Disorders: A Systematic Review

    ERIC Educational Resources Information Center

    Davis, Tonya N.; O'Reilly, Mark; Kang, Soyeon; Lang, Russell; Rispoli, Mandy; Sigafoos, Jeff; Lancioni, Giulio; Copeland, Daelynn; Attai, Shanna; Mulloy, Austin

    2013-01-01

    Chelation treatment is used to eliminate specific metals from the body, such as mercury. It has been hypothesized that mercury poisoning may be a factor in autism and data suggest that perhaps 7% of individuals with autism spectrum disorder (ASD) have received chelation treatment. It would therefore seem timely to review studies investigating the…

  3. Reusable chelating resins concentrate metal ions from highly dilute solutions

    NASA Technical Reports Server (NTRS)

    Bauman, A. J.; Weetal, H. H.; Weliky, N.

    1966-01-01

    Column chromatographic method uses new metal chelating resins for recovering heavy-metal ions from highly dilute solutions. The absorbed heavy-metal cations may be removed from the chelating resins by acid or base washes. The resins are reusable after the washes are completed.

  4. Chelate-assisted phytoextraction of lead from contaminated soils

    SciTech Connect

    Cooper, E.M.; Sims, J.T.; Cunningham, S.D.; Huang, J.W.; Berti, W.R.

    1999-12-01

    Phytoextraction, a remediation strategy for lead (Pb)-contaminated soils that removes soil Pb through plant uptake and harvest, may be enhanced by use of synthetic chelates. The authors evaluated Pb desorption from four contaminated soils by seven chelates (CDTA, DTPA, EDDHA, EFTA, HEDTA, HEIDA, and NTA) at three rates. The three most effective chelates (CDTA, DTPA, and HEDTA) were used in greenhouse studies with an uncontaminated soil and a Pb-contaminated soil to determine the effect of chelate type and rate on growth, Pb uptake, and plant elemental composition. Lead desorption varied with chelate and soil and increased with chelate rate, averaging 948 mg Pb kg{sup {minus}1} at the 20 mmol kg{sup {minus}1} rate vs. 28 mg Pb kg{sup {minus}1} by the control. The general ranking of chelate effectiveness, based on total Pb desorbed, was HEDTA > CDTA > DTPA > EGTA > HEIDA > EDDHA {approximately} NTA. Plant uptake of Pb from the contaminated soil was enhanced by CDTA, DTPA, and HEDTA, but with even the most effective treatment (corn, high CDTA rate), the amount of Pb extracted by plants was rather low. Lead extractable by the Toxicity Characteristic Leaching Procedure (TCLP) was increased from 9 mg L{sup {minus}1} in the control to from 47 to 174 mg L{sup {minus}1} in soils treated with 20 mmol kg{sup {minus}1} CDTA or DTPA and chelates generally caused a shift in Pb from resistant to more soluble chemical fractions.

  5. Chelation Treatment for Autism Spectrum Disorders: A Systematic Review

    ERIC Educational Resources Information Center

    Davis, Tonya N.; O'Reilly, Mark; Kang, Soyeon; Lang, Russell; Rispoli, Mandy; Sigafoos, Jeff; Lancioni, Giulio; Copeland, Daelynn; Attai, Shanna; Mulloy, Austin

    2013-01-01

    Chelation treatment is used to eliminate specific metals from the body, such as mercury. It has been hypothesized that mercury poisoning may be a factor in autism and data suggest that perhaps 7% of individuals with autism spectrum disorder (ASD) have received chelation treatment. It would therefore seem timely to review studies investigating the…

  6. Clawing Back: Broadening the Notion of Metal Chelators in Medicine

    PubMed Central

    Franz, Katherine J.

    2013-01-01

    The traditional notion of chelation therapy is the administration of a chemical agent to remove metals from the body. But formation of a metal-chelate can have biological ramifications that are much broader than metal elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. This review highlights recent examples that showcase four general strategies of using principles of metal chelation in medicinal contexts beyond the traditional notion of chelation therapy. These strategies include altering metal biodistribution, inhibiting specific metalloenzymes associated with disease, enhancing the reactivity of a metal complex to promote cytotoxicity, and conversely, passivating the reactivity of metals by site-activated chelation to prevent cytotoxicity. PMID:23332666

  7. Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals.

    PubMed

    Cai, Zhengxin; Anderson, Carolyn J

    2014-04-01

    The development of chelating agents for copper radionuclides in positron emission tomography radiopharmaceuticals has been a highly active and important area of study in recent years. The rapid evolution of chelators has resulted in highly specific copper chelators that can be readily conjugated to biomolecules and efficiently radiolabeled to form stable complexes in vivo. Chelators are not only designed for conjugation to monovalent biomolecules but also for incorporation into multivalent targeting ligands such as theranostic nanoparticles. These advancements have strengthened the role of copper radionuclides in the fields of nuclear medicine and molecular imaging. This review emphasizes developments of new copper chelators that have most greatly advanced the field of copper-based radiopharmaceuticals over the past 5 years. © 2013 The Authors. J. Label Compd. Radiopharm published by John Wiley & Sons Ltd.

  8. Chelation in metal intoxication XXI: chelation in lead intoxication during vitamin B complex deficiency

    SciTech Connect

    Not Available

    1986-09-01

    The vitamin B-complex deficiency increases the vulnerability to neuro- and systemic toxicity of Pb in young rats. Thus, the nutritional status of vitamins like that of protein or minerals seems to influence the etiology of Pb toxicity and may be expected to affect the response toward Pb chelators. 2,3 dimercaptosuccinic acid (DMSA) and N-(2-hydroxyethyl) ethylene-diamine triacetic acid (HEDTA) have been found to be effective antidotes to Pb intoxication. In the present study, these selective metal chelating agents were compared for their ability to reduce the body burden of Pb and restore the altered biochemical parameters in young developing Pb intoxicated rats maintained on normal or vitamin B-complex deficient diet. The investigation was aimed to suggest suitable prophylaxis of Pb poisoning prevalent among children who may also be suffering from vitamin deficiency in developing and poor countries.

  9. Chelating ionic liquids for reversible zinc electrochemistry.

    PubMed

    Kar, Mega; Winther-Jensen, Bjorn; Forsyth, Maria; MacFarlane, Douglas R

    2013-05-21

    Advanced, high energy-density, metal-air rechargeable batteries, such as zinc-air, are of intense international interest due to their important role in energy storage applications such as electric and hybrid vehicles, and to their ability to deal with the intermittency of renewable energy sources such as solar and wind. Ionic liquids offer a number of ideal thermal and physical properties as potential electrolytes in such large-scale energy storage applications. We describe here the synthesis and characterisation of a family of novel "chelating" ILs designed to chelate and solubilize the zinc ions to create electrolytes for this type of battery. These are based on quaternary alkoxy alkyl ammonium cations of varying oligo-ether side chains and anions such as p-toluene sulfonate, bis(trifluoromethylsulfonyl)amide and dicyanoamides. This work shows that increasing the ether chain length in the cation from two to four oxygens can increase the ionic conductivity and reduce the melting point from 67 °C to 15 °C for the tosylate system. Changing the anion also plays a significant role in the nature of the zinc deposition electrochemistry. We show that zinc can be reversibly deposited from [N(222(20201))][NTf2] and [N(222(202020201))][NTf2] beginning at -1.4 V and -1.7 V vs. SHE, respectively, but not in the case of tosylate based ILs. This indicates that the [NTf2] is a weaker coordinating anion with the zinc cation, compared to the tosylate anion, allowing the coordination of the ether chain to dominate the behavior of the deposition and stripping of zinc ions.

  10. Fixation kinetics of chelated and non-chelated zinc in semi-arid alkaline soils: application to zinc management

    NASA Astrophysics Data System (ADS)

    Udeigwe, Theophilus K.; Eichmann, Madeleine; Menkiti, Matthew C.

    2016-07-01

    This study was designed to examine the fixation pattern and kinetics of zinc (Zn) in chelated (ethylenediaminetetraacetic acid, EDTA) and non-chelated mixed micronutrient systems of semi-arid alkaline soils from the Southern High Plains, USA. Soils were characterized for a suite of chemical and physical properties and data obtained from extraction experiments fitted to various kinetic models. About 30 % more plant-available Zn was fixed in the non-chelated system within the first 14 days with only about 18 % difference observed between the two systems by day 90, suggesting that the effectiveness of the chelated compounds tended to decrease over time. The strengths of the relationships of change in available Zn with respect to other micronutrients (copper, iron, and manganese) were higher and more significant in the non-chelated system (average R2 of 0.83), compared to the chelated (average R2 of 0.42). Fixation of plant-available Zn was best described by the power-function model (R2 = 0.94, SE = 0.076) in the non-chelated system, and was poorly described by all the models examined in the chelated system. Reaction rate constants and relationships generated from this study can serve as important tools for micronutrient management and for future micronutrient modeling studies on these soils and other semi-arid regions of the world.

  11. Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

    SciTech Connect

    Wilson, Justin J.; Ferrier, Maryline; Radchenko, Valery; Maassen, Joel R.; Engle, Jonathan W.; Batista, Enrique R.; Martin, Richard L.; Nortier, Francois M.; Fassbender, Michael E.; John, Kevin D.; Birnbaum, Eva R.

    2015-05-01

    The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope ²¹³Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi³⁺, however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (Lpy), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (Lpz), were prepared by a previously reported method and investigated here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)- cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, ²⁰⁷Bi (t1/2 = 32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi³⁺ and the generator parent ion Ac³⁺.In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi³⁺ in the presence of the parent isotope Ac³⁺. Among the four tested, Lpy was found to exhibit optimal Bi³⁺-binding kinetics and complex stability. Lpy complexes

  12. DNA nuclease activity of Rev-coupled transition metal chelates.

    PubMed

    Joyner, Jeff C; Keuper, Kevin D; Cowan, J A

    2012-06-07

    Artificial nucleases containing Rev-coupled metal chelates based on combinations of the transition metals Fe(2+), Co(2+), Ni(2+), and Cu(2+) and the chelators DOTA, DTPA, EDTA, NTA, tripeptide GGH, and tetrapeptide KGHK have been tested for DNA nuclease activity. Originally designed to target reactive transition metal chelates (M-chelates) to the HIV-1 Rev response element mRNA, attachment to the arginine-rich Rev peptide also increases DNA-binding affinity for the attached M-chelates. Apparent K(D) values ranging from 1.7 to 3.6 µM base pairs for binding of supercoiled pUC19 plasmid DNA by Ni-chelate-Rev complexes were observed, as a result of electrostatic attraction between the positively-charged Rev peptide and negatively-charged DNA. Attachment of M-chelates to the Rev peptide resulted in enhancements of DNA nuclease activity ranging from 1-fold (no enhancement) to at least 13-fold (for Cu-DTPA-Rev), for the rate of DNA nicking, with second order rate constants for conversion of DNA(supercoiled) to DNA(nicked) up to 6 × 10(6) M(-1) min(-1), and for conversion of DNA(nicked) to DNA(linear) up to 1 × 10(5) M(-1) min(-1). Freifelder-Trumbo analysis and the ratios of linearization and nicking rate constants (k(lin)/k(nick)) revealed concerted mechanisms for nicking and subsequent linearization of plasmid DNA for all of the Rev-coupled M-chelates, consistent with higher DNA residency times for the Rev-coupled M-chelates. Observed rates for Rev-coupled M-chelates were less skewed by differing DNA-binding affinities than for M-chelates lacking Rev, as a result of the narrow range of DNA-binding affinities observed, and therefore relationships between DNA nuclease activity and other catalyst properties, such as coordination unsaturation, the ability to consume ascorbic acid and generate diffusible radicals, and the identity of the metal center, are now clearly illustrated in light of the similar DNA-binding affinities of all M-chelate-Rev complexes. This work

  13. Method for quantitative proteomics research by using metal element chelated tags coupled with mass spectrometry.

    PubMed

    Liu, Huiling; Zhang, Yangjun; Wang, Jinglan; Wang, Dong; Zhou, Chunxi; Cai, Yun; Qian, Xiaohong

    2006-09-15

    The mass spectrometry-based methods with a stable isotope as the internal standard in quantitative proteomics have been developed quickly in recent years. But the use of some stable isotope reagents is limited by the relative high price and synthetic difficulties. We have developed a new method for quantitative proteomics research by using metal element chelated tags (MECT) coupled with mass spectrometry. The bicyclic anhydride diethylenetriamine-N,N,N',N' ',N' '-pentaacetic acid (DTPA) is covalently coupled to primary amines of peptides, and the ligand is then chelated to the rare earth metals Y and Tb. The tagged peptides are mixed and analyzed by LC-ESI-MS/MS. Peptides are quantified by measuring the relative signal intensities for the Y and Tb tag pairs in MS, which permits the quantitation of the original proteins generating the corresponding peptides. The protein is then identified by the corresponding peptide sequence from its MS/MS spectrum. The MECT method was evaluated by using standard proteins as model sample. The experimental results showed that metal chelate-tagged peptides chromatographically coeluted successfully during the reversed-phase LC analysis. The relative quantitation results were accurate for proteins using MECT. DTPA modification of the N-terminal of peptides promoted cleaner fragmentation (only y-series ions) in mass spectrometry and improved the confidence level of protein identification. The MECT strategy provides a simple, rapid, and economical alternative to current mass tagging technologies available.

  14. Bifunctional thermoelectric tube made of tilted multilayer material as an alternative to standard heat exchangers.

    PubMed

    Takahashi, Kouhei; Kanno, Tsutomu; Sakai, Akihiro; Tamaki, Hiromasa; Kusada, Hideo; Yamada, Yuka

    2013-01-01

    Enormously large amount of heat produced by human activities is now mostly wasted into the environment without use. To realize a sustainable society, it is important to develop practical solutions for waste heat recovery. Here, we demonstrate that a tubular thermoelectric device made of tilted multilayer of Bi(0.5)Sb(1.5)Te3/Ni provides a promising solution. The Bi(0.5)Sb(1.5)Te3/Ni tube allows tightly sealed fluid flow inside itself, and operates in analogy with the standard shell and tube heat exchanger. We show that it achieves perfect balance between efficient heat exchange and high-power generation with a heat transfer coefficient of 4.0 kW/m(2)K and a volume power density of 10 kW/m(3) using low-grade heat sources below 100°C. The Bi(0.5)Sb(1.5)Te3/Ni tube thus serves as a power generator and a heat exchanger within a single unit, which is advantageous for developing new cogeneration systems in factories, vessels, and automobiles where cooling of excess heat is routinely carried out.

  15. Bifunctional thermoelectric tube made of tilted multilayer material as an alternative to standard heat exchangers

    PubMed Central

    Takahashi, Kouhei; Kanno, Tsutomu; Sakai, Akihiro; Tamaki, Hiromasa; Kusada, Hideo; Yamada, Yuka

    2013-01-01

    Enormously large amount of heat produced by human activities is now mostly wasted into the environment without use. To realize a sustainable society, it is important to develop practical solutions for waste heat recovery. Here, we demonstrate that a tubular thermoelectric device made of tilted multilayer of Bi0.5Sb1.5Te3/Ni provides a promising solution. The Bi0.5Sb1.5Te3/Ni tube allows tightly sealed fluid flow inside itself, and operates in analogy with the standard shell and tube heat exchanger. We show that it achieves perfect balance between efficient heat exchange and high-power generation with a heat transfer coefficient of 4.0 kW/m2K and a volume power density of 10 kW/m3 using low-grade heat sources below 100°C. The Bi0.5Sb1.5Te3/Ni tube thus serves as a power generator and a heat exchanger within a single unit, which is advantageous for developing new cogeneration systems in factories, vessels, and automobiles where cooling of excess heat is routinely carried out. PMID:23511347

  16. Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy

    PubMed Central

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A.

    2010-01-01

    Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood–brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter. PMID:20013176

  17. In vitro copper-chelating properties of flavonoids.

    PubMed

    Ríha, Michal; Karlícková, Jana; Filipský, Tomáš; Jahodár, Ludek; Hrdina, Radomír; Mladenka, Premysl

    2014-10-01

    Copper is an indispensable trace element for human body and the association between a disruption of copper homeostasis and a series of pathological states has been well documented. Flavonoids influence the human health in a complex way and the chelation of transient metal ions indisputably contributes to their mechanism of the action, however, the information about their copper-chelating properties have been sparse. This in vitro study was thus aimed at the detailed examination of flavonoids-copper interactions by two spectrophotometric assays at four (patho)physiologically relevant pH conditions (4.5-7.5), with the emphasis on the structure-activity relationship. The tested flavonoids were compared with the clinically used copper chelator, trientine. Most of the 26 flavonoids chelated copper ions, however, in a variable extent. Only flavones and flavonols were able to form stable complexes with both cupric and cuprous ions. The 3-hydroxy-4-keto group and 5,6,7-trihydroxyl group represented the most efficient chelation sites in flavonols and flavones, respectively, and the 2,3-double bond was essential for the stable copper chelation. Interestingly, the 3´,4´-dihydroxyl (catechol) group was associated only with a weak activity. Although none of the tested flavonoids were more potent than trientine at physiological or slightly acidic conditions, 3-hydroxyflavone, kaempferol and partly baicalein surpassed trientine at acidic conditions. Conclusively, flavonoids containing appropriate structural features were efficient copper chelators and some of them were even more potent than trientine under acidic conditions.

  18. Affinity purification of copper chelating peptides from chickpea protein hydrolysates.

    PubMed

    Megías, Cristina; Pedroche, Justo; Yust, Maria M; Girón-Calle, Julio; Alaiz, Manuel; Millan, Francisco; Vioque, Javier

    2007-05-16

    Chickpea protein hydrolysates obtained with alcalase and flavourzyme were used for purification of copper chelating peptides by affinity chromatography using copper immobilized on solid supports. The chelating activity of purified peptides was indirectly measured by the inhibition of beta-carotene oxidation in the presence of copper. Two protein hydrolysates, obtained after 10 and 100 min of hydrolysis, were the most inhibitory of beta-carotene oxidation. Purified copper chelating peptides from these protein hydrolysates contained 19.7 and 35.1% histidine, respectively, in comparison to 2.7 and 2.6% in the protein hydrolysates. Chelating peptides from hydrolysate obtained after 10 min of hydrolysis were the most antioxidative being 8.3 times more antioxidative than the hydrolysate, while chelating peptides purified from protein hydrolysate obtained after 100 min were 3.1 times more antioxidative than its hydrolysate. However, the histidine content was higher in peptides derived from the 100 min hydrolysate (19.7 against 35.1% in 10 min hydrolysate), indicating that this amino acid is not the only factor involved in the antioxidative activity, and other factors such as peptide size or amino acid sequence are also determinant. This manuscript shows that affinity chromatography is a useful procedure for purification of copper chelating peptides. This method can be extended to other metals of interest in nutrition, such as calcium, iron, or zinc. Purified chelating peptides, in addition to their antioxidative properties, may also be useful in food mineral fortification for increasing the bioavailability of these metals.

  19. Synthetic and natural iron chelators: therapeutic potential and clinical use

    PubMed Central

    Hatcher, Heather C; Singh, Ravi N; Torti, Frank M; Torti, Suzy V

    2013-01-01

    Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade®) and deferiprone (Ferriprox®), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry. PMID:21425984

  20. Nanoparticle and iron chelators as a potential novel Alzheimer therapy.

    PubMed

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A

    2010-01-01

    Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter.

  1. Nanoparticle and other metal chelation therapeutics in Alzheimer disease.

    PubMed

    Liu, Gang; Garrett, Matthew R; Men, Ping; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2005-09-25

    Current therapies for Alzheimer disease (AD) such as the anticholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of disease, but do not arrest disease progression or supply meaningful remission. As such, new approaches to disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. In this review, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show a unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may prove to be a safe and effective means of reducing the metal load in neural tissue thus staving off the harmful effects of oxidative damage and its sequelae.

  2. Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review

    PubMed Central

    Sears, Margaret E.

    2013-01-01

    Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation, that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic disease. PMID:23690738

  3. Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

    PubMed Central

    Popelová, Olga; Vávrová, Anna; Jirkovský, Eduard; Kovaříková, Petra; Geršl, Vladimír

    2013-01-01

    Abstract Significance: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. Recent Advances: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. Critical Issues: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Future Directions: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation. Antioxid. Redox Signal. 00, 000–000. PMID:22794198

  4. A novel bifunctional electrocatalyst for unitized regenerative fuel cell

    NASA Astrophysics Data System (ADS)

    Zhang, Yining; Zhang, Huamin; Ma, Yuanwei; Cheng, Jinbin; Zhong, Hexiang; Song, Shidong; Ma, Haipeng

    5 wt.% of platinum (Pt) nanoparticles are highly dispersed on the surface of IrO 2 by chemical reduction, and the catalyst is mixed with Pt black to be used as a novel bifunctional oxygen electrocatalyst for the unitized regenerative fuel cell (URFC). The novel cell has been evaluated in the hydrogen and oxygen fuel cell and water electrolysis modes, and compared to a similar cell with an oxygen electrode using conventional mixed Pt black and IrO 2 catalyst. With the novel oxygen electrode catalyst, the highest fuel cell power density is 1160 mW cm -2 at 2600 mA cm -2; the overall performance is close to that with the commercial Pt supported on carbon catalyst and about 1.8 times higher than that with the conventional mixed Pt black and IrO 2 catalyst. Additionally, the cell performance for water electrolysis is also slightly improved, which is probably the result of lower interparticle catalyst resistance with 5 wt.% Pt on IrO 2 compared to no Pt on IrO 2.

  5. Development of Benzophenone-Alkyne Bifunctional Sigma Receptor Ligands

    PubMed Central

    Guo, Lian-Wang; Hajipour, Abdol R.; Karaoglu, Kerim; Mavlyutov, Timur A.; Ruoho, Arnold E.

    2012-01-01

    Sigma (σ) receptors represent unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been identified to contain σ2 receptor-like binding properties, highlighting the need to understand the biological function of an 18-kDa protein that exhibits σ2-like photoaffinity labeling (herein denoted as σ2-18k) but the amino acid sequence of which is not known. In order to provide novel tools for the study of the σ2-18k protein, we have developed bifunctional sigma receptor ligands that bear a benzophenone photo-crosslinking moiety and an alkyne group, to which an azide-containing biotin affinity tag can be covalently attached via click chemistry following photo-crosslink. While several compounds showed favorable σ2 binding properties, compound 22 exhibited the highest affinity (2 nM) and the greatest potency in blocking photolabeling of the σ2-18k by a radioactive photoaffinity ligand. Thus, these benzophenone-alkyne sigma receptor ligands may be amenable for studying the σ2-18k protein via chemical biology approaches. To our knowledge, these compounds represent the first reported benzophenone-containing clickable sigma receptor ligands, which may potentially serve broad applications by “plugging” in various tags. PMID:23001760

  6. Bioinspired Bifunctional Membrane for Efficient Clean Water Generation.

    PubMed

    Liu, Yang; Lou, Jinwei; Ni, Mengtian; Song, Chengyi; Wu, Jianbo; Dasgupta, Neil P; Tao, Peng; Shang, Wen; Deng, Tao

    2016-01-13

    Solving the problems of water pollution and water shortage is an urgent need for the sustainable development of modern society. Different approaches, including distillation, filtration, and photocatalytic degradation, have been developed for the purification of contaminated water and the generation of clean water. In this study, we explored a new approach that uses solar light for both water purification and clean water generation. A bifunctional membrane consisting of a top layer of TiO2 nanoparticles (NPs), a middle layer of Au NPs, and a bottom layer of anodized aluminum oxide (AAO) was designed and fabricated through multiple filtration processes. Such a design enables both TiO2 NP-based photocatalytic function and Au NP-based solar-driven plasmonic evaporation. With the integration of these two functions into a single membrane, both the purification of contaminated water through photocatalytic degradation and the generation of clean water through evaporation were demonstrated using simulated solar illumination. Such a demonstration should also help open up a new strategy for maximizing solar energy conversion and utilization.

  7. Gemini, a Bifunctional Enzymatic and Fluorescent Reporter of Gene Expression

    PubMed Central

    Endy, Drew

    2009-01-01

    Background The development of collections of quantitatively characterized standard biological parts should facilitate the engineering of increasingly complex and novel biological systems. The existing enzymatic and fluorescent reporters that are used to characterize biological part functions exhibit strengths and limitations. Combining both enzymatic and fluorescence activities within a single reporter protein would provide a useful tool for biological part characterization. Methodology/Principal Findings Here, we describe the construction and quantitative characterization of Gemini, a fusion between the β-galactosidase (β-gal) α-fragment and the N-terminus of full-length green fluorescent protein (GFP). We show that Gemini exhibits functional β-gal activity, which we assay with plates and fluorometry, and functional GFP activity, which we assay with fluorometry and microscopy. We show that the protein fusion increases the sensitivity of β-gal activity and decreases the sensitivity of GFP. Conclusions/Significance Gemini is therefore a bifunctional reporter with a wider dynamic range than the β-gal α-fragment or GFP alone. Gemini enables the characterization of gene expression, screening assays via enzymatic activity, and quantitative single-cell microscopy or FACS via fluorescence activity. The analytical flexibility afforded by Gemini will likely increase the efficiency of research, particularly for screening and characterization of libraries of standard biological parts. PMID:19888458

  8. Preparation of proton conducting membranes containing bifunctional titania nanoparticles

    NASA Astrophysics Data System (ADS)

    Aslan, Ayşe; Bozkurt, Ayhan

    2013-07-01

    Throughout this work, the synthesis and characterization of novel proton conducting nanocomposite membranes including binary and ternary mixtures of sulfated nano-titania (TS), poly(vinyl alcohol) (PVA), and nitrilotri(methyl phosphonic acid) (NMPA) are discussed. The materials were produced by means of two different approaches where in the first, PVA and TS (10-15 nm) were admixed to form a binary system. The second method was the ternary nanocomposite membranes including PVA/TS/NMPA that were prepared at several compositions to get PVA-TS-(NMPA) x . The interaction of functional nano particles and NMPA in the host matrix was explored by FT-IR spectroscopy. The homogeneous distribution of bifunctional nanoparticles in the membrane was confirmed by SEM micrographs. The spectroscopic measurements and water/methanol uptake studies suggested a complexation between PVA and NMPA, which inhibited the leaching of the latter. The thermogravimetry analysis results verified that the presence of TS in the composite membranes suppressed the formation of phosphonic acid anhydrides up to 150 °C. The maximum proton conductivity has been measured for PVA-TS-(NMPA)3 as 0.003 S cm-1 at 150 °C.

  9. Identification of a Bifunctional Maize C- and O-Glucosyltransferase*

    PubMed Central

    Falcone Ferreyra, María Lorena; Rodriguez, Eduardo; Casas, María Isabel; Labadie, Guillermo; Grotewold, Erich; Casati, Paula

    2013-01-01

    Flavonoids accumulate in plant vacuoles usually as O-glycosylated derivatives, but several species can also synthesize flavonoid C-glycosides. Recently, we demonstrated that a flavanone 2-hydroxylase (ZmF2H1, CYP93G5) converts flavanones to the corresponding 2-hydroxy derivatives, which are expected to serve as substrates for C-glycosylation. Here, we isolated a cDNA encoding a UDP-dependent glycosyltransferase (UGT708A6), and its activity was characterized by in vitro and in vivo bioconversion assays. In vitro assays using 2-hydroxyflavanones as substrates and in vivo activity assays in yeast co-expressing ZmF2H1 and UGT708A6 show the formation of the flavones C-glycosides. UGT708A6 can also O-glycosylate flavanones in bioconversion assays in Escherichia coli as well as by in vitro assays with the purified recombinant protein. Thus, UGT708A6 is a bifunctional glycosyltransferase that can produce both C- and O-glycosidated flavonoids, a property not previously described for any other glycosyltransferase. PMID:24045947

  10. A novel bifunctional transcriptional regulator of riboflavin metabolism in Archaea.

    PubMed

    Rodionova, Irina A; Vetting, Matthew W; Li, Xiaoqing; Almo, Steven C; Osterman, Andrei L; Rodionov, Dmitry A

    2017-01-09

    Riboflavin (vitamin B2) is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide, which are essential coenzymes in all free-living organisms. Riboflavin biosynthesis in many Bacteria but not in Archaea is controlled by FMN-responsive riboswitches. We identified a novel bifunctional riboflavin kinase/regulator (RbkR), which controls riboflavin biosynthesis and transport genes in major lineages of Crenarchaeota, Euryarchaeota and Thaumarchaeota. RbkR proteins are composed of the riboflavin kinase domain and a DNA-binding winged helix-turn-helix-like domain. Using comparative genomics, we predicted RbkR operator sites and reconstructed RbkR regulons in 94 archaeal genomes. While the identified RbkR operators showed significant variability between archaeal lineages, the conserved core of RbkR regulons includes riboflavin biosynthesis genes, known/predicted vitamin uptake transporters and the rbkR gene. The DNA motifs and CTP-dependent riboflavin kinase activity of two RbkR proteins were experimentally validated in vitro The DNA binding activity of RbkR was stimulated by CTP and suppressed by FMN, a product of riboflavin kinase. The crystallographic structure of RbkR from Thermoplasma acidophilum was determined in complex with CTP and its DNA operator revealing key residues for operator and ligand recognition. Overall, this study contributes to our understanding of metabolic and regulatory networks for vitamin homeostasis in Archaea.

  11. A bifunctional spin detector made of quantum anomalous Hall insulator

    NASA Astrophysics Data System (ADS)

    Shi, Zhangsheng; Wu, Jiansheng

    2016-10-01

    The spin selection of the topological boundary states (TBS) which are protected by the chiral-like symmetry in quantum anomalous Hall insulator (QAHI) can be used to construct a bifunctional spin detector (SD). Such device made of QAHIs in parallel with opposite chirality can divide an incoming spin-polarized current into two outgoing currents. The agreement between numerical and analytical calculation proves that the SD device functions as both spin filter and spin separator well in reflecting the spin polarization of source material from the ratio of two currents. The monotonic relation of spin polarization and current ratio suggests that using such kind of device, the spin polarization can be obtained directly. We also find that such device has a broad working energy region attributed by the TBS within the bulk gap. Combining with the result that the current ratio is barely dependent on the coupling between candidate materials and device, it is reasonable to apply this technique with a stable measuring accuracy. Furthermore, the features such as having simple geometry, being manipulated without external magnetic field, and the prospect of working at room temperature make this proposed device seem promising in developing future low-power-consumption spintronic device.

  12. A conserved regulatory mechanism in bifunctional biotin protein ligases.

    PubMed

    Wang, Jingheng; Beckett, Dorothy

    2017-08-01

    Class II bifunctional biotin protein ligases (BirA), which catalyze post-translational biotinylation and repress transcription initiation, are broadly distributed in eubacteria and archaea. However, it is unclear if these proteins all share the same molecular mechanism of transcription regulation. In Escherichia coli the corepressor biotinoyl-5'-AMP (bio-5'-AMP), which is also the intermediate in biotin transfer, promotes operator binding and resulting transcription repression by enhancing BirA dimerization. Like E. coli BirA (EcBirA), Staphylococcus aureus, and Bacillus subtilis BirA (Sa and BsBirA) repress transcription in vivo in a biotin-dependent manner. In this work, sedimentation equilibrium measurements were performed to investigate the molecular basis of this biotin-responsive transcription regulation. The results reveal that, as observed for EcBirA, Sa, and BsBirA dimerization reactions are significantly enhanced by bio-5'-AMP binding. Thus, the molecular mechanism of the Biotin Regulatory System is conserved in the biotin repressors from these three organisms. © 2017 The Protein Society.

  13. Gold-Copper Nanoparticles: Nanostructural Evolution and Bifunctional Catalytic Sites

    SciTech Connect

    Yin, Jun; Shan, Shiyao; Yang, Lefu; Mott, Derrick; Malis, Oana; Petkov, Valeri; Cai, Fan; Ng, Mei; Luo, Jin; Chen, Bing H.; Engelhard, Mark H.; Zhong, Chuan-Jian

    2012-12-12

    Understanding of the atomic-scale structure is essential for exploiting the unique catalytic properties of any nanoalloy catalyst. This report describes novel findings of an investigation of the nanoscale alloying of gold-copper (AuCu) nanoparticles and its impact on the surface catalytic functions. Two pathways have been explored for the formation of AuCu nanoparticles of different compositons, including wet chemical synthesis from mixed Au- and Cu-precursor molecules, and nanoscale alloying via an evolution of mixed Au- and Cu-precursor nanoparticles near the nanoscale melting temperatures. For the evolution of mixed precursor nanoparticles, synchrotron x-ray based in-situ real time XRD was used to monitor the structural changes, revealing nanoscale alloying and reshaping towards an fcc-type nanoalloy (particle or cube) via a partial melting–resolidification mechanism. The nanoalloys supported on carbon or silica were characterized by in-situ high-energy XRD/PDFs, revealing an intriguing lattice "expanding-shrinking" phenomenon depending on whether the catalyst is thermochemically processed under oxidative or reductive atmosphere. This type of controllable structural changes is found to play an important role in determining the catalytic activity of the catalysts for carbon monoxide oxidation reaction. The tunable catalytic activities of the nanoalloys under thermochemically oxidative and reductive atmospheres are also discussed in terms of the bifunctional sites and the surface oxygenated metal species for carbon monoxide and oxygen activation.

  14. Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease.

    PubMed

    Page, Clive; Cazzola, Mario

    2014-08-01

    Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting β2-agonist and an inhaled corticosteroid, and combinations of long-acting β2-agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of "triple-inhaler" fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called "bifunctional drugs". In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/anti-inflammatory drugs and bifunctional anti-inflammatory drugs.

  15. Single flexible nanofiber to achieve simultaneous photoluminescence-electrical conductivity bifunctionality.

    PubMed

    Sheng, Shujuan; Ma, Qianli; Dong, Xiangting; Lv, Nan; Wang, Jinxian; Yu, Wensheng; Liu, Guixia

    2015-02-01

    In order to develop new-type multifunctional composite nanofibers, Eu(BA)3 phen/PANI/PVP bifunctional composite nanofibers with simultaneous photoluminescence and electrical conductivity have been successfully fabricated via electrospinning technology. Polyvinyl pyrrolidone (PVP) is used as a matrix to construct composite nanofibers containing different amounts of Eu(BA)3 phen and polyaniline (PANI). X-Ray diffractometry (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), fluorescence spectroscopy and a Hall effect measurement system are used to characterize the morphology and properties of the composite nanofibers. The results indicate that the bifunctional composite nanofibers simultaneously possess excellent photoluminescence and electrical conductivity. Fluorescence emission peaks of Eu(3+) ions are observed in the Eu(BA)3 phen/PANI/PVP photoluminescence-electrical conductivity bifunctional composite nanofibers. The electrical conductivity reaches up to the order of 10(-3)  S/cm. The luminescent intensity and electrical conductivity of the composite nanofibers can be tuned by adjusting the amounts of Eu(BA)3 phen and PANI. The obtained photoluminescence-electrical conductivity bifunctional composite nanofibers are expected to possess many potential applications in areas such as microwave absorption, molecular electronics, biomedicine and future nanomechanics. More importantly, the design concept and construction technique are of universal significance to fabricate other bifunctional one-dimensional naonomaterials. Copyright © 2014 John Wiley & Sons, Ltd.

  16. Perovskite-nitrogen-doped carbon nanotube composite as bifunctional catalysts for rechargeable lithium-air batteries.

    PubMed

    Park, Hey Woong; Lee, Dong Un; Park, Moon Gyu; Ahmed, Raihan; Seo, Min Ho; Nazar, Linda F; Chen, Zhongwei

    2015-03-01

    Developing an effective bifunctional catalyst is a significant issue, as rechargeable metal-air batteries are very attractive for future energy systems. In this study, a facile one-pot process is introduced to prepare an advanced bifunctional catalyst (op-LN) incorporating nitrogen-doped carbon nanotubes (NCNTs) into perovskite La0.5 Sr0.5 Co0.8 Fe0.2 O3 nanoparticles (LSCF-NPs). Confirmed by half-cell testing, op-LN exhibits synergistic effects of LSCF-NP and NCNT with excellent bifunctionality for both the oxygen reduction reaction and the oxygen evolution reaction. Furthermore, op-LN exhibits comparable performances in these reactions to Pt/C and Ir/C, respectively, which highlights its potential for use as a commercially viable bifunctional catalyst. Moreover, the results obtained by testing op-LN in a practical Li-air battery demonstrate improved and complementary charge/discharge performance compared to those of LSCF-NP and NCNT, and this confirms that simply prepared op-LN is a promising candidate as a highly effective bifunctional catalyst for rechargeable metal-air batteries.

  17. D-bifunctional protein deficiency: a cause of neonatal onset seizures and hypotonia.

    PubMed

    Nascimento, João; Mota, Céu; Lacerda, Lúcia; Pacheco, Sara; Chorão, Rui; Martins, Esmeralda; Garrido, Cristina

    2015-05-01

    Peroxisomal disorders are classified in two major groups: (1) peroxisome biogenesis disorders and (2) single peroxisomal enzyme/transporter deficiencies. D-bifunctional protein deficiency (OMIM #261515) is included in this last group of rare diseases and leads to an impaired peroxisomal beta-oxidation. D-bifunctional protein deficiencies are divided into four types based on the degree of activity of the 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units. We present the first Portuguese reported type II D-bifunctional protein deficiency patient, whose neonatal clinical picture is indistinguishable from a Zellweger spectrum disease. The clinical features and the neuroimaging findings of polymicrogyria raised suspicion of the diagnosis. After biochemical analysis, D-bifunctional protein deficiency was confirmed with the identification of a homozygous p.Asn457Tyr (N457Y) mutation of the HSD17B4 gene. The patient's parents were carriers of the mutated allele, confirming the patient homozygosity status and allowing prenatal diagnosis in future pregnancies. D-bifunctional protein deficiency is a rare, severe disease and the final diagnosis can only be accomplished after HSD17B4 gene sequencing. Treatment is supportive, aimed at improving nutrition and growth, controlling the central nervous system symptoms, and limiting the eventual progression of liver disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Probing chelation motifs in HIV integrase inhibitors

    PubMed Central

    Agrawal, Arpita; DeSoto, Jamie; Fullagar, Jessica L.; Maddali, Kasthuraiah; Rostami, Shahrzad; Richman, Douglas D.; Pommier, Yves; Cohen, Seth M.

    2012-01-01

    A series of HIV integrase (HIV-1 IN) inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. A total of 21 different raltegravir-chelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3′-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance. PMID:22308350

  19. Characterization of the bisintercalative DNA binding mode of a bifunctional platinum–acridine agent

    PubMed Central

    Choudhury, Jayati Roy; Bierbach, Ulrich

    2005-01-01

    The DNA interactions of PT-BIS(ACRAMTU) ([Pt(en)(ACRAMTU)2](NO3)4; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, en = ethylenediamine), a bifunctional platinum–acridine conjugate, have been studied in native and synthetic double-stranded DNAs and model duplexes using various biophysical techniques. These include ethidium-DNA fluorescence quenching and thermal melting experiments, circular dichroism (CD) spectroscopy and plasmid unwinding assays. In addition, the binding mode was studied in a short octamer by NMR spectroscopy in conjunction with molecular modeling. In alternating copolymers, PT-BIS(ACRAMTU) shows a distinct preference for poly(dA-dT)2, which is ∼3-fold higher than that of ACRAMTU. In the ligand-oligomer complex, d(GCTATAGC)2·PT-BIS(ACRAMTU) (complex I*), PT-BIS(ACRAMTU) increases the thermal stability of the B-form host duplex by ΔTm > 30 K (CD and UV melting experiments). The agent unwinds pSP73 plasmid DNA by 44(±2)° per bound molecule, indicating bisintercalative binding. A 2-D NMR study unequivocally demonstrates that PT-BIS(ACRAMTU)'s chromophores deeply bisintercalate into the 5′-TA/TA base pair steps in I*, while the platinum linker lies in the minor groove. An AMBER model reflecting the NMR results shows that bracketing of the central AT base pairs in a classical nearest neighbor excluded fashion is feasible. PT-BIS(ACRAMTU) inhibits DNA hydrolysis by BstZ17 I at the enzyme's restriction site, GTA↓TAC. Possible consequences for other relevant DNA–protein interactions, such as those involved in TATA-box-mediated transcription initiation and the utility of the platinum-intercalator technology for the design of sequence-specific agents are discussed. PMID:16192574

  20. Complementary and Alternative Therapies in ALS

    PubMed Central

    Bedlack, Richard S.; Joyce, Nanette; Carter, Gregory T.; Pagononi, Sabrina; Karam, Chafic

    2015-01-01

    Synopsis Given the severity of their illness and lack of effective disease modifying agents, it is not surprising that most patients with ALS consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation and energy healing. This chapter reviews these in detail. We also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy and shared decision making. Finally, we review a program called ALSUntangled which using shared shared decision making to review alternative therapies for ALS. PMID:26515629

  1. Double diastereocontrol in bifunctional thiourea organocatalysis: iterative Michael-Michael-Henry sequence regulated by the configuration of chiral catalysts.

    PubMed

    Varga, Szilárd; Jakab, Gergely; Drahos, László; Holczbauer, Tamás; Czugler, Mátyás; Soós, Tibor

    2011-10-21

    The importance and reactivity consequences of the double diastereocontrol in noncovalent bifunctional organocatalysis were studied. The results suggest that the bifunctional thioureas can have synthetic limitations in multicomponent domino or autotandem catalysis. Nevertheless, we provided a means to exploit this behavior and used the configuration of the chiral catalyst as a control element in organo-sequential reactions.

  2. An efficient chelator for complexation of thorium-227.

    PubMed

    Ramdahl, Thomas; Bonge-Hansen, Hanne T; Ryan, Olav B; Larsen, Smund; Herstad, Gunnar; Sandberg, Marcel; Bjerke, Roger M; Grant, Derek; Brevik, Ellen M; Cuthbertson, Alan S

    2016-09-01

    We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the ɛ-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology. Copyright © 2016. Published by Elsevier Ltd.

  3. Comparing potential copper chelation mechanisms in Parkinson's disease protein

    NASA Astrophysics Data System (ADS)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2011-03-01

    We have implemented the nudged elastic band (NEB) as a guided dynamics framework for our real-space multigrid method of DFT-based quantum simulations. This highly parallel approach resolves a minimum energy pathway (MEP) on the energy hypersurface by relaxing intermediates in a chain-of-states. As an initial application we present an investigation of chelating agents acting on copper ion bound to α -synuclein, whose misfolding is implicated in Parkinson's disease (PD). Copper ions are known to act as highly effective misfolding agents in a-synuclein and are thus an important target in understanding PD. Furthermore, chelation therapy has shown promise in the treatment of Alzheimer's and other neuro-degenerative diseases with similar metal-correlated pathologies. At present, our candidate chelating agents include nicotine, curcumin and clioquinol. We examine their MEP activation barriers in the context of a PD onset mechanism to assess the viability of various chelators for PD remediation.

  4. An Evaluation of the Chelating Agent EDDS for Marigold Production

    USDA-ARS?s Scientific Manuscript database

    Aminopolycarboxylic acid (APCA) ligands (chelating agents) like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) are commonly used in soluble fertilizers to supply copper (Cu), iron (Fe), manganese (Mn), and/or zinc (Zn) to plants. The offsite runoff and contamina...

  5. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth; Xu, Jide

    1999-01-01

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity.

  6. NIR emitting ytterbium chelates for colourless luminescent solar concentrators.

    PubMed

    Sanguineti, Alessandro; Monguzzi, Angelo; Vaccaro, Gianfranco; Meinardi, Franco; Ronchi, Elisabetta; Moret, Massimo; Cosentino, Ugo; Moro, Giorgio; Simonutti, Roberto; Mauri, Michele; Tubino, Riccardo; Beverina, Luca

    2012-05-14

    A new oxyiminopyrazole-based ytterbium chelate enables NIR emission upon UV excitation in colorless single layer luminescent solar concentrators for building integrated photovoltaics. This journal is © the Owner Societies 2012

  7. Thermodynamic remarks on chelating ligands for aluminium related diseases.

    PubMed

    Crisponi, Guido; Nurchi, Valeria Marina

    2011-11-01

    Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the actions that have drastically reduced the occurrence of dialysis diseases, they so far constitute a cause of great medical concern. Being aluminium chelators strictly related to iron chelators, a comparison is made of the complex formation properties of these two hard metal ions towards ligands characterized by charged oxygen donor groups. Empirical correlations between aluminium(III) and iron(III) complex formation constants, and their behavior are discussed in terms of structural and thermodynamic stabilities. Insertion of proper substituents to enhance the chelator binding capacity is debated on the bases of substituent effects on protonation and complex formation constants. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.; Xu, J.

    1999-04-06

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. 2 figs.

  9. Piperazine derivatives as iron chelators: a potential application in neurobiology.

    PubMed

    Abdelsayed, S; Duong, N T Ha; Bureau, C; Michel, P P; Hirsch, E C; Chahine, J M El Hage; Serradji, N

    2015-12-01

    Polysubstituted piperazine derivatives, designed as new iron chelators, were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopy. Their potential to prevent iron-induced neurotoxicity was assessed using a cellular model of Parkinson disease. We demonstrated their ability to provide sustained neuroprotection to dopaminergic neurons that are vulnerable in this pathology. The iron chelating properties of the new compounds were determined by spectrophotometric titration illustrating that high affinity for iron is not associated with important neuroprotective effects.

  10. Scaling-Relation-Based Analysis of Bifunctional Catalysis: The Case for Homogeneous Bimetallic Alloys

    DOE PAGES

    Andersen, Mie; Medford, Andrew J.; Norskov, Jens K.; ...

    2017-04-14

    Here, we present a generic analysis of the implications of energetic scaling relations on the possibilities for bifunctional gains at homogeneous bimetallic alloy catalysts. Such catalysts exhibit a large number of interface sites, where second-order reaction steps can involve intermediates adsorbed at different active sites. Using different types of model reaction schemes, we show that such site-coupling reaction steps can provide bifunctional gains that allow for a bimetallic catalyst composed of two individually poor catalyst materials to approach the activity of the optimal monomaterial catalyst. However, bifunctional gains cannot result in activities higher than the activity peak of the monomaterialmore » volcano curve as long as both sites obey similar scaling relations, as is generally the case for bimetallic catalysts. These scaling-relation-imposed limitations could be overcome by combining different classes of materials such as metals and oxides.« less

  11. Nickel sulfide microsphere film on Ni foam as an efficient bifunctional electrocatalyst for overall water splitting.

    PubMed

    Zhu, Wenxin; Yue, Xiaoyue; Zhang, Wentao; Yu, Shaoxuan; Zhang, Yuhuan; Wang, Jing; Wang, Jianlong

    2016-01-25

    Developing low-cost, efficient, and bifunctional electrocatalysts for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is an appealing yet challenging task. Herein, for the first time, a NiS microsphere film was grown in situ on Ni foam (NiS/Ni foam) via a sulfurization reaction as an efficient bifunctional electrocatalyst for overall water splitting with superior activity and good durability. This NiS/Ni foam electrode delivers 20 mA cm(-2) at an overpotential of 158 mV for the HER and 50 mA cm(-2) at an overpotential of 335 mV for the OER in 1.0 M KOH. This bifunctional electrode also enables a high-efficiency alkaline water electrolyzer with 10 mA cm(-2) at a cell voltage of only 1.64 V, which could be promising in water splitting devices for large-scale hydrogen production.

  12. Watt-Level Continuous-Wave Emission from a Bifunctional Quantum Cascade Laser/Detector

    PubMed Central

    2017-01-01

    Bifunctional active regions, capable of light generation and detection at the same wavelength, allow a straightforward realization of the integrated mid-infrared photonics for sensing applications. Here, we present a high performance bifunctional device for 8 μm capable of 1 W single facet continuous wave emission at 15 °C. Apart from the general performance benefits, this enables sensing techniques which rely on continuous wave operation, for example, heterodyne detection, to be realized within a monolithic platform and demonstrates that bifunctional operation can be realized at longer wavelength, where wavelength matching becomes increasingly difficult and that the price to be paid in terms of performance is negligible. In laser operation, the device has the same or higher efficiency compared to the best lattice-matched QCLs without same wavelength detection capability, which is only 30% below the record achieved with strained material at this wavelength. PMID:28540324

  13. Enhanced Bifunctional Oxygen Catalysis in Strained LaNiO3 Perovskites

    SciTech Connect

    Petrie, Jonathan R.; Cooper, Valentino R.; Freeland, John W.; Meyer, Tricia L.; Zhang, Zhiyong; Lutterman, Daniel A.; Lee, Ho Nyung

    2016-03-02

    Strain is known to greatly influence low temperature oxygen electro catalysis on noble metal films, leading to significant enhancements in bifunctional activity essential for fuel cells and Metal-air batteries. However, its catalytic impact on transition-metal oxide thin films, such as perovskites, is not widely understood. Here, we epitaxially strain the conducting perovskite LaNiO3 to systematically determine its influence on both the oxygen reduction and oxygen evolution reaction. Uniquely, we found that compressive strain could significantly enhance both reactions, yielding a bifunctional catalyst that surpasses the performance of noble metals' such as Pt. We attribute the improved bifunctionality to strain induced splitting of the e(g) Orbitals, which can customize orbital asymmetry at the surface. Analogous to strain induced shifts in the d-band center of noble metals relative to the Fermi level, :such splitting can dramatically affect catalytic activity in this perovskite and other potentially more active Oxides.

  14. Polymer-Supported Reagents: The Role of Bifunctionality in the Design of Ion-Selective Complexants

    SciTech Connect

    Alexandratos, S. D.

    2001-06-01

    The importance of multi-functionality in the preparation of ion-selective polymers is evident from the structure of enzymes where specific metal ions are bound through cooperative interactions among different amino acids. In synthetic polymers, ionic selectivity is enhanced when a chemical reaction is superimposed on an ion-exchange process. The concept of reactive ion exchange has been extended through the synthesis of crosslinked polymers whose metal ion selectivity is a function of reduction, coordination or precipitation reactions as determined by various covalently bound ligands. Development of three classes of dual mechanism bifunctional polymers, a new series of bifunctional diphosphonate polymers, and novel bifunctional ion-selective polymers with enhanced ionic accessibility has been accomplished.

  15. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    SciTech Connect

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-10-25

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

  16. Lead chelation to immobilised Symphytum officinale L. (comfrey) root tannins.

    PubMed

    Chin, Lily; Leung, David W M; Harry Taylor, H

    2009-07-01

    Reported correlations between tannin level and metal accumulation within plant tissues suggest that metal-chelating tannins may help plants to tolerate toxic levels of heavy metal contaminants. This paper supports such correlations using a new method that demonstrated the ability of plant tannins to chelate heavy metals, and showed that the relative levels of tannins in tissues were quantitatively related to lead chelation in vitro. Using this in vitro metal chelation method, we showed that immobilised tannins prepared from lateral roots of Symphytum officinale L., that contained high tannin levels, chelated 3.5 times more lead than those from main roots with lower tannin levels. This trend was confirmed using increasing concentrations of tannins from a single root type, and using purified tannins (tannic acid) from Chinese gallnuts. This study presents a new, simple, and reliable method that demonstrates direct lead-tannin chelation. In relation to phytoremediation, it also suggests that plant roots with more 'built-in' tannins may advantageously accumulate more lead.

  17. Extraction of metals using supercritical fluid and chelate forming ligand

    DOEpatents

    Wai, C.M.; Laintz, K.E.

    1998-03-24

    A method of extracting metalloid and metal species from a solid or liquid material by exposing the material to a supercritical fluid solvent containing a chelating agent is described. The chelating agent forms chelates that are soluble in the supercritical fluid to allow removal of the species from the material. In preferred embodiments, the extraction solvent is supercritical carbon dioxide and the chelating agent is a fluorinated {beta}-diketone. In especially preferred embodiments the extraction solvent is supercritical carbon dioxide, and the chelating agent comprises a fluorinated {beta}-diketone and a trialkyl phosphate, or a fluorinated {beta}-diketone and a trialkylphosphine oxide. Although a trialkyl phosphate can extract lanthanides and actinides from acidic solutions, a binary mixture comprising a fluorinated {beta}-diketone and a trialkyl phosphate or a trialkylphosphine oxide tends to enhance the extraction efficiencies for actinides and lanthanides. The method provides an environmentally benign process for removing contaminants from industrial waste without using acids or biologically harmful solvents. The method is particularly useful for extracting actinides and lanthanides from acidic solutions. The chelate and supercritical fluid can be regenerated, and the contaminant species recovered, to provide an economic, efficient process. 7 figs.

  18. Iron chelators target both proliferating and quiescent cancer cells

    PubMed Central

    Fryknäs, Mårten; Zhang, Xiaonan; Bremberg, Ulf; Senkowski, Wojciech; Olofsson, Maria Hägg; Brandt, Peter; Persson, Ingmar; D’Arcy, Padraig; Gullbo, Joachim; Nygren, Peter; Schughart, Leoni Kunz; Linder, Stig; Larsson, Rolf

    2016-01-01

    Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells. PMID:27924826

  19. Extraction of metals using supercritical fluid and chelate forming legand

    DOEpatents

    Wai, Chien M.; Laintz, Kenneth E.

    1998-01-01

    A method of extracting metalloid and metal species from a solid or liquid material by exposing the material to a supercritical fluid solvent containing a chelating agent is described. The chelating agent forms chelates that are soluble in the supercritical fluid to allow removal of the species from the material. In preferred embodiments, the extraction solvent is supercritical carbon dioxide and the chelating agent is a fluorinated .beta.-diketone. In especially preferred embodiments the extraction solvent is supercritical carbon dioxide, and the chelating agent comprises a fluorinated .beta.-diketone and a trialkyl phosphate, or a fluorinated .beta.-diketone and a trialkylphosphine oxide. Although a trialkyl phosphate can extract lanthanides and actinides from acidic solutions, a binary mixture comprising a fluorinated .beta.-diketone and a trialkyl phosphate or a trialkylphosphine oxide tends to enhance the extraction efficiencies for actinides and lanthanides. The method provides an environmentally benign process for removing contaminants from industrial waste without using acids or biologically harmful solvents. The method is particularly useful for extracting actinides and lanthanides from acidic solutions. The chelate and supercritical fluid can be regenerated, and the contaminant species recovered, to provide an economic, efficient process.

  20. The role of citric acid in oral peptide and protein formulations: relationship between calcium chelation and proteolysis inhibition.

    PubMed

    Welling, Søren H; Hubálek, František; Jacobsen, Jette; Brayden, David J; Rahbek, Ulrik L; Buckley, Stephen T

    2014-04-01

    The excipient citric acid (CA) has been reported to improve oral absorption of peptides by different mechanisms. The balance between its related properties of calcium chelation and permeation enhancement compared to a proteolysis inhibition was examined. A predictive model of CA's calcium chelation activity was developed and verified experimentally using an ion-selective electrode. The effects of CA, its salt (citrate, Cit) and the established permeation enhancer, lauroyl carnitine chloride (LCC) were compared by measuring transepithelial electrical resistance (TEER) and permeability of insulin and FD4 across Caco-2 monolayers and rat small intestinal mucosae mounted in Ussing chambers. Proteolytic degradation of insulin was determined in rat luminal extracts across a range of pH values in the presence of CA. CA's capacity to chelate calcium decreased ~10-fold for each pH unit moving from pH 6 to pH 3. CA was an inferior weak permeation enhancer compared to LCC in both in vitro models using physiological buffers. At pH 4.5 however, degradation of insulin in rat luminal extracts was significantly inhibited in the presence of 10mM CA. The capacity of CA to chelate luminal calcium does not occur significantly at the acidic pH values where it effectively inhibits proteolysis, which is its dominant action in oral peptide formulations. On account of insulin's low basal permeability, inclusion of alternative permeation enhancers is likely to be necessary to achieve sufficient oral bioavailability since this is a weak property of CA.

  1. Synthesis, characterization and catalytic activity of acid-base bifunctional materials through protection of amino groups

    SciTech Connect

    Shao, Yanqiu; Liu, Heng; Yu, Xiaofang; Guan, Jingqi; Kan, Qiubin

    2012-03-15

    Graphical abstract: Acid-base bifunctional mesoporous material SO{sub 3}H-SBA-15-NH{sub 2} was successfully synthesized under low acidic medium through protection of amino groups. Highlights: Black-Right-Pointing-Pointer The acid-base bifunctional material SO{sub 3}H-SBA-15-NH{sub 2} was successfully synthesized through protection of amino groups. Black-Right-Pointing-Pointer The obtained bifunctional material was tested for aldol condensation. Black-Right-Pointing-Pointer The SO{sub 3}H-SBA-15-NH{sub 2} catalyst containing amine and sulfonic acid groups exhibited excellent acid-basic properties. -- Abstract: Acid-base bifunctional mesoporous material SO{sub 3}H-SBA-15-NH{sub 2} was successfully synthesized under low acidic medium through protection of amino groups. X-ray diffraction (XRD), N{sub 2} adsorption-desorption, transmission electron micrographs (TEM), back titration, {sup 13}C magic-angle spinning (MAS) NMR and {sup 29}Si magic-angle spinning (MAS) NMR were employed to characterize the synthesized materials. The obtained bifunctional material was tested for aldol condensation reaction between acetone and 4-nitrobenzaldehyde. Compared with monofunctional catalysts of SO{sub 3}H-SBA-15 and SBA-15-NH{sub 2}, the bifunctional sample of SO{sub 3}H-SBA-15-NH{sub 2} containing amine and sulfonic acid groups exhibited excellent acid-basic properties, which make it possess high activity for the aldol condensation.

  2. The magnesium chelation step in chlorophyll biosynthesis

    SciTech Connect

    Weinstein, J.

    1990-11-01

    In photosynthetic organisms, the biogenesis of energy transducing membranes requires the coordinate synthesis of prosthetic groups, proteins, and various lipids. Two of the major prosthetic groups, chlorophyll and heme, share a common biosynthetic pathway that diverges at the point of metal insertion into protoporphyrin IX (Proto). Insertion of iron leads to the formation of hemes, while insertion of magnesium is the first step unique to chlorophyll formation. This project is directed toward identifying the enzyme(s) responsible for magnesium chelation and elucidating the mechanism which regulates the flux of precursors through the branch point enzymes in isolated chloroplasts. Using intact chloroplasts from greening cucumber cotyledons, we have confirmed the ATP requirement for Mg-Proto formation. Use of non-hydrolyzable ATP analogs, uncouplers and ionophores has led to the conclusions that ATP hydrolysis is necessary, but that this hydrolysis is not linked to the requirement for membrane intactness by transmembrane ion gradients or electrical potentials. The enzyme(s) are flexible with respect to the porphyrin substrate specificity, accepting porphyrins with -vinyl, -ethyl, or -H substituents at the 2 and 4 positions. The activity increases approximately four-fold during greening. Possible physiological feedback inhibitors such as heme, protochlorophyllide, and chlorophyllide had no specific effect on the activity. The activity has now been assayed in barely, corn and peas, with the system from peas almost ten-fold more active than the cucumber system. Work is continuing in pea chloroplasts with the development of a continuous assay and investigation of the feasibility of characterizing an active, organelle-free preparation. 6 figs.

  3. Reaction Current Phenomenon in Bifunctional Catalytic Metal-Semiconductor Nanostructures

    NASA Astrophysics Data System (ADS)

    Hashemian, Mohammad Amin

    Energy transfer processes accompany every elementary step of catalytic chemical processes on material surface including molecular adsorption and dissociation on atoms, interactions between intermediates, and desorption of reaction products from the catalyst surface. Therefore, detailed understanding of these processes on the molecular level is of great fundamental and practical interest in energy-related applications of nanomaterials. Two main mechanisms of energy transfer from adsorbed particles to a surface are known: (i) adiabatic via excitation of quantized lattice vibrations (phonons) and (ii) non-adiabatic via electronic excitations (electron/hole pairs). Electronic excitations play a key role in nanocatalysis, and it was recently shown that they can be efficiently detected and studied using Schottky-type catalytic nanostructures in the form of measureable electrical currents (chemicurrents) in an external electrical circuit. These nanostructures typically contain an electrically continuous nanocathode layers made of a catalytic metal deposited on a semiconductor substrate. The goal of this research is to study the direct observations of hot electron currents (chemicurrents) in catalytic Schottky structures, using a continuous mesh-like Pt nanofilm grown onto a mesoporous TiO2 substrate. Such devices showed qualitatively different and more diverse signal properties, compared to the earlier devices using smooth substrates, which could only be explained on the basis of bifunctionality. In particular, it was necessary to suggest that different stages of the reaction are occurring on both phases of the catalytic structure. Analysis of the signal behavior also led to discovery of a formerly unknown (very slow) mode of the oxyhydrogen reaction on the Pt/TiO2(por) system occurring at room temperature. This slow mode was producing surprisingly large stationary chemicurrents in the range 10--50 microA/cm2. Results of the chemicurrent measurements for the bifunctional

  4. Opioid bifunctional ligands from morphine and the opioid pharmacophore Dmt-Tic.

    PubMed

    Balboni, Gianfranco; Salvadori, Severo; Marczak, Ewa D; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Si, Yu Gui; Neumeyer, John L

    2011-02-01

    Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  5. Design, synthesis and DNA-binding capacity of a new peptidic bifunctional intercalating agent.

    PubMed Central

    Bernier, J L; Henichart, J P; Catteau, J P

    1981-01-01

    A lysyl-lysine bifunctional derivative of 9-aminoacridine has been synthesized and its DNA-binding capacity established by electron-paramagnetic-resonance study. For this purpose the binding parameters of a spin-labelled aminoacridine probe were estimated and the affinities of the lysylacridinyl-lysyldiamino-octane dimer and of 9-amino-acridine could be evaluated by competitive assays. The competition study provided quantitative results concerning the dissociation constant (KD) of the dimer. The obtained value was closely similar to the KD of 9-aminoacridine determined by the same method and to the KD previously reported for the anti-tumour and antibiotic bifunctional intercalator quinomycins. PMID:6280671

  6. Engineering Bifunctional Laccase-Xylanase Chimeras for Improved Catalytic Performance*

    PubMed Central

    Ribeiro, Lucas F.; Furtado, Gilvan P.; Lourenzoni, Marcos R.; Costa-Filho, Antonio J.; Santos, Camila R.; Nogueira, Simone C. Peixoto; Betini, Jorge A.; Polizeli, Maria de Lourdes T. M.; Murakami, Mario T.; Ward, Richard J.

    2011-01-01

    Two bifunctional enzymes exhibiting combined xylanase and laccase activities were designed, constructed, and characterized by biochemical and biophysical methods. The Bacillus subtilis cotA and xynA genes were used as templates for gene fusion, and the xynA coding sequence was inserted into a surface loop of the cotA. A second chimera was built replacing the wild-type xynA gene by a thermostable variant (xynAG3) previously obtained by in vitro molecular evolution. Kinetic measurements demonstrated that the pH and temperature optima of the catalytic domains in the chimeras were altered by less than 0.5 pH units and 5 °C, respectively, when compared with the parental enzymes. In contrast, the catalytic efficiency (kcat/Km) of the laccase activity in both chimeras was 2-fold higher than for the parental laccase. Molecular dynamics simulations of the CotA-XynA chimera indicated that the two domains are in close contact, which was confirmed by the low resolution structure obtained by small angle x-ray scattering. The simulation also indicates that the formation of the inter-domain interface causes the dislocation of the loop comprising residues Leu-558 to Lys-573 in the laccase domain, resulting in a more accessible active site and exposing the type I Cu2+ ion to the solvent. These structural changes are consistent with the results from UV-visible electronic and EPR spectroscopy experiments of the type I copper between the native and chimeric enzymes and are likely to contribute to the observed increase in catalytic turnover number. PMID:22006920

  7. Physical properties of bifunctional BST/LSMO nanocomposites

    SciTech Connect

    Beltran-Huarac, Juan Morell, Gerardo; Martinez, Ricardo

    2014-02-28

    We report the fabrication of bifunctional nanocomposites consisting of ferroelectric Ba{sub 0.7}Sr{sub 0.3}TiO{sub 3} (BST) and ferromagnetic La{sub 0.67}Sr{sub 0.33}MnO{sub 3} (LSMO) at different concentrations via a high-temperature solid state route. The structural, dielectric, electrical, magnetodielectric (MD), magnetoelectric (ME) and magnetic properties of BST/LSMO nanocomposites were systematically investigated over a wide range of temperatures and frequencies. The X-Ray Diffraction analyses reveal the nanocrystalline nature of the heterostructures, wherein both perovskite phases co-exist. No parasitic phases were observed. The study of the dielectric properties shows that the nanocomposites exhibit relaxor ferroelectric character, with ferroelectric-paraelectric phase transition temperatures around 287–292 K that do not follow the Curie-Weiss law. The electrical measurements indicate that ac conductivities of the nanocomposites follow the Jonscher's universal power law, with activation energies of 0.42–0.63 eV based on Arrhenius-type behavior at high temperatures. The nanocomposites exhibit well-defined ferromagnetic hysteresis loops at room temperature (RT). The MD and ME measurements at RT indicate that BST/LSMO exhibits a nonlinear ME effect at low frequencies, with a threshold near 0.5 T. The magnetocapacitance (MC{sub p}) measurements evidence a quadratic dependence on magnetic field, further confirming the multiferroic nature of BST/LSMO. The order of MC{sub p} was found to be ∼7% per Tesla. The analysis of the MC{sub p} measurements indicates that one of the BST/LSMO compositions studied can be considered as a new multiferroic compound.

  8. Bifunctional Ligands Allow Deliberate Extrinsic Reprogramming of the Glucocorticoid Receptor

    PubMed Central

    Højfeldt, Jonas W.; Cruz-Rodríguez, Osvaldo; Imaeda, Yasuhiro; Van Dyke, Aaron R.; Carolan, James P.; Mapp, Anna K.

    2014-01-01

    Therapies based on conventional nuclear receptor ligands are extremely powerful, yet their broad and long-term use is often hindered by undesired side effects that are often part of the receptor's biological function. Selective control of nuclear receptors such as the glucocorticoid receptor (GR) using conventional ligands has proven particularly challenging. Because they act solely in an allosteric manner, conventional ligands are constrained to act via cofactors that can intrinsically partner with the receptor. Furthermore, effective means to rationally encode a bias for specific coregulators are generally lacking. Using the (GR) as a framework, we demonstrate here a versatile approach, based on bifunctional ligands, that extends the regulatory repertoire of GR in a deliberate and controlled manner. By linking the macrolide FK506 to a conventional agonist (dexamethasone) or antagonist (RU-486), we demonstrate that it is possible to bridge the intact receptor to either positively or negatively acting coregulatory proteins bearing an FK506 binding protein domain. Using this strategy, we show that extrinsic recruitment of a strong activation function can enhance the efficacy of the full agonist dexamethasone and reverse the antagonist character of RU-486 at an endogenous locus. Notably, the extrinsic recruitment of histone deacetylase-1 reduces the ability of GR to activate transcription from a canonical GR response element while preserving ligand-mediated repression of nuclear factor-κB. By providing novel ways for the receptor to engage specific coregulators, this unique ligand design approach has the potential to yield both novel tools for GR study and more selective therapeutics. PMID:24422633

  9. Monodisperse Magneto-Fluorescent Bifunctional Nanoprobes for Bioapplications

    NASA Astrophysics Data System (ADS)

    Zhang, Hongwang; Huang, Heng; Pralle, Arnd; Zeng, Hao

    2013-03-01

    We present the work on the synthesis of dye-doped monodisperse Fe/SiO2 core/shell nanoparticles as bifunctional probes for bioapplications. Magnetic nanoparticles (NP) have been widely studied as nano-probes for bio-imaging, sensing as well as for cancer therapy. Among all the NPs, Fe NPs have been the focus because they have very high magnetization. However, Fe NPs are usually not stable in ambient due to the fast surface oxidation of the NPs. On the other hand, dye molecules have long been used as probes for bio-imaging. But they are sensitive to environmental conditions. It requires passivation for both so that they can be stable for applications. In this work, monodisperse Fe NPs with sizes ranging from 13-20 nm have been synthesized through the chemical thermal-decomposition in a solution. Silica shells were then coated on the Fe NPs by a two-phase oil-in-water method. Dye molecules were first bonded to a silica precursor and then encapsulated into the silica shell during the coating process. The silica shells protect both the Fe NPs and dye molecules, which makes them as robust probes. The dye doped Fe/SiO2 core/shell NPs remain both highly magnetic and highly fluorescent. The stable dye doped Fe/SiO2NPs have been used as a dual functional probe for both magnetic heating and local nanoscale temperature sending, and their performance will be reported. Research supported by NSF DMR 0547036, DMR1104994.

  10. Fabrication and Characterization of Luminescent Magnetic Bifunctional Nanocomposite Based on TbPO4·H2O Nanowires and Fe3O4 Nanoparticles

    NASA Astrophysics Data System (ADS)

    Huong, Nguyen Thanh; Hung, Nguyen Manh; Lien, Pham Thi; Van, Nguyen Duc; Nam, Pham Hong; Binh, Nguyen Thanh; Minh, Le Quoc

    2016-07-01

    The fabrication and properties of luminescent magnetic bifunctional nanocomposites comprised of TbPO4·H2O nanowires as a core and magnetite nanoparticles as a shell are presented. TbPO4·H2O nanowires were synthesized by a microwave-assisted method while the grafting process of freshly-formed superparamagnetic magnetite nanoparticles on the surface of luminescent nanowires was carried out by a co-precipitate method. The effects of the Fe3O4/TbPO4·H2O mass ratio on the luminescent and magnetic properties of the obtained nanocomposite were also investigated. The results showed that, for the optimized bifunctional nanocomposites, green luminescent emissions at 488 nm, 542 nm, 585 nm, 620 nm and superparamagnetic behavior with saturation magnetization M s of 6 emu/g were achieved. With a hyperthermia temperature of ~43.5°C under an alternating current (AC) magnetic field, the obtained TbPO4·H2O/Fe3O4 nanocomposite was expected to be used for both optical probing and hyperthermia cancer treatments in biomedical applications.

  11. Method for preparing radionuclide-labeled chelating agent-ligand complexes

    DOEpatents

    Meares, Claude F.; Li, Min; DeNardo, Sally J.

    1999-01-01

    Radionuclide-labeled chelating agent-ligand complexes that are useful in medical diagnosis or therapy are prepared by reacting a radionuclide, such as .sup.90 Y or .sup.111 In, with a polyfunctional chelating agent to form a radionuclide chelate that is electrically neutral; purifying the chelate by anion exchange chromatography; and reacting the purified chelate with a targeting molecule, such as a monoclonal antibody, to form the complex.

  12. The Effect of Different Tea Varieties on Iron Chelation

    NASA Astrophysics Data System (ADS)

    Truong, S. K.; Karim, R.

    2016-12-01

    The chief objectives of this experiment are to distinguish which type of tea of four variants, pomegranate blackberry green, green, lemon chamomile (herbal), and earl grey (black), are capable of chelating the most iron (III) chloride (FeCl3) through titration. We hypothesized that if each tea variety chelates differing amounts of iron chloride, and if we conduct an experiment in which four different teas are mixed in the same amount of water, iron chloride, and iron chloride indicator EDTA, then the pomegranate blackberry green tea will bind to the most iron due to its large amount of fruit antioxidants. To summarize our methodology, we prepared three solutions of each tea, dissolved with 1 gram of FeCl3 to test three trials per tea variety. The chelation process took place overnight as teas cooled. Six drops of iron chloride indicator added to each solution began the titration. The necessary amount of 0.1M EDTA (ethylenediaminetetraacetic acid) drops required for each solution to turn to a universal amber color from its original dark tone indicates how many free iron molecules were left unbound by the tea solution. After careful analysis of the data, we discovered that blackberry pomegranate green tea possessed the best chelating abilities with 97.48% of FeCl3 adsorbed. Green tea followed with 96.67%. Herbal tea chelated 94.24% of the iron while earl grey absorbed the least amount at 93.43%. From our conclusion, we drew that since blackberry pomegranate green tea contained the highest amount of polyphenols and antioxidants as well as epigallocatechin gallate (EGCG) found in green teas, it was able to chelate the most amount of iron. The substances mentioned in blackberry pomegranate green tea possess the ability to form strong bonds with multiple heavy metals, such as iron (III) chloride atoms. Overall, each variety of tea contains different organic substances. Each of these substances possesses a unique chelating ability, determining how well the type of tea can

  13. Regional siderosis: a new challenge for iron chelation therapy

    PubMed Central

    Cabantchik, Zvi Ioav; Munnich, Arnold; Youdim, Moussa B.; Devos, David

    2013-01-01

    The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g., sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson's disease). We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation of dual activity, one based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The “scavenging and redeployment” mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson's disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic functions. PMID:24427136

  14. Alternative security

    SciTech Connect

    Weston, B.H. )

    1990-01-01

    This book contains the following chapters: The Military and Alternative Security: New Missions for Stable Conventional Security; Technology and Alternative Security: A Cherished Myth Expires; Law and Alternative Security: Toward a Just World Peace; Politics and Alternative Security: Toward a More Democratic, Therefore More Peaceful, World; Economics and Alternative Security: Toward a Peacekeeping International Economy; Psychology and Alternative Security: Needs, Perceptions, and Misperceptions; Religion and Alternative Security: A Prophetic Vision; and Toward Post-Nuclear Global Security: An Overview.

  15. Hydroxyiminodisuccinic acid (HIDS): A novel biodegradable chelating ligand for the increase of iron bioavailability and arsenic phytoextraction.

    PubMed

    Rahman, M Azizur; Hasegawa, H; Kadohashi, K; Maki, T; Ueda, K

    2009-09-01

    The influence of biodegradable chelating ligands on arsenic and iron uptake by hydroponically grown rice seedlings (Oryza sativa L.) was investigated. Even though the growth solution contained sufficient Fe, the growth of rice seedlings gradually decreased up to 76% with the increase of pH of the solution from 7 to 11. Iron forms insoluble ferric hydroxide complexes at neutral or alkaline pH in oxic condition. Chelating ligands produce soluble 'Fe-ligand complex' which assist Fe uptake in plants. The biodegradable chelating ligand hydroxyiminodisuccinic acid (HIDS) was more efficient then those of ethylenediaminetetraacetic acid (EDTA), ethylenediaminedisuccinic acid (EDDS), and iminodisuccinic acid (IDS) in the increase of Fe uptake and growth of rice seedling. A total of 79+/-20, 87+/-6, 116+/-15, and 63+/-18mg dry biomass of rice seedlings were produced with the addition of 0.5mM of EDDS, EDTA, HIDS, and IDS in the nutrient solution, respectively. The Fe concentrations in rice tissues were 117+/-15, 82+/-8, 167+/-25, and 118+/-22micromolg(-1) dry weights when 0.25mM of EDDS, EDTA, HIDS, and IDS were added to the nutrient solution, respectively. Most of the Fe accumulated in rice tissues was stored in roots after the addition of chelating ligands in the solution. The results indicate that the HIDS would be a potential alternative to environmentally persistent EDTA for the increase of Fe uptake and plant growth. The HIDS also increased As uptake in rice root though its translocation from root to shoot was not augmented. This study reports HIDS for the first time as a promising chelating ligand for the enhancement of Fe bioavailability and As phytoextraction.

  16. Mercury exposure: evaluation and intervention the inappropriate use of chelating agents in the diagnosis and treatment of putative mercury poisoning.

    PubMed

    Risher, John F; Amler, Sherlita N

    2005-08-01

    Public awareness of the potential for mercury to cause health problems has increased dramatically in the last 15 years. It is now widely recognized that significant exposure to all forms of mercury (elemental/metallic and both inorganic and organic compounds) can result in a variety of adverse health effects, including neurological, renal, respiratory, immune, dermatologic, reproductive, and developmental sequellae. And while the various media have made the general population cognizant of the need to avoid unnecessary exposure to this naturally occurring element, there has also evolved a growing tendency to attribute unexplainable neurologic, as well as other, signs and symptoms to mercury, whether or not significant exposure to mercury has actually occurred. For the physician, making a diagnosis of mercury intoxication can be difficult, because many of the clinical signs and symptoms of mercury exposure can also be attributed to any number of causes, including undiagnosed neurological diseases, pharmacotherapy, vitamin or mineral deficiencies, and psychological stress. The physician must be able to recognize the clinical manifestations of mercury intoxication, and understand the importance of biological markers in making a definitive diagnosis of mercury poisoning. In a desire to treat the patient complaining of symptoms similar to some that can be caused by mercury, a growing number of physicians, particularly those in alternative medicine fields, result to chelation to "rid" the body of the mercury, believed to be the cause of the ailments. And although the use of chelation is increasing, controlled studies showing that this procedure actually improves outcome are lacking. If chelation therapy is considered to be indicated, the attending physician should communicate the risks of chelation to the patient before beginning treatment with metal-chelating drugs.

  17. Sequestration of chelated copper by structural Fe(II): Reductive decomplexation and transformation of Cu(II)-EDTA.

    PubMed

    He, Hongping; Wu, Deli; Zhao, Linghui; Luo, Cong; Dai, Chaomeng; Zhang, Yalei

    2016-05-15

    Chelated coppers, such as Cu(II)-EDTA, are characteristically refractory and difficult to break down because of their high stability and solubility. Cu(II)-EDTA sequestration by structural Fe(II) (Fe(II)) was investigated intensively in this study. Up to 101.21mgCu(II)/gFe(II) was obtained by Fe(II) in chelated copper sequestration under near neutral pH condition (pH 7.70). The mechanism of Cu(II)-EDTA sequestration by Fe(II) was concluded as follows: 3Cu(II)-EDTA+7Fe(II)+9H2O → Cu(0)↓+ Cu2O↓(the major product)+2Fe2O3·H2O↓+3Fe(II)-EDTA +14H(+) Novel results strongly indicate that Cu(II) reductive transformation induced by surface Fe(II) was mainly responsible for chelated copper sequestration. Cu(0) generation was initially facilitated, and subsequent reduction of Cu(II) into Cu(I) was closely combined with the gradual increase of ORP (Oxidation-Reduction Potential). Cu-containing products were inherently stable, but Cu2O would be reoxidized to Cu(II) with extra-aeration, resulting in the release of copper, which was beneficial to Cu reclamation. Concentration diminution of Cu(II)-EDTA within the electric double layer and competitive adsorption were responsible for the negative effects of Ca(2+), Mg(2+). By generating vivianite, PO4(3-) was found to decrease surface Fe(II) content. This study is among the first ones to identify the indispensible role of reductive decomplexation in chelated copper sequestration. Given the high feasibility and reactivity, Fe(II) may provide a potential alternative in chelated metals pollution controlling.

  18. Oxidation-Induced Degradable Nanogels for Iron Chelation

    NASA Astrophysics Data System (ADS)

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-02-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells.

  19. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Xu, Jide

    1997-01-01

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of said chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to said 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities.

  20. Chelation in metal intoxication--Principles and paradigms.

    PubMed

    Aaseth, Jan; Skaug, Marit Aralt; Cao, Yang; Andersen, Ole

    2015-01-01

    The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review.

  1. Essential Metalloelement Chelates Facilitate Repair of Radiation Injury

    PubMed Central

    Soderberg, Lee S. F.; Chang, Louis W.; Walker, Richard B.

    2001-01-01

    Treatment with essential metalloelement (Cu, Fe, Mn, and Zn) chelates or combinations of them before and/or after radiation injury is a useful approach to overcoming radiation injury. No other agents are known to increase survival when they are used to treat after irradiation, in a radiorecovery treatment paradigm. These chelates may be useful in facilitating de novo syntheses of essential metalloelement-dependent enzymes required to repair radiation injury. Reports of radioprotection, which involves treatment before irradiation, with calcium-channel blockers, acyl Melatonin homologs, and substituted anilines, which may serve as chelating agents after biochemical modification in vivo, as well as Curcumin, which is a chelating agent, have been included in this review. These inclusions are intended to suggest additional approaches to combination treatments that may be useful in facilitating radiation recovery. These approaches to radioprotection and radiorecovery offer promise in facilitating recovery from radiation-induced injury experienced by patients undergoing radiotherapy for neoplastic disease and by individuals who experience environmental, occupational, or accidental exposure to ultraviolet, x-ray, or γ-ray radiation. Since there are no existing treatments of radiation-injury intended to facilitate tissue repair, studies of essential metalloelement chelates and combinations of them, as well as combinations of them with existing organic radioprotectants, seem worthwhile. PMID:18475999

  2. Ab initio coordination chemistry for nickel chelation motifs.

    PubMed

    Sudan, R Jesu Jaya; Kumari, J Lesitha Jeeva; Sudandiradoss, C

    2015-01-01

    Chelation therapy is one of the most appreciated methods in the treatment of metal induced disease predisposition. Coordination chemistry provides a way to understand metal association in biological structures. In this work we have implemented coordination chemistry to study nickel coordination due to its high impact in industrial usage and thereby health consequences. This paper reports the analysis of nickel coordination from a large dataset of nickel bound structures and sequences. Coordination patterns predicted from the structures are reported in terms of donors, chelate length, coordination number, chelate geometry, structural fold and architecture. The analysis revealed histidine as the most favored residue in nickel coordination. The most common chelates identified were histidine based namely HHH, HDH, HEH and HH spaced at specific intervals. Though a maximum coordination number of 8 was observed, the presence of a single protein donor was noted to be mandatory in nickel coordination. The coordination pattern did not reveal any specific fold, nevertheless we report preferable residue spacing for specific structural architecture. In contrast, the analysis of nickel binding proteins from bacterial and archeal species revealed no common coordination patterns. Nickel binding sequence motifs were noted to be organism specific and protein class specific. As a result we identified about 13 signatures derived from 13 classes of nickel binding proteins. The specifications on nickel coordination presented in this paper will prove beneficial for developing better chelation strategies.

  3. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.N.; Xu, J.

    1997-04-29

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities. 2 figs.

  4. Three plutonium chelation cases at Los Alamos National Laboratory.

    PubMed

    Bertelli, Luiz; Waters, Tom L; Miller, Guthrie; Gadd, Milan S; Eaton, Michelle C; Guilmette, Raymond A

    2010-10-01

    Chelation treatments with dosages of 1 g of either Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or Zn-DTPA (Trisodium zinc diethylenetriaminepentaacetate) were undertaken at Los Alamos Occupational Medicine in three recent cases of wounds contaminated with metallic forms of Pu. All cases were finger punctures, and each chelation injection contained the same dosage of DTPA. One subject was treated only once, while the other two received multiple injections. Additional measurements of wound, urine, and excised tissues were taken for one of the cases. These additional measurements served to improve the estimate of the efficacy of the chelation treatment. The efficacy of the chelation treatments was compared for the three cases. Results were interpreted using models, and useful heuristics for estimating the intake amount and final committed doses were presented. In spite of significant differences in the treatments and in the estimated intake amounts and doses amongst the three cases, a difference of four orders of magnitude was observed between the highest excretion data point and the values observed at about 100 d for all cases. Differences between efficacies of Zn-DTPA and Ca-DTPA could not be observed in this study. An efficacy factor of about 50 was observed for a chelation treatment, which was administered at about 1.5 y after the incident, though the corresponding averted dose was very small (LA-UR 09-02934).

  5. Supercritical Fluid Extraction of Metal Chelate: A Review.

    PubMed

    Ding, Xin; Liu, Qinli; Hou, Xiongpo; Fang, Tao

    2017-03-04

    Supercritical fluid extraction (SFE), as a new green extraction technology, has been used in extracting various metal species. The solubilities of chelating agents and corresponding metal chelates are the key factors which influence the efficiency of SFE. Other main properties of them such as stability and selectivity are also reviewed. The extraction mechanisms of mainly used chelating agents are explained by typical examples in this paper. This is the important aspect of SFE of metal ions. Moreover, the extraction efficiencies of metal species also depend on other factors such as temperature, pressure, extraction time and matrix effect. The two main complexation methods namely in-situ and on-line chelating SFE are described in detail. As an efficient chelating agent, tributyl phosphate-nitric acid (TBP-HNO3) complex attracts much attention. The SFE of metal ions, lanthanides and actinides as well as organometallic compounds are also summarized. With the proper selection of ligands, high efficient extraction of metal species can be obtained. As an efficient sample analysis method, supercritical fluid chromatography (SFC) is introduced in this paper. Recently, the extraction method combining ionic liquids (ILs) with supercritical fluid has been becoming a novel technology for treating metal ions. The kinetics related to SFE of metal species is discussed with some specific examples.

  6. Oxidation-Induced Degradable Nanogels for Iron Chelation

    PubMed Central

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-01-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells. PMID:26868174

  7. Ab Initio Coordination Chemistry for Nickel Chelation Motifs

    PubMed Central

    Jesu Jaya Sudan, R.; Lesitha Jeeva Kumari, J.; Sudandiradoss, C.

    2015-01-01

    Chelation therapy is one of the most appreciated methods in the treatment of metal induced disease predisposition. Coordination chemistry provides a way to understand metal association in biological structures. In this work we have implemented coordination chemistry to study nickel coordination due to its high impact in industrial usage and thereby health consequences. This paper reports the analysis of nickel coordination from a large dataset of nickel bound structures and sequences. Coordination patterns predicted from the structures are reported in terms of donors, chelate length, coordination number, chelate geometry, structural fold and architecture. The analysis revealed histidine as the most favored residue in nickel coordination. The most common chelates identified were histidine based namely HHH, HDH, HEH and HH spaced at specific intervals. Though a maximum coordination number of 8 was observed, the presence of a single protein donor was noted to be mandatory in nickel coordination. The coordination pattern did not reveal any specific fold, nevertheless we report preferable residue spacing for specific structural architecture. In contrast, the analysis of nickel binding proteins from bacterial and archeal species revealed no common coordination patterns. Nickel binding sequence motifs were noted to be organism specific and protein class specific. As a result we identified about 13 signatures derived from 13 classes of nickel binding proteins. The specifications on nickel coordination presented in this paper will prove beneficial for developing better chelation strategies. PMID:25985439

  8. Asymmetric Michael addition reactions of nitroalkanes to 2-furanones catalyzed by bifunctional thiourea catalysts.

    PubMed

    Bai, Zhushuang; Ji, Ling; Ge, Zemei; Wang, Xin; Li, Runtao

    2015-05-21

    The first bifunctional thiourea catalyzed asymmetric Michael addition reactions of nitroalkanes to 2-furanones are described. The highly functionalized γ-lactones with two or three consecutive stereogenic carbons were obtained in high yields (up to 99%), high diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

  9. Liquid phase in situ hydrodeoxygenation of biomass-derived phenolic compounds to hydrocarbons over bifunctional catalysts

    Treesearch

    Junfeng Feng; Chung-yun Hse; Zhongzhi Yang; Kui Wang; Jianchun Jiang; Junming Xu

    2017-01-01

    The objective of this study was to find an effective method for converting renewable biomass-derived phenolic compounds into hydrocarbons bio-fuel via in situ catalytic hydrodeoxygenation. The in situ hydrodeoxygenation of biomass-derived phenolic compounds was carried out in methanol-water solvent over bifunctional catalysts of Raney Ni and HZSM-5 or H-Beta. In the in...

  10. Preparation of bi-functional silica particles for antibacterial and self cleaning surfaces.

    PubMed

    Hebalkar, Neha Y; Acharya, Snigdhatanu; Rao, Tata N

    2011-12-01

    Synthesis of bi-functional silica particles by a simple wet chemical method is described where the mixture of ultra fine nanoparticles (1-3 nm) of titania and silver were attached on the silica particle surface in a controlled way to form a core-shell structure. The silica surface showed efficient bi-functional activity of photo-catalytically self cleaning and antibacterial activity due to nanotitania and nanosilver mutually benefiting each other's function. The optimum silver concentration was found where extremely small silver nanoparticles are formed and the total composite particle remains white in color. This is an important property in view of certain applications such as antibacterial textiles where the original fabric color has to be retained even after applying the nanosilver on it. The particles were characterized at each step of the synthesis by X-ray photoelectron spectroscopy, UV-visible spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy and electron energy loss spectroscopy. Bi-functional silica particles showed accelerated photocatalytic degradation of methylene blue as well as enhanced antibacterial property when tested as such particles and textiles coated with these bi-functional silica particles even at lower silver concentration.

  11. Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

    PubMed Central

    Yamamoto, Yoshiharu

    2016-01-01

    Summary An asymmetric α-amination of β-keto esters with azodicarboxylate in the presence of a guanidine–bisurea bifunctional organocatalyst was investigated. The α-amination products were obtained in up to 99% yield with up to 94% ee. PMID:26977179

  12. Metagenomic Analysis of Apple Orchard Soil Reveals Antibiotic Resistance Genes Encoding Predicted Bifunctional Proteins▿

    PubMed Central

    Donato, Justin J.; Moe, Luke A.; Converse, Brandon J.; Smart, Keith D.; Berklein, Flora C.; McManus, Patricia S.; Handelsman, Jo

    2010-01-01

    To gain insight into the diversity and origins of antibiotic resistance genes, we identified resistance genes in the soil in an apple orchard using functional metagenomics, which involves inserting large fragments of foreign DNA into Escherichia coli and assaying the resulting clones for expressed functions. Among 13 antibiotic-resistant clones, we found two genes that encode bifunctional proteins. One predicted bifunctional protein confers resistance to ceftazidime and contains a natural fusion between a predicted transcriptional regulator and a β-lactamase. Sequence analysis of the entire metagenomic clone encoding the predicted bifunctional β-lactamase revealed a gene potentially involved in chloramphenicol resistance as well as a predicted transposase. A second clone that encodes a predicted bifunctional protein confers resistance to kanamycin and contains an aminoglycoside acetyltransferase domain fused to a second acetyltransferase domain that, based on nucleotide sequence, was predicted not to be involved in antibiotic resistance. This is the first report of a transcriptional regulator fused to a β-lactamase and of an aminoglycoside acetyltransferase fused to an acetyltransferase not involved in antibiotic resistance. PMID:20453147

  13. Nanosheet Supported Single-Metal Atom Bifunctional Catalyst for Overall Water Splitting.

    PubMed

    Ling, Chongyi; Shi, Li; Ouyang, Yixin; Zeng, Xiao Cheng; Wang, Jinlan

    2017-08-09

    Nanosheet supported single-atom catalysts (SACs) can make full use of metal atoms and yet entail high selectivity and activity, and bifunctional catalysts can enable higher performance while lowering the cost than two separate unifunctional catalysts. Supported single-atom bifunctional catalysts are therefore of great economic interest and scientific importance. Here, on the basis of first-principles computations, we report a design of the first single-atom bifunctional eletrocatalyst, namely, isolated nickel atom supported on β12 boron monolayer (Ni1/β12-BM), to achieve overall water splitting. This nanosheet supported SAC exhibits remarkable electrocatalytic performance with the computed overpotential for oxygen/hydrogen evolution reaction being just 0.40/0.06 V. The ab initio molecular dynamics simulation shows that the SAC can survive up to 800 K elevated temperature, while enacting a high energy barrier of 1.68 eV to prevent isolated Ni atoms from clustering. A viable experimental route for the synthesis of Ni1/β12-BM SAC is demonstrated from computer simulation. The desired nanosheet supported single-atom bifunctional catalysts not only show great potential for achieving overall water splitting but also offer cost-effective opportunities for advancing clean energy technology.

  14. Improved bone morphogenetic protein-2 retention in an injectable collagen matrix using bifunctional peptides.

    PubMed

    Hamilton, Paul T; Jansen, Michelle S; Ganesan, Sathya; Benson, R Edward; Hyde-Deruyscher, Robin; Beyer, Wayne F; Gile, Joseph C; Nair, Shrikumar A; Hodges, Jonathan A; Grøn, Hanne

    2013-01-01

    To promote healing of many orthopedic injuries, tissue engineering approaches are being developed that combine growth factors such as Bone Morphogenetic Proteins (BMP) with biomaterial carriers. Although these technologies have shown great promise, they still face limitations. We describe a generalized approach to create target-specific modular peptides that bind growth factors to implantable biomaterials. These bifunctional peptide coatings provide a novel way to modulate biology on the surface of an implant. Using phage display techniques, we have identified peptides that bind with high affinity to BMP-2. The peptides that bind to BMP-2 fall into two different sequence clusters. The first cluster of peptide sequences contains the motif W-X-X-F-X-X-L (where X can be any amino acid) and the second cluster contains the motif F-P-L-K-G. We have synthesized bifunctional peptide linkers that contain BMP-2 and collagen-binding domains. Using a rat ectopic bone formation model, we have injected rhBMP-2 into a collagen matrix with or without a bifunctional BMP-2: collagen peptide (BC-1). The presence of BC-1 significantly increased osteogenic cellular activity, the area of bone formed, and bone maturity at the site of injection. Our results suggest that bifunctional peptides that can simultaneously bind to a growth factor and an implantable biomaterial can be used to control the delivery and release of growth factors at the site of implantation.

  15. Bifunctional N-heterocyclic carbene-catalyzed highly enantioselective synthesis of spirocyclic oxindolo-β-lactams.

    PubMed

    Zhang, Han-Ming; Gao, Zhong-Hua; Ye, Song

    2014-06-06

    The N-heterocyclic carbene-catalyzed Staudinger reaction of ketenes with isatin-derived ketimines was investigated. The bifunctional NHCs with a free hydroxyl group were demonstrated as efficient catalysts for the reaction, giving the corresponding spirocyclic oxindolo-β-lactams in high yields with excellent diastereo- and enantioselectivities.

  16. The role of chelation in the treatment of other metal poisonings.

    PubMed

    Smith, Silas W

    2013-12-01

    These proceedings will review the role of chelation in five metals-aluminum, cadmium, chromium, cobalt, and uranium-in order to illustrate various chelation concepts. The process of "chelation" can often be oversimplified, leading to incorrect assumptions and risking patient harm. For chelation to be effective, two critical assumptions must be fulfilled: the presumed "metal toxicity" must correlate with a given body or a particular compartment burden, and reducing this compartmental or the body burden (through chelation) attenuates toxicity. Fulfilling these assumptions requires an established dose-response relationship, a validated, reproducible means of toxicity assessment (clinical, biochemical, or radiographical), and an appropriate assessment mechanisms of body or compartment burden. While a metal might "technically" be capable of chelation (and readily demonstrable in urine or feces), this is an insufficient endpoint. Clinical relevance must be affirmed. Deferoxamine is an accepted chelator for appropriately documented aluminum toxicity. There is a very minimal treatment window in order to address chelation in cadmium toxicity. In acute toxicity, while no definitive chelation benefit is described, succimer (DMSA), diethylenetriaminepentaacetate (DTPA), and potentially ethylenediaminetetraacetic acid (EDTA) have been considered. In chronic toxicity, chelation is unsupported. There is little evidence to suggest that currently available chromium chelators are efficacious. Similarly, scant human evidence exists with which to provide recommendation for cobalt chelation. DTPA has been recommended for cobalt radionuclide chelation, although DMSA, EDTA, and N-acetylcysteine have also been suggested. DTPA is unsupported for uranium chelation. Sodium bicarbonate is currently recommended, although animal evidence is conflicting.

  17. Inflammation induced by photocoagulation laser is minimized by copper chelators

    PubMed Central

    Cui, Jing Z.; Wang, Xue-Feng; Hsu, Lena

    2014-01-01

    The effect of trientine hydrochloride (TRIEN), a copper-selective chelating agent, on retinal inflammation induced by photocoagulation laser treatment was studied. Nine Long-Evans rats were treated with TRIEN (0.5 mmol/kg per day, intraperitoneal injection) for 9 days. On day 8, each animal underwent unilateral photocoagulation laser treatment with an argon dye laser. On day 9, animals were killed and the eyes processed for immunohistochemistry and light microscopy. In the TRIEN-treated group, retinal thickness and number of macrophages (ED-1) were both significantly lower than in the saline-treated, control group exposed to laser photocoagulation. The results support the hypothesis that selective copper chelation prior to laser treatment may inhibit ocular inflammation. The results suggest that pretreatment with a selective copper-chelating compound can minimize retinal inflammation secondary to laser photocoagulation treatment, which may improve overall outcome of photocoagulation treatment for diabetic retinopathy. PMID:18566852

  18. Inflammation induced by photocoagulation laser is minimized by copper chelators.

    PubMed

    Cui, Jing Z; Wang, Xue-Feng; Hsu, Lena; Matsubara, Joanne A

    2009-07-01

    The effect of trientine hydrochloride (TRIEN), a copper-selective chelating agent, on retinal inflammation induced by photocoagulation laser treatment was studied. Nine Long-Evans rats were treated with TRIEN (0.5 mmol/kg per day, intraperitoneal injection) for 9 days. On day 8, each animal underwent unilateral photocoagulation laser treatment with an argon dye laser. On day 9, animals were killed and the eyes processed for immunohistochemistry and light microscopy. In the TRIEN-treated group, retinal thickness and number of macrophages (ED-1) were both significantly lower than in the saline-treated, control group exposed to laser photocoagulation. The results support the hypothesis that selective copper chelation prior to laser treatment may inhibit ocular inflammation. The results suggest that pretreatment with a selective copper-chelating compound can minimize retinal inflammation secondary to laser photocoagulation treatment, which may improve overall outcome of photocoagulation treatment for diabetic retinopathy.

  19. Characterization of a metal-chelating substance in coffee.

    PubMed

    Takenaka, Makiko; Sato, Naoko; Asakawa, Hiromi; Wen, Xu; Murata, Masatsune; Homma, Seiichi

    2005-01-01

    A metal-chelating substance in brewed coffee was separated and characterized by its chemical structure. This substance was a brown polymer. The contents of sugars, amino acids and phenolics in the substance were evaluated. This polymer contained small amounts of sugars and amino acids in its partial structure. After being decomposed by alkaline fusion, the decomposition products were identified by HPLC and GC-MS. Several phenolics were detected in the decomposed products. To characterize this substance, various types of model compounds were prepared by roasting chlorogenic acid, sucrose, and (or) protein with cellulose powder. Among these model compounds, the polymer-forming ability was highest in the model prepared from all four of materials, but the metal-chelating ability was the highest in the model prepared from chlorogenic acid and cellulose. These results suggest that this metal-chelating substance was a melanoidin-like polymer formed by the decomposition and polymerization of sugars, amino acids and phenolics.

  20. Molecular nanotechnologies of gelatin-immobilization using macrocyclic metal chelates

    PubMed Central

    Mikhailov, Oleg V.

    2014-01-01

    This article is a review of recent developments in the self-assembled nanostructures based on chelate coordination compounds. Molecular nanotechnologies of self-assembly of 3d-element aza- and thiazametalmacrocyclic complexes that happen in nanoreactors on the basis of metal hexacyanoferrate(II) gelatin-immobilized matrix under their contact with water solutions containing various (N,O,S)-donor atomic ligands and organic compounds having one or two carbonyl groups have been considered in this review. It has been noted that the assortment of macrocyclic metal chelates obtained as a result of using molecular nanotechnologies in such specific conditions considerably differs from the assortment of metal chelates formed at the conditions traditional for chemical synthesis. PMID:24516711

  1. Kinetics of dissociation of trivalent actinide chelates of TMDTA

    SciTech Connect

    Muscatello, A.C.; Choppin, G.R.; D'Olieslager, W. )

    1989-03-22

    Measurements by a radiotracer technique show that the dissociation of TMDTA (trimethylenediamine-N,N-tetraacetic acid) chelates with Am, Cm, Bk, Cf, and Eu proceeds through an acid-catalyzed pathway. The rates of dissociation of An(TMDTA){sup {minus}} are 2 orders of magnitude faster than those of the corresponding EDTA chelates, presumably due to the greater lability of the nitrogen atom in the six-membered nitrogen-metal-nitrogen ring of TMDTA chelates. The rate of dissociation also decreased with decreasing metal ion radius. A proton-catalyzed mechanism similar to that for dissociation of EDTA complexes of lanthanide and actinide cations is consistent with the rate data. 19 refs., 6 figs., 2 tabs.

  2. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.

    PubMed

    Vlachodimitropoulou, Evangelia; Chen, Yu-Lin; Garbowski, Maciej; Koonyosying, Pimpisid; Psaila, Bethan; Sola-Visner, Martha; Cooper, Nichola; Hider, Robert; Porter, John

    2017-09-01

    Eltrombopag (ELT) is a thrombopoietin receptor agonist, also reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β2=35). Clinically achievable concentrations (1μM) progressively mobilised cellular iron from hepatocyte, cardiomyocyte and pancreatic cell lines, rapidly decreasing intracellular ROS and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paraleled total cellular iron removal, particularly in hepatocytes. Iron mobilisation from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilisation, this being greater than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilisation by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilisation when combined with clinically available chelators. Copyright © 2017 American Society of Hematology.

  3. Chelation therapy in the JCR:LA-cp rat: experimental assessment of a putative antiatherosclerotic treatment.

    PubMed

    O'Brien, S F; Kelly, S E; Dolphin, P J; Russell, J C

    2000-04-01

    To test the efficacy of chelation therapy, an alternative medical treatment, as an antiatherosclerotic procedure, using an animal model of insulin resistance and vascular disease. A prospective animal experiment with procedures modelled on human chelation treatments. The JCR:LA-cp rat, a strain that, if homozygous for the autosomal recessive cp gene, becomes obese and insulin resistant, with marked hyperinsulinemia and hypertriglyceridemia, and is unique in the spontaneous development of atherosclerosis and ischemic myocardial lesions. Eight-month-old, obese, male JCR:LA-cp rats were fitted with indwelling venous cannulae and infused over 4 weeks with ethylenediaminetetraacetic acid (EDTA) 5 days a week at a daily dose of 40 mg/kg body weight. At the end of the treatment period, samples were taken for assay of blood parameters and for mineral content of bone. The rats were sacrificed and perfusion-fixed for scanning electron microscopy of the aortic arch. Plasma cholesterol concentrations were not changed by the EDTA treatment. In contrast, plasma triglyceride concentrations were raised significantly (74%, p < 0.05). Lean control rats showed minimal abnormality of the aortic arch, whereas the obese control rats had raised intimal lesions, frequent adherent macrophages and endothelial damage. The frequency of these vascular abnormalities in the EDTA-treated rats was not different from that seen in the obese controls. The bone contents of calcium and magnesium were not significantly reduced. Chelation therapy using intravenous EDTA has no beneficial effects on the arterial lesions in the atherosclerotic JCR:LA-cp rat. The increase in plasma triglyceride concentrations would be grounds for concern in human patients.

  4. Metal distribution and spectroscopic analysis after soil washing with chelating agents and humic substances.

    PubMed

    Tsang, Daniel C W; Hartley, Neil R

    2014-03-01

    Biodegradable chelating agents ([S,S]-ethylenediamine-N,N-disuccinic acid (EDDS) and glutamic-N,N-diacetic acid (GLDA)) and natural humic substances (lignite-derived, standard, and commercially available humic acids) are potentially useful for enhancing soil remediation of timber treatment sites. This study integrated macroscopic and spectroscopic analyses to assess their influence on the distribution and chemical speciation of the remaining metals as well as their interaction with the soil surface after 48-h washing of a field-contaminated soil. The results demonstrated that EDDS and GLDA were an appealing alternative to non-biodegradable ethylenediamine-tetraacetic acid, but the three humic substances were less effective. As shown by sequential extractions, Cu was primarily extracted from the carbonate fraction while Cr and As extraction resulted from (co-)dissolution of the oxide fraction. As a result, the relative proportion of strongly bound organic matter and residual fractions increased by 7-16 %. However, it was noteworthy that the exchangeable fraction also increased by 5-11 %, signifying that a portion of the remaining metals was destabilized by chelating agents and transformed to be more labile in the treated soil. The X-ray photoelectron spectroscopy spectra confirmed the substantial removal of readily accessible Cu from the soil surface, but Cr maintained its original chemical forms of trivalent chromium oxides and iron-chromium coprecipitates, whereas As remained as arsenic trioxide/pentoxide and copper arsenate precipitates. On the other hand, the absence of characteristic peaks of adsorbed carboxylate groups in the Fourier-transform infrared (FTIR) spectra inferred that the extent of adsorption of chelating agents and humic substances on the bulk soil was insufficient to be characterized by FTIR analysis. These results suggested that attention should be paid to the exchangeable fraction of Cu and oxides/coprecipitates of As prior to possible on

  5. A bis(3-hydroxy-4-pyridinone)-EDTA derivative as a strong chelator for M3+ hard metal ions: complexation ability and selectivity.

    PubMed

    Gama, Sofia; Dron, Paul; Chaves, Silvia; Farkas, Etelka; Santos, M Amélia

    2009-08-21

    The study of chelating compounds is very important to solve problems related to human metal overload. 3-Hydroxy-3-pyridinones (HP), namely deferiprone, have been clinically used for chelating therapy of Fe and Al over the last decade. A multi-disciplinary search for alternative molecules led us to develop poly-(3-hydroxy-4-pyridinones) to increase metal chelation efficacy. We present herein a complexation study of a new bis-(3-hydroxy-4-pyridinone)-EDTA derivative with a set of M(3+) hard metal ions (M = Fe, Al, Ga), as well as Zn(2+), a biologically relevant metal ion. Thus a systematic aqueous solution equilibrium study was performed using potentiometric and spectroscopic techniques (UV-Vis, NMR methods). These set of results enables the establishment of specific models as well as the determination of thermodynamic stability constants and coordination modes of the metal complexes. The results indicate that this ligand has a higher affinity for chelating to these hard metal ions than deferiprone, and that the coordination occurs mostly through the HP moieties. Furthermore, it was also found that this ligand has a higher selectivity for chelating to M(3+) hard metal ions (M = Fe, Al, Ga) than Zn(2+).

  6. Efficacy of orally administered amphipathic polyaminocarboxylic acid chelators for the removal of plutonium and americium: comparison with injected Zn-DTPA in the rat.

    PubMed

    Miller, Scott C; Liu, Gang; Bruenger, Fred W; Lloyd, Ray D

    2006-01-01

    Chelators are used to promote excretion of actinides and some other metals, but few are orally effective. The relative efficacies of orally administered triethylenetetraminepentaacetic acids (TT) with varying lipophilic properties on the removal of 241Am and 239Pu and comparison with parenteral Zn-DTPA was determined. The actinides were administered to adult rats 2 weeks prior to initiation of 30 d of chelation treatment. The TT compounds were given orally while Zn-DTPA was given twice weekly by injection. Total body content of 241Am was measured before and during the treatment period and organ contents of 241Am and 239Pu were measured at the end of the study. Significant reductions in 241Am occurred within the first week, with Zn-DTPA being the most effective. By 3 weeks, the most lipophilic chelator, C22TT was as effective as Zn-DTPA. After 30 d, reductions in organ content of 239Pu and 241Am directly correlated with increasing lipophilicity of the TT chelators. Oral C22TT was as effective as injected Zn-DTPA in liver and bone, the major organs of actinide deposition. The removal of 239Pu from the liver and reduction of redeposition of 239Pu in newly formed bone by C22TT was confirmed by neutron-induced autoradiographs. The amphipathic TT chelators may be useful as orally administered alternatives to current parenteral DTPA for the removal of actinide elements from the body, particularly for longer-term therapeutic applications.

  7. The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties.

    PubMed

    Alphandéry, Edouard; Amor, Matthieu; Guyot, François; Chebbi, Imène

    2012-11-01

    The introduction of various iron-chelating agents to the Magnetospirillum magneticum strain AMB-1 bacterial growth medium stimulated the growth of M. magneticum strain AMB-1 magnetotactic bacteria and enhanced the production of magnetosomes. After 7 days of growth, the number of bacteria and the production of magnetosomes were increased in the presence of iron-chelating agents by factors of up to ∼2 and ∼6, respectively. The presence of iron-chelating agents also produced an increase in magnetosome size and chain length and yielded improved magnetosome heating properties. The specific absorption rate of suspensions of magnetosome chains isolated from M. magneticum strain AMB-1 magnetotactic bacteria, measured under the application of an alternating magnetic field of average field strength ∼20 mT and frequency 198 kHz, increased from ∼222 W/g(Fe) in the absence of iron-chelating agent up to ∼444 W/g(Fe) in the presence of 4 μM rhodamine B and to ∼723 W/g(Fe) in the presence of 4 μM EDTA. These observations were made at an iron concentration of 20 μM and iron-chelating agent concentrations below 40 μM.

  8. Heavy metal displacement in chelate-irrigated soil during phytoremediation

    NASA Astrophysics Data System (ADS)

    Madrid, F.; Liphadzi, M. S.; Kirkham, M. B.

    2003-03-01

    Heavy metals in wastewater sewage sludge (biosolids), applied to land, contaminate soils. Phytoremediation, the use of plants to clean up toxic heavy metals, might remove them. Chelating agents are added to soil to solubilize the metals for enhanced phytoextraction. Yet no studies follow the displacement and leaching of heavy metals in soil with and without roots following solubilization with chelates. The objective of this work was to determine the mobility of heavy metals in biosolids applied to the surface of soil columns (76 cm long; 17 cm diam.) with or without plants (barley; Hordeum vulgare L.). Three weeks after barley was planted, all columns were irrigated with the disodium salt of the chelating agent, EDTA (ethylenediamine tetraacetic acid) (0.5 g/kg soil). Drainage water, soil, and plants were analyzed for heavy metals (Cd, Cu, Fe, Mn, Ni, Pb, Zn). Total concentrations of the heavy metals in all columns at the end of the experiment generally were lower in the top 30 cm of soil with EDTA than without EDTA. The chelate increased concentrations of heavy metals in shoots. With or without plants, the EDTA mobilized Cd, Fe, Mn, Ni, Pb, and Zn, which leached to drainage water. Drainage water from columns without EDTA had concentrations of these heavy metals below detection limits. Only Cu did not leach in the presence of EDTA. Even though roots retarded the movement of Cd, Fe, Mn, Ni, Pb, and Zn through the EDTA-treated soil from 1 d (Cd) to 5 d (Fe), the drainage water from columns with EDTA had concentrations of Cd, Fe, Mn, and Pb that exceeded drinking water standards by 1.3, 500, 620, and 8.6 times, respectively. Because the chelate rendered Cd, Fe, Mn, Ni, Pb, and Zn mobile, it is suggested that the theory for leaching of soluble salts, put forward by Nielsen and associates in 1965, could be applied to control movement of the heavy metals for maximum uptake during chelate-assisted phytoremediation.

  9. Efficacy of chelation therapy to remove aluminium intoxication.

    PubMed

    Fulgenzi, Alessandro; De Giuseppe, Rachele; Bamonti, Fabrizia; Vietti, Daniele; Ferrero, Maria Elena

    2015-11-01

    There is a distinct correlation between aluminium (Al) intoxication and neurodegenerative diseases (ND). We demonstrated how patients affected by ND showing Al intoxication benefit from short-term treatment with calcium disodium ethylene diamine tetraacetic acid (EDTA) (chelation therapy). Such therapy further improved through daily treatment with the antioxidant Cellfood. In the present study we examined the efficacy of long-term treatment, using both EDTA and Cellfood. Slow intravenous treatment with the chelating agent EDTA (2 g/10 mL diluted in 500 mL physiological saline administered in 2 h) (chelation test) removed Al, which was detected (using inductively coupled plasma mass spectrometry) in urine samples collected from patients over 12 h. Patients that revealed Al intoxication (expressed in μg per g creatinine) underwent EDTA chelation therapy once a week for ten weeks, then once every two weeks for a further six or twelve months. At the end of treatment (a total of 22 or 34 chelation therapies, respectively), associated with daily assumption of Cellfood, Al levels in the urine samples were analysed. In addition, the following blood parameters were determined: homocysteine, vitamin B12, and folate, as well as the oxidative status e.g. reactive oxygen species (ROS), total antioxidant capacity (TAC), oxidized LDL (oxLDL), and glutathione. Our results showed that Al intoxication reduced significantly following EDTA and Cellfood treatment, and clinical symptoms improved. After treatment, ROS, oxLDL, and homocysteine decreased significantly, whereas vitamin B12, folate and TAC improved significantly. In conclusion, our data show the efficacy of chelation therapy associated with Cellfood in subjects affected by Al intoxication who have developed ND.

  10. Interaction of chelating agents with cadmium in mice and rats.

    PubMed Central

    Eybl, V; Sýkora, J; Koutenský, J; Caisová, D; Schwartz, A; Mertl, F

    1984-01-01

    The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl2 and on the whole body retention and tissue distribution of cadmium after the IV application of 115mCdCl2 was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatment of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination of the retention and distribution of Cd in mice, it was demonstrated that the combined application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl2 and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of 115mCd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes. PMID:6734561

  11. Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells.

    PubMed

    Shackelford, Rodney E; Fu, Yumei; Manuszak, Ryan P; Brooks, Torrie C; Sequeira, Adrian P; Wang, Suming; Lowery-Nordberg, Mary; Chen, Anping

    2006-11-08

    Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure.

  12. Interaction of chelating agents with cadmium in mice and rats

    SciTech Connect

    Eybl, V.; Sykora, J.; Koutensky, J.; Caisova, D.; Schwartz, A.; Mertl, F.

    1984-03-01

    The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl/sub 2/ and on the whole body retention and tissue distribution of cadmium after the IV application of /sup 115mCdCl/sub 2/ was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatement of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl/sub 2/ and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of /sup 115m/Cd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes.

  13. Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

    SciTech Connect

    Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J.S.

    2009-10-15

    Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

  14. Lauriston S. Taylor Lecture: the quest for therapeutic actinide chelators.

    PubMed

    Durbin, Patricia W

    2008-11-01

    All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

  15. Clinical monitoring and management of complications related to chelation therapy in patients with β-thalassemia.

    PubMed

    Saliba, Antoine N; El Rassi, Fuad; Taher, Ali T

    2016-01-01

    Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with β-thalassemia in an attempt to reduce morbidity and mortality related to siderosis. Each of the approved iron chelating agents has its own advantages over the others and also has its own risks, whether related to over-chelation or not. In this review, we briefly discuss the methods to monitor the efficacy of iron chelation therapy (ICT) and the evidence behind the use of each iron chelating agent. We also portray the risks and complications associated with each iron chelating agent and recommend strategies to manage adverse events.

  16. SEPARATION OF PLUTONIUM FROM LANTHANUM BY CHELATION-EXTRACTION

    DOEpatents

    James, R.A.; Thompson, S.G.

    1958-12-01

    Plutonium can be separated from a mixture of plutonlum and lanthanum in which the lanthanum to plutonium molal ratio ls at least five by adding the ammonium salt of N-nitrosoarylhydroxylamine to an aqueous solution having a pH between about 3 and 0.2 and containing the plutonium in a valence state of at least +3, to form a plutonium chelate compound of N-nitrosoarylhydroxylamine. The plutonium chelate compound may be recovered from the solution by extracting with an immiscible organic solvent such as chloroform.

  17. Removal of phenol from saline water by polyamine chelating resin.

    PubMed

    Yamada, Arisa; Matsui, Akihiro; Tsuji, Hideyuki

    2013-01-01

    Removal of phenol from saline water was carried out with chelating resin. A polyamine chelating resin, Diaion CR-20, removed phenol compounds selectively from industrial wastewater containing 2% salt. From saline water containing 20 mg/L phenol, 70% of the phenol was removed. After treatment, phenol was eluted from the resin by aqueous NaOH, and the resin could also be regenerated by heating in air. Diaion CR-20 adsorbed phenol even in the presence of FeCl3, indicating that treatment with this resin of wastewater containing metal can remove phenol and metal cations in a single step.

  18. Dendritic poly-chelator frameworks for multimeric bioconjugation.

    PubMed

    Reich, Dominik; Wurzer, Alexander; Wirtz, Martina; Stiegler, Veronika; Spatz, Philipp; Pollmann, Julia; Wester, Hans-Jürgen; Notni, Johannes

    2017-02-23

    Starting from multifunctional triazacyclononane-triphosphinate chelator cores, dendritic molecules with the ability to bind metal ions within their framework were synthesized. A cooperative interaction of the chelator cages resulted in a markedly increased affinity towards (67/68)Ga(III). A hexameric PSMA inhibitor conjugate with high affinity (IC50 = 1.2 nM) and favorable in vivo PET imaging properties demonstrated practical applicability. The novel scaffolds are useful for synthesis of structurally well-defined multimodal imaging probes or theranostics.

  19. Bi-functional CD22 ligands use multimeric immunoglobulins as protein scaffolds in assembly of immune complexes on B cells

    PubMed Central

    O'Reilly, Mary K.; Collins, Brian E.; Han, Shoufa; Liao, Liang; Rillahan, Cory; Kitov, Pavel I.; Bundle, David R.; Paulson, James C.

    2008-01-01

    CD22 is a B cell specific sialic-acid-binding immunoglobulin-like lectin (Siglec) whose function as a regulator of B cell signaling is modulated by its interaction with glycan ligands bearing the sequence NeuAcα2-6Gal. To date, only highly multivalent polymeric ligands (n=450) have achieved sufficient avidity to bind to CD22 on native B cells. Here we demonstrate that a synthetic bi-functional molecule comprising a ligand of CD22 linked to an antigen (nitrophenol; NP) can use a monoclonal anti-NP-IgM as a decavalent protein scaffold to efficiently drive assembly of IgM-CD22 complexes on the surface of native B cells. Surprisingly, anti-NP antibodies of lower valency, IgA (n =4) and IgG (n =2), were also found to drive complex formation, though with lower avidity. Ligands bearing alternate linkers of variable length and structure were constructed to establish the importance of a minimal length requirement, and versatility in the structural requirement. We show that the ligand drives assembly of IgM complexes exclusively on the surface of B cells and not other classes of white blood cells that do not express CD22, which lends itself to the possibility of targeting B cells in certain hematopoietic malignancies. PMID:18505252

  20. Efficacy of a novel chelator BPCBG for removing uranium and protecting against uranium-induced renal cell damage in rats and HK-2 cells

    SciTech Connect

    Bao, Yizhong; Wang, Dan; Li, Zhiming; Hu, Yuxing; Xu, Aihong; Wang, Quanrui; Shao, Chunlin; Chen, Honghong

    2013-05-15

    Chelation therapy is a known effective method to increase the excretion of U(VI) from the body. Until now, no any uranium chelator has been approved for emergency medical use worldwide. The present study aimed to evaluate the efficacy of new ligand BPCBG containing two catechol groups and two aminocarboxylic acid groups in decorporation of U(VI) and protection against acute U(VI) nephrotoxicity in rats, and further explored the detoxification mechanism of BPCBG for U(VI)-induced nephrotoxicity in HK-2 cells with comparison to DTPA-CaNa{sub 3}. Chelating agents were administered at various times before or after injections of U(VI) in rats. The U(VI) levels in urine, kidneys and femurs were measured 24 h after U(VI) injections. Histopathological changes in the kidney and serum urea and creatinine and urine protein were examined. After treatment of U(VI)-exposed HK-2 cells with chelating agent, the intracellular U(VI) contents, formation of micronuclei, lactate dehydrogenase (LDH) activity and production of reactive oxygen species (ROS) were assessed. It was found that prompt, advanced or delayed injections of BPCBG effectively increased 24 h-urinary U(VI) excretion and decreased the levels of U(VI) in kidney and bone. Meanwhile, BPCBG injection obviously reduced the severity of the U(VI)-induced histological alterations in the kidney, which was in parallel with the amelioration noted in serum indicators, urea and creatinine, and urine protein of U(VI) nephrotoxicity. In U(VI)-exposed HK-2 cells, immediate and delayed treatment with BPCBG significantly decreased the formation of micronuclei and LDH release by inhibiting the cellular U(VI) intake, promoting the intracellular U(VI) release and inhibiting the production of intracellular ROS. Our data suggest that BPCBG is a novel bi-functional U(VI) decorporation agent with a better efficacy than DTPA-CaNa{sub 3}. - Highlights: ► BPCBG accelerated the urine U(VI) excretion and reduced the tissues U(VI) in rats.

  1. Bifunctional phosphine-catalyzed cross-Rauhut-Currier/Michael/aldol condensation triple domino reaction: synthesis of functionalized cyclohexenes.

    PubMed

    Xie, Peizhong; Huang, You; Lai, Wenqing; Meng, Xiangtai; Chen, Ruyu

    2011-10-07

    A novel bifunctional phosphine-catalyzed reaction was developed. Cross-Rauhut-Currier, Michael and aldol reactions were successfully combined into a domino process. This method offers a powerful approach to the construction of highly substituted cyclohexene skeletons.

  2. Energetic methods to study bifunctional biotin operon repressor.

    PubMed

    Beckett, D

    1998-01-01

    measurements. The results of quantitative studies of the biotin regulatory system can be interpreted in the context of the biological function of the system. The biotin holoenzyme ligases are a class of enzymes found across the evolutionary spectrum. Only a subset of these enzymes, including BirA, also function as transcriptional repressors. The tight binding of the allosteric effector may be understood in light of the bifunctional nature of the BirA-bio-5'-AMP complex. It is possible that the unusually high thermodynamic and kinetic stability of the complex ensures that the most probable state of the protein in vivo is the adenylate-bound form. This complex, not the unliganded protein, is active in both enzymatic transfer of biotin and site-specific DNA binding. This ensures that on depletion of the intracellular pool of apoBCCP, BirA-bio-5'-AMP accumulates and binds to bioO to repress transcription of the biotin biosynthesis operon. The intracellular demand for and synthesis of biotin are, consequently, tightly coupled in the system. The dimerization that accompanies adenylate binding to BirA appears to be significant for site-specific binding of the protein to bioO. Functionally, the simultaneous binding of the two monomers to the two operator half-sites, regardless of the kinetic mechanism by which it occurs, ensures coordinate regulation of transcription initiation from both biotin operon promoters. The multifaceted approach utilized in studies of the biotin regulatory system can serve as a model for studies of any complex transcriptional regulatory system. It is critical in elucidating the functional energetics of any of these systems that the assembly first be dissected into the constituent interactions and that each of these interactions be studied in isolation. This is not only critical for understanding the physicochemical properties of each individual contributing interaction, but is also a necessary precursor to studies of thermodynamic linkage in the system. (AB

  3. New developments and controversies in iron metabolism and iron chelation therapy

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies. PMID:27019793

  4. New developments and controversies in iron metabolism and iron chelation therapy.

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

    haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.

  5. A Metal-Amino Acid Complex-Derived Bifunctional Oxygen Electrocatalyst for Rechargeable Zinc-Air Batteries.

    PubMed

    Ding, Yanjun; Niu, Yuchen; Yang, Jia; Ma, Liang; Liu, Jianguo; Xiong, Yujie; Xu, Hangxun

    2016-10-01

    Bifunctional oxygen electrocatalyst: A metal-amino acid complex is developed to prepare high-performance mesoporous carbon electrocatalyst for both oxygen reduction and oxygen evolution reactions. Such prepared catalyst can be used to assemble rechargeable zinc-air batteries with excellent durability. This work represents a new route toward low-cost, highly active, and durable bifunctional electrocatalysts for cutting-edge energy conversion devices.

  6. Chelation And Extraction Of Metals For GC-MS Analysis

    NASA Technical Reports Server (NTRS)

    Sinha, Mahadeva P.

    1995-01-01

    Chelation followed by supercritical-fluid extraction enables mass-spectrometric analysis. When fully developed, method implemented in field-portable apparatus for detection and quantification of metals in various matrices without need for elaborate preparation of samples. Used to analyze soil samples for toxic metals.

  7. Evaluation of intakes of transuranics influenced by chelation therapy

    SciTech Connect

    LaBone, T.R.

    1994-02-01

    Once an intake of transuranics occurs, there are only three therapeutic procedures available to the physician for reducing the intake and mitigating the dose: excision of material from wounds, removal of material from the lungs with lavage, and chelation therapy. The only chelation agents approved in the United States for the treatment of occupational intakes of transuranics are the zinc and calcium salts of diethylene-triamine-pentaacetic acid, better known as Zn-DTPA and Ca-DTPA. In the past 35 years, approximately 3000 doses of DTPA have been administrated to over 500 individuals who had intakes of transuranics. The drug is considered to be quiet safe and has few side effects. For the internal dosimetrist, perhaps the most important aspects of chelation therapy is that if enhances the excretion rate of a transuranic and perturbs the shape of the urinary excretion curve. These perturbations last for months and are so great that standard urinary excretion models cannot be used to evaluate the intake. We review here a method for evaluating intakes of transuranics influenced by chelation therapy that has been used with some degree of success at the Savannah River Site for over 20 years.

  8. Desferrithiocin: A Search for Clinically Effective Iron Chelators

    PubMed Central

    2015-01-01

    The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure–activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials. PMID:25207964

  9. Technical Report Summary: Metal Chelate, Eu-QCTME

    SciTech Connect

    Richter, James, A.

    2008-05-08

    A novel fluorescent metal complex, Eu-QCTME has shown promise for the early stage detection of cancer. This material has been shown to bind preferentially to xenographic tumors. The study, using HT29 murine xenographic tumors was performed to determine if the chelate preferentially binds to tumor tissue and the potential for an early stage diagnostic test and treatment for epithelial cell cancers.

  10. Chelation And Extraction Of Metals For GC-MS Analysis

    NASA Technical Reports Server (NTRS)

    Sinha, Mahadeva P.

    1995-01-01

    Chelation followed by supercritical-fluid extraction enables mass-spectrometric analysis. When fully developed, method implemented in field-portable apparatus for detection and quantification of metals in various matrices without need for elaborate preparation of samples. Used to analyze soil samples for toxic metals.

  11. Efficacy of reversal of aortic calcification by chelating agents

    PubMed Central

    Lei, Yang; Sinha, Aditi; Vyavahare, Naren

    2013-01-01

    Elastin specific medial vascular calcification, termed Monckeberg’s sclerosis has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA) and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium (Ca) from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly (lactic-co-glycolic acid) (PLGA) nanoparticles regressed elastin specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents. PMID:23963635

  12. Efficacy of reversal of aortic calcification by chelating agents.

    PubMed

    Lei, Yang; Grover, Arjun; Sinha, Aditi; Vyavahare, Naren

    2013-11-01

    Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly(lactic-co-glycolic acid) nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.

  13. Scintigraphic monitoring of immunotoxins using radionuclides and heterobifunctional chelators

    SciTech Connect

    Reardan, D.; Bernhard, S.

    1991-10-22

    This patent describes a method for in vivo radioimmunodetection of cytotoxic immunotoxin. It comprises administering internally to a mammal a radio-labeled immunotoxin, wherein a heterobifunctional chelating agent provides a chemical bridge between a radiolabel and a cytotoxic component bound to the antigen-binding component of the immunotoxin, and detecting externally the distribution of the immunotoxin in the mammal.

  14. Chelation of thallium by combining deferasirox and desferrioxamine in rats.

    PubMed

    Saljooghi, Amir Shokooh; Babaie, Maryam; Mendi, Fatemeh Delavar; Zahmati, Maliheh; Saljooghi, Zoheir Shokouh

    2016-01-01

    The hypothesis that two known chelators deferasirox (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) and desferrioxamine (DFO) might be more efficient as combined treatment than as monotherapies in removing thallium from the body was tested in a new acute rat model. 7-week-old male Wistar rats received chelators: deferasirox (orally), DFO (intraperitoneal; i.p.), or deferasirox + DFO as 75 or 150 mg/kg dose half an hour after a single i.p. administration of 8 mg thallium/kg body weight in the form of chloride. Serum thallium concentration, urinary thallium, and iron excretions were determined by graphite furnace atomic absorption spectrometry. Both chelators were effective only at the higher dose level, while DFO was more effective than deferasirox in enhancing urinary thallium excretion, deferasirox was more effective than DFO in enhancing urinary iron excretion. In the combined treatment group, deferasirox did not increase the DFO effect on thallium and DFO did not increase the effect of deferasirox on iron elimination. Our results support the usefulness of this animal model for preliminary in vivo testing of thallium chelators. Urinary values were more useful because of the high variability of serum results. © The Author(s) 2013.

  15. Iron chelating active packaging: Influence of competing ions and pH value on effectiveness of soluble and immobilized hydroxamate chelators.

    PubMed

    Ogiwara, Yoshiko; Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2016-04-01

    Many packaged foods utilize synthetic chelators (e.g. ethylenediaminetetraacetic acid, EDTA) to inhibit iron-promoted oxidation or microbial growth which would result in quality loss. To address consumer demands for all natural products, we have previously developed a non-migratory iron chelating active packaging material by covalent immobilization of polyhydroxamate and demonstrated its efficacy in delaying lipid oxidation. Herein, we demonstrate the ability of this hydroxamate-functionalized iron chelating active packaging to retain iron chelating capacity; even in the presence of competing ions common in food. Both immobilized and soluble hydroxamate chelators retained iron chelating capacity in the presence of calcium, magnesium, and sodium competing ions, although at pH 5.0 the presence of calcium reduced immobilized hydroxamate iron chelation. A strong correlation was found between colorimetric and mass spectral analysis of iron chelation by the chelating packaging material. Such chelating active packaging may support reducing additive use in product formulations, while retaining quality and shelf life.

  16. Cations reduce antimicrobial efficacy of lysozyme-chelator combinations.

    PubMed

    Boland, J S; Davidson, P M; Bruce, B; Weiss, J

    2004-02-01

    Reduction of the antimicrobial efficacy of lysozyme-chelator combinations against two Escherichia coli O157:H7 strains on addition of mineral salts was studied. The objective of the study was to determine the effect of type and concentration of mono-, di-, and trivalent mineral salts on the antimicrobial effectiveness of lysozyme and various chelators against E. coli O157:H7. Seven salts (Al3+, Ca2+, Fe2+, Fe3+, K+, Mg2+, and Na+) at 1 to 10 mM were added to aqueous solutions of lysozyme and disodium ethylenediamine tetraacetic acid (EDTA), disodium pyrophosphate (DSPP), or pentasodium tripolyphosphate (PSTPP) at pH 6, 7, or 8 and applied to cultures of E. coli O157:H7 strains 932 and H1730. Inhibitory activity of lysozyme chelator combinations against both strains was completely lost after addition of > or = 1 mM Ca2+ and Mg2+ at pH 7 and 8. At pH 6, antimicrobial activity of lysozyme-EDTA against both strains was retained in the presence of calcium or magnesium cations. DSPP-lysozyme inhibited strain H1730 at pH 6 despite the presence of Mg2+. Concentrations above 4 mM Fe2+ neutralized activity of all lysozyme-chelator combinations. Reversal of inhibition by lysozyme-chelator complexes by the monovalent Na+ and K+ ions depended on E. coli O157:H7 strain type. Neither monovalent cation reversed inhibition of strain 932. However, Na+ and K+ reversed lysozyme-chelator inhibition of strain H1730. The addition of > or = 1 mM Fe3+ or Al3+ was effective in reversing inhibition of both strains by lysozyme and EDTA at pH 6, 7, and 8. Isothermal titration calorimetry was used to determine the amount of ion-specific competitive binding of free cations by EDTA-lysozyme combinations. A mechanistic model for the antimicrobial functionality of chelator-lysozyme combinations is proposed.

  17. Copper chelators: chemical properties and bio-medical applications.

    PubMed

    Tegoni, M; Valensin, D; Toso, L; Remelli, M

    2014-01-01

    Copper is present in different concentrations and chemical forms throughout the earth crust, surface and deep water and even, in trace amounts, in the atmosphere itself. Copper is one of the first metals used by humans, the first artifacts dating back 10,000 years ago. Currently, the world production of refined copper exceeds 16,000 tons/year. Copper is a micro-element essential to life, principally for its red-ox properties that make it a necessary cofactor for many enzymes, like cytochrome-c oxidase and superoxide dismutase. In some animal species (e.g. octopus, snails, spiders, oysters) copper-hemocyanins also act as carriers of oxygen instead of hemoglobin. However, these red-ox properties also make the pair Cu(+)/Cu(2+) a formidable catalyst for the formation of reactive oxygen species, when copper is present in excess in the body or in tissues. The treatment of choice in cases of copper overloading or intoxication is the chelation therapy. Different molecules are already in clinical use as chelators or under study or clinical trial. It is worth noting that chelation therapy has also been suggested to treat some neurodegenerative diseases or cardiovascular disorders. In this review, after a brief description of the homeostasis and some cases of dyshomeostasis of copper, the main (used or potential) chelators are described; their properties in solution, even in relation to the presence of metal or ligand competitors, under physiological conditions, are discussed. The legislation of the most important Western countries, regarding both the use of chelating agents and the limits of copper in foods, drugs and cosmetics, is also outlined.

  18. EDTA Chelation Therapy, Without Added Vitamin C, Decreases Oxidative DNA Damage and Lipid Peroxidation

    USDA-ARS?s Scientific Manuscript database

    Chelation therapy is thought to not only remove contaminating metals, but also to decrease free radical production. However, in standard EDTA chelation therapy high doses of vitamin C with potential prooxidant effects are often added to the chelation solution. We demonstrated previously that the in...

  19. Picture of a chelate in exchange: the crystal structure of NaHoDOTMA, a 'semi'-hydrated chelate.

    PubMed

    Payne, Katherine M; Valente, Edward J; Aime, Silvio; Botta, Mauro; Woods, Mark

    2013-03-21

    Crystallography generally only provides static structural information. This can render it an ineffective technique for probing dynamic solution state processes. A crystal of HoDOTMA affords unique structures that effectively represent that of a lanthanide tetra-acetate chelate mid-way through the water exchange process.

  20. The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

    PubMed

    Yoshii, J; Yoshiji, H; Kuriyama, S; Ikenaka, Y; Noguchi, R; Okuda, H; Tsujinoue, H; Nakatani, T; Kishida, H; Nakae, D; Gomez, D E; De Lorenzo, M S; Tejera, A M; Fukui, H

    2001-12-15

    Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy. Copyright 2001 Wiley-Liss, Inc.

  1. Organically modified porous hydroxyapatites: A comparison between alkylphosphonate grafting and citrate chelation

    SciTech Connect

    El-Hammari, L.; Marroun, H.; Laghzizil, A.; Saoiabi, A.; Roux, C.; Livage, J.; Coradin, T.

    2008-04-15

    Two alternative methods to prepare organically modified porous hydroxyapatites following a 'one pot' approach were compared. The partial substitution of inorganic phosphates by alkylphosphonates leads to mesoporous materials with high specific surface area (>200 m{sup 2} g{sup -1}). The incorporation of the organic moieties within the hydroxyapatite structure is confirmed by Infra-red and solid-state NMR spectroscopy and depends on the nature of the alkyl chain. However, it induces a significant loss of the material crystallinity. In contrast, the introduction of citrate, a calcium-chelating agent, to the precursor solution does not improve the material specific surface area but allows a better control of the hydroxyapatite structure, both in terms of crystallinity and pore size distribution. - Graphical abstract: Evolution of pore size distribution of hydroxyapatite (HAp) after alkylphosphonate grafting (20% TPOH) or citrate addition (c-HAp) demonstrates the formation of organically modified mesoporous materials.

  2. Increasing round trip efficiency of hybrid Li-air battery with bifunctional catalysts

    SciTech Connect

    Huang, K; Li, YF; Xing, YC

    2013-07-30

    Previously it was shown that Pt as cathode catalyst ha's a large overpotential during charge in rechargeable hybrid Li-air battery with sulfuric acid catholyte. This article demonstrates that a bifunctional catalyst composed of Pt and IrO2 supported on carbon nanotubes can address this problem. The specially designed and synthesized bifunctional catalyst showed significant overpotential reduction and achieved a round trip energy efficiency of 81% after 10 cycles, higher than many achieved in aprotic Li-O-2 batteries. The hybrid Li-air battery was discharged and recharged for 20 cycles at 0.2 mA/cm(2), showing a fairly stable cell performance. A specific capacity of 306 mAh/g and a specific energy of 1110 Wh/kg were obtained for the hybrid Li-air battery in terms of acid weight. (c) 2013 Elsevier Ltd. All rights reserved.

  3. Tethering metal ions to photocatalyst particulate surfaces by bifunctional molecular linkers for efficient hydrogen evolution.

    PubMed

    Yu, Weili; Isimjan, Tayirjan; Del Gobbo, Silvano; Anjum, Dalaver H; Abdel-Azeim, Safwat; Cavallo, Luigi; Garcia-Esparza, Angel T; Domen, Kazunari; Xu, Wei; Takanabe, Kazuhiro

    2014-09-01

    A simple and versatile method for the preparation of photocatalyst particulates modified with effective cocatalysts is presented; the method involves the sequential soaking of photocatalyst particulates in solutions containing bifunctional organic linkers and metal ions. The modification of the particulate surfaces is a universal and reproducible method because the molecular linkers utilize strong covalent bonds, which in turn result in modified monolayer with a small but controlled quantity of metals. The photocatalysis results indicated that the CdS with likely photochemically reduced Pd and Ni, which were initially immobilized via ethanedithiol (EDT) as a linker, were highly efficient for photocatalytic hydrogen evolution from Na2S-Na2SO3-containing aqueous solutions. The method developed in this study opens a new synthesis route for the preparation of effective photocatalysts with various combinations of bifunctional linkers, metals, and photocatalyst particulate materials.

  4. Bifunctional nanoarrays for probing the immune response at the single-molecule level.

    PubMed

    Cai, Haogang; Depoil, David; Palma, Matteo; Sheetz, Michael P; Dustin, Michael L; Wind, Shalom J

    2013-11-01

    Bifunctional nanoarrays were created to simulate the immunological synapse and probe the T-cell immune response at the single-molecule level. Sub-5 nm AuPd nanodot arrays were fabricated using both e-beam and nanoimprint lithography. The nanoarrays were then functionalized by two costimulatory molecules: antibody UCHT1 Fab, which binds to the T-cell receptor (TCR) and activates the immune response, bound to metallic nanodots; and intercellular adhesion molecule-1, which enhances cell adhesion, on the surrounding area. Initial T-cell experiments show successful attachment and activation on the bifunctional nanoarrays. This nanoscale platform for single-molecule control of TCR in living T-cells provides a new approach to explore how its geometric arrangement affects T-cell activation and behavior, with potential applications in immunotherapy. This platform also serves as a general model for single-molecule nanoarrays where more than one molecular species is required.

  5. Bifunctional metamaterials with simultaneous and independent manipulation of thermal and electric fields.

    PubMed

    Lan, Chuwen; Bi, Ke; Fu, Xiaojian; Li, Bo; Zhou, Ji

    2016-10-03

    Metamaterials offer a powerful way to manipulate a variety of physical fields ranging from wave fields (electromagnetic field, acoustic field, elastic wave, etc.), static fields (static magnetic field, static electric field) to diffusive fields (thermal field, diffusive mass). However, the relevant reports and studies are usually limited to a single physical field or functionality. In this study, we proposed and experimentally demonstrated a bifunctional metamaterial which could manipulate thermal and electric fields simultaneously and independently. Specifically, a composite with independently controllable thermal and electric conductivity was introduced, on the basis of which a bifunctional device capable of shielding thermal flux and concentrating electric current simultaneously was designed, fabricated and characterized. This work provides an encouraging example of metamaterials transcending their natural limitations, which offers a promising future in building a broad platform for the manipulation of multi-physics fields.

  6. Design and applications of bifunctional small molecules: Why two heads are better than one

    PubMed Central

    Corson, Timothy W.; Aberle, Nicholas; Crews, Craig M.

    2009-01-01

    Induction of protein-protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based “Chemical Inducers of Dimerization”, but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACS), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This review discusses these and other advances in the design and use of bifunctional small molecules, and potential strategies for future systems. PMID:19112665

  7. Engineered bifunctional proteins and stem cells: next generation of targeted cancer therapeutics.

    PubMed

    Choi, Sung Hugh; Shah, Khalid

    2016-09-01

    Redundant survival signaling pathways and their crosstalk within tumor and/or between tumor and their microenvironment are key impediments to developing effective targeted therapies for cancer. Therefore developing therapeutics that target multiple receptor signaling pathways in tumors and utilizing efficient platforms to deliver such therapeutics are critical to the success of future targeted therapies. During the past two decades, a number of bifunctional multi-targeting antibodies, fusion proteins, and oncolytic viruses have been developed and various stem cell types have been engineered to efficiently deliver them to tumors. In this review, we discuss the design and efficacy of therapeutics targeting multiple pathways in tumors and the therapeutic potential of therapeutic stem cells engineered with bifunctional agents.

  8. Alternative Fuels

    EPA Pesticide Factsheets

    Alternative fuels include gaseous fuels such as hydrogen, natural gas, and propane; alcohols such as ethanol, methanol, and butanol; vegetable and waste-derived oils; and electricity. Overview of alternative fuels is here.

  9. Alternative Therapies

    MedlinePlus

    ... Late Effects of Poliomyelitis for Physicians and Survivors © Alternative Therapies Alternative therapies, also called complementary, can support ... of motion, pain, and fatigue are often reported. Energy work includes acupuncture and acupressure, traditional Chinese medicine ...

  10. Examining the fixation kinetics of chelated and non-chelated copper and the applications to micronutrient management in semiarid alkaline soils

    NASA Astrophysics Data System (ADS)

    Udeigwe, T. K.; Eichmann, M. B.; Menkiti, M. C.; Kusi, N. Y. O.

    2016-02-01

    This study examined and compared the fixation and fixation kinetics of copper (Cu) in chelated (ethylene diamine tetraacetic acid, EDTA) and non-chelated mixed systems of micronutrients in the semiarid soils of the Southern High Plains, USA, using findings from Cu extraction studies and kinetic models. Approximately, 22 % more Cu was fixed in the non-chelated system compared to the chelated within the first 14 days with only 7 % difference between the two systems by day 90. Findings suggest a decrease in the effectiveness of chelated micronutrients over time, highlighting the significance of timing even when chelated micronutrients are used. The strengths of the relationship of change in available Cu with respect to other micronutrients (iron (Fe), manganese (Mn), and zinc (Zn)) were higher in the non-chelated system (R2: 0.68-0.94), compared to the chelated (R2: 0.42-0.81), with slopes of 0.40 (Cu-Fe), 0.31 (Cu-Mn), and 1.04 (Cu-Zn) in the non-chelated system and 0.26 (Cu-Fe), 0.22 (Cu-Mn), and 0.90 (Cu-Zn) in the chelated system. Reduction in the amount of available Cu was best described by the power function model (R2 = 0.91, SE = 0.081) in the non-chelated system and second-order model (R2 = 0.95, SE = 0.010) in the chelated system. The applications generated from this study could be used as tools for improved micronutrient management and also provide baseline data for future work in other semiarid/arid alkaline soils of the world. Findings are also more applicable to field settings, an improvement over related previous studies.

  11. 3D Ordered Mesoporous Bifunctional Oxygen Catalyst for Electrically Rechargeable Zinc-Air Batteries.

    PubMed

    Park, Moon Gyu; Lee, Dong Un; Seo, Min Ho; Cano, Zachary Paul; Chen, Zhongwei

    2016-05-01

    To enhance energy efficiency and durability, a highly active and durable 3D ordered mesoporous cobalt oxide framework has been developed for rechargeable zinc-air batteries. The bifunctional air electrode consisting of 3DOM Co3 O4 having high active surface area and robust structure, results in superior charge and discharge battery voltages, and durable performance for electrically rechargeable zinc-air batteries.

  12. Phase-Transfer Catalysis via a Proton Sponge: A Bifunctional Role for Biscyclopropenimine.

    PubMed

    Belding, Lee; Stoyanov, Peter; Dudding, Travis

    2016-01-15

    The use of a bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge as a bifunctional phase-transfer catalyst is reported. Experimental studies and DFT calculations suggest it operates simultaneously as a hydrogen bond donor and a phase-transfer catalyst, facilitating the movement of charged intermediates from the interface to the organic phase via favorable partitioning of hydrophilic/hydrophobic surface areas, resulting in high catalytic activity.

  13. Synthesis of acid-base bifunctional mesoporous materials by oxidation and thermolysis

    SciTech Connect

    Yu, Xiaofang; Zou, Yongcun; Wu, Shujie; Liu, Heng; Guan, Jingqi; Kan, Qiubin

    2011-06-15

    Graphical abstract: A novel and efficient method has been developed for the synthesis of acid-base bifunctional catalyst. The obtained sample of SO{sub 3}H-MCM-41-NH{sub 2} containing amine and sulfonic acids exhibits excellent catalytic activity in aldol condensation reaction. Research highlights: {yields} Synthesize acid-base bifunctional mesoporous materials SO{sub 3}H-MCM-41-NH{sub 2}. {yields} Oxidation and then thermolysis to generate acidic site and basic site. {yields} Exhibit good catalytic performance in aldol condensation reaction between acetone and various aldehydes. -- Abstract: A novel and efficient method has been developed for the synthesis of acid-base bifunctional catalyst SO{sub 3}H-MCM-41-NH{sub 2}. This method was achieved by co-condensation of tetraethylorthosilicate (TEOS), 3-mercaptopropyltrimethoxysilane (MPTMS) and (3-triethoxysilylpropyl) carbamicacid-1-methylcyclohexylester (3TAME) in the presence of cetyltrimethylammonium bromide (CTAB), followed by oxidation and then thermolysis to generate acidic site and basic site. X-ray diffraction (XRD) and transmission electron micrographs (TEM) show that the resultant materials keep mesoporous structure. Thermogravimetric analysis (TGA), X-ray photoelectron spectra (XPS), back titration, solid-state {sup 13}C CP/MAS NMR and solid-state {sup 29}Si MAS NMR confirm that the organosiloxanes were condensed as a part of the silica framework. The bifunctional sample (SO{sub 3}H-MCM-41-NH{sub 2}) containing amine and sulfonic acids exhibits excellent acid-basic properties, which make it possess high activity in aldol condensation reaction between acetone and various aldehydes.

  14. Design and Testing of Bi-functional, P-loop Targeted MDM2 Inhibitors

    DTIC Science & Technology

    2008-03-01

    based on the discovery that nucleotides can bind to the P-loop of MDM2 and cause its relocalization to the nucleolus. Such bifunctional compounds will be...developed a high-throughput docking assay based on Mdm2’s RING domain structure and (4) developed a high-throughput compatible luciferase- based ...target. Based on previous mutational studies on the RING domain (Poyurovsky et al. 2003.) and molecular dynamics simulations we predicted the ATP

  15. Bifunctional ruthenium(II) hydride complexes with pendant strong Lewis acid moieties: structure, dynamics, and cooperativity.

    PubMed

    Ostapowicz, Thomas G; Merkens, Carina; Hölscher, Markus; Klankermayer, Jürgen; Leitner, Walter

    2013-02-13

    The synthesis of a novel class of bifunctional ruthenium hydride complexes incorporating Lewis acidic BR(2) moieties is reported. Determination of the molecular structures in the solid state and in solution provided evidence for tunable interaction between the two functionalities. Cooperative effects on the reactivity of the complexes were demonstrated including the activation of small Lewis basic molecules by reversible anchoring at the boron center.

  16. Kinetic and inhibition studies on substrate channelling in the bifunctional enzyme catalysing C-terminal amidation.

    PubMed Central

    Moore, A B; May, S W

    1999-01-01

    A series of experiments has been conducted to investigate the possibility that substrate channelling might occur in the bifunctional forms of enzymes carrying out C-terminal amidation, a post-translational modification essential to the biological activity of many neuropeptides. C-terminal amidation entails sequential action by peptidylglycine mono-oxygenase (PAM, EC 1.14.17.3) and peptidylamidoglycolate lyase (PGL, EC 4.3.2.5), with the mono-oxygenase catalysing conversion of a glycine-extended pro-peptide into the corresponding alpha-hydroxyglycine derivative, which is then converted by the lyase into amidated peptide plus glyoxylate. Since the mono-oxygenase and lyase reactions exhibit tandem reaction stereospecificities, channelling of the alpha-hydroxy intermediate might occur, as is the case for some other multifunctional enzymes. Selective inhibition of the mono-oxygenase domain by competitive ester inhibitors, as well as mechanism-based mono-oxygenase inactivation by the novel olefinic inhibitor 5-acetamido-4-oxo-6-phenylhex-2-enoate (N-acetylphenylalanyl acrylate), has little to no effect on the kinetic parameters of the lyase domain of the AE from Xenopus laevis. Similarly, inhibition of the lyase domain by the potent dioxo inhibitor 2,4-dioxo-5-acetamido-6-phenylhexanoate has little effect on the activity of the monooxygenase domain in the bifunctional enzyme. A series of experiments on intermediate accumulation and conversion were also carried out, along with kinetic investigations of the reactivities of the monofunctional and bifunctional forms of PAM and PGL towards substrates and inhibitors. Taken together, the results demonstrate the kinetic independence of the mono-oxygenase and lyase domains, and provide no evidence for substrate channelling between these domains in the bifunctional amidating enzyme. PMID:10377242

  17. Grafting of bifunctional phosphonic and carboxylic acids on Phynox: Impact of induction heating

    NASA Astrophysics Data System (ADS)

    Devillers, S.; Lanners, L.; Delhalle, J.; Mekhalif, Z.

    2011-05-01

    Phynox, a cobalt-chromium alloy, exhibits interesting mechanical properties making it a valuable material for a number of applications. However, its applications (especially biomedical ones) often require specific surface properties that can be imparted via suitable surface functionalizations. Based on Faraday's law of induction, induction heating is a widely used method to heat metallic substrates directly and contactless. The aim of this work is to compare the influence of induction heating and a conventional heating method on the functionalization of Phynox surfaces with bifunctional (6-phosphonohexanoic and 11-phosphoundecanoic acids) monolayers in order to create a platform for a large variety of post-grafting chemical reactions, e.g. with alcohols and amines, to modify and control the surface properties. In a first part, we assess the influence of the heating method on the interaction between the two terminal moieties of the 6-phosphonohexanoic and 11-phosphoundecanoic acids and the Phynox surface by studying the grafting of n-dodecylphosphonic acid and n-dodecanoic acid separately. The suitability of such bifunctional molecules for post-grafting chemical reactions has then been assessed by studying the post-grafting of a fluorinated alcohol by the Steglich esterification reaction between the carboxylic end of the grafted bifunctional molecules and the alcohol function of the post-grafted molecule. It has been shown that induction heating can lead to a much more selective adsorption of bifunctional molecules on the surface of Phynox, leaving a higher amount of free carboxylic acid functions to react during the second modification step.

  18. L-Proline Derived Bifunctional Organocatalysts: Enantioselective Michael Addition of Dithiomalonates to trans-β-Nitroolefins.

    PubMed

    Jin, Hui; Kim, Seung Tae; Hwang, Geum-Sook; Ryu, Do Hyun

    2016-04-15

    A series of novel L-proline derived tertiary amine bifunctional organocatalysts 9 are reported, which were applied to the asymmetric Michael addition of dithiomalonates 2 to trans-β-nitroolefins 1. The reaction proceeded in high yields (up to 99%) with high enantioselectivities (up to 97% ee). The synthetic utility of this methodology was demonstrated in the short synthesis of (R)-phenibut in high yield.

  19. Enantioselective, organocatalytic reduction of ketones using bifunctional thiourea-amine catalysts.

    PubMed

    Li, De Run; He, Anyu; Falck, J R

    2010-04-16

    Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl.

  20. Enantioselective, Organocatalytic Reduction of Ketones using Bifunctional Thiourea-Amine Catalysts

    PubMed Central

    Li, De Run; He, Anyu; Falck, J. R.

    2010-01-01

    Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl. PMID:20334398

  1. Synthesis and Evaluation of Nanoglobular Macrocyclic Mn(II) Chelate Conjugates As Non-Gadolinium(III) MRI Contrast Agents

    PubMed Central

    Tan, Mingqian; Ye, Zhen; Jeong, Eun-Kee; Wu, Xueming; Parker, Dennis L.; Lu, Zheng-Rong

    2011-01-01

    Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in the patients with impaired renal functions, there is a strong interest on developing alternative contrast agents for MRI. In this study, lysine dendrimers with a silsesquioxane core acted as nanoglobular carriers that were conjugated to Mn(II)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate monoamide (Generation 2, 3, 4-DOTA-Mn) to synthesize non-Gd(III) based contrast agents for magnetic resonance imaging (MRI). A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T1 and T2 relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T1 relaxivity of G2, G3, G4 nanoglobular Mn(II)-DOTA conjugates was 3.3, 2.8, 2.4 mM−1sec−1 per Mn(II) chelate at 3 T, respectively. The T1 relaxivity of G3-NOTA-Mn was 3.80 mM−1sec−1 per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less non-specific liver enhancement than MnCl2 and were effective for contrast enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising non-gadolinium based MRI contrast agents. PMID:21473650

  2. Bifunctional Catalysts for Upgrading of Biomass-Derived Oxygenates: A Review

    SciTech Connect

    Robinson, Allison M.; Hensley, Jesse E.; Medlin, J. Will

    2016-08-05

    Deoxygenation is an important reaction in the conversion of biomass-derived oxygenates to fuels and chemicals. A key route for biomass refining involves the production of pyrolysis oil through rapid heating of the raw biomass feedstock. Pyrolysis oil as produced is highly oxygenated, so the feasibility of this approach depends in large part on the ability to selectively deoxygenate pyrolysis oil components to create a stream of high-value finished products. Identification of catalytic materials that are active and selective for deoxygenation of pyrolysis oil components has therefore represented a major research area. One catalyst is rarely capable of performing the different types of elementary reaction steps required to deoxygenate biomass-derived compounds. For this reason, considerable attention has been placed on bifunctional catalysts, where two different active materials are used to provide catalytic sites for diverse reaction steps. Here, we review recent trends in the development of catalysts, with a focus on catalysts for which a bifunctional effect has been proposed. We summarize recent studies of hydrodeoxygenation (HDO) of pyrolysis oil and model compounds for a range of materials, including supported metal and bimetallic catalysts as well as transition-metal oxides, sulfides, carbides, nitrides, and phosphides. Particular emphasis is placed on how catalyst structure can be related to performance via molecular-level mechanisms. These studies demonstrate the importance of catalyst bifunctionality, with each class of materials requiring hydrogenation and C-O scission sites to perform HDO at reasonable rates.

  3. Comparison of Dynamical Behaviors Between Monofunctional and Bifunctional Two-Component Signaling Modules

    NASA Astrophysics Data System (ADS)

    Yang, Xiyan; Wu, Yahao; Yuan, Zhanjiang

    2015-06-01

    Two-component signaling modules exist extensively in bacteria and microbes. These modules can be, based on their distinct network structures, divided into two types: the monofunctional system (denoted by MFS) where the sensor kinase (SK) modulates only phosphorylation of the response regulator (RR), and the bifunctional system (denoted by BFS) where the SK catalyzes both phosphorylation and dephosphorylation of the RR. Here, we analyze dynamical behaviors of these two systems based on stability theory, focusing on differences between them. The analysis of the deterministic behavior indicates that there is no difference between the two modules, that is, each system has the unique stable steady state. However, there are significant differences in stochastic behavior between them. Specifically, if the mean phosphorylated SK level is kept the same for the two modules, then the variance and the Fano factor for the phosphorylated RR in the BFS are always no less than those in the MFS, indicating that bifunctionality always enhances fluctuations. The correlation between the phosphorylated SK and the phosphorylated RR in the BFS is always positive mainly due to competition between system components, but this correlation in the MFS may be positive, almost zero, or negative, depending on the ratio between two rate constants. Our overall analysis indicates that differences between dynamical behaviors of monofunctional and bifunctional signaling modules are mainly in the stochastic rather than deterministic aspect.

  4. Bifunctional catalysts for upgrading of biomass-derived oxygenates: A review

    DOE PAGES

    Robinson, Allison M.; Hensley, Jesse E.; Medlin, J. Will

    2016-06-21

    Deoxygenation is an important reaction in the conversion of biomass-derived oxygenates to fuels and chemicals. A key route for biomass refining involves the production of pyrolysis oil through rapid heating of the raw biomass feedstock. Pyrolysis oil as produced is highly oxygenated, so the feasibility of this approach depends in large part on the ability to selectively deoxygenate pyrolysis oil components to create a stream of high-value finished products. Identification of catalytic materials that are active and selective for deoxygenation of pyrolysis oil components has therefore represented a major research area. One catalyst is rarely capable of performing the differentmore » types of elementary reaction steps required to deoxygenate biomass-derived compounds. For this reason, considerable attention has been placed on bifunctional catalysts, where two different active materials are used to provide catalytic sites for diverse reaction steps. Here, we review recent trends in the development of catalysts, with a focus on catalysts for which a bifunctional effect has been proposed. We summarize recent studies of hydrodeoxygenation (HDO) of pyrolysis oil and model compounds for a range of materials, including supported metal and bimetallic catalysts as well as transition-metal oxides, sulfides, carbides, nitrides, and phosphides. Particular emphasis is placed on how catalyst structure can be related to performance via molecular-level mechanisms. Finally, these studies demonstrate the importance of catalyst bifunctionality, with each class of materials requiring hydrogenation and C-O scission sites to perform HDO at reasonable rates.« less

  5. Enhanced Bifunctional Oxygen Catalysis in Strained LaNiO3 Perovskites

    DOE PAGES

    Petrie, Jonathan R.; Cooper, Valentino R.; Freeland, John W.; ...

    2016-02-11

    Strain is known to greatly influence low-temperature oxygen electrocatalysis on noble metal films, leading to significant enhancements in bifunctional activity essential for fuel cells and metal-air batteries. Still, its catalytic impact on transition-metal oxide thin films, such as perovskites, is not widely understood. Here, we epitaxially strain the conducting perovskite LaNiO3 to systematically determine its influence on both the oxygen reduction and oxygen evolution reaction. Uniquely, we found that compressive strain could significantly enhance both reactions, yielding a bifunctional catalyst that surpasses the performance of noble metals such as Pt. We attribute the improved bifunctionality to strain-induced splitting of themore » eg orbitals, which can customize orbital asymmetry at the surface. Lastly, analogous to strain-induced shifts in the d-band center of noble metals relative to the Fermi level, such splitting can dramatically affect catalytic activity in this perovskite and other potentially more active oxides.« less

  6. Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein

    PubMed Central

    Germain, Claire; Campigna, Emmanuelle; Salhi, Imed; Morisseau, Sébastien; Navarro-Teulon, Isabelle; Mach, Jean-Pierre; Pèlegrin, André; Robert, Bruno

    2008-01-01

    Natural killer (NK) cells are at the crossroad between innate and adaptive immunity and play a major role in cancer immunosurveillance. NK cell stimulation depends on a balance between inhibitory and activating receptors, such as the stimulatory lectinlike receptor NKG2D. To redirect NK cells against tumor cells we designed bifunctional proteins able to specifically bind tumor cells and to induce their lysis by NK cells, after NKG2D engagement. To this aim, we used the “knob into hole” heterodimerization strategy, in which “knob” and “hole” variants were generated by directed mutagenesis within the CH3 domain of human IgG1 Fc fragments fused to an anti-CEA or anti-HER2 scFv or to the H60 murine ligand of NKG2D, respectively. We demonstrated the capacity of the bifunctional proteins produced to specifically coat tumor cells surface with H60 ligand. Most importantly, we demonstrated that these bifunctional proteins were able to induce an NKG2D-dependent and antibody-specific tumor cell lysis by murine NK cells. Overall, the results show the possibility to redirect NK cytotoxicity to tumor cells by a new format of recombinant bispecific antibody, opening the way of potential NK cell-based cancer immunotherapies by specific activation of the NKG2D receptor at the tumor site. PMID:18790793

  7. Mechanical Characterization of a Bi-functional Tetronic Hydrogel Adhesive for Soft Tissues

    PubMed Central

    Sanders, Lindsey; Stone, Roland; Webb, C. Kenneth; Mefford, O. Thompson; Nagatomi, Jiro

    2014-01-01

    Although a number of tissue adhesives and sealants for surgical use are currently available, attaining a useful balance in high strength, high compliance, and low swelling has proven difficult. Recent studies have demonstrated that a 4-arm poly(propylene oxide)-poly(ethylene oxide) (PPO-PEO) block copolymer, Tetronic, can be chemically modified to form a hydrogel tissue adhesive21–23. Building on the success of these studies, the present study explored bi-functionalization of Tetronic with acrylates for chemical crosslinking of the hydrogel and N-hydroxysuccinimide (NHS) for reaction with tissue amines. The adhesive bond strengths of various uni- and bi-functional Tetronic blends (T1107 ACR: T1107 ACR/NHS) determined by lap shear testing ranged between 8 and 74 kPa, with the 75:25 (T1107 ACR: T1107 ACR/NHS) blend displaying the highest value. These results indicated that addition of NHS led to improvement of tissue bond strength over acrylation alone Furthermore, ex vivo pressure tests using the rat bladder demonstrated that the bi-functional Tetronic adhesive exhibited high compliance and maintained pressures under hundreds of filling and emptying cycles. Together, the results of the present study provided evidence that the bi-functional Tetronic adhesive with a proper blend ratio may be used to achieve an accurate balance in bulk and tissue bond strengths, as well as the compliance and durability for soft tissue such as the bladder. PMID:25111445

  8. Bifunctional bridging linker-assisted synthesis and characterization of TiO2/Au nanocomposites

    NASA Astrophysics Data System (ADS)

    Žunič, Vojka; Kurtjak, Mario; Suvorov, Danilo

    2016-11-01

    Using a simple organic bifunctional bridging linker, titanium dioxide (TiO2) nanoparticles were coupled with the Au nanoparticles to form TiO2/Au nanocomposites with a variety of Au loadings. This organic bifunctional linker, meso-2,3-dimercaptosuccinic acid, contains two types of functional groups: (i) the carboxyl group, which enables binding to the TiO2, and (ii) the thiol group, which enables binding to the Au. In addition, the organic bifunctional linker acts as a stabilizing agent to prevent the agglomeration and growth of the Au particles, resulting in the formation of highly dispersed Au nanoparticles. To form the TiO2/Au nanocomposites in a simple way, we deliberately applied a synthetic method that simultaneously ensures: (i) the capping of the Au nanoparticles and (ii) the binding of different amounts of Au to the TiO2. The TiO2/Au nanocomposites formed with this method show enhanced UV and Vis photocatalytic activities when compared to the pure TiO2 nanopowders.

  9. Bifunctional Transition Metal Hydroxysulfides: Room-Temperature Sulfurization and Their Applications in Zn-Air Batteries.

    PubMed

    Wang, Hao-Fan; Tang, Cheng; Wang, Bin; Li, Bo-Quan; Zhang, Qiang

    2017-07-17

    Bifunctional electrocatalysis for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) constitutes the bottleneck of various sustainable energy devices and systems like rechargeable metal-air batteries. Emerging catalyst materials are strongly requested toward superior electrocatalytic activities and practical applications. In this study, transition metal hydroxysulfides are presented as bifunctional OER/ORR electrocatalysts for Zn-air batteries. By simply immersing Co-based hydroxide precursor into solution with high-concentration S(2-) , transition metal hydroxides convert to hydroxysulfides with excellent morphology preservation at room temperature. The as-obtained Co-based metal hydroxysulfides are with high intrinsic reactivity and electrical conductivity. The electron structure of the active sites is adjusted by anion modulation. The potential for 10 mA cm(-2) OER current density is 1.588 V versus reversible hydrogen electrode (RHE), and the ORR half-wave potential is 0.721 V versus RHE, with a potential gap of 0.867 V for bifunctional oxygen electrocatalysis. The Co3 FeS1.5 (OH)6 hydroxysulfides are employed in the air electrode for a rechargeable Zn-air battery with a small overpotential of 0.86 V at 20.0 mA cm(-2) , a high specific capacity of 898 mAh g(-1) , and a long cycling life, which is much better than Pt and Ir-based electrocatalyst in Zn-air batteries. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Enhanced Bifunctional Oxygen Catalysis in Strained LaNiO3 Perovskites

    SciTech Connect

    Petrie, Jonathan R.; Cooper, Valentino R.; Freeland, John W.; Meyer, Tricia L.; Zhang, Zhiyong; Lutterman, Daniel A.; Lee, Ho Nyung

    2016-02-11

    Strain is known to greatly influence low-temperature oxygen electrocatalysis on noble metal films, leading to significant enhancements in bifunctional activity essential for fuel cells and metal-air batteries. Still, its catalytic impact on transition-metal oxide thin films, such as perovskites, is not widely understood. Here, we epitaxially strain the conducting perovskite LaNiO3 to systematically determine its influence on both the oxygen reduction and oxygen evolution reaction. Uniquely, we found that compressive strain could significantly enhance both reactions, yielding a bifunctional catalyst that surpasses the performance of noble metals such as Pt. We attribute the improved bifunctionality to strain-induced splitting of the eg orbitals, which can customize orbital asymmetry at the surface. Lastly, analogous to strain-induced shifts in the d-band center of noble metals relative to the Fermi level, such splitting can dramatically affect catalytic activity in this perovskite and other potentially more active oxides.

  11. Bifunctional Electrophiles Cross-Link Thioredoxins with Redox Relay Partners in Cells

    PubMed Central

    Naticchia, Matthew R.; Brown, Haley A.; Garcia, Francisco J.; Lamade, Andrew M.; Justice, Samantha L.; Herrin, Rachelle P.; Morano, Kevin A.; West, James D.

    2013-01-01

    Thioredoxin protects cells against oxidative damage by reducing disulfide bonds in improperly oxidized proteins. Previously, we found that the baker's yeast cytosolic thioredoxin Trx2 undergoes cross-linking to form several protein-protein complexes in cells treated with the bifunctional electrophile divinyl sulfone (DVSF). Here, we report that the peroxiredoxin Tsa1 and the thioredoxin reductase Trr1, both of which function in a redox relay network with thioredoxin, become cross-linked in complexes with Trx2 upon DVSF treatment. Treatment of yeast with other bifunctional electrophiles, including diethyl acetylenedicarboxylate (DAD), mechlorethamine (HN2), and 1,2,3,4-diepoxybutane (DEB), resulted in the formation of similar cross-linked complexes. Cross-linking of Trx2 and Tsa1 to other proteins by DVSF and DAD is dependent on modification of the active site Cys residues within these proteins. In addition, the human cytosolic thioredoxin, cytosolic thioredoxin reductase, and peroxiredoxin 2 form cross-linked complexes to other proteins in the presence of DVSF, although each protein shows different susceptibilities to modification by DAD, HN2, and DEB. Taken together, our results indicate that bifunctional electrophiles potentially disrupt redox homeostasis in yeast and human cells by forming cross-linked complexes between thioredoxins and their redox partners. PMID:23414292

  12. Bifunctional sensor of pentachlorophenol and copper ions based on nanostructured hybrid films of humic acid and exfoliated layered double hydroxide via a facile layer-by-layer assembly.

    PubMed

    Yuan, Shuang; Peng, Dinghua; Hu, Xianluo; Gong, Jingming

    2013-06-27

    A new, highly sensitive bifunctional electrochemical sensor for the simultaneous determination of pentachlorophenol (PCP) and copper ions (Cu(2+)) has been developed, where organic-inorganic hybrid ultrathin films were fabricated by alternate assembly of humic acid (HA) and exfoliated Mg-Al-layered double hydroxide (LDH) nanosheets onto ITO substrates via a layer-by-layer (LBL) approach. The multilayer films were then characterized by means of UV-vis spectrometry, scanning electron microscopy (SEM), and atomic force microscope (AFM). These films were found to have a relatively smooth surface with almost equal amounts of HA incorporated in each cycle. Its electrochemical performance was systematically investigated. Our results demonstrate that such a newly designed (LDH/HA)n multilayer films, combining the individual properties of HA (dual recognition ability for organic herbicides and metal ions) together with LDH nanosheets (a rigid inorganic matrix), can be applied to the simultaneous analysis of PCP and Cu(II) without interference from each other. The LBL assembled nanoarchitectures were further investigated by X-ray photoelectron spectroscopy (XPS) and infrared spectroscopy (IR), which provides insight for bifunctional sensing behavior. Under the optimized conditions, the detection limit was found to be as low as 0.4 nM PCP, well below the guideline value of PCP in drinking water (3.7 nM) set by the United States Environmental Protection Agency (U.S. EPA), and 2.0 nM Cu(2+), much below the guideline value (2.0 mg L(-1), ~31.2 nM) from the World Health Organization (WHO), respectively. Toward the goal for practical applications, this simple and cost-effective probe was further evaluated by monitoring PCP and Cu(II) in water samples. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Design of a bifunctional fusion protein for ovarian cancer drug delivery: single-chain anti-CA125 core-streptavidin fusion protein.

    PubMed

    Wang, Welson Wen-Shang; Das, Dipankar; McQuarrie, Stephen A; Suresh, Mavanur R

    2007-03-01

    We have developed a universal ovarian cancer cell targeting vehicle that can deliver biotinylated therapeutic drugs. A single-chain antibody variable domain (scFv) that recognizes the CA125 antigen of ovarian cancer cells was fused with a core-streptavidin domain (core-streptavidin-VL-VH and VL-VH-core-streptavidin orientations) using recombinant DNA technology and then expressed in Escherichia coli using the T7 expression system. The bifunctional fusion protein (bfFp) was expressed in a shaker flask culture, extracted from the periplasmic soluble protein, and affinity purified using an IMAC column. The two distinct activities (biotin binding and anti-CA125) of the bfFp were demonstrated using ELISA, Western blot and confocal laser-scanning microscopy (CLSM). The ELISA method utilized human NIH OVCAR-3 cells along with biotinylated bovine serum albumin (B-BSA) or biotinylated liposomes, whereas, the Western blot involved probing with B-BSA. The CLSM study has shown specificity in binding to the OVCAR-3 cell-line. ELISA and Western blot studies have confirmed the bifunctional activity and specificity. In the presence of bfFp, there was enhanced binding of biotinylated antigen and liposome to OVCAR-3 cells. In contrast, the control EMT6 cells, which do not express the CA125 antigen, showed minimal binding of the bfFp. Consequently, bfFp based targeting of biotinylated therapeutic drugs, proteins, liposomes, or nanoparticles could be an alternative, convenient method to deliver effective therapy to ovarian cancer patients. Peritoneal infusion of the bfFp-therapeutic complex could also be effective in locally targeting the most common site of metastatic spread.

  14. Alternative strategies: a better alternative.

    PubMed

    Doody, Dennis

    2010-05-01

    Alternatives can be defined as being any financial asset other than traditional stocks and bonds. They include marketable alternatives, private capital, and equity real estate. There are two primary reasons for investing in alternatives: the potential for greater return and the opportunity to diversify a portfolio. Although alternatives were challenged in the highly volatile environment that existed in 2008 and early 2009, they generally lived up to expectations.

  15. MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

    SciTech Connect

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-07-13

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

  16. A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

    PubMed Central

    Dragset, Marte S.; Poce, Giovanna; Alfonso, Salvatore; Padilla-Benavides, Teresita; Ioerger, Thomas R.; Kaneko, Takushi; Sacchettini, James C.; Biava, Mariangela; Parish, Tanya; Argüello, José M.

    2015-01-01

    Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound. PMID:25645825

  17. Removal of cadmium from fish sauce using chelate resin.

    PubMed

    Sasaki, Tetsuya; Araki, Ryohei; Michihata, Toshihide; Kozawa, Miyuki; Tokuda, Koji; Koyanagi, Takashi; Enomoto, Toshiki

    2015-04-15

    Fish sauce that is prepared from squid organs contains cadmium (Cd), which may be present at hazardous concentrations. Cd molecules are predominantly protein bound in freshly manufactured fish sauce, but are present in a liberated form in air-exposed fish sauce. In the present study, we developed a new method for removing both Cd forms from fish sauce using chelate resin and a previously reported tannin treatment. Sixteen-fold decreases in Cd concentrations were observed (0.78-0.05 mg/100 mL) following the removal of liberated Cd using chelate resin treatment, and the removal of protein-bound Cd using tannin treatment. Major nutritional components of fish sauce were maintained, including free amino acids and peptides, and angiotensin I-converting enzyme inhibitory and antioxidant activities.

  18. Synthetic methodologies and spatial organization of metal chelate dendrimers and star and hyperbranched polymers.

    PubMed

    Dzhardimalieva, Gulzhian I; Uflyand, Igor E

    2017-08-08

    The synthetic methodologies, physico-chemical peculiarities, properties, and structure of metal chelate dendrimers and star and hyperbranched polymers are considered. These compounds are subdivided into molecular, intracomplex, and macrocyclic types which in turn are classified depending on the nature of the donor atoms (N,N-, N,O-, N,S-, O,O-, O,S-, S,S-, P,P-chelates, etc.). Special attention is paid to the features of the preparation of metal chelate star polymers by "arm-first", "core-first" and click-to-chelate approaches. The main data on the synthesis, spatial structure and properties of the metal chelate hyperbranched polymers are summarized. The basic concepts and synthetic strategies leading to the different types of supramolecular metal chelate dendrimers are analyzed. The problems and future prospects of metal chelate dendrimers and star and hyperbranched polymers are outlined. The bibliography includes papers published after 2010.

  19. EFFECT OF TEMPERATURE ON THE SORPTION OF CHELATED RADIONUCLIDES.

    USGS Publications Warehouse

    Maest, Ann S.; Crerar, David A.; Dillon, Edward C.; Trehu, Stephen M.; Rountree, Tamara N.; ,

    1985-01-01

    Temperature effects in the near-field radioactive waste disposal environment can result in changes in the adsorptive capacity and character of the substrate and the chemistry of the reacting fluids. This work examines the effect of temperature on 1) the kinetics of radionuclide sorption onto clays from 25 degree -75 degree C and 2) the degradation and metal-binding ability of two organic complexing agents found in chelated radioactive wastes and natural groundwaters.

  20. Targeting Chelatable Iron as a Therapeutic Modality in Parkinson's Disease

    PubMed Central

    Moreau, Caroline; Devedjian, Jean Christophe; Kluza, Jérome; Petrault, Maud; Laloux, Charlotte; Jonneaux, Aurélie; Ryckewaert, Gilles; Garçon, Guillaume; Rouaix, Nathalie; Duhamel, Alain; Jissendi, Patrice; Dujardin, Kathy; Auger, Florent; Ravasi, Laura; Hopes, Lucie; Grolez, Guillaume; Firdaus, Wance; Sablonnière, Bernard; Strubi-Vuillaume, Isabelle; Zahr, Noel; Destée, Alain; Corvol, Jean-Christophe; Pöltl, Dominik; Leist, Marcel; Rose, Christian; Defebvre, Luc; Marchetti, Philippe; Cabantchik, Z. Ioav; Bordet, Régis

    2014-01-01

    Abstract Aims: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. Results: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. Innovation: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. Conclusions: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD. Antioxid

  1. Flue gas desulfurization/denitrification using metal-chelate additives

    DOEpatents

    Harkness, J.B.L.; Doctor, R.D.; Wingender, R.J.

    1985-08-05

    A method of simultaneously removing SO/sub 2/ and NO from oxygen-containing flue gases resulting from the combustion of carbonaceous material by contacting the flue gas with an aqueous scrubber solution containing an aqueous sulfur dioxide sorbent and an active metal chelating agent which promotes a reaction between dissolved SO/sub 2/ and dissolved NO to form hydroxylamine N-sulfonates. The hydroxylamine sulfonates are then separated from the scrubber solution which is recycled. 3 figs.

  2. Lipophilic chelator inhibition of electron transport in Escherichia coli.

    PubMed Central

    Crane, R T; Sun, I L; Crane, F L

    1975-01-01

    The lipophilic chelator bathophenanthroline inhibits electron transport in membranes from Escherichia coli. The less lipophilic 1,10-phenanthroline, bathophenanthroline sulfonate, and alpha,alpha-dipyridyl have little effect. Reduced nicotinamide adenine dinucleotide oxidase is more sensitive to bathophenanthroline inhibition than lactate oxidase activity. Evidence for two sites of inhibition comes from the fact that both reduced nicotinamide adenine dinucleotide menadione reductase and duroquinol oxidase activities are inhibited. Addition of uncouplers of phosphorylation before bathophenanthroline protects against inhibition. PMID:1092663

  3. Mineral Levels in Thalassaemia Major Patients Using Different Iron Chelators.

    PubMed

    Genc, Gizem Esra; Ozturk, Zeynep; Gumuslu, Saadet; Kupesiz, Alphan

    2016-03-01

    The goal of the present study was to determine the levels of minerals in chronically transfused thalassaemic patients living in Antalya, Turkey and to determine mineral levels in groups using different iron chelators. Three iron chelators deferoxamine, deferiprone and deferasirox have been used to remove iron from patients' tissues. There were contradictory results in the literature about minerals including selenium, zinc, copper, and magnesium in thalassaemia major patients. Blood samples from the 60 thalassaemia major patients (the deferoxamine group, n = 19; the deferiprone group, n = 20 and the deferasirox group, n = 21) and the controls (n = 20) were collected. Levels of selenium, zinc, copper, magnesium, and iron were measured, and all of them except iron showed no significant difference between the controls and the patients regardless of chelator type. Serum copper levels in the deferasirox group were lower than those in the control and deferoxamine groups, and serum magnesium levels in the deferasirox group were higher than those in the control, deferoxamine and deferiprone groups. Iron levels in the patient groups were higher than those in the control group, and iron levels showed a significant correlation with selenium and magnesium levels. Different values of minerals in thalassaemia major patients may be the result of different dietary intake, chelator type, or regional differences in where patients live. That is why minerals may be measured in thalassaemia major patients at intervals, and deficient minerals should be replaced. Being careful about levels of copper and magnesium in thalassaemia major patients using deferasirox seems to be beneficial.

  4. Decontamination of process equipment using recyclable chelating solvent

    SciTech Connect

    Jevec, J.; Lenore, C.; Ulbricht, S.

    1995-10-01

    The Department of Energy (DOE) is now faced with the task of meeting decontamination and decommissioning obligations at numerous facilities by the year 2019. Due to the tremendous volume of material involved, innovative decontamination technologies are being sought that can reduce the volumes of contaminated waste materials and secondary wastes requiring disposal. This report describes the results of the performance testing of chelates and solvents for the dissolution of uranium.

  5. Chelate-Assisted Heavy Metal Movement Through the Root Zone

    NASA Astrophysics Data System (ADS)

    Kirkham, M.; Madrid, F.; Liphadzi, M. S.

    2001-12-01

    Chelating agents are added to soil as a means to mobilize heavy metals for plant uptake during phytoremediation. Yet almost no studies follow the displacement of heavy metals through the vadose zone following solubilization with chelating agents. The objective of this work was to determine the movement of heavy metals through the soil profile and their absorption by barley (Hordeum vulgare L.) in a soil amended with biosolids and in the presence of a chelating agent (EDTA). Twelve columns 75 cm in height and 17 in diameter were packed with a Haynie very fine sandy loam (coarse-silty, mixed, calcareous, mesic Mollic Udifluvents) and watered with liquid biosolids applied at the surface at a rate of 120 kg N/ha. Three weeks after plants germinated, soil was irrigated with a solution of the disodium salt of EDTA added at a rate of 0.5 g/kg soil. Four treatments were imposed: columns with no plants and no EDTA; columns with no plants plus EDTA; columns with plants and no EDTA; and columns with plants and EDTA. Columns were watered intensively for 35 days until two pore volumes of water had been added, and the leachates were collected daily. With or without plants, columns with EDTA had lower total concentrations of Cu, Zn, Cd, Ni, and Pb in the surface 20 cm than columns without EDTA. Concentrations of the heavy metals in this layer were not afffected by the presence of roots. Iron in leachate was followed as an indicator metal for movement to groundwater. No iron appeared in the leachate without EDTA, either in the columns with plants or without plants. The peak concentration of iron in the leachate occurred three days earlier in the columns without plants and EDTA compared to the columns with plants and EDTA. The results indicated the importance of vegetation on retarding heavy metal leaching to groundwater during chelate-facilitated phytoremediation.

  6. Flue gas desulfurization/denitrification using metal-chelate additives

    DOEpatents

    Harkness, John B. L.; Doctor, Richard D.; Wingender, Ronald J.

    1986-01-01

    A method of simultaneously removing SO.sub.2 and NO from oxygen-containing flue gases resulting from the combustion of carbonaceous material by contacting the flue gas with an aqueous scrubber solution containing an aqueous sulfur dioxide sorbent and an active metal chelating agent which promotes a reaction between dissolved SO.sub.2 and dissolved NO to form hydroxylamine N-sulfonates. The hydroxylamine sulfonates are then separated from the scrubber solution which is recycled.

  7. Examining the fixation kinetics of chelated and non-chelated copper micronutrient and the applications to micronutrient management in semi-arid alkaline soils

    NASA Astrophysics Data System (ADS)

    Udeigwe, T. K.; Eichmann, M. B.; Menkiti, M. C.

    2015-10-01

    The relationship between the deficiency of a nutrient in plants and its total concentration in the soil is complex. This study examined and compared the fixation and fixation kinetics of copper (Cu) in chelated (Ethylene diamine tetraacetic acid, EDTA) and non-chelated mixed systems of micronutrients in the semi-arid soils of the Southern High Plains, US using findings from Cu extraction studies and kinetic models. Approximately, 22 % more Cu was fixed in the non-chelated system within the first 14 days with only 7 % difference between the two systems by day 90. Findings suggest a decrease in the effectiveness of chelated micronutrient over time, highlighting the significance of timing even when chelated micronutrients are applied. The strengths of the relationship of change in available Cu with respect to other micronutrients [iron (Fe), manganese (Mn), and zinc (Zn)] were higher in the non-chelated system (R2: 0.68-0.94), compared to the chelated (R2: 0.42-0.81) with slopes of 0.40 (Cu-Fe), 0.31 (Cu-Mn), and 1.04 (Cu-Zn) in the non-chelated system and 0.26 (Cu-Fe), 0.22 (Cu-Mn), and 0.90 (Cu-Zn) in the chelated. Reduction in the amount of available Cu was best described by the power function model (R2 = 0.91, SE = 0.081) in the non-chelated system and second order model (R2 = 0.95, SE = 0.010) in the chelated system. The applications generated from this study could be used as tools for improved micronutrient management and also provide baseline data for future work in other semi-arid/arid alkaline soils of the world. Findings are also more applicable to field settings, an improvement over related previous studies.

  8. Hydroxyurea Could Be a Good Clinically Relevant Iron Chelator

    PubMed Central

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2013-01-01

    Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl’s Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination. PMID:24349400

  9. Hydroxyurea could be a good clinically relevant iron chelator.

    PubMed

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2013-01-01

    Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  10. Copper chelation therapy in intrahepatic cholestasis of childhood.

    PubMed Central

    Evans, J; Zerpa, H; Nuttall, L; Boss, M; Sherlock, S

    1983-01-01

    The effect of copper chelation was studied in a group of children with intrahepatic cholestasis of childhood (IHCC) and increased liver copper levels. Initial therapy was D-penicillamine (10 mg/kg/day), being replaced by triethylenetetramine dihydrochloride (20 mg/kg/day) when side-effects of D-penicillamine occurred. Eight children completed two years of copper chelation. Pruritus remained the main symptom and did not improve. Two patients developed D-penicillamine side-effects - one patient after nine months (marked anorexia, lassitude) and one other patient after 19 months (thrombocytopenia). Two patients died during the study, in one of these normal hepatic copper concentration was achieved. Hepatic copper concentrations decreased in seven of eight patients from 8.6 (2.7 +/- 16.2) mumol/g to 3.4 (0.6-16.5) mumol/g (median and range (0.05 less than 0.01) and serum aspartate transaminase increased in seven of eight patients (p less than 0.05). Histological assessment of serial liver sections revealed increased fibrosis and cholestasis despite reductions in hepatic copper levels during the study. This study showed that D-penicillamine therapy was associated with significant side-effects, while marked clinical, biochemical, or histological improvement did not follow effective copper chelation therapy in intrahepatic cholestasis of childhood. PMID:6848432

  11. Regeneration of the heart in diabetes by selective copper chelation.

    PubMed

    Cooper, Garth J S; Phillips, Anthony R J; Choong, Soon Y; Leonard, Bridget L; Crossman, David J; Brunton, Dianne H; Saafi, 'Etuate L; Dissanayake, Ajith M; Cowan, Brett R; Young, Alistair A; Occleshaw, Christopher J; Chan, Yih-Kai; Leahy, Fiona E; Keogh, Geraldine F; Gamble, Gregory D; Allen, Grant R; Pope, Adèle J; Boyd, Peter D W; Poppitt, Sally D; Borg, Thomas K; Doughty, Robert N; Baker, John R

    2004-09-01

    Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

  12. Copper and Zinc Chelation as a Treatment of Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Hodak, Miroslav; Bernholc, Jerry

    2014-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. The cause of the disease remains unknown, but amyloid- β (A β), a short peptide, is considered causal its pathogenesis. At cellular level, AD is characterized by deposits mainly composed of A β that also contain elevated levels of transition metals ions. Targeting metals is a promising new strategy for AD treatment, which uses moderately strong metal chelators to sequester them from A β or the environment. PBT2 is a chelating compound that has been the most promising in clinical trials. In our work, we use computer simulations to investigate complexes of a close analog of PBT2 with Cu2+ and Zn2+ ions. The calculations employ KS/FD DFT method, which combines Kohn-Sham DFT with the frozen-density DFT to achieve efficient description of explicit solvent beyond the first solvation shell. Our work is based on recent experiments and examines both 1:1 and 2:1 chelator-metal stochiometries detected experimentally. The results show that copper attaches more strongly than zinc, find that 1:1 complexes involve water in the first coordination shell and determine which one of several possible 2:1 geometries is the most preferable.

  13. Proteomic profiling reveals that collismycin A is an iron chelator

    PubMed Central

    Kawatani, Makoto; Muroi, Makoto; Wada, Akira; Inoue, Gyo; Futamura, Yushi; Aono, Harumi; Shimizu, Kenshirou; Shimizu, Takeshi; Igarashi, Yasuhiro; Takahashi-Ando, Naoko; Osada, Hiroyuki

    2016-01-01

    Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth. PMID:27922079

  14. Mercury removal in utility wet scrubber using a chelating agent

    DOEpatents

    Amrhein, Gerald T.

    2001-01-01

    A method for capturing and reducing the mercury content of an industrial flue gas such as that produced in the combustion of a fossil fuel or solid waste adds a chelating agent, such as ethylenediaminetetraacetic acid (EDTA) or other similar compounds like HEDTA, DTPA and/or NTA, to the flue gas being scrubbed in a wet scrubber used in the industrial process. The chelating agent prevents the reduction of oxidized mercury to elemental mercury, thereby increasing the mercury removal efficiency of the wet scrubber. Exemplary tests on inlet and outlet mercury concentration in an industrial flue gas were performed without and with EDTA addition. Without EDTA, mercury removal totaled 42%. With EDTA, mercury removal increased to 71%. The invention may be readily adapted to known wet scrubber systems and it specifically provides for the removal of unwanted mercury both by supplying S.sup.2- ions to convert Hg.sup.2+ ions into mercuric sulfide (HgS) and by supplying a chelating agent to sequester other ions, including but not limited to Fe.sup.2+ ions, which could otherwise induce the unwanted reduction of Hg.sup.2+ to the form, Hg.sup.0.

  15. Investigating Chelating Sulfonamides and their use in Metalloproteinase Inhibitors

    PubMed Central

    Tanakit, Alisa; Rouffet, Matthieu; Martin, David P.; Cohen, Seth M.

    2013-01-01

    Matrix metalloproteinase inhibitors (MMPi) utilize zinc-binding groups (ZBGs) to chelate the catalytic Zn(II) ion resulting in enzyme inhibition. Adapting findings from the literature of Zn(II) ion sensors, we previously reported chelating sulfonamide inhibitors of MMP-2, some of which showed excellent selectivity over other gelatinases (MMP-9). Herein, we greatly expand our investigation of chelating sulfonamides as MMP inhibitors (MMPi) with the synthesis and screening of several new libraries consisting of 2-phenyl-7-sulfonamidobenzimidazole, 2-phenyl-7-sulfonamidobenzoxazole, 7-sulfonamidobenzimidazole, 7-sulfonamidobenzoxazole, and 2-(2-sulfonamidophenyl)-quinoline ZBG derivatives. A novel microwave irradiation synthetic procedure was utilized to rapidly and efficiently prepare these molecules. To better understand the coordination chemistry underlying these ZBGs, crystal structures of representative molecules with several first row transition metals were determined and differences in coordination preferences were considered. Surprisingly, only compounds with the 2-phenyl-7-sulfonamidobenzimidazole ZBG showed inhibition of MMP-2, suggesting that the specific structure of the ZBG can have a pronounced effect of inhibitory activity. PMID:22411188

  16. Chelation therapy and vanadium: effect on reproductive organs in rats.

    PubMed

    Shrivastava, Sadhana; Jadon, Anjana; Shukla, Sangeeta; Mathur, Ramesh

    2007-06-01

    Present investigation was planned to evaluate the therapeutic effectiveness of chelating agents against vanadium intoxication on blood and reproductive organs of rats. Male and female albino rats were injected vanadyl sulphate (7.5 mg/kg, po, for 21 days, 5 days in a week). Chelating agents tiron (T) alone and in combination with lipoic acid (LA), vitamin E (vit E) and selenium (Se) were given for 2 days/week. With the administration of vanadyl sulphate to rats fructose level in seminal vesicles was significantly (P< or =0.05) declined. The activities of alkaline phosphatase and adenosine triphosphatase were also decreased, whereas glycogen content and acid phosphatase activity increased in testis, seminal vesicles, ovaries and uterus after toxicant exposure. Significant changes in serum transaminases, serum alkaline phosphatase and lactate dehydrogenase were recouped by chelation therapy. Lipid peroxidation, reduced glutathione level and triglycerides levels altered significantly after exposure to vanadium in rats. The ultrastructural damage in spermatogenic stages in treated animals showed recovery pattern after therapy. Co-treatment with antioxidants restored these activities. The most effective combination was tiron + selenium followed by tiron + vitamin E, and tiron + lipoic acid.

  17. Alternative fuels

    SciTech Connect

    Not Available

    1991-07-01

    This paper presents the preliminary results of a review, of the experiences of Brazil, Canada, and New Zealand, which have implemented programs to encourage the use of alternative motor fuels. It will also discuss the results of a separate completed review of the Department of Energy's (DOE) progress in implementing the Alternative Motor Fuels Act of 1988. The act calls for, among other things, the federal government to use alternative-fueled vehicles in its fleet. The Persian Gulf War, environmental concerns, and the administration's National Energy Strategy have greatly heightened interest in the use of alternative fuels in this country.

  18. Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease.

    PubMed

    Xu, San-qing; Li, Xu-fang; Zhu, Hui-yun; Liu, Yan; Fang, Feng; Chen, Ling

    2013-10-01

    The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.

  19. Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators.

    PubMed

    Delangle, Pascale; Mintz, Elisabeth

    2012-06-07

    Wilson's disease is an orphan disease due to copper homeostasis dysfunction. Mutations of the ATP7B gene induces an impaired functioning of a Cu-ATPase, impaired Cu detoxification in the liver and copper overload in the body. Indeed, even though copper is an essential element, which is used as cofactor by many enzymes playing vital roles, it becomes toxic when in excess as it promotes cytotoxic reactions leading to oxidative stress. In this perspective, human copper homeostasis is first described in order to explain the mechanisms promoting copper overload in Wilson's disease. We will see that the liver is the main organ for copper distribution and detoxification in the body. Nowadays this disease is treated life-long by systemic chelation therapy, which is not satisfactory in many cases. Therefore the design of more selective and efficient drugs is of great interest. A strategy to design more specific chelators to treat localized copper accumulation in the liver will then be presented. In particular we will show how bioinorganic chemistry may help in the design of such novel chelators by taking inspiration from the biological copper cell transporters.

  20. Overexpression of a bifunctional enzyme, CrtS, enhances astaxanthin synthesis through two pathways in Phaffia rhodozyma.

    PubMed

    Chi, Shuang; He, Yanfeng; Ren, Jie; Su, Qian; Liu, Xingchao; Chen, Zhi; Wang, Mingan; Li, Ying; Li, Jilun

    2015-06-18

    A moderate-temperature, astaxanthin-overproducing mutant strain (termed MK19) of Phaffia rhodozyma was generated in our laboratory. The intracellular astaxanthin content of MK19 was 17-fold higher than that of wild-type. The TLC profile of MK19 showed a band for an unknown carotenoid pigment between those of β-carotene and astaxanthin. In the present study, we attempted to identify the unknown pigment and to enhance astaxanthin synthesis in MK19 by overexpression of the crtS gene that encodes astaxanthin synthase (CrtS). A crtS-overexpressing strain was constructed without antibiotic marker. A recombinant plasmid with lower copy numbers was shown to be stable in MK19. In the positive recombinant strain (termed CSR19), maximal astaxanthin yield was 33.5% higher than MK19, and the proportion of astaxanthin as a percentage of total carotenoids was 84%. The unknown carotenoid was identified as 3-hydroxy-3',4'-didehydro-β,Ψ-carotene-4-one (HDCO) by HPLC, mass spectrometry, and NMR spectroscopy. CrtS was found to be a bifunctional enzyme that helped convert HDCO to astaxanthin. Enhancement of crtS transcriptional level increased transcription levels of related genes (crtE, crtYB, crtI) in the astaxanthin synthesis pathway. A scheme of carotenoid biosynthesis in P. rhodozyma involving alternative bicyclic and monocyclic pathways is proposed. CrtS overexpression leads to up-regulation of synthesis-related genes and increased astaxanthin production. The transformant CSR19 is a stable, secure strain suitable for feed additive production. The present findings help clarify the regulatory mechanisms that underlie metabolic fluxes in P. rhodozyma carotenoid biosynthesis pathways.

  1. Unusual non-bifunctional mechanism for Co-PNP complex catalyzed transfer hydrogenation governed by the electronic configuration of metal center.

    PubMed

    Hou, Cheng; Jiang, Jingxing; Li, Yinwu; Zhang, Zhihan; Zhao, Cunyuan; Ke, Zhuofeng

    2015-10-07

    The mimic of hydrogenases has unleashed a myriad of bifunctional catalysts, which are widely used in the catalytic hydrogenation of polar multiple bonds. With respect to ancillary ligands, the bifunctional mechanism is generally considered to proceed via the metal-ligand cooperation transition state. Inspired by the interesting study conducted by Hanson et al. (Chem Commun., 2013, 49, 10151), we present a computational study of a distinctive example, where a Co(II)-PNP catalyst with an ancillary ligand exhibits efficient transfer hydrogenation through a non-bifunctional mechanism. Both the bifunctional and non-bifunctional mechanisms are discussed. The calculated results, which are based on a full model of the catalyst, suggest that the inner-sphere non-bifunctional mechanism is more favorable (by ∼11 kcal mol(-1)) than the outer-sphere bifunctional mechanism, which is in agreement with the experimental observations. The origin of this mechanistic preference of the Co(II)-PNP catalyst can be attributed to its preference for the square planar geometry. A traditional bifunctional mechanism is less plausible for Co(II)-PNP due to the high distortion energy caused by the change in electronic configuration with the varied ligand field. Considering previous studies that focus on the development of ligands more often, this computational study indicates that the catalytic hydrogenation mechanism is controlled not only by the structure of the ligand but also by the electronic configuration of the metal center.

  2. Performance of Nonmigratory Iron Chelating Active Packaging Materials in Viscous Model Food Systems.

    PubMed

    Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2015-09-01

    Many packaged food products undergo quality deterioration due to iron promoted oxidative reactions. Recently, we have developed a nonmigratory iron chelating active packaging material that represents a novel approach to inhibit oxidation of foods while addressing consumer demands for "cleanˮ labels. A challenge to the field of nonmigratory active packaging is ensuring that surface-immobilized active agents retain activity in a true food system despite diffusional limitations. Yet, the relationship between food viscosity and nonmigratory active packaging activity retention has never been characterized. The objective of this study was to investigate the influence of food viscosity on iron chelation by a nonmigratory iron chelating active packaging material. Methyl cellulose was added to aqueous buffered iron solutions to yield model systems with viscosities ranging from ∼1 to ∼10(5)  mPa·s, representing viscosities ranging from beverage to mayonnaise. Iron chelation was quantified by material-bound iron content using colorimetry and inductively coupled plasma-optical emission spectrometry (ICP-OES).  Maximum iron chelation was reached in solutions up to viscosity ∼10(2)  mPa·s. In more viscous solutions (up to ∼10(4)  mPa·s), there was a significant decrease in iron chelating capacity (P < 0.05). However, materials still retained at least 76% iron chelating capacity. Additionally, the influence of different food hydrocolloids on the performance of nonmigratory iron chelating active packaging was characterized. Methyl cellulose and carrageenan did not compete with the material for specific iron chelation (P > 0.05). Materials retained 32% to 45% chelating capacity when in contact with competitively chelating hydrocolloids guar gum, locust bean gum, and xanthan gum. This work demonstrates the potential application of nonmigratory iron chelating active packaging in liquid and semi-liquid foods to allow for the removal of synthetic chelators, while

  3. Alternative Assessment.

    ERIC Educational Resources Information Center

    Stefonek, Tom; And Others

    1991-01-01

    This special double issue focuses on the issue of alternative assessment and its place in educational reform. "Alternative Assessment: A National Perspective" (T. Stefonek) emphasizes that the fundamental purposes of new assessment methods are grounded in educational goals, meaningful outcomes, and curricular and instructional programs…

  4. Alternative Schools.

    ERIC Educational Resources Information Center

    Annett, Larry D.

    A model is presented for the categorizing of alternative schools, then the nature of the free school, which represents the essence of the alternative school movement, is examined. Strengths and weaknesses of court, legislative, and administrative approaches to resolve governance issues are set forth. This is followed by an analysis of three…

  5. Pleasant Alternatives.

    ERIC Educational Resources Information Center

    Unks, Gerald

    1981-01-01

    The author feels that the current wave of political conservatism may prove beneficial to education if the national mood of decentralization and decontrol leads to a resurgence of community involvement and locally-developed alternatives. He cites several examples of successful urban alternative schools. (SJL)

  6. A metal chelate process for removal of nitric oxide from flue gas

    SciTech Connect

    Littlejohn, D.; Pham, E.K.; Chang, S.G.

    1994-12-31

    Control of sulfur dioxide (SO{sub 2}) in flue gases has been achieved by utilization of its high solubility in aqueous solutions. Unlike sulfur dioxide, nitric oxide (NO) has low solubility in aqueous solutions. Consequently, achieving simultaneous control of sulfur dioxide and nitric oxide in flue gas has been difficult to achieve. Nitric oxide can be oxidized to nitrogen dioxide (NO{sub 2}), which is more soluble. However, many oxidants are expensive and some of the oxidant material may consumed by the oxidation of dissolved sulfur dioxide. Much of the effort of research for the control of nitric oxide has focused on the development of additives that enhance the solubility of nitric oxide in aqueous solutions. Of the additives investigated, the most promising compounds appear to be metal chelates which are capable of reacting with nitric oxide to form nitrosyl complexes. In recent years, we have investigated thiol-based ligands complexed with ferrous ions that have superior oxidation resistance and NO absorbing capacity. We report here the results of our study of a new thiol-based iron complex using 2,3-dimercapto-1-propane sulfonate (DMPS). It is superior to Fe{sup +2}(EDTA) chelate in three aspects: (1) the ability to reduce Fe{sup +3} to Fe{sup +2}, (2) the absence of nitrogen-sulfur byproducts, and (3) the ease of regeneration using electrochemical reduction. We present here results of the NO removal chemistry of Fe{sup +2}(DMPS){sub 2} and the electro-chemical regeneration of Fe{sup +2}(DMPS){sub 2}. Also presented are results of NO thermal desorption studies, which is an alternative regeneration method.

  7. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy

    SciTech Connect

    Cory-Slechta, D.A.; Weiss, B.; Cox, C.

    1987-12-01

    After its successful application to the treatment of acute Pb poisoning, Ca disodium EDTA came into routine clinical use for diagnosis and treatment of subacute and chronic Pb poisoning. Despite widespread use, few definitive conclusions have emerged about the sources of Pb mobilized by Ca disodium EDTA. Furthermore, the possibility that mobilized Pb may be redistributed has been suggested. The current studies indicate that the standard therapeutic protocol for Ca disodium EDTA has little impact on critical organs such as brain and liver and moreover, that diagnostic Ca disodium EDTA chelation may even increase the concentration of Pb in these tissues. After a 3 to 4 month exposure to Pb acetate in drinking water, different groups of rats received daily i.p. injections of saline (control), 75 or 150 mg/kg of Ca disodium EDTA for either 1, 2, 3, 4 or 5 days and were then sacrificed 24 hr after the final injection. Tissue analyses indicated that Pb was mobilized from bone and kidney and redistributed initially to both brain and liver. Levels in both brain and liver declined with subsequent Ca disodium EDTA injections, but no net loss from either tissue occurred over the 5-day treatment period despite a decline in blood Pb levels and a marked enhancement of urinary Pb excretion. These findings stress the need for further investigation of Ca disodium EDTAs effects and for parallel evaluation of alternate chelating agents, and suggest that a re-evaluation of both the diagnostic and therapeutic roles of Ca disodium EDTA may be advisable.

  8. Removal of heavy metals from water effluents using supermacroporous metal chelating cryogels.

    PubMed

    Onnby, Linda; Giorgi, Camilla; Plieva, Fatima M; Mattiasson, Bo

    2010-01-01

    Applications of IDA in, for example, immobilized metal ion affinity chromatography for purification of His-tagged proteins are well recognized. The use of IDA as an efficient chelating adsorbent for environmental separations, that is, for the capture of heavy metals, is not studied. Adsorbents based on supermacroporous gels (cryogels) bearing metal chelating functionalities (IDA residues and ligand derived from derivatization of epoxy-cryogel with tris(2-aminoethyl)amine followed by the treatment with bromoacetic acid (defined as TBA ligand)) have been prepared and evaluated on capture of heavy metal ions. The cryogels were prepared in plastic carriers, resulting in desired mechanical stability and named as macroporous gel particles (MGPs). Sorption and desorption experiments for different metals (Cu²+, Zn²+, Cd²+, and Ni²+ with IDA adsorbent and Cu²+ and Zn²+ with TBA adsorbent) were carried out in batch and monolithic modes, respectively. Obtained capacities with Cu²+ were 74 μmol/mL (TBA) and 19 μmol/mL gel (IDA). The metal removal was higher for pH values between pH 3 and 5. Both adsorbents showed improved sorption at lower temperatures (10°C) than at higher (40°C) and the adsorption significantly dropped for the TBA adsorbent and Zn²+ at 40°C. Desorption of Cu²+ by using 1 M HCl and 0.1 M EDTA was successful for the IDA adsorbent whereas the desorption with the TBA adsorbent needs further attention. The result of this work has demonstrated that MGPs are potential treatment alternatives within the field of environmental separations and the removal of heavy metals from water effluents.

  9. Nanostructured Perovskite LaCo1-xMnxO3 as Bifunctional Catalysts for Rechargeable Metal-Air Batteries

    NASA Astrophysics Data System (ADS)

    Ge, Xiaoming; Li, Bing; Wuu, Delvin; Sumboja, Afriyanti; An, Tao; Hor, T. S. Andy; Zong, Yun; Liu, Zhaolin

    2015-09-01

    Bifunctional catalyst that is active for both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is one of the most important components of rechargeable metal-air batteries. Nanostructured perovskite bifunctional catalysts comprising La, Co and Mn(LaCo1-xMnxO3, LCMO) are synthesized by hydrothermal methods. The morphology, structure and electrochemical activity of the perovskite bifunctional catalysts are characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and rotating disk electrode (RDE) techniques. Nanorod, nanodisc and nanoparticle are typical morphologies of LCMO. The electrocatalytic activity of LCMO is significantly improved by the addition of conductive materials such as carbon nanotube. To demonstrate the practical utilization, LCMO in the composition of LaCo0.8Mn0.2O3(LCMO82) is used as air cathode catalysts for rechargeable zinc-air batteries. The battery prototype can sustain 470 h or 40 discharge-charge cycles equivalent.

  10. Cysteine-Specific Cu2+ Chelating Tags Used as Paramagnetic Probes in Double Electron Electron Resonance

    PubMed Central

    Cunningham, Timothy F.; Shannon, Matthew D.; Putterman, Miriam R.; Arachchige, Rajith J.; Sengupta, Ishita; Gao, Min; Jaroniec, Christopher P.; Saxena, Sunil

    2015-01-01

    Double electron electron resonance (DEER) is an attractive technique that is utilized for gaining insight into protein structure and dynamics via nanometer-scale distance measurements. The most commonly used paramagnetic tag in these measurements is a nitroxide spin label, R1. Here, we present the application of two types of high-affinity Cu2+ chelating tags, based on the EDTA and cyclen metal-binding motifs as alternative X-band DEER probes, using the B1 immunoglobulin-binding domain of protein G (GB1) as a model system. Both types of tags have been incorporated into a variety of protein secondary structure environments and exhibit high spectral sensitivity. In particular, the cyclen-based tag displays distance distributions with comparable distribution widths and most probable distances within 1–3 Å when compared to homologous R1 distributions. The results display the viability of the cyclen tag as an alternative to the R1 side chain for X-band DEER distance measurements in proteins. PMID:25608028

  11. Bifunctional heterogeneous catalysts from oil palm empty fruit bunches ash and alum for biodiesel synthesis simultaneously

    NASA Astrophysics Data System (ADS)

    Astar, Ismail; Usman, Thamrin; Wahyuni, Nelly; Rudiyansyah, Alimuddin, Andi Hairil

    2017-03-01

    Free fatty acids (FFA) contained in crude palm oil (CPO) and sludge oil has been used as the base material of biodiesel with the aid of a catalyst in the transesterification and esterification reactions. This study aims to synthesize and characterize bifunctional catalysts were synthesized from the ashes of palm empty fruit bunches (EFB) and alum based on the analysis of XRD, XRF and acidity test. Bifunctional catalyst obtained was used as a catalyst to production of biodiesel with different levels of FFA. The optimum ratio alum added was 0.2 mol at 3 hours of reaction time and 3% of catalyst by the FFA samples were used 67,40%. The catalyst with optimum alum mole variations subsequently used on samples with varying levels of FFA, namely 1.29%, 4.98%, 29.21%, 67.40% and 74.47%. Optimum conversion of methyl ester in the esterification reaction occurs in the sample with 67.40% FFA content, which reached 86.17%, while the conversion of methyl ester transesterification process optimum amounted to 45.70% in the samples with 4.98% FFA content. Methyl ester produced has a refractive index of 1.448 (29.8 ° C), density of 0.883 g / mL (25 °C) and a viscosity of 8.933 cSt (25 ° C). The results of GC-MS analysis showed that the main composition of methyl ester result of esterification of sludge oil methyl palmitate (36.84%), while the CPO transesterification shows the main composition of methyl ester is methyl oleic (38.87%). Based on the research results, the catalyst synthesized from alum and EFB ash can be used as a Bifunctional catalysts for biodiesel synthesis.

  12. Monolithic column modified with bifunctional ionic liquid and styrene stationary phases for capillary electrochromatography.

    PubMed

    Mao, Zhenkun; Chen, Zilin

    2017-01-13

    A novel monolithic column with ionic liquid and styrene-modified bifunctional group was prepared for capillary electrochromatography (CEC) by in situ copolymerization in a ternary porogenic solvent. Ionic liquid (1-allyl-methylimidazolium chloride, AlMeIm(+)Cl(-)) and styrene served as the bifunctional monomer, while ethylene dimethacrylate (EDMA) was used as the cross-linker. The monomer of AlMeIm(+)Cl(-) was introduced as anion-exchange group, while styrene as hydrophobic and aromatic group; the similar conjugated structure in AlMeIm(+)Cl(-) and styrene was beneficial for offeing obvious synergistic effect. The bifunctional stationary phase possessed powerful selectivity for the separation of neutral compounds, acidic analytes and phenols. The highest column efficiency was 2.70×10(5) platesm(-1) (theoretical plates, N) for toluene. A relatively strong electroosmotic flow (EOF) was obtained in a wide range of pH values from 2.0 to 12.0, which could successfully achieve the rapid separation of the analytes within 10min. The proposed monolithic column was characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR). The results indicated that the resultant monolithic column had good permeability and excellent mechanical stability. Good reproducibility was obtained with relative standard deviations (RSDs) of the retention time in the range of 0.24-0.47% and 0.81-2.17% for run-to-run (n=5) and day-to-day (n=5), while 1.09-2.70% and 0.98-1.70% for column-to-column (n=3) and batch-to-batch (n=3), respectively. The combination of AlMeIm(+)Cl(-) and styrene was a promising option in the fabrication of the organic polymer monolithic column. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. A bifunctional locus (BIO3-BIO1) required for biotin biosynthesis in Arabidopsis.

    PubMed

    Muralla, Rosanna; Chen, Elve; Sweeney, Colleen; Gray, Jennifer A; Dickerman, Allan; Nikolau, Basil J; Meinke, David

    2008-01-01

    We identify here the Arabidopsis (Arabidopsis thaliana) gene encoding the third enzyme in the biotin biosynthetic pathway, dethiobiotin synthetase (BIO3; At5g57600). This gene is positioned immediately upstream of BIO1, which is known to be associated with the second reaction in the pathway. Reverse genetic analysis demonstrates that bio3 insertion mutants have a similar phenotype to the bio1 and bio2 auxotrophs identified using forward genetic screens for arrested embryos rescued on enriched nutrient medium. Unexpectedly, bio3 and bio1 mutants define a single genetic complementation group. Reverse transcription-polymerase chain reaction analysis demonstrates that separate BIO3 and BIO1 transcripts and two different types of chimeric BIO3-BIO1 transcripts are produced. Consistent with genetic data, one of the fused transcripts is monocistronic and encodes a bifunctional fusion protein. A splice variant is bicistronic, with distinct but overlapping reading frames. The dual functionality of the monocistronic transcript was confirmed by complementing the orthologous auxotrophs of Escherichia coli (bioD and bioA). BIO3-BIO1 transcripts from other plants provide further evidence for differential splicing, existence of a fusion protein, and localization of both enzymatic reactions to mitochondria. In contrast to most biosynthetic enzymes in eukaryotes, which are encoded by genes dispersed throughout the genome, biotin biosynthesis in Arabidopsis provides an intriguing example of a bifunctional locus that catalyzes two sequential reactions in the same metabolic pathway. This complex locus exhibits several unusual features that distinguish it from biotin operons in bacteria and from other genes known to encode bifunctional enzymes in plants.

  14. A Review on Iron Chelators in Treatment of Iron Overload Syndromes

    PubMed Central

    Mobarra, Naser; Shanaki, Mehrnoosh; Ehteram, Hassan; Nasiri, Hajar; Sahmani, Mehdi; Saeidi, Mohsen; Goudarzi, Mehdi; Pourkarim, Hoda; Azad, Mehdi

    2016-01-01

    Iron chelation therapy is used to reduce iron overload development due to its deposition in various organs such as liver and heart after regular transfusion. In this review, different iron chelators implicated in treatment of iron overload in various clinical conditions have been evaluated using more up-to-date studies focusing on these therapeutic agents. Deferoxamine, Deferiprone and Deferasirox are the most important specific US FDA-approved iron chelators. Each of these chelators has their own advantages and disadvantages, various target diseases, levels of deposited iron and clinical symptoms of the afflicted patients which may affect their selection as the best modality. Taken together, in many clinical disorders, choosing a standard chelator does not have an accurate index which requires further clarifications. The aim of this review is to introduce and compare the different iron chelators regarding their advantages and disadvantages, usage dose and specific applications. PMID:27928480

  15. A Review on Iron Chelators in Treatment of Iron Overload Syndromes.

    PubMed

    Mobarra, Naser; Shanaki, Mehrnoosh; Ehteram, Hassan; Nasiri, Hajar; Sahmani, Mehdi; Saeidi, Mohsen; Goudarzi, Mehdi; Pourkarim, Hoda; Azad, Mehdi

    2016-10-01

    Iron chelation therapy is used to reduce iron overload development due to its deposition in various organs such as liver and heart after regular transfusion. In this review, different iron chelators implicated in treatment of iron overload in various clinical conditions have been evaluated using more up-to-date studies focusing on these therapeutic agents. Deferoxamine, Deferiprone and Deferasirox are the most important specific US FDA-approved iron chelators. Each of these chelators has their own advantages and disadvantages, various target diseases, levels of deposited iron and clinical symptoms of the afflicted patients which may affect their selection as the best modality. Taken together, in many clinical disorders, choosing a standard chelator does not have an accurate index which requires further clarifications. The aim of this review is to introduce and compare the different iron chelators regarding their advantages and disadvantages, usage dose and specific applications.

  16. CCCCC pentadentate chelates with planar Möbius aromaticity and unique properties

    PubMed Central

    Zhu, Congqing; Yang, Caixia; Wang, Yongheng; Lin, Gan; Yang, Yuhui; Wang, Xiaoyong; Zhu, Jun; Chen, Xiaoyuan; Lu, Xin; Liu, Gang; Xia, Haiping

    2016-01-01

    The coordinating atoms in polydentate chelates are primarily heteroatoms. We present the first examples of pentadentate chelates with all binding atoms of the chelating agent being carbon atoms, denoted as CCCCC chelates. Having up to five metal-carbon bonds in the equatorial plane has not been previously observed in transition metal chemistry. Density functional theory calculations showed that the planar metallacycle has extended Craig-Möbius aromaticity arising from 12-center–12-electron dπ-pπ π-conjugation. These planar chelates have broad absorption in the ultraviolet-visible–near-infrared region and, thus, notable photothermal performance upon irradiation by an 808-nm laser, indicating that these chelates have potential applications in photothermal therapy. The combination of facile synthesis, high stability, and broad absorption of these complexes could make the polydentate carbon chain a novel building block in coordination chemistry. PMID:27574707

  17. Radiation protection and radiation recovery with essential metalloelement chelates

    SciTech Connect

    Sorenson, J.R.J.; Soderberg, L.S.F.; Chang, L.W.

    1995-12-01

    This review presents the roles of some essential metalloelement-dependent enzymes in tissue maintenance and function, and their responses to radiation injury in accounting for radiation protection and recovery effects observed for nontoxic doses of essential metalloelement compounds. Effects of biochemicals including water undergoing bond radiolysis and the effects of free radicals derived from diatomic oxygen account for the acute and chronic aspects of radiation injury. Copper chelates have radiation protection and radiation recovery activities and cause rapid recovery of immunocompetency and recovery from radiation-induced histopathology. Mice treated with Cu(II){sub 2}(3,5-disopropylsalicy-late){sub 4}[Cu(II){sub 2}(3,5-DIPS){sub 4}] had increased survival and corresponding increases in numbers of myeloid and multipotential progenitor cells early after irradiation and earlier recovery of immune reactivity. Examination of radiation-induced histopathology in spleen, bone marrow, thymus, and small intestine also revealed Cu(II){sub 2}(3,5-DIPS){sub 4}-mediated rapid recovery of radiation-induced histopathology. Most recently, Fe, Mn, and Zn complexes have also been found to prevent death in lethally irradiated mice. These pharmacological effects of essential metalloelement chelates can be understood as due to facilitation of de novo synthesis of essential metalloelement-dependent enzymes which have roles in preventing the accumulation of pathological concentrations of oxygen radicals or repairing biochemical damage caused by radiation-induced bond homolysis. Essential metalloelement chelates offer a physiological approach to prevention and/or treatment of radiation injury. 97 refs., 5 figs., 1 tab.

  18. A Proton-Switchable Bifunctional Ruthenium Complex That Catalyzes Nitrile Hydroboration.

    PubMed

    Geri, Jacob B; Szymczak, Nathaniel K

    2015-10-14

    A new bifunctional pincer ligand framework bearing pendent proton-responsive hydroxyl groups was prepared and metalated with Ru(II) and subsequently isolated in four discrete protonation states. Stoichiometric reactions with H2 and HBPin showed facile E-H (E = H or BPin) activation across a Ru(II)-O bond, providing access to unusual Ru-H species with strong interactions with neighboring proton and boron atoms. These complexes were found to promote the catalytic hydroboration of ketones and nitriles under mild conditions, and the activity was highly dependent on the ligand's protonation state. Mechanistic experiments revealed a crucial role of the pendent hydroxyl groups for catalytic activity.

  19. Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones.

    PubMed

    Di Mola, Antonia; Tiffner, Maximilian; Scorzelli, Francesco; Palombi, Laura; Filosa, Rosanna; De Caprariis, Paolo; Waser, Mario; Massa, Antonio

    2015-01-01

    New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.

  20. Recovery of uranium from acid media by macroporous bifunctional phosphinic acid resin

    SciTech Connect

    Sabharwal, K.N.; Srinivasan, T.G.; Rao, P.R.V.; Nandy, K.K.

    1996-11-01

    The extraction of uranium from various acid media such as nitric acid, sulphuric acid, hydrochloric acid, phosphoric acid and perchloric acid by a macroporous bifunctional phosphinic acid resin (MPBPA) has been studied. The distribution coefficients for the extraction of uranium by the MPBPA resin are compared with the corresponding values reported in literature for the conventional sulphonic acid resin. The results clearly indicate the suitability of the MPBPA resin to recover uranium from different types of acid solutions of widely ranging acidities. 17 refs., 6 figs., 5 tabs.

  1. Acid–base bifunctional shell cross-linked micelle nanoreactor for one-pot tandem reaction

    DOE PAGES

    Lee, Li -Chen; Lu, Jie; Weck, Marcus; ...

    2015-12-29

    In shell cross-linked micelles (SCMs) containing acid sites in the shell and base sites in the core are prepared from amphiphilic poly(2-oxazoline) triblock copolymers. These materials are utilized as two-chamber nanoreactors for a prototypical acid-base bifunctional tandem deacetalization-nitroaldol reaction. Furthermore, the acid and base sites are localized in different regions of the micelle, allowing the two steps in the reaction sequence to largely proceed in separate compartments, akin to the compartmentalization that occurs in biological systems.

  2. An efficient bifunctional electrocatalyst for water splitting based on cobalt phosphide.

    PubMed

    Yang, Libin; Qi, Honglan; Zhang, Chengxiao; Sun, Xuping

    2016-06-10

    The development of highly efficient electrocatalysts for water splitting is critical for various renewable-energy technologies. In this letter, we demonstrate a cobalt phosphide nanowire array grown on a Ti mesh (CoP/TM) behaving as a bifunctional electrocatalyst for water splitting. The CoP/TM electrode delivers 10 mA cm(-2) at an overpotential of 72 mV for the hydrogen evolution reaction (HER) and 310 mV for the oxygen evolution reaction (OER) in 1.0 M KOH. Furthermore, its corresponding two-electrode alkaline electrolyzer displays 10 mA cm(-2) at 1.64 V.

  3. Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

    PubMed Central

    Di Mola, Antonia; Tiffner, Maximilian; Scorzelli, Francesco; Palombi, Laura; Filosa, Rosanna; De Caprariis, Paolo

    2015-01-01

    Summary New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications. PMID:26734105

  4. Controlled Covalent Functionalization of Thermally Reduced Graphene Oxide To Generate Defined Bifunctional 2D Nanomaterials

    PubMed Central

    Faghani, Abbas; Donskyi, Ievgen S.; Fardin Gholami, Mohammad; Ziem, Benjamin; Lippitz, Andreas; Unger, Wolfgang E. S.; Böttcher, Christoph; Rabe, Jürgen P.

    2017-01-01

    Abstract A controlled, reproducible, gram‐scale method is reported for the covalent functionalization of graphene sheets by a one‐pot nitrene [2+1] cycloaddition reaction under mild conditions. The reaction between commercially available 2,4,6‐trichloro‐1,3,5‐triazine and sodium azide with thermally reduced graphene oxide (TRGO) results in defined dichlorotriazine‐functionalized sheets. The different reactivities of the chlorine substituents on the functionalized graphene allow stepwise post‐modification by manipulating the temperature. This new method provides unique access to defined bifunctional 2D nanomaterials, as exemplified by chiral surfaces and multifunctional hybrid architectures. PMID:28165179

  5. Bifunctional Organic Polymeric Catalysts with a Tunable Acid-Base Distance and Framework Flexibility

    PubMed Central

    Chen, Huanhui; Wang, Yanan; Wang, Qunlong; Li, Junhui; Yang, Shiqi; Zhu, Zhirong

    2014-01-01

    Acid-base bifunctional organic polymeric catalysts were synthesized with tunable structures. we demonstrated two synthesis approaches for structural fine-tune. In the first case, the framework flexibility was tuned by changing the ratio of rigid blocks to flexible blocks within the polymer framework. In the second case, we precisely adjusted the acid-base distance by distributing basic monomers to be adjacent to acidic monomers, and by changing the chain length of acidic monomers. In a standard test reaction for the aldol condensation of 4-nitrobenzaldehyde with acetone, the catalysts showed good reusability upon recycling and maintained relatively high conversion percentage. PMID:25267260

  6. An efficient bifunctional electrocatalyst for water splitting based on cobalt phosphide

    NASA Astrophysics Data System (ADS)

    Yang, Libin; Qi, Honglan; Zhang, Chengxiao; Sun, Xuping

    2016-06-01

    The development of highly efficient electrocatalysts for water splitting is critical for various renewable-energy technologies. In this letter, we demonstrate a cobalt phosphide nanowire array grown on a Ti mesh (CoP/TM) behaving as a bifunctional electrocatalyst for water splitting. The CoP/TM electrode delivers 10 mA cm-2 at an overpotential of 72 mV for the hydrogen evolution reaction (HER) and 310 mV for the oxygen evolution reaction (OER) in 1.0 M KOH. Furthermore, its corresponding two-electrode alkaline electrolyzer displays 10 mA cm-2 at 1.64 V.

  7. Tunable catalytic properties of bi-functional mixed oxides in ethanol conversion to high value compounds

    SciTech Connect

    Ramasamy, Karthikeyan K.; Gray, Michel J.; Job, Heather M.; Smith, Colin D.; Wang, Yong

    2016-04-10

    tA highly versatile ethanol conversion process to selectively generate high value compounds is pre-sented here. By changing the reaction temperature, ethanol can be selectively converted to >C2alcohols/oxygenates or phenolic compounds over hydrotalcite derived bi-functional MgO–Al2O3cata-lyst via complex cascade mechanism. Reaction temperature plays a role in whether aldol condensationor the acetone formation is the path taken in changing the product composition. This article containsthe catalytic activity comparison between the mono-functional and physical mixture counterpart to thehydrotalcite derived mixed oxides and the detailed discussion on the reaction mechanisms.

  8. Tunable catalytic properties of bi-functional mixed oxides in ethanol conversion to high value compounds

    DOE PAGES

    Ramasamy, Karthikeyan K.; Gray, Michel; Job, Heather; ...

    2016-02-03

    Here, a highly versatile ethanol conversion process to selectively generate high value compounds is presented here. By changing the reaction temperature, ethanol can be selectively converted to >C2 alcohols/oxygenates or phenolic compounds over hydrotalcite derived bi-functional MgO–Al2O3 catalyst via complex cascade mechanism. Reaction temperature plays a role in whether aldol condensation or the acetone formation is the path taken in changing the product composition. This article contains the catalytic activity comparison between the mono-functional and physical mixture counterpart to the hydrotalcite derived mixed oxides and the detailed discussion on the reaction mechanisms.

  9. Tunable catalytic properties of bi-functional mixed oxides in ethanol conversion to high value compounds

    SciTech Connect

    Ramasamy, Karthikeyan K.; Gray, Michel; Job, Heather; Smith, Colin; Wang, Yong

    2016-02-03

    Here, a highly versatile ethanol conversion process to selectively generate high value compounds is presented here. By changing the reaction temperature, ethanol can be selectively converted to >C2 alcohols/oxygenates or phenolic compounds over hydrotalcite derived bi-functional MgO–Al2O3 catalyst via complex cascade mechanism. Reaction temperature plays a role in whether aldol condensation or the acetone formation is the path taken in changing the product composition. This article contains the catalytic activity comparison between the mono-functional and physical mixture counterpart to the hydrotalcite derived mixed oxides and the detailed discussion on the reaction mechanisms.

  10. Bifunctional Organic Polymeric Catalysts with a Tunable Acid-Base Distance and Framework Flexibility

    NASA Astrophysics Data System (ADS)

    Chen, Huanhui; Wang, Yanan; Wang, Qunlong; Li, Junhui; Yang, Shiqi; Zhu, Zhirong

    2014-09-01

    Acid-base bifunctional organic polymeric catalysts were synthesized with tunable structures. we demonstrated two synthesis approaches for structural fine-tune. In the first case, the framework flexibility was tuned by changing the ratio of rigid blocks to flexible blocks within the polymer framework. In the second case, we precisely adjusted the acid-base distance by distributing basic monomers to be adjacent to acidic monomers, and by changing the chain length of acidic monomers. In a standard test reaction for the aldol condensation of 4-nitrobenzaldehyde with acetone, the catalysts showed good reusability upon recycling and maintained relatively high conversion percentage.

  11. A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells

    PubMed Central

    He, Huan; Li, Dong-Wei; Yang, Li-Yun; Fu, Li; Zhu, Xun-Jin; Wong, Wai-Kwok; Jiang, Feng-Lei; Liu, Yi

    2015-01-01

    Mitochondria have recently emerged as novel targets for cancer therapy due to its important roles in fundamental cellular function. Discovery of new chemotherapeutic agents that allow for simultaneous treatment and visualization of cancer is urgent. Herein, we demonstrate a novel bifunctional mitochondria-targeted anticancer agent (FPB), exhibiting both imaging capability and anticancer activity. It can selectively accumulate in mitochondria and induce cell apoptosis. Notably, it results in much higher toxicity toward cancer cells owing to much higher uptake by cancer cells. These features make it highly attractive in cancer imaging and treatment. PMID:26337336

  12. Au@Cu(II)-MOF: Highly Efficient Bifunctional Heterogeneous Catalyst for Successive Oxidation-Condensation Reactions.

    PubMed

    Wang, Jing-Si; Jin, Fa-Zheng; Ma, Hui-Chao; Li, Xiao-Bo; Liu, Ming-Yang; Kan, Jing-Lan; Chen, Gong-Jun; Dong, Yu-Bin

    2016-07-05

    A new composite Au@Cu(II)-MOF catalyst has been synthesized via solution impregnation and full characterized by HRTEM, SEM-EDS, XRD, gas adsorption-desorption, XPS, and ICP analysis. It has been shown here that the Cu(II)-framework can be a useful platform to stabilize and support gold nanoparticles (Au NPs). The obtained Au@Cu(II)-MOF exhibits a bifunctional catalytic behavior and is able to promote selective aerobic benzyl alcohol oxidation-Knoevenagel condensation in a stepwise way.

  13. MoO3 nanoparticle anchored graphene as bifunctional agent for water purification

    NASA Astrophysics Data System (ADS)

    Lahan, Homen; Roy, Raju; Namsa, Nima D.; Das, Shyamal K.

    2016-10-01

    We report here a facile one step hydrothermal method to anchor MoO3 nanoparticles in graphene. The bifunctionality of graphene-MoO3 nanoparticles is demonstrated via dye adsorption and antibacterial activities. The nanocomposite showed excellent adsorption of methylene blue, a cationic dye, from water compared to pristine MoO3 and graphene. However, it showed negligible adsorption of methyl orange, an anionic dye. Again, the graphene-MoO3 nanoparticles exhibited bacteriostatic property against both Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria.

  14. Asymmetric Synthesis of Rauhut-Currier type Products by a Regioselective Mukaiyama Reaction under Bifunctional Catalysis.

    PubMed

    Frias, María; Mas-Ballesté, Rubén; Arias, Saira; Alvarado, Cuauhtemoc; Alemán, José

    2017-01-18

    The reactivity and the regioselective functionalization of silyl-diene enol ethers under a bifunctional organocatalyst provokes a dramatic change in the regioselectivity, from the 1,5- to the 1,3-functionalization. This variation makes possible the 1,3-addition of silyl-dienol ethers to nitroalkenes, giving access to the synthesis of tri- and tetrasubstituted double bonds in Rauhut-Currier type products. The process takes place under smooth conditions, nonanionic conditions, and with a high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments.

  15. The bifunctional catalytic role of water clusters in the formation of acid rain.

    PubMed

    Romero-Montalvo, Eduardo; Guevara-Vela, José Manuel; Vallejo Narváez, Wilmer Esteban; Costales, Aurora; Pendás, Ángel Martín; Hernández-Rodríguez, Marcos; Rocha-Rinza, Tomás

    2017-03-23

    State-of-the-art chemical bonding analyses show that water clusters have a bifunctional catalytic role in the formation of H2SO4 in acid rain. The embedded H2O monomers mitigate the change in the chemical bonding scenario of the rate-limiting step, reducing thereby the corresponding activation energy in accordance with Hammond's postulate. We expect that the insights given herein will prove useful in the elucidation of the catalytic mechanisms of water in inorganic and organic aqueous chemistry.

  16. Clickable tyrosine binding bifunctional linkers for preparation of DNA-protein conjugates.

    PubMed

    Bauer, Dennis M; Ahmed, Ishtiaq; Vigovskaya, Antonina; Fruk, Ljiljana

    2013-06-19

    We have prepared bifunctional linkers containing clickable functional groups that enable preparation of protein-DNA conjugates through binding onto tyrosine residues. Mild conjugation strategy was demonstrated using two proteins, streptavidin(STV) and myoglobin (Mb) and it resulted in conjugates with preserved functionality of both the proteins and DNA strands. Furthermore, we show that protein-DNA conjugates can be successfully immobilized onto solid surface containing complementary DNA strands and the enzymatic activity of Mb-DNA conjugates is even higher than that of corresponding conjugates prepared through Lys binding.

  17. Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

    PubMed Central

    Ceballos, Miriam; Maestro, Alicia; Sanz, Isabel

    2016-01-01

    Summary The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-β-nitrostyrene derivatives. The activity of the catalysts depends on the length of the tether linking the chiral thiourea to the polymer. The best results were obtained with the thiourea derived from (L)-valine and 1,6-hexanediamine. The catalysts can be used in only 2 mol % loading, and reused for at least four cycles in neat conditions. The ball milling promoted additions also worked very well. PMID:27340453

  18. Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions.

    PubMed

    Andrés, José M; Ceballos, Miriam; Maestro, Alicia; Sanz, Isabel; Pedrosa, Rafael

    2016-01-01

    The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-β-nitrostyrene derivatives. The activity of the catalysts depends on the length of the tether linking the chiral thiourea to the polymer. The best results were obtained with the thiourea derived from (L)-valine and 1,6-hexanediamine. The catalysts can be used in only 2 mol % loading, and reused for at least four cycles in neat conditions. The ball milling promoted additions also worked very well.

  19. Cobalt nanoparticles embedded in N-doped carbon as an efficient bifunctional electrocatalyst for oxygen reduction and evolution reactions

    NASA Astrophysics Data System (ADS)

    Su, Yunhe; Zhu, Yihua; Jiang, Hongliang; Shen, Jianhua; Yang, Xiaoling; Zou, Wenjian; Chen, Jianding; Li, Chunzhong

    2014-11-01

    Cobalt based catalysts are promising bifunctional electrocatalysts for both oxygen reduction and oxygen evolution reactions (ORR and OER) in unitized regenerative fuel cells (URFCs) operating with alkaline electrolytes. Here we report a hybrid composite of cobalt nanoparticles embedded in nitrogen-doped carbon (Co/N-C) via a solvothermal carbonization strategy. With the synergistic effect arising from the N-doped carbon and cobalt nanoparticles in the composite, the Co/N-C hybrid catalyst exhibits highly efficient bifunctional catalytic activity and excellent stability toward both ORR and OER. The ΔE (oxygen electrode activity parameter for judging the overall electrocatalytic activity of a bifunctional electrocatalyst) value for Co/N-C is 0.859 V, which is smaller than those of Pt/C and most of the non-precious metal catalysts in previous studies. Furthermore, the Co/N-C composite also shows better bifunctional catalytic activity than its oxidative counterparts, which could be attributed to the high specific surface area and the efficient charge transfer ability of the composite, as well as the good synergistic effect between N-doped carbon and the Co nanoparticles in the Co/N-C composite.Cobalt based catalysts are promising bifunctional electrocatalysts for both oxygen reduction and oxygen evolution reactions (ORR and OER) in unitized regenerative fuel cells (URFCs) operating with alkaline electrolytes. Here we report a hybrid composite of cobalt nanoparticles embedded in nitrogen-doped carbon (Co/N-C) via a solvothermal carbonization strategy. With the synergistic effect arising from the N-doped carbon and cobalt nanoparticles in the composite, the Co/N-C hybrid catalyst exhibits highly efficient bifunctional catalytic activity and excellent stability toward both ORR and OER. The ΔE (oxygen electrode activity parameter for judging the overall electrocatalytic activity of a bifunctional electrocatalyst) value for Co/N-C is 0.859 V, which is smaller than those

  20. Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging.

    PubMed

    Khan, Aneal; Wei, Xing-Chang; Snyder, Floyd F; Mah, Jean K; Waterham, Hans; Wanders, Ronald J A

    2010-12-01

    We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal.