Science.gov

Sample records for acyclic ditopic ligand

  1. Heteroligand molecular "stirrups" using conformationally flexible ditopic pyridyl-pyrazolyl ligands.

    PubMed

    Lu, Jinzhen; Turner, David R; Harding, Lindsay P; Batten, Stuart R

    2009-08-17

    Heteroligand molecular "stirrups" form by the self-assembly of flexible ditopic ligands in combination with 4,4'-bipyridine and [(dppp)Pd)](2+). Crystallographic analysis shows that the ligands, bis[3-(4-pyridyl)pyrazolyl]-m-xylene (mXy(4py3pz)) and bis[4-(4-pyridyl)pyrazolyl]-p-xylene (pXy(4py4pz)) form complexes of the type [{(dppp)Pd}(2)(4,4'-bipy)(L)].4OTf (1.4OTf and 2.4OTf, respectively) in the solid state, with remarkably similar structures considering the differences in substitution patterns between the two ligands. The self-assembly of both 1(4+) and 2(4+) is assisted by face-to-face pi interactions on the exterior of the macrocycle between the phenyl rings of the dppp ligands and the pyridyl groups of the ditopic ligands. PMID:19594137

  2. Redox-Active-Ligand-Mediated Formation of an Acyclic Trinuclear Ruthenium Complex with Bridging Nitrido Ligands.

    PubMed

    Bagh, Bidraha; Broere, Daniël L J; Siegler, Maxime A; van der Vlugt, Jarl Ivar

    2016-07-11

    Coordination of a redox-active pyridine aminophenol ligand to Ru(II) followed by aerobic oxidation generates two diamagnetic Ru(III) species [1 a (cis) and 1 b (trans)] with ligand-centered radicals. The reaction of 1 a/1 b with excess NaN3 under inert atmosphere resulted in the formation of a rare bis(nitrido)-bridged trinuclear ruthenium complex with two nonlinear asymmetrical Ru-N-Ru fragments. The spontaneous reduction of the ligand centered radical in the parent 1 a/1 b supports the oxidation of a nitride (N(3-) ) to half an equivalent of N2 . The trinuclear omplex is reactive toward TEMPO-H, tin hydrides, thiols, and dihydrogen. PMID:27321547

  3. Structural diversity in manganese, iron and cobalt complexes of the ditopic 1,2-bis(2,2'-bipyridyl-6-yl)ethyne ligand and observation of epoxidation and catalase activity of manganese compounds.

    PubMed

    Madhu, Vedichi; Ekambaram, Balaraman; Shimon, Linda J W; Diskin, Yael; Leitus, Gregory; Neumann, Ronny

    2010-08-21

    A ditopic 1,2-bis(2,2'-bipyridyl-6-yl)ethyne ligand, L, has been synthesized for the first time by consecutive Suzuki and Sonogashira coupling reactions either in a one- or two-step synthesis. Coordination of L with some first-row transition metals, Fe, Mn and Co showed a very rich structural diversity that can be obtained with this ligand. Reaction of L with Mn(II)(OAc)(2) yielded a dimanganese(II) complex, [Mn(2)L(mu-OAc)(3)]PF(6), (1) where the two somewhat inequivalent trigonal-bipyramidal Mn atoms separated by 3.381 A are bridged by L and three acetate moieties. A similar reaction of L with Mn(III)(OAc)(3) yielded a very different dimanganese complex [Mn(2)L'(OH)(OAc)(2)(DMF)(2)]PF(6) x DMF (2) where L' is a E-1,2-bis(2,2'-bipyridyl-6-yl)ethene fragment that was formed in situ. The L' ligand bridges between the two Mn centers, despite its trans configuration, which leads to a very strained ethene bridging moiety. The Mn atoms are also bridged by two acetate ligands and a hydroxy group that bridges between the Mn atoms and the ethene fragment; DMF completes the octahedral coordination around each Mn atom which are separated by 3.351 A. A comproportionation reaction of L with Mn(II)(OAc)(2) and n-Bu(4)NMnO(4) yielded a tetramanganese compound, [Mn(4)(mu(3)-O)(2)(OAc)(4)(H(2)O)(2)L(2)](PF(6))(2) x 2 CH(3)CN (3). Compound 3 has a dimer of dimers structure of the tetranuclear Mn core that consists of binuclear [Mn(2)O(OAc)(2)L](+) fragment and a PF(6) anion. BVS calculations indicate that 3 is a mixed-valent 2Mn(II) plus 2Mn(III) compound where two [Mn(II)(2)O(OAc)(2)L](+) fragments are held together by Mn(III)-O inter-fragment linkers which have a distorted octahedral geometry. The Mn atoms in the [Mn(2)O(OAc)(2)L](+) fragments have a capped square-pyramid configuration where an aqua ligand is capped on one of the faces. Although the aqua ligand is well within a bonding distance to a carbon atom of the proximal ethyne bridge, there does not appear to be an oxygen

  4. Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Zhao, Xiao-Guang; Bigner, Darell D.; Zalutsky, Michael R.

    2010-01-01

    Introduction Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with177Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine- pentaacetic acid (CHX-A″-DTPA) and 2-(4-Isothiocyanatobenzyl)-6-methyldiethylene- triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4- Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.)EGFR glioma xenografts over a period of 1 to 8 days to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Results Except with C-DOTA, tumor uptake for the 177Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor:normal tissue ratios for 177Lu-1B4M-DTPA-L8A4 and to an even greater extent, 177Lu-MeO-DOTA-L8A4, were higher than those for [125I]SGMIB-L8A4 in most other tissues. Conclusions Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for 177Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application. PMID:20870149

  5. Synthesis, spectroscopic studies and inhibitory activity against bactria and fungi of acyclic and macrocyclic transition metal complexes containing a triamine coumarine Schiff base ligand

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, A. A.; Linert, Wolfgang

    2015-04-01

    Two series of new mono and binuclear complexes with a Schiff base ligand derived from the condensation of 3-acetylcoumarine and diethylenetriamine, in the molar ratio 2:1 have been prepared. The ligand was characterized by elemental analysis, IR, UV-visible, 1H-NMR and mass spectra. The reaction of the Schiff base ligand with cobalt(II), nickel(II), copper(II), zinc(II) and oxovanadium(IV) lead to mono or binuclear species of cyclic or macrocyclic complexes, depending on the mole ratio of metal to ligand and as well as on the method of preparation. The Schiff base ligand behaves as a cyclic bidentate, tetradendate or pentaentadentae ligand. The formation of macrocyclic complexes depends significantly on the dimension of the internal cavity, the rigidity of the macrocycles, the nature of its donor atoms and on the complexing properties of the anion involved in the coordination. Electronic spectra and magnetic moments of the complexes indicate that the geometries of the metal centers are either square pyramidal or octahedral for acyclic or macro-cyclic complexes. The structures are consistent with the IR, UV-visible, ESR, 1H-NMR, mass spectra as well as conductivity and magnetic moment measurements. The Schiff base ligand and its metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

  6. H2CHXdedpa and H4CHXoctapa-chiral acyclic chelating ligands for (67/68)Ga and (111)In radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Cawthray, Jacqueline F; Boros, Eszter; Ferreira, Cara L; Patrick, Brian O; Adam, Michael J; Orvig, Chris

    2015-02-16

    The chiral acyclic ligands H2CHXdedpa (N4O2), H2CHXdedpa-bb (N4O2), and H4CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H2dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H4octapa = N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) were synthesized, complexed with Ga(III) and/or In(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H2dedpa and octadentate H4octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga(CHXdedpa)](+) showed very similar properties to those of [Ga(dedpa)](+), with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga(dedpa)](+), [Ga(CHXdedpa)](+) exhibited exceptionally high thermodynamic stability constants (log KML = 28.11(8)), and the chelate retained the ability to label (67)Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10(-5) M. In vitro kinetic inertness assays demonstrated the [(67)Ga(CHXdedpa)](+) complex to be more stable than [(67)Ga(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of (67)Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H4CHXoctapa with In(III) demonstrated [In(CHXoctapa)](-) to have an equivalently high thermodynamically stable constant as [In(octapa)](-), with log KML values of 27.16(9) and 26.76(14), respectively. The [(111)In(CHXoctapa)](-) complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [(111)In(octapa)](-) values, and an improved stability compared to the current industry "gold standards" 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA

  7. Lanthanide-directed synthesis of luminescent self-assembly supramolecular structures and mechanically bonded systems from acyclic coordinating organic ligands.

    PubMed

    Barry, Dawn E; Caffrey, David F; Gunnlaugsson, Thorfinnur

    2016-06-01

    Herein some examples of the use of lanthanide ions (f-metal ions) to direct the synthesis of luminescent self-assembly systems (architectures) will be discussed. This area of lanthanide supramolecular chemistry is fast growing, thanks to the unique physical (magnetic and luminescent) and coordination properties of the lanthanides, which are often transferred to the resulting supermolecule. The emphasis herein will be on systems that are luminescent, and hence, generated by using either visibly emitting ions (such as Eu(III), Tb(III) and Sm(III)) or near infrared emitting ions (like Nd(III), Yb(III) and Er(III)), formed through the use of templating chemistry, by employing structurally simple ligands, possessing oxygen and nitrogen coordinating moieties. As the lanthanides have high coordination requirements, their use often allows for the formation of coordination compounds and supramolecular systems such as bundles, grids, helicates and interlocked molecules that are not synthetically accessible through the use of other commonly used templating ions such as transition metal ions. Hence, the use of the rare-earth metal ions can lead to the formation of unique and stable species in both solution and in the solid state, as well as functional and responsive structures. PMID:27137947

  8. Labeling Internalizing Anti-Epidermal Growth Factor Receptor Variant III Monoclonal Antibody with 177Lu: In Vitro Comparison of Acyclic and Macrocyclic Ligands

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Welsh, Phil; Zalutsky, Michael R.

    2009-01-01

    Introduction The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor specific mAb with the low energy β-emitter 177Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. Materials and Methods L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA), 2-(4-Isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA), and 2-(4-Isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA) and the macrocyclic ligands S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.ΔEGFR glioma cells over 24-h to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using either Iodogen or N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of 177Lu to 125I activity retained in U87.ΔEGFR cells. Results All chelates demonstrated higher retention of internalized activity compared with mAb labeled using Iodogen, with 177Lu/125I ratios of >20 observed for the 3 DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for 125I was higher than 177Lu from 1–8 h with the opposite behavior observed thereafter. At 24 h, 177Lu/125I ratios were between 1.5 and 3, with higher values observed for the 3 DTPA chelates. Conclusions The nature of the chelate used to label this

  9. Ion-pair triple helicates and mesocates self-assembled from ditopic 2,2 -bipyridine-bis(urea) ligands and Ni(II) and Fe(II) sulfate salts

    SciTech Connect

    Custelcean, Radu; Bonnesen, Peter V; Roach, Benjamin D; Duncan, Nathan C

    2012-01-01

    NiSO{sub 4} and FeSO{sub 4} self-assemble with heteroditopic ligands (L) comprising 2,2{prime}-bipyridine and o-phenylene-(bis)urea cation- and anion-binding sites, respectively, into [ML{sub 3}SO{sub 4}] (M = Ni{sup 2+}, Fe{sup 2+}) triple-stranded ion-pair helicates and mesocates.

  10. Synthesis of mononuclear copper(II) complexes of acyclic Schiff's base ligands: Spectral, structural, electrochemical, antibacterial, DNA binding and cleavage activity

    NASA Astrophysics Data System (ADS)

    Jayamani, Arumugam; Thamilarasan, Vijayan; Sengottuvelan, Nallathambi; Manisankar, Paramasivam; Kang, Sung Kwon; Kim, Young-Inn; Ganesan, Vengatesan

    2014-03-01

    The mononuclear copper(II) complexes (1&2) of ligands L1 [N,N";-bis(2-hydroxy-5-methylbenzyl)-1,4-bis(3-iminopropyl)piperazine] or L2 [N,N";-bis(2-hydroxy-5-bromobenzyl)-1,4-bis(3-iminopropyl) piperazine] have been synthesized and characterised. The single crystal X-ray study had shown that ligands L1 and L2 crystallize in a monoclinic crystal system with P21/c space group. The mononuclear copper(II) complexes show one quasireversible cyclic voltammetric response near cathodic region (-0.77 to -0.85 V) in DMF assignable to the Cu(II)/Cu(I) couple. Binding interaction of the complexes with calf thymus DNA (CT DNA) investigated by absorption studies and fluorescence spectral studies show good binding affinity to CT DNA, which imply both the copper(II) complexes can strongly interact with DNA efficiently. The copper(II) complexes showed efficient oxidative cleavage of plasmid pBR322 DNA in the presence of 3-mercaptopropionic acid as reducing agent through a mechanistic pathway involving formation of singlet oxygen as the reactive species. The Schiff bases and their Cu(II) complexes have been screened for antibacterial activities which indicates that the complexes exhibited higher antimicrobial activity than the free ligands.

  11. Optical and relaxometric properties of monometallic (Eu(III), Tb(III), Gd(III)) and heterobimetallic (Re(I)/Gd(III)) systems based on a functionalized bipyridine-containing acyclic ligand.

    PubMed

    Leygue, Nadine; Boulay, Alexandre; Galaup, Chantal; Benoist, Eric; Laurent, Sophie; Vander Elst, Luce; Mestre-Voegtlé, Béatrice; Picard, Claude

    2016-05-17

    A series of lanthanide complexes of [LnL(H2O)](2-) composition where Ln = Eu(III), Tb(III) or Gd(III) has been studied for determining their photophysical and relaxometric properties in aqueous solution. The bifunctional ligand L (H5BPMNTA) is an acyclic chelator based on a central functionalized 2,2'-bipyridine core and two iminodiacetate coordinating arms. The mono-aqua Eu(III) and Tb(III) complexes display attractive spectroscopic properties with an excitation wavelength at 316 nm, similar excited state lifetimes and overall quantum yields (in the ranges 0.5-0.6 ms and 10-13%, respectively) in Tris buffer (pH 7.4). The proton longitudinal relaxivity, r1, of the Gd(III) complex is 4.4 mM(-1) s(-1) at 20 MHz and 310 K, which is comparable to that of the clinically used Gd-DTPA (Magnevist®). Interestingly, the water exchange rate between the coordination site and the bulk solvent is very fast (Kex = 2.6 × 10(8) s(-1) at 310 K). The ability of the complex to bind non-covalently to human serum albumin (HSA) was also examined by relaxometric measurements. We also report the synthesis and properties of a bimetallic complex based on Gd-BPMNTA and Re(I)(bpy)(CO)3 components. In this system, the Re core exhibits interesting photophysical properties (λem = 588 nm, Φ = 1.4%) and the Gd-BPMNTA core displays improved relaxivity (r1 = 6.6 mM(-1) s(-1) at 20 MHz and 310 K), due to an increase of the rotational correlation time. Besides these appealing optical and relaxometric properties, the presence of a reactive function on the structure proposes this potential dual imaging probe for conjugation to biomolecules or nanomaterials. PMID:27109253

  12. Conformation-selective coordination-driven self-assembly of a ditopic donor with Pd(II) acceptors.

    PubMed

    Howlader, Prodip; Mukherjee, Sandip; Saha, Rajat; Mukherjee, Partha Sarathi

    2015-12-21

    Coordination-driven self-assembly of 3-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)pyridine (L) was investigated with 90°cis-blocked Pd(II) acceptors and tetratopic Pd(NO3)2. Although the ligand is capable of binding in several different conformations (acting as a ditopic donor through the pyridyl nitrogens), the experimental results (including X-ray structures) showed that it adopts a particular conformation when it binds with 90°cis-blocked Pd(II) acceptors (two available sites) to yield [2 + 2] self-assembled macrocycles. On the other hand, with Pd(NO3)2 (where four available sites are present) a different conformer of the same donor was selectively bound to form a molecular cubic cage. The experimental findings were corroborated well with the density functional theory (B3LYP) calculations. The tetratopic Pd(NO3)2 yielded a [6 + 12] self-assembled Pd6L12 molecular cube, which contains a potential void occupied by nitrate and perchlorate ions. Being a triazole based ligand, the free space inside the cage is enriched with several sp(2) hybridised nitrogen atoms with lone pairs of electrons to act as Lewis basic sites. Knoevenagel condensation reactions of several aromatic aldehydes with active methylene compounds were successfully performed in reasonably high yields in the presence of the cage. PMID:26544720

  13. Acyclic colorings of graphs with bounded degree

    NASA Astrophysics Data System (ADS)

    Fiedorowicz, Anna; Sidorowicz, Elżbieta

    2016-07-01

    A $k$-colouring (not necessarily proper) of vertices of a graph is called {\\it acyclic}, if for every pair of distinct colours $i$ and $j$ the subgraph induced by the edges whose endpoints have colours $i$ and $j$ is acyclic. In the paper we consider some generalised acyclic $k$-colourings, namely, we require that each colour class induces an acyclic or bounded degree graph. Mainly we focus on graphs with maximum degree 5. We prove that any such graph has an acyclic $5$-colouring such that each colour class induces an acyclic graph with maximum degree at most 4. We prove that the problem of deciding whether a graph $G$ has an acyclic 2-colouring in which each colour class induces a graph with maximum degree at most 3 is NP-complete, even for graphs with maximum degree 5. We also give a linear-time algorithm for an acyclic $t$-improper colouring of any graph with maximum degree $d$ assuming that the number of colors is large enough.

  14. Minimalistic Ditopic Ligands: An α-S,N-Donor-Substituted Alkyne as Effective Intermetallic Conjugation Linker.

    PubMed

    Rüger, Julia; Timmermann, Christopher; Villinger, Alexander; Hinz, Alexander; Hollmann, Dirk; Seidel, Wolfram W

    2016-08-01

    The capability of donor-substituted alkynes to link different metal ions in a side-on carbon donor-chelate coordination mode is extended from the donor centers S and P to the second period element N. The complex [Tp'W(CO)2 {η(2) -C2 (S)(NHBn)}] (Tp'=hydrido-tris(3,5-dimethylpyrazolyl)borate, Bn=benzyl) bearing a terminal sulfur atom and a secondary amine substituent is accessible by a metal-template synthesis. Subsequent deprotonation allowed the formation of remarkably stable heterobimetallic complexes with the [(η(5) -C5 H5 )Ru(PPh3 )] and the [Ir(ppy)2 ] moiety. Electrochemical and spectroscopic investigations (cyclic voltammetry, IR, UV/Vis, luminescence, EPR), as well as DFT calculations, and X-ray structure determinations of the W-Ru complex in two oxidation states reveal a strong metal-metal coupling but also a limited delocalization of excited states. PMID:27272102

  15. Cardioleader use in acyclic types of sports

    NASA Technical Reports Server (NTRS)

    Bondin, V. I.

    1980-01-01

    The use of the cardioleader method in regulating training loads and tests for athletes in acyclic sports was investigated. It was found that the use of this method increases the effectiveness of the training process.

  16. Understanding Zinc Quantification with Existing and Advanced Ditopic Fluorescent Zinpyr Sensors

    PubMed Central

    Buccella, Daniela; Horowitz, Joshua A.; Lippard, Stephen J.

    2011-01-01

    Treatment of aqueous zinc solutions with incremental additions of a ditopic fluorescent sensor of the Zinpyr family, based on pyridine/pyrazine-containing metal recognition units, affords a fluorescence titration curve with a sharp maximum at a sensor:Zn2+ ratio of 0.5 (Zhang, X-a.; Hayes, D.; Smith, S. J.; Friedle, S.; Lippard, S. J. J. Am. Chem Soc. 2008, 130, 15788–15789). This fluorescence response enables the quantification of readily chelatable zinc in biological samples by a simple titration protocol. In the present work a new set of ditopic fluorescence zinc sensors functionalized with pyridine/pyrazine-containing metal chelating units is described, and through detailed studies the principles governing the characteristic “OFF-ON-OFF” fluorescence behavior and quantification capabilities of the family are delineated. Incorporation of carboxylate/ester groups in the 6 position of the fluorescein allows for control of the spatial distribution of the sensor for selective extra- or intracellular imaging of mobile zinc, without introducing significant changes in zinc-binding properties. A combination of spectrophotometric and potentiometric measurements provided a complete description of the H+ and Zn2+ binding properties of the compounds and their correlation with the observed fluorescence profile. The first zinc-binding event has an apparent affinity, K1′, of 1.9–3.1×109 M−1, whereas for coordination of the second Zn2+ ion, responsible for fluorescence turn on, the apparent formation constant K2′ is 5.5–6.9×107 M−1. A detailed chemical and mathematical analysis of the system demonstrated that the difference in emission efficiencies of the dimetalated (LZn2) vs. monometalated (LZn) and metal free (L) forms, a consequence of the combined quenching effects of the two metal-chelating units, significantly influences the shape of the titration curve. The scope of the titration method was investigated mathematically, and a lower boundary for the

  17. Understanding zinc quantification with existing and advanced ditopic fluorescent Zinpyr sensors.

    PubMed

    Buccella, Daniela; Horowitz, Joshua A; Lippard, Stephen J

    2011-03-23

    Treatment of aqueous zinc solutions with incremental additions of a ditopic fluorescent sensor of the Zinpyr family, based on pyridine/pyrazine-containing metal recognition units, affords a fluorescence titration curve with a sharp maximum at a sensor:Zn(2+) ratio of 0.5 (Zhang, X-a.; Hayes, D.; Smith, S. J.; Friedle, S.; Lippard, S. J. J. Am. Chem. Soc.2008, 130, 15788-15789). This fluorescence response enables the quantification of readily chelatable zinc in biological samples by a simple titration protocol. In the present work a new set of ditopic fluorescence zinc sensors functionalized with pyridine/pyrazine-containing metal chelating units is described, and through detailed studies the principles governing the characteristic OFF-ON-OFF fluorescence behavior and quantification capabilities of the family are delineated. Incorporation of carboxylate/ester groups in the 6 position of the fluorescein allows for control of the spatial distribution of the sensor for selective extra- or intracellular imaging of mobile zinc, without introducing significant changes in zinc-binding properties. A combination of spectrophotometric and potentiometric measurements provided a complete description of the H(+)- and Zn(2+)-binding properties of the compounds and their correlation with the observed fluorescence profile. The first zinc-binding event has an apparent affinity, K(1)', of 1.9 × 10(9)-3.1 × 10(9) M(-1), whereas for coordination of the second Zn(2+) ion, responsible for fluorescence turn-on, the apparent formation constant, K(2)', is 5.5 × 10(7)-6.9 × 10(7) M(-1). A detailed chemical and mathematical analysis of the system demonstrated that the difference in emission efficiencies of the dimetalated (LZn(2)) vs monometalated (LZn) and metal-free (L) forms, a consequence of the combined quenching effects of the two metal-chelating units, significantly influences the shape of the titration curve. The scope of the titration method was investigated mathematically, and a

  18. Amphiphilic Ditopic Bis-Aqua Gd-AAZTA-like Complexes Enhance Relaxivity of Lipidic MRI Nanoprobes.

    PubMed

    Gambino, Giuseppe; Tei, Lorenzo; Carniato, Fabio; Botta, Mauro

    2016-08-01

    Two amphiphilic mono- and dimeric GdAAZTA-like chelates composed of stable bis-aquo Gd(III) complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r1 ≈60 mm(-1)  s(-1) , at 30 MHz and 310 K). The presence of two metal-bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes. PMID:27325181

  19. Biodegradation of acyclic isoprenoids by Pseudomonas species.

    PubMed Central

    Cantwell, S G; Lau, E P; Watt, D S; Fall, R R

    1978-01-01

    The ability of various pseudomonads to utilize acyclic isoprenoids as a sole carbon source was investigated. Tests for utilization of acyclic isoprenols such as citronellol and geraniol were complicated by toxic effects of these alcohols, and most species tested were killed by exposure to citronellol or geraniol (0.1%, vol/vol) in liquid culture. In the case of Pseudomonas citronellolis, sensitivity to isoprenols is reduced by prior induction of the isoprenoid degradative pathway via either growth on succinate in the presence of citronellol or growth on citronellic acid. For this species, citronellic acid proved to be the best isoprenoid growth substrate tested. Geraniol utilization as a taxonomic indicator for different subgroups of pseudomonads is discussed. Only a few of the species tested were able to utilize acyclic isoprenoids. Two species which utilize C10 acyclic isoprenoids, P. aeruginosa and P. mendocina, were shown to contain the inducible enzyme geranyl-coenzyme A carboxylase, one of the unique enzymes in the isoprenol degradative pathway known to occur in P. citronellolis. Of the species which utilized geranitol, none showed definite growth on the homologous C15 and C20 isoprenols. PMID:681275

  20. CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol

    PubMed Central

    Hatcher, Elizabeth; Guvench, Olgun; MacKerell, Alexander D.

    2009-01-01

    Parametrization of the additive all-atom CHARMM force field for acyclic polyalcohols, acyclic carbohydrates and inositol is conducted. Initial parameters were transferred from the alkanes and hexopyranose carbohydrates, with subsequent development and optimization of parameters unique to the molecules considered in this study. Using the model compounds acetone and acetaldehyde, nonbonded parameters for carbonyls were optimized targeting quantum mechanical interaction data for solute-water pairs and pure solvent thermodynamic data. Bond and angle parameters were adjusted by comparing optimized geometries to small molecule crystal survey data and by performing vibrational analyses on acetone, acetaldehyde and glycerol. C-C-C-C, C-C-C-O, C-C-OH and O-C-C-O torsional parameters for polyol chains were fit to quantum mechanical dihedral potential energy scans comprising over 1500 RIMP2/cc-pVTZ//MP2/6-31G(d) conformations using an automated Monte Carlo simulated annealing procedure. Comparison of computed condensed-phase data, including crystal lattice parameters and densities, NMR proton-proton couplings, densities and diffusion coefficients of aqueous solutions, to experimental data validated the optimized parameters. Parameter development for these compounds proved particularly challenging because of the flexibility of the acyclic sugars and polyalcohols as well as the intramolecular hydrogen bonding between vicinal hydroxyls for all of the compounds. The newly optimized additive CHARMM force field parameters are anticipated to be of utility for atomic level of detail simulations of acyclic polyalcohols, acyclic carbohydrates and inositol in solution. PMID:20160980

  1. Recent Applications of Acyclic (Diene)iron Complexes and (Dienyl)iron Cations in Organic Synthesis

    PubMed Central

    Chaudhury, Subhabrata

    2009-01-01

    Complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. Furthermore, the Fe(CO)3 moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). Recent applications of these reactivities to the synthesis of polyene, cyclopropane, cycloheptadiene and cyclohexenone containing natural products or analogs will be presented. PMID:21709767

  2. Ion pair complexes and anion binding in the solution of a ditopic receptor.

    PubMed

    Mäkelä, T; Rissanen, K

    2016-04-21

    The synthesis and crystal structures with alkali halides of a ditopic benzo-15-crown-5 bis-urea receptor have been presented. In addition, the anion binding properties of and its alkali metal complexes in solution are presented. A comprehensive single-crystal X-ray crystallographic study of , all together 13 crystal structures, including the ion pair complexes with NaCl, NaBr, NaI, KF, KCl, KBr, KI, RbF, RbCl, and RbI, give a detailed view of how behaves in the solid-state with different alkali halides depending on the size of the cation and anion. In the solid-state forms a 1 : 1 complex with a sodium cation and the anion is complexed as a contact (NaCl) or a separate ion pair (NaBr, NaI). With larger potassium and rubidium cations assembles into a 2 : 1 complex and forms a separated ion pair complex with the anion. Reflecting the crystal structures the forms a 1 : 1 complex with Na(+) in solution, and a 2 : 1 complex with K(+), which were verified by Job's plot analysis in 4 : 1 CDCl3/dimethyl sulfoxide. The binding strength of the monomeric [·Na](+) and the dimeric [2·K](+) toward chloride, bromide and iodide anions was studied by (1)H NMR titrations in 4 : 1 CDCl3/DMSO, and a clear turn-on effect of the cation complexation compared to the neutral receptor alone (Ka with for Cl(-), Br(-) and I(-) being 832, 174 and 32 M(-1), respectively) was observed. The monomeric [·Na](+) binds chloride 9, bromide 8, and iodide 12 times stronger than , while for the dimeric [2K](+) the corresponding increase in binding is 51 (Cl(-)), 84 (Br(-)), and 22 (I(-)) times with the same stoichiometric ratios as observed for the ion pair complexes in the solid-state. PMID:26953675

  3. Acyclic Lipids in Amazon Shelf Waters

    NASA Astrophysics Data System (ADS)

    Elias, V. O.; Cardoso, J. N.; Simoneit, B. R. T.

    2000-02-01

    Acyclic lipids were analysed for dissolved (<1·2 μm) and particulate (>1·2 μm) material from surface water of the Amazon continental shelf to correlate the direct inputs with diagenetic processes of the organic matter and to assess the differences in compound distribution patterns of the samples. The dissolved samples contained n -alkanes with an unusual even-to-odd carbon number predominance acyclic lipids indicates an origin from micro-organisms, probably diatoms. Although minor, a contribution of components derived from plant waxes are more abundant in the particulate phase with profiles indicating a remineralized residue. Plant waxes are effectively biodegraded in the shelf waters during downstream transport in the Amazon River. Furthermore, the Pr/Ph ratios calculated for the dissolved samples indicate that the organic matter in the surface of the highly turbid waters passed through an anaerobic stage. The differences in the acyclic hydrocarbon profiles of the dissolved and particulate phases show that organic inputs are preserved differently in smaller and larger particles.

  4. Directed Acyclic Graphs for Oral Disease Research.

    PubMed

    Akinkugbe, A A; Sharma, S; Ohrbach, R; Slade, G D; Poole, C

    2016-07-01

    Directed acyclic graphs (DAGs) are nonparametric graphical tools used to depict causal relations in the epidemiologic assessment of exposure-outcome associations. Although their use in dental research was first advocated in 2002, DAGs have yet to be widely adopted in this field. DAGs help identify threats to causal inference such as confounders, bias due to subject selection, and inappropriate handling of missing data. DAGs can also inform the data analysis strategy based on relations among variables depicted on it. This article uses the example of a study of temporomandibular disorders (TMDs), investigating causal effects of facial injury on subsequent risk of TMD. We illustrate how DAGs can be used to identify 1) potential confounders, 2) mediators and the consequences of attempt to estimate direct causal effects, 3) colliders and the consequences of conditioning on colliders, and 4) variables that are simultaneously mediators and confounders and the consequences of adjustment for such variables. For example, one DAG shows that statistical adjustment for the pressure pain threshold would necessarily bias the causal relation between facial injury and TMD. Finally, we discuss the usefulness of DAGs during study design, subject selection, and choosing variables to be measured in a study. PMID:27000052

  5. On the acyclicity of the solution sets of operator equations

    SciTech Connect

    Gel'man, Boris D

    2010-12-07

    A parameter-dependent completely continuous map is considered. The acyclicity of the set of fixed points of this map is proved for some fixed value of the parameter under the assumption that for close values of the parameter the map has a unique fixed point. The results obtained are used to prove the acyclicity of the set of fixed points of a 'nonscattering' map, as well as to study the topological structure of the set of fixed points of an abstract Volterra map. Bibliography: 13 titles.

  6. New acyclic diterpenic acids from yacon (Smallanthus sonchifolius) leaves.

    PubMed

    Mercado, María I; Coll Aráoz, María V; Grau, Alfredo; Catalán, César A N

    2010-11-01

    Two new acyclic diterpenoids, smaditerpenic acid E (1a) and F (2a), along with nineteen melampolide-type sesquiterpene lactones, six of them not previously reported in yacon, were isolated from the methylene chloride leaf rinse extract. Their structures were elucidated from 1D and 2D NMR experiments and gas chromatography coupled to mass spectrometry. PMID:21213966

  7. Synthesis, spectroscopic and biological activities studies of acyclic and macrocyclic mono and binuclear metal complexes containing a hard-soft Schiff base

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, Azza A. A.; Linert, Wolfgang

    Mono- and bi-nuclear acyclic and macrocyclic complexes with hard-soft Schiff base, H2L, ligand derived from the reaction of 4,6-diacetylresorcinol and thiocabohydrazide, in the molar ratio 1:2 have been prepared. The H2L ligand reacts with Co(II), Ni(II), Cu(II), Zn(II), Mn(II) and UO2(VI) nitrates, VO(IV) sulfate and Ru(III) chloride to get acyclic binuclear complexes except for VO(IV) and Ru(III) which gave acyclic mono-nuclear complexes. Reaction of the acyclic mono-nuclear VO(IV) and Ru(III) complexes with 4,6-diacetylresorcinol afforded the corresponding macrocyclic mono-nuclear VO(IV) and Ru(IIII) complexes. Template reactions of the 4,6-diacetylresorcinol and thiocarbohydrazide with either VO(IV) or Ru(III) salts afforded the macrocyclic binuclear VO(IV) and Ru(III) complexes. The Schiff base, H2L, ligand acts as dibasic with two NSO-tridentate sites and can coordinate with two metal ions to form binuclear complexes after the deprotonation of the hydrogen atoms of the phenolic groups in all the complexes, except in the case of the acyclic mononuclear Ru(III) and VO(IV) complexes, where the Schiff base behaves as neutral tetradentate chelate with N2S2 donor atoms. The ligands and the metal complexes were characterized by elemental analysis, IR, UV-vis 1H-NMR, thermal gravimetric analysis (TGA) and ESR, as well as the measurements of conductivity and magnetic moments at room temperature. Electronic spectra and magnetic moments of the complexes indicate the geometries of the metal centers are either tetrahedral, square planar or octahedral. Kinetic and thermodynamic parameters were calculated using Coats-Redfern equation, for the different thermal decomposition steps of the complexes. The ligands and the metal complexes were screened for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria, and Pseudomonas fluorescens as Gram-negative bacteria in addition to Fusarium oxysporum fungus. Most of the complexes exhibit mild

  8. Molecular recognition of trigonal oxyanions using a ditopic salt receptor: evidence for anisotropic shielding surface around nitrate anion.

    PubMed

    Mahoney, Joseph M; Stucker, Kenneth A; Jiang, Hua; Carmichael, Ian; Brinkmann, Nicole R; Beatty, Alicia M; Noll, Bruce C; Smith, Bradley D

    2005-03-01

    A ditopic, macrobicyclic receptor with adjacent anion and cation binding sites is able to extract a range of monovalent salts into chloroform solution. The structures of the receptor complexed with KAcO, LiNO(3), NaNO(3), KNO(3), and NaNO(2) are characterized in solution by NMR spectroscopy and in the solid state by X-ray crystallography. The sodium and potassium salts are bound to the receptor as contact ion-pairs, with the metal cation located in the receptor's crown ether ring and the trigonal oxyanion hydrogen bonded to the receptor NH residues. The solid-state structure of the LiNO(3) complex has a bridging water molecule between the cation and anion. In all solid-state structures, the trigonal oxyanion is not located symmetrically inside the receptor cavity. It appears that anion orientation is controlled by a complex interplay of steric factors, coordination bonding to the metal cation, and hydrogen bonding with the receptor NH residues. An important feature with this latter effect is the fact that hydrogen bonds directed toward the oxygen lone pairs on a trigonal oxyanion are stronger than hydrogen bonds to the pi-electrons. In solution, the (1)H NMR spectra of the nitrate and nitrite salt complexes are noteworthy because several receptor signals, including the NH protons, undergo unusual upfield movements in chemical shift upon complexation. This is a reflection of the diamagnetic anisotropy of these trigonal oxyanions. The magnetic shielding surface for the NO(3)(-) anion is calculated using density functional theory and shown to have a shielding region directly above the central nitrogen. PMID:15740128

  9. Medicinal chemistry of fluorinated cyclic and acyclic nucleoside phosphonates.

    PubMed

    Baszczyňski, Ondřej; Janeba, Zlatko

    2013-11-01

    The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties. PMID:23893552

  10. Hexagon wreaths: self-assembly of discrete supramolecular fractal architectures using multitopic terpyridine ligands.

    PubMed

    Wang, Ming; Wang, Chao; Hao, Xin-Qi; Liu, Jingjing; Li, Xiaohong; Xu, Chenglong; Lopez, Alberto; Sun, Luyi; Song, Mao-Ping; Yang, Hai-Bo; Li, Xiaopeng

    2014-05-01

    In this study, we overcame a challenge in conventional self-assembly of macrocycles that uses ditopic 2,2':6',2″-terpyridine (tpy) building blocks with a 120° angle between two ligating moieties, which generally produces a mixture of multiple macrocycles instead of a single hexagon. Two supramolecular hexagon wreaths, [Zn9LA6] and [Zn12LB6], were designed and self-assembled from tritopic and tetratopic tpy ligands with Zn(II) ions, respectively. These multitopic ligands, bearing multiple binding sites, increased the total density of coordination sites and provided high geometric constraints to induce the formation of discrete structures. Such hexagon wreaths, which were constructed by simple recursion of small hexagons around a central hexagon, exhibit fractal geometry features with self-similarity at different levels. The shapes, sizes, and structures were fully characterized by NMR, ESI-MS, traveling-wave ion mobility mass spectrometry (TWIM-MS), and transmission electron microscopy. With diameters around 5.5 nm for [Zn9LA6] and 5.8 nm for [Zn12LB6], the remarkable rigidity of these fractal architectures was supported by TWIM-MS, in contrast to the high flexibility of macrocycles assembled by ditopic tpy ligands. PMID:24731215

  11. Acyclic nucleoside/nucleotide analogues with an imidazole ring skeleton.

    PubMed

    Chen, H M; Hosmane, R S

    2001-08-01

    Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4, 5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicyano-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC50 of <2.5 microg/mL and an SI value of > 176. PMID:11554548

  12. Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc.

    PubMed

    Alexakis, Alexandre; Polet, Damien; Rosset, Stéphane; March, Sébastien

    2004-08-20

    Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins. PMID:15307737

  13. Iridium-Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α-Alkoxy Ketones.

    PubMed

    Jiang, Xingyu; Chen, Wenyong; Hartwig, John F

    2016-05-01

    The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Reported herein are diastereoselective and enantioselective allylic substitutions with acyclic α-alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α-alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity. PMID:27038004

  14. Forming Stereogenic Centers in Acyclic Systems from Alkynes.

    PubMed

    Vabre, Roxane; Island, Biana; Diehl, Claudia J; Schreiner, Peter R; Marek, Ilan

    2015-08-17

    The combined carbometalation/zinc homologation followed by reactions with α-heterosubstituted aldehydes and imines proceed through a chair-like transition structure with the substituent of the incoming aldehyde residue preferentially occupying a pseudo-axial position to avoid the two gauche interactions. The heteroatom in the axial position produces a chelated intermediate (and not a Cornforth-Evans transition structure for α-chloro aldehydes and imines) leading to a face differentiation in the allylation reaction. This method provides access to functionalized products in which three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary one, were created in acyclic systems in a single-pot operation from simple alkynes. PMID:26130570

  15. Tautomerism and stereodynamics of acyclic. beta. -diketo esters

    SciTech Connect

    Romas, A.D.; Esakov, S.M.; Petrov, Al.An.; Ershov, B.A.

    1986-04-10

    The tautomeric transformations and stereodynamics of a series of ring-substituted acyclic ..beta..-diketo esters p-XC/sub 6/H/sub 4/COCH(CH/sub 3/CO)CO/sub 2/CH/sub 3/ in hexachlorobutadiene and nitrobenzene were investigated by proton and carbon magnetic resonance spectroscopy. The enolization of the compounds is accompanied by the formation of two cis-enol forms (of the three theoretically possible forms) with nonchelated benzene of methoxycarbonyl groups respectively. The form with the nonchelated methoxycarbonyl group predominates in the equilibrium on account of the smaller loss of entropy during its formation compared with the enol containing the nonchelated benzoyl group. The kinetic characteristics of the mutual transformations of the enolic forms in hexachlorobutadiene and nitrobenzene respectively were determined by integration and dynamic nuclear magnetic resonance.

  16. Analyzing microarray data with transitive directed acyclic graphs.

    PubMed

    Phan, Vinhthuy; Olusegun George, E; Tran, Quynh T; Goodwin, Shirlean; Bodreddigari, Sridevi; Sutter, Thomas R

    2009-02-01

    Post hoc assignment of patterns determined by all pairwise comparisons in microarray experiments with multiple treatments has been proven to be useful in assessing treatment effects. We propose the usage of transitive directed acyclic graphs (tDAG) as the representation of these patterns and show that such representation can be useful in clustering treatment effects, annotating existing clustering methods, and analyzing sample sizes. Advantages of this approach include: (1) unique and descriptive meaning of each cluster in terms of how genes respond to all pairs of treatments; (2) insensitivity of the observed patterns to the number of genes analyzed; and (3) a combinatorial perspective to address the sample size problem by observing the rate of contractible tDAG as the number of replicates increases. The advantages and overall utility of the method in elaborating drug structure activity relationships are exemplified in a controlled study with real and simulated data. PMID:19226664

  17. Structural Interactions within Lithium Salt Solvates. Acyclic Carbonates and Esters

    SciTech Connect

    Afroz, Taliman; Seo, D. M.; Han, Sang D.; Boyle, Paul D.; Henderson, Wesley A.

    2015-03-06

    Solvate crystal structures serve as useful models for the molecular-level interactions within the diverse solvates present in liquid electrolytes. Although acyclic carbonate solvents are widely used for Li-ion battery electrolytes, only three solvate crystal structures with lithium salts are known for these and related solvents. The present work, therefore, reports six lithium salt solvate structures with dimethyl and diethyl carbonate: (DMC)2:LiPF6, (DMC)1:LiCF3SO3, (DMC)1/4:LiBF4, (DEC)2:LiClO4, (DEC)1:LiClO4 and (DEC)1:LiCF3SO3 and four with the structurally related methyl and ethyl acetate: (MA)2:LiClO4, (MA)1:LiBF4, (EA)1:LiClO4 and (EA)1:LiBF4.

  18. Unusual Recognition and Separation of Hydrated Metal Sulfates [M2(μ-SO4)2(H2O)n, M = Zn(II), Cd(II), Co(II), Mn(II)] by a Ditopic Receptor.

    PubMed

    Ghosh, Tamal Kanti; Dutta, Ranjan; Ghosh, Pradyut

    2016-04-01

    A ditopic receptor L1, having metal binding bis(2-picolyl) donor and anion binding urea group, is synthesized and explored toward metal sulfate recognition via formation of dinuclear assembly, (L1)2M2(SO4)2. Mass spectrometric analysis, (1)H-DOSY NMR, and crystal structure analysis reveal the existence of a dinuclear assembly of MSO4 with two units of L1. (1)H NMR study reveals significant downfield chemical shift of -NH protons of urea moiety of L1 selectively with metal sulfates (e.g., ZnSO4, CdSO4) due to second-sphere interactions of sulfate with the urea moiety. Variable-temperature (1)H NMR studies suggest the presence of intramolecular hydrogen bonding interaction toward metal sulfate recognition in solution state, whereas intermolecular H-bonding interactions are observed in solid state. In contrast, anions in their tetrabutylammonium salts fail to interact with the urea -NH probably due to poor acidity of the tertiary butyl urea group of L1. Metal sulfate binding selectivity in solution is further supported by isothermal titration calorimetric studies of L1 with different Zn salts in dimethyl sulfoxide (DMSO), where a binding affinity is observed for ZnSO4 (Ka = 1.23 × 10(6)), which is 30- to 50-fold higher than other Zn salts having other counteranions in DMSO. Sulfate salts of Cd(II)/Co(II) also exhibit binding constants in the order of ∼1 × 10(6) as in the case of ZnSO4. Positive role of the urea unit in the selectivity is confirmed by studying a model ligand L2, which is devoid of anion recognition urea unit. Structural characterization of four MSO4 [M = Zn(II), Cd(II), Co(II), Mn(II)] complexes of L1, that is, complex 1, [(L1)2(Zn)2(μ-SO4)2]; complex 2, [(L1)2(H2O)2(Cd)2(μ-SO4)2]; complex 3, [(L1)2(H2O)2(Co)2(μ-SO4)2]; and complex 4, [(L1)2(H2O)2(Mn)2(μ-SO4)2], reveal the formation of sulfate-bridged eight-membered crownlike binuclear complexes, similar to one of the concentration-dependent dimeric forms of MSO4 as observed in solid state

  19. Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

    NASA Astrophysics Data System (ADS)

    Ma, Da; Hettiarachchi, Gaya; Nguyen, Duc; Zhang, Ben; Wittenberg, James B.; Zavalij, Peter Y.; Briken, Volker; Isaacs, Lyle

    2012-06-01

    The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.

  20. Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres.

    PubMed

    Minko, Yury; Marek, Ilan

    2014-10-28

    Reactions that involve metal enolate species are amongst the most versatile carbon-carbon bond forming processes available to synthetic chemists. Enolate species are involved in a multitude of powerful applications in asymmetric organic synthesis, but the generation of fully substituted enolates in a geometrically defined form is not easily achieved especially in acyclic systems. In this Feature Article we focus on the most prominent examples reported in the literature describing the formation of highly diastereo- and enantiomerically enriched quaternary stereocentres in acyclic molecules derived from stereodefined non-cyclic trisubstituted metal enolates. PMID:25054432

  1. Acyclic and star colorings of joins of graphs and an algorithm for cographs.

    SciTech Connect

    Lyons, A.; Mathematics and Computer Science; Univ. of Chicago

    2009-01-01

    An acyclic coloring of a graph is a proper vertex coloring such that the subgraph induced by the union of any two color classes is a disjoint collection of trees. The more restricted notion of star coloring requires that the union of any two color classes induces a disjoint collection of stars. The acyclic and star chromatic numbers of a graph G are defined analogously to the chromatic number {chi}(G) and are denoted by {chi}{sub a}(G) and {chi}{sub s}(G), respectively. In this paper, we consider acyclic and star colorings of graphs that are decomposable with respect to the join operation, which builds a new graph from a collection of two or more disjoint graphs by adding all possible edges between them. In particular, we present a recursive formula for the acyclic chromatic number of joins of graphs and show that a similar formula holds for the star chromatic number. We also demonstrate the algorithmic implications of our results for the cographs, which have the unique property that they are recursively decomposable with respect to the join and disjoint union operations.

  2. RIBOSE MODIFIED NUCLEOSIDES AND NUCLEOTIDES AS LIGANDS FOR PURINE RECEPTORS

    PubMed Central

    Ravi, R. G.; Nandanan, E.; Kim, H. S.; Moro, S.; Kim, Y. C.; Lee, K.; Barak, D.; Marquez, V. E.; Ji, X. D.

    2016-01-01

    Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3′,5′-bisphosphate derivatives act as selective P2Y1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y1 and A1 and A3ARs. PMID:11563046

  3. N-Branched acyclic nucleoside phosphonates as monomers for the synthesis of modified oligonucleotides.

    PubMed

    Hocková, Dana; Rosenbergová, Šárka; Ménová, Petra; Páv, Ondřej; Pohl, Radek; Novák, Pavel; Rosenberg, Ivan

    2015-04-21

    Protected N-branched nucleoside phosphonates containing adenine and thymine bases were prepared as the monomers for the introduction of aza-acyclic nucleotide units into modified oligonucleotides. The phosphotriester and phosphoramidite methods were used for the incorporation of modified and natural units, respectively. The solid phase synthesis of a series of nonamers containing one central modified unit was successfully performed in both 3'→5' and 5'→3' directions. Hybridization properties of the prepared oligoribonucleotides and oligodeoxyribonucleotides were evaluated. The measurement of thermal characteristics of the complexes of modified nonamers with the complementary strand revealed a considerable destabilizing effect of the introduced units. We also examined the substrate/inhibitory properties of aza-acyclic nucleoside phosphono-diphosphate derivatives (analogues of nucleoside triphosphates) but neither inhibition of human and bacterial DNA polymerases nor polymerase-mediated incorporation of these triphosphate analogues into short DNA was observed. PMID:25766752

  4. Acyclic monoterpenes in tree essential oils as a shrinking agent for waste-expanded polystyrene.

    PubMed

    Shimotori, Yasutaka; Hattori, Kazuyuki; Aoyama, Masakazu; Miyakoshi, Tetsuo

    2011-01-01

    We examined the dissolution of polystyrene (PS) into acyclic monoterpenes present in tree essential oils, to develop an environmentally friendly shrinking agent for waste-expanded polystyrene (EPS). The dissolving powers of geranyl acetate, geranylacetone, and geranyl formate [221.8-241.2 g PS (100 g solvent)(-1)] compared favorably with that of (R)-limonene [181.7 g PS (100 g solvent)(-1)]. Their favorable dissolving powers for PS can be explained by their flexible linear structures, which may be more accessible to the inside of bulk PS compared with cyclic monoterpenes. These acyclic monoterpenes and PS were recovered almost quantitatively by simple steam distillation of the PS solution. PMID:21644162

  5. Regulation of the survival and differentiation of hepatic stem/progenitor cells by acyclic retinoid.

    PubMed

    Kamiya, Akihide

    2015-01-01

    During embryonic liver development, hepatic stem/progenitor cells (HpSCs) have a high proliferative ability and bipotency to differentiate into hepatocytes and cholangiocytes. Retinoic acid is a derivative of vitamin A and is involved in the proliferation and differentiation of stem/progenitor cells in several tissues. However, whether retinoic acid regulates the characteristics of HpSCs in the normal liver is still unknown. A recent study has shown that acyclic retinoid regulates the survival and proliferation of HpSCs derived from mouse foetal liver. Acyclic retinoid suppressed the expansion of CD29(+)CD49f(+) HpSCs through the induction of hepatocytic differentiation and progression of apoptosis. PMID:26021438

  6. [Synthesis of acyclic 1,3-polyols and its application to structural study of natural products].

    PubMed

    Mori, Y

    1993-06-01

    A 1,3-polyhydroxylated chain is often found on the backbone of biologically important natural products. The acyclic nature and the regular array of many hydroxyl groups are main obstacles to structural and synthetic studies, and many efforts have been made to this end. We have developed a new general synthetic method of 1,3-polyols based on the coupling of a chiral dithiane, a four-carbon unit, and an epoxide, followed by 1,3-diastereoselective reduction. We applied the method to the synthesis of polymethoxy-1-alkenes isolated from blue-green algae to establish their absolute stereochemistry. Moreover, a general procedure for assigning the absolute stereochemistry of acyclic 1,3-polyols by the difference circular dichroism (CD) method have been established. Combination of the method and a reiterative degradation enables one to determine the absolute configuration of 1,3-polyols, even if the relative stereochemistry is unknown. PMID:8355146

  7. Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

    PubMed Central

    Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J.

    2013-01-01

    A study of the reactivity and diastereoselectivity of the Lewis acid-promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone, followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic ynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID:23724905

  8. Seven-coordinate iron complex as a ditopic receptor for lithium salts: study of host-guest interactions and substitution behavior.

    PubMed

    Sarauli, David; Popova, Vesselina; Zahl, Achim; Puchta, Ralph; Ivanović-Burmazović, Ivana

    2007-09-17

    Interactions between the seven-coordinate tweezerlike [Fe(dapsox)(H2O)2]ClO4 complex (H2dapsox = 2,6-diacetylpyridine-bis(semioxamazide)) with different lithium salts (LiOTf, LiClO4, LiBF4, and LiPF6) in CH3CN have been investigated by electrochemical, spectrophotometric, 7Li and 19F NMR, kinetic, and DFT methods. It has been demonstrated that this complex acts as ditopic receptor, showing spectral and electrochemical ion-pair-sensing capability for different lithium salts. In general, the apparent binding constants for lithium salts increase in the order LiOTf < LiClO4 < LiBF4. From the electrochemical measurements, the apparent lithium salt binding constants for the Fe(III) and Fe(II) forms of the complex have been obtained, suggesting a stronger host-guest interaction with the reduced form of the complex. In the presence of LiPF6, the solution chemistry is more complex because of the hydrolysis of PF6-. The kinetics of the complexation of [Fe(dapsox)(CH3CN)2]+ by thiocyanate at -15 degrees C in acetonitrile in the presence of 0.2 M NBu4OTf shows two steps with the following rate constants and activation parameters: k(1) = 411 +/- 14 M(-1) s(-1); DeltaH(1) not equal = 9 +/- 2 kJ mol(-1); DeltaS1 not equal = -159 +/- 6 J K(-1) mol(-1); k(2) = 52 +/- 1 M(-1) s(-1); DeltaH(2) not equal = 4 +/- 1 kJ mol(-1); DeltaS(2) not equal = -195 +/- 3 J K(-1) mol(-1). The very negative DeltaS not equal values are consistent with an associative (A) mechanism. Under the same conditions but with 0.2 M LiOTf, k1Li and k2Li are 1605 +/- 51 and 106 +/- 2 M(-1) s(-1), respectively. The increased rate constants for the {[Fe(dapsox)(CH3CN)2] x LiOTf}+ adduct are in agreement with an associative mechanism. Kinetic and spectrophotometric titration measurements show stronger interaction between the lithium salt and the anion-substituted forms, [Fe(dapsox)(CH3CN)(NCS)] and [Fe(dapsox)(NCS)2]-, of the complex. These experiments demonstrate that in nonaqueous media lithium salts cannot be

  9. Triphosgene-Pyridine Mediated Stereoselective Chlorination of Acyclic Aliphatic 1,3-Diols†

    PubMed Central

    Villalpando, Andrés; Saputra, Mirza A.; Tugwell, Thomas H.; Kartika, Rendy

    2015-01-01

    We describe a strategy to chlorinate stereocomplementary acyclic aliphatic 1,3-diols using a mixture of triphosgene and pyridine. While 1,3-anti diols readily led to 1,3-anti dichlorides, 1,3-syn diols must be converted to 1,3-syn diol monosilylethers to access the corresponding 1,3-syn dichlorides. These dichlorination protocols were operationally simple, very mild, and readily tolerated by advanced synthetic intermediates. PMID:26323232

  10. Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

    PubMed Central

    Clinch, Keith; Crump, Douglas R.; Evans, Gary B.; Hazleton, Keith Z.; Mason, Jennifer M.; Schramm, Vern L.

    2013-01-01

    The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. PMID:23810424

  11. Characterization of cyclic and acyclic alkanes in Forties and Kuwait petroleum crudes

    SciTech Connect

    Jones, D.W. ); Pakdel, H. ); Bartle, K.D. )

    1990-01-01

    Alkane hydrocarbon fractions from Forties (North Sea) and Kuwait petroleum crudes, separated by distillation, solvent extraction and silicagel column chromatography and sub-fractionated by molecular-sieve adsorption, have been examined by gas chromatography (GC), {sup 1}H and {sup 13}C NMR spectroscopy, GC-mass spectrometry (MS) and field desorption (FD)MS. GC indicates that Forties contains rather more acyclic isoprenoids and cyclic alkanes than Kuwait; FDMS of Kuwait shows molecular-weight ranges for mono-, di-, tri-, tetra-, and pentacyclic alkanes. {sup 13}C NMR spectra provide evidence of higher aromatic carbon, C{sub A}, in Forties than Kuwait and longer T{sub 1} relaxation times.

  12. A Practical Approach for Scalable Conjunctive Query Answering on Acyclic {EL}^+ Knowledge Base

    NASA Astrophysics Data System (ADS)

    Mei, Jing; Liu, Shengping; Xie, Guotong; Kalyanpur, Aditya; Fokoue, Achille; Ni, Yuan; Li, Hanyu; Pan, Yue

    Conjunctive query answering for {EL}^{++} ontologies has recently drawn much attention, as the Description Logic {EL}^{++} captures the expressivity of many large ontologies in the biomedical domain and is the foundation for the OWL 2 EL profile. In this paper, we propose a practical approach for conjunctive query answering in a fragment of {EL}^{++}, namely acyclic {EL}^+, that supports role inclusions. This approach can be implemented with low cost by leveraging any existing relational database management system to do the ABox data completion and query answering. We conducted a preliminary experiment to evaluate our approach using a large clinical data set and show our approach is practical.

  13. A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system.

    PubMed

    Nishide, K; Hagimoto, Y; Hasegawa, H; Shiro, M; Node, M

    2001-11-21

    X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible conformation. PMID:12240092

  14. A new strategy to construct acyclic nucleosides via Ag(I)-catalyzed addition of pronucleophiles to 9-allenyl-9H-purines.

    PubMed

    Wei, Tao; Xie, Ming-Sheng; Qu, Gui-Rong; Niu, Hong-Ying; Guo, Hai-Ming

    2014-02-01

    A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60-98% yields). Meanwhile, these reactions exhibited high chemoselectivities and E-selectivities. PMID:24437554

  15. Cyclodextrin-based PNN supramolecular assemblies: a new class of pincer-type ligands for aqueous organometallic catalysis.

    PubMed

    Menuel, S; Bertaut, E; Monflier, E; Hapiot, F

    2015-08-14

    Water-soluble cyclodextrins (CDs) bearing two nitrogen atoms as metal coordinating sites have been synthesized. An appropriate phosphane could be included within their cavity through the primary face to form self-assembled PNN supramolecular edifices. Once the PNN ligands were coordinated to platinum, the resulting complexes proved to be very effective as catalysts in a domino reaction, where a Pt-catalyzed reduction of nitrobenzene was followed by a Paal-Knorr pyrrole reaction. In the nitrobenzene reduction, the modified CDs acted both as first- and second-sphere ligands. Contrary to an acyclic glucopyranose-based NN ligand unable to interact with a phosphane ligand, the CD-based PNN ligands stabilized the catalytic species in water by supramolecular means. Interestingly, the product and the water-soluble Pt-catalyst could be recovered in two different phases once the reaction was complete. PMID:26148430

  16. Investigation of diastereoselective acyclic α-alkoxydithioacetal substitutions involving thiacarbenium intermediates.

    PubMed

    Prévost, Michel; Dostie, Starr; Waltz, Marie-Ève; Guindon, Yvan

    2014-11-01

    Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals. PMID:25280088

  17. Synthesis and antiviral activity evaluation of acyclic 2'-azanucleosides bearing a phosphonomethoxy function in the side chain.

    PubMed

    Koszytkowska-Stawińska, Mariola; De Clercq, Erik; Balzarini, Jan

    2009-06-01

    Acyclic 2'-azanucleosides with a phosphonomethoxy function in the side chain were obtained by coupling of diethyl {2-[N-(pivaloyloxymethyl)-N-(p-toluenesulfonyl)amino]ethoxymethyl}phosphonate with the pyrimidine nucleobases via the Vorbrüggen-type protocol. The compounds were evaluated in vitro for activity against a broad variety of RNA and DNA viruses. PMID:19442526

  18. Anomalous Reactivity and Selectivity in the Intermolecular Diels-Alder Reactions of Multisubstituted Acyclic Dienes with Geometrical Isomers of Enals.

    PubMed

    Zhou, Jia-Hui; Cai, Sai-Hu; Xu, Yun-He; Loh, Teck-Peng

    2016-05-20

    A Lewis-acid catalyzed intermolecular Diels-Alder reaction between multisubstituted acyclic dienes and the E and Z isomers of α,β-enals was studied. It was found that the diene reacted selectively with the Z-isomer of the α,β-enal. PMID:27132468

  19. Structural and thermodiffractometric analysis of coordination polymers. Part II: zinc and cadmium derivatives of the Bim ligand [Bim = bis(1-imidazolyl)methane].

    PubMed

    Masciocchi, Norberto; Pettinari, Claudio; Alberti, Enrica; Pettinari, Riccardo; Nicola, Corrado Di; Albisetti, Alessandro Figini; Sironi, Angelo

    2007-12-10

    New polynuclear coordination species containing the ditopic bis(1-imidazolyl)methane (Bim) ligand have been prepared as microcrystalline powders and structurally characterized by ab initio X-ray powder diffraction methods. [Zn(CH3COO)2(Bim)]n contains 1D chains with tetrahedral metal atoms bridged by Bim ligands; [CdBr2(Bim)]n shows a dense packing with hexacoordinated Cd(II) ions and mu-Br and mu-Bim bridges; at variance, the isomorphous [ZnCl2(Bim)]n and [ZnBr2(Bim)]n species contain cyclic dimers based on tetrahedral Zn(II) ions. Thermodiffractometric analysis allowed estimation of the linear thermal expansion coefficients and strain tensors derived there from. Bim-rich phases, with 2:1 ligand-to-metal ratio, were also isolated: ZnBr2(Bim)2(H2O)3 and [Cd(CH3COO)2(Bim)2]n containing cis and trans MN4O2 chromophores, respectively, show 1D polymers built upon M2Bim2 cycles, hinged on the metal ions. In all species the conformation of the Bim ligands is Cs (or nearly so), while in the few sparse reports of similar coordination polymers the alternative C2 one was preferentially observed. PMID:18001119

  20. Resistance of human immunodeficiency virus type 1 to acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidines.

    PubMed Central

    Nguyen, M H; Schinazi, R F; Shi, C; Goudgaon, N M; McKenna, P M; Mellors, J W

    1994-01-01

    Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy. PMID:7840579

  1. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification

    PubMed Central

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs). PMID:26985826

  2. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification.

    PubMed

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs). PMID:26985826

  3. Halogen bonding in water results in enhanced anion recognition in acyclic and rotaxane hosts.

    PubMed

    Langton, Matthew J; Robinson, Sean W; Marques, Igor; Félix, Vítor; Beer, Paul D

    2014-12-01

    Halogen bonding (XB), the attractive interaction between an electron-deficient halogen atom and a Lewis base, has undergone a dramatic development as an intermolecular force analogous to hydrogen bonding (HB). However, its utilization in the solution phase remains underdeveloped. Furthermore, the design of receptors capable of strong and selective recognition of anions in water remains a significant challenge. Here we demonstrate the superiority of halogen bonding over hydrogen bonding for strong anion binding in water, to the extent that halide recognition by a simple acyclic mono-charged receptor is achievable. Quantification of iodide binding by rotaxane hosts reveals the strong binding by the XB-rotaxane is driven exclusively by favourable enthalpic contributions arising from the halogen-bonding interactions, whereas weaker association with the HB-rotaxanes is entropically driven. These observations demonstrate the unique nature of halogen bonding in water as a strong alternative interaction to the ubiquitous hydrogen bonding in molecular recognition and assembly. PMID:25411880

  4. Diversity-oriented synthesis of acyclic nucleosides via ring-opening of vinyl cyclopropanes with purines.

    PubMed

    Niu, Hong-Ying; Du, Cong; Xie, Ming-Sheng; Wang, Yong; Zhang, Qian; Qu, Gui-Rong; Guo, Hai-Ming

    2015-02-25

    The diversity-oriented synthesis of acyclic nucleosides has been achieved via ring-opening of vinyl cyclopropanes with purines. With Pd2(dba)3·CHCl3 as a catalyst, the 1,5-ring-opening reaction proceeded well and afforded N9 adducts as the major form, in which the C=C bonds in the side chain were exclusively E-form. In the presence of AlCl3, the 1,3-ring-opening reaction occurred smoothly, giving N9 adducts as the dominate products. Meanwhile, when MgI2 was used as the catalyst, the 1,3-ring-opening reaction also worked well to form N7 adducts. PMID:25572827

  5. Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases.

    PubMed

    Hocková, Dana; Janeba, Zlatko; Naesens, Lieve; Edstein, Michael D; Chavchich, Marina; Keough, Dianne T; Guddat, Luke W

    2015-09-01

    Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors--the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads. PMID:26275679

  6. Molecular Motion of the Junction Points in Model Networks Prepared by Acyclic Triene Metathesis.

    PubMed

    da Silva, Lucas Caire; Bowers, Clifford R; Graf, Robert; Wagener, Kenneth B

    2016-03-01

    The junction dynamics in a selectively deuterated model polymer network containing junctions on every 21st chain carbon is studied by solid state (2) H echo NMR. Polymer networks are prepared via acyclic triene metathesis of deuteron-labeled symmetric trienes with deuteron probes precisely placed at the alpha carbon relative to the junction point. The effect of decreasing the cross-link density on the junction dynamics is studied by introduction of polybutadiene chains in-between junctions. The networks are characterized by swelling, gel content, and solid state (1) H MAS NMR. Line shape analysis of the (2) H quadrupolar echo spectra reveals that the degree of motion anisotropy and the distribution of motion correlation times depend on the cross-link density and structural heterogeneity of the polymer networks. A detailed model of the junction dynamics at different temperatures is proposed and explained in terms of the intermolecular cooperativity in densely-packed systems. PMID:26787457

  7. The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

    NASA Astrophysics Data System (ADS)

    Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.; Kaneko, Shuichi

    2014-04-01

    Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

  8. Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis

    NASA Astrophysics Data System (ADS)

    Hashimoto, Takuya; Kimura, Hidenori; Kawamata, Yu; Maruoka, Keiji

    2011-08-01

    Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of N‧-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β-hydrazino esters and phosphonates with excellent enantioselectivities.

  9. Versatile synthesis of oxime-containing acyclic nucleoside phosphonates--synthetic solutions and antiviral activity.

    PubMed

    Solyev, Pavel N; Jasko, Maxim V; Kleymenova, Alla A; Kukhanova, Marina K; Kochetkov, Sergey N

    2015-11-28

    New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N(9)/N(7) product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 μM. PMID:26383895

  10. Acyclic Immucillin Phosphonates. Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase

    SciTech Connect

    Hazelton, Keith Z.; Ho, Meng-Chaio; Cassera, Maria B.; Clinch, Keith; Crump, Douglas R.; Rosario Jr., Irving; Merino, Emilio F.; Almo, Steve C.; Tyler, Peter C.; Schramm, Vern L.

    2012-06-22

    We found that Plasmodium falciparum is the primary cause of deaths from malaria. It is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. We present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

  11. Acyclic N-halamine-immobilized polyurethane: Preparation and antimicrobial and biofilm-controlling functions

    PubMed Central

    Luo, Jie; Porteous, Nuala; Lin, Jiajin; Sun, Yuyu

    2015-01-01

    Hydroxyl groups were introduced onto polyurethane surfaces through 1,6-hexamethylene diisocyanate activation, followed by diethanolamine hydroxylation. Polymethacrylamide was covalently attached to the hydroxylated polyurethane through surface grafting polymerization of methacrylamide using cerium (IV) ammonium nitrate as an initiator. After bleach treatment, the amide groups of the covalently bound polymethacrylamide chains were transformed into N-halamines. The new N-halamine-immobilized polyurethane provided a total sacrifice of 107–108 colony forming units per milliliter of Staphylococcus aureus (Gram-positive bacteria), Escherichia coli (Gram-negative bacteria), and Candida albicans (fungi) within 10 min and successfully prevented bacterial and fungal biofilm formation. The antimicrobial and biofilm-controlling effects were both durable and rechargeable, pointing to great potentials of the new acyclic N-halamine-immobilized polyurethane for a broad range of related applications. PMID:26089593

  12. Acyclic hydrocarbon environments ⩾ n-C 18 on the early terrestrial planets

    NASA Astrophysics Data System (ADS)

    Marcano, Vicente; Benitez, Pedro; Palacios-Prü, Ernesto

    2003-03-01

    The possible occurrence on the surface of the early Earth, Mars and Venus of hydrocarbon environments mainly composed by acyclic alkane molecules ⩾ n-C 18 has been revised. These hydrocarbons could be accumulated from the contribution of endogenous Fischer-Tropsh-type reactions and post-impact recombination reactions, as well as from exogenous sources such as comets, meteorites and dust particles. Such heavy alkane environments could offer protection for the synthesis and survival of biomolecules on the early terrestrial planets. Amounts of heavy n-alkanes delivered by large impactors, dust particles or produced by post-impact recombination on Venus would have been higher than those delivered or produced by the same sources on Earth and Mars before 3600 Myr ago. However, the high values of the total frequency of impacts by bolides >14-km in diameter estimated in this time period (viz. 3.9×10 3, Mars; 2.2×10 4, Earth, and 3.8×10 4 Venus) and the high surface temperatures generated by those impactors suggest the existence of very unstable conditions on the early terrestrial planets for the survival and long-term accumulation of acyclic hydrocarbons. Therefore, the most significant accumulation of n-alkanes could have occurred only during the longer intervals (10 5- 10 7 yr) between each impact through the contribution mainly of IDPs, and thereby a high decomposition rate would be expected for the accumulated n-alkanes by successive impacts. Amounts of n-alkanes accumulated from IDPs in these intervals have been estimated between 2.3×10 9 and 2.2×10 10 kg 3600- 3800 Myr ago. These processes are expected to occur on other planetary bodies or satellites belonging to our solar system and probably in analogs of the early solar system.

  13. Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril-Type Molecular Containers.

    PubMed

    Lu, Xiaoyong; Isaacs, Lyle

    2016-07-01

    The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. (1) H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host-hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution. PMID:27169688

  14. Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures.

    PubMed

    Varga, Szilárd; Jakab, Gergely; Csámpai, Antal; Soós, Tibor

    2015-09-18

    An organocatalytic iterative assembly line has been developed in which nitromethane was sequentially coupled with two different enones using a combination of pseudoenantiomeric cinchona-based thiourea catalysts. Application of unsaturated aldehydes and ketones in the second step of the iterative sequence allows the construction of cyclic syn-ketols and acyclic compounds with multiple contiguous stereocenters. The combination of the multifunctional substrates and ambident electrophiles rendered some organocatalytic transformations possible that have not yet been realized in bifunctional noncovalent organocatalysis. PMID:26301563

  15. Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols.

    PubMed

    Mo, Xiaobin; Hall, Dennis G

    2016-08-31

    A ferrocenium boronic acid salt activates allylic alcohols to generate transient carbocations that react with in situ-generated chiral enamines from branched aldehydes. The optimized conditions afford the desired acyclic products embedding a methyl-aryl quaternary carbon center with up to 90% yield and 97:3 enantiomeric ratio, with only water as the byproduct. This noble-metal-free method complements alternative methods that are incompatible with carbon-halogen bonds and other sensitive functional groups. PMID:27518200

  16. Investigating temporary acyclicity in a captive group of Asian elephants (Elephas maximus): Relationship between management, adrenal activity and social factors.

    PubMed

    Edwards, Katie L; Trotter, Jessica; Jones, Martin; Brown, Janine L; Steinmetz, Hanspeter W; Walker, Susan L

    2016-01-01

    Routine faecal steroid monitoring has been used to aid the management of five captive Asian elephant (Elephas maximus) females at Chester Zoo, UK, since 2007. Progestagen analysis initially revealed synchronised oestrous cycles among all females. However, a 14- to 20-week period of temporary acyclicity subsequently occurred in three females, following several management changes (increased training, foot-care and intermittent matriarch removal for health reasons) and the initiation of pregnancy in another female. The aim of this study was to retrospectively investigate whether these management changes were related to increased adrenal activity and disruption of ovarian activity, or whether social factors may have been involved in the temporary cessation of cyclicity. Faecal samples collected every other day were analysed to investigate whether glucocorticoid metabolites were related to reproductive status (pregnant, cycling, acyclic) or management (training, foot-care, matriarch presence). Routine training and foot-care were not associated with adrenal activity; however, intensive foot-care to treat an abscess in one female was associated with increased glucocorticoid concentration. Matriarch presence influenced adrenal activity in three females, being lower when the matriarch was separated from the group at night compared to being always present. However, in the females that exhibited temporary acyclicity, there was no consistent relationship between glucocorticoids and cyclicity state. Although the results of this study do not fully explain this occurrence, the highly synchronised nature of oestrous cycles within this group, and the concurrent acyclicity in three females, raises the question of whether social factors could have been involved in the temporary disruption of ovarian activity. PMID:26393308

  17. Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics

    PubMed Central

    Clinch, Keith; Evans, Gary B.; Fröhlich, Richard F. G.; Gulab, Shivali A.; Gutierrez, Jemy A.; Mason, Jennifer M.; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

    2012-01-01

    Several acyclic hydroxy-methylthio-amines with 3 to 5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and E. coli and N. meningitidis MTANs and gave Ki values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4-methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon–carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts. PMID:22854195

  18. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study.

    PubMed

    Roux, Loïc; Priet, Stéphane; Payrot, Nadine; Weck, Clément; Fournier, Maëlenn; Zoulim, Fabien; Balzarini, Jan; Canard, Bruno; Alvarez, Karine

    2013-05-01

    9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. PMID:23603046

  19. beta-Lactamase-catalyzed hydrolysis of acyclic depsipeptides and acyl transfer to specific amino acid acceptors.

    PubMed Central

    Pratt, R F; Govardhan, C P

    1984-01-01

    beta-Lactamases from all three classes, A, B, and C, catalyze the hydrolysis of specific acyclic depsipeptide (PhCH2CONHCR1R2CO2CHR3CO2H) analogs of acyl-D-alanyl-D-alanine peptides. The depsipeptides investigated, which are chemically as reactive toward nucleophiles as penicillins, are in general poor substrates, although differences between the classes of beta-lactamases have been observed: the order of effectiveness seems to be C greater than B greater than A. Certain class A and C beta-lactamases also catalyze phenylacetylglycyl transfer between phenylacetylglycyl depsipeptides and specific amino acid acceptors, a type of reaction hitherto identified more closely with D-alanyl-D-alanine transpeptidases than with beta-lactamases. Preliminary indications of an acyl-enzyme intermediate in these reactions have been obtained. These results support the suggestion [Tipper, D.J. and Strominger, J.L. (1965) Proc. Natl. Acad. Sci. USA 54, 1133-1141] that beta-lactamases are evolutionary descendants of bacterial cell wall D-alanyl-D-alanine transpeptidases. PMID:6424114

  20. Source diagnostic and weathering indicators of tar balls utilizing acyclic, polycyclic and S-heterocyclic components.

    PubMed

    Hegazi, A H; Andersson, J T; Abu-Elgheit, M A; El-Gayar, M Sh

    2004-05-01

    This study represents a forensic chemical analysis to define the liability for the coastal bitumens polluting the beaches of the Mediterranean city of Alexandria. Six tar balls collected from several locations along the coast of the city were analyzed for their acyclic and polycyclic hydrocarbons as well as sulfur heterocycles using GC/FID, GC/AED and gas chromatography/mass spectrometry techniques. The analysis of one Egyptian crude oil is also included as a possible source oil. The tar ball samples were at early stages of weathering. Based on the GC traces and biomarker signatures, the tar balls could be genetically different. One sample collected from the Eastern Harbor region appears to be a Bunker C type fuel produced from Egyptian crudes. The refining process has removed the low molecular weight components. On the other hand, the wide n-alkane distribution together with the absence of an unresolved complex mixture suggests that crude oils probably from tank washings, ballast discharges or accident spills from tankers could have contributed significantly to the other tar ball samples. The distribution of source specific hopane and sterane markers revealed that the tar samples probably originate from different oil fields. PMID:15051374

  1. In vitro susceptibility of fungi to acyclic inhibitors of 2,3-oxidosqualene cyclases.

    PubMed

    Airaudi, D; Ceruti, M; Bianco, C; Filipello Marchisio, V

    1996-01-01

    In the present study we determine the antifungal properties of two acyclic inhibitors of 2,3-oxidosqualene cyclases: 22,23-epoxy-2-aza-2,3-dihydrosqualene (EAS) and azasqualene alcohol (ASA). Fungistatic and fungicidal activity towards dermatophytes and other fungi involved in cutaneous and systemic infections was tested (48 isolates from 10 species). The tests were carried out by inoculating 10 microliters of mycelial homogenate in 1 ml of Sabouraud glucose liquid medium containing serial dilutions of 100 to 0.25 micrograms ml-1 of the substance. For each isolate, the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of both compounds were determined. EAS was more active (MIC range 1.5-25 micrograms ml-1) than ASA (MIC range 3-50 micrograms ml-1). At the highest concentration tested, EAS also showed fungicidal action towards some isolates of Trichophyton mentagrophytes, T. terrestre, Epidermophyton floccosum, Microsporum canis and Scopulariopsis brumptii. The most sensitive species was T. mentagrophytes, the most resistant T. rubrum. PMID:8786759

  2. Executive Summary of Ares V: Lunar Capabilities Concept Review Through Phase A-Cycle 3

    NASA Technical Reports Server (NTRS)

    Holladay, J. B.; Baggett, K. E.; Feldman, S. M.

    2011-01-01

    This Technical Memorandum (TM) was generated as an overall Ares V summary from the Lunar Capabilities Concept Review (LCCR) through Phase A-Cycle 3 (PA-C3) with the intent that it may be coupled with separately published appendices for a more detailed, integrated narrative. The Ares V has evolved from the initial point of departure (POD) 51.00.48 LCCR configuration to the current candidate POD, PA-C3D, and the family of vehicles concept that contains vehicles PA-C3A through H. The logical progression from concept to POD vehicles is summarized in this TM and captures the trade space and performance of each. The family-of-vehicles concept was assessed during PA-C3 and offered flexibility in the path forward with the ability to add options deemed appropriate. A description of each trade space is given in addition to a summary of each Ares V element. The Ares V contributions to a Mars campaign are also highlighted with the goal of introducing Ares V capabilities within the trade space. The assessment of the Ares V vehicle as it pertains to Mars missions remained locked to the architecture presented in Mars Design Reference Authorization 5.0 using the PA-C3D vehicle configuration to assess Mars transfer vehicle options, in-space EDS capabilities, docking adaptor and propellant transfer assessments, and lunar and Mars synergistic potential.

  3. Computer simulations of cyclic and acyclic cholinergic agonists: conformational search and molecular dynamics simulations.

    PubMed Central

    McGroddy, K A; Brady, J W; Oswald, R E

    1994-01-01

    Molecular dynamics simulations have been performed on aqueous solutions of two chemically similar nicotinic cholinergic agonists in order to compare their structural and dynamical differences. The cyclic 1,1-dimethyl-4-acetylpiperazinium iodide (HPIP) molecule was previously shown to be a strong agonist for nicotinic acetylcholine receptors (McGroddy et al., 1993), while the acyclic N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide (HTED) derivative is much less potent. These differences were expected to arise from differences in the solution structures and internal dynamics of the two molecules. HPIP was originally thought to be relatively rigid; however, molecular dynamics simulations suggest that the acetyl portion of the molecule undergoes significant ring dynamics on a psec timescale. The less constrained HTED molecule is relatively rigid, with only one transition observed about any of the major dihedrals in four 100 psec simulations, each started from a different conformation. The average structures obtained from the simulations are very similar to the starting minimized structure in each case, except for the HTED simulation where a single rotation about the N-C-C-N(+) backbone occurred. In each case, HTED had three to five more water molecules in its primary solvation shell than HPIP, indicating that differences in the energetics of desolvation before binding may partially explain the increased potency of HPIP as compared to HTED. Images FIGURE 1 FIGURE 2 PMID:8161685

  4. Amino acids of the Murchison meteorite. I - Six carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Gandy, W. E.; Pizzarello, S.

    1981-01-01

    Six of the seven chain isomers of six-carbon acyclic primary alpha-amino alkanoic acids (leucine isomers) have been either identified or confirmed in hot-water extracts of the Murchison meteorite using combined gas chromatography-mass spectrometry (GC-MS) and ion exchange chromatography. 2-Amino-2-ethylbutyric acid, 2-amino-2,3-dimethylbutyric acid, pseudoleucine, and 2-methylnorvaline were positively identified by GC-MS. These amino acids have not been previously reported to occur in natural materials and may be uniquely meteoritic in origin. The presence of leucine and isoleucine (including the diastereoisomer, alloisoleucine) was confirmed. Peaks corresponding to norleucine were seen by ion-exchange and gas chromatography but characteristic mass spectra were not obtained. The alpha-branched chain isomers in this series are quantitatively the most significant. These results are compared with literature data on amino acid synthesis by electrical discharge and Fischer-Tropsch-type catalysis. Neither model system produces an amino acid suite that is completely comparable to that found in the Murchison meteorite.

  5. Amino acids of the Murchison meteorite. III - Seven carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, John R.; Pizzarello, Sandra

    1986-01-01

    All of the eighteen possible seven-carbon acyclic primary alpha-amino alkanoic acids have been positively identified in a hot-water extract of the Murchison meteorite by the combined use of gas chromatography-mass spectrometry, ion exchange chromatography and reversed-phase chromatography. None of these amino acids has previously been found in meteorites or in any other natural material. They range in concentration from less than or equal to 0.5 to 5.3 nmol/g. Configuration assignments were made for 2-amino-3,4-dimethylpentanoic acid and allo-2-amino-3,4-dimethylpentanoic acid and the diasteromer ratio was determined. Fifty-five amino acids have now been positively identified in the Murchison meteorite, 36 of which are unknown in terrestrial materials. This unique suite of amino acids is characterized by the occurrence of all structural isomers within the two major classes of amino acids represented, by the predominance of branched chain isomers, and by an exponential decline in amount with increasing carbon chain length within homologous series. These characteristics of the Murchison amino acids are suggestive of synthesis before incorporation into a parent body.

  6. Flotation properties of some oxygen-containing compounds of the acyclic series

    SciTech Connect

    Shreider, E.M.; Para, S.F.; Galanov, M.E.; Trachik, T.L.; Lagutina, L.V.

    1981-01-01

    In the monatomic alcohols series, maximum flotation activity is reached at 6 to 8 carbon atoms in the radical. It was decided to investigate the reagent properties of some other substances containing hydroxyl radicals which have not previously been considered. Oxygen-containing compounds in the acyclic series were examined, including alcohols: I - ethanol, ethylene-glycol, glycerol, pentaerythrytol, D-mannitol; II - dulcitol, D-sorbitol, D-mannitol, xylitol; glycols - monoethyleneglycol, diethyleneglycol, triethyleneglycol, polyethyleneglycol; and ethanolamines - ethanolamine, triethanolamine. The flotation properties of the reagents were determined in a Mekhanobr laboratory flotation machine with a chamber volume of 1.5 liter and an impeller speed of 1800 rpm. The materials tested were the <1 mm size fractions from run-of-plant charge and slurry from the radial thickeners. The samples were first dried and averaged. The pulp density was 200 g/l. The reagent conditions were kept constant throughout (50% of the total added at the start of a test, 25% after 2 min and 25% after 4 min from the start). The reagent additions were 1.0 to 1.4 kg/ton. All of these compounds had a very weak flotation activity.

  7. Polarizable Empirical Force Field for Acyclic Poly-Alcohols Based on the Classical Drude Oscillator

    PubMed Central

    He, Xibing; Lopes, Pedro E. M.; MacKerell, Alexander D.

    2014-01-01

    A polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator is presented. The model is optimized with an emphasis on the transferability of the developed parameters among molecules of different sizes in this series and on the condensed-phase properties validated against experimental data. The importance of the explicit treatment of electronic polarizability in empirical force fields is demonstrated in the cases of this series of molecules with vicinal hydroxyl groups that can form cooperative intra- and intermolecular hydrogen bonds. Compared to the CHARMM additive force field, improved treatment of the electrostatic interactions avoids overestimation of the gas-phase dipole moments, results in significant improvement in the treatment of the conformational energies, and leads to the correct balance of intra- and intermolecular hydrogen bonding of glycerol as evidenced by calculated heat of vaporization being in excellent agreement with experiment. Computed condensed phase data, including crystal lattice parameters and volumes and densities of aqueous solutions are in better agreement with experimental data as compared to the corresponding additive model. Such improvements are anticipated to significantly improve the treatment of polymers in general, including biological macromolecules. PMID:23703219

  8. Analytic Bounds on Causal Risk Differences in Directed Acyclic Graphs Involving Three Observed Binary Variables

    PubMed Central

    Kaufman, Sol; Kaufman, Jay S.; MacLehose, Richard F.

    2009-01-01

    We apply a linear programming approach which uses the causal risk difference (RDC) as the objective function and provides minimum and maximum values that RDC can achieve under any set of linear constraints on the potential response type distribution. We consider two scenarios involving binary exposure X, covariate Z and outcome Y. In the first, Z is not affected by X, and is a potential confounder of the causal effect of X on Y. In the second, Z is affected by X and intermediate in the causal pathway between X and Y. For each scenario we consider various linear constraints corresponding to the presence or absence of arcs in the associated directed acyclic graph (DAG), monotonicity assumptions, and presence or absence of additive-scale interactions. We also estimate Z-stratum-specific bounds when Z is a potential effect measure modifier and bounds for both controlled and natural direct effects when Z is affected by X. In the absence of any additional constraints deriving from background knowledge, the well-known bounds on RDc are duplicated: −Pr(Y≠X) ≤ RDC ≤ Pr(Y=X). These bounds have unit width, but can be narrowed by background knowledge-based assumptions. We provide and compare bounds and bound widths for various combinations of assumptions in the two scenarios and apply these bounds to real data from two studies. PMID:20161106

  9. Phosphonylated Acyclic Guanosine Analogues with the 1,2,3-Triazole Linker.

    PubMed

    Głowacka, Iwona E; Andrei, Graciela; Schols, Dominique; Snoeck, Robert; Piotrowska, Dorota G

    2015-01-01

    A novel series of {4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates and {4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates as acyclic analogues of guanosine were synthesized and assessed for antiviral activity against a broad range of DNA and RNA viruses and for their cytostatic activity toward three cancerous cell lines (HeLa, L1210 and CEM). They were devoid of antiviral activity; however, several phosphonates were found slightly cytostatic against HeLa cells at an IC50 in the 80-210 µM range. Compounds (1R,2S)-17k and (1S,2S)-17k showed the highest inhibitory effects (IC50=15-30 µM) against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines. PMID:26501246

  10. New Proton-Ionizable, Calixarene-Based Ligands for Selective Metal Ion Separations

    SciTech Connect

    Bartsch, Richard A.

    2012-06-04

    The project objective was the discovery of new ligands for performing metal ion separations. The research effort entailed the preparation of new metal ion complexing agents and polymers and their evaluation in metal ion separation processes of solvent extraction, synthetic liquid membrane transport, and sorption. Structural variations in acyclic, cyclic, and bicyclic organic ligands were used to probe their influence upon the efficiency and selectivity with which metal ion separations can be performed. A unifying feature of the ligand structures is the presence of one (or more) side arm with a pendent acidic function. When a metal ion is complexed within the central cavity of the ligand, ionization of the side arm(s) produces the requisite anion(s) for formation of an overall electroneutral complex. This markedly enhances extraction/transport efficiency for separations in which movement of aqueous phase anions of chloride, nitrate, or sulfate into an organic medium would be required. Through systematic structural variations, new ligands have been developed for efficient and selective separations of monovalent metal ions (e.g., alkali metal, silver, and thallium cations) and of divalent metal ion species (e.g., alkaline earth metal, lead, and mercury cations). Research results obtained in these fundamental investigations provide important insight for the design and development of ligands suitable for practical metal ion separation applications.

  11. Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands

    PubMed Central

    Abou-Hussein, Azza A.; Linert, Wolfgang

    2014-01-01

    Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet–visible spectra, as well as 1H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, 1H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms. PMID:24070648

  12. Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, Azza A.; Linert, Wolfgang

    2014-01-01

    Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet-visible spectra, as well as 1H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, 1H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms.

  13. Alteration in substrate specificity of horse liver alcohol dehydrogenase by an acyclic nicotinamide analog of NAD(+).

    PubMed

    Malver, Olaf; Sebastian, Mina J; Oppenheimer, Norman J

    2014-11-01

    A new, acyclic NAD-analog, acycloNAD(+) has been synthesized where the nicotinamide ribosyl moiety has been replaced by the nicotinamide (2-hydroxyethoxy)methyl moiety. The chemical properties of this analog are comparable to those of β-NAD(+) with a redox potential of -324mV and a 341nm λmax for the reduced form. Both yeast alcohol dehydrogenase (YADH) and horse liver alcohol dehydrogenase (HLADH) catalyze the reduction of acycloNAD(+) by primary alcohols. With HLADH 1-butanol has the highest Vmax at 49% that of β-NAD(+). The primary deuterium kinetic isotope effect is greater than 3 indicating a significant contribution to the rate limiting step from cleavage of the carbon-hydrogen bond. The stereochemistry of the hydride transfer in the oxidation of stereospecifically deuterium labeled n-butanol is identical to that for the reaction with β-NAD(+). In contrast to the activity toward primary alcohols there is no detectable reduction of acycloNAD(+) by secondary alcohols with HLADH although these alcohols serve as competitive inhibitors. The net effect is that acycloNAD(+) has converted horse liver ADH from a broad spectrum alcohol dehydrogenase, capable of utilizing either primary or secondary alcohols, into an exclusively primary alcohol dehydrogenase. This is the first example of an NAD analog that alters the substrate specificity of a dehydrogenase and, like site-directed mutagenesis of proteins, establishes that modifications of the coenzyme distance from the active site can be used to alter enzyme function and substrate specificity. These and other results, including the activity with α-NADH, clearly demonstrate the promiscuity of the binding interactions between dehydrogenases and the riboside phosphate of the nicotinamide moiety, thus greatly expanding the possibilities for the design of analogs and inhibitors of specific dehydrogenases. PMID:25280628

  14. Cell Tracking Accuracy Measurement Based on Comparison of Acyclic Oriented Graphs.

    PubMed

    Matula, Pavel; Maška, Martin; Sorokin, Dmitry V; Matula, Petr; Ortiz-de-Solórzano, Carlos; Kozubek, Michal

    2015-01-01

    Tracking motile cells in time-lapse series is challenging and is required in many biomedical applications. Cell tracks can be mathematically represented as acyclic oriented graphs. Their vertices describe the spatio-temporal locations of individual cells, whereas the edges represent temporal relationships between them. Such a representation maintains the knowledge of all important cellular events within a captured field of view, such as migration, division, death, and transit through the field of view. The increasing number of cell tracking algorithms calls for comparison of their performance. However, the lack of a standardized cell tracking accuracy measure makes the comparison impracticable. This paper defines and evaluates an accuracy measure for objective and systematic benchmarking of cell tracking algorithms. The measure assumes the existence of a ground-truth reference, and assesses how difficult it is to transform a computed graph into the reference one. The difficulty is measured as a weighted sum of the lowest number of graph operations, such as split, delete, and add a vertex and delete, add, and alter the semantics of an edge, needed to make the graphs identical. The measure behavior is extensively analyzed based on the tracking results provided by the participants of the first Cell Tracking Challenge hosted by the 2013 IEEE International Symposium on Biomedical Imaging. We demonstrate the robustness and stability of the measure against small changes in the choice of weights for diverse cell tracking algorithms and fluorescence microscopy datasets. As the measure penalizes all possible errors in the tracking results and is easy to compute, it may especially help developers and analysts to tune their algorithms according to their needs. PMID:26683608

  15. Cell Tracking Accuracy Measurement Based on Comparison of Acyclic Oriented Graphs

    PubMed Central

    Sorokin, Dmitry V.; Matula, Petr; Ortiz-de-Solórzano, Carlos; Kozubek, Michal

    2015-01-01

    Tracking motile cells in time-lapse series is challenging and is required in many biomedical applications. Cell tracks can be mathematically represented as acyclic oriented graphs. Their vertices describe the spatio-temporal locations of individual cells, whereas the edges represent temporal relationships between them. Such a representation maintains the knowledge of all important cellular events within a captured field of view, such as migration, division, death, and transit through the field of view. The increasing number of cell tracking algorithms calls for comparison of their performance. However, the lack of a standardized cell tracking accuracy measure makes the comparison impracticable. This paper defines and evaluates an accuracy measure for objective and systematic benchmarking of cell tracking algorithms. The measure assumes the existence of a ground-truth reference, and assesses how difficult it is to transform a computed graph into the reference one. The difficulty is measured as a weighted sum of the lowest number of graph operations, such as split, delete, and add a vertex and delete, add, and alter the semantics of an edge, needed to make the graphs identical. The measure behavior is extensively analyzed based on the tracking results provided by the participants of the first Cell Tracking Challenge hosted by the 2013 IEEE International Symposium on Biomedical Imaging. We demonstrate the robustness and stability of the measure against small changes in the choice of weights for diverse cell tracking algorithms and fluorescence microscopy datasets. As the measure penalizes all possible errors in the tracking results and is easy to compute, it may especially help developers and analysts to tune their algorithms according to their needs. PMID:26683608

  16. Structural and thermodiffractometric analysis of coordination polymers. Part I: tin derivatives of the Bim ligand [Bim = Bis(1-imidazolyl)methane]).

    PubMed

    Masciocchi, Norberto; Pettinari, Claudio; Alberti, Enrica; Pettinari, Riccardo; Nicola, Corrado Di; Albisetti, Alessandro Figini; Sironi, Angelo

    2007-12-10

    New polynuclear coordination species containing the ditopic bis(1-imidazolyl)methane (Bim) ligand have been prepared as microcrystalline powders and structurally characterized by ab initio X-ray powder diffraction methods. [Bim(Me2SnCl2)]n (1), [Bim(nBu2SnCl2)]n (3), [Bim(Ph2SnCl2)]n (4), [Bim(MeSnCl3)]n (5), and [Bim(PhSnCl3)]n (6) all contain 1D chains with octahedral tin atoms with trans N-Sn-N linkages (but 4, which displays a cis N-Sn-N linkage). Their thermodiffractometric analysis allowed the estimation of the linear thermal expansion coefficients and strain tensors derived there from. The potential-energy surface of the free Bim ligand (as defined by two torsional degrees of freedom about the two N-CH2 bonds), eventually controlling the length of the repeating unit (polymer elongation), has been estimated using molecular mechanics and correlated with experimental observations. PMID:18001118

  17. Acyclic CB[n]-Type Molecular Containers: Effect of Solubilizing Group on their Function as Solubilizing Excipients

    PubMed Central

    Zhang, Ben; Zavalij, Peter Y.; Isaacs, Lyle

    2014-01-01

    We report the synthesis and x-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The x-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion-dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion-ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α–ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents. PMID:24595500

  18. Amino acids of the Murchison meteorite. II - Five carbon acyclic primary beta-, gamma-, and delta-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Pizzarello, S.; Yuen, G. U.

    1985-01-01

    The five-carbon acyclic primary beta, gamma, and delta amino alkanoic acids of the Murchison meteorite are studied using gas chromatography-mass spectrometry and ion exchange chromatography. The chromatograms reveal that alpha is the most abundant monoamino alkanoic acid followed by gamma and beta, and an exponential increase in the amount of amino acid is observed as the carbon number increases in the homologous series. The influence of frictional heating, spontaneous thermal decomposition, and radiation of the synthesis of amino acids is examined. The data obtained support an amino acid synthesis process involving random combination of single-carbon precursors.

  19. The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells

    PubMed Central

    Qin, Xian-Yang; Wei, Feifei; Tanokura, Masaru; Ishibashi, Naoto; Shimizu, Masahito; Moriwaki, Hisataka; Kojima, Soichi

    2013-01-01

    Background/Purpose Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. Methodology/Principal Findings NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5′-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively). Conclusions/Significance The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in

  20. Metal-ligand cooperation.

    PubMed

    Khusnutdinova, Julia R; Milstein, David

    2015-10-12

    Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed. PMID:26436516

  1. Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases.

    PubMed

    Kaiser, Martin M; Hocková, Dana; Wang, Tzu-Hsuan; Dračínský, Martin; Poštová-Slavětínská, Lenka; Procházková, Eliška; Edstein, Michael D; Chavchich, Marina; Keough, Dianne T; Guddat, Luke W; Janeba, Zlatko

    2015-10-01

    Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG. PMID:26368337

  2. A new class of acyclic nucleoside phosphonates: synthesis and biological activity of 9-[[(phosphonomethyl)aziridin-1-yl]methyl]guanine (PMAMG) and analogues.

    PubMed

    Abu Sheikha, Ghassan; La Colla, Paolo; Loi, Anna Giulia

    2002-10-01

    A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl

  3. Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives

    PubMed Central

    Masuno, Hiroyuki; Ikura, Teikichi; Morizono, Daisuke; Orita, Isamu; Yamada, Sachiko; Shimizu, Masato; Ito, Nobutoshi

    2013-01-01

    The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR), although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3)]. Here, we have determined the crystal structures of the ligand-binding domain of rat VDR (VDR-LBD) in ternary complexes with a synthetic partial peptide of the coactivator MED1 (mediator of RNA polymerase II transcription subunit 1) and four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, with the goal of elucidating their agonistic mechanism. LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR-LBD that 1,25(OH)2D3 binds to, but in the opposite orientation; their A-ring is positioned at the top of the LBP, whereas their acyclic tail is located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions observed in the complex with 1,25(OH)2D3 are reproduced in the complexes with LCA and its derivatives. Additional interactions between VDR-LBD and the C-3 substituents of the A-ring are also observed in the complexes with LCA and its derivatives. These may result in the observed difference in the potency among the LCA-type ligands. PMID:23723390

  4. Recurrence of hyperprolactinemia and continuation of ovarian acyclicity in captive African elephants (Loxodonta africana) treated with cabergoline.

    PubMed

    Morfeld, Kari A; Ball, Ray L; Brown, Janine L

    2014-09-01

    Hyperprolactinemia is associated with reproductive acyclicity in zoo African elephants (Loxodonta africana) and may contribute to the non-self-sustainability of the captive population in North America. It is a common cause of infertility in women and other mammals and can be treated with the dopamine agonist cabergoline. The objectives of this study were to assess prolactin responses to cabergoline treatment in hyperprolactinemic, acyclic African elephants and to determine the subsequent impact on ovarian cyclic activity. Five elephants, diagnosed as hyperprolactinemic (>11 ng/ml prolactin) and acyclic (maintenance of baseline progestagens for at least 1 yr), were treated with 1-2 mg cabergoline orally twice weekly for 16-82 wk. Cabergoline reduced (P < 0.05) serum prolactin concentrations during the treatment period compared to pretreatment levels in four of five elephants (11.5 +/- 3.2 vs. 9.1 +/- 3.4 ng/ml; 20.3 +/- 16.7 vs. 7.9 +/- 9.8 ng/ml; 26.4 +/- 15.0 vs. 6.8 +/- 1.5 ng/ml; 42.2 +/- 22.6 vs. 18.6 +/- 8.9 ng/ml). However, none of the females resumed ovarian cyclicity based on serum progestagen analyses up to 1 yr posttreatment. In addition, within 1 to 6 wk after cessation of oral cabergoline, serum prolactin concentrations returned to concentrations that were as high as or higher than before treatment (P < 0.05). One elephant that exhibited the highest pretreatment prolactin concentration (75.2 +/- 10.5 ng/ml) did not respond to cabergoline and maintained elevated levels throughout the study. Thus, oral cabergoline administration reduced prolactin concentrations in elephants with hyperprolactinemia, but there was no resumption of ovarian cyclicity, and a significant prolactin rebound effect was observed. It is possible that higher doses or longer treatment intervals may be required for cabergoline treatment to result in permanent suppression of prolactin secretion and to mitigate associated ovarian cycle problems. PMID:25314824

  5. Ligand modeling and design

    SciTech Connect

    Hay, B.P.

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  6. Synthesis and antiviral activity of novel acyclic nucleoside analogues of 5-(1-azido-2-haloethyl)uracils.

    PubMed

    Kumar, R; Sharma, N; Nath, M; Saffran, H A; Tyrrell, D L

    2001-11-22

    We present the discovery of a novel category of 5-substituted acyclic pyrimidine nucleosides as potent antiviral agents. A series of 1-[(2-hydroxyethoxy)methyl] (5-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] (8-10), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl] (11-13) derivatives of 5-(1-azido-2-haloethyl)uracil were synthesized and evaluated for their biological activity in cell culture. 1-[4-Hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azido-2-chloroethyl)uracil (12) was the most effective antiviral agent in the in vitro assays against DHBV (EC(50) = 0.31-1.55 microM) and HCMV (EC(50) = 3.1 microM). None of the compounds investigated showed any detectable toxicity to several stationary and proliferating host cells. PMID:11708924

  7. On the strong difference in reactivity of acyclic and cyclic diazodiketones with thioketones: experimental results and quantum-chemical interpretation

    PubMed Central

    Mereshchenko, Andrey S; Ivanov, Alexey V; Baranovskii, Viktor I; Rodina, Ludmila L

    2015-01-01

    Summary The 1,3-dipolar cycloaddition of acyclic 2-diazo-1,3-dicarbonyl compounds (DDC) and thioketones preferably occurs with Z,E-conformers and leads to the formation of transient thiocarbonyl ylides in two stages. The thermodynamically favorable further transformation of C=S ylides bearing at least one acyl group is identified as the 1,5-electrocyclization into 1,3-oxathioles. However, in the case of diazomalonates, the dominating process is 1,3-cyclization into thiiranes followed by their spontaneous desulfurization yielding the corresponding alkenes. Finally, carbocyclic diazodiketones are much less reactive under similar conditions due to the locked cyclic structure and are unfavorable for the 1,3-dipolar cycloaddition due to the Z,Z-conformation of the diazo molecule. This structure results in high, positive values of the Gibbs free energy change for the first stage of the cycloaddition process. PMID:25977725

  8. Synthesis, characterization, X-ray structure and photoluminescence properties of two Ce(III) complexes derived from pentadentate ligands

    NASA Astrophysics Data System (ADS)

    Köse, Muhammet; Akgün, Eyup; Ceyhan, Gökhan

    2015-12-01

    In this study, two new Ce(III) complexes [Ce(L1)(NO3)3]•H2O and [Ce(L2)(NO3)3]•H2O were synthesized and characterized by spectroscopic and analytical methods where L1 and L2 are pentadentate diimine ligands. Molecular structure of [Ce(L1)(NO3)3]•H2O was determined by single crystal X-ray diffraction study. The complex was found to crystallize as [Ce(L1)(NO3)3] H2O. In the complex, the ligand L1 coordinates to the Ce(III) ion with the N3O2 donor set and the Ce(III) ion sits within the cavity of acyclic ligand. The Ce(III) ion is 11-coordinated by three nitrogen atoms from the ligand and eight O atoms, six of which come from three nitrate ions, two from the ligand. In the structure of the complex, water molecules link molecules together to form a 3D hydrogen bond network. Thermal behavior of the Schiff base ligands and their Ce(III) complexes metal complexes were studied under nitrogen atmosphere in the temperature range of 20-800 °C. Thermal stability of the ligands increased upon complexation with Ce(III) ion. In the UV-Vis spectra of Ce(III) complexes, new absorption bands appeared at 340-450 nm and these new bands were attributed to metal-ligand (M-L) charge transitions. Photoluminescence properties of the ligands and their Ce(III) complexes were examined.

  9. Ligand modeling and design

    SciTech Connect

    Hay, B.

    1996-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used tin applications for the cost-effective removal of specific radionuclides from nuclear waste streams.

  10. Dinuclear gold(I) complexes of bridging bidentate carbene ligands: synthesis, structure and spectroscopic characterisation.

    PubMed

    Barnard, Peter J; Baker, Murray V; Berners-Price, Susan J; Skelton, Brian W; White, Allan H

    2004-04-01

    Eight dinuclear Au(i)-carbene complexes have been synthesized from various imidazolium-linked cyclophanes and related acyclic bis(imidazolium) salts, by treatment of the imidazolium salts with [Au(i)(SMe(2))Cl] in the presence of a carboxylate base. Single crystal structural studies showed that the Au(i)-carbene compounds contain dinuclear (AuL)(2) cations in which a pair of gold(i) centres are linked by a pair of bridging dicarbenoid ligands. Interestingly, the structural studies revealed short AuAu contacts of 3.0485(3)[Angstrom] and 3.5425(6)[Angstrom] in two of these complexes. NMR studies showed that the (AuL)(2) cations constructed from the cyclophane-based ligands retain a relatively rigid structure in solution, whilst those of the non-cyclophane ligand systems are fluxional in solution. The electronic absorption and emission spectra of the complexes in solution at room temperature were recorded and the complex with the shortest AuAu contact was found to emit intensely at 400 nm and more weakly at 780 nm upon excitation at 260 nm. The compounds with longer AuAu separations were not emissive under these conditions. PMID:15252682

  11. The role of minerals in the thermal alteration of organic matter. IV - Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments

    NASA Technical Reports Server (NTRS)

    Huizinga, Bradley J.; Tannenbaum, Eli; Kaplan, Isaac R.

    1987-01-01

    The effect of common sedimentary minerals (illite, Na-montmorillonite, or calcite) under different water concentrations on the generation and release of n-alkanes, acyclic isoprenoids, and select alkenes from oil-prone kerogens was investigated. Matrices containing Green River Formation kerogen or Monterey Formation kerogen, alone or in the presence of minerals, were heated at 200 or 300 C for periods of up to 1000 hours, and the pyrolysis products were analyzed. The influence of the first two clay minerals was found to be critically dependent on the water content. Under the dry pyrolysis conditions, both minerals significantly reduced alkene formation; the C12+ n-alkanes and acyclic isoprenoids were mostly destroyed by montmorillonite, but underwent only minor alteration with illite. Under hydrous conditions (mineral/water of 2/1), the effects of both minerals were substantially reduced. Calcite had no significant effect on the thermal evolution of the hydrocarbons.

  12. Effect of electron-donor ancillary ligands on the heteroleptic ruthenium complexes: synthesis, characterization, and application in high-performance dye-sensitized solar cells.

    PubMed

    Chen, Wang-Chao; Kong, Fan-Tai; Liu, Xue-Peng; Guo, Fu-Ling; Zhou, Li; Ding, Yong; Li, Zhao-Qian; Dai, Song-Yuan

    2016-04-20

    Three heteroleptic ruthenium complexes, , and , with sulfur- or oxygen-containing electron-donor, phenylpyridine-based ancillary ligands, are synthesized. The influence of the different electron donors-the acyclic electron donors methylthio and methoxyl, and the cyclic electron donor methylenedioxy-on the photophysical and electrochemical behavior in dye sensitizers and photovoltaic performance in DSSCs are investigated. Compared to the conventional dye , all the dyes demonstrate superior performance in the form of molar absorptivity, photocurrent density (JSC) and conversion efficiency (η). The DSSCs based on and , with only a two-atom change in the acyclic electron donor, exhibit analogous photovoltaic performance (9.28% for and 9.32% for ). The highest photocurrent density (19.06 mA cm(-2)) and conversion efficiency (9.74%) are recorded for , which contains the cyclic electron donor. Transient absorption (TAS) and time-resolved photoluminescence (TRPL) measurements are carried out to investigate the sensitizers' regeneration and the behavior of excited electron decay kinetics. Furthermore, electrochemical impedance spectroscopy (EIS) is operated to explain the charge recombination and the electron lifetime. These consequences reveal substantial dependences on the different configurations of the electron-donor ancillary ligands. PMID:27053153

  13. Phenylalanine Ammonia-Lyase-Catalyzed Deamination of an Acyclic Amino Acid: Enzyme Mechanistic Studies Aided by a Novel Microreactor Filled with Magnetic Nanoparticles.

    PubMed

    Weiser, Diána; Bencze, László Csaba; Bánóczi, Gergely; Ender, Ferenc; Kiss, Róbert; Kókai, Eszter; Szilágyi, András; Vértessy, Beáta G; Farkas, Ödön; Paizs, Csaba; Poppe, László

    2015-11-01

    Phenylalanine ammonia-lyase (PAL), found in many organisms, catalyzes the deamination of l-phenylalanine (Phe) to (E)-cinnamate by the aid of its MIO prosthetic group. By using PAL immobilized on magnetic nanoparticles and fixed in a microfluidic reactor with an in-line UV detector, we demonstrated that PAL can catalyze ammonia elimination from the acyclic propargylglycine (PG) to yield (E)-pent-2-ene-4-ynoate. This highlights new opportunities to extend MIO enzymes towards acyclic substrates. As PG is acyclic, its deamination cannot involve a Friedel-Crafts-type attack at an aromatic ring. The reversibility of the PAL reaction, demonstrated by the ammonia addition to (E)-pent-2-ene-4-ynoate yielding enantiopure l-PG, contradicts the proposed highly exothermic single-step mechanism. Computations with the QM/MM models of the N-MIO intermediates from L-PG and L-Phe in PAL show similar arrangements within the active site, thus supporting a mechanism via the N-MIO intermediate. PMID:26345352

  14. Design and synthesis of novel 5-substituted acyclic pyrimidine nucleosides as potent and selective inhibitors of hepatitis B virus.

    PubMed

    Kumar, Rakesh; Nath, Mahendra; Tyrrell, D Lorne J

    2002-05-01

    A novel class of 5-substituted acyclic pyrimidine nucleosides, 1-[(2-hydroxyethoxy)methyl]-5-(1-azidovinyl)uracil (9a), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-(1-azidovinyl)uracil (9b), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azidovinyl)uracil (9c), were synthesized by regiospecific addition of bromine azide to the 5-vinyl substituent of the respective 5-vinyluracils (2a-c) followed by treatment of the obtained 5-(1-azido-2-bromoethyl) compounds (3a-c) with t-BuOK, to affect the base-catalyzed elimination of HBr. Thermal decomposition of 9b and 9c at 110 degrees C in dioxane yielded corresponding 5-[2-(1-azirinyl)]uracil analogues (10b,c). The 5-(1-azidovinyl)uracil derivatives 9a-c were found to exhibit potent and selective in vitro anti-HBV activity against duck hepatitis B virus (DHBV) infected primary duck hepatocytes at low concentrations (EC(50) = 0.01-0.1 microg/mL range). The most active anti-DHBV agent (9c), possessing a [4-hydroxy-3-(hydroxymethyl)-1-butyl] substituent at N-1, exhibited an activity (EC(50) of 0.01-0.05 microg/mL) comparable to that of reference compound (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3-TC) (EC(50) = 0.01-0.05 microg/mL). In contrast, related 5-[2-(1-azirinyl)]uracil analogues (10b,c) were devoid of anti-DHBV activity, indicating that an acyclic side chain at C-5 position of the pyrimidine ring is essential for anti-HBV activity. The pyrimidine nucleosides (9a-c, 10b,c) exhibited no cytotoxic activity against a panel of 60 human cancer cell lines. All of the compounds investigated did not show any detectable toxicity to several stationary and proliferating host cell lines or to mitogen stimulated proliferating human T lymphocytes, up to the highest concentration tested. PMID:11985471

  15. Analysis of cyclic and acyclic nicotinic cholinergic agonists using radioligand binding, single channel recording, and nuclear magnetic resonance spectroscopy.

    PubMed Central

    McGroddy, K A; Carter, A A; Tubbert, M M; Oswald, R E

    1993-01-01

    The relationship between the structure and function of a series of nicotinic cholinergic agonists has been studied using radioligand binding, single channel recording, and nuclear magnetic resonance spectroscopy. The cyclic compound 1,1-dimethyl-4-acetylpiperazinium iodide and its trifluoromethyl analogue (F3-PIP) interact with nicotinic acetylcholine receptors (nAChRs) from both Torpedo electroplaque and BC3H-1 cells at lower concentrations than the acyclic derivatives, N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide and its fluorinated analogue (F3-TED). The magnitude of the difference in potencies depends on the type of measurement. In binding experiments, the differences between the two classes of compounds depends mainly on the conditions of the experiment. In measurements of the initial interaction with the nAChR, the PIP compounds have an affinity approximately one order of magnitude higher than that of the TED compounds. Longer incubations indicated that the PIP compounds were able to induce a time-dependent shift in receptor affinity consistent with desensitization, whereas the TED compounds were unable to induce such a shift. The activation of single channel currents by the cyclic compounds occurs at concentrations approximately two orders of magnitude lower than for the acyclic compounds, but the TED compounds exhibit a larger degree of channel blockade than the PIP compounds. Previous work (McGroddy, K.A., and R.E. Oswald. 1992. Biophys. J. 64:314-324) has shown that the TED compounds can exist in two energetically distinct conformational states related by an isomerization of the amide bond. 19F nuclear magnetic resonance experiments suggest that the higher energy population of the TED compounds may interact preferentially with the ACh binding sites on the nAChRs and that a significant fraction of the difference between the initial affinity of the PIP and TED compounds may be accounted for by the predominance in solution of a conformational state

  16. Enzymatic synthesis of acyclic nucleoside thiophosphonate diphosphates: effect of the α-phosphorus configuration on HIV-1 RT activity.

    PubMed

    Priet, Stéphane; Roux, Loic; Saez-Ayala, Magali; Ferron, François; Canard, Bruno; Alvarez, Karine

    2015-05-01

    The acyclic nucleosides thiophosphonates (9-[2-(thiophosphonomethoxy)ethyl]adenine (S-PMEA) and (R)-9-[2-(thiophosphonomethoxy)propyl]adenine (S-PMPA), exhibit antiviral activity against HIV-1, -2 and HBV. Their diphosphate forms S-PMEApp and S-PMPApp, synthesized as stereoisomeric mixture, are potent inhibitors of wild-type (WT) HIV-1 RT. Understanding HIV-1 RT stereoselectivity, however, awaits resolution of the diphosphate forms into defined stereoisomers. To this aim, thiophosphonate monophosphates S-PMEAp and S-PMPAp were synthesized and used in a stereocontrolled enzyme-catalyzed phosphoryl transfer reaction involving either nucleoside diphosphate kinase (NDPK) or creatine kinase (CK) to obtain thiophosphonate diphosphates as separated isomers. We then quantified substrate preference of recombinant WT HIV-1 RT toward pure stereoisomers using in vitro steady-state kinetic analyses. The crystal structure of a complex between Dictyostelium NDPK and S-PMPApp at 2.32Å allowed to determine the absolute configuration at the α-phosphorus atom in relation to the stereo-preference of studied enzymes. The RP isomer of S-PMPApp and S-PMEApp are the preferred substrate over SP for both NDPK and HIV-1 RT. PMID:25766862

  17. 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

  18. Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells

    PubMed Central

    Shrestha, R; Tatsukawa, H; Shrestha, R; Ishibashi, N; Matsuura, T; Kagechika, H; Kose, S; Hitomi, K; Imamoto, N; Kojima, S

    2015-01-01

    Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2-dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) 466AEKEETGMAMRIRV479 in the ‘C' domain and a leucine-rich nuclear export signal (NES) 657LHMGLHKL664 in the ‘D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-α and importin-β independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR. PMID:26633708

  19. Acyclic monoterpene primary alcohol:NADP+ oxidoreductase of Rauwolfia serpentina cells: the key enzyme in biosynthesis of monoterpene alcohols.

    PubMed

    Ikeda, H; Esaki, N; Nakai, S; Hashimoto, K; Uesato, S; Soda, K; Fujita, T

    1991-02-01

    Acyclic monoterpene primary alcohol:NADP+ oxidoreductase, a key enzyme in the biosynthesis of monoterpene alcohols in plants, is unstable and has been only poorly characterized. However we have established conditions which stabilize the enzyme from Rauwolfia serpentina cells, and then purified it to homogeneity. It is a monomer with a molecular weight of about 44,000 and contains zinc ions. Various branched-chain allylic primary alcohols such as nerol, geraniol, and 10-hydroxygeraniol were substrates, but ethanol was inert. The enzyme exclusively requires NADP+ or NADPH as the cofactor. Steady-state kinetic studies showed that the nerol dehydrogenation proceeds by an ordered Bi-Bi mechanism. NADP+ binds the enzyme first and then NADPH is the second product released from it. Gas chromatography-mass spectrometric analysis of the reaction products showed that 10-hydroxygeraniol undergoes a reversible dehydrogenation to produce 10-oxogeraniol or 10-hydroxygeranial, which are oxidized further to give 10-oxogeranial, the direct precursor of iridodial. The enzyme has been found to exclusively transfer the pro-R hydrogen of NADPH to neral. The N-terminal sequence of the first 21 amino acids revealed no significant homology with those of various other proteins including the NAD(P)(+)-dependent alcohol dehydrogenases registered in a protein data bank. PMID:1864846

  20. Intramolecular OH⋅⋅⋅Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif

    PubMed Central

    Linclau, Bruno; Peron, Florent; Bogdan, Elena; Wells, Neil; Wang, Zhong; Compain, Guillaume; Fontenelle, Clement Q; Galland, Nicolas; LeQuestel, Jean-Yves; Graton, Jérôme

    2015-01-01

    Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design. PMID:26494542

  1. LigandRNA: computational predictor of RNA–ligand interactions

    PubMed Central

    Philips, Anna; Milanowska, Kaja; Łach, Grzegorz; Bujnicki, Janusz M.

    2013-01-01

    RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA–small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA–ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a “meta-predictor” leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl. PMID:24145824

  2. Analysis of macromolecules, ligands and macromolecule-ligand complexes

    DOEpatents

    Von Dreele, Robert B.

    2008-12-23

    A method for determining atomic level structures of macromolecule-ligand complexes through high-resolution powder diffraction analysis and a method for providing suitable microcrystalline powder for diffraction analysis are provided. In one embodiment, powder diffraction data is collected from samples of polycrystalline macromolecule and macromolecule-ligand complex and the refined structure of the macromolecule is used as an approximate model for a combined Rietveld and stereochemical restraint refinement of the macromolecule-ligand complex. A difference Fourier map is calculated and the ligand position and points of interaction between the atoms of the macromolecule and the atoms of the ligand can be deduced and visualized. A suitable polycrystalline sample of macromolecule-ligand complex can be produced by physically agitating a mixture of lyophilized macromolecule, ligand and a solvent.

  3. EGF receptor ligands: recent advances

    PubMed Central

    Singh, Bhuminder; Carpenter, Graham; Coffey, Robert J.

    2016-01-01

    Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR.

  4. New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects.

    PubMed

    Muñoz Acuña, Ulyana; Carcache, Peter J Blanco; Matthew, Susan; Carcache de Blanco, Esperanza J

    2016-07-01

    The bioassay-guided fractionation of the aril of Myristica fragrans (mace spice) yielded five phenolic compounds, one new acyclic bis phenylpropanoid (1) and four previously known phenolic compounds: compounds (1) (S) 1-(3,4,5-trimethoxyphenyl)-2-(3-methoxy-5-(prop-1-yl) phenyl)-propan-1-ol, (2) benzenemethanol; α-[1-[2,6-dimethoxy-4-(2-propen-1-yl)phenoxy]ethyl]-3,4-dimethoxy-1-acetate, (3) odoratisol A, phenol, 4-[(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-propenyl-2-benzofuranyl]-2,6-dimethoxy, (4) 1,3-benzodioxate-5-methanol,α-[1-[2,6-dimethoxy-4-(2-propenyl)phenoxy]ethyl]-acetate, (5) licarin C; benzofuran,2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-yl-2-(3,4,5-trimethoxyphenyl). An NMR tube Mosher ester reaction was used in an approach to characterize and determine the assignment of the absolute configuration of the new isolated chiral alcohol (1). The PARP-1 inhibitory activity was evaluated for compound (1) (IC50=3.04μM), compound (2) (IC50=0.001μM), compound (4) (IC50=22.07μM) and compound (5) (IC50=3.11μM). Furthermore, the isolated secondary metabolites were tested for NF-κB and K-Ras inhibitory activities. When tested in the p65 assay, compounds (2) and (4) displayed potent NF-κB inhibition (IC50=1.5 nM and 3.4nM, respectively). PMID:26920294

  5. Acyclic Cucurbit[n]uril-Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents.

    PubMed

    Sigwalt, David; Moncelet, Damien; Falcinelli, Shane; Mandadapu, Vijaybabu; Zavalij, Peter Y; Day, Anthony; Briken, Volker; Isaacs, Lyle

    2016-05-01

    Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue with a (CH2 )3 linker (M2, 14 mm) studied previously. (1) H NMR dilution experiments show that M2C2 and M2C4 do not self-associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2, M2C2, M2C4, hydroxypropyl-β-cyclodextrin (HP-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) toward 15 insoluble drugs. We found that M2C2 and M2C4-as gauged by the slope of their PSDs-are less potent solubilizing agents than M2. However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE-β-CD were similar in many cases, with Krel values averaging 23 and 12, respectively, relative to HP-β-CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2. PMID:26990780

  6. Acyclic Identification of Aptamers for Human alpha-Thrombin Using Over-Represented Libraries and Deep Sequencing

    PubMed Central

    Kupakuwana, Gillian V.; Crill, James E.; McPike, Mark P.; Borer, Philip N.

    2011-01-01

    Background Aptamers are oligonucleotides that bind proteins and other targets with high affinity and selectivity. Twenty years ago elements of natural selection were adapted to in vitro selection in order to distinguish aptamers among randomized sequence libraries. The primary bottleneck in traditional aptamer discovery is multiple cycles of in vitro evolution. Methodology/Principal Findings We show that over-representation of sequences in aptamer libraries and deep sequencing enables acyclic identification of aptamers. We demonstrated this by isolating a known family of aptamers for human α-thrombin. Aptamers were found within a library containing an average of 56,000 copies of each possible randomized 15mer segment. The high affinity sequences were counted many times above the background in 2–6 million reads. Clustering analysis of sequences with more than 10 counts distinguished two sequence motifs with candidates at high abundance. Motif I contained the previously observed consensus 15mer, Thb1 (46,000 counts), and related variants with mostly G/T substitutions; secondary analysis showed that affinity for thrombin correlated with abundance (Kd = 12 nM for Thb1). The signal-to-noise ratio for this experiment was roughly 10,000∶1 for Thb1. Motif II was unrelated to Thb1 with the leading candidate (29,000 counts) being a novel aptamer against hexose sugars in the storage and elution buffers for Concanavilin A (Kd = 0.5 µM for α-methyl-mannoside); ConA was used to immobilize α-thrombin. Conclusions/Significance Over-representation together with deep sequencing can dramatically shorten the discovery process, distinguish aptamers having a wide range of affinity for the target, allow an exhaustive search of the sequence space within a simplified library, reduce the quantity of the target required, eliminate cycling artifacts, and should allow multiplexing of sequencing experiments and targets. PMID:21625587

  7. Macrocyclic ligands for uranium complexation. Final report, August 1, 1986--March 31, 1993

    SciTech Connect

    Potts, K.T.

    1993-12-31

    Macrocycles, designed for complexation of the uranyl ion by computer modeling studies and utilizing six ligating atoms in the equatorial plane of the uranyl ions, have been prepared and their complexation of the uranyl ions evaluated. The ligating atoms, either oxygen or sulfur, were part of acylurea, biuret or thiobiuret subunits with alkane chains or pyridine units completing the macrocyclic periphery. These macrocycles with only partial preorganization formed uranyl complexes in solution but no crystalline complexes were isolated. Refinement of the cavity diameter by variation of the peripheral functional groups is currently studied to achieve an optimized cavity diameter of 4.7--5.2 {angstrom}. Acyclic ligands containing the same ligating atoms in equivalent functional entities were found to form a crystalline 1:1 uranyl-ligand complex (stability constant log K = 10.7) whose structure was established by X-ray data. This complex underwent a facile, DMSO-induced rearrangement to a 2:1 uranyl-ligand complex whose structure was also established by X-ray data. The intermediates to the macrocycles all behaved as excellent ligands for the complexation of transition metals. Acylthiourea complexes of copper and nickel as well as intermolecular, binuclear copper and nickel complexes of bidentate carbonyl thioureas formed readily and their structures were established in several representative instances by X-ray structural determinations. Tetradentate bis(carbonylthioureas) were found to be very efficient selective reagents for the complexation of copper in the presence of nickel ions. Several preorganized macrocycles were also prepared but in most instances these macrocycles underwent ring-opening under complexation conditions.

  8. Selective electrochemical discrimination between dopamine and phenethylamine-derived psychotropic drugs using electrodes modified with an acyclic receptor containing two terminal 3-alkoxy-5-nitroindazole rings.

    PubMed

    Doménech, Antonio; Navarro, Pilar; Arán, Vicente J; Muro, Beatriz; Montoya, Noemí; García-España, Enrique

    2010-06-01

    Electrochemical discrimination between dopamine and psychotropic drugs which have in common a skeletal structure of phenethylamine, can be obtained using acyclic receptors L(1) and L(2), containing two terminal 3-alkoxy-5-nitroindazole rings. Upon attachment to graphite electrodes, L(1) and L(2) exhibit a well-defined, essentially reversible solid state electrochemistry in contact with aqueous media, based on electrolyte-assisted reduction processes involving successive cation and anion insertion/binding. As a result, a distinctive, essentially Nernstian electrochemical response is obtained for phenethylammonium ions of methamphetamine (METH), p-methoxyamphetamine (PMA), amphetamine (AMPH), mescaline (MES), homoveratrylamine (HOM), phenethylamine (PEA) and dopamine (DA) in aqueous media. PMID:20407681

  9. Platinum(II) and palladium(II) metallomacrocycles derived from cationic 4,4'-bipyridinium, 3-aminopyrazinium and 2-aminopyrimidinium ligands.

    PubMed

    Schilter, David; Clegg, Jack K; Harding, Margaret M; Rendina, Louis M

    2010-01-01

    A series of cationic, ditopic N-donor ligands based on 4,4'-bipyridine (4,4'-bipy), 3-aminopyrazine (apyz) and 2-aminopyrimidine (apym), each incorporating two positively-charged N-heterocycles linked by a conformationally-flexible spacer unit, have been synthesised and treated with palladium(II) or platinum(II) precursors [M(2,2'-bipy)(NO(3))(2)] (M = Pd(II) or Pt(II)) to form highly cationic metallocyclic species. Treatment of 1,6-bis(4,4'-bipyridinium)hexane nitrate with [M(2,2'-bipy)(NO(3))(2)] in aqueous solution, followed by the addition of KPF(6), resulted in the formation of the [2+2] species [M(2)(2,2'-bipy)(2){4,4'-bipy(CH(2))(6)4,4'-bipy}(2)](PF(6))(8). Treatment of [Pd(PhCN)(2)Cl(2)] with 1,3-bis(4,4'-bipyridinium)propane hexafluorophosphate in MeCN afforded [Pd(2)Cl(4){4,4'-bipy(CH(2))(3)4,4'-bipy}(2)](PF(6))(4). When the cationic apyz or apym ligands were used in aqueous solution, the analogous metallomacrocycles did not form. Instead, deprotonation of the exocyclic amino group occurred upon coordination of the ligand to afford a tetranuclear [4+2] species in the case of platinum(II), with Pt(II)...Pt(II) bonding supported by strong UV-vis absorption at lambda = 428 nm which was assigned to a metal-metal-to-ligand charge transfer (MMLCT) band. Thus, treatment of 1,6-bis(3-aminopyrazinium)hexane nitrate with [Pt(2,2'-bipy)(NO(3))(2)], followed by the addition of KPF(6), led to the formation of the red species [Pt(4)(2,2'-bipy)(4){apyz(CH(2))(6)apyz-2H}(2)](PF(6))(8). No related products could be identified with palladium(II), consistent with the low propensity for this metal ion to form strong Pd(II)...Pd(II) bonding interactions. PMID:20023956

  10. Induction of ovulation in the acyclic postpartum ewe following continuous, low-dose subcutaneous infusion of GnRH.

    PubMed

    Fray, M D; Lamming, G E; Haresign, W

    1995-04-15

    Pituitary and ovarian responses to subcutaneous infusion of GnRH were investigated in acyclic, lactating Mule ewes during the breeding season. Thirty postpartum ewes were split into 3 equal groups; Group G received GnRH (250 ng/h) for 96 h; Group P + G was primed with progestagen for 10 d then received GnRH (250 ng/h) for 96 h; and Group P received progestagen priming and saline vehicle only. The infusions were delivered via osmotic minipumps inserted 26.6 +/- 0.45 d post partum (Day 0 of the study). Blood samples were collected for LH analysis every 15 min from 12 h before until 8 h after minipump insertion, then every 2 h for a further 112 h. Daily blood samples were collected for progesterone analysis on Days 1 to 10 following minipump insertion, then every third day for a further 25 d. In addition, the reproductive tract was examined by laparoscopy on Day -5 and Day +7 and estrous behavior was monitored between Day -4 and Day +7. Progestagen priming suppressed (P < 0.05) plasma LH levels (0.27 +/- 0.03 vs 0.46 +/- 0.06 ng/ml) during the preinfusion period, but the GnRH-induced LH release was similar for Group G and Group P + G. The LH surge began significantly (P < 0.05) earlier (32.0 +/- 3.0 vs 56.3 +/- 4.1 h) and was of greater magnitude (32.15 +/- 3.56 vs 18.84 +/- 4.13 ng/ml) in the unprimed than the primed ewes. None of the ewes infused with saline produced a preovulatory LH surge. The GnRH infusion induced ovulation in 10/10 unprimed and 7/9 progestagen-primed ewes, with no significant difference in ovulation rate (1.78 +/- 0.15 and 1.33 +/- 0.21, respectively). Ovulation was followed by normal luteal function in 4/10 Group-G ewes, while the remaining 6 ewes had short luteal phases. In contrast, each of the 7 Group-P + G ewes that ovulated secreted progesterone for at least 10 d, although elevated plasma progesterone levels were maintained in 3/7 unmated ewes for >35 d. Throughout the study only 2 ewes (both from Group P + G) displayed estrus. These data

  11. Flexible Acyclic Polyol-Chloride Anion Complexes and Their Characterization by Photoelectron Spectroscopy and Variable Temperature Binding Constant Determinations.

    PubMed

    Shokri, Alireza; Wang, Xue-Bin; Wang, Yanping; O'Doherty, George A; Kass, Steven R

    2016-03-17

    Flexible acyclic alcohols with one to five hydroxyl groups were bound to a chloride anion and these complexes were interrogated by negative ion photoelectron spectroscopy and companion density functional theory computations. The resulting vertical detachment energies are reproduced on average to 0.10 eV by M06-2X/aug-cc-pVTZ predictions and range from 4.45-5.96 eV. These values are 0.84-2.35 eV larger than the adiabatic detachment energy of Cl(-) as a result of the larger hydrogen bond networks in the bigger polyols. Adiabatic detachment energies of the alcohol-Cl(-) clusters are more difficult to determine both experimentally and computationally. This is due to the large geometry changes that occur upon photodetachment and the large bond dissociation energy of H-Cl which enables the resulting chlorine atom to abstract a hydrogen from any of the methylene (CH2) or methine (CH) positions. Both ionic and nonionic hydrogen bonds (i.e., OH···Cl(-) and OH···OH···Cl(-)) form in the larger polyols complexes and are found to be energetically comparable. Subtle structural differences, consequently can lead to the formation of different types of hydrogen bonds, and maximizing the ionic ones is not always preferred. Solution equilibrium binding constants between the alcohols and tetrabutylammonium chloride (TBACl) in acetonitrile at -24.2, +22.0, and +53.6 °C were also determined. The free energies of association are nearly identical for all of the substrates (i.e., ΔG° = -2.8 ± 0.7 kcal mol(-1)). Compensating enthalpy and entropy values reveal, contrary to expectation and the intrinsic gas-phase preferences, that the bigger systems with more hydroxyl groups are entropically favored and enthalpically disfavored relative to the smaller species. This suggests that more solvent molecules are released upon binding TBACl to alcohols with more hydroxyl groups and is consistent with the measured negative heat capacities. These quantities increase with molecular

  12. Ovarian acyclicity in zoo African elephants (Loxodonta africana) is associated with high body condition scores and elevated serum insulin and leptin.

    PubMed

    Morfeld, Kari A; Brown, Janine L

    2016-04-01

    The purpose of the present study was to determine whether excessive body fat and altered metabolic hormone concentrations in the circulation were associated with ovarian acyclicity in the world's largest land mammal, the African elephant. We compared body condition, glucose, insulin and leptin concentrations and the glucose-to-insulin ratio (G:I) between cycling (n=23; normal 14-16 week cycles based on serum progestagens for at least 2 years) and non-cycling (n=23; consistent baseline progestagen concentrations for at least 2 years) females. A validated body condition score (BCS) index (five-point scale; 1=thinnest, 5=fattest) was used to assess the degree of fatness of the study elephants. The mean BCS of non-cycling elephants was higher than that of their cycling counterparts. There were differences in concentrations of serum metabolic biomarkers, with non-cycling elephants in the BCS 5 category having higher leptin and insulin concentrations and a lower G:I ratio than cycling BCS 5 females. Using 'non-cycling' as the outcome variable in regression models, high BCS was a strong predictor of a non-cycling status. This study provides the first evidence that ovarian acyclicity in zoo African elephants is associated with body condition indicative of obesity, as well as elevated, perturbed biomarkers of metabolic status. PMID:25375263

  13. Acyclic Cucurbit[n]uril-type Molecular Containers: Influence of Aromatic Walls on their Function as Solubilizing Excipients for Insoluble Drugs

    PubMed Central

    2015-01-01

    We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a–1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M–1). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a–1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a–1e, lower concentrations of 1a–1e are required to achieve identical [drug]. PMID:25369565

  14. Galanin Receptors and Ligands

    PubMed Central

    Webling, Kristin E. B.; Runesson, Johan; Bartfai, Tamas; Langel, Ülo

    2012-01-01

    The neuropeptide galanin was first discovered 30 years ago. Today, the galanin family consists of galanin, galanin-like peptide (GALP), galanin-message associated peptide (GMAP), and alarin and this family has been shown to be involved in a wide variety of biological and pathological functions. The effect is mediated through three GPCR subtypes, GalR1-3. The limited number of specific ligands to the galanin receptor subtypes has hindered the understanding of the individual effects of each receptor subtype. This review aims to summarize the current data of the importance of the galanin receptor subtypes and receptor subtype specific agonists and antagonists and their involvement in different biological and pathological functions. PMID:23233848

  15. Al(+)-ligand binding energies

    NASA Technical Reports Server (NTRS)

    Sodupe, M.; Bauschlicher, Charles W., Jr.

    1991-01-01

    Ab initio calculations are used to optimize the structure and determine the binding energies of Al(+) to a series of ligands. For Al(+)-CN, the bonding was found to have a large covalent component. For the remaining ligands, the bonding is shown to be electrostatic in origin. The results obtained for Al(+) are compared with those previously reported for Mg(+).

  16. 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.

  17. The maximal affinity of ligands

    PubMed Central

    Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A.

    1999-01-01

    We explore the question of what are the best ligands for macromolecular targets. A survey of experimental data on a large number of the strongest-binding ligands indicates that the free energy of binding increases with the number of nonhydrogen atoms with an initial slope of ≈−1.5 kcal/mol (1 cal = 4.18 J) per atom. For ligands that contain more than 15 nonhydrogen atoms, the free energy of binding increases very little with relative molecular mass. This nonlinearity is largely ascribed to nonthermodynamic factors. An analysis of the dominant interactions suggests that van der Waals interactions and hydrophobic effects provide a reasonable basis for understanding binding affinities across the entire set of ligands. Interesting outliers that bind unusually strongly on a per atom basis include metal ions, covalently attached ligands, and a few well known complexes such as biotin–avidin. PMID:10468550

  18. Predicting target-ligand interactions using protein ligand-binding site and ligand substructures

    PubMed Central

    2015-01-01

    Background Cell proliferation, differentiation, Gene expression, metabolism, immunization and signal transduction require the participation of ligands and targets. It is a great challenge to identify rules governing molecular recognition between chemical topological substructures of ligands and the binding sites of the targets. Methods We suppose that the ligand-target interactions are determined by ligand substructures as well as the physical-chemical properties of the binding sites. Therefore, we propose a fragment interaction model (FIM) to describe the interactions between ligands and targets, with the purpose of facilitating the chemical interpretation of ligand-target binding. First we extract target-ligand complexes from sc-PDB database, based on which, we get the target binding sites and the ligands. Then we represent each binding site as a fragment vector based on a target fragment dictionary that is composed of 199 clusters (denoted as fragements in this work) obtained by clustering 4200 trimers according to their physical-chemical properties. And then, we represent each ligand as a substructure vector based on a dictionary containing 747 substructures. Finally, we build the FIM by generating the interaction matrix M (representing the fragment interaction network), and the FIM can later be used for predicting unknown ligand-target interactions as well as providing the binding details of the interactions. Results The five-fold cross validation results show that the proposed model can get higher AUC score (92%) than three prevalence algorithms CS-PD (80%), BLM-NII (85%) and RF (85%), demonstrating the remarkable predictive ability of FIM. We also show that the ligand binding sites (local information) overweight the sequence similarities (global information) in ligand-target binding, and introducing too much global information would be harmful to the predictive ability. Moreover, The derived fragment interaction network can provide the chemical insights on

  19. Synthesis and characterization of d{sup 10} metal complexes with mixed 1,3-di(1H-imidazol-4-yl)benzene and multicarboxylate ligands

    SciTech Connect

    Chen, Zhi-Hao; Zhao, Yue; Chen, Shui-Sheng; Wang, Peng; Sun, Wei-Yin

    2013-06-15

    Seven new coordination polymers [Zn(H{sub 2}L)(mbdc)] (1), [Zn(H{sub 3}L)(btc)] (2), [Zn(H{sub 2}L)(Hbtc)] (3), [Zn(H{sub 2}L)(Hbtc)]·H{sub 2}O (4), [Zn{sub 2}(H{sub 2}L)(btc)(μ{sub 2}-OH)] (5), [Cd(H{sub 2}L)(mbdc)] (6) and [Cd{sub 3}(H{sub 2}L){sub 2}(btc){sub 2}(H{sub 2}O)]·5H{sub 2}O (7) were synthesized by reactions of the corresponding metal salt with rigid ligand 1,3-di(1H-imidazol-4-yl)benzene (H{sub 2}L) and different carboxylic acids of 1,3-benzenedicarboxylic acid (H{sub 2}mbdc) and benzene-1,3,5-tricarboxylic acid (H{sub 3}btc), respectively. The results of X-ray crystallographic analysis indicate that complex 1 is 1D chain while 2 is a (3,3)-connected 2D network with Point (Schläfli) symbol of (4,8{sup 2}). Complexes 3 and 6 are 2D networks, 4 is a 3-fold interpenetrating 3D framework with Point (Schläfli) symbol of (6{sup 5},8) and 5 is a (3,8)-connected 2D network with Point (Schläfli) symbol of (3,4{sup 2}){sub 2}(3{sup 4},4{sup 6},5{sup 6},6{sup 8},7{sup 3},8), while 7 is a (3,10)-connected 3D net with Schläfli symbol of (3,4,5){sub 2}(3{sup 4},4{sup 8},5{sup 18},6{sup 12},7{sup 2},8). The thermal stability and photoluminescence of the complexes were investigated. Furthermore, DFT calculations were performed for 2–4 to discuss the temperature controlled self-assembly of the complexes. - Graphical abstract: Seven new coordination polymers with multicarboxylate and rigid ditopic 4-imidazole containing ligands have been obtained and found to show different structures and topologies. - Highlights: • Metal complexes with diverse structures of 1D chain, 2D network and 3D framework. • Mixed ligands of 1,3-di(1H-imidazol-4-yl)benzene and multicarboxylate. • Photoluminescence property.

  20. A new method for predicting the heats of combustion of polynitro arene, polynitro heteroarene, acyclic and cyclic nitramine, nitrate ester and nitroaliphatic compounds.

    PubMed

    Keshavarz, Mohammad Hossein; Saatluo, Bahman Ebrahimi; Hassanzadeh, Ali

    2011-01-30

    A new method is presented for estimating the gross and net heats of combustion of important classes of energetic compounds including polynitro arene, polynitro heteroarene, acyclic and cyclic nitramine, nitrate ester and nitroaliphatic compounds. Elemental compositions as well as the presence of some specific polar groups and molecular fragments are important parameters in the new model. The novel method can be easily used for any complex organic compounds with at least one nitro, nitramine or nitrate functional groups by which the predictions of their heats of combustion by the available methods are inaccurate or difficult. The predicted results show that this method gives reliable predictions of heats of combustion with respect to group additivity method and computed values based on atom-type electrotopological state indices for several energetic compounds where the models can be applied. PMID:21035254

  1. Difurazano[3,4-b:3',4'-f]-4,5-diaza-1,8-dioxacyclododecine and an acyclic analogue.

    PubMed

    Averkiev, Boris B; Timofeeva, Tatiana V; Sheremetev, Aleksey B; Shatunova, Elena V; Antipin, Mikhail Yu

    2004-07-01

    The novel title furazan-containing macrocycle (systematic name: 6,9,14,17-tetraoxa-2,3,5,7,16,18-hexaazatricyclo[13.3.0.0(4,8)]octadeca-4,7,15,18-tetraene), C8H10N6O4, (I), is the first macrocycle where the furazan rings are connected via a hydrazine group. In spite of the strain in the 12-membered macrocycle of (I), the geometry of the furazan fragment is the same in (I) and in its acyclic analogue 1,8-bis(5-aminofurazan-4-yloxy)-3,6-dioxaoctane, C10H16N6O6, (II). In both compounds, the participation of the furazan rings in intermolecular hydrogen bonding equalizes the N-O bonds within the furazan rings, in contrast with rings which do not participate in such interactions. PMID:15237185

  2. Ligand Identification Scoring Algorithm (LISA)

    PubMed Central

    Zheng, Zheng; Merz, Kenneth M.

    2011-01-01

    A central problem in de novo drug design is determining the binding affinity of a ligand with a receptor. A new scoring algorithm is presented that estimates the binding affinity of a protein-ligand complex given a three-dimensional structure. The method, LISA (Ligand Identification Scoring Algorithm), uses an empirical scoring function to describe the binding free energy. Interaction terms have been designed to account for van der Waals (VDW) contacts, hydrogen bonding, desolvation effects and metal chelation to model the dissociation equilibrium constants using a linear model. Atom types have been introduced to differentiate the parameters for VDW, H-bonding interactions and metal chelation between different atom pairs. A training set of 492 protein-ligand complexes was selected for the fitting process. Different test sets have been examined to evaluate its ability to predict experimentally measured binding affinities. By comparing with other well known scoring functions, the results show that LISA has advantages over many existing scoring functions in simulating protein-ligand binding affinity, especially metalloprotein-ligand binding affinity. Artificial Neural Network (ANN) was also used in order to demonstrate that the energy terms in LISA are well designed and do not require extra cross terms. PMID:21561101

  3. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    SciTech Connect

    Kiwamoto, R. Spenkelink, A.; Rietjens, I.M.C.M.; Punt, A.

    2015-01-01

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.

  4. Why mercury prefers soft ligands

    SciTech Connect

    Riccardi, Demian M; Guo, Hao-Bo; Gu, Baohua; Parks, Jerry M; Summers, Anne; Miller, S; Liang, Liyuan; Smith, Jeremy C

    2013-01-01

    Mercury (Hg) is a major global pollutant arising from both natural and anthropogenic sources. Defining the factors that determine the relative affinities of different ligands for the mercuric ion, Hg2+, is critical to understanding its speciation, transformation, and bioaccumulation in the environment. Here, we use quantum chemistry to dissect the relative binding free energies for a series of inorganic anion complexes of Hg2+. Comparison of Hg2+ ligand interactions in the gaseous and aqueous phases shows that differences in interactions with a few, local water molecules led to a clear periodic trend within the chalcogenide and halide groups and resulted in the well-known experimentally observed preference of Hg2+ for soft ligands such as thiols. Our approach establishes a basis for understanding Hg speciation in the biosphere.

  5. Fluorescent Ligands for Adenosine Receptors

    PubMed Central

    Kozma, Eszter; Jayasekara, P Suresh; Squarcialupi, Lucia; Paoletta, Silvia; Moro, Stefano; Federico, Stephanie; Spalluto, Giampiero; Jacobson, Kenneth A.

    2012-01-01

    Interest is increasing in developing fluorescent ligands for characterization of adenosine receptors (ARs), which hold a promise of usefulness in the drug discovery process. The size of a strategically labeled AR ligand can be greatly increased after the attachment of a fluorophore. The choice of dye moiety (e.g. Alexa Fluor 488), attachment point and linker length can alter the selectivity and potency of the parent molecule. Fluorescent derivatives of adenosine agonists and antagonists (e.g. XAC and other heterocyclic antagonist scaffolds) have been synthesized and characterized pharmacologically. Some are useful AR probes for flow cytometry, fluorescence correlation spectroscopy, fluorescence microscopy, fluorescence polarization, fluorescence resonance energy transfer, and scanning confocal microscopy. Thus, the approach of fluorescent labeled GPCR ligands, including those for ARs, is a growing dynamic research field. PMID:23200243

  6. What are Nuclear Receptor Ligands?

    PubMed Central

    Sladek, Frances M.

    2010-01-01

    Nuclear receptors (NRs) are a family of highly conserved transcription factors that regulate transcription in response to small lipophilic compounds. They play a role in every aspect of development, physiology and disease in humans. They are also ubiquitous in and unique to the animal kingdom suggesting that they may have played an important role in their evolution. In contrast to the classical endocrine receptors that originally defined the family, recent studies suggest that the first NRs might have been sensors of their environment, binding ligands that were external to the host organism. The purpose of this review is to provide a broad perspective on NR ligands and address the issue of exactly what constitutes a NR ligand from historical, biological and evolutionary perspectives. This discussion will lay the foundation for subsequent reviews in this issue as well as pose new questions for future investigation. PMID:20615454

  7. Molecular Recognition and Ligand Association

    NASA Astrophysics Data System (ADS)

    Baron, Riccardo; McCammon, J. Andrew

    2013-04-01

    We review recent developments in our understanding of molecular recognition and ligand association, focusing on two major viewpoints: (a) studies that highlight new physical insight into the molecular recognition process and the driving forces determining thermodynamic signatures of binding and (b) recent methodological advances in applications to protein-ligand binding. In particular, we highlight the challenges posed by compensating enthalpic and entropic terms, competing solute and solvent contributions, and the relevance of complex configurational ensembles comprising multiple protein, ligand, and solvent intermediate states. As more complete physics is taken into account, computational approaches increase their ability to complement experimental measurements, by providing a microscopic, dynamic view of ensemble-averaged experimental observables. Physics-based approaches are increasingly expanding their power in pharmacology applications.

  8. Multifunctional Ligands in Transition Metal Catalysis

    SciTech Connect

    Crabtree, Robert H

    2011-01-01

    Sophisticated ligands are now being designed that do far more than just fulfil their traditional spectator roles by binding to the metal and providing a sterically-defined binding pocket for the substrate in homogeneous transition metal catalysis. This Focus review emphasizes selected cases in which ligands carry additional functional groups that change the properties of the ligand as a result of an external stimulus or undergo catalytically-relevant ligand-based reactivity. These include proton responsive ligands capable of gaining or losing one or more protons, ligands having a hydrogen bonding function, electroresponsive ligands capable of gaining or losing one or more electrons, and photoresponsive ligands capable of undergoing a useful change of properties upon irradiation. Molecular recognition ligands and proton coupled electron transfer (PCET) are briefly discussed.

  9. Acyclic diterpene glycosides, capsianosides VIII, IX, X, XIII, XV and XVI from the fruits of Paprika Capsicum annuum L. var. grossum BAILEY and Jalapeño Capsicum annuum L. var. annuum.

    PubMed

    Lee, Jong-Hyun; Kiyota, Naoko; Ikeda, Tsuyoshi; Nohara, Toshihiro

    2006-10-01

    Paprika and Jalapeño are used as vegetables and spices. We have obtained six new acyclic diterpene glycosides, called capsianosides XIII (2), XV (3), IX (4), XVI (5), X (6) and VIII (7) together with known capsianoside II (1) from the fruits of the Paprika and Jalapeño. The structures of these compounds have been elucidated by the (1)H- and (13)C-NMR spectra and two-dimensional NMR methods. PMID:17015971

  10. Polypharmacology of dopamine receptor ligands.

    PubMed

    Butini, S; Nikolic, K; Kassel, S; Brückmann, H; Filipic, S; Agbaba, D; Gemma, S; Brogi, S; Brindisi, M; Campiani, G; Stark, H

    2016-07-01

    Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular. PMID:27234980

  11. Reductive metalation of cyclic and acyclic pseudopeptidic bis-disulfides and back conversion of the resulting diamidato/dithiolato complexes to bis-disulfides.

    PubMed

    Desbenoît, Nicolas; Galardon, Erwan; Frapart, Yves; Tomas, Alain; Artaud, Isabelle

    2010-09-20

    Cyclic and acyclic pseudopeptidic bis-disulfides built on an o-phenylene diamine scaffold were prepared: (N(2)H(2)S(2))(2), 1a, N(2)H(2)(S-SCH(3))(2), 1b, and N(2)H(2)(S-StBu)(2), 1c. Reductive metalation of these disulfides with (PF(6))[Cu(CH(3)CN)(4)] in the presence of Et(4)NOH as a base, or with (Et(4)N)[Fe(SEt)(4)] and Et(4)NCl, yields the corresponding diamidato/dithiolato copper(III) or iron(III) complex, (Et(4)N)[Cu(N(2)S(2))], 2, or (Et(4)N)(2)[Fe(N(2)S(2))Cl], 5. These complexes display characteristics similar to those previously described in the literature. The mechanism of the metalation with copper has been investigated by X-band electron paramagnetic resonance (EPR) spectroscopy at 10 K. After metalation of the bis-disulfide 1c and deprotonation of the amide nitrogens, the reductive cleavage of the S-S bonds occurs by two one-electron transfers leading to the intermediate formation of a copper(II) complex and a thyil radical. Complexes 2 and 5 can be converted back to the cyclic bis-disulfide 1a with iodine in an 80% yield. Reaction of 5 with iodine in the presence of CH(3)S-SCH(3) affords a 1/1 mixture of the acyclic N(2)H(2)(S-SCH(3))(2) disulfide 1b and cyclic bis-disulfide 1a. From 2, the reaction was monitored by (1)H NMR and gives 1b as major product. While there is no reaction of 2 or 5 with tBuS-StBu and iodine, reaction with an excess of tBuSI affords quantitatively the di-tert-butyl disulfide 1c. To assess the role of the Cu(III) oxidation state, control experiments were carried out under strictly anaerobic conditions with the copper(II) complex, (Et(4)N)(2)[Cu(N(2)S(2))], 6. Complex 6 is oxidized to 2 by iodine, and it reacts with an excess of tBuSI, yielding 1c as final product, through the intermediate formation of complex 2. PMID:20718487

  12. Alkene to carbyne: tandem Lewis acid activation and dehydrogenation of a molybdenum ethylene complex.

    PubMed

    Stennett, Tom E; Haddow, Mairi F; Wass, Duncan F

    2013-10-18

    Carbyne formation: Treatment of a molybdenum ethylene complex with B(C6 F5 )3 induces ditopic activation of an ethylene ligand and acceptor-assisted ethane elimination to generate a novel type of zwitterionic carbyne complex. PMID:24038792

  13. Efficient pseudo-enantiomeric carbohydrate olefin ligands.

    PubMed

    Grugel, Holger; Albrecht, Fabian; Minuth, Tobias; Boysen, Mike M K

    2012-07-20

    Highly efficient pseudo-enantiomeric olefin ligands were designed from D-glucose and D-galactose. These ligands yield consistently excellent levels of enantioselectivity in Rh(I)-catalyzed 1,4-additions of aryl- and alkenylboronic acids to achiral enones and high diastereoselectivity with chiral substrates. Contrary to established olefin ligands, they are obtained enantiomerically pure via short syntheses without racemic resolution steps, making them a valuable addition to the arsenal of chiral ligands with olefinic donor sites. PMID:22780685

  14. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins. PMID:20301131

  15. Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR-ligand binding modes.

    PubMed

    Schultes, Sabine; Engelhardt, Harald; Roumen, Luc; Zuiderveld, Obbe P; Haaksma, Eric E J; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

    2013-01-01

    SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation. PMID:23161844

  16. Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model.

    PubMed

    Qin, Xian-Yang; Tatsukawa, Hideki; Hitomi, Kiyotaka; Shirakami, Yohei; Ishibashi, Naoto; Shimizu, Masahito; Moriwaki, Hisataka; Kojima, Soichi

    2016-03-01

    Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation-mediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis. PMID:26744170

  17. Ligand chain length conveys thermochromism.

    PubMed

    Ganguly, Mainak; Panigrahi, Sudipa; Chandrakumar, K R S; Sasmal, Anup Kumar; Pal, Anjali; Pal, Tarasankar

    2014-08-14

    Thermochromic properties of a series of non-ionic copper compounds have been reported. Herein, we demonstrate that Cu(II) ion with straight-chain primary amine (A) and alpha-linolenic (fatty acid, AL) co-jointly exhibit thermochromic properties. In the current case, we determined that thermochromism becomes ligand chain length-dependent and at least one of the ligands (A or AL) must be long chain. Thermochromism is attributed to a balanced competition between the fatty acids and amines for the copper(II) centre. The structure-property relationship of the non-ionic copper compounds Cu(AL)2(A)2 has been substantiated by various physical measurements along with detailed theoretical studies based on time-dependent density functional theory. It is presumed from our results that the compound would be a useful material for temperature-sensor applications. PMID:24943491

  18. Mg(+)-ligand binding energies

    NASA Technical Reports Server (NTRS)

    Bauschlicher, Charles W., Jr.; Partridge, Harry

    1991-01-01

    Ab initio calculations are used to optimize the structures and determine the binding energies of Mg(+) to a series of ligands. Mg(+) bonds electrostatically with benzene, acetone, H2, CO, and NH3 and a self-consistent-field treatment gives a good description of the bonding. The bonding in MgCN(+) and MgCH3(+) is largely covalent and a correlated treatment is required.

  19. Presentation of Ligands on Hydroxylapatite

    NASA Technical Reports Server (NTRS)

    Chu, Barbara C. F.; Orgel, Leslie E.

    1997-01-01

    Conjugates of biotin with the decamer of glutamic acid (glu(sub 10)) and the trimer of D,L-2-amino-5-phosphonovaleric acid (I) have been synthesized, and it has been shown that they mediate the binding of avidin to hydroxylapatite. In a similar way a conjugate of methotrexate with glu(sub 10) mediates the binding of dihydrofolate reductase to the mineral. The presentation of ligands on the hydroxylapatite component of bone may find applications in clinical medicine.

  20. Unusual ligand coordination for cesium

    SciTech Connect

    Bryan, J.C.; Kavallieratos, K.; Sachleben, R.A.

    2000-04-03

    When complexed by tetrabenzo-24-crown-8, the cesium ion can accommodate unprecedented ligation. The structures of the complexes are presented. These structures are the first reported examples of linear {eta}{sup 2}-acetonitrile coordination to any metal ion and the first structures illustrating {eta}{sup 2}-acetonitrile and dichloromethane ligation to an alkali metal ion. Possible steric and electronic origins of these unusual metal-ligand interactions are discussed.

  1. Absolute Ligand Discrimination by Dimeric Signaling Receptors.

    PubMed

    Fathi, Sepehr; Nayak, Chitra R; Feld, Jordan J; Zilman, Anton G

    2016-09-01

    Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor. PMID:27602720

  2. Bifunctional crosslinking ligands for transthyretin

    PubMed Central

    Mangione, P. Patrizia; Deroo, Stéphanie; Ellmerich, Stephan; Bellotti, Vittorio; Kolstoe, Simon; Wood, Stephen P.; Robinson, Carol V.; Smith, Martin D.; Tennent, Glenys A.; Broadbridge, Robert J.; Council, Claire E.; Thurston, Joanne R.; Steadman, Victoria A.; Vong, Antonio K.; Swain, Christopher J.; Pepys, Mark B.; Taylor, Graham W.

    2015-01-01

    Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms. PMID:26400472

  3. Tumor Targeting via Integrin Ligands

    PubMed Central

    Marelli, Udaya Kiran; Rechenmacher, Florian; Sobahi, Tariq Rashad Ali; Mas-Moruno, Carlos; Kessler, Horst

    2013-01-01

    Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells. PMID:24010121

  4. What a difference a carbon makes: H₄octapa vs H₄C3octapa, ligands for In-111 and Lu-177 radiochemistry.

    PubMed

    Price, Eric W; Zeglis, Brian M; Cawthray, Jacqueline F; Lewis, Jason S; Adam, Michael J; Orvig, Chris

    2014-10-01

    The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal-ligand matching. It was found that [In(C3octapa)](-) and [Lu(C3octapa)](-) were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by (1)H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)](-) and [Lu(octapa)](-) revealed very symmetric complexes; in contrast, the [In(C3octapa)](-) and [Lu(C3octapa)](-) complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log K(ML), pM) were ~2 units lower for the In(3+) and Lu(3+) complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (~2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with (111)In and (177)Lu. Over a 5 day stability challenge experiment in blood serum, (111)In-octapa- and (111)In-C3octapa-trastuzumab immunoconjugates were determined to be ~91 and ~24% stable, respectively, and (177)Lu-octapa- and (177)Lu-C3octapa-trastuzumab, ~89% and ~4% stable, respectively. This work suggests that 5

  5. What a Difference a Carbon Makes: H4octapa vs H4C3octapa, Ligands for In-111 and Lu-177 Radiochemistry

    PubMed Central

    2015-01-01

    The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5

  6. Ligand identification using electron-density mapcorrelations

    SciTech Connect

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn,Judith D.

    2006-12-01

    A procedure for the identification of ligands bound incrystal structuresof macromolecules is described. Two characteristics ofthe density corresponding to a ligand are used in the identificationprocedure. One is the correlation of the ligand density with each of aset of test ligands after optimization of the fit of that ligand to thedensity. The other is the correlation of a fingerprint of the densitywith the fingerprint of model density for each possible ligand. Thefingerprints consist of an ordered list of correlations of each the testligands with the density. The two characteristics are scored using aZ-score approach in which the correlations are normalized to the mean andstandard deviation of correlations found for a variety of mismatchedligand-density pairs, so that the Z scores are related to the probabilityof observing a particular value of the correlation by chance. Theprocedure was tested with a set of 200 of the most commonly found ligandsin the Protein Data Bank, collectively representing 57 percent of allligands in the Protein Data Bank. Using a combination of these twocharacteristics of ligand density, ranked lists of ligand identificationswere made for representative (F-o-F-c) exp(i phi(c)) difference densityfrom entries in the Protein Data Bank. In 48 percent of the 200 cases,the correct ligand was at the top of the ranked list of ligands. Thisapproach may be useful in identification of unknown ligands in newmacromolecular structures as well as in the identification of whichligands in a mixture have bound to a macromolecule.

  7. NKG2D ligands as therapeutic targets

    PubMed Central

    Spear, Paul; Wu, Ming-Ru; Sentman, Marie-Louise; Sentman, Charles L.

    2013-01-01

    The Natural Killer Group 2D (NKG2D) receptor plays an important role in protecting the host from infections and cancer. By recognizing ligands induced on infected or tumor cells, NKG2D modulates lymphocyte activation and promotes immunity to eliminate ligand-expressing cells. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present a useful target for immunotherapeutic approaches in cancer. Novel therapies targeting NKG2D ligands for the treatment of cancer have shown preclinical success and are poised to enter into clinical trials. In this review, the NKG2D receptor and its ligands are discussed in the context of cancer, infection, and autoimmunity. In addition, therapies targeting NKG2D ligands in cancer are also reviewed. PMID:23833565

  8. Synthesis, spectroscopic studies, thermal analyses, biological activity of tridentate coordinated transition metal complexes of bi(pyridyl-2-ylmethyl)amine]ligand

    NASA Astrophysics Data System (ADS)

    Abd El-Halim, Hanan F.; Mohamed, Gehad G.

    2016-01-01

    A new tridentate acyclic pincer ligand, [bi(pyridin-2-methyl)amine] (bpma, HL), was synthesized and reacted to form complexes with copper(II), nickel(II), iron(II), cobalt(II) and zinc(II) ions. Both the ligand and its complexes were characterized using elemental analysis, molar conductance, infrared, 1H-NMR-spectroscopy, mass and thermal analyses. According to the spectroscopic data, all of the complexes share the same coordination environment around the metal atoms, consisting two nitrogen-pyridine entities, one nitrogen-methylamine entity, one/two water molecules and/or one/two chloride or bromide ions. Complexes also showed molar conductivity according to the presence of two halide anions outer the coordination sphere except Co(II) and Zn(II) complexes are non electrolytes. Analysis indicates that the metal ions have trigonal bipyramidal structure. Cu(II), Ni(II), Fe(II), Co(II), and Zn(II) metal complexes were screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus (G+) and Escherichia coli, and Pseudomonas aeruginosa (G-) bacteria. They showed remarkable antimicrobial activity.

  9. Design, Synthesis, Protein−Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance

    SciTech Connect

    Ghosh, Arun K.; Kulkarni, Sarang; Anderson, David D.; Hong, Lin; Baldridge, Abigail; Wang, Yuan-Fang; Chumanevich, Alexander A.; Kovalevsky, Andrey Y.; Tojo, Yasushi; Amano, Masayuki; Koh, Yasuhiro; Tang, Jordan; Weber, Irene T.; Mitsuya, Hiroaki

    2010-04-05

    The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.

  10. Canonical and non-canonical Notch ligands

    PubMed Central

    D’SOUZA, BRENDAN; MELOTY-KAPELLA, LAURENCE; WEINMASTER, GERRY

    2015-01-01

    Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity. PMID:20816393

  11. Conformational readout of RNA by small ligands

    PubMed Central

    Kligun, Efrat; Mandel-Gutfreund, Yael

    2013-01-01

    RNA molecules have highly versatile structures that can fold into myriad conformations, providing many potential pockets for binding small molecules. The increasing number of available RNA structures, in complex with proteins, small ligands and in free form, enables the design of new therapeutically useful RNA-binding ligands. Here we studied RNA ligand complexes from 10 RNA groups extracted from the protein data bank (PDB), including adaptive and non-adaptive complexes. We analyzed the chemical, physical, structural and conformational properties of binding pockets around the ligand. Comparing the properties of ligand-binding pockets to the properties of computed pockets extracted from all available RNA structures and RNA-protein interfaces, revealed that ligand-binding pockets, mainly the adaptive pockets, are characterized by unique properties, specifically enriched in rare conformations of the nucleobase and the sugar pucker. Further, we demonstrate that nucleotides possessing the rare conformations are preferentially involved in direct interactions with the ligand. Overall, based on our comprehensive analysis of RNA-ligand complexes, we suggest that the unique conformations adopted by RNA nucleotides play an important role in RNA recognition by small ligands. We term the recognition of a binding site by a ligand via the unique RNA conformations “RNA conformational readout.” We propose that “conformational readout” is a general way by which RNA binding pockets are recognized and selected from an ensemble of different RNA states. PMID:23618839

  12. Ligand placement based on prior structures: the guided ligand-replacement method

    SciTech Connect

    Klei, Herbert E.; Moriarty, Nigel W. Echols, Nathaniel; Terwilliger, Thomas C.; Baldwin, Eric T.; Pokross, Matt; Posy, Shana; Adams, Paul D.

    2014-01-01

    A new module, Guided Ligand Replacement (GLR), has been developed in Phenix to increase the ease and success rate of ligand placement when prior protein-ligand complexes are available. The process of iterative structure-based drug design involves the X-ray crystal structure determination of upwards of 100 ligands with the same general scaffold (i.e. chemotype) complexed with very similar, if not identical, protein targets. In conjunction with insights from computational models and assays, this collection of crystal structures is analyzed to improve potency, to achieve better selectivity and to reduce liabilities such as absorption, distribution, metabolism, excretion and toxicology. Current methods for modeling ligands into electron-density maps typically do not utilize information on how similar ligands bound in related structures. Even if the electron density is of sufficient quality and resolution to allow de novo placement, the process can take considerable time as the size, complexity and torsional degrees of freedom of the ligands increase. A new module, Guided Ligand Replacement (GLR), was developed in Phenix to increase the ease and success rate of ligand placement when prior protein–ligand complexes are available. At the heart of GLR is an algorithm based on graph theory that associates atoms in the target ligand with analogous atoms in the reference ligand. Based on this correspondence, a set of coordinates is generated for the target ligand. GLR is especially useful in two situations: (i) modeling a series of large, flexible, complicated or macrocyclic ligands in successive structures and (ii) modeling ligands as part of a refinement pipeline that can automatically select a reference structure. Even in those cases for which no reference structure is available, if there are multiple copies of the bound ligand per asymmetric unit GLR offers an efficient way to complete the model after the first ligand has been placed. In all of these applications, GLR

  13. Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues.

    PubMed

    Głowacka, Iwona E; Balzarini, Jan; Andrei, Graciela; Snoeck, Robert; Schols, Dominique; Piotrowska, Dorota G

    2014-07-15

    The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50=20μM-visual CPE score; EC50=18μM-MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50=9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50=2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50=4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4-50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4-7μM range). PMID:24906510

  14. Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

    PubMed

    Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

    2016-03-01

    Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs. PMID:26756920

  15. Pituitary and ovarian responses of post-partum acyclic beef cows to continuous long-term GnRH and GnRH agonist treatment.

    PubMed

    D'Occhio, M J; Gifford, D R; Earl, C R; Weatherly, T; von Rechenberg, W

    1989-03-01

    Post-partum acyclic beef cows received continuous long-term treatment with GnRH (200 or 400 ng/kg body wt/h) or the GnRH agonist buserelin (5.5 or 11 ng/kg body wt/h) using s.c. osmotic minipumps which were designed to remain active for 28 days. All treatments increased circulating LH concentrations whereas FSH remained unchanged. Ovulation and corpus luteum (CL) formation as judged by progesterone concentrations greater than or equal to 1 ng/ml occurred in 0/5 control, 4/5 200 ng GnRH, 4/4 400 ng GnRH, 4/5 5.5 ng buserelin and 3/5 11 ng buserelin cows. The outstanding features of the progesterone profiles were the synchrony, both within and across groups, in values greater than or equal to 1 ng/ml around Day 6, and the fact that most CL were short-lived (4-6 days). Only 3 cows, one each from the 400 ng GnRH, 5.5 ng buserelin and 11 ng buserelin groups, showed evidence of extended CL function. Cows failed to show a second ovulation which was anticipated around Day 10 and this could have been due to insufficient FSH to stimulate early follicular development, or the absence of an endogenously driven LH surge. The highest LH concentrations for the respective groups were observed on Days 2 and 6 and by Day 10 LH was declining, although concentrations did remain higher than in controls up to Day 20.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2495359

  16. A universal rule for organic ligand exchange.

    PubMed

    You, Hongjun; Wang, Wenjin; Yang, Shengchun

    2014-11-12

    Most synthetic routes to high-quality nanocrystals with tunable morphologies predominantly employ long hydro-carbon molecules as ligands, which are detrimental for electronic and catalytic applications. Here, a rule is found that the adsorption energy of an organic ligand is related to its carbon-chain length. Using the density functional theory method, the adsorption energies of some commonly used ligand molecules with different carbon-chain lengths are calculated, including carboxylate, hydroxyl, and amine molecules adsorbed on metal or metal oxide crystal surface. The results indicate that the adsorption energy of the ligand molecule with a long carbon chain is weaker than that of a smaller molecule with same functional group. This rule provides a theoretical support for a new kind of ligand exchange method in which large organic ligand molecules can be exchanged by small molecules with same functional group to improve the catalytic properties. PMID:25335915

  17. Ligand-targeted liposomes for cancer treatment.

    PubMed

    Sapra, Puja; Tyagi, Pradeep; Allen, Theresa M

    2005-10-01

    Selective targeting of ligand-targeted liposomes containing anticancer drugs or therapeutic genes to cell surface receptors expressed on cancer cells is a recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics or gene therapeutics. Some recent advances in the field of ligand-targeted liposomes for the treatment of cancer are summarized including: selection criteria for the receptors to be targeted, choice of targeting ligands and choice of encapsulated therapeutics. Targeting of liposomes to solid tumors, versus angiogenic endothelial cells versus vascular targets is discussed. Ligand-targeted liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development. PMID:16305440

  18. Allosterism at muscarinic receptors: ligands and mechanisms.

    PubMed

    Birdsall, N J M; Lazareno, S

    2005-06-01

    The evaluation of allosteric ligands at muscarinic receptors is discussed in terms of the ability of the experimental data to be interpreted by the allosteric ternary complex model. The compilation of useful SAR information of allosteric ligands is not simple, especially for muscarinic receptors, where there are multiple allosteric sites and complex interactions. PMID:15974931

  19. Autocrine signal transmission with extracellular ligand degradation

    NASA Astrophysics Data System (ADS)

    Muratov, C B; Posta, F; Shvartsman, S Y

    2009-03-01

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand-receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers.

  20. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N'-propyl-2-NI ligands for (64)Cu(ii) radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Boros, Eszter; Patrick, Brian O; Zeisler, Stefan K; Kumlin, Joel; Adam, Michael J; Schaffer, Paul; Orvig, Chris

    2016-08-16

    The chiral acyclic "pa" ligand (pa = picolinic acid) H2CHXdedpa (N4O2) and two NI-containing dedpa analogues (H2CHXdedpa-N,N'-propyl-2-NI, H2dedpa-N,N'-propyl-2-NI, NI = nitroimidazole) were studied as chelators for copper radiopharmaceuticals (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). The hexadentate ligand H2CHXdedpa was previously established as a superb system for (67/68)Ga radiochemistry. The solid state X-ray crystal structures of [Cu(CHXdedpa-N,N'-propyl-2-NI)] and [Cu(dedpa-N,N'-propyl-2-NI)] reveal the predicted hexadentate, distorted octahedral binding of the copper(ii) ion. Cyclic voltammetry of [Cu(dedpa-N,N'-propyl-2-NI)] shows that there is one reversible couple associated with the NI redox, and one irreversible but reproducible couple attributed to the Cu(ii)/Cu(i) redox cycle. Quantitative radiolabeling (>99%) of CHXdedpa(2-) and (dedpa-N,N'-propyl-2-NI)(2-) with (64)Cu was achieved under fast and efficient labeling conditions (10 min, RT, 0.5 M sodium acetate buffer, pH 5.5) at ligand concentrations as low as 10(-6) M. In vitro kinetic inertness studies of the (64)Cu labelled complexes were studied in human serum at 37 °C over 24 hours; [(64)Cu(CHXdedpa)] was found to be 98% stable compared to previously investigated [(64)Cu(dedpa)] which was only 72% intact after 24 hours. PMID:27161975

  1. Protein-ligand-based pharmacophores: generation and utility assessment in computational ligand profiling.

    PubMed

    Meslamani, Jamel; Li, Jiabo; Sutter, Jon; Stevens, Adrian; Bertrand, Hugues-Olivier; Rognan, Didier

    2012-04-23

    Ligand profiling is an emerging computational method for predicting the most likely targets of a bioactive compound and therefore anticipating adverse reactions, side effects and drug repurposing. A few encouraging successes have already been reported using ligand 2-D similarity searches and protein-ligand docking. The current study describes the use of receptor-ligand-derived pharmacophore searches as a tool to link ligands to putative targets. A database of 68,056 pharmacophores was first derived from 8,166 high-resolution protein-ligand complexes. In order to limit the number of queries, a maximum of 10 pharmacophores was generated for each complex according to their predicted selectivity. Pharmacophore search was compared to ligand-centric (2-D and 3-D similarity searches) and docking methods in profiling a set of 157 diverse ligands against a panel of 2,556 unique targets of known X-ray structure. As expected, ligand-based methods outperformed, in most of the cases, structure-based approaches in ranking the true targets among the top 1% scoring entries. However, we could identify ligands for which only a single method was successful. Receptor-ligand-based pharmacophore search is notably a fast and reliable alternative to docking when few ligand information is available for some targets. Overall, the present study suggests that a workflow using the best profiling method according to the protein-ligand context is the best strategy to follow. We notably present concrete guidelines for selecting the optimal computational method according to simple ligand and binding site properties. PMID:22480372

  2. Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand.

    PubMed

    Li, Linqing; Xu, Weiwei; Lü, Qiang

    2015-11-01

    Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, based on the RosettaLigand protocol. This approach incorporates the flexibility of interfacial water molecules and modeling of the interface of the receptor into the original RosettaLigand. In a coarse sampling step, SWRosettaLigand pre-optimizes the initial position of the water molecules, docks the ligand to the receptor with explicit water molecules, and minimizes the predicted structure with water molecules. The receptor backbone interface is treated as a loop and perturbed and refined by kinematic closure, or cyclic coordinate descent algorithm, with the presence of the ligand. In two cross-docking test sets, it was identified that for 8 out of 14, and 16 out of 22, test instances, the top-ranked structures by SWRosettaLigand achieved better accuracy than other protocols. PMID:26515196

  3. Ligand engineering of nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton

    Semiconductor nanoparticles (NP) are promising materials to build cheap and efficient solar cells. One of the key challenges in their utilization for solar energy conversion is the control of NP surfaces and ligand-NP interfaces. Recent experiments have shown that by carefully choosing the ligands terminating the NPs, one can tailor electronic and optical absorption properties of NP assemblies, along with their transport properties. By using density functional theory based methods, we investigated how the opto-electronic properties of lead chalcogenide NPs may be tuned by using diverse organic and inorganic ligands. We interpreted experiments, and we showed that an essential prerequisite to avoid detrimental trap states is to ensure charge balance at the ligand-NP interface, possibly with the help of hydrogen treatment Work supported by the Center for Advanced Solar Photophysics, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences.

  4. Ultrafast dynamics of ligands within heme proteins.

    PubMed

    Vos, Marten H

    2008-01-01

    Physiological bond formation and bond breaking events between proteins and ligands and their immediate consequences are difficult to synchronize and study in general. However, diatomic ligands can be photodissociated from heme, and thus in heme proteins ligand release and rebinding dynamics and trajectories have been studied on timescales of the internal vibrations of the protein that drive many biochemical reactions, and longer. The rapidly expanding number of characterized heme proteins involved in a large variety of functions allows comparative dynamics-structure-function studies. In this review, an overview is given of recent progress in this field, and in particular on initial sensing processes in signaling proteins, and on ligand and electron transfer dynamics in oxidases and cytochromes. PMID:17996720

  5. The Retinoid X Receptors and Their Ligands

    PubMed Central

    Dawson, Marcia I.; Xia, Zebin

    2014-01-01

    This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. PMID:22020178

  6. Bioisosteric matrices for ligands of serotonin receptors.

    PubMed

    Warszycki, Dawid; Mordalski, Stefan; Staroń, Jakub; Bojarski, Andrzej J

    2015-04-01

    The concept of bioisosteric replacement matrices is applied to explore the chemical space of serotonin receptor ligands, aiming to determine the most efficient ways of manipulating the affinity for all 5-HT receptor subtypes. Analysis of a collection of over 1 million bioisosteres of compounds with measured activity towards serotonin receptors revealed that an average of 31 % of the ligands for each target are mutual bioisosteres. In addition, the collected dataset allowed the development of bioisosteric matrices-qualitative and quantitative descriptions of the biological effects of each predefined type of bioisosteric substitution, providing favored paths of modifying the compounds. The concept exemplified here for serotonin receptor ligands can likely be more broadly applied to other target classes, thus representing a useful guide for medicinal chemists designing novel ligands. PMID:25772514

  7. Glutamate receptor ligands as anxiolytics.

    PubMed

    Chojnacka-Wójcik, E; Kłodzinska, A; Pilc, A

    2001-08-01

    The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines. PMID:11892923

  8. PLIC: protein-ligand interaction clusters.

    PubMed

    Anand, Praveen; Nagarajan, Deepesh; Mukherjee, Sumanta; Chandra, Nagasuma

    2014-01-01

    Most of the biological processes are governed through specific protein-ligand interactions. Discerning different components that contribute toward a favorable protein- ligand interaction could contribute significantly toward better understanding protein function, rationalizing drug design and obtaining design principles for protein engineering. The Protein Data Bank (PDB) currently hosts the structure of ∼68 000 protein-ligand complexes. Although several databases exist that classify proteins according to sequence and structure, a mere handful of them annotate and classify protein-ligand interactions and provide information on different attributes of molecular recognition. In this study, an exhaustive comparison of all the biologically relevant ligand-binding sites (84 846 sites) has been conducted using PocketMatch: a rapid, parallel, in-house algorithm. PocketMatch quantifies the similarity between binding sites based on structural descriptors and residue attributes. A similarity network was constructed using binding sites whose PocketMatch scores exceeded a high similarity threshold (0.80). The binding site similarity network was clustered into discrete sets of similar sites using the Markov clustering (MCL) algorithm. Furthermore, various computational tools have been used to study different attributes of interactions within the individual clusters. The attributes can be roughly divided into (i) binding site characteristics including pocket shape, nature of residues and interaction profiles with different kinds of atomic probes, (ii) atomic contacts consisting of various types of polar, hydrophobic and aromatic contacts along with binding site water molecules that could play crucial roles in protein-ligand interactions and (iii) binding energetics involved in interactions derived from scoring functions developed for docking. For each ligand-binding site in each protein in the PDB, site similarity information, clusters they belong to and description of

  9. Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand

    PubMed Central

    DeLuca, Samuel; Khar, Karen; Meiler, Jens

    2015-01-01

    RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial ‘low-resolution’ docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10–15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the ‘high-resolution’ full atom refinement step. PMID:26207742

  10. Water exchange on seven-coordinate Mn(II) complexes with macrocyclic pentadentate ligands: insight in the mechanism of Mn(II) SOD mimetics.

    PubMed

    Dees, Anne; Zahl, Achim; Puchta, Ralph; Hommes, Nico J R van Eikema; Heinemann, Frank W; Ivanović-Burmazović, Ivana

    2007-04-01

    Seven-coordinate manganese(II) complexes [Mn(L)(H2O)2]2+, where L represents an equatorial pentadentate macrocyclic ligand with five nitrogen donor atoms, were studied with regard to their acid-base properties, water-exchange rate constants, and corresponding activation parameters (DeltaH, DeltaS, and DeltaV). Three of the studied complexes without imine bonds in the macrocyclic ligand are proven superoxide dismutase (SOD) mimetics. Their water-exchange parameters were compared with those of the imino groups containing complex [Mn(L1)(Cl)2] (dichloro-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]-octadeca-1(18),2,12,14,16-pentaenemanganese(II)), which does not show SOD activity. In addition the X-ray crystal structure of a new complex, dichloro-2,6-bis[1-(2-(N-methylamino)ethylimino)ethyl]pyridine-manganese(II) [Mn(L2)(Cl)2], which is the acyclic analog of [Mn(L1)(Cl)2], is reported. Stability constants of the complexes and the pKa values of the ligands were measured by potentiometric titration. The titrations of [Mn(L1)(H2O)2]2+ and [Mn(L2)(H2O)2]2+ led to complicated species distribution curves because of their ligands containing imine bonds. Water exchange was measured by temperature- and pressure-dependent 17O NMR techniques. In addition to the measurements on [Mn(EDTA)(H2O)]2- and its derivatives, this is the only study of water exchange on seven-coordinate manganese complexes. The water exchange rate constants vary between 1.6 x 107 s-1 and 5.8 x 107 s-1 at 25 degrees C and are mainly controlled by the pi-acceptor abilities of the ligands. The exchange rate constant of the diaqua-1,4,7,10,13-pentaazacyclopentadecanemanganese(II) [Mn([15]aneN5)(H2O)2]2+ complex seems to be even higher but could not be exactly determined. On the basis of the obtained activation parameters, the exchange mechanism of the studied seven-coordinate manganese(II) complexes follows a dissociative pathway (Id mechanism). DFT calculations (UB3LYP/LANL2DZp) were performed to obtain

  11. Synthesis and characterization of mixed ligand chiral nanoclusters.

    PubMed

    Guven, Zekiye P; Ustbas, Burcin; Harkness, Kellen M; Coskun, Hikmet; Joshi, Chakra P; Besong, Tabot M D; Stellacci, Francesco; Bakr, Osman M; Akbulut, Ozge

    2016-07-28

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. While the chiral ligand led mostly to the formation of nanoparticles, the presence of the achiral ligand drastically increased the yield of nanoclusters with enhanced chiral properties. PMID:27362744

  12. Time, the Forgotten Dimension of Ligand Binding Teaching

    ERIC Educational Resources Information Center

    Corzo, Javier

    2006-01-01

    Ligand binding is generally explained in terms of the equilibrium constant K[subscript d] for the protein-ligand complex dissociation. However, both theoretical considerations and experimental data point to the life span of the protein-ligand complex as an important, but generally overlooked, aspect of ligand binding by macromolecules. Short-lived…

  13. Dinuclear Zinc-Catalyzed Asymmetric Desymmetrization of Acyclic 2-Substituted-1,3-Propanediols: A Powerful Entry into Chiral Building Blocks

    PubMed Central

    Trost, Barry M.; Malhotra, Sushant; Mino, Takashi; Rajapaksa, Naomi S.

    2008-01-01

    The asymmetric acylation of meso 2-substituted-1,3-propanediols using an amphoteric chiral dinuclear zinc catalyst is described. It is has been demonstrated that both 2-alkyl- and 2-aryl-1,3-propanediols can be desymmetrized in high yields and enantioselectivities using the same family of ligands. Given that both antipodes of the chiral catalyst are available, both enantiomers of the desymmetrized product can be obtained from the same starting material. The synthetic utility of the desymmetrized products has been demonstrated by the synthesis of several chiral building blocks with high enantiomeric purities. PMID:18655088

  14. Sliding tethered ligands add topological interactions to the toolbox of ligand-receptor design

    NASA Astrophysics Data System (ADS)

    Bauer, Martin; Kékicheff, Patrick; Iss, Jean; Fajolles, Christophe; Charitat, Thierry; Daillant, Jean; Marques, Carlos M.

    2015-09-01

    Adhesion in the biological realm is mediated by specific lock-and-key interactions between ligand-receptor pairs. These complementary moieties are ubiquitously anchored to substrates by tethers that control the interaction range and the mobility of the ligands and receptors, thus tuning the kinetics and strength of the binding events. Here we add sliding anchoring to the toolbox of ligand-receptor design by developing a family of tethered ligands for which the spacer can slide at the anchoring point. Our results show that this additional sliding degree of freedom changes the nature of the adhesive contact by extending the spatial range over which binding may sustain a significant force. By introducing sliding tethered ligands with self-regulating length, this work paves the way for the development of versatile and reusable bio-adhesive substrates with potential applications for drug delivery and tissue engineering.

  15. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    PubMed Central

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming

    2014-01-01

    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  16. Dockomatic - automated ligand creation and docking

    PubMed Central

    2010-01-01

    Background The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI) application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management. PMID:21059259

  17. Determining ligand specificity of Ly49 receptors.

    PubMed

    Lavender, Kerry J; Kane, Kevin P

    2010-01-01

    Ly49 receptors in rodents, like KIR in humans, play an integral role in the regulation of NK cell activity. Some inhibitory Ly49 are known to interact with specific MHC I alleles to maintain tolerance to self tissues, and NK activation is triggered upon the loss of inhibitory signals due to pathological downregulation of self MHC I. Although a virally encoded ligand has been identified that can trigger NK cytotoxicity through an activating Ly49, some activating Ly49 also recognize MHC I and the role of most activating receptors in NK effector function remains poorly defined. As many Ly49 remain orphan receptors, we describe methods to unambiguously discern receptor-ligand pairs. Additionally, we describe a method for the mutagenesis of Ly49 and MHC ligands that can be used to define the motifs conferring receptor specificity for their ligands. Further elucidation of Ly49 ligands is required to continue to define the role of Ly49 in regulating NK cell effector function and may give vital clues to the role of KIR in human health and disease. PMID:20033649

  18. Controlling Gold Nanoclusters by Diphospine Ligands

    SciTech Connect

    Chen, Jing; Zhang, Qianfan; Bonaccorso, Timary A.; Williard, Paul G.; Wang, Lai S.

    2014-01-08

    We report the synthesis and structure determination of a new Au22 nanocluster coordinated by six bidentate diphosphine ligands: 1,8-bis(diphenylphosphino) octane (L8 for short). Single crystal x-ray crystallography and electrospray ionization mass spectrometry show that the cluster assembly is neutral and can be formulated as Au22(L8)6. The Au22 core consists of two Au11 units clipped together by four L8 ligands, while the additional two ligands coordinate to each Au11 unit in a bidentate fashion. Eight gold atoms at the interface of the two Au11 units are not coordinated by any ligands. Four short gold-gold distances (2.64?2.65 Å) are observed at the interface of the two Au11 clusters as a result of the clamping force of the four clipping ligands and strong electronic interactions. The eight uncoordinated surface gold atoms in the Au22(L8)6 nanocluster are unprecedented in atom-precise gold nanoparticles and can be considered as potential in-situ active sites for catalysis.

  19. Ligand-responsive RNA mechanical switches.

    PubMed

    Boerneke, Mark A; Hermann, Thomas

    2015-01-01

    Ligand-responsive RNA mechanical switches represent a new class of simple switching modules that adopt well-defined ligand-free and bound conformational states, distinguishing them from metabolite-sensing riboswitches. Initially discovered in the internal ribosome entry site (IRES) of hepatitis C virus (HCV), these RNA switch motifs were found in the genome of diverse other viruses. Although large variations are seen in sequence and local secondary structure of the switches, their function in viral translation initiation that requires selective ligand recognition is conserved. We recently determined the crystal structure of an RNA switch from Seneca Valley virus (SVV) which is able to functionally replace the switch of HCV. The switches from both viruses recognize identical cognate ligands despite their sequence dissimilarity. Here, we describe the discovery of 7 new switches in addition to the previously established 5 examples. We highlight structural and functional features unique to this class of ligand-responsive RNA mechanical switches and discuss implications for therapeutic development and the construction of RNA nanostructures. PMID:26158858

  20. A screening cascade to identify ERβ ligands

    PubMed Central

    Filgueira, Carly S.; Benod, Cindy; Lou, Xiaohua; Gunamalai, Prem S.; Villagomez, Rosa A.; Strom, Anders; Gustafsson, Jan-Åke; Berkenstam, Anders L.; Webb, Paul

    2014-01-01

    The establishment of effective high throughput screening cascades to identify nuclear receptor (NR) ligands that will trigger defined, therapeutically useful sets of NR activities is of considerable importance. Repositioning of existing approved drugs with known side effect profiles can provide advantages because de novo drug design suffers from high developmental failure rates and undesirable side effects which have dramatically increased costs. Ligands that target estrogen receptor β (ERβ) could be useful in a variety of diseases ranging from cancer to neurological to cardiovascular disorders. In this context, it is important to minimize cross-reactivity with ERα, which has been shown to trigger increased rates of several types of cancer. Because of high sequence similarities between the ligand binding domains of ERα and ERβ, preferentially targeting one subtype can prove challenging. Here, we describe a sequential ligand screening approach comprised of complementary in-house assays to identify small molecules that are selective for ERβ. Methods include differential scanning fluorimetry, fluorescence polarization and a GAL4 transactivation assay. We used this strategy to screen several commercially-available chemical libraries, identifying thirty ERβ binders that were examined for their selectivity for ERβ versus ERα, and tested the effects of selected ligands in a prostate cancer cell proliferation assay. We suggest that this approach could be used to rapidly identify candidates for drug repurposing. PMID:25422593

  1. 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. PMID:15366904

  2. Ligand identification using electron-density map correlations

    SciTech Connect

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn, Judith D.

    2007-01-01

    An automated ligand-fitting procedure is applied to (F{sub o} − F{sub c})exp(iϕ{sub c}) difference density for 200 commonly found ligands from macromolecular structures in the Protein Data Bank to identify ligands from density maps. A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (F{sub o} − F{sub c})exp(iϕ{sub c}) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule.

  3. Characteristic molecular vibrations of adenosine receptor ligands.

    PubMed

    Chee, Hyun Keun; Yang, Jin-San; Joung, Je-Gun; Zhang, Byoung-Tak; Oh, S June

    2015-02-13

    Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t-tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. PMID:25622891

  4. Lanthanide clusters with azide capping ligands.

    PubMed

    Moore, Brian F; Emge, Thomas J; Brennan, John G

    2013-05-20

    Weakly binding azide ligands have been used as surface caps in the synthesis of lanthanide oxo and selenido clusters. Addition of NaN3 and Na2O to in situ prepared solutions of Ln(SePh)3 in pyridine results in the formation of (py)18Sm6Na2O2(N3)16 or (py)10Ln6O2(N3)12(SePh)2 (Ln = Ho, Er), with the Sm and Er compounds characterized by low temperature single crystal X-ray diffraction. Attempts to prepare chalcogenido derivatives by ligand-based redox reactions using elemental Se were successful in the preparation of (py)10Er6O2(SeSe)2(N3)10, a diselenido cluster having crystallographic disorder due to some site sharing of both SeSe and N3 ligands. These compounds all detonate when heated. PMID:23639142

  5. The first scorpionate ligand based on diazaphosphole.

    PubMed

    Mlateček, Martin; Dostál, Libor; Růžičková, Zdeňka; Honzíček, Jan; Holubová, Jana; Erben, Milan

    2015-12-14

    The reaction of PhBCl2 with 1H-1,2,4-λ(3)-diazaphosphole in the presence of NEt3 gives a new scorpionate ligand, phenyl-tris(1,2,4-diazaphospholyl)borate (PhTdap). The coordination behaviour of this ligand toward transition and non-transition metals has been comprehensively studied. In the thallium(I) complex, Tl(PhTdap), κ(2)-N,N bonding supported with intramolecular η(3)-phenyl coordination has been observed in the solid state. Tl(PhTdap) also shows unusual intermolecular π-interactions between five-membered diazaphosphole rings and the thallium atom giving infinite molecular chains in the crystal. In the square planar complex [Pd(C,N-C6H4CH2NMe2)(PhTdap)], κ(2)-bonded scorpionate has been detected in both solution and in the solid state. For other studied compounds with the central metal ion Ti(IV), Mo(II), Mn(I), Fe(II), Ru(II), Co(II), Co(III), Ni(II) and Cd(II), the κ(3)-N,N,N coordination pattern was observed. Electronic properties of PhTdap and its ligand-field strength were elucidated from UV-Vis spectra of transition-metal species. The CH/P replacement on going from tris(pyrazolyl)borate to the ligand PhTdap causes a slight increase in electronic density rendered to the central metal atom. The following order of ligand-field strength has been established: HB(3,5-Me2pz)3 < PhB(pz)3 < HB(1,2,4-triazolyl) < HB(pz)3 < PhB(1,2,4-triazolyl) < PhTdap. The crystal structures of ten metal complexes bearing the new ligand are reported. The possibility of PhTdap coordination through the phosphorus atom is also briefly discussed. PMID:26537349

  6. Multifunctional Ligands in Transition Metal Catalysis (invited 'Focus' article),

    SciTech Connect

    Crabtree, Robert H

    2011-01-01

    Sophisticated ligands are now being designed that do far more than just fulfil their traditional spectator roles by binding to the metal and providing a sterically-defined binding pocket for the substrate in homogeneous transition metal catalysis. This Focus review emphasizes selected cases in which ligands carry additional functional groups that change the properties of the ligand as a result of an external stimulus or undergo catalytically-relevant ligand-based reactivity. These include proton responsive ligands capable of gaining or losing one or more protons, ligands having a hydrogen bonding function, electroresponsive ligands capable of gaining or losing one or more electrons, and photoresponsive ligands capable of undergoing a useful change of properties upon irradiation. Molecular recognition ligands and proton coupled electron transfer (PCET) are briefly discussed.

  7. Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites

    PubMed Central

    2015-01-01

    Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where “nonspecific” interactions contribute to biological function. PMID:26064949

  8. Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites.

    PubMed

    Marsh, Lorraine

    2015-01-01

    Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where "nonspecific" interactions contribute to biological function. PMID:26064949

  9. Ligand configurational entropy and protein binding

    PubMed Central

    Chang, Chia-en A.; Chen, Wei; Gilson, Michael K.

    2007-01-01

    The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing ∼25 kcal/mol (4.184 kJ/kcal) to ΔG°. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. PMID:17242351

  10. MOESSBAUER EFFECT IN HEMOGLOBIN WITH DIFFERENT LIGANDS.

    PubMed

    GONSER, U; GRANT, R W; KREGZDE, J

    1964-02-14

    Recoil-free nuclear gamma-ray resonance adsorption was observed in the iron-57 of blood. The spectral parameters are dependent on the ligand bound to the iron atoms in hemoglobin. The results are interpreted in terms of isomeric shifts and quad rupole splittings. PMID:14081237

  11. Identification of ligands for bacterial sensor proteins.

    PubMed

    Fernández, Matilde; Morel, Bertrand; Corral-Lugo, Andrés; Rico-Jiménez, Miriam; Martín-Mora, David; López-Farfán, Diana; Reyes-Darias, José Antonio; Matilla, Miguel A; Ortega, Álvaro; Krell, Tino

    2016-02-01

    Bacteria have evolved a variety of different signal transduction mechanisms. However, the cognate signal molecule for the very large amount of corresponding sensor proteins is unknown and their functional annotation represents a major bottleneck in the field of signal transduction. The knowledge of the signal molecule is an essential prerequisite to understand the signalling mechanisms. Recently, the identification of signal molecules by the high-throughput protein screening of commercially available ligand collections using differential scanning fluorimetry has shown promise to resolve this bottleneck. Based on the analysis of a significant number of different ligand binding domains (LBDs) in our laboratory, we identified two issues that need to be taken into account in the experimental design. Since a number of LBDs require the dimeric state for ligand recognition, it has to be assured that the protein analysed is indeed in the dimeric form. A number of other examples demonstrate that purified LBDs can contain bound ligand which prevents further binding. In such cases, the apo-form can be generated by denaturation and subsequent refolding. We are convinced that this approach will accelerate the functional annotation of sensor proteins which will help to understand regulatory circuits in bacteria. PMID:26511375

  12. Micropatterned Surfaces with Controlled Ligand Tethering

    PubMed Central

    Petrie, Timothy A.; Stanley, Brandon T.; García, Andrés J.

    2008-01-01

    Microcontact printing (μ-CP) is a facile, cost-effective, and versatile soft-lithography technique to create 2-dimensional patterns of domains with distinct functionalities that provides a robust platform to generate micropatterned biotechnological arrays and cell culture substrates. Current μ-CP approaches rely on non-specific immobilization of biological ligands, either by direct printing or adsorption from solution, onto micropatterned domains surrounded by a non-fouling background. This technique is limited by insufficient control over ligand density. We present a modified μ-CP protocol involving stamping mixed ratios of carboxyl- and tri(ethylene glycol)-terminated alkanethiols that provides for precise covalent tethering of single or multiple ligands to prescribed micropatterns via standard peptide chemistry. Processing parameters were optimized to identify conditions that control relevant endpoint pattern characteristics. This technique provides a facile method to generate micropatterned arrays with tailorable and controlled presentation of biological ligands for biotechnological applications and analyses of cell-material interactions. PMID:18570314

  13. Determination of Ligand Pathways in Globins

    PubMed Central

    Salter, Mallory D.; Blouin, George C.; Soman, Jayashree; Singleton, Eileen W.; Dewilde, Sylvia; Moens, Luc; Pesce, Alessandra; Nardini, Marco; Bolognesi, Martino; Olson, John S.

    2012-01-01

    Although molecular dynamics simulations suggest multiple interior pathways for O2 entry into and exit from globins, most experiments indicate well defined single pathways. In 2001, we highlighted the effects of large-to-small amino acid replacements on rates for ligand entry and exit onto the three-dimensional structure of sperm whale myoglobin. The resultant map argued strongly for ligand movement through a short channel from the heme iron to solvent that is gated by the distal histidine (His-64(E7)) near the solvent edge of the porphyrin ring. In this work, we have applied the same mutagenesis mapping strategy to the neuronal mini-hemoglobin from Cerebratulus lacteus (CerHb), which has a large internal tunnel from the heme iron to the C-terminal ends of the E and H helices, a direction that is 180° opposite to the E7 channel. Detailed comparisons of the new CerHb map with expanded results for Mb show unambiguously that the dominant (>90%) ligand pathway in CerHb is through the internal tunnel, and the major (>75%) ligand pathway in Mb is through the E7 gate. These results demonstrate that: 1) mutagenesis mapping can identify internal pathways when they exist; 2) molecular dynamics simulations need to be refined to address discrepancies with experimental observations; and 3) alternative pathways have evolved in globins to meet specific physiological demands. PMID:22859299

  14. Ligand iron catalysts for selective hydrogenation

    DOEpatents

    Casey, Charles P.; Guan, Hairong

    2010-11-16

    Disclosed are iron ligand catalysts for selective hydrogenation of aldehydes, ketones and imines. A catalyst such as dicarbonyl iron hydride hydroxycyclopentadiene) complex uses the OH on the five member ring and hydrogen linked to the iron to facilitate hydrogenation reactions, particularly in the presence of hydrogen gas.

  15. Ligand configurational entropy and protein binding.

    PubMed

    Chang, Chia-en A; Chen, Wei; Gilson, Michael K

    2007-01-30

    The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing approximately 25 kcal/mol (4.184 kJ/kcal) to DeltaG degrees. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. PMID:17242351

  16. Nanoparticle ligand presentation for targeting solid tumors.

    PubMed

    Duskey, Jason T; Rice, Kevin G

    2014-10-01

    Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success. PMID:24927668

  17. Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand

    NASA Astrophysics Data System (ADS)

    Askevold, Bjorn; Nieto, Jorge Torres; Tussupbayev, Samat; Diefenbach, Martin; Herdtweck, Eberhardt; Holthausen, Max C.; Schneider, Sven

    2011-07-01

    Bioinspired hydrogenation of N2 to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H2 remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N2 splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with π-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H2 at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting.

  18. Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand.

    PubMed

    Askevold, Bjorn; Nieto, Jorge Torres; Tussupbayev, Samat; Diefenbach, Martin; Herdtweck, Eberhardt; Holthausen, Max C; Schneider, Sven

    2011-07-01

    Bioinspired hydrogenation of N(2) to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H(2) remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N(2) splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with π-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H(2) at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting. PMID:21697873

  19. I. Enabling Single-Chain Surfactants to Form Vesicles by Nonamphiphilic Liquid Crystals in Water II. Controlling Attachment and Ligand-Mediated Adherence of Candida albicans on Monolayers

    NASA Astrophysics Data System (ADS)

    Varghese, Nisha

    . Adhesion of C. albicans to a surface is a complex process and is governed by nonspecific attachment or multiple ligand-receptor interactions. The work demonstrates that the multiple ligand-receptor interactions used by C. albicans for adherence to a surface can be individually studied using self-assembled monolayers (SAMs) decorated with minimal motif of the ligands. The SAMs were also used to differentiate between the interactions of the two different morphological forms of C. albicans.. Chapter 5 presents a study on small molecules that were used to inhibit biofilm formed by C. albicans. The acyclic triazoles used in the study were not toxic to the C. albicans and were capable of inhibiting biofilm formed by C. albicans. The acyclic triazole can be used as promising candidates to design new antifungal agents. The chapter also reports the synthesis of squarylated homoserine lactones (SHLs) structural mimics of bacterial acyl homoserine lactones (AHLs) to study the inhibitory effects of SHLs on fungal biofilm. The bacterial AHLs are known to repress the growth of C. albicans and control fungal biofilm in native host environment. The synthesized SHLs were non-toxic to C. albicans and failed to inhibit biofilm formed by C. albicans. . Chapter 6 uses gradient nanotopography combined with controlled surface chemistry to confine bacterial biofilm formed by Escherichia coli. The E. coli biofilm were confined within micrometer sized regions of hydrophobic SAMs surrounded by polyol-terminated SAMs. The study reveals that surface with higher topography enhances the ability of the bioinert SAMs to resist bacterial adherence to surface.

  20. All-Inorganic Germanium Nanocrystal Films by Cationic Ligand Exchange.

    PubMed

    Wheeler, Lance M; Nichols, Asa W; Chernomordik, Boris D; Anderson, Nicholas C; Beard, Matthew C; Neale, Nathan R

    2016-03-01

    We introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and (1)H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport in germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications. PMID:26796765

  1. All-inorganic Germanium nanocrystal films by cationic ligand exchange

    DOE PAGESBeta

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; Anderson, Nicholas C.; Beard, Matthew C.; Neale, Nathan R.

    2016-01-21

    In this study, we introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and 1H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport inmore » germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.« less

  2. Quantum.Ligand.Dock: protein-ligand docking with quantum entanglement refinement on a GPU system.

    PubMed

    Kantardjiev, Alexander A

    2012-07-01

    Quantum.Ligand.Dock (protein-ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein-ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments-the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein-ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html. PMID:22669908

  3. Affinity thermoprecipitatin: Contribution of the efficiency of ligand-protein interaction and access of the ligand.

    PubMed

    Galaev, I Y; Mattiasson, B

    1993-05-01

    Conjugates to two thermoprecipitating polymers, poly(N-vinyl caprolactam) and poly(N-isopropylacrylmide), with soybean trypsin inhibitor, Cibacron Blue 3GA, Cu-iminodiacetic acid, and p-aminobenzamidine were synthesized. The interaction of these conjugates with trypsin and lactate dehydrogenase was studied. Coupling of the ligand to a polymer resulted in a 100-1000-fold decrease in enzyme-affinity. Rough theoretical estimates revealed that a successful affinity precipitation required that the binding of a target protein and a ligand coupled to a polymer have binding constants on the order of 10(-7)-10(-8) M. Such strong affinity of low molecular weight ligands that can provide binding constants of 10(-9)-10(-11) M or alternatively multipoint attachment of the target protein molecule. The ligand in the ligand-polymer conjugate is still accessible to the protein after thermoprecipitation, and the latter can bind with the particle of the dispersion of thermoprecipitated ligand-polymer precipitate may result in stripping of enzyme molecules from the surface of the particles. PMID:18601296

  4. Role of ligand-ligand vs. core-core interactions in gold nanoclusters.

    PubMed

    Milowska, Karolina Z; Stolarczyk, Jacek K

    2016-05-14

    The controlled assembly of ligand-coated gold nanoclusters (NCs) into larger structures paves the way for new applications ranging from electronics to nanomedicine. Here, we demonstrate through rigorous density functional theory (DFT) calculations employing novel functionals accounting for van der Waals forces that the ligand-ligand interactions determine whether stable assemblies can be formed. The study of NCs with different core sizes, symmetry forms, ligand lengths, mutual crystal orientations, and in the presence of a solvent suggests that core-to-core van der Waals interactions play a lesser role in the assembly. The dominant interactions originate from combination of steric effects, augmented by ligand bundling on NC facets, and related to them changes in electronic properties induced by neighbouring NCs. We also show that, in contrast to standard colloidal theory approach, DFT correctly reproduces the surprising experimental trends in the strength of the inter-particle interaction observed when varying the length of the ligands. The results underpin the importance of understanding NC interactions in designing gold NCs for a specific function. PMID:27097887

  5. Amino Acids in Nine Ligand-Prefer Ramachandran Regions

    PubMed Central

    Cao, Chen; Wang, Lincong; Chen, Xiaoyang; Zou, Shuxue; Wang, Guishen; Xu, Shutan

    2015-01-01

    Several secondary structures, such as π-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-prefer ϕ/ψ box residues are exposed more to solvents, whereas amino acids following ligand-prefer ϕ/ψ box residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function. PMID:26491686

  6. Protein Ligand Complex Guided Approach for Virtual Screening.

    PubMed

    Karthikeyan, Muthukumarasamy; Pandit, Deepak; Vyas, Renu

    2015-01-01

    The target ligand association data is a rich source of information which is not exploited enough for drug design efforts in virtual screening. A java based open-source toolkit for Protein Ligand Network Extraction (J-ProLiNE) focused on protein-ligand complex analysis with several features integrated in a distributed computing network has been developed. Sequence alignment and similarity search components have been automated to yield local, global alignment scores along with similarity and distance scores. 10000 proteins with co-crystallized ligands from pdb and MOAD databases were extracted and analyzed for revealing relationships between targets, ligands and scaffolds. Through this analysis, we could generate a protein ligand network to identify the promiscuous and selective scaffolds for multiple classes of proteins targets. Using J-ProLiNE we created a 507 x 507 matrix of protein targets and native ligands belonging to six enzyme classes and analyzed the results to elucidate the protein-protein, protein-ligand and ligand-ligand interactions. In yet another application of the J-ProLiNE software, we were able to process kinase related information stored in US patents to construct disease-gene-ligand-scaffold networks. It is hoped that the studies presented here will enable target ligand knowledge based virtual screening for inhibitor design. PMID:26138572

  7. Receptor-ligand interactions: Advanced biomedical applications.

    PubMed

    Guryanov, Ivan; Fiorucci, Stefano; Tennikova, Tatiana

    2016-11-01

    Receptor-ligand interactions (RLIs) are at the base of all biological events occurring in living cells. The understanding of interactions between complementary macromolecules in biological systems represents a high-priority research area in bionanotechnology to design the artificial systems mimicking natural processes. This review summarizes and analyzes RLIs in some cutting-edge biomedical fields, in particular, for the preparation of novel stationary phases to separate complex biological mixtures in medical diagnostics, for the design of ultrasensitive biosensors for identification of biomarkers of various diseases at early stages, as well as in the development of innovative biomaterials and approaches for regenerative medicine. All these biotechnological fields are closely related, because their success depends on a proper choice, combination and spatial disposition of the single components of ligand-receptor pairs on the surface of appropriately designed support. PMID:27524092

  8. Targeting mitochondrial energy metabolism with TSPO ligands.

    PubMed

    Gut, Philipp

    2015-08-01

    The translocator protein (18 kDa) (TSPO) resides on the outer mitochondrial membrane where it is believed to participate in cholesterol transport and steroid hormone synthesis. Although it is almost ubiquitously expressed, what TSPO does in non-steroidogenic tissues is largely unexplored. Recent studies report changes in glucose homoeostasis and cellular energy production when TSPO function is modulated by selective ligands or by genetic loss-of-function. This review summarizes findings that connect TSPO function with the regulation of mitochondrial energy metabolism. The juxtaposition of TSPO at the cytosolic/mitochondrial interface and the existence of endogenous ligands that are regulated by metabolism suggest that TSPO functions to adapt mitochondrial to cellular metabolism. From a pharmacological perspective the specific up-regulation of TSPO in neuro-inflammatory and injury-induced conditions make TSPO an interesting, druggable target of mitochondrial metabolism. PMID:26551690

  9. [Opioid receptors and their selective ligands].

    PubMed

    Piestrzeniewicz, Mariola Katarzyna; Fichna, Jakub; Michna, Jakub; Janecka, Anna

    2006-01-01

    Opioid receptors (micro, delta, and kappa) belong to a large family of G protein-coupled receptors and play an important physiological role. Stimulation of these receptors triggers analgesic effects and affects the function of gastrointestinal tract. The discovery of opioid peptides, which are endogenous ligands of opioid receptors, including delta-selective enkephalins, kappa-selective dynorphins, and micro-selective endomorphins, initiated their structure-activity relationship studies. For the last 30 years, hundreds of analogs of opioid peptides have been synthesized in an effort to obtain the compounds more active, selective, and resistant to biodegradation than the endogenous ligands. Different unnatural amino acids, as well as cyclisation procedures, leading to conformationaly restricted analogs, were employed. All these modifications resulted in obtaining very selective agonists and antagonists with high affinity at micro-, dlta-, and kappa-opioid receptors, which are extremely useful tools in further studies on the pharmacology of opioid receptors in a mammalian organism. PMID:17201067

  10. Enhanced ligand sampling for relative protein-ligand binding free energy calculations.

    PubMed

    Kaus, Joseph W; McCammon, J Andrew

    2015-05-21

    Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein-ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

  11. Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

    PubMed Central

    2016-01-01

    Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

  12. Targeting Selectins and Their Ligands in Cancer

    PubMed Central

    Natoni, Alessandro; Macauley, Matthew S.; O’Dwyer, Michael E.

    2016-01-01

    Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development. PMID:27148485

  13. Container molecules based on imine type ligands.

    PubMed

    Schulze, A Carina; Oppel, Iris M

    2012-01-01

    This chapter will give a short overview about container molecules, their synthesis and possible applications. The main focus is on those which are based on imine type ligands. These containers can be used for example for guest exchange, gas separation, as chemical sensors or for the stabilisation of white phosphorus under water. The described cages have wide openings or tightly closed ones. For one cage the reversible opening and closing is also described. PMID:22076078

  14. Inhaled innate immune ligands to prevent pneumonia

    PubMed Central

    Evans, Scott E; Tuvim, Michael J; Fox, Cory J; Sachdev, Nidhi; Gibiansky, Leonid; Dickey, Burton F

    2011-01-01

    Epithelial surfaces throughout the body continuously sample and respond to environmental stimuli. The accessibility of lung epithelium to inhaled therapies makes it possible to stimulate local antimicrobial defences with aerosolized innate immune ligands. This strategy has been shown to be effective in preclinical models, as delivery of innate immune ligands to the lungs of laboratory animals results in protection from subsequent challenge with microbial pathogens. Survival of the animal host in this setting correlates directly with killing of pathogens within the lungs, indicating the induction of a resistance mechanism. Resistance appears to be mediated primarily by activated epithelial cells rather than recruited leucocytes. Resistance reaches a peak within hours and persists for several days. Innate immune ligands can interact synergistically under some circumstances, and synergistic combinations of innate ligands delivered by aerosol are capable of inducing a high level of broad host resistance to bacteria, fungi and viruses. The induction of innate antimicrobial resistance within the lungs could have clinical applications in the prevention of lower respiratory tract infection in subjects transiently at high risk. These include cancer patients undergoing myeloablative chemotherapy, intubated patients being mechanically ventilated, vulnerable individuals during seasonal influenza epidemics, asthmatic subjects experiencing a respiratory viral infection, and healthy subjects exposed to virulent pathogens from a bioterror attack or emergent pandemic. In summary, stimulation of the lung epithelium to induce localized resistance to infection is a novel strategy whose clinical utility will be assessed in the near future. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21250981

  15. Targeting Selectins and Their Ligands in Cancer.

    PubMed

    Natoni, Alessandro; Macauley, Matthew S; O'Dwyer, Michael E

    2016-01-01

    Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development. PMID:27148485

  16. Selective oxoanion separation using a tripodal ligand

    DOEpatents

    Custelcean, Radu; Moyer, Bruce A.; Rajbanshi, Arbin

    2016-02-16

    The present invention relates to urea-functionalized crystalline capsules self-assembled by sodium or potassium cation coordination and by hydrogen-bonding water bridges to selectively encapsulate tetrahedral divalent oxoanions from highly competitive aqueous alkaline solutions and methods using this system for selective anion separations from industrial solutions. The method involves competitive crystallizations using a tripodal tris(urea) functionalized ligand and, in particular, provides a viable approach to sulfate separation from nuclear wastes.

  17. Diamine Ligands in Copper-Catalyzed Reactions

    PubMed Central

    Surry, David S.

    2012-01-01

    The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this review we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials. PMID:22384310

  18. galectin-3 ligand — EDRN Public Portal

    Cancer.gov

    Galectin-3 is an endogenous lectin that binds glycan epitopes of cell membrane and some extracellular glycoproteins such as integrins and laminin. Galectin-3 is involved in several biological activities including regulation of cellular cycle, modulation of adhesion and tumor progression and metastasis. Serum galectin-3 ligands have been shown to modulate the immune reaction against tumors and viruses and their level increases in sera of several neoplastic diseases.

  19. Ligand binding and hexacoordination in synechocystis hemoglobin.

    PubMed

    Hvitved, A N; Trent, J T; Premer, S A; Hargrove, M S

    2001-09-14

    A large and phylogenetically diverse group of organisms contain truncated hemoglobins, including the unicellular cyanobacterium Synechocystis (Pesce, A., Couture, M., Dewilde, S., Guertin, M., Yamauchi, K., Ascenzi, P., Moens, L., and Bolognesi, M. (2000) EMBO J. 19, 2424-2434). Synechocystis hemoglobin is also hexacoordinate, with a heme pocket histidine that reversibly coordinates the ligand binding site. Hexacoordinate hemoglobins are ubiquitous in plants and are now being identified in a diverse array of organisms including humans (Arredondo-Peter, R., Hargrove, M. S., Moran, J. F., Sarath, G., and Klucas, R. V. (1998) Plant Physiol. 118, 1121-1125; Trent, J. T., III, Watts, R. A., and Hargrove, M. S. (2001) J. Biol. Chem. 276, 30106-30110). Rate constants for association and dissociation of the hexacoordinating amino acid side chain in Synechocystis hemoglobin have been measured along with bimolecular rate constants for association of oxygen and carbon monoxide following laser flash photolysis. These values were compared with ligand binding initiated by rapid mixing. Site-directed mutagenesis was used to determine the roles of several heme pocket amino acids in facilitating hexacoordination and stabilizing bound oxygen. It is demonstrated that Synechocystis hemoglobin contains a very reactive binding site and that ligand migration through the protein is rapid. Rate constants for hexacoordination by His(46) are also large and facilitated by other heme pocket amino acids including Gln(43). PMID:11438545

  20. Assessment of automatic ligand building in ARP/wARP

    SciTech Connect

    Evrard, Guillaume X. Langer, Gerrit G.; Lamzin, Victor S.

    2007-01-01

    The performance of the ligand-building module of the ARP/wARP software suite is assessed through a large-scale test on known protein–ligand complexes. The results provide a detailed benchmark and guidelines for future improvements. The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement.

  1. A Annealing Algorithm for Designing Ligands from Receptor Structures.

    NASA Astrophysics Data System (ADS)

    Zielinski, Peter J.

    DEenspace NOVO, a simulated annealing method for designing ligands is described. At a given temperature, ligand fragments are randomly selected and randomly placed within the given receptor cavity, often replacing existing ligand fragments. For each new ligand fragment combination, bonded, nonbonded, polarization and solvation energies of the new ligand-receptor system are compared to the previous system. Acceptance or rejection of the new system is decided using the Boltzmann distribution. Thus, energetically unfavorable fragment switches are sometimes accepted, sacrificing immediate energy gains in the interest of finding the system with the globally minimum energy. By lowering the temperature, the rate of unfavorable switches decreases and energetically favorable combinations become difficult to change. The process is halted when the frequency of switches becomes too small. As a test of the method, DEenspace NOVO predicted the positions of important ligand fragments for neuraminidase that are in accord with the natural ligand, sialic acid.

  2. The selective cytotoxic activity in breast cancer cells by an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal is mediated by endoplasmic reticulum stress-induced apoptosis.

    PubMed

    Caba, Octavio; Rodríguez-Serrano, Fernando; Díaz-Gavilán, Mónica; Conejo-García, Ana; Ortiz, Raúl; Martínez-Amat, Antonio; Alvarez, Pablo; Gallo, Miguel A; Campos, Joaquín M; Marchal, Juan A; Aránega, Antonia

    2012-04-01

    Advance in the knowledge of molecular biology has thrown light on many aspects of apoptosis regulation mechanisms. This has allowed a change in anti-cancer therapy trends, from classic cytotoxic strategies to the development of new non-harmful therapies which target the apoptosis response selectively only in tumour cells. We have selected an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal (5) to carry out the anti-cancer studies. This compound shows activity as a potent growth inhibitor of the tumour cell line MCF-7 at a very low concentration. Moreover, when this compound was administered to the non-neoplastic cell line, MCF-10A displayed less toxicity resulting in lower rates of apoptosis. Further studies by microarray hybridization, real-time PCR and western blot showed that when administered to human breast cancer cells, MCF-7, 5 had no activity against classic pro-apoptotic genes such as p53, and even induced the down-regulation of anti-apoptotic genes such as Bcl-2. In contrast, several pro-apoptotic genes related with the endoplasmic reticulum (ER)-stress-induced apoptosis, such as BBC3 and Noxa, appeared up-regulated. These results seem to show that the mechanism of action and selectivity of 5 was via the activation of the ER stress-induced apoptosis. The selective activity of this compound against tumour cells via the ER stress-induced apoptosis supposes a great advantage for future therapeutic use. PMID:22373735

  3. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: implications for drug taxonomy.

    PubMed

    van der Westhuizen, Emma T; Breton, Billy; Christopoulos, Arthur; Bouvier, Michel

    2014-03-01

    The concepts of functional selectivity and ligand bias are becoming increasingly appreciated in modern drug discovery programs, necessitating more informed approaches to compound classification and, ultimately, therapeutic candidate selection. Using the β2-adrenergic receptor as a model, we present a proof of concept study that assessed the bias of 19 β-adrenergic ligands, including many clinically used compounds, across four pathways [cAMP production, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, calcium mobilization, and receptor endocytosis] in the same cell background (human embryonic kidney 293S cells). Efficacy-based clustering placed the ligands into five distinct groups with respect to signaling signatures. In some cases, apparent functional selectivity originated from off-target effects on other endogenously expressed adrenergic receptors, highlighting the importance of thoroughly assessing selectivity of the responses before concluding receptor-specific ligand-biased signaling. Eliminating the nonselective compounds did not change the clustering of the 10 remaining compounds. Some ligands exhibited large differences in potency for the different pathways, suggesting that the nature of the receptor-effector complexes influences the relative affinity of the compounds for specific receptor conformations. Calculation of relative effectiveness (within pathway) and bias factors (between pathways) for each of the compounds, using an operational model of agonism, revealed a global signaling signature for all of the compounds relative to isoproterenol. Most compounds were biased toward ERK1/2 activation over the other pathways, consistent with the notion that many proximal effectors converge on this pathway. Overall, we demonstrate a higher level of ligand texture than previously anticipated, opening perspectives for the establishment of pluridimensional correlations between signaling profiles, drug classification, therapeutic efficacy, and

  4. Defining the property space for chromatographic ligands from a homologous series of mixed-mode ligands.

    PubMed

    Woo, James A; Chen, Hong; Snyder, Mark A; Chai, Yiming; Frost, Russell G; Cramer, Steven M

    2015-08-14

    A homologous ligand library based on the commercially-available Nuvia cPrime ligand was generated to systematically explore various features of a multimodal cation-exchange ligand and to identify structural variants that had significantly altered chromatographic selectivity. Substitution of the polar amide bond with more hydrophobic chemistries was found to enhance retention while remaining hydrophobically-selective for aromatic residues. In contrast, increasing the solvent exposure of the aromatic ring was observed to strengthen the ligand affinity for both types of hydrophobic residues. An optimal linker length between the charged and hydrophobic moieties was also observed to enhance retention, balancing the steric accessibility of the hydrophobic moiety with its ability to interact independently of the charged group. The weak pKa of the carboxylate charge group was found to have a notable impact on protein retention on Nuvia cPrime at lower pH, increasing hydrophobic interactions with the protein. Substituting the charged group with a sulfonic acid allowed this strong MM ligand to retain its electrostatic-dominant character in this lower pH range. pH gradient experiments were also carried out to further elucidate this pH dependent behavior. A single QSAR model was generated using this accumulated experimental data to predict protein retention across a range of multimodal and ion exchange systems. This model could correctly predict the retention of proteins on resins that were not included in the original model and could prove quite powerful as an in silico approach toward designing more effective and differentiated multimodal ligands. PMID:26162668

  5. Synthesis and Photophysical Studies of Iridium Complexes Having Different Ligands

    NASA Astrophysics Data System (ADS)

    Rho, Hyeon Hee; Park, Gui Youn; Ha, Yunkyoung; Kim, Young Sik

    2006-01-01

    The synthesis and photophysical study of efficient phosphorescent iridium(III) complexes having two different (C∧N) ligands are reported. In order to improve the luminescence efficiency by avoiding triplet-triplet (T-T) annihilation, the iridium complexes, Ir(ppy)2(piq) and Ir(ppy)2(piq-F), are designed and prepared where ppy, piq and piq-F represent 2-phenylpyridine, 1-(phenyl)isoquinoline and 2-(4'-fluorophenyl)isoquinoline, respectively. Two ppy ligands and a piq derivative act as a source of energy supply and a piq derivative acts as a chromophore. Since Ir(ppy)3, Ir(piq)3 and Ir(piq-F)3 can be placed in the metal-to-ligand charge transfer (MLCT) excited state, they absorb light effectively. When Ir(ppy)2(piq-F) is placed in excited state, the excitation energy is neither quenched nor deactivated but quickly intramolecular transferred from two ppy ligands to one luminescent piq-F ligand. This can occure because the triplet energy level of ppy is higher than that of piq-F and light is emitted from piq-F ligand in the end. Thus, Ir(ppy)2(piq-F) shows strong photoluminescence originated from piq-F ligand because piq-F ligand is known to have a shorter lifetime than that of ppy ligand. To analyze luminescent mechanism, we calculated these complexes having two different ligand sets theoretically by using computational method.

  6. Landscape of protein-small ligand binding modes.

    PubMed

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    Elucidating the mechanisms of specific small-molecule (ligand) recognition by proteins is a long-standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein-ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all-against-all comparison of 20,040 protein-ligand complexes provided the landscape of the protein-ligand binding modes and its relationships with protein- and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R(2)  = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein-ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them. PMID:27327045

  7. Including Ligand Induced Protein Flexibility into Protein Tunnel Prediction

    PubMed Central

    Kingsley, Laura J.; Lill, Markus A.

    2014-01-01

    In proteins with buried active sites, understanding how ligands migrate through the tunnels that connect the exterior of the protein to the active site can shed light on substrate specificity and enzyme function. A growing body of evidence highlights the importance of protein flexibility in the binding site upon ligand binding; however, the influence of protein flexibility throughout the body of the protein during ligand entry and egress is much less characterized. We have developed a novel tunnel prediction and evaluation method named IterTunnel, which includes the influence of ligand-induced protein flexibility, guarantees ligand egress, and provides detailed free energy information as the ligand proceeds along the egress route. IterTunnel combines geometric tunnel prediction with steered MD in an iterative process to identify tunnels that open as a result of ligand migration and calculates the potential of mean force (PMF) of ligand egress through a given tunnel. Applying this new method to cytochrome P450 2B6 (CYP2B6), we demonstrate the influence of protein flexibility on the shape and accessibility of tunnels. More importantly, we demonstrate that the ligand itself, while traversing through a tunnel, can reshape tunnels due to its interaction with the protein. This process results in the exposure of new tunnels and the closure of pre-existing tunnels as the ligand migrates from the active site. PMID:25043499

  8. Transmutable nanoparticles with reconfigurable surface ligands.

    PubMed

    Kim, Youngeun; Macfarlane, Robert J; Jones, Matthew R; Mirkin, Chad A

    2016-02-01

    Unlike conventional inorganic materials, biological systems are exquisitely adapted to respond to their surroundings. Proteins and other biological molecules can process a complex set of chemical binding events as informational inputs and respond accordingly via a change in structure and function. We applied this principle to the design and synthesis of inorganic materials by preparing nanoparticles with reconfigurable surface ligands, where interparticle bonding can be programmed in response to specific chemical cues in a dynamic manner. As a result, a nascent set of "transmutable nanoparticles" can be driven to crystallize along multiple thermodynamic trajectories, resulting in rational control over the phase and time evolution of nanoparticle-based matter. PMID:26912697

  9. Helix-helix interfaces and ligand binding.

    PubMed

    Kurochkina, Natalya; Choekyi, Tsering

    2011-08-21

    Helix-helix parallel interfaces can be characterized by certain combinations of amino acids, which repeatedly occur at core positions a and d (leucine zipper nomenclature) in homologous and nonhomologous proteins and influence interhelical angles. Applied for the prediction of interhelical angles in glutathione S-transferase, intracellular chloride channel and annexin molecules from various sources, correct results were achieved in 58 out of 62 proteins. Interhelical angles are found to correlate with the conformation of the glutathione S-transferase ligands glutathione, s-hexylglutathione, glutathione sulfonic acid, and glutathione-s-dinitrobenzene. PMID:21620863

  10. Transmutable nanoparticles with reconfigurable surface ligands

    NASA Astrophysics Data System (ADS)

    Kim, Youngeun; Macfarlane, Robert J.; Jones, Matthew R.; Mirkin, Chad A.

    2016-02-01

    Unlike conventional inorganic materials, biological systems are exquisitely adapted to respond to their surroundings. Proteins and other biological molecules can process a complex set of chemical binding events as informational inputs and respond accordingly via a change in structure and function. We applied this principle to the design and synthesis of inorganic materials by preparing nanoparticles with reconfigurable surface ligands, where interparticle bonding can be programmed in response to specific chemical cues in a dynamic manner. As a result, a nascent set of “transmutable nanoparticles” can be driven to crystallize along multiple thermodynamic trajectories, resulting in rational control over the phase and time evolution of nanoparticle-based matter.