A ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity

NASA Astrophysics Data System (ADS)

Lee, Yen-Chun; Patil, Sumersing; Golz, Christopher; Strohmann, Carsten; Ziegler, Slava; Kumar, Kamal; Waldmann, Herbert

2017-02-01

The selective transformation of different starting materials by different metal catalysts under individually optimized reaction conditions to structurally different intermediates and products is a powerful approach to generate diverse molecular scaffolds. In a more unified albeit synthetically challenging strategy, common starting materials would be exposed to a common metal catalysis, leading to a common intermediate and giving rise to different scaffolds by tuning the reactivity of the metal catalyst through different ligands. Herein we present a ligand-directed synthesis approach for the gold(I)-catalysed cycloisomerization of oxindole-derived 1,6-enynes that affords distinct molecular scaffolds following different catalytic reaction pathways. Varying electronic properties and the steric demand of the gold(I) ligands steers the fate of a common intermediary gold carbene to selectively form spirooxindoles, quinolones or df-oxindoles. Investigation of a synthesized compound collection in cell-based assays delivers structurally novel, selective modulators of the Hedgehog and Wnt signalling pathways, autophagy and of cellular proliferation.

Tuning the structure, dimensionality and luminescent properties of lanthanide metal-organic frameworks under ancillary ligand influence.

PubMed

D'Vries, Richard F; Gomez, German E; Hodak, José H; Soler-Illia, Galo J A A; Ellena, Javier

2016-01-14

This manuscript addresses the synthesis, structural characterization and optical properties of a 1D coordination polymer (CPs) and 2D and 3D Metal-Organic Frameworks (MOFs) obtained from lanthanide metals, 3-hydroxinaftalene-2,7-disulfonic acid (3-OHNDS) and two different phenanthroline derivates as ancillary ligands. The first is a family of 2D compounds with formula [Ln(3-OHNDS)(H2O)2], where Ln = La(), Pr(), Nd() and Sm(). The addition of 1,10-phenanthroline (phen) in the reaction produces 1D compounds with general formula [Ln(3-OHNDS)(phen)(H2O)]·3H2O, where Ln = La(), Pr(), Nd() and Sm(). Finally, the synthesis with 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-TMPhen) as an ancillary ligand results in the formation of the 3D [La(3-OHNDS)(3,4,7,8-TMphen)(H2O)] () compound. The photoluminescence (PL) properties of 1D and 2D compounds were fully investigated in comparison with the 3-OHNDS ligand. One of the most important results was the obtaining of a white-light single-emitter without adding dopant atoms in the structure. With all these results in mind it was possible to establish structure-property relationships.

Synthesis and characterization β-ketoamine ligands

NASA Astrophysics Data System (ADS)

Zaid, Nurzati Amani Mohamed; Hassan, Nur Hasyareeda; Karim, Nurul Huda Abd

2018-04-01

β-ketoamine ligands are important members of heterodonor ligand because of their ease of preparation and modification of both steric and/or electronic effects. Complexes with β-ketoamine has received much less attention and there has been no study about this complex with β-ketoamine in ionic liquid reported. Two type of β-ketoamine ligands which are 4-amino-3-pentene-2-onato (A) and 3-amino-2-butenoic acid methyl ester (B) have been synthesized in this work. The resulting compound formed was characterized using standard spectroscopic and structural techniques which includes 1H and 13C, NMR spectroscopy and FTIR spectroscopy. The 1H and 13C NMR spectrum displayed all the expected signals with correct integration and multiplicity. And it is proved that there are some differences between two ligands as observed in NMR and FTIR spectrum.

Synthesis, structural characterization and antitumor activity of a Ca(II) coordination polymer based on 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai, Xi-Shi, E-mail: taixs@wfu.edu.cn; Wang, Xin

2017-03-15

A new Ca(II) coordination polymer, ([CaL(H{sub 2}O){sub 4}] · (H{sub 2}O){sub 4}){sub n} (L = 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide) has been prepared by one-pot synthesis method. And it was characterized by elemental analysis, IR and thermal analysis. The result of X-ray single-crystal diffraction analysis shows that the Ca(II) complex molecules form one-dimensional chain structure by the bridging oxygen atoms. The anti-tumor activity of L ligand and the Ca(II) coordination polymer has also been studied.

Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.

PubMed

Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd W; Porecca, Frank; Hruby, Victor J

2016-01-15

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results. Copyright © 2015 Elsevier Ltd. All rights reserved.

Iron-based magnetic superhalogens with pseudohalogens as ligands: An unbiased structure search

PubMed Central

Ping Ding, Li; Shao, Peng; Lu, Cheng; Hui Zhang, Fang; Wang, Li Ya

2017-01-01

We have performed an unbiased structure search for a series of neutral and anionic FeL4 (L = BO2, CN, NO2, NO3, OH, CH3, NH2, BH4 and Li2H3) clusters using the CALYPSO (Crystal structure Analysis by Particle Swarm Optimization) structure search method. To probe the superhalogen properties of neutral and anionic FeL4 clusters, we used density-functional theory with the B3LYP functional to examine three factors, including distribution of extra electron, pattern of bonding and the nature of the ligands. Theoretical results show that Fe(BO2)4, Fe(NO3)4 and Fe(NO2)4 can be classified as magnetic superhalogen due to that their electron affinities even exceed those of the constituent ligands. The magnetic moment of Fe atom is almost entirly maintained when it is decorated with various ligands except for neutral and anionic (Li2H3)4. Moreover, the current work is also extended to the salt moieties formed by hyperhalogen/superhalogen anion and Na+ ion. It is found that these salts against dissociation into Na + FeL4 are thermodynamic stable except for Na[Fe(OH)4]. These results provides a wealth of electronic structure information about FeL4 magnetic superhalogens and offer insights into the synthesis mechanisms. PMID:28327547

Ligand structure and mechanical properties of single-nanoparticle-thick membranes.

PubMed

Salerno, K Michael; Bolintineanu, Dan S; Lane, J Matthew D; Grest, Gary S

2015-06-01

The high mechanical stiffness of single-nanoparticle-thick membranes is believed to result from the local structure of ligand coatings that mediate interactions between nanoparticles. These ligand structures are not directly observable experimentally. We use molecular dynamics simulations to observe variations in ligand structure and simultaneously measure variations in membrane mechanical properties. We have shown previously that ligand end group has a large impact on ligand structure and membrane mechanical properties. Here we introduce and apply quantitative molecular structure measures to these membranes and extend analysis to multiple nanoparticle core sizes and ligand lengths. Simulations of nanoparticle membranes with a nanoparticle core diameter of 4 or 6 nm, a ligand length of 11 or 17 methylenes, and either carboxyl (COOH) or methyl (CH(3)) ligand end groups are presented. In carboxyl-terminated ligand systems, structure and interactions are dominated by an end-to-end orientation of ligands. In methyl-terminated ligand systems large ordered ligand structures form, but nanoparticle interactions are dominated by disordered, partially interdigitated ligands. Core size and ligand length also affect both ligand arrangement within the membrane and the membrane's macroscopic mechanical response, but are secondary to the role of the ligand end group. Moreover, the particular end group (COOH or CH(3)) alters the nature of how ligand length, in turn, affects the membrane properties. The effect of core size does not depend on the ligand end group, with larger cores always leading to stiffer membranes. Asymmetry in the stress and ligand density is observed in membranes during preparation at a water-vapor interface, with the stress asymmetry persisting in all membranes after drying.

Ligand structure and mechanical properties of single-nanoparticle thick membranes

DOE PAGES

Salerno, Kenneth Michael; Bolintineanu, Dan S.; Lane, J. Matthew D.; ...

2015-06-16

We believe that the high mechanical stiffness of single-nanoparticle-thick membranes is the result of the local structure of ligand coatings that mediate interactions between nanoparticles. These ligand structures are not directly observable experimentally. We use molecular dynamics simulations to observe variations in ligand structure and simultaneously measure variations in membrane mechanical properties. We have shown previously that ligand end group has a large impact on ligand structure and membrane mechanical properties. Here we introduce and apply quantitative molecular structure measures to these membranes and extend analysis to multiple nanoparticle core sizes and ligand lengths. Simulations of nanoparticle membranes with amore » nanoparticle core diameter of 4 or 6 nm, a ligand length of 11 or 17 methylenes, and either carboxyl (COOH) or methyl (CH 3) ligand end groups are presented. In carboxyl-terminated ligand systems, structure and interactions are dominated by an end-to-end orientation of ligands. In methyl-terminated ligand systems large ordered ligand structures form, but nanoparticle interactions are dominated by disordered, partially interdigitated ligands. Core size and ligand length also affect both ligand arrangement within the membrane and the membrane's macroscopic mechanical response, but are secondary to the role of the ligand end group. Additionally, the particular end group (COOH or CH 3) alters the nature of how ligand length, in turn, affects the membrane properties. The effect of core size does not depend on the ligand end group, with larger cores always leading to stiffer membranes. Asymmetry in the stress and ligand density is observed in membranes during preparation at a water-vapor interface, with the stress asymmetry persisting in all membranes after drying.« less

Synthesis of heterocycles: Indolo (2,1-a) isoquinolines, renewables, and aptamer ligands for cellular imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beasley, Jonathan

2013-01-01

In this thesis, we explore both total syntheses and methodologies of several aromatic heterocyclic molecules. Extensions of the Kraus indole synthesis toward 2-substituted and 2,3-disubstituted indoles, as well as biologically attractive indolo[2,1-a]isoquinolines are described. Recent renewable efforts directed to commodity maleic acid and the first reported furan-based ionic liquids are described. Our total synthesis of mRNA aptamer ligand PDC-Gly, and its dye coupled forms, plus aminoglycoside dye coupled ligands used in molecular imaging, are described.

Synthesis and characterization of crystalline structures based on phenylboronate ligands bound to alkaline earth cations.

PubMed

Reinholdt, Marc; Croissant, Jonas; Di Carlo, Lidia; Granier, Dominique; Gaveau, Philippe; Bégu, Sylvie; Devoisselle, Jean-Marie; Mutin, P Hubert; Smith, Mark E; Bonhomme, Christian; Gervais, Christel; van der Lee, Arie; Laurencin, Danielle

2011-08-15

We describe the preparation of the first crystalline compounds based on arylboronate ligands PhB(OH)(3)(-) coordinated to metal cations: [Ca(PhB(OH)(3))(2)], [Sr(PhB(OH)(3))(2)]·H(2)O, and [Ba(PhB(OH)(3))(2)]. The calcium and strontium structures were solved using powder and single-crystal X-ray diffraction, respectively. In both cases, the structures are composed of chains of cations connected through phenylboronate ligands, which interact one with each other to form a 2D lamellar structure. The temperature and pH conditions necessary for the formation of phase-pure compounds were investigated: changes in temperature were found to mainly affect the morphology of the crystallites, whereas strong variations in pH were found to affect the formation of pure phases. All three compounds were characterized using a wide range of analytical techniques (TGA, IR, Raman, XRD, and high resolution (1)H, (11)B, and (13)C solid-state NMR), and the different coordination modes of phenylboronate ligands were analyzed. Two different kinds of hydroxyl groups were identified in the structures: those involved in hydrogen bonds, and those that are effectively "free" and not involved in hydrogen bonds of any significant strength. To position precisely the OH protons within the structures, an NMR-crystallography approach was used: the comparison of experimental and calculated NMR parameters (determined using the Gauge Including Projector Augmented Wave method, GIPAW) allowed the most accurate positions to be identified. In the case of the calcium compound, it was found that it is the (43)Ca NMR data that are critical to help identify the best model of the structure. © 2011 American Chemical Society

Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK

PubMed Central

Bührmann, Mike; Wiedemann, Bianca M.; Müller, Matthias P.; Hardick, Julia; Ecke, Maria

2017-01-01

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography. PMID:28892510

Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2′ Ligands of Darunavir

PubMed Central

Fyvie, W. Sean; Brindisi, Margherita; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

2018-01-01

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2′ ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2′ subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2′ ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pM and antiviral activity of 6.2 and 3.9 nM, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2′ subsite. PMID:29110408

Ruthenium(II) bipyridine complexes bearing new keto-enol azoimine ligands: synthesis, structure, electrochemistry and DFT calculations.

PubMed

Al-Noaimi, Mousa; Awwadi, Firas F; Mansi, Ahmad; Abdel-Rahman, Obadah S; Hammoudeh, Ayman; Warad, Ismail

2015-01-25

The novel azoimine ligand, Ph-NH-N=C(COCH3)-NHPh(C≡CH) (H2L), was synthesized and its molecular structure was determined by X-ray crystallography. Catalytic hydration of the terminal acetylene of H2L in the presence of RuCl3·3H2O in ethanol at reflux temperature yielded a ketone (L1=Ph-N=N-C(COCH3)=N-Ph(COCH3) and an enol (L2=Ph-N=N-C(COCH3)=N-PhC(OH)=CH2) by Markovnikov addition of water. Two mixed-ligand ruthenium complexes having general formula, trans-[Ru(bpy)(Y)Cl2] (1-2) (where Y=L1 (1) and Y=L2 (2), bpy is 2.2'-bipyrdine) were achieved by the stepwise addition of equimolar amounts of (H2L) and bpy ligands to RuCl3·3H2O in absolute ethanol. Theses complexes were characterized by elemental analyses and spectroscopic (IR, UV-Vis, and NMR (1D (1)H NMR, (13)C NMR, (DEPT-135), (DEPT-90), 2D (1)H-(1)H and (13)C-(1)H correlation (HMQC) spectroscopy)). The two complexes exhibit a quasi-reversible one electron Ru(II)/Ru(III) oxidation couple at 604 mV vs. ferrocene/ferrocenium (Cp2Fe(0/+)) couple along with one electron ligand reduction at -1010 mV. The crystal structure of complex 1 showed that the bidentate ligand L1 coordinates to Ru(II) by the azo- and imine-nitrogen donor atoms. The complex adopts a distorted trans octahedral coordination geometry of chloride ligands. The electronic spectra of 1 and 1+ in dichloromethane have been modeled by time-dependent density functional theory (TD-DFT). Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis, structure and property of diorganotin complexes with chiral N-(5-chlorosalicylidene)valinate ligand

NASA Astrophysics Data System (ADS)

Tian, Laijin; Yao, Yanze; Wang, Yuhua; Liu, Jin

2018-03-01

Six new diorganotin N-[(5-chloro-2-oxyphenyl)methylene]valinates, R2SnL (R = Me, 1; Et, 2; L = 5-Cl-2-OC6H3CH = NCH(i-Pr)COO: (S)-, a; (R)-, b; (RS)-, c), have been synthesized from the reaction of R2SnCl2 with the chiral ligand KHL (potassium salt of HL) in different solvents and characterized by elemental analysis, IR, NMR (1H, 13C and 119Sn) spectra. In benzene, the configuration of the chiral ligand was retained. (S)-Enantiomers (1a and 2a) and (R)-enantiomers (1b and 2b) display discrete molecular structures with distorted trigonal bipyramidal geometries in which two C atoms of organic groups (R) and the imino N atom occupy the equatorial positions and a phenoxide O and an unidentate carboxylate group O atom are in the axial orientation. In the methanol, the chiral ligand was racemized. 1cṡMeOH is a centrosymmetric dimers formed by (R)- and (S)- enantiomers through two Snsbnd OṡṡṡSn bridges. The coordination geometry of the Sn atom can be described as a distorted pentagonal bipyramid with two methyl groups in axial positions. The crystal of 2c is composed of two threefold symmetric trimers, a [Et2SnL-(R)]3 and a [Et2SnL-(S)]3, with a macrocyclic 12-membered ring structure formed by the bidenate bridging coordination of carboxylate group to tin atoms. Each tin atom is six-coordinated in distorted [SnC2NO3] octahedron geometry. The fluorescence properties of ligand KHL and complexes 1 (1a-1c) and 2 (2a-2c) have been measured. The results show the complexes may be explored for potential luminescent materials.

Synthesis and structures of ligand-dominated one-dimensional silver(I)–bis(pyridylmethyl)amine coordination chains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Hung-Jui; Liu, Yu-Chiao; Tseng, Yu-Jui

2016-10-15

Reactants slow diffusion of Ag(I) salts with 3,4′-bis(pyridylmethyl)amine (3,4′-bpma), an unsymmetric bis-pyridyl ligand equipped with a non-innocent amine backbone, afforded polymeric coordination adducts 1–5 having a general formula ([Ag(3,4′-bpma)(solv)]X){sub n} (solv = H{sub 2}O, CH{sub 3}OH, and none; X= CF{sub 3}CO{sub 2}{sup –}, BF{sub 4}{sup –}, ClO{sub 4}{sup –}, CF{sub 3}SO{sub 3}{sup –}, and SbF{sub 6}{sup –}). Single-crystal X-ray diffraction (SCXRD) analyses reveal that colorless crystals of Ag(I) coordination polymers (CPs) 1–5 have very similar one-dimensional (1D) non-flat chain structures, which are preferentially depicted as a “zipper-like” rather than a ladder-like or a double-stranded chain topologies. The 3,4′-bpma ligand inmore » these Ag(I) CPs displays a μ{sub 3}-bridging mode with a gauche–trans (1,4, and 5) and a trans–trans (2 and 3) conformations. Noteworthy, anions do not show strong influence on structural modulation of Ag(I) CPs in the solid state, but really affect CP conformations and packing fashions, indicative of a ligand-dominated assembly process for such a Ag(I)–3,4′-bpma system. Thermal stabilities and solid-state photoluminescence properties of crystalline materials 1–5 were investigated. - Graphical abstract: This work has addressed five ligand-dominated Ag(I)–3,4′-bpma polymeric adducts, which show similar one-dimensional non-flat chain structures depicting a “zipper-like” topology rather than a ladder-like or a double-stranded chain structures.« less

Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations

PubMed Central

Seeliger, Daniel; de Groot, Bert L.

2010-01-01

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available. PMID:20066034

Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach

NASA Astrophysics Data System (ADS)

Lam, Polo C.-H.; Abagyan, Ruben; Totrov, Maxim

2018-01-01

Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace.

Synthesis and characterization of new complexes of nickel (II), palladium (II) and platinum(II) with derived sulfonamide ligand: Structure, DFT study, antibacterial and cytotoxicity activities

NASA Astrophysics Data System (ADS)

Bouchoucha, Afaf; Zaater, Sihem; Bouacida, Sofiane; Merazig, Hocine; Djabbar, Safia

2018-06-01

The synthesis, characterization and biological study of new nickel (II), palladium (II), and platinum (II) complexes with sulfamethoxazole ligand used in pharmaceutical field, were reported. [MLCl2].nH2O is the general formula obtained for Pd(II) and Pt(II) complexes. These complexes have been prepared and characterized by elemental analysis, FTIR, 1HNMR spectral, magnetic measurements, UV-Visible spectra, and conductivity. The DFT calculation was applied to optimize the geometric structure of the Pd(II) and Pt(II) complexes. A new single-crystal X-ray structure of the Ni(II) complex has been determined. It crystallized in monoclinic system with P 21/c space group and Z = 8. The invitro antibacterial activity of ligand and complexes against Escherichia coli, P. aeruginosa, Klebsiella pneumoniae, S. aureus, Bacillus subtilis species has been carried out and compared using agar-diffusion method. The Pd(II) and Pt(II) complexes showed a remarkable inhibition against bacteria tested. The invitro cytotoxicity assay of the complexes against three cell lines chronic myelogenous leukaemia (K562), human colon adenocarcinoma (HT-29) and breast cancer (MCF-7) was also reported.

Application of a novel design paradigm to generate general nonpeptide combinatorial templates mimicking beta-turns: synthesis of ligands for melanocortin receptors.

PubMed

Webb, Thomas R; Jiang, Luyong; Sviridov, Sergey; Venegas, Ruben E; Vlaskina, Anna V; McGrath, Douglas; Tucker, John; Wang, Jian; Deschenes, Alain; Li, Rongshi

2007-01-01

We report the further application of a novel approach to template and ligand design by the synthesis of agonists of the melanocortin receptor. This design method uses the conserved structural data from the three-dimensional conformations of beta-turn peptides to design rigid nonpeptide templates that mimic the orientation of the main chain C-alpha atoms in a peptide beta-turn. We report details on a new synthesis of derivatives of template 1 that are useful for the synthesis of exploratory libraries. The utility of this technique is further exemplified by several iterative rounds of high-throughput synthesis and screening, which result in new partially optimized nonpeptide agonists for several melanocortin receptors.

Nonlinear optical and G-Quadruplex DNA stabilization properties of novel mixed ligand copper(II) complexes and coordination polymers: Synthesis, structural characterization and computational studies

NASA Astrophysics Data System (ADS)

Rajasekhar, Bathula; Bodavarapu, Navya; Sridevi, M.; Thamizhselvi, G.; RizhaNazar, K.; Padmanaban, R.; Swu, Toka

2018-03-01

The present study reports the synthesis and evaluation of nonlinear optical property and G-Quadruplex DNA Stabilization of five novel copper(II) mixed ligand complexes. They were synthesized from copper(II) salt, 2,5- and 2,3- pyridinedicarboxylic acid, diethylenetriamine and amide based ligand (AL). The crystal structure of these complexes were determined through X-ray diffraction and supported by ESI-MAS, NMR, UV-Vis and FT-IR spectroscopic methods. Their nonlinear optical property was studied using Gaussian09 computer program. For structural optimization and nonlinear optical property, density functional theory (DFT) based B3LYP method was used with LANL2DZ basis set for metal ion and 6-31G∗ for C,H,N,O and Cl atoms. The present work reveals that pre-polarized Complex-2 showed higher β value (29.59 × 10-30e.s.u) as compared to that of neutral complex-1 (β = 0.276 × 10-30e.s.u.) which may be due to greater advantage of polarizability. Complex-2 is expected to be a potential material for optoelectronic and photonic technologies. Docking studies using AutodockVina revealed that complex-2 has higher binding energy for both G-Quadruplex DNA (-8.7 kcal/mol) and duplex DNA (-10.1 kcal/mol). It was also observed that structure plays an important role in binding efficiency.

A one pot organic/CdSe nanoparticle hybrid material synthesis with in situ π-conjugated ligand functionalization.

PubMed

Mazzio, Katherine A; Okamoto, Ken; Li, Zhi; Gutmann, Sebastian; Strein, Elisabeth; Ginger, David S; Schlaf, Rudy; Luscombe, Christine K

2013-02-14

A one pot method for organic/colloidal CdSe nanoparticle hybrid material synthesis is presented. Relative to traditional ligand exchange processes, these materials require smaller amounts of the desired capping ligand, shorter syntheses and fewer processing steps, while maintaining nanoparticle morphology.

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands.

PubMed

Chen, Weiping; Mbafor, William; Roberts, Stanley M; Whittall, John

2006-03-29

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands has been developed. On the basis of this new methodology, several new families of ferrocene-based phosphine ligands have been prepared coupling chirality at phosphorus with other, more standard stereogenic features. The introduction of P-chirality into ferrocene-based phosphine ligands enhances the enantioselective discrimination produced by the corresponding Rh catalyst when a matching among the planar chirality, carbon chirality, and the chirality of phosphorus is achieved.

Dispersed metal cluster catalysts by design. Synthesis, characterization, structure, and performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arslan, Ilke; Dixon, David A.; Gates, Bruce C.

2015-09-30

To understand the class of metal cluster catalysts better and to lay a foundation for the prediction of properties leading to improved catalysts, we have synthesized metal catalysts with well-defined structures and varied the cluster structures and compositions systematically—including the ligands bonded to the metals. These ligands include supports and bulky organics that are being tuned to control both the electron transfer to or from the metal and the accessibility of reactants to influence catalytic properties. We have developed novel syntheses to prepare these well-defined catalysts with atomic-scale control the environment by choice and placement of ligands and applied state-of-themore » art spectroscopic, microscopic, and computational methods to determine their structures, reactivities, and catalytic properties. The ligands range from nearly flat MgO surfaces to enveloping zeolites to bulky calixarenes to provide controlled coverages of the metal clusters, while also enforcing unprecedented degrees of coordinative unsaturation at the metal site—thereby facilitating bonding and catalysis events at exposed metal atoms. With this wide range of ligand properties and our arsenal of characterization tools, we worked to achieve a deep, fundamental understanding of how to synthesize robust supported and ligand-modified metal clusters with controlled catalytic properties, thereby bridging the gap between active site structure and function in unsupported and supported metal catalysts. We used methods of organometallic and inorganic chemistry combined with surface chemistry for the precise synthesis of metal clusters and nanoparticles, characterizing them at various stages of preparation and under various conditions (including catalytic reaction conditions) and determining their structures and reactivities and how their catalytic properties depend on their compositions and structures. Key characterization methods included IR, NMR, and EXAFS spectroscopies to

Lanthanide complexes with aromatic o-phosphorylated ligands: synthesis, structure elucidation and photophysical properties.

PubMed

Shuvaev, Sergey; Utochnikova, Valentina; Marciniak, Łukasz; Freidzon, Alexandra; Sinev, Ilya; Van Deun, Rik; Freire, Ricardo O; Zubavichus, Yan; Grünert, Wolfgang; Kuzmina, Natalia

2014-02-28

Lanthanide complexes LnL3 (Ln = Sm, Eu, Tb, Dy, Tm, Yb, Lu) with aromatic o-phosphorylated ligands (HL(1) and HL(2)) have been synthesized and identified. Their molecular structure was proposed on the basis of a new complex approach, including DFT calculations, Sparkle/PM3 modelling, EXAFS spectroscopy and luminescent probing. The photophysical properties of all of the complexes were investigated in detail to obtain a deeper insight into the energy transfer processes.

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

NASA Astrophysics Data System (ADS)

Costanzi, Stefano; Tikhonova, Irina G.; Harden, T. Kendall; Jacobson, Kenneth A.

2009-11-01

Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

Photochemical Synthesis and Ligand Exchange Reactions of Ru(CO)[subscript 4] (Eta[superscript 2]-Alkene) Compounds

ERIC Educational Resources Information Center

Cooke, Jason; Berry, David E.; Fawkes, Kelli L.

2007-01-01

The photochemical synthesis and subsequent ligand exchange reactions of Ru(CO)[subscript 4] (eta[superscript2]-alkene) compounds has provided a novel experiment for upper-level inorganic chemistry laboratory courses. The experiment is designed to provide a system in which the changing electronic properties of the alkene ligands could be easily…

Synthesis and structural characterization of lithium, sodium and potassium complexes supported by a tridentate amino-bisphenolate ligand

NASA Astrophysics Data System (ADS)

Durango-García, Clara J.; Rufino-Felipe, Ernesto; López-Cardoso, Marcela; Muñoz-Hernández, Miguel-Ángel; Montiel-Palma, Virginia

2018-07-01

Reactions of methylamino-N,N-bis(2-methylene-4,6-di-tert-butylphenol) (1) with one or two equivalents of bulk Li, Na or K metals in THF or DMSO render mono or dialkali metal complexes depending on the stoichiometric ratio of the reactants. The metal-methylamino-N-(2-methylene-4,6-tert-butylphenol)sbnd N-(2-methylene-4,6-tert-butylphenolate) complexes, 2Li, 2Na and 2K, are generated upon the substitution of a single phenol hydrogen of 1. In the solid state, complex 2Na is a dimer due to the establishment of two symmetric hydrogen bonds between two adjacent molecules. The Na center also engages into the formation of a ten-membered metallacycle ring with a butterfly-like structure. Due to dimerization, an intermolecular six-membered core is formed involving two sodium and four oxygen atoms. The weakly coordinated nitrogen atom from the ligand is nearly perpendicular to the hexagonal core. The dimetal-methylamino-N,N‧-bis(2-methylene-4,6-di-tert-butylphenolate) complexes, 3Li, 3Na and 3K result from metal substitution of the two phenol hydrogens from ligand 1. The SC-XRD structures of 3Li and 3Na are discreet, each incorporating two metal atoms in different coordination environments. Ten-membered rings with boat-boat conformations are also observed as are rhombic central M2O2 cores. The molecular structure of 3K in DMSO shows a higher degree of aggregation. It effectively comprises four K atoms, two ligand backbones and seven solvent molecules forming a central four-membered K2O2 ring perpendicular to an eight-membered structure formed also by K and O atoms spanning over the two ligand moieties.

New Synthetic Approach for the Incorporation of 3,2-Hydroxypyridinone (HOPO) Ligands: Synthesis of Structurally Diverse Poly HOPO Chelators

PubMed Central

Arumugam, Jayanthi; Brown, Hayley A.; Jacobs, Hollie K.; Gopalan, Aravamudan S.

2011-01-01

The HOPO sulfonamide reagent, 3, was prepared from commercial 2,3-dihydroxypyridine in four steps in good yields. Sulfonamide 3 readily underwent selective alkylation with dibromides in the presence of base or could be coupled to alcohols using Mitsunobu conditions. The utility of this nucleophilic HOPO reagent was demonstrated by the synthesis some tris and tetraHOPO chelators. This approach for tethering HOPO ligands is unique and flexible as shown by the preparation of HOPO/iminocarboxylic acid chelator 17. PMID:21709749

Carbene complexes of rhodium and iridium from tripodal N-heterocyclic carbene ligands: synthesis and catalytic properties.

PubMed

Mas-Marzá, Elena; Poyatos, Macarena; Sanaú, Mercedes; Peris, Eduardo

2004-03-22

Two tripodal trisimidazolium ligand precursors have been tested in the synthesis of new N-heterocyclic carbene rhodium and iridium complexes. [Tris(3-methylbenzimidazolium-1-yl)]methane sulfate gave products with coordination of the decomposed precursor. [1,1,1-Tris(3-butylimidazolium-1-yl)methyl]ethane trichloride (TIMEH(3)(Bu)) coordinated to the metal in a chelate and bridged-chelate form, depending on the reaction conditions. The crystal structures of two of the products are described. The compounds resulting from the coordination with TIME(Bu) were tested in the catalytic hydrosilylation of terminal alkynes.

The use of small-molecule structures to complement protein–ligand crystal structures in drug discovery

PubMed Central

Cole, Jason C.

2017-01-01

Many ligand-discovery stories tell of the use of structures of protein–ligand complexes, but the contribution of structural chemistry is such a core part of finding and improving ligands that it is often overlooked. More than 800 000 crystal structures are available to the community through the Cambridge Structural Database (CSD). Individually, these structures can be of tremendous value and the collection of crystal structures is even more helpful. This article provides examples of how small-molecule crystal structures have been used to complement those of protein–ligand complexes to address challenges ranging from affinity, selectivity and bioavailability though to solubility. PMID:28291759

Synthesis of imine bond containing insoluble polymeric ligand and its transition metal complexes, structural characterization and catalytic activity on esterification reaction.

PubMed

Gönül, İlyas; Ay, Burak; Karaca, Serkan; Saribiyik, Oguz Yunus; Yildiz, Emel; Serin, Selahattin

2017-01-01

In this study, synthesis of insoluble polymeric ligand (L) and its transition metal complexes [Cu(L)Cl 2 ]·2H 2 O (1) , [Co(L)Cl 2 (H 2 O) 2 ] (2) and [Ni(L)Cl 2 (H 2 O) 2 ] (3) , having the azomethine groups, were synthesized by the condensation reactions of the diamines and dialdehydes. The structural properties were characterized by the analytical and spectroscopic methods using by elemental analysis, Fourier Transform Infrared, Thermo Gravimetric Analysis, Powder X-ray Diffraction, magnetic susceptibility and Inductively Coupled Plasma. The solubilities of the synthesized polymeric materials were also investigated and found as insoluble some organic and inorganic solvents. Additionally, their catalytic performance was carried out for the esterification reaction of acetic acid and butyl acetate. The highest conversion rate is 75.75% by using catalyst 1 . The esterification of butanol gave butyl acetate with 100% selectivity.

Synthesis of imine bond containing insoluble polymeric ligand and its transition metal complexes, structural characterization and catalytic activity on esterification reaction

PubMed Central

Gönül, İlyas; Ay, Burak; Karaca, Serkan; Saribiyik, Oguz Yunus; Yildiz, Emel; Serin, Selahattin

2017-01-01

Abstract In this study, synthesis of insoluble polymeric ligand (L) and its transition metal complexes [Cu(L)Cl2]·2H2O (1), [Co(L)Cl2(H2O)2] (2) and [Ni(L)Cl2(H2O)2] (3), having the azomethine groups, were synthesized by the condensation reactions of the diamines and dialdehydes. The structural properties were characterized by the analytical and spectroscopic methods using by elemental analysis, Fourier Transform Infrared, Thermo Gravimetric Analysis, Powder X-ray Diffraction, magnetic susceptibility and Inductively Coupled Plasma. The solubilities of the synthesized polymeric materials were also investigated and found as insoluble some organic and inorganic solvents. Additionally, their catalytic performance was carried out for the esterification reaction of acetic acid and butyl acetate. The highest conversion rate is 75.75% by using catalyst 1. The esterification of butanol gave butyl acetate with 100% selectivity. PMID:29491815

Synthesis, physico-chemical properties and complexing abilities of new amphiphilic ligands from D-galacturonic acid.

PubMed

Allam, Anas; Behr, Jean-Bernard; Dupont, Laurent; Nardello-Rataj, Véronique; Plantier-Royon, Richard

2010-04-19

This paper describes a convenient and efficient synthesis of new complexing surfactants from d-galacturonic acid and n-octanol as renewable raw materials in a two-step sequence. In the first step, simultaneous O-glycosidation-esterification under Fischer conditions was achieved. The anomeric ratio of the products was studied based on the main experimental parameters and the activation mode (thermal or microwave). In the second step, aminolysis of the n-octyl ester was achieved with various functionalized primary amines under standard thermal or microwave activation. The physico-chemical properties of these new amphiphilic ligands were measured and these compounds were found to exhibit interesting surface properties. Complexing abilities of one uronamide ligand functionalized with a pyridine moiety toward Cu(II) ions was investigated in solution by EPR titrations. A solid compound was also synthesized and characterized, its relative structure was deduced from spectroscopic data. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Synthesis, crystal structures and antitumor activities of copper(II) complexes with a 2-acetylpyrazine isonicotinoyl hydrazone ligand

NASA Astrophysics Data System (ADS)

Xu, Jun; Zhou, Tao; Xu, Zhou-Qing; Gu, Xin-Nan; Wu, Wei-Na; Chen, Hong; Wang, Yuan; Jia, Lei; Zhu, Tao-Feng; Chen, Ru-Hua

2017-01-01

Five complexes, [Cu(L)2]·4.5H2O (1), [Cu(HL)2](NO3)2·CH3OH (2) {[Cu2(L)2(NO3)(H2O)2]·(NO3)}n (3), [Cu2(HL)2(SO4)2]·2CH3OH (4) and [Cu4(L)4Cl4]·5H2O (5) based on HL (where HL = 2-acetylpyrazine isonicotinoyl hydrazone) have been synthesized and characterized by X-ray diffraction analyses. The counter anion and organic base during the synthesis procedure influence the structures of the complexes efficiently, which generate five complexes as mono-, bi-, tetra-nuclear and one-dimensional structures. The antitumor activities of the complexes 1-5 (except for complex 3 with the poor solubility) against the Patu8988 human pancreatic cancer, ECA109 human esophagus cancer and SGC7901 human gastric cancer cell lines are screened by MTT assay. The results indicate that the chelation of Cu(II) with the ligand is responsible for the observed high cytotoxicity of the copper(II) complexes and the 1:2 copper species 1 and 2 demonstrate lower antitumor activities than that of the 1:1 copper species 4 and 5. In addition, the in vitro apoptosis inducing activity of the copper(II) complex 5 against SGC7901 cell line is determined. And the results show that the complex can bring about apoptosis of the cancerous cells in vitro.

Cationic copper (I) complexes with bulky 1,4-diaza-1,3-butadiene ligands - Synthesis, solid state structure and catalysis

NASA Astrophysics Data System (ADS)

Anga, Srinivas; Kottalanka, Ravi K.; Pal, Tigmansu; Panda, Tarun K.

2013-05-01

We report the full characterization of two glyoxal-based ligands N,N bis(diphenylmethyl)-1,4-diaza-1,3-butadiene ligand (DADPh2, 1) and more bulky N,N bis(triphenylmethyl)-1,4-diaza-1,3-butadiene ligand (DADPh3, 2) by the condensation reaction of glyoxal and diphenylmethanamine and triphenyl-methanamine respectively. The copper (I) complex of composition [Cu(DADPh2)2]PF6 (3) having two neutral bidentate N,N bis(diphenyl-methyl)-1,4-diaza-1,3-butadiene ligand was prepared by the reaction of [Cu(CH3CN)4]PF6 and 1 in 1:2 ratio in dichloromethane. In a similar reaction with N,N bis(triphenylmethyl)-1,4-diaza-1,3-butadiene ligand (2) and [Cu(CH3CN)4]PF6 in dichloromethane yielded corresponding heteroleptic copper (I) complex [Cu(DADPh3)(CH3CN)2]PF6 (4). Another copper (I) complex [Cu(DADPh2)(PPh3)]PF6 (5) can also be obtained by the one pot reaction involving ligand 1, [Cu(CH3CN)4]PF6 and triphenylphosphine. Solid state structures of all the five compounds were established by single crystal X-ray diffraction analysis. The solid state structures of the copper complexes 3-5 reveal a distorted tetrahedral geometry around the copper (I) centers. The copper complexes 3-5 were tested as catalysts for the coupling reaction of o-iodophenol and phenyl acetylene and it was observed that complex 4 exhibits the highest catalytic activity.

PDBToSDF: Create ligand structure files from PDB file.

PubMed

Muppalaneni, Naresh Babu; Rao, Allam Appa

2011-01-01

Protein Data Bank (PDB) file contains atomic data for protein and ligand in protein-ligand complexes. Structure data file (SDF) contains data for atoms, bonds, connectivity and coordinates of molecule for ligands. We describe PDBToSDF as a tool to separate the ligand data from pdb file for the calculation of ligand properties like molecular weight, number of hydrogen bond acceptors, hydrogen bond receptors easily.

Biferrocene-Based Diphosphine Ligands: Synthesis and Application of Walphos Analogues in Asymmetric Hydrogenations

PubMed Central

2013-01-01

A total of four biferrocene-based Walphos-type ligands have been synthesized, structurally characterized, and tested in the rhodium-, ruthenium- and iridium-catalyzed hydrogenation of alkenes and ketones. Negishi coupling conditions allowed the biferrocene backbone of these diphosphine ligands to be built up diastereoselectively from the two nonidentical and nonracemic ferrocene fragments (R)-1-(N,N-dimethylamino)ethylferrocene and (SFc)-2-bromoiodoferrocene. The molecular structures of (SFc)-2-bromoiodoferrocene, the coupling product, two ligands, and the two complexes ([PdCl2(L)] and [RuCl(p-cymene)(L)]PF6) were determined by X-ray diffraction. The structural features of complexes and the catalysis results obtained with the newly synthesized biferrocene-based ligands were compared with those of the corresponding Walphos ligands. PMID:23457421

Structural direction of hybrid organic-inorganic materials: Synthesis of vanadium oxyfluoride, copper vanadate, and copper molybdate solid state materials through solvuthermal and solution methods

NASA Astrophysics Data System (ADS)

Deburgomaster, Paul

The vast structural complexity of inorganic oxides with structure directing organocations, nitrogen containing ligands and organophosphonate ligands was explored. The hydrothermal reaction conditions utilized herein include the variables of temperature, pH, fill volume and stoichiometry. The systems studied included: (1) the complex materials rendered from reactions of organoamine cations on the structure of vanadium oxides, oxyfluorides and fluorides. As with other systems, the influence of the mineralizer HF was not limited to pH as fluorine incorporation was not uncommon. In specific cases this coincided with reduction of vanadium sites. (2) The copper-organonitrogen ligand/vanadium oxide/aromatic phosphonate system has been studied. The rigid aromatic di- and tri-phosphonate tethers have provided a series of materials which are structurally distinct from the previously investigated aliphatic series. The inclusion of copper-coordinated nitrogen bi- and tri-dentate ligands also provided structural diversity. Product composition was highly influenced by the HF/V ratio. A similar study was conducted with the ligand 1,4-carboxy-phenylphosphonic acid. (3) The preparation of a series of bimetallic organic-inorganic hybrid materials of the M(II)/VxOy/organonitrogen ligand class was further evidence of the utility of thermodynamically driven hydrothermal synthesis. (4) While decomposition of the spherical Keplerate molybdenum clusters is encountered under hydrothermal conditions, this highly soluble form of molybdate was investigated for the development of hybrid organic-inorganic room temperature solution synthesis.

Structural variability in Cu(I) and Ag(I) coordination polymers with a flexible dithione ligand: Synthesis, crystal structure, microbiological and theoretical studies

NASA Astrophysics Data System (ADS)

Beheshti, Azizolla; Nozarian, Kimia; Babadi, Susan Soleymani; Noorizadeh, Siamak; Motamedi, Hossein; Mayer, Peter; Bruno, Giuseppe; Rudbari, Hadi Amiri

2017-05-01

Two new compounds namely [Cu(SCN)(μ-L)]n (1) and {[Ag (μ2-L)](ClO4)}n (2) have been synthesized at room temperature by one-pot reactions between the 1,1-(1,4-butanediyl)bis(1,3-dihydro-3-methyl-1H-imidazole- 2-thione) (L) and appropriate copper(I) and silver(I) salts. These polymers have been characterized by single crystal X-ray diffraction, XRPD, TGA, elemental analysis, infrared spectroscopy, antibacterial activity and scanning probe microscopy studies. In the crystal structure of 1, copper atoms have a distorted trigonal planar geometry with a CuS2N coordination environment. Each of the ligands in the structure of 1 acting as a bidentate S-bridging ligand to form a 1D chain structure. Additionally, the adjacent 1D chains are interconnected by the intermolecular C-H…S interactions to create a 2D network structure. In contrast to 1, in the cationic 3D structure of 2 each of the silver atoms exhibits an AgS4 tetrahedral geometry with 4-membered Ag2S2 rings. In the structure of 2, the flexible ligand adopts two different conformations; gauche-anti-gauche and anti-anti-anti. The antibacterial studies of these polymers showed that polymer 2 is more potent antibacterial agent than 1. Scanning probe microscopy (SPM) study of the treated bacteria was carried out to investigate the structural changes cause by the interactions between the polymers and target bacteria. Theoretical study of polymer 1 investigated by the DFT calculations indicates that observed transitions at 266 nm and 302 nm in the UV-vis spectrum could be attributed to the π→π* and MLCT transitions, respectively.

Models of protein–ligand crystal structures: trust, but verify

PubMed Central

Deller, Marc C.

2015-01-01

X-ray crystallography provides the most accurate models of protein–ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein–ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein–ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein–ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein–ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein–ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein–ligand models for their computational and biological studies, and we provide an overview of how this can be achieved. PMID:25665575

Models of protein-ligand crystal structures: trust, but verify.

PubMed

Deller, Marc C; Rupp, Bernhard

2015-09-01

X-ray crystallography provides the most accurate models of protein-ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein-ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein-ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein-ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein-ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein-ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein-ligand models for their computational and biological studies, and we provide an overview of how this can be achieved.

Synthesis, X-ray crystal structures and catecholase activity investigation of new chalcone ligands

NASA Astrophysics Data System (ADS)

Thabti, Salima; Djedouani, Amel; Rahmouni, Samra; Touzani, Rachid; Bendaas, Abderrahmen; Mousser, Hénia; Mousser, Abdelhamid

2015-12-01

The reaction of dehydroacetic acid DHA carboxaldehyde and RCHO derivatives (R = quinoleine-8-; indole-3-; pyrrol-2- and 4-(dimethylamino)phenyl - afforded four new chalcone ligands (4-hydroxy-6-methyl-3-[(2E)-3-quinolin-8-ylprop-2-enoyl]-2H-pyran-2-one) L1, (4-hydroxy-3-[(2E)-3-(1H-indol-3-yl)prop-2-enoyl]-6-methyl-2H-pyran-2-one) L2, (4-hydroxy-6-methyl-3-[(2E)-3-(1H-pyrrol-2-yl)prop-2-enoyl]-2H-pyran-2-one) L3, and (3-{(2E)-3-[4-(dimethylamino)phenyl]prop-2-enoyl}-4-hydroxy-6-methyl-2H-pyran-2-one) L4. L3 and L4 were characterized by X-ray crystallography. Molecules crystallize with four and two molecules in the asymmetric unit, respectively and adopt an E conformation about the Cdbnd C bond. Both structures are stabilized by an extended network O-H … O. Furthermore, N-H … O and C-H … O hydrogen bonds are observed in L3 and L4 structures, respectively. The in situ generated copper (II) complexes of the four compounds L1, L2, L3 and L4 were examined for their catalytic activities and were found to catalyze the oxidation reaction of catechol to o-quinone under atmospheric dioxygen. The rates of this oxidation depend on three parameters: ligand, ion salts and solvent nature and the combination L2[Cu (CH3COO)2] leads to the faster catalytic process.

Volume-confined synthesis of ligand-free gold nanoparticles with tailored sizes for enhanced catalytic activity

NASA Astrophysics Data System (ADS)

Shaik, Firdoz; Zhang, Weiqing; Niu, Wenxin; Lu, Xianmao

2014-10-01

Ligand-free Au nanoparticles with controlled sizes are synthesized via a volume-confined method. In this synthesis, mesoporous hollow silica shells (mHSS) are used as nano-containers for the impregnation of HAuCl4 solution before they are separated from the bulk solution. With a simple heating process, the Au precursor confined within the cavity of the isolated hollow shells is converted into ligand-free Au nanoparticles. The size of the Au nanoparticles can be tuned precisely by loading HAuCl4 solution of different concentrations, or by using mHSS with different cavity volumes. The ligand-free Au nanoparticles demonstrate superior catalytic activity than sodium citrate-capped Au nanoparticles.

Fluorescence-based strategies to investigate the structure and dynamics of aptamer-ligand complexes

NASA Astrophysics Data System (ADS)

Perez-Gonzalez, Cibran; Lafontaine, Daniel; Penedo, J.

2016-08-01

In addition to the helical nature of double-stranded DNA and RNA, single-stranded oligonucleotides can arrange themselves into tridimensional structures containing loops, bulges, internal hairpins and many other motifs. This ability has been used for more than two decades to generate oligonucleotide sequences, so-called aptamers, that can recognize certain metabolites with high affinity and specificity. More recently, this library of artificially-generated nucleic acid aptamers has been expanded by the discovery that naturally occurring RNA sequences control bacterial gene expression in response to cellular concentration of a given metabolite. The application of fluorescence methods has been pivotal to characterize in detail the structure and dynamics of these aptamer-ligand complexes in solution. This is mostly due to the intrinsic high sensitivity of fluorescence methods and also to significant improvements in solid-phase synthesis, post-synthetic labelling strategies and optical instrumentation that took place during the last decade. In this work, we provide an overview of the most widely employed fluorescence methods to investigate aptamer structure and function by describing the use of aptamers labelled with a single dye in fluorescence quenching and anisotropy assays. The use of 2-aminopurine as a fluorescent analog of adenine to monitor local changes in structure and fluorescence resonance energy transfer (FRET) to follow long-range conformational changes is also covered in detail. The last part of the review is dedicated to the application of fluorescence techniques based on single-molecule microscopy, a technique that has revolutionized our understanding of nucleic acid structure and dynamics. We finally describe the advantages of monitoring ligand-binding and conformational changes, one molecule at a time, to decipher the complexity of regulatory aptamers and summarize the emerging folding and ligand-binding models arising from the application of these

Fluorescence-Based Strategies to Investigate the Structure and Dynamics of Aptamer-Ligand Complexes

PubMed Central

Perez-Gonzalez, Cibran; Lafontaine, Daniel A.; Penedo, J. Carlos

2016-01-01

In addition to the helical nature of double-stranded DNA and RNA, single-stranded oligonucleotides can arrange themselves into tridimensional structures containing loops, bulges, internal hairpins and many other motifs. This ability has been used for more than two decades to generate oligonucleotide sequences, so-called aptamers, that can recognize certain metabolites with high affinity and specificity. More recently, this library of artificially-generated nucleic acid aptamers has been expanded by the discovery that naturally occurring RNA sequences control bacterial gene expression in response to cellular concentration of a given metabolite. The application of fluorescence methods has been pivotal to characterize in detail the structure and dynamics of these aptamer-ligand complexes in solution. This is mostly due to the intrinsic high sensitivity of fluorescence methods and also to significant improvements in solid-phase synthesis, post-synthetic labeling strategies and optical instrumentation that took place during the last decade. In this work, we provide an overview of the most widely employed fluorescence methods to investigate aptamer structure and function by describing the use of aptamers labeled with a single dye in fluorescence quenching and anisotropy assays. The use of 2-aminopurine as a fluorescent analog of adenine to monitor local changes in structure and fluorescence resonance energy transfer (FRET) to follow long-range conformational changes is also covered in detail. The last part of the review is dedicated to the application of fluorescence techniques based on single-molecule microscopy, a technique that has revolutionized our understanding of nucleic acid structure and dynamics. We finally describe the advantages of monitoring ligand-binding and conformational changes, one molecule at a time, to decipher the complexity of regulatory aptamers and summarize the emerging folding and ligand-binding models arising from the application of these

Identification of the Ah-Receptor Structural Determinants for Ligand Preferences

PubMed Central

Xing, Yongna

2012-01-01

The aryl hydrocarbon receptor (AHR) is a transcription factor that responds to diverse ligands and plays a critical role in toxicology, immune function, and cardiovascular physiology. The structural basis of the AHR for ligand promiscuity and preferences is critical for understanding AHR function. Based on the structure of a closely related protein HIF2α, we modeled the AHR ligand binding domain (LBD) bound to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BaP) and identified residues that control ligand preferences by shape and H-bond potential. Mutations to these residues, particularly Q377 and G298, resulted in robust and opposite changes in the potency of TCDD and BaP and up to a 20-fold change in the ratio of TCDD/BaP efficacy. The model also revealed a flexible “belt” structure; molecular dynamic (MD) simulation suggested that the “belt” and several other structural elements in the AHR-LBD are more flexible than HIF2α and likely contribute to ligand promiscuity. Molecular docking of TCDD congeners to a model of human AHR-LBD ranks their binding affinity similar to experimental ranking of their toxicity. Our study reveals key structural basis for prediction of toxicity and understanding the AHR signaling through diverse ligands. PMID:22659362

A grand unified model for liganded gold clusters

NASA Astrophysics Data System (ADS)

Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

2016-12-01

A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three `flavours' (namely, bottom, middle and top) to represent three possible valence states. The `composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design.

A grand unified model for liganded gold clusters

PubMed Central

Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

2016-01-01

A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three ‘flavours' (namely, bottom, middle and top) to represent three possible valence states. The ‘composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design. PMID:27910848

Design and Synthesis of Self-Assembled Monolayers on Mesoporous Supports (SAMMS): The Importance of Ligand Posture in Functional Nanomaterials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fryxell, Glen E.; Mattigod, Shas V.; Lin, Yuehe

2007-07-01

Water, and water quality, are issues of critical importance to the future of humankind. The Earth’s water supplies have been contaminated by a wide variety of industrial, military and natural sources. The need exists for an efficient separation technology to remove heavy metal and radionuclide contamination from water. Surfactant templated synthesis of mesoporous ceramics provides a versatile foundation upon which to build high efficiency environmental sorbents. These nanoporous ceramics condense a huge amount of surface area into a very small volume. These mesoporous architectures can be subsequently functionalized through molecular self-assembly. These functional mesoporous materials offer significant capabilities in termsmore » of removal of heavy metals and radionuclides from a variety of liquid media, including groundwater, contaminated oils and contaminated chemical weapons. They are highly efficient sorbents, whose rigid, open pore structure allows for rapid, efficient sorption kinetics. Their interfacial chemistry can be fine-tuned to selectively sequester a specific target species, such as heavy metals, tetrahedral oxometallate anions and radionuclides. This manuscript provides a review of the design, synthesis and performance of the sorbent materials. The role that ligand posture plays in the chemistry of these interfacial ligand fields is discussed.« less

Synthesis of β-galactosylamides as ligands of the peanut lectin. Insights into the recognition process.

PubMed

Cano, María Emilia; Varela, Oscar; García-Moreno, María Isabel; García Fernández, José Manuel; Kovensky, José; Uhrig, María Laura

2017-04-18

The synthesis of mono and divalent β-galactosylamides linked to a hydroxylated chain having a C2 symmetry axis derived from l-tartaric anhydride is reported. Reference compounds devoid of hydroxyl groups in the linker were also prepared from β-galactosylamine and succinic anhydride. After functionalization with an alkynyl residue, the resulting building blocks were grafted onto different azide-equipped scaffolds through the copper catalyzed azide-alkyne cycloaddition. Thus, a family of structurally related mono and divalent β-N-galactopyranosylamides was obtained and fully characterized. The binding affinities of the ligands towards the model lectin PNA were measured by the enzyme-linked lectin assay (ELLA). The IC 50 values were significantly higher than that of galactose but the presence of hydroxyl groups in the aglycone chain improved lectin recognition. Docking and molecular dynamics experiments were in accordance with the hypothesis that a hydroxyl group properly disposed in the linker could mimic the Glc O3 in the recognition process. On the other hand, divalent presentation of the ligands led to lectin affinity enhancements. Copyright © 2017 Elsevier Ltd. All rights reserved.

Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives.

PubMed

Franchini, Silvia; Battisti, Umberto Maria; Prandi, Adolfo; Tait, Annalisa; Borsari, Chiara; Cichero, Elena; Fossa, Paola; Cilia, Antonio; Prezzavento, Orazio; Ronsisvalle, Simone; Aricò, Giuseppina; Parenti, Carmela; Brasili, Livio

2016-04-13

Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synthesis, structural characterization, reactivity, and catalytic properties of copper(I) complexes with a series of tetradentate tripodal tris(pyrazolylmethyl)amine ligands.

PubMed

Haldón, Estela; Delgado-Rebollo, Manuela; Prieto, Auxiliadora; Alvarez, Eleuterio; Maya, Celia; Nicasio, M Carmen; Pérez, Pedro J

2014-04-21

Novel tris(pyrazolylmethyl)amine ligands Tpa(Me3), Tpa*(,Br), and Tpa(Br3) have been synthesized and structurally characterized. The coordination chemistries of these three new tetradentate tripodal ligands and the already known Tpa and Tpa* have been explored using different copper(I) salts as starting materials. Cationic copper(I) complexes [Tpa(x)Cu]PF6 (1-4) have been isolated from the reaction of [Cu(NCMe)4]PF6 and 1 equiv of the ligand. Complexes 2 (Tpa(x) = Tpa*) and 3 (Tpa(x) = Tpa(Me3)) have been characterized by X-ray studies. The former is a 1D helical coordination polymer, and the latter is a tetranuclear helicate. In both structures, the Tpa(x) ligand adopts a μ(2):κ(2):κ(1)-coordination mode. However, in solution, all of the four complexes form fluxional species. When CuI is used as the copper(I) source, neutral compounds 5-8 have been obtained. Complexes 6-8 exhibit a 1:1 metal-to-ligand ratio, whereas 5 presents 2:1 stoichiometry. Its solid-state structure has been determined by X-ray diffraction, revealing its 3D polymeric nature. The polymer is composed by the assembly of [Tpa2Cu4I4] units, in which Cu4I4 presents a step-stair structure. The Tpa ligands bridge the Cu4I4 clusters, adopting also a μ(2):κ(2):κ(1)-coordination mode. As observed for the cationic derivatives, the NMR spectra of 5-8 show the equivalence of the three pyrazolyl arms of the ligands in these complexes. The reactivities of cationic copper(I) derivatives 1-4 with PPh3 and CO have been explored. In all cases, 1:1 adducts [Tpa(x)CuL]PF6 [L = PPh3 (9-11), CO (12-15)] have been isolated. The crystal structure of [Tpa*Cu(PPh3)]PF6 (9) has been obtained, showing that the coordination geometry around copper(I) is trigonal-pyramidal with the apical position occupied by the tertiary amine N atom. The Tpa* ligand binds the Cu center to three of its four N atoms, with one pyrazolyl arm remaining uncoordinated. In solution, the carbonyl adducts 13-15 exist as a mixture of two

A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding.

PubMed

Lin, Ying-Ting

2013-04-30

A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. A PPARγ (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis.

The use of supramolecular structures as protein ligands.

PubMed

Stopa, Barbara; Jagusiak, Anna; Konieczny, Leszek; Piekarska, Barbara; Rybarska, Janina; Zemanek, Grzegorz; Król, Marcin; Piwowar, Piotr; Roterman, Irena

2013-11-01

Congo red dye as well as other eagerly self-assembling organic molecules which form rod-like or ribbon-like supramolecular structures in water solutions, appears to represent a new class of protein ligands with possible wide-ranging medical applications. Such molecules associate with proteins as integral clusters and preferentially penetrate into areas of low molecular stability. Abnormal, partly unfolded proteins are the main binding target for such ligands, while well packed molecules are generally inaccessible. Of particular interest is the observation that local susceptibility for binding supramolecular ligands may be promoted in some proteins as a consequence of function-derived structural changes, and that such complexation may alter the activity profile of target proteins. Examples are presented in this paper.

Testing inhomogeneous solvation theory in structure-based ligand discovery.

PubMed

Balius, Trent E; Fischer, Marcus; Stein, Reed M; Adler, Thomas B; Nguyen, Crystal N; Cruz, Anthony; Gilson, Michael K; Kurtzman, Tom; Shoichet, Brian K

2017-08-15

Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.

Unexpected self-sorting self-assembly formation of a [4:4] sulfate:ligand cage from a preorganized tripodal urea ligand.

PubMed

Pandurangan, Komala; Kitchen, Jonathan A; Blasco, Salvador; Boyle, Elaine M; Fitzpatrick, Bella; Feeney, Martin; Kruger, Paul E; Gunnlaugsson, Thorfinnur

2015-04-07

The design and synthesis of tripodal ligands 1-3 based upon the N-methyl-1,3,5-benzenetricarboxamide platform appended with three aryl urea arms is reported. This ligand platform gives rise to highly preorganized structures and is ideally suited for binding SO4 (2-) and H2 PO4 (-) ions through multiple hydrogen-bonding interactions. The solid-state crystal structures of 1-3 with SO4 (2-) show the encapsulation of a single anion within a cage structure, whereas the crystal structure of 1 with H2 PO4 (-) showed that two anions are encapsulated. We further demonstrate that ligand 4, based on the same platform but consisting of two bis-urea moieties and a single ammonium moiety, also recognizes SO4 (2-) to form a self-assembled capsule with [4:4] SO4 (2-) :4 stoichiometry in which the anions are clustered within a cavity formed by the four ligands. This is the first example of a self-sorting self-assembled capsule where four tetrahedrally arranged SO4 (2-) ions are embedded within a hydrophobic cavity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quaternary Cu2ZnSnS4 quantum dot-sensitized solar cells: Synthesis, passivation and ligand exchange

NASA Astrophysics Data System (ADS)

Bai, Bing; Kou, Dongxing; Zhou, Wenhui; Zhou, Zhengji; Tian, Qingwen; Meng, Yuena; Wu, Sixin

2016-06-01

The quaternary Cu2ZnSnS4 (CZTS) QDs had been successfully introduced into quantum dot-sensitized solar cells (QDSC) via hydrolysis approach in our previous work [Green Chem. 2015, vol. 17, p. 4377], but the obtained cell efficiency was still limited by low open-circuit voltage and fill factor. Herein, we use 1-dodecanethiol (DDT) as capping ligand for fairly small-sized CZTS QDs synthesis to improve their intrinsic properties. Since this strong bonded capping ligand can not be replaced by 3-mercaptopropionic acid (MPA) directly, the nature cation (Cu, Zn or Sn)-DDT units of QDs are first exchanged by the preconjugated Cd-oleate via successive ionic layer adsorption and reaction (SILAR) procedure accompanied with the formation of a core/shell structure. The weak bonded oleic acid (OA) can be finally replaced by MPA and the constructed water soluble CZTS/CdSe QDSC achieves an impressive conversion efficiency of 4.70%. The electron transport and recombination dynamic processes are confirmed by intensity-modulated photocurrent spectroscopy (IMPS)/intensity-modulated photovoltage spectroscopy (IMVS) measurements. It is found that the removal of long alkyl chain is conducive to improve the electron transport process and the type-II core/shell structure is beneficial to accelerate electron transport and retard charge recombination. This effective ligand removal strategy is proved to be more convenient for the applying of quaternary QDs in QDSC and would boost a more powerful efficiency in the future work.

Vancomycin: ligand recognition, dimerization and super-complex formation.

PubMed

Jia, ZhiGuang; O'Mara, Megan L; Zuegg, Johannes; Cooper, Matthew A; Mark, Alan E

2013-03-01

The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance. © 2013 The Authors Journal compilation © 2013 FEBS.

Synthesis and characterization of the tetranuclear iron(III) complex of a new asymmetric multidentate ligand. A structural model for purple acid phosphatases.

PubMed

Boudalis, Athanassios K; Aston, Robyn E; Smith, Sarah J; Mirams, Ruth E; Riley, Mark J; Schenk, Gerhard; Blackman, Allan G; Hanton, Lyall R; Gahan, Lawrence R

2007-11-28

The ligand, 2-((2-hydroxy-5-methyl-3-((pyridin-2-ylmethylamino)methyl)benzyl)(2-hydroxybenzyl)amino)acetic acid (H(3)HPBA), which contains a donor atom set that mimics that of the active site of purple acid phosphatase is described. Reaction of H(3)HPBA with iron(III) or iron(II) salts results in formation of the tetranuclear complex, [Fe(4)(HPBA)(2)(OAc)(2)(mu-O)(mu-OH)(OH(2))(2)]ClO(4) x 5H(2)O. X-Ray structural analysis reveals the cation consists of four iron(III) ions, two HPBA(3-) ligands, two bridging acetate ligands, a bridging oxide ion and a bridging hydroxide ion. Each binucleating HPBA(3-) ligand coordinates two structurally distinct hexacoordinate iron(III) ions. The two metal ions coordinated to a HPBA(3-) ligand are linked to the two iron(III) metal ions of a second, similar binuclear unit by intramolecular oxide and hydroxide bridging moieties to form a tetramer. The complex has been further characterised by elemental analysis, mass spectrometry, UV-vis and MCD spectroscopy, X-ray crystallography, magnetic susceptibility measurements and variable-temperature Mössbauer spectroscopy.

Synthesis of ligand-stabilized metal oxide nanocrystals and epitaxial core/shell nanocrystals via a lower-temperature esterification process.

PubMed

Ito, Daisuke; Yokoyama, Shun; Zaikova, Tatiana; Masuko, Keiichiro; Hutchison, James E

2014-01-28

The properties of metal oxide nanocrystals can be tuned by incorporating mixtures of matrix metal elements, adding metal ion dopants, or constructing core/shell structures. However, high-temperature conditions required to synthesize these nanocrystals make it difficult to achieve the desired compositions, doping levels, and structural control. We present a lower temperature synthesis of ligand-stabilized metal oxide nanocrystals that produces crystalline, monodisperse nanocrystals at temperatures well below the thermal decomposition point of the precursors. Slow injection (0.2 mL/min) of an oleic acid solution of the metal oleate complex into an oleyl alcohol solvent at 230 °C results in a rapid esterification reaction and the production of metal oxide nanocrystals. The approach produces high yields of crystalline, monodisperse metal oxide nanoparticles containing manganese, iron, cobalt, zinc, and indium within 20 min. Synthesis of tin-doped indium oxide (ITO) can be accomplished with good control of the tin doping levels. Finally, the method makes it possible to perform epitaxial growth of shells onto nanocrystal cores to produce core/shell nanocrystals.

Structural and Electrochemical Consequences of [Cp*] Ligand Protonation.

PubMed

Peng, Yun; Ramos-Garcés, Mario V; Lionetti, Davide; Blakemore, James D

2017-09-05

There are few examples of the isolation of analogous metal complexes bearing [η 5 -Cp*] and [η 4 -Cp*H] (Cp* = pentamethylcyclopentadienyl) complexes within the same metal/ligand framework, despite the relevance of such structures to catalytic applications. Recently, protonation of Cp*Rh(bpy) (bpy = 2,2'-bipyridyl) has been shown to yield a complex bearing the uncommon [η 4 -Cp*H] ligand, rather than generating a [Rh III -H] complex. We now report the purification and isolation of this protonated species, as well as characterization of analogous complexes of 1,10-phenanthroline (phen). Specifically, reaction of Cp*Rh(bpy) or Cp*Rh(phen) with 1 equiv of Et 3 NH + Br - affords rhodium compounds bearing endo-η 4 -pentamethylcyclopentadiene (η 4 -Cp*H) as a ligand. NMR spectroscopy and single-crystal X-ray diffraction studies confirm protonation of the Cp* ligand, rather than formation of metal hydride complexes. Analysis of new structural data and electronic spectra suggests that phen is significantly reduced in Cp*Rh(phen), similar to the case of Cp*Rh(bpy). Backbonding interactions with olefinic motifs are activated by formation of [η 4 -Cp*H]; protonation of [Cp*] stabilizes the low-valent metal center and results in loss of reduced character on the diimine ligands. In accord with these changes in electronic structure, electrochemical studies reveal a distinct manifold of redox processes that are accessible in the [Cp*H] complexes in comparison with their [Cp*] analogues; these processes suggest new applications in catalysis for the complexes bearing endo-η 4 -Cp*H.

Structural variability in Cu(I) and Ag(I) coordination polymers with a flexible dithione ligand: Synthesis, crystal structure, microbiological and theoretical studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beheshti, Azizolla, E-mail: a.beheshti@scu.ac.ir; Nozarian, Kimia; Babadi, Susan Soleymani

Two new compounds namely [Cu(SCN)(µ-L)]{sub n} (1) and ([Ag (µ{sub 2}-L)](ClO{sub 4})){sub n} (2) have been synthesized at room temperature by one-pot reactions between the 1,1-(1,4-butanediyl)bis(1,3-dihydro-3-methyl-1H-imidazole- 2-thione) (L) and appropriate copper(I) and silver(I) salts. These polymers have been characterized by single crystal X-ray diffraction, XRPD, TGA, elemental analysis, infrared spectroscopy, antibacterial activity and scanning probe microscopy studies. In the crystal structure of 1, copper atoms have a distorted trigonal planar geometry with a CuS{sub 2}N coordination environment. Each of the ligands in the structure of 1 acting as a bidentate S-bridging ligand to form a 1D chain structure. Additionally, themore » adjacent 1D chains are interconnected by the intermolecular C-H…S interactions to create a 2D network structure. In contrast to 1, in the cationic 3D structure of 2 each of the silver atoms exhibits an AgS{sub 4} tetrahedral geometry with 4-membered Ag{sub 2}S{sub 2} rings. In the structure of 2, the flexible ligand adopts two different conformations; gauche-anti-gauche and anti-anti-anti. The antibacterial studies of these polymers showed that polymer 2 is more potent antibacterial agent than 1. Scanning probe microscopy (SPM) study of the treated bacteria was carried out to investigate the structural changes cause by the interactions between the polymers and target bacteria. Theoretical study of polymer 1 investigated by the DFT calculations indicates that observed transitions at 266 nm and 302 nm in the UV–vis spectrum could be attributed to the π→π* and MLCT transitions, respectively. - Graphical abstract: Two new Cu(I) and Ag(I) coordination polymers have been have been synthesized by one-pot reactions. Copper complex has a 2D non-covalent structure, but silver compound is a 3D coordination compound. These compounds have effective antibacterial activity. - Highlights: • Cu(I) and Ag(I) based coordination

Mononuclear mercury(II) complexes containing bipyridine derivatives and thiocyanate ligands: Synthesis, characterization, crystal structure determination, and luminescent properties

NASA Astrophysics Data System (ADS)

Amani, Vahid; Alizadeh, Robabeh; Alavije, Hanieh Soleimani; Heydari, Samira Fadaei; Abafat, Marzieh

2017-08-01

A series of mercury(II) complexes, [Hg(Nsbnd N)(SCN)2] (Nsbnd N is 4,4‧-dimethyl-2,2‧-bipyridine in 1, 5,5‧-dimethyl-2,2‧-bipyridine in 2, 6,6‧-dimethyl-2,2‧-bipyridine in 3 and 6-methyl-2,2‧-bipyridine in 4), were prepared from the reactions of Hg(SCN)2 with mentioned ligands in methanol. Suitable crystals of these complexes were obtained for X-ray diffraction measurement by methanol diffusion into a DMSO solution. The four complexes were thoroughly characterized by spectral methods (IR, UV-Vis, 13C{1H}NMR, 1H NMR and luminescence), elemental analysis (CHNS) and single crystal X-ray diffraction. The X-ray structural analysis indicated that in the structures of these complexes, the mercury(II) cation is four-coordinated in a distorted tetrahedral configuration by two S atoms from two thiocyanate anions and two N atoms from one chelating 2,2‧-bipyridine derivative ligand. Also, in these complexes intermolecular interactions, for example Csbnd H⋯N hydrogen bonds (in 1-4), Csbnd H⋯S hydrogen bonds (in 1, 2 and 4), π … π interactions (in 2-4), Hg⋯N interactions (in 2) and S⋯S interactions (in 4), are effective in the stabilization of the crystal structures and the formation of the 3D supramolecular complexes. Furthermore, the luminescence spectra of the title complexes show that the intensity of their emission bands are stronger than the emission bands for the free bipyridine derivative ligands.

Synthesis, spectral and electrochemical studies of binuclear Ru(III) complexes containing dithiosemicarbazone ligand

NASA Astrophysics Data System (ADS)

Kanchana Devi, A.; Ramesh, R.

2014-01-01

Synthesis of several new octahedral binuclear ruthenium(III) complexes of the general composition [(EPh3)2(X)Ru-L-Ru(X)(EPh3)2] containing benzene dithiosemicarbazone ligands (where E = P or As; X = Cl or Br; L = binucleating ligands) is presented. All the complexes have been fully characterized by elemental analysis, FT-IR, UV-vis and EPR spectroscopy together with magnetic susceptibility measurements. IR study shows that the dithiosemicarbazone ligands behave as dianionic tridentate ligands coordinating through the oxygen atom of the deprotonated phenolic group, nitrogen atom of the azomethine group and thiolate sulphur. In DMF solution, all the complexes exhibit intense d-d transition and ligand-to-metal charge transfer (LMCT) transition in the visible region. The magnetic moment values of the complexes are in the range 1.78-1.82 BM, which reveals the presence of one unpaired electron on each metal ion. The EPR spectra of the liquid samples at LNT show the presence of three different 'g' values (gx ≠ gy ≠ gz) indicate a rhombic distortion around the ruthenium ion. All the complexes exhibit two quasi-reversible one electron oxidation responses (RuIII-RuIII/RuIII-RuIV; RuIII-RuIV/RuIV-RuIV) within the E1/2 range of 0.61-0.74 V and 0.93-0.98 V respectively, versus Ag/AgCl.

An efficient and highly stereoselective synthesis of new P-chiral 1,5-diphosphanylferrocene ligands and their use in enantioselective hydrogenation.

PubMed

Chen, Weiping; Roberts, J Stanley M; Whittall, John; Steiner, Alexander

2006-07-21

An efficient and highly stereoselective synthesis of P-chiral 1,5-diphosphanylferrocene ligands has been developed, and the introduction of P-chirality in ferrocene-based phosphine ligands enhances the enantioselective discrimination produced by the corresponding catalyst when matching of the planar chirality, the chirality at carbon and the chirality at phosphorus occurs.

Influence of ionic liquids on the syntheses and structures of Mn(II) coordination polymers based on multidentate N-heterocyclic aromatic ligands and bridging carboxylate ligands.

PubMed

Qin, Jian-Hua; Wang, Hua-Rui; Pan, Qi; Zang, Shuang-Quan; Hou, Hongwei; Fan, Yaoting

2015-10-28

Seven Mn(ii) coordination polymers, namely {[Mn2(ptptp)Cl2(H2O)3]·H2O}n (1), {[Mn(μ-ptptp)3]2[Mn3(μ3-Cl)]2}·2Cl·16H2O (2), {[Mn2(ptptp)(ip)2(H2O)3]·H2O}n (3), {[Mn2(ptptp)(5-CH3-ip)2(H2O)3]·H2O}n (4), {[Mn4(ptptp)(5-Br-ip)3(H2O)3]·4H2O}n (5), {[Mn2(ptptp)(Hbtc)(H2O)2]·2H2O}n (6) and {[Mn2(ptptp)(tdc)(H2O)2]·1.5H2O}n (7), have been prepared based on multidentate N-heterocyclic aromatic ligands and bridging carboxylate ligands (H2ptptp = 2-(5-{6-[5-(pyrazin-2-yl)-1H-1,2,4-triazol-3-yl]pyridin-2-yl}-1H-1,2,4-triazol-3-yl)pyrazine; R-isophthalic acids, H2ip-R: R = -H (3), -CH3 (4), -Br (5); H3btc = trimesic acid (6); H2tdc = thiophene-2,5-dicarboxylic acid (7)), in order to further probe the multiple roles of [RMI]Br ionic liquids in the hydro/solvothermal synthesis (RMI = 1-alkyl-3-methylimidazolium, R = ethyl, or propyl, or butyl). The successful syntheses of complexes 2-6 suggest that in hydro/solvothermal synthesis the addition of a small amount of [RMI]Br plays a crucial role. Complex 1 exhibits single right-handed helices constructed by ptptp ligands and Mn(ii) ions. Complex 2 possesses octanuclear helicate structures in which two propeller-shaped [Mn(μ-ptptp)3](4-) units embrace two [Mn3(μ3-Cl)](5+) cluster cores inside. Complexes 3 and 4 are isostructural and display a 1D double chain formed by two kinds of pseudo meso-helices: (Mn-ptptp)n and (Mn-5-R-ip)n. Complex 5 has a 2D structure containing 1D Mn(ii) ion chains formed through carboxylates and [ptptp](2-)-N,N bridges. Complex 6 shows a 2D structure formed by a meso-helix (Mn-ptptp)n and the partly deprotonated Hbtc ligands. Complex 7 features a heterochiral [2 + 2] coaxially nested double-helical column formed by using the outer double-helices (Mn-ptptp)n as a template to encapsulate the inner double-helices (Mn-tdc)n with opposite orientation. All complexes were characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, single-crystal X-ray crystallography and powder X

Promoted Iron Nanocrystals Obtained via Ligand Exchange as Active and Selective Catalysts for Synthesis Gas Conversion

PubMed Central

2017-01-01

Colloidal synthesis routes have been recently used to fabricate heterogeneous catalysts with more controllable and homogeneous properties. Herein a method was developed to modify the surface composition of colloidal nanocrystal catalysts and to purposely introduce specific atoms via ligands and change the catalyst reactivity. Organic ligands adsorbed on the surface of iron oxide catalysts were exchanged with inorganic species such as Na2S, not only to provide an active surface but also to introduce controlled amounts of Na and S acting as promoters for the catalytic process. The catalyst composition was optimized for the Fischer–Tropsch direct conversion of synthesis gas into lower olefins. At industrially relevant conditions, these nanocrystal-based catalysts with controlled composition were more active, selective, and stable than catalysts with similar composition but synthesized using conventional methods, possibly due to their homogeneity of properties and synergic interaction of iron and promoters. PMID:28824820

Dinuclear Cu(II) complexes of isomeric bis-(3-acetylacetonate)benzene ligands: synthesis, structure, and magnetic properties.

PubMed

Rancan, Marzio; Dolmella, Alessandro; Seraglia, Roberta; Orlandi, Simonetta; Quici, Silvio; Sorace, Lorenzo; Gatteschi, Dante; Armelao, Lidia

2012-05-07

Highly versatile coordinating ligands are designed and synthesized with two β-diketonate groups linked at the carbon 3 through a phenyl ring. The rigid aromatic spacer is introduced in the molecules to orient the two acetylacetone units along different angles and coordination vectors. The resulting para, meta, and ortho bis-(3-acetylacetonate)benzene ligands show efficient chelating properties toward Cu(II) ions. In the presence of 2,2'-bipyridine, they promptly react and yield three dimers, 1, 2, and 3, with the bis-acetylacetonate unit in bridging position between two metal centers. X-ray single crystal diffraction shows that the compounds form supramolecular chains in the solid state because of intermolecular interactions. Each of the dinuclear complexes shows a magnetic behavior which is determined by the combination of structural parameters and spin polarization effects. Notably, the para derivative (1) displays a moderate antiferromagnetic coupling (J = -3.3 cm(-1)) along a remarkably long Cu···Cu distance (12.30 Å).

Ranking Enzyme Structures in the PDB by Bound Ligand Similarity to Biological Substrates.

PubMed

Tyzack, Jonathan D; Fernando, Laurent; Ribeiro, Antonio J M; Borkakoti, Neera; Thornton, Janet M

2018-04-03

There are numerous applications that use the structures of protein-ligand complexes from the PDB, such as 3D pharmacophore identification, virtual screening, and fragment-based drug design. The structures underlying these applications are potentially much more informative if they contain biologically relevant bound ligands, with high similarity to the cognate ligands. We present a study of ligand-enzyme complexes that compares the similarity of bound and cognate ligands, enabling the best matches to be identified. We calculate the molecular similarity scores using a method called PARITY (proportion of atoms residing in identical topology), which can conveniently be combined to give a similarity score for all cognate reactants or products in the reaction. Thus, we generate a rank-ordered list of related PDB structures, according to the biological similarity of the ligands bound in the structures. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Synthesis, crystal structures, and luminescent properties of Cd(II) coordination polymers assembled from semi-rigid multi-dentate N-containing ligand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Gang; Shao, Kui-Zhan; Chen, Lei

2012-12-15

Three new polymers, [Cd(L){sub 2}(H{sub 2}O){sub 2}]{sub n} (1), [Cd{sub 3}(L){sub 2}({mu}{sub 3}-OH){sub 2}({mu}{sub 2}-Cl){sub 2}(H{sub 2}O){sub 2}]{sub n} (2), {l_brace}[Cd{sub 2}(L){sub 2}(nic){sub 2}(H{sub 2}O){sub 2}]{center_dot}H{sub 2}O{r_brace}{sub n} (3) (HL=5-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-1H-tetrazole, Hnic=nicotinic acid) have been prepared and structurally characterized. Compounds 1 and 2 display 2D monomolecular layers built by the inter-linking single helical chains and L{sup -} ligands connecting chain-like [Cd({mu}{sub 3}-OH)({mu}{sub 2}-Cl)]{sub n} secondary building units, respectively. Compound 3 is constructed from the mixed ligands and possesses a (3,4)-connected framework with (4{center_dot}8{sup 2})(4{center_dot}8{sup 2}{center_dot}10{sup 3}) topology. Moreover, the fluorescent properties of HL ligand and compounds 1-3 are also been investigated.more » - Graphical abstract: Three new coordination polymers based on the semi-rigid multidentate N-donor ligand have been successfully synthesized by hydrothermal reaction. Complexes 1 and 2 exhibit the 2D layers formed by inter-linking single helices and L{sup -} anions bridging 1D chain-like SBUs, respectively. Complex 3 is buit by L{sup -} and assistant nic{sup -} ligands connecting metal centers and possesses a (3,4)-connected framework with (4 Multiplication-Sign 8{sup 2})(4 Multiplication-Sign 8{sup 2} Multiplication-Sign 10{sup 3}) topology. Moreover, these complexes display fluorescent properties indicating that they may have potential applications as optical materials. Highlights: Black-Right-Pointing-Pointer Three Cd-compounds were prepared from semi-rigid HL ligand with different N-containing groups. Black-Right-Pointing-Pointer They exhibit diverse structures from 2D monomolecular layer to 3D covalent framework. Black-Right-Pointing-Pointer The HL ligands displayed various coordination modes under different reaction conditions. Black-Right-Pointing-Pointer These compounds

Synthesis, structures and properties of three copper complexes with dibutyldithiocarbamate ligand

NASA Astrophysics Data System (ADS)

Wang, Chen; Niu, Jiao; Li, Jun; Ma, Xiaoxun

2017-05-01

Three copper complexes constructed with sulfur-containing dibutyldithiocarbamate ligand (DDTC), [(Et2NCS2)4Cu2] (1), [(Et2NCS2)(EtO)Cu]2 (2) and [(Et2NCS2)6Cu13I10]n (3) have been synthesized through the reaction of CuI with different mole ratios of DDTC under solution-diffusion conditions. The single crystal X-ray diffraction revealed that divalent Cu cations in complexes 1 and 2 imply that the reactant, Cu(I), was involved in the redox process. They formed binuclear complexes according to bridging S from DDTC ligands and O atoms from ethanol molecules respectively. The mixed valence Cu cations had two types of coordination environments in complex 3 and formed a two-dimensional layered coordination polymer by bridging the five-core Cu(I) clusters and Cu(II). The powder X-ray diffraction, luminescent, thermogravimetric analysis, etc. were also studied in this paper.

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

NASA Astrophysics Data System (ADS)

Könst, Zef A.; Szklarski, Anne R.; Pellegrino, Simone; Michalak, Sharon E.; Meyer, Mélanie; Zanette, Camila; Cencic, Regina; Nam, Sangkil; Voora, Vamsee K.; Horne, David A.; Pelletier, Jerry; Mobley, David L.; Yusupova, Gulnara; Yusupov, Marat; Vanderwal, Christopher D.

2017-11-01

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

Two New Families of Lanthanide Mixed-Ligand Complexes, Oxalate-Carbonate and Oxalate-Formate: Synthesis and Structure of [Ce(H 2O)] 2(C 2O 4) 2(CO 3)·2.5 H 2O and Ce(C 2O 4)(HCO 2)

NASA Astrophysics Data System (ADS)

Romero, S.; Mosset, A.; Trombe, J. C.

1996-12-01

Two new families of lanthanide complexes associating the ligands oxalate and carbonate or oxalate and formate have been prepared under autogenous pressure at 200°C using a pseudo-hydrothermal method. The two families have been extended to some lanthanides ( Ln): oxalate-carbonate Ln= Ce, Pr, Nd, and Eu; oxalate-formate Ln= La, Ce, and Sm. The starting suspension contains either oxalate or a mixture of oxalate and oxalic acid. The structures have been solved for the element cerium. In both cases, the structure is built up from cerium atoms sharing all their oxygen atoms with oxalate and carbonate or oxalate and formate ligands, thus forming a three-dimensional network. The cerium polyhedra share either faces or edges or corners. The coordination scheme of the oxalate ligands is variable: bischelating, bischelating and monodentate, or bischelating and bismonodentate. The carbonate group acts as a bischelating and bismonodentate ligand while the formate group is chelating and monodentate. The characterization of these two original families by infrared spectra and thermal behavior is presented for some pure phases. A tentative explanation of the synthesis of these two phases will be emphasized.

Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.

PubMed

Rodríguez, David; Brea, José; Loza, María Isabel; Carlsson, Jens

2014-08-05

The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. Copyright © 2014 Elsevier Ltd. All rights reserved.

Structural and theoretical basis for ligand exchange on thiolate monolayer protected gold nanoclusters.

PubMed

Heinecke, Christine L; Ni, Thomas W; Malola, Sami; Mäkinen, Ville; Wong, O Andrea; Häkkinen, Hannu; Ackerson, Christopher J

2012-08-15

Ligand exchange reactions are widely used for imparting new functionality on or integrating nanoparticles into devices. Thiolate-for-thiolate ligand exchange in monolayer protected gold nanoclusters has been used for over a decade; however, a firm structural basis of this reaction has been lacking. Herein, we present the first single-crystal X-ray structure of a partially exchanged Au(102)(p-MBA)(40)(p-BBT)(4) (p-MBA = para-mercaptobenzoic acid, p-BBT = para-bromobenzene thiol) with p-BBT as the incoming ligand. The crystal structure shows that 2 of the 22 symmetry-unique p-MBA ligand sites are partially exchanged to p-BBT under the initial fast kinetics in a 5 min timescale exchange reaction. Each of these ligand-binding sites is bonded to a different solvent-exposed Au atom, suggesting an associative mechanism for the initial ligand exchange. Density functional theory calculations modeling both thiol and thiolate incoming ligands postulate a mechanistic pathway for thiol-based ligand exchange. The discrete modification of a small set of ligand binding sites suggests Au(102)(p-MBA)(44) as a powerful platform for surface chemical engineering.

Evaluation of Tris-Bipyridine Chromium Complexes for Flow Battery Applications: Impact of Bipyridine Ligand Structure on Solubility and Electrochemistry.

PubMed

Cabrera, Pablo J; Yang, Xingyi; Suttil, James A; Brooner, Rachel E M; Thompson, Levi T; Sanford, Melanie S

2015-11-02

This report describes the design, synthesis, solubility, and electrochemistry of a series of tris-bipyridine chromium complexes that exhibit up to six reversible redox couples as well as solubilities approaching 1 M in acetonitrile. We have systematically modified both the ligand structure and the oxidation state of these complexes to gain insights into the factors that impact solubility and electrochemistry. The results provide a set of structure-solubility-electrochemistry relationships to guide the future development of electrolytes for nonaqueous flow batteries. In addition, we have identified a promising candidate from the series of chromium complexes for further electrochemical and battery assessment.

Synthesis, crystal structure, fluorescence and electrochemical studies of a new tridentate Schiff base ligand and its nickel(II) and palladium(II) complexes

NASA Astrophysics Data System (ADS)

Shafaatian, Bita; Soleymanpour, Ahmad; Kholghi Oskouei, Nasim; Notash, Behrouz; Rezvani, Seyyed Ahmad

2014-07-01

A new unsymmetrical tridentate Schiff base ligand was derived from the 1:1 M condensation of ortho-vanillin with 2-mercaptoethylamine. Nickel and palladium complexes were obtained by the reaction of the tridentate Schiff base ligand with nickel(II) acetate tetrahydrate and palladium(II) acetate in 2:1 M ratio. In nickel and palladium complexes the ligand was coordinated to metals via the imine N and enolic O atoms. The S groups of Schiff bases were not coordinated to the metals and S-S coupling was occured. The complexes have been found to possess 1:2 Metal:Ligand stoichiometry and the molar conductance data revealed that the metal complexes were non-electrolytes. The complexes exhibited octahedral coordination geometry. The emission spectra of the ligand and its complexes were studied in methanol. Electrochemical properties of the ligand and its metal complexes were investigated in the CH3CN solvent at the 100 mV s-1 scan rate. The ligand and metal complexes showed both reversible and quasi-reversible processes at this scan rate. The Schiff base and its complexes have been characterized by IR, 1H NMR, UV/Vis, elemental analyses and conductometry. The crystal structure of nickel complex has been determined by single crystal X-ray diffraction.

Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meza-Avina, Maria Elena; Wei, Lianhu; Liu, Yan

2010-06-14

In recent years, orotidine-5{prime}-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridine-based non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to designmore » novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.« less

Hydroxyalkylation with cyclic sulfates: synthesis of carbazole derived CB(2) ligands with increased polarity.

PubMed

Lueg, Corinna; Galla, Fabian; Frehland, Bastian; Schepmann, Dirk; Daniliuc, Constantin G; Deuther-Conrad, Winnie; Brust, Peter; Wünsch, Bernhard

2014-01-01

In order to increase the polarity of the potent CB2 ligand 1a, the homologous hydroxyalkyl carbazoles 2a-c were prepared and pharmacologically evaluated. An important step in the synthesis is the hydroxyalkylation of carbazole with cyclic sulfates providing the 2-hydroxyethyl and 3-hydroxypropyl derivatives 5a and 5b in a one-step reaction. The final propionamides 2a-c were prepared using the recently reported coupling reagent COMU®. The X-ray crystal structure of 2c displays an almost coplanar arrangement of the 3-phenyl-1,2,4-oxadiazole biaryl system. The increased polarity of 2a is associated with an almost 100-fold reduced CB2 affinity. The 3-hydroxypropyl derivative 2b represents the best compromise between lipophilicity and CB2 affinity (Ki  = 33 nM). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Monodisperse hexagonal silver nanoprisms: synthesis via thiolate-protected cluster precursors and chiral, ligand-imprinted self-assembly.

PubMed

Cathcart, Nicole; Kitaev, Vladimir

2011-09-27

Silver nanoprisms of a predominantly hexagonal shape have been prepared using a ligand combination of a strongly binding thiol, captopril, and charge-stabilizing citrate together with hydrogen peroxide as an oxidative etching agent and a strong base that triggered nanoprism formation. The role of the reagents and their interplay in the nanoprism synthesis is discussed in detail. The beneficial role of chloride ions to attain a high degree of reproducibility and monodispersity of the nanoprisms is elucidated. Control over the nanoprism width, thickness, and, consequently, plasmon resonance in the system has been demonstrated. One of the crucial factors in the nanoprism synthesis was the slow, controlled aggregation of thiolate-stabilized silver nanoclusters as the intermediates. The resulting superior monodispersity (better than ca. 10% standard deviation in lateral size and ca. 15% standard deviation in thickness (<1 nm variation)) and charge stabilization of the produced silver nanoprisms enabled the exploration of the rich diversity of the self-assembled morphologies in the system. Regular columnar assemblies of the self-assembled nanoprisms spanning 2-3 μm in length have been observed. Notably, the helicity of the columnar phases was evident, which can be attributed to the chirality of the strongly binding thiol ligand. Finally, the enhancement of Raman scattering has been observed after oxidative removal of thiolate ligands from the AgNPR surface. © 2011 American Chemical Society

New synthetic routes toward enantiopure nitrogen donor ligands.

PubMed

Sala, Xavier; Rodríguez, Anna M; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; von Zelewsky, Alexander; Llobet, Antoni; Benet-Buchholz, Jordi

2006-12-08

New polypyridylic chiral ligands, having either C3 or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-alpha-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability of the method. The coordinative ability of the ligands has been tested through the synthesis and characterization of complexes [Mn((-)-19)Br2], (-)-20, and [RuCl((-)-10)(bpy)](BF4), (-)-21. Some preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium complex are also presented.

Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

PubMed

Ekengard, Erik; Kumar, Kamlesh; Fogeron, Thibault; de Kock, Carmen; Smith, Peter J; Haukka, Matti; Monari, Magda; Nordlander, Ebbe

2016-03-07

The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

Ruthenium(II) carbonyl complexes bearing CCC-pincer bis-(carbene) ligands: synthesis, structures and activities toward recycle transfer hydrogenation reactions.

PubMed

Naziruddin, Abbas Raja; Huang, Zhao-Jiunn; Lai, Wei-Chih; Lin, Wan-Jung; Hwang, Wen-Shu

2013-09-28

A new series of ruthenium(II) carbonyl complexes with benzene-based CCC-pincer bis-(carbene) ligands, [((R)CCC(R))Ru(CO)2(X)](0/+) and [((R)CCC(R))Ru(CO)(NN)](+) ((R)CCC(R) = 2,6-bis-(1-alkylimidazolylidene)benzene, R = Me or (n)Bu; X = I, Br, CH3CN, or 6-(aminomethyl)pyridine (ampy); NN = 2·CH3CN, or chelating ampy or bipyridine), was synthesized and fully characterized. X-Ray structure determinations revealed that these eight complexes have pseudo-octahedral configurations around the ruthenium center with the pincer ligand occupying three meridional sites. These complexes prove to be efficient precatalysts demonstrating very good activity and reusability for the transfer hydrogenation of ketones.

Synthesis and crystal structure of novel fluorescent 1,3,4-oxadiazole-containing carboxylate ligands

NASA Astrophysics Data System (ADS)

Mikhailov, Igor E.; Popov, Leonid D.; Tkachev, Valery V.; Aldoshin, Sergey M.; Dushenko, Galina A.; Revinskii, Yurii V.; Minkin, Vladimir I.

2018-04-01

Novel chelating ligands, 3-(5-aryl-1,3,4-oxadiazol-2-yl)acrylic acids and their zinc complexes were synthesized and their spectral and luminescent properties studied. The compounds intensively (quantum efficiencies φ = 0.18-0.76) luminesce in nonpolar solvents in the blue-green region (λmaxPL = 458-504 nm) of the spectrum. Molecular and crystal structures of 3-[5-(4-dimethylaminophenyl)-1,3,4-oxadiazol-2-yl]acrylic acid were established using X-ray crystallography. In crystal, the infinite chains of the molecules lie in the parallel planes and are arranged by the "head to tail" type to provide for strong π-π stacking interactions between the layers facilitating appearance of high electron transport properties and formation of excimers.

LS-align: an atom-level, flexible ligand structural alignment algorithm for high-throughput virtual screening.

PubMed

Hu, Jun; Liu, Zi; Yu, Dong-Jun; Zhang, Yang

2018-02-15

Sequence-order independent structural comparison, also called structural alignment, of small ligand molecules is often needed for computer-aided virtual drug screening. Although many ligand structure alignment programs are proposed, most of them build the alignments based on rigid-body shape comparison which cannot provide atom-specific alignment information nor allow structural variation; both abilities are critical to efficient high-throughput virtual screening. We propose a novel ligand comparison algorithm, LS-align, to generate fast and accurate atom-level structural alignments of ligand molecules, through an iterative heuristic search of the target function that combines inter-atom distance with mass and chemical bond comparisons. LS-align contains two modules of Rigid-LS-align and Flexi-LS-align, designed for rigid-body and flexible alignments, respectively, where a ligand-size independent, statistics-based scoring function is developed to evaluate the similarity of ligand molecules relative to random ligand pairs. Large-scale benchmark tests are performed on prioritizing chemical ligands of 102 protein targets involving 1,415,871 candidate compounds from the DUD-E (Database of Useful Decoys: Enhanced) database, where LS-align achieves an average enrichment factor (EF) of 22.0 at the 1% cutoff and the AUC score of 0.75, which are significantly higher than other state-of-the-art methods. Detailed data analyses show that the advanced performance is mainly attributed to the design of the target function that combines structural and chemical information to enhance the sensitivity of recognizing subtle difference of ligand molecules and the introduces of structural flexibility that help capture the conformational changes induced by the ligand-receptor binding interactions. These data demonstrate a new avenue to improve the virtual screening efficiency through the development of sensitive ligand structural alignments. http

Synthesis, structure and catalytic activities of nickel(II) complexes bearing N4 tetradentate Schiff base ligand

NASA Astrophysics Data System (ADS)

Sarkar, Saikat; Nag, Sanat Kumar; Chattopadhyay, Asoke Prasun; Dey, Kamalendu; Islam, Sk. Manirul; Sarkar, Avijit; Sarkar, Sougata

2018-05-01

Two new nickel(II) complexes [Ni(L)Cl2] (1) and [Ni(L)(NCS)2] (2) of a neutral tetradentate mono-condensed Schiff base ligand, 3-(2-(2-aminoethylamino)ethylimino)butan-2-one oxime (L) have been synthesized and characterized using different physicochemical techniques e.g. elemental analyses, spectroscopic (IR, Electronic, NMR) methods, conductivity and molecular measurements. The crystal structure of complex (2) has been determined by using single crystal X-ray diffraction method and it suggests a distorted octahedral geometry around nickel(II) having a NiN6 coordinating atmosphere. The non-coordinated Osbnd H group on the ligand L remain engaged in H-bonding interactions with the S end of the coordinated thiocyanate moiety. These H-bonding interactions lead to Osbnd S separations of 3.132 Å and play prominent role in crystal packing. It is observed that the mononuclear units are glued together with such Osbnd H…S interactions and finally results in an 1D supramolecular sheet-like arrangement. DFT/TDDFT based theoretical calculations were also performed on the ligand and the complexes aiming at the accomplishment of idea regarding their optimized geometry, electronic transitions and the molecular energy levels. Finally the catalytic behavior of the complexes for oxidation of styrene has also been carried out. A variety of reaction conditions like the effect of solvent, effect of temperature and time as well as the effect of ratio of substrate to oxidant were thoroughly studied to judge the catalytic efficiency of the Ni(II) coordination entity.

1,2,4-Benzothiadiazine-1,1-dioxide derivatives as ionotropic glutamate receptor ligands: synthesis and structure-activity relationships.

PubMed

Varano, Flavia; Catarzi, Daniela; Colotta, Vittoria; Squarcialupi, Lucia; Matucci, Rosanna

2014-11-01

Ionotropic glutamate receptor (iGluR) modulators, specially AMPA receptor antagonists, are potential tools for numerous therapeutic applications in neurological disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, chronic pain, and neuropathology ensuing from cerebral ischemia or cardiac arrest. In this work, the synthesis and binding affinities at the Gly/NMDA, AMPA, and kainic acid (KA) receptors of a new series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are reported. The results show that 1,2,4-benzothiadiazine-1,1-dioxide is a new scaffold for obtaining iGluR ligands. Moreover, this work has led us to the 7-(3-formylpyrrol-1-yl)-6-trifluoromethyl substituted compound 7, which displays the highest AMPA receptor affinity and high selectivity versus the Gly/NMDA (90-fold) and KA (46-fold) receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, spectral, thermal and biological studies of mixed ligand complexes with newly prepared Schiff base and 1,10-phenanthroline ligands

NASA Astrophysics Data System (ADS)

Abd El-Halim, Hanan F.; Mohamed, Gehad G.; Khalil, Eman A. M.

2017-10-01

A series of mixed ligand complexes were prepared from the Schiff base (L1) as a primary ligand, prepared by condensation of oxamide and furan-2-carbaldehyde, and 1,10-phenanthroline (1,10-phen) as a secondary ligand. The Schiff base ligand and its mixed ligand chelates were characterized based on elemental analysis, IR, 1H NMR, thermal analysis, UV-Visible, mass, molar conductance, magnetic moment. X-ray diffraction, solid reflectance and ESR also have been studied. The mixed ligand complexes were found to have the formulae of [M(L1) (1,10-phen)]Clm.nH2O (M = Cr(III) and Fe(III) (m = 3) (n = 0); M = Mn(II), Cu(II) and Cd(II) (m = 2) (n = 0); and M = Co(II) (m = 2) (n = 1), Ni(II) (m = 2) (n = 2) and Zn(II) (m = 2) (n = 3)) and that the geometrical structure of the complexes were octahedral. The parameters of thermodynamic using Coats-Redfern and Horowitz-Metzger equations were calculated. The synthesized Schiff base ligand, 1,10-phenanthroline ligand and Their mixed ligand complexes were also investigated for their antibacterial and antifungal activity against bacterial species (Gram-Ve bacteria: Pseudomonas aeruginosa and Escherichia coli) and (Gram + Ve bacteria: Bacillus subtilis and Streptococcus pneumonia) and fungi (Aspergillus fumigates and Candida albicans). The anticancer activity of the new compounds had been tested against breast (MFC7) and colon (HCT-116) cell lines. The results showed high activity for the synthesized compounds.

Synthesis, spectroscopic, thermogravimetric and antimicrobial studies of mixed ligands complexes

NASA Astrophysics Data System (ADS)

Mahmoud, Walaa H.; Mahmoud, Nessma F.; Mohamed, Gehad G.; El-Sonbati, Adel Z.; El-Bindary, Ashraf A.

2015-09-01

An interesting series of mixed ligand complexes have been synthesized by the reaction of metal chloride with guaifenesin (GFS) in the presence of 2-aminoacetic acid (HGly) (1:1:1 molar ratio). The elemental analysis, magnetic moments, molar conductance, spectral (UV-Vis, IR, 1H NMR and ESR) and thermal studies were used to characterize the isolated complexes. The molecular structure of GFS is optimized theoretically and the quantum chemical parameters are calculated. The IR showed that the ligand (GFS) acts as monobasic tridentate through the hydroxyl, phenoxy etheric and methoxy oxygen atoms and co-ligand (HGly) as monobasic bidentate through the deprotonated carboxylate oxygen atom and nitrogen atom of amino group. The molar conductivities showed that all the complexes are non-electrolytes except Cr(III) complex is electrolyte. Electronic and magnetic data proposed the octahedral structure for all complexes under investigation. ESR spectrum for Cu(II) revealed data which confirm the proposed structure. Antibacterial screening of the compounds were carried out in vitro on gram positive (Bacillus subtilis and Staphylococcus aureus), gram negative (Escherichia coli and Neisseria gonorrhoeae) bacteria and for in vitro antifungal activity against Candida albicans organism. However, some complexes showed more chemotherapeutic efficiency than the parent GFS drug. The complexes were also screened for their in vitro anticancer activity against the breast cell line (MFC7) and the results obtained showed that they exhibit a considerable anticancer activity.

Novel CoIII complexes containing fluorescent coumarin-N-acylhydrazone hybrid ligands: Synthesis, crystal structures, solution studies and DFT calculations

NASA Astrophysics Data System (ADS)

Areas, Esther S.; Bronsato, Bruna Juliana da S.; Pereira, Thiago M.; Guedes, Guilherme P.; Miranda, Fábio da S.; Kümmerle, Arthur E.; da Cruz, Antônio G. B.; Neves, Amanda P.

2017-12-01

A series of new CoIII complexes of the type [Co(dien)(L1 -L3)]ClO4 (1-3), containing fluorescent coumarin-N-acylhydrazonate hybrid ligands, (E)-N‧-(1-(7-oxido-2-oxo-2H-chromen-3-yl)ethylidene)-4-R-benzohydrazonate [where R = H (L12 -), OCH3 (L22 -) or Cl (L32 -)], were obtained and isolated in the low spin CoIII configuration. Single-crystal X-ray diffraction showed that the coumarin-N-acylhydrazones act as tridentate ligands in their deprotonated form (L2 -). The cation (+ 1) complexes contain a diethylenetriamine (dien) as auxiliary ligand and their structures were calculated by DFT studies which were also performed for the CoII (S = 1/2 and S = 3/2) configurations. The LS CoII (S = 1/2) concentrated the spin density on the O-Co-O axis while the HS CoII (S = 3/2) exhibited a broad spin density distribution around the metallic center. Cyclic voltammetry studies showed that structural modifications made in the L2 - ligands caused a slight influence on the electronic density of the metal center, and the E1/2 values for the CoIII/CoII redox couple increased following the electronic effect of the R-substituent, in the order: 2 (R = OCH3) < 1 (R = H) < 3 (R = Cl). The theoretical redox potentials (E°) of the process CoIII → CoII were calculated for both CoII spin states (S = 1/2 and S = 3/2) and a better correlation was found for CoIII → CoII (S = 1/2), compared with experimental values vs SHE (E°calc = - 0.37, - 0.36 and - 0.32 V vs E°exp. = - 0.371, - 0.406 and - 0.358 V, for 1-3 respectively). Complexes 1-3 exhibited a very intense absorption band around 470 nm, assigned by DFT calculations as π-π* transitions from the delocalized coumarin-N-acylhydrazone system. 1-3 were very stable in MeOH for several days. Likewise, 1-3 were stable in phosphate buffer containing sodium ascorbate after 15 h, which was attributed to the high chelate effect and σ-donor ability of the L2 - and dien ligands.

Fold independent structural comparisons of protein-ligand binding sites for exploring functional relationships.

PubMed

Gold, Nicola D; Jackson, Richard M

2006-02-03

The rapid growth in protein structural data and the emergence of structural genomics projects have increased the need for automatic structure analysis and tools for function prediction. Small molecule recognition is critical to the function of many proteins; therefore, determination of ligand binding site similarity is important for understanding ligand interactions and may allow their functional classification. Here, we present a binding sites database (SitesBase) that given a known protein-ligand binding site allows rapid retrieval of other binding sites with similar structure independent of overall sequence or fold similarity. However, each match is also annotated with sequence similarity and fold information to aid interpretation of structure and functional similarity. Similarity in ligand binding sites can indicate common binding modes and recognition of similar molecules, allowing potential inference of function for an uncharacterised protein or providing additional evidence of common function where sequence or fold similarity is already known. Alternatively, the resource can provide valuable information for detailed studies of molecular recognition including structure-based ligand design and in understanding ligand cross-reactivity. Here, we show examples of atomic similarity between superfamily or more distant fold relatives as well as between seemingly unrelated proteins. Assignment of unclassified proteins to structural superfamiles is also undertaken and in most cases substantiates assignments made using sequence similarity. Correct assignment is also possible where sequence similarity fails to find significant matches, illustrating the potential use of binding site comparisons for newly determined proteins.

Design and synthesis of a tetradentate '3-amine-1-carboxylate' ligand to mimic the metal binding environment at the non-heme iron(II) oxidase active site.

PubMed

Dungan, Victoria J; Ortin, Yannick; Mueller-Bunz, Helge; Rutledge, Peter J

2010-04-07

Non-heme iron(II) oxidases (NHIOs) catalyse a diverse array of oxidative chemistry in Nature. As part of ongoing efforts to realize biomimetic, iron-mediated C-H activation, we report the synthesis of a new 'three-amine-one-carboxylate' ligand designed to complex with iron(II) and mimic the NHIO active site. The tetradentate ligand has been prepared as a single enantiomer in nine synthetic steps from N-Cbz-L-alanine, pyridine-2,6-dimethanol and diphenylamine, using Seebach oxazolidinone chemistry to control the stereochemistry. X-Ray crystal structures are reported for two important intermediates, along with variable temperature NMR experiments to probe the hindered interconversion of conformational isomers of several key intermediates, 2,6-disubstituted pyridine derivatives. The target ligand and an N-Cbz-protected precursor were each then complexed with iron(II) and tested for their ability to promote alkene dihydroxylation, using hydrogen peroxide as the oxidant.

Structural Basis of Cooperative Ligand Binding by the Glycine Riboswitch

DOE Office of Scientific and Technical Information (OSTI.GOV)

E Butler; J Wang; Y Xiong

2011-12-31

The glycine riboswitch regulates gene expression through the cooperative recognition of its amino acid ligand by a tandem pair of aptamers. A 3.6 {angstrom} crystal structure of the tandem riboswitch from the glycine permease operon of Fusobacterium nucleatum reveals the glycine binding sites and an extensive network of interactions, largely mediated by asymmetric A-minor contacts, that serve to communicate ligand binding status between the aptamers. These interactions provide a structural basis for how the glycine riboswitch cooperatively regulates gene expression.

Classification of ligand molecules in PDB with graph match-based structural superposition.

PubMed

Shionyu-Mitsuyama, Clara; Hijikata, Atsushi; Tsuji, Toshiyuki; Shirai, Tsuyoshi

2016-12-01

The fast heuristic graph match algorithm for small molecules, COMPLIG, was improved by adding a structural superposition process to verify the atom-atom matching. The modified method was used to classify the small molecule ligands in the Protein Data Bank (PDB) by their three-dimensional structures, and 16,660 types of ligands in the PDB were classified into 7561 clusters. In contrast, a classification by a previous method (without structure superposition) generated 3371 clusters from the same ligand set. The characteristic feature in the current classification system is the increased number of singleton clusters, which contained only one ligand molecule in a cluster. Inspections of the singletons in the current classification system but not in the previous one implied that the major factors for the isolation were differences in chirality, cyclic conformations, separation of substructures, and bond length. Comparisons between current and previous classification systems revealed that the superposition-based classification was effective in clustering functionally related ligands, such as drugs targeted to specific biological processes, owing to the strictness of the atom-atom matching.

WONKA: objective novel complex analysis for ensembles of protein-ligand structures.

PubMed

Bradley, A R; Wall, I D; von Delft, F; Green, D V S; Deane, C M; Marsden, B D

2015-10-01

WONKA is a tool for the systematic analysis of an ensemble of protein-ligand structures. It makes the identification of conserved and unusual features within such an ensemble straightforward. WONKA uses an intuitive workflow to process structural co-ordinates. Ligand and protein features are summarised and then presented within an interactive web application. WONKA's power in consolidating and summarising large amounts of data is described through the analysis of three bromodomain datasets. Furthermore, and in contrast to many current methods, WONKA relates analysis to individual ligands, from which we find unusual and erroneous binding modes. Finally the use of WONKA as an annotation tool to share observations about structures is demonstrated. WONKA is freely available to download and install locally or can be used online at http://wonka.sgc.ox.ac.uk.

Molecular and electronic structures of mononuclear iron complexes using strongly electron-donating ligands and their oxidized forms.

PubMed

Strautmann, Julia B H; George, Serena DeBeer; Bothe, Eberhard; Bill, Eckhard; Weyhermüller, Thomas; Stammler, Anja; Bögge, Hartmut; Glaser, Thorsten

2008-08-04

The ligand L (2-) (H 2L = N, N'-dimethyl- N, N'-bis(3,5-di- t-butyl-2-hydroxybenzyl)-1,2-diaminoethane) has been employed for the synthesis of two mononuclear Fe (III) complexes, namely, [LFe(eta (2)-NO 3)] and [LFeCl]. L (2-) is comprised of four strongly electron-donating groups (two tert-amines and two phenolates) that increase the electron density at the coordinated ferric ions. This property should facilitate oxidation of the complexes, that is, stabilization of the oxidized species. The molecular structures in the solid state have been established by X-ray diffraction studies. [LFeCl] is five-coordinate in a square-pyramidal coordination environment with the ligand adopting a trans-conformation, while [LFe(eta (2)-NO 3)] is six-coordinate in a distorted octahedral environment with the ligand in a beta-cis conformation. The electronic structures have been studied using magnetization, EPR, Mossbauer (with and without applied field), UV-vis-NIR, and X-ray absorption spectroscopies, which demonstrate highly anisotropic covalency from the strong sigma- and pi-donating phenolates. This analysis is supported by DFT calculations on [LFeCl]. The variations of the well-understood spectroscopic data in the solid state to the spectroscopic data in solution have been used to obtain insight in the molecular structure of the two complexes in solution. While the molecular structures of the solid states are retained in solutions of nonpolar aprotic solvents, there is, however, one common molecular structure in all protic polar solvents. The analysis of the LMCT transitions and the rhombicity E/ D clearly establish that both compounds exhibit a beta-cis conformation in these protic polar solvents. These two open coordination sites, cis to each other, allow access for two potential ligands in close proximity. Electrochemical analysis establishes two reversible oxidation waves for [LFeCl] at +0.55 V and +0.93 V vs Fc (+)/Fc and one reversible oxidation wave at +0.59 V with an

Free-Energy Landscape of Protein-Ligand Interactions Coupled with Protein Structural Changes.

PubMed

Moritsugu, Kei; Terada, Tohru; Kidera, Akinori

2017-02-02

Protein-ligand interactions are frequently coupled with protein structural changes. Focusing on the coupling, we present the free-energy surface (FES) of the ligand-binding process for glutamine-binding protein (GlnBP) and its ligand, glutamine, in which glutamine binding accompanies large-scale domain closure. All-atom simulations were performed in explicit solvents by multiscale enhanced sampling (MSES), which adopts a multicopy and multiscale scheme to achieve enhanced sampling of systems with a large number of degrees of freedom. The structural ensemble derived from the MSES simulation yielded the FES of the coupling, described in terms of both the ligand's and protein's degrees of freedom at atomic resolution, and revealed the tight coupling between the two degrees of freedom. The derived FES led to the determination of definite structural states, which suggested the dominant pathways of glutamine binding to GlnBP: first, glutamine migrates via diffusion to form a dominant encounter complex with Arg75 on the large domain of GlnBP, through strong polar interactions. Subsequently, the closing motion of GlnBP occurs to form ligand interactions with the small domain, finally completing the native-specific complex structure. The formation of hydrogen bonds between glutamine and the small domain is considered to be a rate-limiting step, inducing desolvation of the protein-ligand interface to form the specific native complex. The key interactions to attain high specificity for glutamine, the "door keeper" existing between the two domains (Asp10-Lys115) and the "hydrophobic sandwich" formed between the ligand glutamine and Phe13/Phe50, have been successfully mapped on the pathway derived from the FES.

Selective synthesis of a series of isostructural MIICuI heterobimetallic complexes spontaneously assembled by an unsymmetrical naphthyridine-based ligand.

PubMed

Nicolay, Amélie; Tilley, T Don

2018-05-31

Metal-metal cooperation is integral to the function of many enzymes and materials, and model complexes hold enormous potential for providing insights into the capabilities of analogous multimetallic cores. However, the selective synthesis of heterobimetallic complexes still presents a significant challenge, especially for systems that hold the metals in close proximity and feature open or reactive coordination sites for both metals. To address this issue, a rigid, naphthyridine-based dinucleating ligand featuring distinct binding environments was synthesized. This ligand enables the selective synthesis of a series of MIICuI bimetallic complexes (M = Mn, Fe, Co, Ni, Cu, Zn), in which each metal center exclusively occupies its preferred binding pocket, from simple chloride salts. The precision of this selectivity is evident from cyclic voltammetry, ESI-MS and anomalous X-ray diffraction measurements. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89

PubMed Central

Xu, Jide; Tatum, David; Magda, Darren

2017-01-01

The development of bifunctional chelators (BFCs) for zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. Differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimization is necessary to enhance 89Zr chelation. PMID:28575044

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

PubMed

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

2017-01-01

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

Integrating structure-based and ligand-based approaches for computational drug design.

PubMed

Wilson, Gregory L; Lill, Markus A

2011-04-01

Methods utilized in computer-aided drug design can be classified into two major categories: structure based and ligand based, using information on the structure of the protein or on the biological and physicochemical properties of bound ligands, respectively. In recent years there has been a trend towards integrating these two methods in order to enhance the reliability and efficiency of computer-aided drug-design approaches by combining information from both the ligand and the protein. This trend resulted in a variety of methods that include: pseudoreceptor methods, pharmacophore methods, fingerprint methods and approaches integrating docking with similarity-based methods. In this article, we will describe the concepts behind each method and selected applications.

Two sodium and lanthanide(III) MOFs based on oxalate and V-shaped 4,4‧-oxybis(benzoate) ligands: Hydrothermal synthesis, crystal structure, and luminescence properties

NASA Astrophysics Data System (ADS)

Wang, Chongchen; Guo, Guangliang; Wang, Peng

2013-01-01

Two lanthanide based metal-organic frameworks, [NaLn(oba)(ox)(H2O)] (Lndbnd6 Eu(1) and Sm(2)) were obtained from 4,4'-oxybisbenzoic acid, sodium oxalate and corresponding lanthanide salts by hydrothermal synthesis. They were characterized by single-crystal X-ray diffraction, IR spectra, and photoluminescent spectra. The crystallographic data reveals that complexes 1 and 2 are isomorphous and isostructural, composed of three-dimensional framework built up of distorted tricapped trigonal EuO9 units, distorted octahedron NaO6 units, 4,4'-oxybis(benzoate) and oxalate. The carboxylate oxygen atoms of the 4,4'-oxybis(benzoate) and oxalate ligand are coordinated to lanthanide ions and sodium ions, resulting into two-dimensional inorganic sheets, which are further linked into three-dimensional network by organic ligands. Thermogravimetric analyses of 1-2 display a considerable thermal stability. Photoluminescent measurements indicated that europium complex 1 displayed strong red emission.

G-LoSA for Prediction of Protein-Ligand Binding Sites and Structures.

PubMed

Lee, Hui Sun; Im, Wonpil

2017-01-01

Recent advances in high-throughput structure determination and computational protein structure prediction have significantly enriched the universe of protein structure. However, there is still a large gap between the number of available protein structures and that of proteins with annotated function in high accuracy. Computational structure-based protein function prediction has emerged to reduce this knowledge gap. The identification of a ligand binding site and its structure is critical to the determination of a protein's molecular function. We present a computational methodology for predicting small molecule ligand binding site and ligand structure using G-LoSA, our protein local structure alignment and similarity measurement tool. All the computational procedures described here can be easily implemented using G-LoSA Toolkit, a package of standalone software programs and preprocessed PDB structure libraries. G-LoSA and G-LoSA Toolkit are freely available to academic users at http://compbio.lehigh.edu/GLoSA . We also illustrate a case study to show the potential of our template-based approach harnessing G-LoSA for protein function prediction.

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

Analysis of macromolecules, ligands and macromolecule-ligand complexes

DOEpatents

Von Dreele, Robert B [Los Alamos, NM

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.

Directional Carrier Transfer in Strongly Coupled Binary Nanocrystal Superlattice Films Formed by Assembly and in Situ Ligand Exchange at a Liquid–Air Interface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Yaoting; Li, Siming; Gogotsi, Natalie

Two species of monodisperse nanocrystals (NCs) can self-assemble into a variety of complex 2D and 3D periodic structures, or binary NC superlattice (BNSL) films, based on the relative number and size of the NCs. BNSL films offer great promise for both fundamental scientific studies and optoelectronic applications; however, the utility of as-assembled structures has been limited by the insulating ligands that originate from the synthesis of NCs. Here we report the application of an in situ ligand exchange strategy at a liquid–air interface to replace the long synthesis ligands with short ligands while preserving the long-range order of BNSL films.more » This approach is demonstrated for BNSL structures consisting of PbSe NCs of different size combinations and ligands of interest for photovoltaic devices, infrared detectors, and light-emitting diodes. To confirm enhanced coupling introduced by ligand exchange, we show ultrafast (~1 ps) directional carrier transfer across the type-I heterojunction formed by NCs of different sizes within ligand-exchanged BNSL films. In conclusion, this approach shows the potential promise of functional BNSL films, where the local and long-range energy landscape and electronic coupling can be adjusted by tuning NC composition, size, and interparticle spacing.« less

New Synthesis and Tritium Labeling of a Selective Ligand for Studying High-affinity γ-Hydroxybutyrate (GHB) Binding Sites

PubMed Central

Vogensen, Stine B.; Marek, Aleš; Bay, Tina; Wellendorph, Petrine; Kehler, Jan; Bundgaard, Christoffer; Frølund, Bente; Pedersen, Martin H.F.; Clausen, Rasmus P.

2013-01-01

3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [3H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity and we demonstrate in vivo brain penetration. In vitro characterization of [3H]-1 binding shows high specificity to the high-affinity GHB binding sites. PMID:24053696

Synthesis and reactivity of mononuclear iron models of [Fe]-hydrogenase that contain an acylmethylpyridinol ligand.

PubMed

Hu, Bowen; Chen, Dafa; Hu, Xile

2014-02-03

[Fe]-hydrogenase has a single iron-containing active site that features an acylmethylpyridinol ligand. This unique ligand environment had yet to be reproduced in synthetic models; however the synthesis and reactivity of a new class of small molecule mimics of [Fe]-hydrogenase in which a mono-iron center is ligated by an acylmethylpyridinol ligand has now been achieved. Key to the preparation of these model compounds is the successful C-O cleavage of an alkyl ether moiety to form the desired pyridinol ligand. Reaction of solvated complex [(2-CH2CO-6-HOC5H3N)Fe(CO)2(CH3CN)2](+)(BF4)(-) with thiols or thiophenols in the presence of NEt3 yielded 5-coordinate iron thiolate complexes. Further derivation produced complexes [(2-CH2CO-6-HOC5H3N)Fe(CO)2(SCH2CH2OH)] and [(2-CH2CO-6-HOC5H3N)Fe(CO)2(CH3COO)], which can be regarded as models of FeGP cofactors of [Fe]-hydrogenase extracted by 2-mercaptoethanol and acetic acid, respectively. When the derivative complexes were treated with HBF4 ⋅Et2O, the solvated complex was regenerated by protonation of the thiolate ligands. The reactivity of several models with CO, isocyanide, cyanide, and H2 was also investigated. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combining on-chip synthesis of a focused combinatorial library with computational target prediction reveals imidazopyridine GPCR ligands.

PubMed

Reutlinger, Michael; Rodrigues, Tiago; Schneider, Petra; Schneider, Gisbert

2014-01-07

Using the example of the Ugi three-component reaction we report a fast and efficient microfluidic-assisted entry into the imidazopyridine scaffold, where building block prioritization was coupled to a new computational method for predicting ligand-target associations. We identified an innovative GPCR-modulating combinatorial chemotype featuring ligand-efficient adenosine A1/2B and adrenergic α1A/B receptor antagonists. Our results suggest the tight integration of microfluidics-assisted synthesis with computer-based target prediction as a viable approach to rapidly generate bioactivity-focused combinatorial compound libraries with high success rates. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, characterization, crystal structure and HSA binding of two new N,O,O-donor Schiff-base ligands derived from dihydroxybenzaldehyde and tert-butylamine

NASA Astrophysics Data System (ADS)

Khosravi, Iman; Hosseini, Farnaz; Khorshidifard, Mahsa; Sahihi, Mehdi; Rudbari, Hadi Amiri

2016-09-01

Two new o-hydroxy Schiff-bases compounds, L1 and L2, were derived from the 1:1 M condensation of 2,3-dihydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde with tert-butylamine and were characterized by elemental analysis, FT-IR, 1H and 13C NMR spectroscopies. The crystal structure of L2 was also determined by single crystal X-ray analysis. The crystal structure of L2 showed that the compound exists as a zwitterionic form in the solid state, with the H atom of the phenol group being transferred to the imine N atom. It adopts an E configuration about the central Cdbnd N double bond. Furthermore, binding of these Schiff base ligands to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation methods. The fluorescence emission of HSA was quenched by ligands. Also, suitable models were used to analyze the UV-vis absorption spectroscopy data for titration of HSA solution by various amounts of Schiff bases. The spectroscopic studies revealed that these Schiff bases formed 1:1 complex with HSA. Energy transfer mechanism of quenching was discussed and the values of 3.35 and 1.57 nm as the mean distances between the bound ligands and the HSA were calculated for L1 and L2, respectively. Molecular docking results indicated that the main active binding site for these Schiff bases ligands is in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, with a slight modification of its tertiary structure.

Two new coordination polymers with flexible alicyclic carboxylate and bipyridyl co-ligands bearing trinuclear [Ni3(COO)6] SBUs: Synthesis, crystal structures, and magnetic properties

NASA Astrophysics Data System (ADS)

Zhu, Xian-Dong; Li, Yong; Gao, Jian-Gang; Wang, Fen-Hua; Li, Qing-Hai; Yang, Hong-Xun; Chen, Lei

2017-02-01

Two new coordination polymers generally formulated as [Ni3(Hchda)2(chda)2(bpy)2(H2O)2]n (1) and [Ni3(Hchda)2(chda)2(bpp)2(H2O)2]n (2) [H2chda = 1,1'-cyclohexanediacetic acid, bpy = 4,4'-bipyridine and bpp = 1,3-bis(4-pyridyl)propane], have been successfully assembled through mixed-ligands synthetic strategy with flexible alicyclic carboxylate and bipyridyl ligands. There structures feature trinuclear nickel secondary building units connected via the bridging bipyridyl spacers to form two-dimensional (4,4) grid layer. The nature of the different N-donor auxiliary ligands leads to the discrepancy in supramolecular structure of the two compounds. Magnetic studies indicate the ferromagnetic intra-complex magnetic interaction in the molecule for 1 and 2.

Convenient divergent strategy for the synthesis of TunePhos-type chiral diphosphine ligands and their applications in highly enantioselective Ru-catalyzed hydrogenations.

PubMed

Sun, Xianfeng; Zhou, Le; Li, Wei; Zhang, Xumu

2008-02-01

A convenient, divergent strategy for the synthesis of a series of modular and fine-tunable C3-TunePhos-type chiral diphosphine ligands and their applications in highly efficient Ru-catalyzed asymmetric hydrogenations were explored. Up to 97 and 99% ee values were achieved for the enantioselective synthesis of beta-methyl chiral amines and alpha-hydroxy acid derivatives, respectively.

Gold(III) complexes with hydroxyquinoline, aminoquinoline and quinoline ligands: Synthesis, cytotoxicity, DNA and protein binding studies.

PubMed

Martín-Santos, Cecilia; Michelucci, Elena; Marzo, Tiziano; Messori, Luigi; Szumlas, Piotr; Bednarski, Patrick J; Mas-Ballesté, Rubén; Navarro-Ranninger, Carmen; Cabrera, Silvia; Alemán, José

2015-12-01

In this article, we report on the synthesis and the chemical and biological characterization of novel gold(III) complexes based on hydroxyl- or amino-quinoline ligands that are evaluated as prospective anticancer agents. To gain further insight into their reactivity and possible mode of action, their interactions with model proteins and standard nucleic acid molecules were investigated. Copyright © 2015 Elsevier Inc. All rights reserved.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

PubMed

Wei, Ning-Ning; Hamza, Adel

2014-01-27

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

New metal-organic complexes based on bis(tetrazole) ligands: Synthesis, structures and properties

NASA Astrophysics Data System (ADS)

Du, Ceng-Ceng; Fan, Jian-Zhong; Wang, Xin-Fang; Zhou, Sheng-Bin; Wang, Duo-Zhi

2017-04-01

In this paper, a series of new complexes, [Zn2(HL1)2(H2O)4]·H2O (1), [Co2(HL1)2]·TEA (2), [Co3(HL1)2(H2L1)2(H2O)4]n (3), [Cu(HL1)(H2O)2]n (4), {[Cu5(HL2)2(OH)4(ClO4)2]·4H2O}n (5) and [Cu2(L3)]n (6) were successfully prepared by utilizing three bis(tetrazole) ligands [bis-(1H-tetrazol-5-ylmethyl)-amine (H3L1), bis-(1H-tetrazol-5-ylethyl)-amine (H3L2) and 1,5-bis(5-tetrazolo)-3-thiapentane (H2L3)], all of which have been characterized by elemental analyses, FT-IR spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analyses as well as single-crystal X-ray diffraction analyses showing different dimensionalities (0D, 1D and 3D). Complexes 1 and 2 are 0D structures, 1 shows a dinuclear structure, 2 displays two crystallographically different mononuclear structures, 1 and 2 are further assembled to form 3D supramolecular framework and 2D supramolecular network by hydrogen-bonding interactions, respectively. Complexes 3, 4 and 5 are 1D structures, 3 features a mononuclear unit and a 1D chain, which are arranged into 3D supramolecular architecture by hydrogen-bonding interactions, 4 presents a zigzag chain, 5 shows an infinite chain structure constructed from pentanuclear Cu(II) subunits and ClO4- anions. Complex 6 exhibits a 3D coordination framework based on cyclic [Cu4(L3)2] dimmer subunits as nodes possessing an 8-connected network topology with the point symbol {424·64}. Further, semiconductor behaviors, the solid-state luminescent properties of the complexes 1-3 and 6 were measured and studied seriously at room temperature.

Synthesis, structural elucidation, biological, antioxidant and nuclease activities of some 5-Fluorouracil-amino acid mixed ligand complexes

NASA Astrophysics Data System (ADS)

Shobana, Sutha; Subramaniam, Perumal; Mitu, Liviu; Dharmaraja, Jeyaprakash; Arvind Narayan, Sundaram

2015-01-01

Some biologically active mixed ligand complexes (1-9) have been synthesized from 5-Fluorouracil (5-FU; A) and amino acids (B) such as glycine (gly), L-alanine (ala) and L-valine (val) with Ni(II), Cu(II) and Zn(II) ions. The synthesized mixed ligand complexes (1-9) were characterized by various physico-chemical, spectral, thermal and morphological studies. 5-Fluorouracil and its mixed ligand complexes have been tested for their in vitro biological activities against some pathogenic bacterial and fungal species by the agar well diffusion method. The in vitro antioxidant activities of 5-Fluorouracil and its complexes have also been investigated by using the DPPH assay method. The results demonstrate that Cu(II) mixed ligand complexes (4-6) exhibit potent biological as well as antioxidant activities compared to 5-Fluorouracil and Ni(II) (1-3) and Zn(II) (7-9) mixed ligand complexes. Further, the cleaving activities of CT DNA under aerobic conditions show moderate activity with the synthesized Cu(II) and Ni(II) mixed ligand complexes (1-6) while no activity is seen with Zn(II) complexes (7-9). Binding studies of CT DNA with these complexes show a decrease in intensity of the charge transfer band to the extent of 5-15% along with a minor red shift. The free energy change values (Δ‡G) calculated from intrinsic binding constants indicate that the interaction between mixed ligand complex and DNA is spontaneous.

Synthesis, stabilization, and characterization of metal nanoparticles

NASA Astrophysics Data System (ADS)

White, Gregory Von, II

Wet chemical synthesis techniques offer the ability to control various nanoparticle characteristics including size, shape, dispersibility in both aqueous and organic solvents, and tailored surface chemistries appropriate for different applications. Large quantities of stabilizing ligands or surfactants are often required during synthesis to achieve these nanoparticle characteristics. Unfortunately, excess reaction byproducts, surfactants, and ligands remaining in solution after nanoparticle synthesis can impede application, and therefore post-synthesis purification must be employed. A liquid-liquid solvent/antisolvent pair (typically ethanol/toluene or ethanol/hexane for gold nanoparticles, GNPs) can be used to both purify and size-selectively fractionate hydrophobically modified nanoparticles. Alternatively, carbon dioxide may be used in place of a liquid antisolvent, a "green" approach, enabling both nanoparticle purification and size-selective fractionation while simultaneously eliminating mixed solvent waste and allowing solvent recycle. We have used small-angle neutron scattering (SANS) to investigate the ligand structure and composition response of alkanethiol modified gold and silver nanoparticles at varying anti-solvent conditions (CO2 or ethanol). The ligand lengths and ligand solvation for alkanethiol gold and silver NPs were found to decrease with increased antisolvent concentrations directly impacting their dispersibility in solution. Calculated Flory-Huggins interaction parameters support our SANS study for dodecanethiol dispersibility in the mixed organic solvents. This research has led to a greater understanding of the liquid-liquid precipitation process for metal nanoparticles, and provides critical results for future interaction energy modeling.

Synthesis of framework isomer MOFs containing zinc and 4-tetrazolyl benzenecarboxylic acid via a structure directing solvothermal approach

DOE PAGES

Ordonez, Carlos; Kinnibrugh, Tiffany L.; Xu, Hongwu; ...

2015-04-02

The solvothermal synthesis of framework isomers was carried out using the hybrid carboxylate and tetrazolate functional ligand, 4-tetrazolyl benzenecarboxylic acid (H₂TBC, TBC = 4-tetrazolyl benzenecarboxylate) and zinc. H₂TBC was also synthesized with the solvothermal approach, and is referred herein as structure 1. Using single-crystal X-ray diffraction, we found that the tetrazolate groups of TBC show an unusual “opposite-on” coordination mode with zinc. Three previously characterized metal-organic frameworks (MOFs) were obtained by systematically changing the solvents of the H₂TBC-Zn reaction, (1) ZnTBC, 2, which has a non-porous structure; (2) Zn₂(TBC)₂(H2O), 3, which has an amphiphilic pore structure and (3) Zn₂(TBC)₂{guest}, 4,more » which is porous and has channels containing uncoordinated N heteroatoms. Fluorescence spectra of 4 reveal a strong blue emission mainly from the TBC ligands.« less

Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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

Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89

DOE PAGES

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

2017-06-02

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

MotiveValidator: interactive web-based validation of ligand and residue structure in biomolecular complexes.

PubMed

Vařeková, Radka Svobodová; Jaiswal, Deepti; Sehnal, David; Ionescu, Crina-Maria; Geidl, Stanislav; Pravda, Lukáš; Horský, Vladimír; Wimmerová, Michaela; Koča, Jaroslav

2014-07-01

Structure validation has become a major issue in the structural biology community, and an essential step is checking the ligand structure. This paper introduces MotiveValidator, a web-based application for the validation of ligands and residues in PDB or PDBx/mmCIF format files provided by the user. Specifically, MotiveValidator is able to evaluate in a straightforward manner whether the ligand or residue being studied has a correct annotation (3-letter code), i.e. if it has the same topology and stereochemistry as the model ligand or residue with this annotation. If not, MotiveValidator explicitly describes the differences. MotiveValidator offers a user-friendly, interactive and platform-independent environment for validating structures obtained by any type of experiment. The results of the validation are presented in both tabular and graphical form, facilitating their interpretation. MotiveValidator can process thousands of ligands or residues in a single validation run that takes no more than a few minutes. MotiveValidator can be used for testing single structures, or the analysis of large sets of ligands or fragments prepared for binding site analysis, docking or virtual screening. MotiveValidator is freely available via the Internet at http://ncbr.muni.cz/MotiveValidator. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Synthesis, structural characterization, and thermal stability studies of heteroleptic cadmium(II) dithiocarbamate with different pyridyl groups

NASA Astrophysics Data System (ADS)

Onwudiwe, Damian C.; Hosten, Eric C.

2018-01-01

The synthesis, characterization and crystal structures of three chloroform solvated adducts of cadmium with mixed ligands of N-alkyl-N-phenyldithiocarbamate and pyridine, 2,2-bipyridine and 1, 10 phenanthroline represented as [CdL1L2 (py)2]·CHCl3(1), [CdL1L2bpy]•CHCl3(2), and [CdL1L2phen]•CHCl3(3) (LI = N-methyl-N-phenyldithiocarbamate, L2 = N-ethyl-N-phenyldithiocarbamate, py = pyridine, bpy = 2,2-bipyridine and phen = 1,10-phenanthroline) respectively are reported. Complex 1, which crystallized in the monoclinic space group P-1, is a centrosymmetric dimeric structure where each Cd center is bonded to two monodentate pyridine, a bidentate terminal dithiocarbamate, and another bidentate bridging dithiocarbamate to form a four-membered ring. Complex 2 crystallized in the monoclinic space group P21/c, with four discrete monomeric molecules in the asymmetric unit. The structure presents a cadmium atom coordinated by two sulphur atoms of a dithiocarbamate ligand and two nitrogen atoms of the 2,2‧-bipyridine to form a CdS4N2 fragment, thus giving the structure around the Cd atom a distorted trigonal prism geometry. Complex 3 contains two discrete monomeric molecules of (phenanthroline) (N, N-methyl phenyl-N, N-ethyl phenyl dithiocarbamato)cadmium (II) per unit cell, and the complex crystallized in the triclinic space group P-1. The structure showed that the Cd atom is bonded to two bidentate dithiocarbamate ligands and to one bidentate phenanthroline ligand in a distorted trigonal prism geometry. All the compounds resulted in CdS as residue upon thermal decomposition process conducted under inert atmosphere.

Synthesis, structure and magnetic study of a novel mixed-valent Co(II)10Co(III)4 shield constructed by mixed pyridine-alcoholate ligands.

PubMed

Peng, Yan; Tian, Chong-Bin; Zhang, Hua-Bin; Li, Zhi-Hua; Lin, Ping; Du, Shao-Wu

2012-04-28

A novel tetradecanuclear mixed-valent cobalt cluster, formulated as [Co(II)(10)Co(III)(4)(OH)(2)O(6)(hmp)(10)(pdm)(4)(CH(3)OH)(2)]·5H(2)O (1), was obtained using mixed ligands of 2-(hydroxymethyl)pyridine (hmpH) and 2,6-pyridinedimethanol (pdmH(2)). The cobalt ions in 1 are connected by ten chelating hmp(-) ligands, four tris-chelating pdm(2-) ligands and six μ(3)-oxide/hydroxide anions, forming a unique shield-like planar structure that is rarely observed for Co-based clusters. Compound 1 displays slight frequency dependence at static zero field below 4.5 K, suggesting that it might be a single molecule magnet (SMM). This journal is © The Royal Society of Chemistry 2012

Solution structure of the chick TGFbeta type II receptor ligand-binding domain.

PubMed

Marlow, Michael S; Brown, Christopher B; Barnett, Joey V; Krezel, Andrzej M

2003-02-28

The transforming growth factor beta (TGFbeta) signaling pathway influences cell proliferation, immune responses, and extracellular matrix reorganization throughout the vertebrate life cycle. The signaling cascade is initiated by ligand-binding to its cognate type II receptor. Here, we present the structure of the chick type II TGFbeta receptor determined by solution NMR methods. Distance and angular constraints were derived from 15N and 13C edited NMR experiments. Torsion angle dynamics was used throughout the structure calculations and refinement. The 20 final structures were energy minimized using the generalized Born solvent model. For these 20 structures, the average backbone root-mean-square distance from the average structure is below 0.6A. The overall fold of this 109-residue domain is conserved within the superfamily of these receptors. Chick receptors fully recognize and respond to human TGFbeta ligands despite only 60% identity at the sequence level. Comparison with the human TGFbeta receptor determined by X-ray crystallography reveals different conformations in several regions. Sequence divergence and crystal packing interactions under low pH conditions are likely causes. This solution structure identifies regions were structural changes, however subtle, may occur upon ligand-binding. We also identified two very well conserved molecular surfaces. One was found to bind ligand in the crystallized human TGFbeta3:TGFbeta type II receptor complex. The other, newly identified area can be the interaction site with type I and/or type III receptors of the TGFbeta signaling complex.

Synthesis and structural characterisation of Pd(II) and Pt(II) complexes with a flexible, ferrocene-based P,S-donor amidophosphine ligand.

PubMed

Tauchman, Jiří; Císařová, Ivana; Stěpnička, Petr

2014-01-28

1'-Diphenylphosphino-1-{[(2-(methylthio)ethyl)amino]carbonyl}ferrocene (1), accessible via amidation of 1'-(diphenylphosphino)ferrocene-1-carboxylic acid (Hdpf) with 2-(methylthio)ethylamine, reacts with [PdCl2(cod)] (cod = cycloocta-1,5-diene) at a 1 : 1 metal-to-ligand ratio to give trans-[PdCl2(1-κ(2)P,S)] (trans-2) as the sole product. A similar reaction with [PtCl2(cod)] affords a mixture of cis- and trans-[PtCl2(1-κ(2)P,S)] (cis- and trans-3), which can be separated by fractional crystallisation. Complexation reactions performed with 2 equiv. of the ligand are less selective, yielding mixtures of the expected bis-phosphine complexes (i.e., trans-[PdCl2(1-κP)2], or a mixture of cis- and trans-[PtCl2(-κP)2]) with the respective monophosphine complexes. The structures of 1, trans-2, cis-3 and trans-3 determined by X-ray diffraction demonstrate the ability of the title ligand to act as a flexible cis- or trans-P,S-chelate donor (the ligand bite angles are 174.03(2)/173.05(2)° for trans-2/3 and 92.86(2)° for cis-3).

Cell-free synthesis of functional human epidermal growth factor receptor: Investigation of ligand-independent dimerization in Sf21 microsomal membranes using non-canonical amino acids

PubMed Central

Quast, Robert B.; Ballion, Biljana; Stech, Marlitt; Sonnabend, Andrei; Varga, Balázs R.; Wüstenhagen, Doreen A.; Kele, Péter; Schiller, Stefan M.; Kubick, Stefan

2016-01-01

Cell-free protein synthesis systems represent versatile tools for the synthesis and modification of human membrane proteins. In particular, eukaryotic cell-free systems provide a promising platform for their structural and functional characterization. Here, we present the cell-free synthesis of functional human epidermal growth factor receptor and its vIII deletion mutant in a microsome-containing system derived from cultured Sf21 cells. We provide evidence for embedment of cell-free synthesized receptors into microsomal membranes and asparagine-linked glycosylation. Using the cricket paralysis virus internal ribosome entry site and a repetitive synthesis approach enrichment of receptors inside the microsomal fractions was facilitated thereby providing analytical amounts of functional protein. Receptor tyrosine kinase activation was demonstrated by monitoring receptor phosphorylation. Furthermore, an orthogonal cell-free translation system that provides the site-directed incorporation of p-azido-L-phenylalanine is characterized and applied to investigate receptor dimerization in the absence of a ligand by photo-affinity cross-linking. Finally, incorporated azides are used to generate stable covalently linked receptor dimers by strain-promoted cycloaddition using a novel linker system. PMID:27670253

Fingerprinting redox and ligand states in haemprotein crystal structures using resonance Raman spectroscopy.

PubMed

Kekilli, Demet; Dworkowski, Florian S N; Pompidor, Guillaume; Fuchs, Martin R; Andrew, Colin R; Antonyuk, Svetlana; Strange, Richard W; Eady, Robert R; Hasnain, S Samar; Hough, Michael A

2014-05-01

It is crucial to assign the correct redox and ligand states to crystal structures of proteins with an active redox centre to gain valid functional information and prevent the misinterpretation of structures. Single-crystal spectroscopies, particularly when applied in situ at macromolecular crystallography beamlines, allow spectroscopic investigations of redox and ligand states and the identification of reaction intermediates in protein crystals during the collection of structural data. Single-crystal resonance Raman spectroscopy was carried out in combination with macromolecular crystallography on Swiss Light Source beamline X10SA using cytochrome c' from Alcaligenes xylosoxidans. This allowed the fingerprinting and validation of different redox and ligand states, identification of vibrational modes and identification of intermediates together with monitoring of radiation-induced changes. This combined approach provides a powerful tool to obtain complementary data and correctly assign the true oxidation and ligand state(s) in redox-protein crystals.

Polymeric networks of copper(II) phenylmalonate with heteroaromatic n-donor ligands: synthesis, crystal structure, and magnetic properties.

PubMed

Pasán, Jorge; Sanchiz, Joaquín; Ruiz-Pérez, Catalina; Lloret, Francesc; Julve, Miguel

2005-10-31

Two new phenylmalonate-bridged copper(II) complexes with the formulas [Cu(4,4'-bpy)(Phmal)](n).2nH(2)O (1) and [Cu(2,4'-bpy)(Phmal)(H(2)O)](n)() (2) (Phmal = phenylmalonate dianion, 4,4'-bpy = 4,4'-bipyridine, 2,4'-bpy = 2,4'-bipyridine) have been synthesized and characterized by X-ray diffraction. Complex 1 crystallizes in monoclinic space group P2(1), Z = 4, with unit cell parameters of a = 9.0837(6) Angstroms, b = 9.3514(4) Angstroms, c = 11.0831(8) Angstroms, and beta = 107.807(6) degrees , whereas complex 2 crystallizes in orthorhombic space group C2cb, Z = 8, with unit cell parameters of a = 10.1579(7) Angstroms, b = 10.3640(8) Angstroms, and c = 33.313(4) Angstroms. The structures of 1 and 2 consist of layers of copper(II) ions with bridging bis-monodentate phenylmalonate (1 and 2) and 4,4'-bpy (1) ligands and terminal monodentate 2,4'-bpy (2) groups. Each layer in 1 contains rectangles with dimensions of 11.08 x 4.99 Angstroms(2), the edges being defined by the Phmal and 4,4'-bpy ligands. The intralayer copper-copper separations in 1 through the anti-syn equatorial-apical carboxylate-bridge and the 4,4'-bpy molecule are 4.9922(4) and 11.083(1) Angstroms, respectively. The anti-syn equatorial-equatorial carboxylate bridge links the copper(II) atoms in complex 2 within each layer with a mean copper-copper separation of 5.3709(8) Angstroms. The presence of 2,4'-bpy as a terminal ligand accounts for the large interlayer separation of 15.22 Angstroms. The copper(II) environment presents a static pseudo-Jahn-Teller disorder which has been studied by EPR and low-temperature X-ray diffraction. Magnetic susceptibility measurements of both compounds in the temperature range 2-290 K show the occurrence of weak antiferromagnetic [J = -0.59(1) cm(-1) (1)] and ferromagnetic [J = +0.77(1) cm(-1) (2)] interactions between the copper(II) ions. The conformation of the phenylmalonate-carboxylate bridge and other structural factors, such as the planarity of the exchange

Improved synthesis and crystal structure of the flexible pillared layer porous coordination polymer: Ni(1,2-bis(4-pyridyl)ethylene)[Ni(CN) 4

DOE PAGES

Wong-Ng, W.; Culp, J. T.; Chen, Y. S.; ...

2013-01-01

This paper reports our synthesis of flexible coordination polymer, Ni(L)[Ni(CN) 4], (L = 1,2-bis(4-pyridyl)ethylene (nicknamed bpene)), and its structural characterization using synchrotron single crystal X-ray diffraction. The structure of the purplish crystals has been determined to be monoclinic, space group P2 1/m, a = 13.5941(12) Å, b = 14.3621(12) Å, c = 14.2561(12) Å, β = 96.141(2)°, V = 2767.4(4) Å 3, Z = 4, D c = 1.46 g cm -1. Ni(bpene)[Ni(CN) 4] assumes a pillared layer structure with layers defined by Ni[Ni(CN) 4] n nets and bpene ligands acting as pillars. With the present crystallization technique which involvesmore » the use of concentrated ammonium hydroxide solution and dimethyl sulfoxide (DMSO), disordered free bpene ligands and solvents of crystallization (DMSO and water molecules) occupy the pores, resulting in a formula of Ni(bpene)[Ni(CN) 4](1/2)bpene∙DMSO 2H 2O, or Ni 2N 7C 24H 25SO 3. Without the inclusion of free bpene ligands and solvent molecules, the free volume is approximately 61% of the total volume; this free volume fraction is reduced to 50% with the free ligands present. Pores without the free ligands were found to have a local diameter of 5.7 Å and a main aperture of 3.5 Å. Based on the successful crystal synthesis, we also devised a new bulk synthetic technique which yielded a polycrystalline material with a significantly improved CO 2 uptake as compared to the originally reported powder material. The improved synthetic technique yielded a polycrystalline material with 40% higher CO 2 uptake compared to the previously reported powder material. An estimated 14.4 molecules of CO 2 per unit cell was obtained.« less

Protein-ligand complex structure from serial femtosecond crystallography using soaked thermolysin microcrystals and comparison with structures from synchrotron radiation.

PubMed

Naitow, Hisashi; Matsuura, Yoshinori; Tono, Kensuke; Joti, Yasumasa; Kameshima, Takashi; Hatsui, Takaki; Yabashi, Makina; Tanaka, Rie; Tanaka, Tomoyuki; Sugahara, Michihiro; Kobayashi, Jun; Nango, Eriko; Iwata, So; Kunishima, Naoki

2017-08-01

Serial femtosecond crystallography (SFX) with an X-ray free-electron laser is used for the structural determination of proteins from a large number of microcrystals at room temperature. To examine the feasibility of pharmaceutical applications of SFX, a ligand-soaking experiment using thermolysin microcrystals has been performed using SFX. The results were compared with those from a conventional experiment with synchrotron radiation (SR) at 100 K. A protein-ligand complex structure was successfully obtained from an SFX experiment using microcrystals soaked with a small-molecule ligand; both oil-based and water-based crystal carriers gave essentially the same results. In a comparison of the SFX and SR structures, clear differences were observed in the unit-cell parameters, in the alternate conformation of side chains, in the degree of water coordination and in the ligand-binding mode.

Vanadate complexes bearing an imidazolidine-bridged bis(aryloxido) ligand: synthesis and solid state and solution structure.

PubMed

Kober, Ewa; Nerkowski, Tomasz; Janas, Zofia; Jerzykiewicz, Lucjan B

2012-05-07

A new imidazolidine-bridged bis(aryloxido) ligand precursor (H(2)L) [H(2)L = 2,2'-(imidazolidine-1,3-diylbis(methylene))bis(4-(1,1,3,3-tetramethylbutyl-2-yl)phenol)] was prepared in a relatively high yield (∼60%) via a single-step Mannich condensation of 4-(1,1,3,3-tetramethylbutyl)phenol, ethylenediamine and paraformaldehyde at 2:1:3 molar ratio and characterized by chemical and physical techniques including X-ray crystallography. Reactions of H(2)L with [VO(OEt)(3)] at 1:1 and 1:2 molar ratios in toluene afforded [V(L-κ(3)O,N,N,O)(O)(OEt)] (1) and [V(2)(μ-L-κ(4)O,N,N,O)(μ-OEt)(2)(O)(2)(OEt)(2)] (2), respectively. Alcoholysis of 1 with EtOH enables elimination of one molecule of H(2)L and the formation of 2. Compounds 1 and 2 were characterized by IR and NMR spectroscopy as well as ES-MS experiments. The definitive molecular structure of 2 was provided by a single-crystal analysis and revealed its dinuclear nature, featuring two octahedral vanadium centres bridged by both OEt groups and the L ligand. The (51)V, (1)H and (13)C NMR spectra as well as ES-MS showed that 2 does not stay intact in solution and undergoes dissociation to give 1 and [VO(OEt)(3)].

Colorimetric detection of hydrogen peroxide by dioxido-vanadium(V) complex containing hydrazone ligand: synthesis and crystal structure

NASA Astrophysics Data System (ADS)

Kurbah, Sunshine D.; Syiemlieh, Ibanphylla; Lal, Ram A.

2018-03-01

Dioxido-vanadium(V) complex has been synthesized in good yield, the complex was characterized by IR, UV-visible and 1H NMR spectroscopy. Single crystal X-ray crystallography techniques were used to assign the structure of the complex. Complex crystallized with monoclinic P21/c space group with cell parameters a (Å) = 39.516(5), b (Å) = 6.2571(11), c (Å) = 17.424(2), α (°) = 90, β (°) = 102.668(12) and γ (°) = 90. The hydrazone ligand is coordinate to metal ion in tridentate fashion through -ONO- donor atoms forming a distorted square pyramidal geometry around the metal ion.

Metallosupramolecular Architectures Obtained from Poly-N-heterocyclic Carbene Ligands.

PubMed

Sinha, Narayan; Hahn, F Ekkehardt

2017-09-19

Over the past two decades, self-assembly of supramolecular architectures has become a field of intensive research due to the wide range of applications for the resulting assemblies in various fields such as molecular encapsulation, supramolecular catalysis, drug delivery, metallopharmaceuticals, chemical and photochemical sensing, and light-emitting materials. For these purposes, a large number of coordination-driven metallacycles and metallacages featuring different sizes and shapes have been prepared and investigated. Almost all of these are Werner-type coordination compounds where metal centers are coordinated by nitrogen and/or oxygen donors of polydentate ligands. With the evolving interest in the coordination chemistry of N-heterocyclic carbenes (NHCs), discrete supramolecular complexes held together by M-C NHC bonds have recently become of interest. The construction of such metallosupramolecular assemblies requires the synthesis of suitable poly-NHC ligands where the NHC donors form labile bonds with metal centers thus enabling the formation of the thermodynamically most stable reaction product. In organometallic chemistry, these conditions are uniquely met by the combination of poly-NHCs and silver(I) ions where the resulting assemblies also offer the possibility to generate new structures by transmetalation of the poly-NHC ligands to additional metal centers forming more stable C NHC -M bonds. Stable metallosupramolecular assemblies obtained from poly-NHC ligands feature special properties such as good solubility in many less polar organic solvents and the presence of the often catalyticlly active {M(NHC) n } moiety as building block. In this Account, we review recent developments in organometallic supramolecular architectures derived from poly-NHC ligands. We describe dinuclear (M = Ag I , Au I , Cu I ) tetracarbene complexes obtained from bis-NHC ligands with an internal olefin or two external coumarin pendants and their postsynthetic modification via a

Organocatalytic atroposelective synthesis of axially chiral styrenes

NASA Astrophysics Data System (ADS)

Zheng, Sheng-Cai; Wu, San; Zhou, Qinghai; Chung, Lung Wa; Ye, Liu; Tan, Bin

2017-05-01

Axially chiral compounds are widespread in biologically active compounds and are useful chiral ligands or organocatalysts in asymmetric catalysis. It is well-known that styrenes are one of the most abundant and principal feedstocks and thus represent excellent prospective building blocks for chemical synthesis. Driven by the development of atroposelective synthesis of axially chiral styrene derivatives, we discovered herein the asymmetric organocatalytic approach via direct Michael addition reaction of substituted diones/ketone esters/malononitrile to alkynals. The axially chiral styrene compounds were produced with good chemical yields, enantioselectivities and almost complete E/Z-selectivities through a secondary amine-catalysed iminium activation strategy under mild conditions. Such structural motifs are important precursors for further transformations into biologically active compounds and synthetic useful intermediates and may have potential applications in asymmetric synthesis as olefin ligands or organocatalysts.

Structural model of dioxouranium(VI) with hydrazono ligands.

PubMed

Mubarak, Ahmed T

2005-04-01

Synthesis and characterization of several new coordination compounds of dioxouranium(VI) heterochelates with bidentate hydrazono compounds derived from 1-phenyl-3-methyl-5-pyrazolone are described. The ligands and uranayl complexes have been characterized by various physico-chemical techniques. The bond lengths and the force constant have been calculated from asymmetric stretching frequency of OUO groups. The infrared spectral studies showed a monobasic bidentate behaviour with the oxygen and hydrazo nitrogen donor system. The effect of Hammett's constant on the bond distances and the force constants were also discussed and drawn. Wilson's matrix method, Badger's formula, Jones and El-Sonbati equations were used to determine the stretching and interaction force constant from which the UO bond distances were calculated. The bond distances of these complexes were also investigated.

Structural model of dioxouranium(VI) with hydrazono ligands

NASA Astrophysics Data System (ADS)

Mubarak, Ahmed T.

2005-04-01

Synthesis and characterization of several new coordination compounds of dioxouranium(VI) heterochelates with bidentate hydrazono compounds derived from 1-phenyl-3-methyl-5-pyrazolone are described. The ligands and uranayl complexes have been characterized by various physico-chemical techniques. The bond lengths and the force constant have been calculated from asymmetric stretching frequency of O sbnd U sbnd O groups. The infrared spectral studies showed a monobasic bidentate behaviour with the oxygen and hydrazo nitrogen donor system. The effect of Hammett's constant on the bond distances and the force constants were also discussed and drawn. Wilson's matrix method, Badger's formula, Jones and El-Sonbati equations were used to determine the stretching and interaction force constant from which the U sbnd O bond distances were calculated. The bond distances of these complexes were also investigated.

Ligand Exchange Governs the Crystal Structures in Binary Nanocrystal Superlattices.

PubMed

Wei, Jingjing; Schaeffer, Nicolas; Pileni, Marie-Paule

2015-11-25

The surface chemistry in colloidal nanocrystals on the final crystalline structure of binary superlattices produced by self-assembly of two sets of nanocrystals is hereby demonstrated. By mixing nanocrystals having two different sizes and the same coating agent, oleylamine (OAM), the binary nanocrystal superlattices that are produced, such as NaCl, AlB2, NaZn13, and MgZn2, are well in agreement with the crystalline structures predicted by the hard-sphere model, their formation being purely driven by entropic forces. By opposition, when large and small nanocrystals are coated with two different ligands [OAM and dodecanethiol (DDT), respectively] while keeping all other experimental conditions unchanged, the final binary structures markedly change and various structures with lower packing densities, such as Cu3Au, CaB6, and quasicrystals, are observed. This effect of the nanocrystals' coating agents could also be extended to other binary systems, such as Ag-Au and CoFe2O4-Ag supracrystalline binary lattices. In order to understand this effect, a mechanism based on ligand exchange process is proposed. Ligand exchange mechanism is believed to affect the thermodynamics in the formation of binary systems composed of two sets of nanocrystals with different sizes and bearing two different coating agents. Hence, the formation of binary superlattices with lower packing densities may be favored kinetically because the required energetic penalty is smaller than that of a denser structure.

A nickel tripeptide as a metallodithiolate ligand anchor for resin-bound organometallics.

PubMed

Green, Kayla N; Jeffery, Stephen P; Reibenspies, Joseph H; Darensbourg, Marcetta Y

2006-05-17

The molecular structure of the acetyl CoA synthase enzyme has clarified the role of individual nickel atoms in the dinickel active site which mediates C-C and C-S coupling reactions. The NiN2S2 portion of the biocatalyst (N2S2 = a cysteine-glycine-cysteine or CGC4- tripeptide ligand) serves as an S-donor ligand comparable to classical bidentate ligands operative in organometallic chemistry, ligating the second nickel which is redox and catalytically active. Inspired by this biological catalyst, the synthesis of NiN2S2 metalloligands, including the solid-phase synthesis of resin-bound Ni(CGC)2-, and sulfur-based derivatization with W(CO)5 and Rh(CO)2+ have been carried out. Through comparison to analogous well-characterized, solution-phase complexes, Attenuated Total Reflectance FTIR spectroscopy establishes the presence of unique heterobimetallic complexes, of the form [Ni(CGC)]M(CO)x, both in solution and immobilized on resin beads. This work provides the initial step toward exploitation of such an evolutionarily optimized nickel peptide as a solid support anchor for hybrid bioinorganic-organometallic catalysts.

Weakly-bridged dimeric diorganotin(IV) compounds derived from pyruvic acid hydrazone Schiff base ligands: Synthesis, characterization and crystal structures

NASA Astrophysics Data System (ADS)

Hong, Min; Yin, Han-Dong; Cui, Ji-Chun

2011-03-01

We report the synthesis of four diorganotin(IV) compounds of Schiff base pyruvic acid hydrazone derivatives formulated as [R 2SnLY] 2, where L 1 is 2-SC 4H 3CON 2C(CH 3)CO 2 with Y = CH 3CH 2CH 2CH 2OH, R = n-Bu ( 1); L 2 is C 6H 5CON 2C(CH 3)CO 2 with Y = CH 3CH 2OH, R = p-F-Bz ( 2); L 3 is 2-HOC 6H 4CON 2C(CH 3)CO 2 with Y dbnd H 2O, R = p-CN -Bz ( 3); and L 4 is 4-NO 2-C 6H 4CON 2C(CH 3)CO 2 with Y dbnd CH 3CH 2OH, R = Bz ( 4). The structures of all compounds have been established by a combination of single-crystal X-ray diffraction analysis, 1H and 119Sn NMR spectroscopy, IR spectroscopy, and elemental analysis. Studies reveal that four ligands present the same coordination mode with tin center, which all present tridentate ONO donor Schiff bases and coordinate to the tin center in an enolic form. In compounds 1- 4, each tin atom is seven-coordinated and exhibits a distorted pentagonal bipyramid with a planar SnO 4N unit and two apical alkyl carbon atoms, thus forming a weakly-bridged dimeric molecule. Additionally, the distance of Sn⋯O bridge in each compound is obviously affected by the choice of different alkyl groups and coordination solvent molecules, which fluctuates in the range of 2.571(5)-2.839(4) Å. Furthermore, the supramolecular structure analysis show that there are two types of supramolecular infrastructures, 1D chain or 2D network, which are formed by intermolecular O-H···N or C-H⋯X (X = O, N or F) hydrogen bonds.

New copper complexes with bipyrazolic ligands: Synthesis, characterization and evaluation of the antibacterial and catalytic properties

NASA Astrophysics Data System (ADS)

Harit, Tarik; Abouloifa, Houssam; Tillard, Monique; Eddike, Driss; Asehraou, Abdeslam; Malek, Fouad

2018-07-01

The synthesis of new bipyrazolic ligands functionalized by carboxyl groups, namely 3-Bis(3‧-carboxyl-5‧-methyl-l'-pyrazolyl) propan-2-ol (L1) and 1,3-Bis(3‧-carboxyl-5‧-methyl-l '-pyrazolyl),2-methyl propane (L2) is reported. Their corresponding [C13H15CuN4O5] (CuL1) and [C14H16CuN4O4] (CuL2) copper (II) complexes are also elaborated and characterized by elemental analysis, FTIR an UV-visible spectroscopy. The crystal structure of the CuL1 complex confirms that copper atom is 4-coordinated, in a distorted square planar geometry within the molecule, and achieves its coordination through weak intermolecular interactions leading to two dimensional slabs. This geometry is in agreement with UV-visible results which also evidence that structure of complexes are affected in DMSO in contrast to methanol. No antibacterial activity against all the tested bacterial strains has been found for the Cu (II) complexes. By contrast, CuL1 is characterized with good catalytic properties in the air-oxidation of catechol substrate to quinone.

Ruthenium(II) Complexes Containing Lutidine-Derived Pincer CNC Ligands: Synthesis, Structure, and Catalytic Hydrogenation of C-N bonds.

PubMed

Hernández-Juárez, Martín; López-Serrano, Joaquín; Lara, Patricia; Morales-Cerón, Judith P; Vaquero, Mónica; Álvarez, Eleuterio; Salazar, Verónica; Suárez, Andrés

2015-05-11

A series of Ru complexes containing lutidine-derived pincer CNC ligands have been prepared by transmetalation with the corresponding silver-carbene derivatives. Characterization of these derivatives shows both mer and fac coordination of the CNC ligands depending on the wingtips of the N-heterocyclic carbene fragments. In the presence of tBuOK, the Ru-CNC complexes are active in the hydrogenation of a series of imines. In addition, these complexes catalyze the reversible hydrogenation of phenantridine. Detailed NMR spectroscopic studies have shown the capability of the CNC ligand to be deprotonated and get involved in ligand-assisted activation of dihydrogen. More interestingly, upon deprotonation, the Ru-CNC complex 5 e(BF4 ) is able to add aldimines to the metal-ligand framework to yield an amido complex. Finally, investigation of the mechanism of the hydrogenation of imines has been carried out by means of DFT calculations. The calculated mechanism involves outer-sphere stepwise hydrogen transfer to the C-N bond assisted either by the pincer ligand or a second coordinated H2 molecule. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Purinergic P2X receptors: structural models and analysis of ligand-target interaction.

PubMed

Dal Ben, Diego; Buccioni, Michela; Lambertucci, Catia; Marucci, Gabriella; Thomas, Ajiroghene; Volpini, Rosaria

2015-01-07

The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Structural Insights into σ₁ Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations.

PubMed

Kurciński, Mateusz; Jarończyk, Małgorzata; Lipiński, Piotr F J; Dobrowolski, Jan Cz; Sadlej, Joanna

2018-02-18

Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ₁ receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ₁ receptor has made elucidating the structure-activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ₁ receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor-ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue-ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands' affinities toward the σ₁ receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand-receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.

Lanthanide coordination polymers: Synthesis, diverse structure and luminescence properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Xue-Qin, E-mail: songxq@mail.lzjtu.cn; Lei, Yao-Kun; Wang, Xiao-Run

2014-10-15

The new semirigid exo-bidentate ligand incorporating furfurysalicylamide terminal groups, namely, 1,4-bis([(2′-furfurylaminoformyl)phenoxyl]methyl)-2,5-bismethylbenzene (L) was synthesized and used as building blocks for constructing lanthanide coordination polymers with luminescent properties. The series of lanthanide nitrate complexes have been characterized by elemental analysis, IR spectroscopy, and X-ray diffraction analysis. The semirigid ligand L, as a bridging ligand, reacts with lanthanide nitrates forming three distinct structure types: chiral noninterpenetrated two-dimensional (2D) honeycomblike (6,3) (hcb, Schläfli symbol 6{sup 3}, vertex symbol 6 6 6) topological network as type I, 1D zigzag chain as type II and 1D trapezoid ladder-like chain as type III. The structural diversitiesmore » indicate that lanthanide contraction effect played significant roles in the structural self-assembled process. The luminescent properties of Eu{sup III}, Tb{sup III} and Dy{sup III} complexes are discussed in detail. Due to the good match between the lowest triplet state of the ligand and the resonant energy level of the lanthanide ion, the lanthanide ions in Eu{sup III}, Tb{sup III} and Dy{sup III} complexes can be efficiently sensitized by the ligand. - Graphical abstract: We present herein six lanthanide coordination polymers of a new semirigid exo-bidentate ligand which not only display diverse structures but also possess strong luminescence properties. - Highlights: • We present lanthanide coordination polymers of a new semirigid exo-bidentate ligand. • The lanthanide coordination polymers exhibit diverse structures. • The luminescent properties of Tb{sup III}, Eu{sup III} and Dy{sup III} complexes are discussed in detail.« less

Validation of ligands in macromolecular structures determined by X-ray crystallography

PubMed Central

Horský, Vladimír; Svobodová Vařeková, Radka; Bendová, Veronika

2018-01-01

Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) play a crucial role in structure-guided drug discovery and design, and also provide atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. The quality with which small-molecule ligands have been modelled in Protein Data Bank (PDB) entries has been, and continues to be, a matter of concern for many investigators. Correctly interpreting whether electron density found in a binding site is compatible with the soaked or co-crystallized ligand or represents water or buffer molecules is often far from trivial. The Worldwide PDB validation report (VR) provides a mechanism to highlight any major issues concerning the quality of the data and the model at the time of deposition and annotation, so the depositors can fix issues, resulting in improved data quality. The ligand-validation methods used in the generation of the current VRs are described in detail, including an examination of the metrics to assess both geometry and electron-density fit. It is found that the LLDF score currently used to identify ligand electron-density fit outliers can give misleading results and that better ligand-validation metrics are required. PMID:29533230

Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures.

PubMed

Doria, Filippo; Nadai, Matteo; Folini, Marco; Di Antonio, Marco; Germani, Luca; Percivalle, Claudia; Sissi, Claudia; Zaffaroni, Nadia; Alcaro, Stefano; Artese, Anna; Richter, Sara N; Freccero, Mauro

2012-04-14

The synthesis, physico-chemical properties and biological effects of a new class of naphthalene diimides (NDIs) capable of reversibly binding telomeric DNA and alkylate it through an electrophilic quinone methide moiety (QM), are reported. FRET and circular dichroism assays showed a marked stabilization and selectivity towards telomeric G4 DNA folded in a hybrid topology. NDI-QMs' alkylating properties revealed a good reactivity on single nucleosides and selectivity towards telomeric G4. A selected NDI was able to significantly impair the growth of melanoma cells by causing telomere dysfunction and down-regulation of telomerase expression. These findings points to our hybrid ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies. This journal is © The Royal Society of Chemistry 2012

SITEHOUND-web: a server for ligand binding site identification in protein structures.

PubMed

Hernandez, Marylens; Ghersi, Dario; Sanchez, Roberto

2009-07-01

SITEHOUND-web (http://sitehound.sanchezlab.org) is a binding-site identification server powered by the SITEHOUND program. Given a protein structure in PDB format SITEHOUND-web will identify regions of the protein characterized by favorable interactions with a probe molecule. These regions correspond to putative ligand binding sites. Depending on the probe used in the calculation, sites with preference for different ligands will be identified. Currently, a carbon probe for identification of binding sites for drug-like molecules, and a phosphate probe for phosphorylated ligands (ATP, phoshopeptides, etc.) have been implemented. SITEHOUND-web will display the results in HTML pages including an interactive 3D representation of the protein structure and the putative sites using the Jmol java applet. Various downloadable data files are also provided for offline data analysis.

Probing the interface between semiconducting nanocrystals and molecular metal chalcogenide surface ligands: insights from first principles

NASA Astrophysics Data System (ADS)

Scalise, Emilio; Wippermann, Stefan; Galli, Giulia; Talapin, Dmitri

Colloidal nanocrystals (NCs) are emerging as cost-effective materials offering exciting prospects for solar energy conversion, light emission and electronic applications. Recent experimental advances demonstrate the synthesis of fully inorganic nanocrystal solids from chemical solution processing. The properties of the NC-solids are heavily determined by the NCs surface and their interactions with the host matrix. However, information on the atomistic structure of such composites is hard to obtain, due to the complexity of the synthesis conditions and the unavailability of robust experimental techniques to probe nanointerfaces at the microscopic level. Here we present a systematic theoretical study of the interaction between InAs and InP NCs with Sn2S64- ligands. Employing a grand canonical ab initio thermodynamic approach we investigate the relative stability of a multitude of configurations possibly realized at the NC-ligand interface. Our study highlights the importance of different structural details and their strong impact on the resulting composite's properties. We show that to obtain a detailed understanding of experimental data it is necessary to take into account complex interfacial structures beyond simplified NC-ligand model interfaces. S. W. acknowledges BMBF NanoMatFutur Grant No. 13N12972. G.G. acknowledges DOE-BES for funding part of this work.

Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

DOE PAGES

Bublitz, Maike; Nass, Karol; Drachmann, Nikolaj D.; ...

2015-06-11

Membrane proteins are key players in biological systems, mediating signalling events and the specific transport ofe.g.ions and metabolites. Consequently, membrane proteins are targeted by a large number of currently approved drugs. Understanding their functions and molecular mechanisms is greatly dependent on structural information, not least on complexes with functionally or medically important ligands. Structure determination, however, is hampered by the difficulty of obtaining well diffracting, macroscopic crystals. Here, the feasibility of X-ray free-electron-laser-based serial femtosecond crystallography (SFX) for the structure determination of membrane protein–ligand complexes using microcrystals of various native-source and recombinant P-type ATPase complexes is demonstrated. The data revealmore » the binding sites of a variety of ligands, including lipids and inhibitors such as the hallmark P-type ATPase inhibitor orthovanadate. By analyzing the resolution dependence of ligand densities and overall model qualities, SFX data quality metrics as well as suitable refinement procedures are discussed. Even at relatively low resolution and multiplicity, the identification of ligands can be demonstrated. This makes SFX a useful tool for ligand screening and thus for unravelling the molecular mechanisms of biologically active proteins.« less

Self-assembly of novel manganese (II) compounds based on bifunctional-group ligands: Synthesis, structures, and magnetic properties

NASA Astrophysics Data System (ADS)

Yan, Juan-zhi; Lu, Li-ping; Zhu, Miao-li; Feng, Si-si

2018-06-01

Four manganese (II) compounds are obtained by the reaction of manganese salts, triazole-derivatives and auxiliary reagents in aqueous solution or mix-solvents by routine or hydrothermal reactions. X-ray crystal structure analyses reveal that a neutral 0D compound [Mn(Hmctrz)2(H2O)2] (1) (H2mctrz = 1H-1,2,4-triazole-3-carboxylic acid) displays a centro-symmetric mononuclear octahedral entity with two Hmctrz- anions and two water molecules; two neutral 2D clusters [Mn(Hdctrz)(H2O)2]n (2) (H3dctrz = 1H-1,2,4-triazole-3,5-dicarboxylic acid) and [Mn2(pbtrz)(btca)]n·4nH2O (3) (pbtrz = 1,3-bis(1,2,4-triazol-1-yl)-propane&H4btca = benzene-1,2,4,5-tetracarboxylic acid) possess layer structures with Hdctrz2- linkers (2) and Mn(II)-pbtrz-Mn(II) building blocks periodically extended by μ-btca4- connectors (3); [Mn(pbtrz)]n·nOAc·nOH (4) shows a 3D diamond-shaped cationic framework with the anion void volume of 49.2%. Nitrogenous bases are used as the auxiliary ligand in compound 3 and the temple ligand in compounds 1, 2, and 4. Compounds 1-4 show antiferromagnetic coupling that has been fitted by different models with the molecular field approximate with D = - 0.129(1) cm-1 for 1, J = - 0.354(4) cm-1 for 2 and J = - 0.696(6) cm-1 for 3, respectively. The magnetic differences can be related to different superexchange interactions transmitted by the crystal lattice and/or the zero field splitting (ZFS) of the 6A1g single-ion states of 1 and the syn-anti-COO- of 2 as well as the mixed magnetic bridges of μ1-O and μ-pbtrz-μ-COO- of 3.

Synthesis, spectroscopic, DFT studies and biological activity of some ruthenium carbonyl derivatives of bis-(salicylaldehyde)phenylenediimine Schiff base ligand

NASA Astrophysics Data System (ADS)

Ramadan, Ramadan M.; Abu Al-Nasr, Ahmad K.; Ali, Omayma A. M.

2018-06-01

Bis-(salicylaldehyde)phenylenediimine Schiff base (H2salphen) reacted oxidatively with the triruthenium dodecacarbonyl complex, [Ru3(CO)12] to give the dicarbonyl derivative [Ru(CO)2(salphen)], 1. In presence of a secondary ligand L (L = pyridine, triphenyl phosphine, 2-aminobenzimidazole or thiourea), the monocarbonyl derivatives [Ru(CO)(salphen)L], 2-5, were isolated. When the bipyridine (bpy) ligand was used as a secondary ligand, the dicarbonyl complex [Ru(CO)2(Hsalphen)(bpy)], 6, was obtained. In complexes 1-5, the Schiff base ligand acted as a tetradentate, while it coordinated as a bidentate in complex 6. The structure and stoichiometry of the complexes were investigated by the conventional analytical and spectroscopic techniques, which revealed that they have several structural arrangements. The structures of ligand and complexes were verified by theoretical calculations based on accurate DFT approximations. The relative reactivities were estimated using chemical descriptors analysis. Biological activities of the complexes against the Escherchia coli and Staphylococcus aureus bacteria were screened.

Two Zinc(II) metal-organic frameworks with mixed ligands of 5-amino-tetrazolate and l,2,4,5-benzenetetracarboxylate: Synthesis, structural diversity and photoluminescent properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Xiao-Bing; Lu, Wen-Guan, E-mail: lwg@sgu.edu.cn; Zhong, Di-Chang

The reactions of Zn(NO{sub 3}){sub 2}·6H{sub 2}O with mixed ligands of 5-amino-tetrazole (Hatz) and l,2,4,5-benzenetetracarboxylic acid (H{sub 4}btec) under hydro(solvo)thermal conditions, gave two three-dimensional (3D) porous metal-organic frameworks (MOFs) of ([Zn{sub 3}(atz){sub 2}(btec)(DMF){sub 2}]·DMF·2H{sub 2}O){sub n} (1) and [Zn{sub 2}(Hprz)(atz)(btec)(H{sub 2}O)]{sub n} (2) in the absence and presence of piperazine (prz), respectively. 1 and 2 were characterized by infrared spectra (IR), elemental analyses (EA) and single-crystal/powder X-ray diffraction. In 1, the adjacent 1D [Zn{sub 3}(btec)]{sub n}{sup 2n+} chains are linked together by atz{sup −} ligands to form a 3D porous MOF with 1D tetragonal channels filled with coordinated and guestmore » DMF, and lattice water molecules. In 2, the adjacent 2D [Zn{sub 2}(btec)]{sub n} wavelike sheets are pillared through atz{sup −} ligands to generate a 3D layered-pillared porous MOF with 1D open channels, which are occupied by coordinated Hprz{sup +} cations and coordinated water molecules. Additionally, thermal stabilities and photoluminescent properties of both compounds in the solid-state at room temperature have been investigated and discussed in detail. - Graphical abstract: Two new MOFs constructed from Zn(II) salts with mixed ligands of 5-amino-tetrazole and l,2,4,5-benzenetetracarboxylic acid were synthesized under different reaction conditions. Structural diversities indicate that the reaction solvent system or the presence of organic base play crucial roles in modulating structures of these compounds. And more, their thermal stability and luminescence are also discussed. - Highlights: • Two new Zn(II) MOFs based on mixed ligands were synthesized. • The two Zn(II) MOFs exhibit different structural motifs. • The two Zn(II) MOFs are photoluminscent in the solid state at room temperature.« less

[Studies on the structure-activity relationship of retinoids--Hansch analysis and 3D-OSAR studies on specific ligands of retinoid x receptor].

PubMed

Huang, N; Chu, F; Guo, Z

1998-06-01

Retinoids (Vitamin A, its metabolites and synthetic analogues) play important roles in a variety of biological processes, including cellular differentiation, proliferation and apoptosis. The many diverse actions of retinoids attribute to the ability of regulating transcription of different target genes through activation of multiple retinoid nuclear receptors (RAR of RXR). So, retinoids with selective binding ability to specific receptor may not only have improved therapeutic indices, but may also be invaluable for elucidating the molecular mechanism of retinoidal transcriptional activation. Based on the two dimensional and three dimensional quantitative structure-activity relationships of specific ligands of RXR, we carried out mimesis of environment of ligands interacting with their receptor and, to some extent, mapping the topological and physico-chemical characteristics of receptor. The knowledge of the QSAR study will offer detailed molecular information for design, synthesis and biological evaluation in drug research and development.

Structural characterization and antimicrobial activities of transition metal complexes of a hydrazone ligand

NASA Astrophysics Data System (ADS)

Bakale, Raghavendra P.; Naik, Ganesh N.; Machakanur, Shrinath S.; Mangannavar, Chandrashekhar V.; Muchchandi, Iranna S.; Gudasi, Kalagouda B.

2018-02-01

A hydrazone ligand has been synthesized by the condensation of 2-nitrobenzaldehyde and hydralazine, and its Co(II), Ni(II), Cu(II) and Zn(II) complexes have been reported. Structural characterization of the ligand and its metal complexes has been performed by various spectroscopic [IR, NMR, UV-Vis, Mass], thermal and other physicochemical methods. The structure of the ligand and its Ni(II) complex has been characterized by single crystal X-ray diffraction studies. All the synthesized compounds have been screened for in vitro antimicrobial activity. The antibacterial activity is tested against Gram-positive strains Enterococcus faecalis, Streptococcus mutans and Staphylococcus aureus and Gram-negative strains Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae using ciprofloxacin as the reference standard. Antifungal activity is tested against Candida albicans, Aspergillus fumigatus and Aspergillus niger using ketoconazole as the reference standard. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standard. Ligand, Cu(II) and Zn(II) complexes have shown excellent activity against Candida albicans.

Ligand Binding Site Detection by Local Structure Alignment and Its Performance Complementarity

PubMed Central

Lee, Hui Sun; Im, Wonpil

2013-01-01

Accurate determination of potential ligand binding sites (BS) is a key step for protein function characterization and structure-based drug design. Despite promising results of template-based BS prediction methods using global structure alignment (GSA), there is a room to improve the performance by properly incorporating local structure alignment (LSA) because BS are local structures and often similar for proteins with dissimilar global folds. We present a template-based ligand BS prediction method using G-LoSA, our LSA tool. A large benchmark set validation shows that G-LoSA predicts drug-like ligands’ positions in single-chain protein targets more precisely than TM-align, a GSA-based method, while the overall success rate of TM-align is better. G-LoSA is particularly efficient for accurate detection of local structures conserved across proteins with diverse global topologies. Recognizing the performance complementarity of G-LoSA to TM-align and a non-template geometry-based method, fpocket, a robust consensus scoring method, CMCS-BSP (Complementary Methods and Consensus Scoring for ligand Binding Site Prediction), is developed and shows improvement on prediction accuracy. The G-LoSA source code is freely available at http://im.bioinformatics.ku.edu/GLoSA. PMID:23957286

Structural basis of ligand recognition in 5-HT3 receptors

PubMed Central

Kesters, Divya; Thompson, Andrew J; Brams, Marijke; van Elk, René; Spurny, Radovan; Geitmann, Matthis; Villalgordo, Jose M; Guskov, Albert; Helena Danielson, U; Lummis, Sarah C R; Smit, August B; Ulens, Chris

2013-01-01

The 5-HT3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation–π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor. PMID:23196367

Secbase: database module to retrieve secondary structure elements with ligand binding motifs.

PubMed

Koch, Oliver; Cole, Jason; Block, Peter; Klebe, Gerhard

2009-10-01

Secbase is presented as a novel extension module of Relibase. It integrates the information about secondary structure elements into the retrieval facilities of Relibase. The data are accessible via the extended Relibase user interface, and integrated retrieval queries can be addressed using an extended version of Reliscript. The primary information about alpha-helices and beta-sheets is used as provided by the PDB. Furthermore, a uniform classification of all turn families, based on recent clustering methods, and a new helix assignment that is based on this turn classification has been included. Algorithms to analyze the geometric features of helices and beta-strands were also implemented. To demonstrate the performance of the Secbase implementation, some application examples are given. They provide new insights into the involvement of secondary structure elements in ligand binding. A survey of water molecules detected next to the N-terminus of helices is analyzed to show their involvement in ligand binding. Additionally, the parallel oriented NH groups at the alpha-helix N-termini provide special binding motifs to bind particular ligand functional groups with two adjacent oxygen atoms, e.g., as found in negatively charged carboxylate or phosphate groups, respectively. The present study also shows that the specific structure of the first turn of alpha-helices provides a suitable explanation for stabilizing charged structures. The magnitude of the overall helix macrodipole seems to have no or only a minor influence on binding. Furthermore, an overview of the involvement of secondary structure elements with the recognition of some important endogenous ligands such as cofactors shows some distinct preference for particular binding motifs and amino acids.

Linked magnolol dimer as a selective PPARγ agonist - Structure-based rational design, synthesis, and bioactivity evaluation.

PubMed

Dreier, Dominik; Latkolik, Simone; Rycek, Lukas; Schnürch, Michael; Dymáková, Andrea; Atanasov, Atanas G; Ladurner, Angela; Heiss, Elke H; Stuppner, Hermann; Schuster, Daniela; Mihovilovic, Marko D; Dirsch, Verena M

2017-10-20

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.

Crystal Structure of Oligomeric β1-Adrenergic G Protein- Coupled Receptors in Ligand-Free Basal State

PubMed Central

Huang, Jianyun; Chen, Shuai; Zhang, J. Jillian; Huang, Xin-Yun

2013-01-01

G protein-coupled receptors (GPCRs) mediate transmembrane signaling. Before ligand binding, GPCRs exist in a basal state. Crystal structures of several GPCRs bound with antagonists or agonists have been solved. However, the crystal structure of the ligand-free basal state of a GPCR, the starting point of GPCR activation and function, has not been determined. Here we report the X-ray crystal structure of the first ligand-free basal state of a GPCR in a lipid membrane-like environment. Oligomeric turkey β1-adrenergic receptors display two alternating dimer interfaces. One interface involves the transmembrane domain (TM) 1, TM2, the C-terminal H8, and the extracellular loop 1. The other interface engages residues from TM4, TM5, the intracellular loop 2 and the extracellular loop 2. Structural comparisons show that this ligand-free state is in an inactive conformation. This provides the structural information regarding GPCR dimerization and oligomerization. PMID:23435379

One pot synthesis of two Mn(II) perchlorate complexes with s-triazine NNN-pincer ligand; molecular structure, Hirshfeld analysis and DFT studies

NASA Astrophysics Data System (ADS)

Soliman, Saied M.; El-Faham, Ayman

2018-07-01

Self assembly of Mn(II) perchlorate and bis(pyrazolo)-s-triazine pincer ligand (L) in methanol-water mixture afforded the homoleptic [MnL2](ClO4)2 complex (1) as plate colorless crystals. Following the crystallization process till the near dryness of the solution, we noted few needle like crystals of the heteroleptic [MnL(H2O)3](ClO4)2·H2O complex (2). Their molecular and supramolecular structures were analyzed using single crystal structure combined with Hirshfeld analysis. The packing of complexes 1 and 2 is dominated by weak Csbnd H⋯O and strong Osbnd H⋯O hydrogen bonds, respectively, as well as anion-π stacking interactions. Using Hirshfeld analysis, the percentages of the O⋯H intermolecular contacts are 32.7% and 36.8% for 1 and 2, respectively. The Mnsbnd N distances correlated well with the atoms in molecules (AIM) topological parameters. The amount of electron density transferred from the ligand units to the manganese centre are nearly the same (0.9 e) in both complexes.

Ligand-tailored single-site silica supported titanium catalysts: Synthesis, characterization and towards cyanosilylation reaction

NASA Astrophysics Data System (ADS)

Xu, Wei; Li, Yani; Yu, Bo; Yang, Jindou; Zhang, Ying; Chen, Xi; Zhang, Guofang; Gao, Ziwei

2015-01-01

A successive anchoring of Ti(NMe2)4, cyclopentadiene and a O-donor ligand, 1-hydroxyethylbenzene (PEA), 1,1‧-bi-2-naphthol (Binol) or 2,3-dihydroxybutanedioic acid diethyl ester (Tartrate), on silica was conducted by SOMC strategy in moderate conditions. The silica, monitored by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR), was pretreated at different temperatures (200, 500 and 800 °C). The ligand tailored silica-supported titanium complexes were characterized by in-situ FT-IR, 13C CP MAS-NMR, X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge structure (XANES) and elemental analysis in detail, verifying that the surface titanium species are single sited. The catalytic activity of the ligand tailored single-site silica supported titanium complexes was evaluated by a cyanosilylation of benzaldehyde. The results showed that the catalytic activity is dependent strongly on the dehydroxylation temperatures of silica and the configuration of the ligands.

Synthesis and Characterization of a Series of Structurally and Electronically Diverse Fe(II) Complexes Featuring a Family of Triphenylamido-Amine Ligands

PubMed Central

Paraskevopoulou, Patrina; Ai, Lin; Wang, Qiuwen; Pinnapareddy, Devender; Acharyya, Rama; Dinda, Rupam; Das, Purak; Çelenligil-Çetin, Remle; Floros, Georgios; Sanakis, Yiannis; Choudhury, Amitava; Rath, Nigam P.; Stavropoulos, Pericles

2009-01-01

A family of triphenylamido-amine ligands of the general stoichiometry LxH3 = [R-NH-(2-C6H4)]3N (R = 4-t-BuPh (L1H3), 3,5-t-Bu2Ph (L2H3), 3,5-(CF3)2Ph (L3H3), CO-t-Bu (L4H3) 3,5-Cl2Ph (L5H3), COPh (L6H3), CO-i-Pr (L7H3), COCF3 (L8H3), i-Pr (L9H3)) has been synthesized and characterized, featuring a rigid triphenylamido-amine scaffold and an array of stereoelectronically diverse aryl, acyl and alkyl substituents (R). These ligands are deprotonated by potassium hydride in THF or DMA and reacted with anhydrous FeCl2 to afford a series of ferrous complexes, exhibiting stoichiometric variation and structural complexity. The prevalent [(Lx)Fe(II)–solv]− structures (Lx = L1, L2, L3, L5, solv = THF; Lx = L8, solv = DMA; Lx = L6, L8, solv = MeCN), reveal a distorted trigonal bipyramidal geometry, featuring ligand-derived [N3,amidoNamine] coordination and solvent attachment trans to the Namine atom. Specifically for [(L8)Fe(II)–DMA]−, an Namido residue is coordinated as the corresponding Nimino moiety (Fe–N(Ar)=C(CF3)–O−). In contrast, compounds [(L4)Fe(II)] −, [(L6)2Fe(II)2]2−, [K(L7)2Fe(II)2]22− and [K(L9)Fe]2 are all solvent-free in their coordination sphere and exhibit four-coordinate geometries of significant diversity. In particular, [(L4)Fe(II)]− demonstrates coordination of one amidato residue via the O-atom end (Fe–O–C(t-Bu)=N(Ar)). Furthermore, [(L6)2Fe(II)2]2− and [K(L7)2Fe(II)2]22− are similar structures exhibiting bridging amidato residues (Fe–N(Ar)–C(R)=O–Fe) in dimeric structural units. Finally the structure of [K(L9)Fe]2 is the only example featuring a minimal [N3,amidoNamine] coordination sphere around each Fe(II) site. All compounds have been characterized by a variety of physicochemical techniques, including Mössbauer spectroscopy and electrochemistry, to reveal electronic attributes that are responsible for a range of Fe(II)/Fe(III) redox potentials exceeding 1.0 V. PMID:19950956

Ligand Depot: a data warehouse for ligands bound to macromolecules.

PubMed

Feng, Zukang; Chen, Li; Maddula, Himabindu; Akcan, Ozgur; Oughtred, Rose; Berman, Helen M; Westbrook, John

2004-09-01

Ligand Depot is an integrated data resource for finding information about small molecules bound to proteins and nucleic acids. The initial release (version 1.0, November, 2003) focuses on providing chemical and structural information for small molecules found as part of the structures deposited in the Protein Data Bank. Ligand Depot accepts keyword-based queries and also provides a graphical interface for performing chemical substructure searches. A wide variety of web resources that contain information on small molecules may also be accessed through Ligand Depot. Ligand Depot is available at http://ligand-depot.rutgers.edu/. Version 1.0 supports multiple operating systems including Windows, Unix, Linux and the Macintosh operating system. The current drawing tool works in Internet Explorer, Netscape and Mozilla on Windows, Unix and Linux.

Synthesis and structural characterization of dinuclear Cd2+, Hg2+ and Fe2+ complexes with neutral bi and tetradentate flexible pyrazole-based ligands

NASA Astrophysics Data System (ADS)

Beheshti, Azizolla; Lalegani, Arash; Behvandi, Fatemeh; Safaeiyan, Forough; Sarkarzadeh, Afsoon; Bruno, Giuseppe; Amiri Rudbari, Hadi

2015-02-01

Four new complexes of [Hg2Cl4(bpp)]n (1), [Hg2Cl4(tdmpp)] (2), [Cd2I4(tdmpp)] (3) and [Fe2Cl4(tdmpp)] (4) were prepared by using the neutral N-donor ligands 1,3-bis(3,5-dimethyl-1-pyrazolyl)propane (bpp) and 1,1,3,3-tetrakis(3,5-dimethyl-1-pyrazolyl)propane (tdmpp) with different flexibility and appropriate metal salts of Cd(II), Hg(II) and Fe(II) ions. These compounds were characterized by the infrared spectroscopy, elemental analysis and X-ray crystallography. Flexible ligands and non-covalent Csbnd H⋯Cl hydrogen bonds play a major role in the crystal packing of compounds 1, 2 and 4. In the two-dimensional non-covalent structure of 1, there are two distinctly different coordination modes for the mercury atoms. One mercury atom has pseudo-trigonal bipyramidal geometry and the other adopts a distorted tetrahedral environment. In the dinuclear structures of 2 and 4 the neutral molecules are linked together by the Csbnd H⋯Cl hydrogen bonds, forming an infinite one-dimensional zigzag chain structure. Compounds 2-4 are isostructural with each other.

Developing Ligands for Palladium(II)-Catalyzed C–H Functionalization: Intimate Dialogue between Ligand and Substrate

PubMed Central

Engle, Keary M.; Yu, Jin-Quan

2013-01-01

Homogeneous transition metal–catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C–H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C–H functionalization logic. In this review, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2′-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery. PMID:23565982

Higher coordinate gold(I) complexes with the weak Lewis base tri(4-fluorophenyl) phosphine. Synthesis, structural, luminescence, and DFT studies

NASA Astrophysics Data System (ADS)

Agbeworvi, George; Assefa, Zerihun; Sykora, Richard E.; Taylor, Jared; Crawford, Carlos

2016-03-01

The structures and spectroscopic properties of two high coordinate gold(I) phosphine complexes with the TFFPP=tri(4-fluorophenyl)phosphine ligand are reported. Synthesis in a 1:3 metal to ligand ratio provided the compound [AuCl(TFFPP)3] (2) that crystallize in the P 1 bar space group, where the asymmetric unit consists of three independent molecules. In all three sites, two sets of bond angles display distinctly different ranges. The three P-Au-P angles have average values of 117.92°, 117.57°, and 114.78° for sites A, B, and C, with the corresponding P-Au-Cl angles of 98.31°, 99.05°, and 103.38°, respectively. The chloride ion coordinates as the fourth ligand, at the corresponding Au-Cl distance of 2.7337, 2.6825, and 2.6951 Å for the three sites. This distance is longer by 0.40-0.45 Å than the Au-Cl distance found in the mono TFFPP complex 1 (2.285 Å) indicating a weakening of the Au-Cl interaction as the coordination number increases. In compound 3, [Au(TFFPP)3]Cl·½CH2Cl2·H2O, the structure consists of three phosphine ligands bound to the gold(I) atom, but the Cl- exists as uncoordinated counter anion. The structural differences observed in the two complexes are attributable to crystal-packing effects caused by the introduction of H-bonding as well as enhanced intra and inter-molecular π-interaction in 3. The photoluminescence of the complexes compared with that of the ligand show ligand centered emission perturbed by the metal coordination. Theoretical DFT studies conducted on these complexes supports assignments of the electronic transitions observed in these systems.

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andersen, Jacob Lauwring, E-mail: jla@mb.au.dk; Schrøder, Tenna Juul; Christensen, Søren

2014-02-01

The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported. Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin–AF40431 complex were obtained bymore » co-crystallization and the structure of the complex was solved to 2.7 Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.« less

Two novel mixed-ligand complexes containing organosulfonate ligands.

PubMed

Li, Mingtian; Huang, Jun; Zhou, Xuan; Fang, Hua; Ding, Liyun

2008-07-01

The structures reported herein, viz. bis(4-aminonaphthalene-1-sulfonato-kappaO)bis(4,5-diazafluoren-9-one-kappa(2)N,N')copper(II), [Cu(C(10)H(8)NO(3)S)(2)(C(11)H(6)N(2)O)(2)], (I), and poly[[[diaquacadmium(II)]-bis(mu-4-aminonaphthalene-1-sulfonato)-kappa(2)O:N;kappa(2)N:O] dihydrate], {[Cd(C(10)H(8)NO(3)S)(2)(H(2)O)(2)].2H(2)O}(n), (II), are rare examples of sulfonate-containing complexes where the anion does not fulfill a passive charge-balancing role, but takes an active part in coordination as a monodentate and/or bridging ligand. Monomeric complex (I) possesses a crystallographic inversion center at the Cu(II) atom, and the asymmetric unit contains one-half of a Cu atom, one complete 4-aminonaphthalene-1-sulfonate (ans) ligand and one 4,5-diazafluoren-9-one (DAFO) ligand. The Cu(II) atom has an elongated distorted octahedral coordination geometry formed by two O atoms from two monodentate ans ligands and by four N atoms from two DAFO molecules. Complex (II) is polymeric and its crystal structure is built up by one-dimensional chains and solvent water molecules. Here also the cation (a Cd(II) atom) lies on a crystallographic inversion center and adopts a slightly distorted octahedral geometry. Each ans anion serves as a bridging ligand linking two Cd(II) atoms into one-dimensional infinite chains along the [010] direction, with each Cd(II) center coordinated by four ans ligands via O and N atoms and by two aqua ligands. In both structures, there are significant pi-pi stacking interactions between adjacent ligands and hydrogen bonds contribute to the formation of two- and three-dimensional networks.

Alkaline earth metallocenes coordinated with ester pendants: synthesis, structural characterization, and application in metathesis reactions.

PubMed

Li, Heng; Zhang, Wen-Xiong; Xi, Zhenfeng

2013-09-16

A variety of ester-substituted cyclopentadiene derivatives have been synthesized by one-pot reactions of 1,4-dilithio-1,3-butadienes, CO, and acid chlorides. Direct deprotonation of the ester-substituted cyclopentadienes with Ae[N(SiMe3 )2 ]2 (Ae=Ca, Sr, Ba) efficiently generated members of a new class of heavier alkaline earth (Ca, Sr, Ba) metallocenes in good to excellent yields. Single-crystal X-ray structural analysis demonstrated that these heavier alkaline earth metallocenes incorporated two intramolecularly coordinated ester pendants and multiply-substituted cyclopentadienyl ligands. The corresponding transition metal metallocenes, such as ferrocene derivatives and half-sandwich cyclopentadienyl tricarbonylrhenium complexes, could be generated highly efficiently by metathesis reactions. The multiply-substituted cyclopentadiene ligands bearing an ester pendant, and the corresponding heavier alkaline earth and transition-metal metallocenes, may have further applications in coordination chemistry, organometallic chemistry, and organic synthesis. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dynamic control of chirality in phosphine ligands for enantioselective catalysis

PubMed Central

Zhao, Depeng; Neubauer, Thomas M.; Feringa, Ben L.

2015-01-01

Chirality plays a fundamental role in biology and chemistry and the precise control of chirality in a catalytic conversion is a key to modern synthesis most prominently seen in the production of pharmaceuticals. In enantioselective metal-based catalysis, access to each product enantiomer is commonly achieved through ligand design with chiral bisphosphines being widely applied as privileged ligands. Switchable phosphine ligands, in which chirality is modulated through an external trigger signal, might offer attractive possibilities to change enantioselectivity in a catalytic process in a non-invasive manner avoiding renewed ligand synthesis. Here we demonstrate that a photoswitchable chiral bisphosphine based on a unidirectional light-driven molecular motor, can be used to invert the stereoselectivity of a palladium-catalysed asymmetric transformation. It is shown that light-induced changes in geometry and helicity of the switchable ligand enable excellent selectivity towards the racemic or individual enantiomers of the product in a Pd-catalysed desymmetrization reaction. PMID:25806856

Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography.

PubMed

Mandal, Kalyaneswar; Uppalapati, Maruti; Ault-Riché, Dana; Kenney, John; Lowitz, Joshua; Sidhu, Sachdev S; Kent, Stephen B H

2012-09-11

Total chemical synthesis was used to prepare the mirror image (D-protein) form of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage display against D-VEGF-A was used to screen designed libraries based on a unique small protein scaffold in order to identify a high affinity ligand. Chemically synthesized D- and L- forms of the protein ligand showed reciprocal chiral specificity in surface plasmon resonance binding experiments: The L-protein ligand bound only to D-VEGF-A, whereas the D-protein ligand bound only to L-VEGF-A. The D-protein ligand, but not the L-protein ligand, inhibited the binding of natural VEGF(165) to the VEGFR1 receptor. Racemic protein crystallography was used to determine the high resolution X-ray structure of the heterochiral complex consisting of {D-protein antagonist + L-protein form of VEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in appropriate stoichiometry gave a racemic protein complex of more than 73 kDa containing six synthetic protein molecules. The structure of the complex was determined to a resolution of 1.6 Å. Detailed analysis of the interaction between the D-protein antagonist and the VEGF-A protein molecule showed that the binding interface comprised a contact surface area of approximately 800 Å(2) in accord with our design objectives, and that the D-protein antagonist binds to the same region of VEGF-A that interacts with VEGFR1-domain 2.

Synthesis, characterization and electrochemistry studies of iron(III) complex with curcumin ligand.

PubMed

Özbolat, Gülüzar; Yegani, Arash Alizadeh; Tuli, Abdullah

2018-05-11

Iron overload is a serious clinical condition for humans and is a key target in drug development. The aim of this study was to investigate the coordination of iron(III) ions with curcumin ligand that may be used in the treatment of iron overload. Iron(III) complex of curcumin was synthesized and structurally characterized in its solid and solution state by FT-IR, UV-Vis, elemental analysis, and magnetic susceptibility. Electrochemical behaviour of the ligand and the complexes were examined using cyclic voltammetry. The cytotoxic activities of the ligand and the iron(III) complex were evaluated by the MTT assay. Curcumin reacted with iron in high concentrations at physiological pH at room temperature. Subsequently, a brown-red complex was formed. Data regarding magnetic susceptibility showed that the complexes with a 1:2 (metal/ligand) mole ratio had octahedral geometry. The complex showed higher anti-oxidant effect towards the cell line ECV304 at IC 50 values of 4.83 compared to curcumin. The complex exhibited very high cytotoxic activity and showed a cytotoxic effect that was much better than that of the ligand. The potentials for redox were calculated as 0.180 V and 0.350 V, respectively. The electrochemistry studies showed that Fe 3+ /Fe 2+ couple redox process occurred at low potentials. This value was within the range of compounds that are expected to show superoxide dismutase activity. This finding indicates that the iron complex is capable of removing free radicals. The observed cytotoxicity could be pursued to obtain a potential drug. Further studies investigating the use of curcumin for this purpose are needed. © 2018 John Wiley & Sons Australia, Ltd.

Structural analysis of the binding modes of minor groove ligands comprised of disubstituted benzenes

PubMed Central

Hawkins, Cheryl A.; Watson, Charles; Yan, Yinfa; Gong, Bing; Wemmer, David E.

2001-01-01

Two-dimensional homonuclear NMR was used to characterize synthetic DNA minor groove-binding ligands in complexes with oligonucleotides containing three different A-T binding sites. The three ligands studied have a C2 axis of symmetry and have the same general structural motif of a central para-substituted benzene ring flanked by two meta-substituted rings, giving the molecules a crescent shape. As with other ligands of this shape, specificity seems to arise from a tight fit in the narrow minor groove of the preferred A-T-rich sequences. We found that these ligands slide between binding subsites, behavior attributed to the fact that all of the amide protons in the ligand backbone cannot hydrogen bond to the minor groove simultaneously. PMID:11160926

New Human CD22/Siglec-2 Ligands with a Triazole Glycoside.

PubMed

Prescher, Horst; Schweizer, Astrid; Kuhfeldt, Elena; Nitschke, Lars; Brossmer, Reinhard

2017-07-04

CD22 is a member of the Siglec family. Considerable attention has been drawn to the design and synthesis of new Siglec ligands to explore target biology and innovative therapies. In particular, CD22-ligand-targeted nanoparticles with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction. Here we report the design, synthesis and affinity evaluation of a new class of Siglec ligands: namely sialic acid derivatives with a triazole moiety replacing the natural glycoside oxygen atom. In addition, we describe important and surprising differences in binding to CD22 expressed at the cell surface for compounds with distinct valences. The new class of compounds might serve as a template for the design of ligands for other members of the Siglec family and next-generation CD22-ligand-based targeted therapies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting G-quadruplex DNA structures in the telomere and oncogene promoter regions by benzimidazole‒carbazole ligands.

PubMed

Kaulage, Mangesh H; Maji, Basudeb; Pasadi, Sanjeev; Ali, Asfa; Bhattacharya, Santanu; Muniyappa, K

2018-03-25

Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes. The fluorescence spectroscopic data indicate that benzimidazole-carbazole ligands bind and stabilize the G-quadruplexes in the promoter region of oncogenes. The molecular docking studies provide insights into the mode and extent of binding of this class of ligands to the G-quadruplexes formed in oncogene promoters. The high stability of these G-quadruplex structures was validated by thermal denaturation and telomerase-catalyzed extension of the 3' end. Notably, benzimidazole-carbazole ligands suppress the expression of oncogenes in cancer cells in a dose-dependent manner. We anticipate that benzimidazole-carbazole ligands, by virtue of their ability to stabilize G-quadruplex structures in the promoter regions of oncogenes, might reduce the risk of cancer through the loss of function in the proteins encoded by these genes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Synthesis and characterization of Pd(II)-methyl complexes with N-heterocyclic carbene-amine ligands.

PubMed

Warsink, Stefan; de Boer, Sandra Y; Jongens, Lianne M; Fu, Ching-Feng; Liu, Shiuh-Tzung; Chen, Jwu-Ting; Lutz, Martin; Spek, Anthony L; Elsevier, Cornelis J

2009-09-21

A number of palladium(ii) complexes with a heteroditopic NHC-amine ligand and their precursor silver(i) carbene complexes have been efficiently prepared and their structural features have been investigated. The heteroditopic coordination of this ligand class was unequivocally shown by NMR-spectroscopy and X-ray crystallographic analysis. The neutral and cationic cis-methyl-palladium(NHC) complexes are not prone to reductive elimination, which is normally a major degenerative pathway for this type of complex. In contrast, under carbon monoxide atmosphere rapid reductive elimination of the acyl-imidazolium salt was observed.

The effect of post-synthesis aging on the ligand exchange activity of iron oxide nanoparticles.

PubMed

Davis, Kathleen; Vidmar, Michael; Khasanov, Airat; Cole, Brian; Ghelardini, Melanie; Mayer, Justin; Kitchens, Christopher; Nath, Amar; Powell, Brian A; Mefford, O Thompson

2018-02-01

Ligand exchange is a widely-used method of controlling the surface chemistry of nanomaterials. Exchange is dependent on many factors including the age of the core particle being modified. Aging of the particles can impact surface structure and composition, which in turn can affect ligand binding. To quantify the effects of aging on ligand exchange, we employed a technique to track the exchange of radiolabeled 14 C-oleic acid with unlabeled, oleic acid bound to iron oxide nanoparticles. Liquid scintillation counting (LSC) was used to determine the amount of 14 C-oleic acid adsorbing to the particles throughout the duration of the exchange for particles aged for 2days, 7days, and 30days. Results revealed an increase in the total amount of ligands exchanged with aging up to 30days. Kinetic analysis of these results revealed a significant decrease in the overall rate of ligand exchange between 2 and 30days. The change in extent of adsorption with age could suggest increased availability of free binding sites. A follow-up study comparing exchange with oxidized and unoxidized particles suggested this increase in ligand adsorption may be due to changes in the Fe 2+ /Fe 3+ ratio on the surface as the particles aged. Copyright © 2017 Elsevier Inc. All rights reserved.

Ligand-tailored single-site silica supported titanium catalysts: Synthesis, characterization and towards cyanosilylation reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Wei; Li, Yani; Yu, Bo

2015-01-15

A successive anchoring of Ti(NMe{sub 2}){sub 4}, cyclopentadiene and a O-donor ligand, 1-hydroxyethylbenzene (PEA), 1,1′-bi-2-naphthol (Binol) or 2,3-dihydroxybutanedioic acid diethyl ester (Tartrate), on silica was conducted by SOMC strategy in moderate conditions. The silica, monitored by in-situ Fourier transform infrared spectroscopy (in-situ FT-IR), was pretreated at different temperatures (200, 500 and 800 °C). The ligand tailored silica-supported titanium complexes were characterized by in-situ FT-IR, {sup 13}C CP MAS-NMR, X-ray photoelectron spectroscopy (XPS), X-ray absorption near edge structure (XANES) and elemental analysis in detail, verifying that the surface titanium species are single sited. The catalytic activity of the ligand tailored single-sitemore » silica supported titanium complexes was evaluated by a cyanosilylation of benzaldehyde. The results showed that the catalytic activity is dependent strongly on the dehydroxylation temperatures of silica and the configuration of the ligands. - Graphical abstract: The ligand-tailored silica supported “single site” titanium complexes were synthesized by SOMC strategy and fully characterized. Their catalytic activity were evaluated by benzaldehyde silylcyanation. - Highlights: • Single-site silica supported Ti active species was prepared by SOMC technique. • O-donor ligand tailored Ti surface species was synthesized. • The surface species was characterized by XPS, {sup 13}C CP-MAS NMR, XANES etc. • Catalytic activity of the Ti active species in silylcyanation reaction was evaluated.« less

Differential global structural changes in the core particle of yeast and mouse proteasome induced by ligand binding

PubMed Central

Arciniega, Marcelino; Beck, Philipp; Lange, Oliver F.; Groll, Michael; Huber, Robert

2014-01-01

Two clusters of configurations of the main proteolytic subunit β5 were identified by principal component analysis of crystal structures of the yeast proteasome core particle (yCP). The apo-cluster encompasses unliganded species and complexes with nonpeptidic ligands, and the pep-cluster comprises complexes with peptidic ligands. The murine constitutive CP structures conform to the yeast system, with the apo-form settled in the apo-cluster and the PR-957 (a peptidic ligand) complex in the pep-cluster. In striking contrast, the murine immune CP classifies into the pep-cluster in both the apo and the PR-957–liganded species. The two clusters differ essentially by multiple small structural changes and a domain motion enabling enclosure of the peptidic ligand and formation of specific hydrogen bonds in the pep-cluster. The immune CP species is in optimal peptide binding configuration also in its apo form. This favors productive ligand binding and may help to explain the generally increased functional activity of the immunoproteasome. Molecular dynamics simulations of the representative murine species are consistent with the experimentally observed configurations. A comparison of all 28 subunits of the unliganded species with the peptidic liganded forms demonstrates a greatly enhanced plasticity of β5 and suggests specific signaling pathways to other subunits. PMID:24979800

Novel unsymmetrical P/O substituted ferrocene ligands and the first structurally characterised hydroxyferrocene derivative.

PubMed

Atkinson, Robert C J; Gibson, Vernon C; Long, Nicholas J; White, Andrew J P; Williams, David J

2004-06-21

Two new unsymmetrical 1'-substituted hydroxyferrocene ligands featuring either phosphine or phosphine oxide substituents have been synthesised and the phosphine oxide derivative has been structurally characterised. A nickel complex of the hydroxyl/phosphine ligand has been formed, along with preliminary evaluation of the complex for catalysis of ethylene polymerisation.

Synthesis, structure, DNA binding and anticancer activity of mixed ligand ruthenium(II) complex

NASA Astrophysics Data System (ADS)

Gilewska, Agnieszka; Masternak, Joanna; Kazimierczuk, Katarzyna; Trynda, Justyna; Wietrzyk, Joanna; Barszcz, Barbara

2018-03-01

In order to obtain a potential chemotherapeutic which is not affected on the normal BALB/3T3 cell line, a new arene ruthenium(II) complex {[RuCl(L1)(η6-p-cymene)]PF6}2 · H2O has been synthesized by a direct reaction of precursor, [{(η6-p-cymene)Ru(μ-Cl)}2Cl2], with N,N-chelating ligand (L1 - 2,2‧-bis(4,5-dimethylimidazole). The compound has been fully characterized by elemental analysis, X-ray diffraction, IR, UV-Vis and 1H, 13C NMR spectroscopies. X-ray analysis have confirmed that the compound crystallized in the monoclinic group Cc as an inversion twin. The asymmetric unit contains two symmetrically independent cationic complexes [RuCl(L1)(η6-p-cymene)]+ whose charge is balanced by two PF6- counterions. The shape of each cationic coordination polyhedral can be described as a distorted dodecahedron and shows a typical piano-stool geometry. In addition, an analysis of the crystal structure and the Hirshfeld surface analysis were used to detect and visualize important hydrogen bonds and intermolecular interaction. Moreover, the antiproliferative behavior of the obtained complex was assayed against three human cells: MV-4-11, LoVo, MCF-7 and BALB/3T3 - normal mice fibroblast cells. To predict a binding mode, a potential interaction of ruthenium complex with calf thymus DNA (CT-DNA) has been explored using UV absorption and circular dichroism (CD).

Scoring ligand similarity in structure-based virtual screening.

PubMed

Zavodszky, Maria I; Rohatgi, Anjali; Van Voorst, Jeffrey R; Yan, Honggao; Kuhn, Leslie A

2009-01-01

Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein-ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein-ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70 000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein-ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein-ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein-ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring

Au13(8e): A secondary block for describing a special group of liganded gold clusters containing icosahedral Au13 motifs

NASA Astrophysics Data System (ADS)

Xu, Wen Wu; Zeng, Xiao Cheng; Gao, Yi

2017-05-01

A grand unified model (GUM) has been proposed recently to understand structure anatomy and evolution of liganded gold clusters. In this work, besides the two types of elementary blocks (triangular Au3(2e) and tetrahedral Au4(2e)), we introduce a secondary block, namely, the icosahedral Au13 with 8e valence electrons, noted as Au13(8e). Using this secondary block, structural anatomy and evolution of a special group of liganded gold nanoclusters containing icosahedral Au13 motifs can be conveniently analyzed. In addition, a new ligand-protected cluster Au49(PR3)10(SR)15Cl2 is predicted to exhibit high chemical and thermal stability, suggesting likelihood of its synthesis in the laboratory.

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands.

PubMed

Rosano, Camillo; Ponassi, Marco; Santolla, Maria Francesca; Pisano, Assunta; Felli, Lamberto; Vivacqua, Adele; Maggiolini, Marcello; Lappano, Rosamaria

2016-01-01

Estrogens influence multiple physiological processes and are implicated in many diseases as well. Cellular responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as ligand-activated transcription factors. Recently, a member of the G protein-coupled receptor (GPCR) superfamily, namely GPER/GPR30, has been identified as a further mediator of estrogen signalling in different pathophysiological conditions, including cancer. Today, computational methods are commonly used in all areas of health science research. Among these methods, virtual ligand screening has become an established technique for hit discovery and optimization. The absence of an established three-dimensional structure of GPER promoted studies of structure-based drug design in order to build reliable molecular models of this receptor. Here, we discuss the results obtained through the structure-based virtual ligand screening for GPER, which allowed the identification and synthesis of different selective agonist and antagonist moieties. These compounds led significant advances in our understanding of the GPER function at the cellular, tissue, and organismal levels. In particular, selective GPER ligands were critical toward the evaluation of the role elicited by this receptor in several pathophysiological conditions, including cancer. Considering that structure-based approaches are fundamental in drug discovery, future research breakthroughs with the aid of computer-aided molecular design and chemo-bioinformatics could generate a new class of drugs that, acting through GPER, would be useful in a variety of diseases as well as in innovative anticancer strategies.

Ligand solvation in molecular docking.

PubMed

Shoichet, B K; Leach, A R; Kuntz, I D

1999-01-01

Solvation plays an important role in ligand-protein association and has a strong impact on comparisons of binding energies for dissimilar molecules. When databases of such molecules are screened for complementarity to receptors of known structure, as often occurs in structure-based inhibitor discovery, failure to consider ligand solvation often leads to putative ligands that are too highly charged or too large. To correct for the different charge states and sizes of the ligands, we calculated electrostatic and non-polar solvation free energies for molecules in a widely used molecular database, the Available Chemicals Directory (ACD). A modified Born equation treatment was used to calculate the electrostatic component of ligand solvation. The non-polar component of ligand solvation was calculated based on the surface area of the ligand and parameters derived from the hydration energies of apolar ligands. These solvation energies were subtracted from the ligand-receptor interaction energies. We tested the usefulness of these corrections by screening the ACD for molecules that complemented three proteins of known structure, using a molecular docking program. Correcting for ligand solvation improved the rankings of known ligands and discriminated against molecules with inappropriate charge states and sizes.

Synthesis, structure and DFT conformation analysis of CpNiX(NHC) and NiX2(NHC)2 (X = SPh or Br) complexes

NASA Astrophysics Data System (ADS)

Malan, Frederick P.; Singleton, Eric; van Rooyen, Petrus H.; Conradie, Jeanet; Landman, Marilé

2017-11-01

The synthesis, density functional theory (DFT) conformational study and structure analysis of novel two-legged piano stool Ni N-heterocyclic carbene (NHC) complexes and square planar Ni bis-N-heterocyclic carbene complexes, all containing either bromido- or thiophenolato ligands, are described. [CpNi(SPh)(NHC)] complexes were obtained from the neutral 18-electron [CpNiBr(NHC)] complexes by substitution of a bromido ligand with SPh, using NEt3 as a base to abstract the proton of HSPh. The 16-electron biscarbene complexes [Ni(SPh)2{NHC}2] were isolated when an excess of HSPh was added to the reaction mixture. Biscarbene complexes of the type [NiBr2(NHC)2] were obtained in the reaction of NiCp2 with a slight excess of the specific imidazolium bromide salt. The molecular and electronic structures of the mono- and bis-N-heterocyclic carbene complexes have been analysed using single crystal diffraction and density functional theory (DFT) calculations, to give insight into their structural properties.

Synthesis and photoluminescence properties of europium(III) complexes sensitized with β-diketonato and N, N-donors ancillary ligands

NASA Astrophysics Data System (ADS)

Bala, Manju; Kumar, Satish; Devi, Rekha; Taxak, V. B.; Boora, Priti; Khatkar, S. P.

2018-05-01

Synthesis of three new europium(III) complexes with 1,3-[bis(4-methoxyphenyl)]propane-1,3-dionato (HBMPD) ligand and ancillary ligands such as 2,2‧-biquinoline (biq) or neocuproine (neo) has been reported in this report. The synthesized complexes were characterized by IR (infrared), 1H and 13C NMR (nuclear magnetic resonance) spectroscopy, CHN (carbon, hydrogen and nitrogen) elemental analysis, XRD (X-ray diffraction), TGA (thermogravimetric analysis) and photoluminescence (PL) spectroscopy. The emission spectra of europium(III) complexes displayed both the low intensity 5D1-3 → 7F0-3 transitions in 410-560 nm blue-green region and high intensity characteristic 5D0 → 7F0-3 transitions in 575-640 nm orange-red region correspond to the emission of ancillary ligands and europium ion respectively, which can lead to white luminescence due to integration of blue, green and red color emissions. The photoluminescence investigations indicate that the absorbed energy of the HBMPD ligand transferred to the central europium(III) ion in an efficient manner, which clearly explained by antenna effect. The excellent results of thermal behavior and photophysical properties like luminescence spectra, CIE (Commission Internationale Eclairage) chromaticity coordinates, luminescence decay curves and high quantum efficiency of the complexes make them a promising component of the white light-emitting diodes in display devices.

SPOT-ligand 2: improving structure-based virtual screening by binding-homology search on an expanded structural template library.

PubMed

Litfin, Thomas; Zhou, Yaoqi; Yang, Yuedong

2017-04-15

The high cost of drug discovery motivates the development of accurate virtual screening tools. Binding-homology, which takes advantage of known protein-ligand binding pairs, has emerged as a powerful discrimination technique. In order to exploit all available binding data, modelled structures of ligand-binding sequences may be used to create an expanded structural binding template library. SPOT-Ligand 2 has demonstrated significantly improved screening performance over its previous version by expanding the template library 15 times over the previous one. It also performed better than or similar to other binding-homology approaches on the DUD and DUD-E benchmarks. The server is available online at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Synthesis and biological activity of small peptides as NOP and opioid receptors' ligands: view on current developments.

PubMed

Naydenova, Emilia; Todorov, Petar; Zamfirova, Rositza

2015-01-01

The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and β-tryptophan analogues will be presented. © 2015 Elsevier Inc. All rights reserved.

Tuning the Emission and Quantum Yield of Gold and Silver Nanoclusters Through Ligand Design and Doping

NASA Astrophysics Data System (ADS)

Mishra, Dinesh

Nanoparticles have been extensively studied in the past few decades due to the possibilities they offer in applications ranging from medicine to energy generation. A new class of ultra-small noble metal nanoparticles consisting of tens to hundreds of atoms, commonly known as clusters or nanoclusters, have drawn interest of the research community recently due to their unique optical, electronic and structural properties. Over the past few years, advances have been made in the synthesis of atomically precise noble metal clusters (for example, silver and gold) with distinct optical properties. Their ultra-small size distinguishes them from conventional plasmonic nanoparticles and the properties are very sensitive to the slight variation in the compositon of the cluster, i.e. the number of the metal atoms and/or the nature of the ligands. These clusters are interesting because of their potential applications in field such as sensing, imaging, catalysis, clean energy, photonics, etc. as well as they provide fundamental insight into the evolution of the optical and electronic properties of these clusters. In this project, we explored the strategies to synthesize luminescent metallic clusters of gold and silver and to promote their solubility and stability in aqueous and biological medium. We focused particularly on the thiolate protected clusters due to the higher affinity of gold and silver to sulfur. Lipoic acid (Thioctic acid) is a bio-molecule with a cyclic disulfide ring, which also acts as a chelating ligand. Due to the higher binding affinity of the cyclic disulfide ring to nanocrystal surface, lipoic acid and chemically modified lipoic acid molecules have been widely reported for the synthesis and functionalization of inorganic nanocrystals. Here, we describe the use of bidentate lipoic acid ligands in the one phase growth of luminescent gold and silver nanoclusters. In addition, we have synthesized a new set of monothiol ligands containing PEG and zwitterion for

Synthesis, Characterization and Biological Evaluation of Transition Metal Complexes Derived from N, S Bidentate Ligands

PubMed Central

Md Yusof, Enis Nadia; Ravoof, Thahira Begum S. A.; Tiekink, Edward R. T.; Veerakumarasivam, Abhimanyu; Crouse, Karen Anne; Mohamed Tahir, Mohamed Ibrahim; Ahmad, Haslina

2015-01-01

Two bidentate NS ligands were synthesized by the condensation reaction of S-2-methylbenzyldithiocarbazate (S2MBDTC) with 2-methoxybenzaldehyde (2MB) and 3-methoxybenzaldehyde (3MB). The ligands were reacted separately with acetates of Cu(II), Ni(II) and Zn(II) yielding 1:2 (metal:ligand) complexes. The metal complexes formed were expected to have a general formula of [M(NS)2] where M = Cu2+, Ni2+, and Zn2+. These compounds were characterized by elemental analysis, molar conductivity, magnetic susceptibility and various spectroscopic techniques. The magnetic susceptibility measurements and spectral results supported the predicted coordination geometry in which the Schiff bases behaved as bidentate NS donor ligands coordinating via the azomethine nitrogen and thiolate sulfur. The molecular structures of the isomeric S2M2MBH (1) and S2M3MBH (2) were established by X-ray crystallography to have very similar l-shaped structures. The Schiff bases and their metal complexes were evaluated for their biological activities against estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cell lines. Only the Cu(II) complexes showed marked cytotoxicity against the cancer cell lines. Both Schiff bases and other metal complexes were found to be inactive. In concordance with the cytotoxicity studies, the DNA binding studies indicated that Cu(II) complexes have a strong DNA binding affinity. PMID:25988384

Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

PubMed

Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

2005-10-06

US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

Cubes, squares, and books: a simple transition metal/bridging ligand combination can lead to a surprising range of structural types with the same metal/ligand proportions.

PubMed

Najar, Adel M; Tidmarsh, Ian S; Adams, Harry; Ward, Michael D

2009-12-21

Reaction of two structurally related bridging ligands L(26Py) and L(13Ph), in which two bidentate chelating pyrazolyl-pyridine units are connected to either a 2,6-pyridine-diyl or 1,3-benzene-diyl central group via methylene spacers, with first-row transition metal dications, results in a surprising variety of structures. The commonest is that of an octanuclear coordination cage [M(8)L(12)]X(16) [M = Co(II) or Zn(II); X = perchlorate or tetrafluoroborate] in which a metal ion is located at each of the eight vertices of an approximate cube, and one bis-bidentate bridging ligand spans each edge. The arrangement of fac and mer tris-chelate metal centers around the inversion center results in approximate (non-crystallographic) S(6) symmetry. Another structural type observed in the solid state is a hexanuclear complex [Co(6)(L(13Ph))(9)](ClO(4))(12) in which the six metal ions are in a rectangular array (two rows of three), folded about the central Co-Co vector like a partially open book, with each metal-metal edge containing one bridging ligand apart from the two outermost metal-metal edges which are spanned by a pair of bridging ligands in a double helical array. The final structural type we observed is a tetranuclear square [Ni(4)(L(26Py))(6)](BF(4))(8), with the four Ni-Ni edges spanned alternately by one and two bridging ligand such that it effectively consists of two dinuclear double helicates cross-linked by additional bridging ligands. A balance between the "cube" and "book" forms, which varied from compound to compound, was observed in solution in many cases by (1)H NMR and ES mass spectrometry studies.

Synthesis and Characterization of PEGylated Toll Like Receptor 7 Ligands

PubMed Central

Chan, Michael; Hayashi, Tomoko; Mathewson, Richard D.; Yao, Shiyin; Gray, Christine; Tawatao, Rommel; Kalenian, Kevin; Zhang, Yanmei; Hayashi, Yuki; Lao, Fitzgerald S.; Cottam, Howard B.; Carson, Dennis A.

2011-01-01

Toll like receptor 7 (TLR7) is located in the endosomal compartment of immune cells. Signaling through TLR7, mediated by the adaptor protein MyD88, stimulates the innate immune system and shapes adaptive immune responses. Previously, we characterized TLR7 ligands conjugated to protein, lipid or polyethylene glycol (PEG). Among the TLR7 ligand conjugates, the addition of PEG chains reduced the agonistic potency. PEGs are safe in humans and widely used for improvement of pharmacokinetics in existing biologics and some low molecular weight compounds. PEGylation could be a feasible method to alter the pharmacokinetics and pharmacodynamics of TLR7 ligands. In this study, we systematically studied the influence of PEG chain length on the in vitro and in vivo properties of potent TLR7 ligands. PEGylation increased solubility of the TLR7 ligands and modulated protein binding. Adding a 6–10 length PEG to the TLR7 ligand reduced its potency toward induction of interleukin (IL)-6 by murine macrophages in vitro and IL-6 and tumor necrosis factor (TNF) in vivo. However, PEGylation with 18 or longer chain restored, and even enhanced, the agonistic activity of the drug. In human peripheral blood mononuclear cells, similar effects of PEGylation were observed for secretion of proinflammatory cytokines, IL-6, IL-12, TNF-α, IL-1β and type 1 interferon, as well for B cell proliferation. In summary, these studies demonstrate that conjugation of PEG chains to a synthetic TLR ligand can impact its potency for cytokine induction depending on the size of the PEG moiety. Thus, PEGylation may be a feasible approach to regulate the pharmacological properties of TLR7 ligands. PMID:21338093

Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography

PubMed Central

Mandal, Kalyaneswar; Uppalapati, Maruti; Ault-Riché, Dana; Kenney, John; Lowitz, Joshua; Sidhu, Sachdev S.; Kent, Stephen B.H.

2012-01-01

Total chemical synthesis was used to prepare the mirror image (D-protein) form of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage display against D-VEGF-A was used to screen designed libraries based on a unique small protein scaffold in order to identify a high affinity ligand. Chemically synthesized D- and L- forms of the protein ligand showed reciprocal chiral specificity in surface plasmon resonance binding experiments: The L-protein ligand bound only to D-VEGF-A, whereas the D-protein ligand bound only to L-VEGF-A. The D-protein ligand, but not the L-protein ligand, inhibited the binding of natural VEGF165 to the VEGFR1 receptor. Racemic protein crystallography was used to determine the high resolution X-ray structure of the heterochiral complex consisting of {D-protein antagonist + L-protein form ofVEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in appropriate stoichiometry gave a racemic protein complex of more than 73 kDa containing six synthetic protein molecules. The structure of the complex was determined to a resolution of 1.6 Å. Detailed analysis of the interaction between the D-protein antagonist and the VEGF-A protein molecule showed that the binding interface comprised a contact surface area of approximately 800 Å2 in accord with our design objectives, and that the D-protein antagonist binds to the same region of VEGF-A that interacts with VEGFR1-domain 2. PMID:22927390

Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.

PubMed

Nimczick, Martin; Pemp, Daniela; Darras, Fouad H; Chen, Xinyu; Heilmann, Jörg; Decker, Michael

2014-08-01

The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB₂R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

Structure-based discovery and binding site analysis of histamine receptor ligands.

PubMed

Kiss, Róbert; Keserű, György M

2016-12-01

The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, the authors review the development of histamine receptor models and their application in drug discovery. Expert opinion: In the authors' opinion, the application of atomistic histamine receptor models has played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery; however, our analysis also demonstrates that for building H3 and H4 receptor homology models, other GPCRs may be more suitable as templates. For these receptors, the authors envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

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.

One-dimensional mercury(II) halide coordination polymers of 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine ligand: Synthesis, crystal structure, spectroscopic and DFT studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saghatforoush, Lotfali, E-mail: saghatforoush@gmail.com; Khoshtarkib, Zeinab; Amani, Vahid

2016-01-15

Three new coordination polymers, [Hg(μ-bptz)X{sub 2}]{sub n} (X=Cl (1), Br (2)) and [Hg{sub 2}(μ-bptz)(μ-I){sub 2}I{sub 2}]{sub n} (3) (bptz=3,6-bis(2-pyridyl)-1,2,4,5-tetrazine) were synthesized. X-ray structural analysis indicated that compounds 1 and 2 are composed of one-dimensional (1D) linear chains while the compound 3 has 1D stair-stepped structure. The electronic band structure along with density of states (DOS) calculated by the DFT method indicates that compound 1 and 2 are direct band gap semiconductors; however, compound 3 is an indirect semiconductor. The linear optical properties of the compounds are also calculated by DFT method. According to the DFT calculations, the observed emission bandmore » of the compounds in solid state is due to electron transfer from an excited bptz-π* state (CBs) to the top of VBs. {sup 1}H NMR spectra of the compounds indicate that, in solution phase, the compounds don’t decompose completely. Thermal stability of the compounds is studied using TG, DTA methods. - Graphical abstract: Synthesis, crystal structure and emission spectra of [Hg(μ-bptz)X{sub 2}]{sub n} (X=Cl and Br) and [Hg{sub 2}(μ-bptz)(μ-I){sub 2}I{sub 2}]{sub n} are presented. The electronic band structure and linear optical properties of the compounds are calculated by the DFT method. - Highlights: • Three 1D Hg(II) halide coordination polymers with bptz ligand have been prepared. • The structures of the compounds are determined by single crystal XRD. • DFT calculations show that [Hg(μ-bptz)X{sub 2}]{sub n} (X=Cl and Br) have a direct band gap. • DFT calculations show that [Hg{sub 2}(μ-bptz)(μ-I){sub 2}I{sub 2}]{sub n} has an indirect band gap. • The compounds show an intraligand electron transfer emission band in solid state.« less

Synthesis of Thieno[3,2-b]indoles via Halogen Dance and Ligand-Controlled One-Pot Sequential Coupling Reaction.

PubMed

Hayashi, Yuki; Okano, Kentaro; Mori, Atsunori

2018-02-16

A two-pot synthesis of thieno[3,2-b]indole from 2,5-dibromothiophene is described. A halogen dance of 2,5-dibromothiophene was performed with LDA, and subsequent Negishi coupling was performed with 2-iodoaniline derivatives to provide the corresponding coupling products. The resulting two bromo groups have different reactivities, which were utilized for the one-pot Suzuki-Miyaura coupling/intramolecular Buchwald-Hartwig amination to produce thieno[3,2-b]indole via an assisted tandem catalysis that involved in situ ligand exchange.

Hafnium(IV) chloride complexes with chelating β-ketiminate ligands: Synthesis, spectroscopic characterization and volatility study

NASA Astrophysics Data System (ADS)

Patil, Siddappa A.; Medina, Phillip A.; Antic, Aleks; Ziller, Joseph W.; Vohs, Jason K.; Fahlman, Bradley D.

2015-09-01

The synthesis and characterization of four new β-ketiminate hafnium(IV) chloride complexes dichloro-bis[4-(phenylamido)pent-3-en-2-one]-hafnium (4a), dichloro-bis[4-(4-methylphenylamido)pent-3-en-2-one]-hafnium (4b), dichloro-bis[4-(4-methoxyphenylamido)pent-3-en-2-one]-hafnium (4c), and dichloro-bis[4-(4-chlorophenylamido)pent-3-en-2-one]-hafnium (4d) are reported. All the complexes (4a-d) were characterized by spectroscopic methods (1H NMR, 13C NMR, IR), and elemental analysis while the compound 4c was further examined by single-crystal X-ray diffraction, revealing that the complex is monomer with the hafnium center in octahedral coordination environment and oxygens of the chelating N-O ligands are trans to each other and the chloride ligands are in a cis arrangement. Volatile trends are established for four new β-ketiminate hafnium(IV) chloride complexes (4a-d). Sublimation enthalpies (ΔHsub) were calculated from thermogravimetric analysis (TGA) data, which show that, the dependence of ΔHsub on the molecular weight (4a-c) and inductive effects from chlorine (4d).

Identification and specificity studies of small-molecule ligands for SH3 protein domains.

PubMed

Inglis, Steven R; Stojkoski, Cvetan; Branson, Kim M; Cawthray, Jacquie F; Fritz, Daniel; Wiadrowski, Emma; Pyke, Simon M; Booker, Grant W

2004-10-21

The Src Homology 3 (SH3) domains are small protein-protein interaction domains that bind proline-rich sequences and mediate a wide range of cell-signaling and other important biological processes. Since deregulated signaling pathways form the basis of many human diseases, the SH3 domains have been attractive targets for novel therapeutics. High-affinity ligands for SH3 domains have been designed; however, these have all been peptide-based and no examples of entirely nonpeptide SH3 ligands have previously been reported. Using the mouse Tec Kinase SH3 domain as a model system for structure-based ligand design, we have identified several simple heterocyclic compounds that selectively bind to the Tec SH3 domain. Using a combination of nuclear magnetic resonance chemical shift perturbation, structure-activity relationships, and site-directed mutagenesis, the binding of these compounds at the proline-rich peptide-binding site has been characterized. The most potent of these, 2-aminoquinoline, bound with Kd = 125 microM and was able to compete for binding with a proline-rich peptide. Synthesis of 6-substituted-2-aminoquinolines resulted in ligands with up to 6-fold improved affinity over 2-aminoquinoline and enhanced specificity for the Tec SH3 domain. Therefore, 2-aminoquinolines may potentially be useful for the development of high affinity small molecule ligands for SH3 domains.

New mixed ligand cobalt(II/III) complexes based on the drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties

NASA Astrophysics Data System (ADS)

Abu Ali, Hijazi; Abu Shamma, Amani; Kamel, Shayma

2017-08-01

New cobalt valproate complexes with different nitrogen based ligands were synthesized and characterized using various techniques such as IR, UV-Vis, single crystal X-ray diffraction as well as other physical properties. The general formula of the prepared complexes is [Con(valp)m(L)z], (n = 1, 2 …; m = 1, 2, …; Z = 1, 2 …). The complexes [Co2(valp)4] (1), [Co(valp)2(2-ampy)2] (2) and [Co2(valp)4(quin)2] (3) showed different carboxylate coordination modes. The crystal structures of the complexes 2 and 3 were determined using single crystal X-ray diffraction. Kinetic studies of hydrolysis reactions of BNPP [bis-(p-nitrophenyl)phosphate] with complexes 2 and 3 were performed. The hydrolysis rate of BNPP was studied at different temperatures, pH and concentrations by UV-Vis spectrophotometric method. The results showed that the hydrolysis rate of BNPP was 7.70 × 102 L mol-1 s-1 for (3) and 2.60 × 10-1 L mol-1 s-1 for (2).

Metal-ligand synergistic effects in the complex Ni(η(2)-TEMPO)2: synthesis, structures, and reactivity.

PubMed

Isrow, Derek; DeYonker, Nathan J; Koppaka, Anjaneyulu; Pellechia, Perry J; Webster, Charles Edwin; Captain, Burjor

2013-12-16

In the current investigation, reactions of the "bow-tie" Ni(η(2)-TEMPO)2 complex with an assortment of donor ligands have been characterized experimentally and computationally. While the Ni(η(2)-TEMPO)2 complex has trans-disposed TEMPO ligands, proton transfer from the C-H bond of alkyne substrates (phenylacetylene, acetylene, trimethylsilyl acetylene, and 1,4-diethynylbenzene) produce cis-disposed ligands of the form Ni(η(2)-TEMPO)(κ(1)-TEMPOH)(κ(1)-R). In the case of 1,4-diethynylbenzene, a two-stage reaction occurs. The initial product Ni(η(2)-TEMPO)(κ(1)-TEMPOH)[κ(1)-CC(C6H4)CCH] is formed first but can react further with another equivalent of Ni(η(2)-TEMPO)2 to form the bridged complex Ni(η(2)-TEMPO)(κ(1)-TEMPOH)[κ(1)-κ(1)-CC(C6H4)CC]Ni(η(2)-TEMPO)(κ(1)-TEMPOH). The corresponding reaction with acetylene, which could conceivably also yield a bridging complex, does not occur. Via density functional theory (DFT), addition mechanisms are proposed in order to rationalize thermodynamic and kinetic selectivity. Computations have also been used to probe the relative thermodynamic stabilities of the cis and trans addition products and are in accord with experimental results. Based upon the computational results and the geometry of the experimentally observed product, a trans-cis isomerization must occur.

Synthesis and characterization of two new zinc(II) coordination polymers with bidentate flexible ligands: Formation of a 2D structure with (44.62)-sql topology

NASA Astrophysics Data System (ADS)

Lalegani, Arash; Khaledi Sardashti, Mohammad; Gajda, Roman; Woźniak, Krzysztof

2017-12-01

Zinc(II) coordination polymers [Zn(bip)2(NCS)2]n (1) and [Zn(μ-bbd)(N3)2]n (2) were synthesized by using the neutral flexible bidentate N-donor ligands 1,4-bis(3,5-dimethylpyrazolyl)butane (bbd) and 1,3-bis(imidazolyl)propane (bip), mono-anionic NCS- or N3-ligand and zinc(II) chloride salts. The results of the X-ray analyses demonstrate that in the structure of 1, the zinc(II) ion is located on an inversion center and exhibits an ZnN6 octahedral arrangement while, in the structure of 2, the zinc(II) ion adopts an ZnN4 tetrahedral geometry. In the polymer 1, the NCS groups are terminally N-bonded to the metal center and the each bip with anti-gauche conformation acts as bridging connecting four zinc(II) ions to form a two-dimensional network with a sql [point symbol (44.62)] topology while, in the polymer 1, the N3 groups are terminally bonded to the metal center and each bbd with anti-anti-anti conformation acts as bridging ligand connecting two zinc(II) ions to form a one-dimensional zig-zag chain. Coordination compounds 1 and 2 have been characterized by infrared spectroscopy, elemental analyses and single-crystal X-ray diffraction. Thermal analyses of polymers were also presented.

Substituent-directed structural and physicochemical controls of diruthenium catecholate complexes with ligand-unsupported Ru-Ru bonds.

PubMed

Chang, Ho-Chol; Mochizuki, Katsunori; Kitagawa, Susumu

2005-05-30

A family of diruthenium complexes with ligand-unsupported Ru-Ru bonds has been systematically synthesized, and their crystal structures and physical properties have been examined. A simple, useful reaction between Ru2(OAc)4Cl (OAc- = acetate) and catechol derivatives in the presence of bases afforded a variety of diruthenium complexes, generally formulated as [Na(n){Ru2(R4Cat)4}] (n = 2 or 3; R4 = -F4, -Cl4, -Br4, -H4, -3,5-di-t-Bu, and -3,6-di-t-Bu; Cat(2-) = catecholate). The most characteristic feature of the complexes is the formation of short ligand-unsupported Ru-Ru bonds (2.140-2.273 A). These comprehensive studies were carried out to evaluate the effects of the oxidation states and the substituents governing the molecular structures and physicochemical properties. The Ru-Ru bond distances, rotational conformations, and bending structures of the complexes were successfully varied. The results presented in this manuscript clearly demonstrate that the complexes with ligand-unsupported Ru-Ru bonds can sensitively respond to redox reactions and ligand substituents on the basis of the greater degree of freedom in their molecular structures.

Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

NASA Astrophysics Data System (ADS)

Capelli, Davide; Cerchia, Carmen; Montanari, Roberta; Loiodice, Fulvio; Tortorella, Paolo; Laghezza, Antonio; Cervoni, Laura; Pochetti, Giorgio; Lavecchia, Antonio

2016-10-01

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites.

PubMed

Konc, Janez; Janežič, Dušanka

2014-07-01

The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Palladium(II) and platinum(II) derivatives of benzothiazoline ligands: Synthesis, characterization, antimicrobial and antispermatogenic activity

NASA Astrophysics Data System (ADS)

Sharma, Krishna; Singh, R. V.; Fahmi, Nighat

2011-01-01

A series of Pd(II) and Pt(II) complexes with two N ∩S donor ligands, 5-chloro-3-(indolin-2-one)benzothiazoline and 6-nitro-3-(indolin-2-one)benzothiazoline, have been synthesized by the reaction of metal chlorides (PdCl 2 and PtCl 2) with ligands in 1:2 molar ratios. All the synthesized compounds were characterized by elemental analyses, melting point determinations and a combination of electronic, IR, 1H NMR and 13C NMR spectroscopic techniques for structure elucidation. In order to evaluate the effect of metal ions upon chelation, both the ligands and their complexes have been screened for their antimicrobial activity against the various pathogenic bacterial and fungal strains. The metal complexes have shown to be more antimicrobial against the microbial species as compared to free ligands. One of the ligands, 5-chloro-3-(indolin-2-one)benzothiazoline and its corresponding palladium and platinum complexes have been tested for their antifertility activity in male albino rats. The marked reduction in sperm motility and density resulted in infertility by 62-90%. Significant alterations were found in biochemical parameters of reproductive organs in treated animals as compared to control group. It is concluded that all these effects may finally impair the fertility of male rats.

Retinal Ligand Mobility Explains Internal Hydration and Reconciles Active Rhodopsin Structures

PubMed Central

Leioatts, Nicholas; Mertz, Blake; Martínez-Mayorga, Karina; Romo, Tod D.; Pitman, Michael C.; Feller, Scott E.; Grossfield, Alan; Brown, Michael F.

2014-01-01

Rhodopsin, the mammalian dim-light receptor, is one of the best-characterized G-protein-coupled receptors, a pharmaceutically important class of membrane proteins that has garnered a great deal of attention because of the recent availability of structural information. Yet the mechanism of rhodopsin activation is not fully understood. Here, we use microsecond-scale all-atom molecular dynamics simulations, validated by solid-state 2H nuclear magnetic resonance spectroscopy, to understand the transition between the dark and metarhodopsin I (Meta I) states. Our analysis of these simulations reveals striking differences in ligand flexibility between the two states. Retinal is much more dynamic in Meta I, adopting an elongated conformation similar to that seen in the recent activelike crystal structures. Surprisingly, this elongation corresponds to both a dramatic influx of bulk water into the hydrophobic core of the protein and a concerted transition in the highly conserved Trp2656.48 residue. In addition, enhanced ligand flexibility upon light activation provides an explanation for the different retinal orientations observed in X-ray crystal structures of active rhodopsin. PMID:24328554

Some metal complexes of three new potentially heptadentate (N4O3) tripodal Schiff base ligands; synthesis, characterizatin and X-ray crystal structure of a novel eight coordinate Gd(III) complex

NASA Astrophysics Data System (ADS)

Golbedaghi, Reza; Moradi, Somaeyh; Salehzadeh, Sadegh; Blackman, Allan G.

2016-03-01

The symmetrical and asymmetrical potentially heptadentate (N4O3) tripodal Schiff base ligands (H3L1-H3L3) were synthesized from the condensation reaction of three tripodal tetraamine ligands tpt (trpn), tris (3-aminopropyl) amine; ppe (abap), (2-aminoethyl)bis(3-aminopropyl)amine, and tren, tris(2-aminoethyl)amine, with 5-methoxysalicylaldehyde. Then, the reaction of Ln(III) (Ln = Gd, La and Sm), Al(III), and Fe(III) metal ions with the above ligands was investigated. The resulting compounds were characterized by IR, mass spectrometry and elemental analysis in all cases and NMR spectroscopy in the case of the Schiff base ligands. The X-ray crystal structure of the Gd complex of H3L3 ligand showed that in addition to all donor atoms of the ligand one molecule of H2O is also coordinated to the metal ion and a neutral eight-coordinate complex is formed.

Biaryl Phosphine Ligands in Palladium-Catalyzed Amination

PubMed Central

Surry, David S.

2012-01-01

Palladium-catalyzed amination of aryl halides has undergone rapid development in the last 12 years. This has been largely driven by implementation of new classes of ligands. Biaryl phosphines have proven to provide especially active catalysts in this context. This review discusses the applications that these catalysts have found in C-N cross-coupling in heterocycle synthesis, pharmaceuticals, materials science and natural product synthesis. PMID:18663711

An NMR-Based Structural Rationale for Contrasting Stoichiometry and Ligand Binding Site(s) in Fatty Acid-binding Proteins†

PubMed Central

He, Yan; Estephan, Rima; Yang, Xiaomin; Vela, Adriana; Wang, Hsin; Bernard, Cédric; Stark, Ruth E.

2011-01-01

Liver fatty acid-binding protein (LFABP) is a 14-kDa cytosolic polypeptide, differing from other family members in number of ligand binding sites, diversity of bound ligands, and transfer of fatty acid(s) to membranes primarily via aqueous diffusion rather than direct collisional interactions. Distinct two-dimensional 1H-15N NMR signals indicative of slowly exchanging LFABP assemblies formed during stepwise ligand titration were exploited, without solving the protein-ligand complex structures, to yield the stoichiometries for the bound ligands, their locations within the protein binding cavity, the sequence of ligand occupation, and the corresponding protein structural accommodations. Chemical shifts were monitored for wild-type LFABP and a R122L/S124A mutant in which electrostatic interactions viewed as essential to fatty acid binding were removed. For wild-type LFABP the results compared favorably with previous tertiary structures of oleate-bound wild-type LFABP in crystals and in solution: there are two oleates, one U-shaped ligand that positions the long hydrophobic chain deep within the cavity and another extended structure with the hydrophobic chain facing the cavity and the carboxylate group lying close to the protein surface. The NMR titration validated a prior hypothesis that the first oleate to enter the cavity occupies the internal protein site. In contrast, 1H/15N chemical shift changes supported only one liganded oleate for R122L/S124A LFABP, at an intermediate location within the protein cavity. A rationale based on protein sequence and electrostatics was developed to explain the stoichiometry and binding site trends for LFABPs and to put these findings into context within the larger protein family. PMID:21226535

Structural diversity of three Cu(II) compounds based on a new tripodal zwitterionic ligand: Syntheses, structures and properties

NASA Astrophysics Data System (ADS)

Zhou, Jie; Zhao, Jing-Song; Feng, Jing; Zhang, Xiao-Feng; Xu, Jian; Du, Lin; Xie, Ming-Jin; Zhao, Qi-Hua

2018-03-01

An exploration of reactions of 1,1‧,1″-(benzene-1,3,5-triyltris(methylene))tris(4-carboxypyridinium)-tribromide (H3LBr3) with Cu(II) salt under different pH conditions has led to the formation of three complexes, [Cu(HL)2(H2O)3]·4(ClO4)·3H2O (1), [Cu2(HL)(μ3-OH)(μ2-H2O)(H2O)2]·4(ClO4)·6H2O (2), and [Cu3(L)2Cl6(H2O)4]·4H2O (3). Single-crystal X-ray analyses revealed that complex 1 displays a discrete mononuclear structure with the ligand in a bowl-shaped configuration. Complex 2 possesses a tetranuclear 1D beaded chain structure. While complex 3 features a discrete trinuclear 'H-type' structure with the ligand in a chair-like configuration. The distinct compositions and structures of 1-3 are mainly ascribed to the different pH values of the reaction solution, the influences of anions, as well as the configurations which the zwitterion ligands adopt. The magnetic properties of 2, and the photoluminescence properties of 2, and 3 have been investigated. Moreover, powder X-ray diffraction, infrared spectroscopy, and elemental analysis were also performed.

The Caenorhabditis elegans DAF-12 nuclear receptor: structure, dynamics, and interaction with ligands.

PubMed

Alvarez, Lautaro D; Mañez, Pau Arroyo; Estrin, Darío A; Burton, Gerardo

2012-07-01

A structure for the ligand binding domain (LBD) of the DAF-12 receptor from Caenorhabditis elegans was obtained from the X-ray crystal structure of the receptor LBD from Strongyloides stercoralis bound to (25R)-Δ(7)-dafachronic acid (DA) (pdb:3GYU). The model was constructed in the presence of the ligand using a combination of Modeller, Autodock, and molecular dynamics (MD) programs, and then its dynamical behavior was studied by MD. A strong ligand binding mode (LBM) was found, with the three arginines in the ligand binding pocket (LBP) contacting the C-26 carboxylate group of the DA. The quality of the ceDAF-12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ceDAF-12 complex with the more active (25S)-Δ(7)-DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25R)-Δ(7)-DA binding was analyzed. The MD simulations showed that in the first case the complex was unstable, consistent with the lack of transactivation activity of (25R)-Δ(7)-DA in this mutant. Instead, in the case of the Arg598Met mutant, known to produce a partial loss of activity, our model predicted smaller effects on the LBM with a more stable MD trajectory. The model also showed that removal of the C-25 methyl does not impede the simultaneous strong interaction of the carboxylate with the three arginines, predicting that 27-nor-DAs are putative ceDAF-12 ligands. Copyright © 2012 Wiley Periodicals, Inc.

Two novel copper(II) complexes constructed from dicarboxylate ligands with different spacer lengths and 2-phenylimidazo[4,5- f]1,10-phenanthroline (PIP): Synthesis, structures and properties

NASA Astrophysics Data System (ADS)

Wang, X.-L.; Chen, Yongqiang; Liu, Guocheng; Lin, Hongyan; Zhang, Jinxia

2009-09-01

Two novel metal-organic coordination polymers [Cu(PIP)(bpea)(H 2O)]·H 2O ( 1) and [Cu(PIP)(1,4-bdc)] ( 2) have been obtained from hydrothermal reaction of copper(II) with the mixed ligands [biphenylethene-4,4'-dicarboxylic acid (bpea) for 1, benzene-1,4-dicarboxylic acid (1,4-H 2bdc) for 2, and 2-phenylimidazo[4,5- f]1,10-phenanthroline (PIP)]. Both complexes have been structurally characterized by elemental analyses, IR and single-crystal X-ray diffraction analyses. Structural analyses reveal that complex 1 possesses infinite one-dimensional zigzag chain, 2 exhibits a two-dimensional (4,4) network, both of which are extended into three-dimensional supramolecular network by weak interactions. The different structures of the title complexes illustrate the influence of the flexibility (the spacer length of carboxyl groups and the structural rigidity of the spacer) of organic dicarboxylate ligands on the formation of such coordination architectures. Moreover, the thermal properties and the voltammetric behavior of complexes 1 and 2 have been reported.

Synthesis, crystal structures and luminescent properties of zinc(II) metal–organic frameworks constructed from terpyridyl derivative ligand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Xiao-Le; Shangguan, Yi-Qing; Hu, Huai-Ming, E-mail: ChemHu1@NWU.EDU.CN

2014-08-15

Five zinc(II) metal–organic frameworks, [Zn{sub 3}(344-pytpy){sub 2}Cl{sub 6}]{sub n}·n(H{sub 2}O) (1), [Zn(344-pytpy)(ox)]{sub n} (2), [Zn{sub 2}(344-pytpy)(bdc){sub 2}]{sub n}·1.5n(H{sub 2}O) (3), [Zn{sub 2}(344-pytpy){sub 2} (sfdb){sub 2}]{sub n}·1.5n(H{sub 2}O) (4) and [Zn{sub 3}(344-pytpy){sub 2}(btc){sub 2}]{sub n}·2n(H{sub 2}O) (5), (344-pytpy=4′-(3-pyridyl)-4,2′:6′,4″-terpyridine, H{sub 2}ox=oxalic acid, H{sub 2}bdc=1,4-benzenedi-carboxylic acid, H{sub 2}sfdb=4,4′-sulfonyldibenzoic acid and H{sub 3}btc=1,3,5-benzene-tricarboxylic acid) have been prepared by hydrothermal reactions. Compound 1 is a 1D chain structure, in which 344-pytpy ligand links three Zn{sup II} centers through three of terminal N-donors. Compound 2 is a 4-connected 3D framework with the dia topological net and the Schläfli symbol of 6{sup 6}. Compound 3 displays amore » unusual 3-fold interpenetrating 3D coordination network which exhibits a new intriguing (3,3,4)-connected topological net with the Schläfli symbol of (4.8{sup 2})(4.8{sup 5})(8{sup 3}). Compound 4 features a two-fold interpenetrating 4-connected 2D framework with the sql topological net and the Schläfli symbol of (4{sup 4}.6{sup 2}). Compound 5 is a new self-interpenetrating (3,3,4,4)-connected topological net with the Schläfli symbol of (6.8{sup 2}){sub 2}(6{sup 2}.8{sup 2}.10.12)(6{sup 2}.8{sup 3}.10){sub 2}(6{sup 2}.8){sub 2}. The luminescence properties of 1–5 have been investigated by emission spectra and they possess great thermal stabilities which can be stable up to around 400 °C. - Graphical abstract: Five new Zn(II) metal–organic frameworks based on dicarboxylate and terpyridyl derivative ligands have been synthesized by hydrothermal reactions, giving networks from 1D to 3D structures. The thermal stability and luminescent property have been investigated. - Highlights: • Five zinc(II) metal–organic frameworks have been prepared under hydrothermal conditions. • Their crystal and

Understanding ligand effects in gold clusters using mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Grant E.; Laskin, Julia

This review summarizes recent research on the influence of phosphine ligands on the size, stability, and reactivity of gold clusters synthesized in solution. Sub-nanometer clusters exhibit size- and composition-dependent properties that are unique from those of larger nanoparticles. The highly tunable properties of clusters and their high surface-to-volume ratio make them promising candidates for a variety of technological applications. However, because “each-atom-counts” toward defining cluster properties it is critically important to develop robust synthesis methods to efficiently prepare clusters of predetermined size. For decades phosphines have been known to direct the size-selected synthesis of gold clusters. Despite the preparation ofmore » numerous species it is still not understood how different functional groups at phosphine centers affect the size and properties of gold clusters. Using electrospray ionization mass spectrometry (ESI-MS) it is possible to characterize the effect of ligand substitution on the distribution of clusters formed in solution at defined reaction conditions. In addition, ligand exchange reactions on preformed clusters may be monitored using ESI-MS. Collision induced dissociation (CID) may also be employed to obtain qualitative insight into the fragmentation of mixed ligand clusters and the relative binding energies of differently substituted phosphines. Quantitative ligand binding energies and cluster stability may be determined employing surface induced dissociation (SID) in a custom-built Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS). Rice-Ramsperger-Kassel-Marcus (RRKM) based modeling of the SID data allows dissociation energies and entropy values to be extracted that may be compared with the results of high-level theoretical calculations. The charge reduction and reactivity of atomically precise gold clusters, including partially ligated species generated in the gas-phase by in source CID, on

Platinum(II) diimine complexes with catecholate ligands bearing imide electron-acceptor groups: synthesis, crystal structures, (spectro)electrochemical and EPR studies, and electronic structure.

PubMed

Shavaleev, Nail M; Davies, E Stephen; Adams, Harry; Best, Jonathan; Weinstein, Julia A

2008-03-03

A series of catechols with attached imide functionality (imide = phthalimide PHT, 1,8-naphthalimide NAP, 1,4,5,8-naphthalenediimide NDI, and NAP-NDI) has been synthesized and coordinated to the Pt (II)(bpy*) moiety, yielding Pt(bpy*)(cat-imide) complexes (bpy* = 4,4'-di- tert-butyl-2,2'-bipyridine). X-ray crystal structures of PHT and NAP complexes show a distorted square-planar arrangement of ligands around the Pt center. Both complexes form "head-to-tail" dimers in the solid state through remarkably short unsupported Pt...Pt contacts of 3.208 (PHT) and 3.378 A (NAP). The Pt(bpy*)(cat-imide) complexes are shown to combine optical (absorption) and electrochemical properties of the catecholate (electron-donor) and imide (electron-acceptor) groups. The complexes show a series of reversible reduction processes in the range from -0.5 to -1.9 V vs Fc (+)/Fc, which are centered on either bpy* or imide groups, and a reversible oxidation process at +0.07 to +0.14 V, which is centered on the catecholate moiety. A combination of UV-vis absorption spectroscopy, cyclic voltammetry, UV-vis spectroelectrochemistry, and EPR spectroscopy has allowed assignment of the nature of frontier orbitals in Pt(bpy*)(cat-imide) complexes. The HOMO in Pt(bpy*)(cat-imide) is centered on the catechol ligand, while the LUMO is localized either on bpy* or on the imide group, depending on the nature of the imide group involved. Despite the variations in the nature of the LUMO, the lowest-detectable electronic transition in all Pt(bpy*)(cat-imide) complexes has predominantly ligand-to-ligand (catechol-to-diimine) charge-transfer nature (LLCT) and involves a bpy*-based unoccupied molecular orbital in all cases. The LLCT transition in all Pt(bpy*)(cat-imide) complexes appears at 530 nm in CH2Cl2 and is strongly negatively solvatochromic. The energy of this transition is remarkably insensitive to the imide group present, indicating lack of electronic communication between the imide and the catechol

Synthesis, structural, DFT studies, docking and antibacterial activity of a xanthene based hydrazone ligand

NASA Astrophysics Data System (ADS)

Naseem, Saira; Khalid, Muhammad; Tahir, Muhammad Nawaz; Halim, Mohammad A.; Braga, Ataualpa A. C.; Naseer, Muhammad Moazzam; Shafiq, Zahid

2017-09-01

Herein, we present the synthesis of novel xanthene-based hydrazone (1). The chemical structure of 1 was resolved using spectroscopic techniques such as NMR, FT-IR, UV-VIS and X-ray crystallographic approaches. X-ray diffraction analysis shows that the compound (1) crystallizes in triclinic crystal lattice with the Pbar1 space group and diffused to form multi-layered structure due to non-covalent interactions such as intramolecular hydrogen bonding (H.B). In addition to experimental investigation, density functional theory (DFT) calculation with M06-2X/6-31G(d,p) and B3LYP/6-31G(d,p) level of theories was performed on compound (1) to obtain optimized geometry, spectroscopic and electronic properties. DFT optimized geometry shows good agreement with the experimental XRD structure. The hyper conjugative interactions and hydrogen bonding network are responsible for the stability of compound (1) as revealed by natural bond orbital (NBO) calculation. Moreover, hydrogen bonding network in the dimer is confirmed by FT-IR and thermodynamic studies showing excellent agreement with XRD and NBO findings. TD-DFT/UV-VIS analysis provides insight that maximum excitation is found in 1 which shows good agreement with experimental UV-VIS result. The global reactivity parameters are calculated using the energies of frontier molecular orbitals also disclosed that the compound is more stable might be due to hydrogen bonding network. Experimental and molecular docking studies indicated that this compound has anti-bacterial and anti-diabetic properties. The binding affinity of this compound against the multidrug efflux pump subunit AcrB OS=Escherichia coli (strain K12) and Human Pancreatic Alpha-Amylase is -9.2 and -10.00 kcal/mol which are higher than the control drugs. Pi-Pi, Pi-anaion, amide-pi and pi-alkyl bonds play key role in drug-protein complexes.

The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening.

PubMed

Xia, Jie; Hsieh, Jui-Hua; Hu, Huabin; Wu, Song; Wang, Xiang Simon

2017-06-26

Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment. Continuing from it, in the present work we attempted to incorporate knowledge collected from diverse protein-ligand interfaces of multiple crystal structures of the same target to build PF ensembles (PFEs). Toward this end, we first constructed a comprehensive data set to meet the requirements of ensemble modeling and validation. This set contains 10 diverse targets, 118 well-prepared X-ray structures of protein-ligand complexes, and large benchmarking actives/decoys sets. Notably, we designed a unique workflow of two-layer classifiers based on the concept of ensemble learning and applied it to the construction of PFEs for all of the targets. Through extensive benchmarking studies, we demonstrated that (1) coupling PFE with Chemgauss4 significantly improves the early enrichment of Chemgauss4 itself and (2) PFEs show greater consistency in boosting early enrichment and larger overall enrichment than our prior PFs. In addition, we analyzed the pairwise topological similarities among cognate ligands used to construct PFEs and found that it is the higher chemical diversity of the cognate ligands that leads to the improved performance of PFEs. Taken together, the results so far prove that the incorporation of knowledge from diverse protein-ligand interfaces by ensemble modeling is able to enhance the screening competence of SBVS scoring functions.

Templated Atom-Precise Galvanic Synthesis and Structure Elucidation of a [Ag24Au(SR)18](-) Nanocluster.

PubMed

Bootharaju, Megalamane S; Joshi, Chakra P; Parida, Manas R; Mohammed, Omar F; Bakr, Osman M

2016-01-18

Synthesis of atom-precise alloy nanoclusters with uniform composition is challenging when the alloying atoms are similar in size (for example, Ag and Au). A galvanic exchange strategy has been devised to produce a compositionally uniform [Ag24Au(SR)18](-) cluster (SR: thiolate) using a pure [Ag25(SR)18](-) cluster as a template. Conversely, the direct synthesis of Ag24Au cluster leads to a mixture of [Ag(25-x)Au(x)(SR)18](-), x=1-8. Mass spectrometry and crystallography of [Ag24Au(SR)18](-) reveal the presence of the Au heteroatom at the Ag25 center, forming Ag24Au. The successful exchange of the central Ag of Ag25 with Au causes perturbations in the Ag25 crystal structure, which are reflected in the absorption, luminescence, and ambient stability of the particle. These properties are compared with those of Ag25 and Ag24Pd clusters with same ligand and structural framework, providing new insights into the modulation of cluster properties with dopants at the single-atom level. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, Structure and Electrochemistry of Tetranuclear Oxygen-Centered Copper(II) Clusters with Acetylacetone and Benz-pyrazole Hydrolyzed Derivatives as Ligand.

PubMed

Vafazadeh, Rasoul; Willis, Anthony C

2016-01-01

Two copper(II) clusters Cu(4)OCl(6)(pyrazole)4, 1, and Cu(4)OBr(6)(Br-pyrazole)4, 2, have been synthesized by reacting acetylacetone and benzohydrazide (1:1 ratio) with CuX(2) (X = Cl for 1 and X= Br for 2) in methanol solutions. The structures of both clusters have been established by X-ray crystallography. The clusters contain four Cu, one O, six μ(2)-X atoms, and four pyrazole ligands. The pyrazoles was prepared in situ by the reaction of acetylacetone with benzohydrazide in methanol under reflux. In 2, the methine hydrogens of the pyrazole ligands have been replaced by bromine atoms. The four copper atoms encapsulate the central O atom in a tetrahedral arrangement. All copper atoms are five-coordinate and have similar coordination environments with slightly distorted trigonal bipyramidal geometry. The cyclic voltammogram of the clusters 1 and 2 show a one-electron quasi-reversible reduction wave in the region 0.485 to 0.731 V, and a one-electron quasi-reversible oxidation wave in the region 0.767 to 0.898 V. In 1, one irreversible oxidative response is observed on the positive of side of the voltammogram at 1.512 V and this can be assigned to Cu(II) to Cu(III) oxidation.

Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand-Binding Domains.

PubMed

Hurt, Darrell E; Suzuki, Shigeru; Mayama, Takafumi; Charmandari, Evangelia; Kino, Tomoshige

2016-02-01

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.

Modification of the 5' terminus of oligodeoxyribonucleotides for conjugation with ligands.

PubMed

Asseline, U; Thuong, N T

2001-08-01

Ligands can be introduced at the 5' terminus of an oligonucleotide by adding a linker to the ligand and modifying the 5' terminus of the oligonucleotide. These are then reacted to give the ligand-oligonucleotide conjugate. This unit describes the addition of carboxylated and aminoalkylated linkers, and phosphorothioate, phosphate, and masked thiol groups to the 5' terminus of an oligonucleotide. The addition of linkers to ligands and the final reaction that produces the ligand-conjugated oligonucleotide are described elsewhere in the series. This approach is particularly useful when there is a limited amount of ligand available, when the ligand is sensitive to chemical conditions required for oligonucleotide deprotection, or when the ligand is weakly soluble in solvents required for phosphoramidite- or H-phosphonate-mediated oligonucleotide synthesis.

Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity†

PubMed Central

Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen; Martínez, Alberto; Estrada, Jesús; Smith, Peter J.; Haukka, Matti; Sánchez-Delgado, Roberto A.; Nordlander, Ebbe

2012-01-01

Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID:22249579

New strategies for the synthesis of naphthoquinones employing Cu(II) complexes: Crystal structures and cytotoxicity

NASA Astrophysics Data System (ADS)

Azeredo, Nathália F. B.; Souza, Fabrícia P.; Demidoff, Felipe C.; Netto, Chaquip D.; Resende, Jackson A. L. C.; Franco, Roberto W. A.; Colepicolo, Pio; Ferreira, Ana M. C.; Fernandes, Christiane

2018-01-01

The syntheses, physico-chemical characterization and cytotoxicity toward three human cell lines (standard and resistant sarcoma cells, and fibroblast) of a new copper(II) complex [Cu(HBPA)(L1)Cl]·3H2O 2 are reported. Complex 2 was obtained through the reaction between the ligand stilbene-quinone (HL1) and Cu[HBPA]Cl21, where HBPA = 2-hydroxybenzyl-2pyridylmethylamine. The synthesis of HL1 was performed in high yield through Heck reaction on PEG-400. X-ray diffraction and solution studies (UV-Vis, EPR, ESI(+)-MS and ESI(+)-MS/MS) were performed for complex 2, in which the copper(II) center is coordinated to the quinone in its deprotonated form, to the ligand HBPA and to a chloro ligand. Similar reaction employing CuCl2·2H2O, instead of Cu[HBPA]Cl21 and HL1, has resulted in the obtainment of a furano-o-naphtoquinone (L2) with 99% selectivity, suggesting a new methodology to cyclize the ligand HL1. In order to obtain the analogous para-isomer (L3), and to evaluate the isomerism influence on cytotoxicity activity, a cyclization reaction of HL1 with NBS (N-bromosuccinimide) was also performed, which resulted in the obtainment of L2 (8%) and L3 (13%). X-ray diffraction studies were performed for L2 and complex 2, and the description of their structure elucidated. Results from MTT assay revealed that complex 2 is more active against sarcoma cell lines (MES-SA/Dx5 and MES-SA) than both the free ligand HL1 and complex 1, reducing cell viability to less than 50 μmol L-1. L2 was the most active in the series, presenting cytotoxicity against resistant MES-SA/Dx5 and its standard MES-SA cell line, respectively, three and ten times higher than the current drug doxorubicin.

Synthesis and structural studies of heterobimetallic alkoxide complexes supported by bis(phenolate) ligands: efficient catalysts for ring-opening polymerization of L-lactide.

PubMed

Chen, Hsuan-Ying; Liu, Mei-Yu; Sutar, Alekha Kumar; Lin, Chu-Chieh

2010-01-18

A series of heterobimetallic titanium(IV) complexes [LTi(O(i)Pr)(mu-O(i)Pr)(2)Li(THF)(2)], [LTi(O(i)Pr)(mu-O(i)Pr)(2)Na(THF)(2)], [LTi(mu-O(i)Pr)(2)Zn(O(i)Pr)(2)], and [LTi(mu-O(i)Pr)(2)Mg(O(i)Pr)(2)] (where L = bidentate bisphenol ligands) have been synthesized and characterized including a structural determination of [L(1)Ti(mu(2)-O(i)Pr)(2)(O(i)Pr)Li(THF)(2)] (1a). These complexes were investigated for their utility in the ring-opening polymerization (ROP) of l-lactide (LA). Polymerization activities have been shown to correlate with the electronic properties of the substituent within the bisphenol ligand. In contrast to monometallic titanium initiator 1e, all the heterobimetallic titanium initiators (Ti-Li, Ti-Na, Ti-Zn, and Ti-Mg) show enhanced catalytic activity toward ring-opening polymerization (ROP) of l-LA. In addition, the use of electron-donating methoxy or methylphenylsulfonyl functional ligands reveals the highest activity. The bisphenol bimetallic complexes give rise to controlled ring-opening polymerization, as shown by the linear relationship between the percentage conversion and the number-average molecular weight. The polymerization kinetics using 2c as an initiator were also studied, and the experimental results indicate that the reaction rate is first-order with respect to both monomer and catalyst concentration with a polymerization rate constant, k = 81.64 M(-1) min(-1).

Synthesis, characterization and electrochemical investigations of mixed-ligand copper(II)-organic supramolecular frameworks

NASA Astrophysics Data System (ADS)

Singh, Sandeep K.; Srivastava, Ashish Kumar; Srivastava, Krishna; Banerjee, Rahul; Prasad, Jagdish

2017-11-01

Two mixed-ligand copper(II)-organic coordination compounds with 5,5‧-dimethyl-2,2‧-bipyridine (5,5‧-Me2bpy) as a primary ligand while aliphatic malonate (Hmal) and aromatic 2-hydroxynicotinate (2-OHNA) as secondary ligands, were synthesized. These complexes are formulated as: [Cu(Hmal)(5,5‧-Me2bpy)(H2O)](ClO4) 1 and [Cu2(2-OHNA)2(5,5‧-Me2bpy)2(NO3)](NO3) 2. These two complexes were structurally characterized by single crystal X-ray diffraction analysis. Characterization was further supported by powder X-ray diffraction analysis, elemental analyses, FT-IR, FAB-MASS and TGA, DSC studies. Cyclic voltammetric and UV-visible spectral studies of these two complexes have also been done. The electrochemical studies of complex 1 in DMSO and DMF have shown that this complex undergoes quasi-reversible diffusion-controlled one-electron transfer reaction without any chemical complication while complex 2 in DMSO undergoes quasi-reversible diffusion-controlled one electron transfer reaction, following EC mechanism. The electrochemical behaviour of complex 2 in DMF is complicated probably due to presence of more than one species in solution phase.

Synthesis and characterization of dihexyldithiocarbamate as a chelating agent in extraction of gold(III)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fatimah, Soja Siti, E-mail: soja-sf@upi.edu; Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Jl. Raya Bandung-Sumedang, Km. 21, Jatinangor; Bahti, Husein H.

2016-02-08

The use of dialkyldithiocarbamates as chelating agents of transition metals have been developing for decades. Many chelating agents have been synthesized and used in the extraction of the metals. Studies on particular aspects of extraction of the metals, such as the effect of increasing hydrophobicity of chelating agents on the effectiveness of the extraction, have been done. However, despite the many studies on the synthesis and applications of this type of chelating agents, interests in the aspect of molecular structure of the synthesized ligands and of their complexes, have been limited. This study aimed at synthesizing and characterizing dihexylthiocarbamate, andmore » using the ligand for the extraction of gold III). Characterization of the ligand and of its metal complex were done by using elemental analysis, DTG, and spectroscopic methods to include NMR, ({sup 1}H, and {sup 13}C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.« less

Synthesis and characterization of dihexyldithiocarbamate as a chelating agent in extraction of gold(III)

NASA Astrophysics Data System (ADS)

Fatimah, Soja Siti; Bahti, Husein H.; Hastiawan, Iwan; Permanasari, Anna

2016-02-01

The use of dialkyldithiocarbamates as chelating agents of transition metals have been developing for decades. Many chelating agents have been synthesized and used in the extraction of the metals. Studies on particular aspects of extraction of the metals, such as the effect of increasing hydrophobicity of chelating agents on the effectiveness of the extraction, have been done. However, despite the many studies on the synthesis and applications of this type of chelating agents, interests in the aspect of molecular structure of the synthesized ligands and of their complexes, have been limited. This study aimed at synthesizing and characterizing dihexylthiocarbamate, and using the ligand for the extraction of gold III). Characterization of the ligand and of its metal complex were done by using elemental analysis, DTG, and spectroscopic methods to include NMR, (1H, and 13C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.

Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.

PubMed

Lane-Serff, Harriet; MacGregor, Paula; Lowe, Edward D; Carrington, Mark; Higgins, Matthew K

2014-12-12

The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the β-subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.

Rational Quantitative Structure-Activity Relationship (RQSAR) Screen for PXR and CAR Isoform-Specific Nuclear Receptor Ligands

PubMed Central

Dring, Ann M.; Anderson, Linnea E.; Qamar, Saima; Stoner, Matthew A.

2010-01-01

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography.

PubMed

Patterson, Stephen; Alphey, Magnus S; Jones, Deuan C; Shanks, Emma J; Street, Ian P; Frearson, Julie A; Wyatt, Paul G; Gilbert, Ian H; Fairlamb, Alan H

2011-10-13

Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

External anion effect on the synthesis of new MOFs based on formate and a twisted divergent ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lago, Ana Belén, E-mail: ablago@uvigo.es; Carballo, Rosa; Lezama, Luis

2015-11-15

New copper(II) metal–organic compounds with the formulae [Cu{sub 3}Cl(HCO{sub 2}){sub 5}(SCS){sub 3}(H{sub 2}O){sub 2}]·8H{sub 2}O·EtOH (1) and [Cu{sub 3}(HCO{sub 2}){sub 4}(SCS){sub 4}(H{sub 2}O){sub 2}](NO{sub 3}){sub 2}·9H{sub 2}O (2) (SCS=bis(4-pyridylthio)methane) have been synthesized after a careful study of the reaction of the SCS ligand with copper(II) formate. The compounds were obtained in the presence of sodium chloride and nitrate salts under microwave irradiation. The influence of the anion at different metal/anion ratios on the final architecture has been studied. The new chloride-MOF 1 has been characterized by electron paramagnetic resonance (EPR), magnetic properties and single crystal X-ray diffraction studies. The thermalmore » stability and topological analysis have also been investigated. - Highlights: • Microwave synthesis of coordination polymers. • Anion-derived structural changes. • Influence of anions at different metal/anion ratios on the final architectures. • EPR and magnetic characterization of a MOF compound.« less

Concerted ligand exchange and the roles of counter anions in the reversible structural switching of crystalline peptide metallo-macrocycles.

PubMed

Miyake, Ryosuke; Shionoya, Mitsuhiko

2014-06-02

To understand reversible structural switching in crystalline materials, we studied the mechanism of reversible crystal-to-crystal transformation of a tetranuclear Ni(II) macrocycle consisting of artificial β-dipeptides. On the basis of detailed structural analyses and thermodynamic measurements made in a comparison of pseudo-isostructural crystals (NO3 and BF4 salts), we herein discuss how ligand-exchange reactions take place in the crystal due to changes in water content and temperature. Observations of the structural transformation of NO3 salt indicated that a pseudo crystalline phase transformation takes place through concerted ligand-exchange reactions at the four Ni(II) centers of the macrocycle with hydrogen bond switching. A mechanism for this ligand exchange was supported by IR spectroscopy. Thermodynamic measurements suggested that the favorable compensation relationship of the enthalpy changes due to water uptake and structural changes are keys to the reversible structural transformation. On the basis of a comparison with the pseudo-isostructural crystals, it is apparent that the crystal packing structure and the types of counter anions are important factors for facilitating reversible ligand exchange with single crystallinity.

The XChemExplorer graphical workflow tool for routine or large-scale protein-ligand structure determination.

PubMed

Krojer, Tobias; Talon, Romain; Pearce, Nicholas; Collins, Patrick; Douangamath, Alice; Brandao-Neto, Jose; Dias, Alexandre; Marsden, Brian; von Delft, Frank

2017-03-01

XChemExplorer (XCE) is a data-management and workflow tool to support large-scale simultaneous analysis of protein-ligand complexes during structure-based ligand discovery (SBLD). The user interfaces of established crystallographic software packages such as CCP4 [Winn et al. (2011), Acta Cryst. D67, 235-242] or PHENIX [Adams et al. (2010), Acta Cryst. D66, 213-221] have entrenched the paradigm that a `project' is concerned with solving one structure. This does not hold for SBLD, where many almost identical structures need to be solved and analysed quickly in one batch of work. Functionality to track progress and annotate structures is essential. XCE provides an intuitive graphical user interface which guides the user from data processing, initial map calculation, ligand identification and refinement up until data dissemination. It provides multiple entry points depending on the need of each project, enables batch processing of multiple data sets and records metadata, progress and annotations in an SQLite database. XCE is freely available and works on any Linux and Mac OS X system, and the only dependency is to have the latest version of CCP4 installed. The design and usage of this tool are described here, and its usefulness is demonstrated in the context of fragment-screening campaigns at the Diamond Light Source. It is routinely used to analyse projects comprising 1000 data sets or more, and therefore scales well to even very large ligand-design projects.

The XChemExplorer graphical workflow tool for routine or large-scale protein–ligand structure determination

PubMed Central

Krojer, Tobias; Talon, Romain; Pearce, Nicholas; Douangamath, Alice; Brandao-Neto, Jose; Dias, Alexandre; Marsden, Brian

2017-01-01

XChemExplorer (XCE) is a data-management and workflow tool to support large-scale simultaneous analysis of protein–ligand complexes during structure-based ligand discovery (SBLD). The user interfaces of established crystallo­graphic software packages such as CCP4 [Winn et al. (2011 ▸), Acta Cryst. D67, 235–242] or PHENIX [Adams et al. (2010 ▸), Acta Cryst. D66, 213–221] have entrenched the paradigm that a ‘project’ is concerned with solving one structure. This does not hold for SBLD, where many almost identical structures need to be solved and analysed quickly in one batch of work. Functionality to track progress and annotate structures is essential. XCE provides an intuitive graphical user interface which guides the user from data processing, initial map calculation, ligand identification and refinement up until data dissemination. It provides multiple entry points depending on the need of each project, enables batch processing of multiple data sets and records metadata, progress and annotations in an SQLite database. XCE is freely available and works on any Linux and Mac OS X system, and the only dependency is to have the latest version of CCP4 installed. The design and usage of this tool are described here, and its usefulness is demonstrated in the context of fragment-screening campaigns at the Diamond Light Source. It is routinely used to analyse projects comprising 1000 data sets or more, and therefore scales well to even very large ligand-design projects. PMID:28291762

Synthesis and crystal structure of the rhodium(I) cyclooctadiene complex with bis(3-tert-butylimidazol-2-ylidene)borate ligand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, F.; Shao, K.-J.; Xiao, Y.-C.

2015-12-15

The rhodium(I) cyclooctadiene complex with the bis(3-tert-butylimidazol-2-ylidene)borate ligand [H{sub 2}B(Im{sup t}Bu){sup 2}]Rh(COD) C{sup 22}H{sup 36}BN{sup 4}Rh, has been prepared, and its crystal structure is determined by X-ray diffraction. Complex exhibits slightly distorted square planar configurations around the metal center, which is coordinated by the bidentate H{sup 2}B(Im{sup t}Bu){sub 2} and one cyclooctadiene group. The Rh–C{sub carbene} bond lengths are 2.043(4) and 2.074(4) Å, and the bond angle C–Rh1–C is 82.59°. The dihedral angle between two imidazol-2-ylidene rings is 67.30°.

Synthesis, characterization, crystal structure, superoxide dismutase and biological activities of nickel (II) complexes with bidentate ligands possessing N and O donor atoms

NASA Astrophysics Data System (ADS)

Sangeeta, S.; Ahmad, K.; Noorussabah, N.; Bharti, S.; Mishra, M. K.; Sharma, S. R.; Choudhary, M.

2017-12-01

Two new Schiff bases 2-((E)-(4-bromo-2-chlorophenylimino)methyl)-4-bromophenol(HL1) and1-((E)-(4-bromo-2-chlorophenylimino)methyl)naphthalene-2-ol (HL2) and their new nickel (II) complexes [Ni(L1)2]·DMF(1) and [Ni(L2)2] (2) have been synthesized and characterized by various physico- chemical and spectroscopic methods. The solid-state structures of synthesized compounds were determined by single crystal X-ray crystallography, which revealed square planar geometry around Ni (II) ion. Infrared spectra, UV-Vis, thermal analysis and magnetic susceptibility measurements agreed with the observed crystal structures. The ligand (HL1) crystallized in the Orthorhombic system of the space group Pbca,a = 7.5485(4)Å, b = 11.5514(5) Å, c = 30.1370(14)Å, α = 90°, β = 90°, γ = 90°and Z = 8. Complex[Ni(L1)2]·DMF(1) crystallized in the Triclinic system of the space group P-1, a = 8.9954(3) Å, b = 9.4593(4) Å, c = 13.2657(5) Å, α = 101.478°, β = 99.595°, γ = 117.651°and Z = 2, whereas complex [Ni(L2)2]·(2) crystallized in the Monoclinic system of the space group P21/c, a = 9.301(9)Å, b = 12.149(8)Å, c = 13.792(10)Å, α = 90°, β = 106.35(4).°, γ = 90°and Z = 2. The Schiff bases (HL1and HL2) behaved as monobasic bidentate ligands possessing N and O donor atoms. The SOD activities of HL1 and its Ni (II) complex[Ni(L1)2]·DMF(1) have been measured using xanthine-xanthine oxidase as a source of superoxide radical and NBT assay as O2- scavenger. In vitro antimicrobial activities of the Ni(II) complexes (1) and (2)against Bacillus cereus and Staphylococcus aureus as Gram + ve and Salmonella typhi, Klebsiella pneumonia and Escherichia coli as Gram-ve species have been investigated comparing with the Schiff base ligands (HL1and HL2).

Syntheses and structural characterization of mercury (II) coordination polymers with neutral bidentate flexible pyrazole-based ligands

NASA Astrophysics Data System (ADS)

Lalegani, Arash; Khaledi Sardashti, Mohammad; Salavati, Hossein; Asadi, Amin; Gajda, Roman; Woźniak, Krzysztof

2016-03-01

Mercury(II) coordination compounds [Hg(μ-bbd)(μ-SCN)4]n(1) and [Hg(bpp)(SCN)2] (2) were synthesized by using the neutral flexible bidentate N-donor ligands 1,4-bis(3,5-dimethypyrazol-1-yl)butane (bbd) and 1,3-bis(3,5-dimethylpyrazolyl)propane (bpp), NCS- ligand and appropriate mercury(II) salts. Compound 1 forms a polymeric network with moieties which are connected by SCN groups and the mercury ions present as HgN3S2 trigonal bipyramides. The crystal structure of 2 is build of monomers and the mercury(II) ion adopts an HgN2S2 tetrahedral geometry. In the complex 1, each bbd acts as bridging ligand connecting Hg(μ-SCN)4 ions, while in the complex 2, the bpp ligand is coordinated to an mercury(II) ion in a cyclic-bidentate fashion forming an eight-membered metallocyclic ring. Moreover, in the tetrahedral structure of 2, the neutral molecules form a 1D chain structure through the C-H···N hydrogen bonds, whereas in 1 no hydrogen bonds are observed. Coordination compounds 1 and 2 have been characterized by infrared spectroscopy, elemental analyses and single-crystal X-ray diffraction.

Enantioselective synthesis of α-phenyl- and α-(dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids.

PubMed

Barsamian, Adam L; Wu, Zhenhua; Blakemore, Paul R

2015-03-28

Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two title product classes. Enantioenriched 2° carbinols generated by oxidative work-up (NaOOH) of initial α-phenylalkylboronate products were obtained in 35-83% yield and 70-96% ee by reaction of B-alkyl and B-aryl neopentyl glycol boronates with a combination of O-(α-lithiobenzyl)-N,N-diisopropylcarbamate and ligand 3,3-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (-78 °C to rt) with MgBr2·OEt2 additive. Enantioenriched α-(dimethylsilylphenylsilyl)alkylboronates were obtained in 35-69% yield and 9-57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]propane in cumene solvent (-45 °C to -95 °C to rt). The stereochemical outcome of the second type of reaction depended on the temperature history of the organolithium·ligand complex indicating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic resolution.

Synthesis, structural characterization, DFT studies and in-vitro antidiabetic activity of new mixed ligand oxovanadium(IV) complex with tridentate Schiff base

NASA Astrophysics Data System (ADS)

Patel, R. N.; Singh, Yogendra Pratap

2018-02-01

The mixed ligand oxovanadium(IV) complex [VO(L1)(L2)] [L1 = N'-[(Z)-phenyl(pyridin-2-yl)methylidene]benzohydrazide and L2 = Benzohydrazide] has been synthesized in aerobic condition. The complex was characterized by elemental analysis spectroscopic (UV-vis, IR, epr) and electrochemical methods. X-ray diffraction pattern was also used to characterize this complex, which has a distorted octahedral structure. Single crystal diffraction analysis reveals that Csbnd H⋯π (aryl/metal chelate rings) interactions contribute to the stabilization of the crystal structure in given dimension. The room temperature magnetic susceptibility data shows paramagnetic nature of the complex. The complex was also tested for in-vitro antidiabetic activity. Moderate α-glucosidase inhibition is shown by this complex, which may be considered as α-glucosidase inhibitors.

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

NASA Astrophysics Data System (ADS)

Paoletta, Silvia; Sabbadin, Davide; von Kügelgen, Ivar; Hinz, Sonja; Katritch, Vsevolod; Hoffmann, Kristina; Abdelrahman, Aliaa; Straßburger, Jens; Baqi, Younis; Zhao, Qiang; Stevens, Raymond C.; Moro, Stefano; Müller, Christa E.; Jacobson, Kenneth A.

2015-08-01

The G protein-coupled P2Y12 receptor (P2Y12R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y12R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y12R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y12R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y12R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y12R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y12R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.

Stereoselective Synthesis of Cyclometalated Iridium (III) Complexes: Characterization and Photophysical Properties

PubMed Central

Yang, Liangru; von Zelewsky, Alex; Nguyen, Huong P.; Muller, Gilles; Labat, Gaël; Stoeckli-Evans, Helen

2009-01-01

The stereoselective synthesis of a highly luminescent neutral Ir(III) complex comprising two bidentate chiral, cyclometalating phenylpyridine derivatives, and one acetylacetonate as ligands is described. The final complex and some intermediates were characterized by X-ray structural analysis, NMR-, CD-, and CPL-spectroscopy. PMID:20161195

Synthesis of triple-stranded complexes using bis(dipyrromethene) ligands.

PubMed

Zhang, Zhan; Dolphin, David

2010-12-20

The reaction of an α-free, β,β'-linked bis(dipyrromethene) ligand with Fe(3+) or Co(3+) led to noninterconvertible triple-stranded helicates and mesocates. In the present context, a stable α-free ligand 2 has been developed and complexation of ligands 1 and 2 with diamagnetic Co(3+), Ga(3+), and In(3+) has been studied. The triple-stranded M(2)1(3) (M = Ga, In) and M(2)2(3) (M = Co, Ga, In) complexes were characterized using matrix-assisted laser desorption ionization time-of-flight spectrometry, (1)H NMR and UV-vis spectroscopy, and X-ray crystallography. Again, the (1)H NMR analysis showed that both the triple-stranded helicates and mesocates were generated in this metal-directed assembly. Consistent with our previous finding on coordinatively inert Co(3+) complexes, variable-temperature NMR spectroscopy indicated that the triple-stranded helicate and mesocate of labile In(3+) did not interconvert in solution, either. However, the diastereoselectivity of the M(2)2(3) complexes was found to improve with an increase in the reaction temperature. Taken together, this study complements the coordination chemistry of poly(dipyrromethene) ligands and provides further insight into the formation of helicates versus mesocates.

Synthesis and luminescence properties of polymer-rare earth complexes containing salicylaldehyde-type bidentate Schiff base ligand.

PubMed

Zhang, Dandan; Gao, Baojiao; Li, Yanbin

2017-08-01

Using molecular design and polymer reactions, two types of bidentate Schiff base ligands, salicylaldehyde-aniline (SAN) and salicylaldehyde-cyclohexylamine (SCA), were synchronously synthesized and bonded onto the side chain of polysulfone (PSF), giving two bidentate Schiff base ligand-functionalized PSFs, PSF-SAN and PSF-SCA, referred to as macromolecular ligands. Following coordination reactions between the macromolecular ligands and Eu(III) and Tb(III) ions (the reaction occurred between the bonded ligands SAN or SCA and the lanthanide ion), two series of luminescent polymer-rare earth complexes, PSF-SAN-Eu(III) and PSF-SCA-Tb(III), were obtained. The two macromolecular ligands were fully characterized by Fourier transform infrared (FTIR), 1 H NMR and UV absorption spectroscopy, and the prepared complexes were also characterized by FTIR, UV absorption spectroscopy and thermo-gravity analysis. On this basis, the photoluminescence properties of these complexes and the relationships between their structure and luminescence were investigated in depth. The results show that the bonded bidentate Schiff base ligands, SAN and SCA, can effectively sensitize the fluorescence emission of Eu(III) and Tb(III) ions, respectively. PSF-SAN-Eu(III) series complexes, namely the binary complex PSF-(SAN) 3 -Eu(III) and the ternary complex PSF-(SAN) 3 -Eu(III)-(Phen) 1 (Phen is the small-molecule ligand 1,10-phenanthroline), produce strong red luminescence, suggesting that the triplet state energy level of SAN is lower and well matched with the resonant energy level of the Eu(III) ion. By contrast, PSF-SAN-Eu(III) series complexes, namely the binary complex PSF-(SCA) 3 -Tb(III) and the ternary complex PSF-(SCA) 3 -Tb(III)-(Phen) 1 , display strong green luminescence, suggesting that the triplet state energy level of SCA is higher and is well matched with the resonant energy level of Tb(III). Copyright © 2017 John Wiley & Sons, Ltd.

Synthesis of branched metal nanostructures with controlled architecture and composition

NASA Astrophysics Data System (ADS)

Ortiz, Nancy

On account of their small size, metal nanoparticles are proven to be outstanding catalysts for numerous chemical transformations and represent promising platforms for applications in the fields of electronics, chemical sensing, medicine, and beyond. Many properties of metal nanoparticles are size-dependent and can be further manipulated through their shape and architecture (e.g., spherical vs. branched). Achieving morphology control of nanoparticles through solution-based techniques has proven challenging due to limited knowledge of morphology development in nanosyntheses. To overcome these complications, a systematic examination of the local ligand environment of metal precursors on nanostructure formation was undertaken to evaluate its contribution to nanoparticle nucleation rate and subsequent growth processes. Specifically, this thesis will provide evidence from ex situ studies---Transmission Electron Microscopy (TEM) and UV-visible spectroscopy (UV-Vis)---that support the hypothesis that strongly coordinated ligands delay burst-like nucleation to generate spherical metal nanoparticles and ligands with intermediate binding affinity regulate the gradual reduction of metal precursors to promote aggregated assembly of nanodendrites. These ex situ studies were coupled with a new in situ perspective, providing detailed understanding of metal precursor transformation, its direct relation to nanoparticle morphology development, and the ligand influence towards the formation of structurally complex metal nanostructures, using in situ synchrotron X-ray Diffraction (XRD) and Ultra Small-Angle X-ray Scattering (USAXS). The principles extracted from the study of monometallic nanostructure formation were also found to be generally applicable to the synthesis of bimetallic nanostructures, e.g., Pd-Pt architectures, with either core-shell or alloyed structures that were readily achieved by ligand selection. These outcomes provide a direct connection between fundamental

Synthesis and crystal structure of a novel Mn(II) coordination polymer with 3-(4-(1H-benzo[d]imidazol-1-yl)-4-methoxyphenyl)-1-phenylprop-2-en-1-one ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.-F., E-mail: wgf1979@126.com; Zhang, X., E-mail: zhangx@hit.edu.cn; Sun, S.-W., E-mail: s-shuwen@163.com

3-(4-(1H-Benzo[d]imidazol-1-yl)-4-methoxyphenyl)-1-phenylprop-2-en-1-one (L{sup 1}, 1) and its Mn(II) complex, [Mn(L{sup 1}){sub 2}(SCN){sub 2}]{sub ∞} (2), were synthesized and characterized by elemental analyses, IR spectroscopy and single-crystal X-ray diffraction. The Mn(II) ion in 2 is six-coordinated to four nitrogen atoms of two L{sup 1} ligands, two SCN-ligands, and two oxygen atoms of other two L{sup 1} ligands to form a distorted octahedral geometry. Therefore, each L{sup 1} links Mn ions through the O and N atoms to generate 2D sheet structure.

Synthesis, Characterization and Application of Water-soluble Gold and Silver Nanoclusters

NASA Astrophysics Data System (ADS)

Kumar, Santosh

The term `nanotechnology' has emerged as a buzzword since the last few decades. It has found widespread applications across disciplines, from medicine to energy. The synthesis of gold and silver nanoclusters has found much excitement, due to their novel material properties. Seminal work by various groups, including ours, has shown that the size of these clusters can be controlled with atomic precision. This control gives access to tuning the optical and electronic properties. The majority of nanoclusters reported thus far are not water soluble, which limit their applications in biology that requires water-solubility. Going from organic to aqueous phase is by no means a simple task, as it is associated with many challenges. Their stability in the presence of oxygen, difficulty in characterization, and separation of pure nanoclusters are some of the major bottlenecks associated with the synthesis of water-soluble gold nanoclusters. Water-soluble gold nanoclusters hold great potential in biological labeling, bio-catalysis and nano-bioconjugates. To overcome this problem, a new ligand with structural rigidity is needed. After considering various possibilities, we chose Captopril as a candidate ligand. In my thesis research, the synthesis of Au25 nanocluster capped with captopril has been reported. Captopril-protected Au25 nanocluster showed significantly higher thermal stability and enhanced chiroptical properties than the Glutathione-capped cluster, which confirms our initial rationale, that the ligand is critical in protecting the nanocluster. The optical absorption properties of these Au25 nanoclusters are studied and compared to the plasmonic nanoparticles. The high thermal stability and solubility of Au25 cluster capped with Captopril motivated us to explore this ligand for the synthesis of other gold clusters. Captopril is a chiral molecule with two chiral centers. The chiral ligand can induce chirality to the overall cluster, even if the core is achiral

Excellent acceleration of the Diels-Alder reaction by microwave irradiation for the synthesis of new fluorine-substituted ligands of NMDA receptor.

PubMed

Sasaki, S; Ishibashi, N; Kuwamura, T; Sano, H; Matoba, M; Nisikawa, T; Maeda, M

1998-11-03

A series of 6,11-ethanobenzo[b]quinolizinium derivatives was synthesized through the Diels-Alder reaction between azoniaanthracne and the corresponding 1,1-disubstituted olefin. After a systematic investigation for achieving rapid synthesis, it was found that the reaction is accelerated in polar media such as H2O and trifluoroethanol. In particular, excellent acceleration was effected by microwave irradiation. The new fluorine-substituted ligands thus obtained exhibited potential affinity toward NMDA receptors.

Approximation concepts for efficient structural synthesis

NASA Technical Reports Server (NTRS)

Schmit, L. A., Jr.; Miura, H.

1976-01-01

It is shown that efficient structural synthesis capabilities can be created by using approximation concepts to mesh finite element structural analysis methods with nonlinear mathematical programming techniques. The history of the application of mathematical programming techniques to structural design optimization problems is reviewed. Several rather general approximation concepts are described along with the technical foundations of the ACCESS 1 computer program, which implements several approximation concepts. A substantial collection of structural design problems involving truss and idealized wing structures is presented. It is concluded that since the basic ideas employed in creating the ACCESS 1 program are rather general, its successful development supports the contention that the introduction of approximation concepts will lead to the emergence of a new generation of practical and efficient, large scale, structural synthesis capabilities in which finite element analysis methods and mathematical programming algorithms will play a central role.

Development of purely structure-based pharmacophores for the topoisomerase I-DNA-ligand binding pocket

NASA Astrophysics Data System (ADS)

Drwal, Malgorzata N.; Agama, Keli; Pommier, Yves; Griffith, Renate

2013-12-01

Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different approaches to cluster and select pharmacophore features are investigated, including hierarchical clustering and energy calculations. In addition, the performance of SBPs is evaluated retrospectively and compared to the performance of ligand- and complex-based pharmacophores. SBPs emerge as a valid method in virtual screening and a complementary approach to ligand-focussed methods. The study further reveals that the choice of pharmacophore feature clustering and selection methods has a large impact on the virtual screening hit lists. A prospective application of the SBPs in virtual screening reveals that they can be used successfully to identify novel topoisomerase inhibitors.

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.

PubMed

Yin, Donghua; He, Yali; Perera, Minoli A; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane D; Dalton, James T

2003-01-01

The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

Molecular dynamics studies of the 3D structure and planar ligand binding of a quadruplex dimer.

PubMed

Li, Ming-Hui; Luo, Quan; Xue, Xiang-Gui; Li, Ze-Sheng

2011-03-01

G-rich sequences can fold into a four-stranded structure called a G-quadruplex, and sequences with short loops are able to aggregate to form stable quadruplex multimers. Few studies have characterized the properties of this variety of quadruplex multimers. Using molecular modeling and molecular dynamics simulations, the present study investigated a dimeric G-quadruplex structure formed from a simple sequence of d(GGGTGGGTGGGTGGGT) (G1), and its interactions with a planar ligand of a perylene derivative (Tel03). A series of analytical methods, including free energy calculations and principal components analysis (PCA), was used. The results show that a dimer structure with stacked parallel monomer structures is maintained well during the entire simulation. Tel03 can bind to the dimer efficiently through end stacking, and the binding mode of the ligand stacked with the 3'-terminal thymine base is most favorable. PCA showed that the dominant motions in the free dimer occur on the loop regions, and the presence of the ligand reduces the flexibility of the loops. Our investigation will assist in understanding the geometric structure of stacked G-quadruplex multimers and may be helpful as a platform for rational drug design.

Exploration of electrostatic interaction in the hydrophobic pocket of lysozyme: Importance of ligand-induced perturbation of the secondary structure on the mode of binding of exogenous ligand and possible consequences.

PubMed

Panja, Sudipta; Halder, Mintu

2016-08-01

Exogenous ligand binding can be adequate to alter the secondary structure of biomolecules besides other external stimuli. In such cases, structural alterations can complicate on the nature of interaction with the exogenous molecules. In order to accommodate the exogenous ligand, the biomolecule has to unfold resulting in a considerable change to its properties. If the bound ligand can be unbound, the biomolecule gets the opportunity to refold back and return to its native state. Keeping this in mind, we have purposely investigated the interaction of tartrazine (TZ), a well abundant azo food colorant, with two homologous lysozymes, namely, human lysozyme (HLZ) and chicken egg white lysozyme (CEWLZ) in physiological pH condition. The binding of TZ with lysozymes has been identified to accompany a ligand-induced secondary structure alteration as indicated by the circular dichroism spectra, and the reduction of α-helical content is more with HLZ than CEWLZ. Interestingly, the binding is identified to occur in the electronic ground state of TZ with lysozyme in its hydrophobic cavity, containing excess of positive charge, predominantly via electrostatic interaction. With increase of salinity of the medium the protein tends to refold back due to wakening of electrostatic forces and consequent reduction of strength of ligand interaction and unbinding. The entropy enthalpy compensation (EEC) has been probed to understand the binding features and it is found that CEWLZ-TZ shows better compensation than HLZ-TZ complex. This is presumably due to the fact that with CEWLZ the binding does not accompany substantial change in the protein secondary structure and hence ineffective to scramble the EEC. The present study initiates the importance of ligand-perturbed structural alteration of biomolecule in controlling the thermodynamics of binding. If there is a considerable alteration of the protein secondary structure due to binding, it is indicative that such changes should bring in

Hollow-structured mesoporous materials: chemical synthesis, functionalization and applications.

PubMed

Li, Yongsheng; Shi, Jianlin

2014-05-28

Hollow-structured mesoporous materials (HMMs), as a kind of mesoporous material with unique morphology, have been of great interest in the past decade because of the subtle combination of the hollow architecture with the mesoporous nanostructure. Benefitting from the merits of low density, large void space, large specific surface area, and, especially, the good biocompatibility, HMMs present promising application prospects in various fields, such as adsorption and storage, confined catalysis when catalytically active species are incorporated in the core and/or shell, controlled drug release, targeted drug delivery, and simultaneous diagnosis and therapy of cancers when the surface and/or core of the HMMs are functionalized with functional ligands and/or nanoparticles, and so on. In this review, recent progress in the design, synthesis, functionalization, and applications of hollow mesoporous materials are discussed. Two main synthetic strategies, soft-templating and hard-templating routes, are broadly sorted and described in detail. Progress in the main application aspects of HMMs, such as adsorption and storage, catalysis, and biomedicine, are also discussed in detail in this article, in terms of the unique features of the combined large void space in the core and the mesoporous network in the shell. Functionalization of the core and pore/outer surfaces with functional organic groups and/or nanoparticles, and their performance, are summarized in this article. Finally, an outlook of their prospects and challenges in terms of their controlled synthesis and scaled application is presented. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.

PubMed

Runge, Steffen; Thøgersen, Henning; Madsen, Kjeld; Lau, Jesper; Rudolph, Rainer

2008-04-25

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic beta-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9-39) solved by the multiwavelength anomalous dispersion method to 2.2A resolution. The structure reveals that Exendin-4(9-39) is an amphipathic alpha-helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined alpha-helix in the N terminus of nGLP-1R and a loop between two antiparallel beta-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.

Two- and three-dimensional networks of gadolinium(III) with dicarboxylate ligands: synthesis, crystal structure, and magnetic properties.

PubMed

Cañadillas-Delgado, Laura; Pasan, Jorge; Fabelo, Oscar; Hernandez-Molina, María; Lloret, Francesc; Julve, Miguel; Ruiz-Pérez, Catalina

2006-12-25

Four gadolinium(III) complexes with dicarboxylate ligands of formulas [Gd2(mal)3(H2O)5]n.2nH2O (1), [Gd2(mal)3(H2O)6]n (2), [NaGd(mal)(ox)(H2O)3]n (3), and [Gd2(ox)3(H2O)6]n.2.5nH2O (4) (mal = malonate; ox = oxalate) have been prepared, and their magnetic properties have been investigated as a function of the temperature. The structures of 1-3 have been determined by X-ray diffraction methods. The crystal structure of 4 was already known, and it is made of hexagonal layers of Gd atoms that are bridged by bis-bidentate oxalate. Compound 1 is isostructural with the europium(III) malonate complex [Eu2(mal)3(H2O)5]n.2nH2O,1 whose structure was reported elsewhere. The Gd atoms in 1 define a two-dimensional network where a terminal bidentate and bridging bidentate/bis-monodentate and tris-bidentate coordination modes of malonate occur. Compound 2 has a three-dimensional structure with a structural phase transition at 226 K, which involves a change of the space group from I2/a to Ia. Although its structure at room temperature was already known, that below 226 K was not. Pairs of Gd atoms with a double oxo-carboxylate bridge occur in both phases, and the main differences between both structures deal with the Gd environment and the H-bond pattern. 3 is also a three-dimensional compound, and it was obtained by reacting Gd(III) ions with malonic acid in a silica gel medium. Oxalic acid results as an oxidized product of the malonic acid, and single crystals of the heteroleptic complex were produced. The Gd atoms in 3 are connected through bis-bidentate oxalate and carboxylate-malonate bridges in the anti-anti and anti-syn coordination modes. Compounds 1 and 2 exhibit weak but significant ferromagnetic couplings between the Gd(III) ions through the single (1) and double (2) oxo-carboxylate bridges, whereas antiferromagnetic interactions across the bis-bidentate oxalate account for the overall antiferromagnetic behavior observed in 3 and 4.

Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone-Based Cannabinoid Receptor Type 2 Ligands.

PubMed

Ragusa, Giulio; Bencivenni, Serena; Morales, Paula; Callaway, Tyra; Hurst, Dow P; Asproni, Battistina; Merighi, Stefania; Loriga, Giovanni; Pinna, Gerard A; Reggio, Patricia H; Gessi, Stefania; Murineddu, Gabriele

2018-03-25

In recent years, cannabinoid type 2 receptors (CB 2 R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB 2 R are devoid of the psychoactive effects typically observed for CB 1 R ligands. Based on our recent studies on a class of pyridazinone 4-carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure-activity relationships for this promising scaffold with the aim to develop potent CB 2 R ligands. In binding assays, two of the new synthesized compounds [6-(3,4-dichlorophenyl)-2-(4-fluorobenzyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (2) and 6-(4-chloro-3-methylphenyl)-cis-N-(4-methylcyclohexyl)-3-oxo-2-pentyl-2,3-dihydropyridazine-4-carboxamide (22)] showed high CB 2 R affinity, with K i values of 2.1 and 1.6 nm, respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB 2 R inverse agonists. Compound 22 displayed the highest CB 2 R selectivity and potency, presenting a favorable in silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle-switch residue, W6.48. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Readily Accessible Chiral NNN Pincer Ligand with a Pyrrole Backbone and Its Ni(II) Chemistry: Syntheses, Structural Chemistry, and Bond Activations.

PubMed

Wenz, Jan; Kochan, Alexander; Wadepohl, Hubert; Gade, Lutz H

2017-03-20

A new class of chiral C 2 -symmetric N-donor pincer ligands, 2,5-bis(2-oxazolinyldimethylmethyl)pyrroles (PdmBox)H, was synthesized starting from the readily available ethyl 2,2-dimethyl-3-oxobutanoate (1). The synthesis of the ligand backbone was achieved by oxidative enole coupling with CuC1 2 followed by Paal-Knorr-type pyrrole synthesis. The corresponding protioligands ( R PdmBox)H (R = iPr: 5a; Ph: 5b) were obtained by condensation with amino alcohols and subsequent zinc-catalyzed cyclization. Reaction of the lithiated ligands with [NiCl 2 (dme)] yielded the corresponding square-planar nickel(II) complexes [( R PdmBox)NiCl] (6a/b). Salt metathesis of 6a with the corresponding alkali or cesium salts in acetone led to the formation of air- and moisture-stable [( iPr PdmBox)NiX] (X = F (7), X = Br (8), X = I (9), X = N 3 (10), X = OAc (11). Furthermore, the conversion of [( iPr PdmBox)NiF] (7) with hydride transfer reagents such as PhSiH 3 led to the stable hydrido species [( iPr PdmBox)NiH] (27), the stoichiometric transformations of which were studied. Treatment of 6a with organometallic reagents such as ZnEt 2 , PhLi, PhC≡CLi, NsLi, or ( 4F Bn) 2 Mg(THF) 2 gave the corresponding alkyl, alkynyl, or aryl complexes. The availability of the new nonisomerizable PdmBox pincer ligands allowed the comparative study of their ligation to square-planar complexes as helically twisted spectator ligands as opposed to the enforced planar rigidity of their iso-PmBox analogues and the way this influences the reactivity of the Ni complexes.

Structure-based design of ligands for protein basic domains: Application to the HIV-1 Tat protein

NASA Astrophysics Data System (ADS)

Filikov, Anton V.; James, Thomas L.

1998-05-01

A methodology has been developed for designing ligands to bind a flexible basic protein domain where the structure of the domain is essentially known. It is based on an empirical binding free energy function developed for highly charged complexes and on Monte Carlo simulations in internal coordinates with both the ligand and the receptor being flexible. HIV-1 encodes a transactivating regulatory protein called Tat. Binding of the basic domain of Tat to TAR RNA is required for efficient transcription of the viral genome. The structure of a biologically active peptide containing the Tat basic RNA-binding domain is available from NMR studies. The goal of the current project is to design a ligand which will bind to that basic domain and potentially inhibit the TAR-Tat interaction. The basic domain contains six arginine and two lysine residues. Our strategy was to design a ligand for arginine first and then a superligand for the basic domain by joining arginine ligands with a linker. Several possible arginine ligands were obtained by searching the Available Chemicals Directory with DOCK 3.5 software. Phytic acid, which can potentially bind multiple arginines, was chosen as a building block for the superligand. Calorimetric binding studies of several compounds to methylguanidine and Arg-/Lys-containing peptides were performed. The data were used to develop an empirical binding free energy function for prediction of affinity of the ligands for the Tat basic domain. Modeling of the conformations of the complexes with both the superligand and the basic domain being flexible has been carried out via Biased Probability Monte Carlo (BPMC) simulations in internal coordinates (ICM 2.6 suite of programs). The simulations used parameters to ensure correct folding, i.e., consistent with the experimental NMR structure of a 25-residue Tat peptide, from a random starting conformation. Superligands for the basic domain were designed by joining together two molecules of phytic acid with

Cd(II)-coordination polymers based on tetracarboxylic acid and diverse bis(imidazole) ligands: Synthesis, structural diversity and photoluminescence properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arıcı, Mürsel, E-mail: marici@ogu.edu.tr; Yeşilel, Okan Zafer; Taş, Murat

Three new Cd(II)-coordination polymers, namely, ([Cd{sub 2}(μ{sub 6}-ao{sub 2}btc)(μ-1,5-bipe){sub 2}]·2H{sub 2}O){sub n} (1), ([Cd{sub 2}(μ{sub 6}-ao{sub 2}btc)(μ-1,4-bix){sub 2}]{sub n}·2DMF) (2) and ([Cd{sub 2}(μ{sub 8}-abtc)(μ-1,4-betix)]·DMF·H{sub 2}O){sub n} (3) (ao{sub 2}btc=di-oxygenated form of 3,3′,5,5′-azobenzenetetracarboxylate, 1,5-bipe: 1,5-bis(imidazol-1yl)pentane, 1,4-bix=1,4-bis(imidazol-1ylmethyl)benzene, 1,4-betix=1,4-bis(2-ethylimidazol-1ylmethyl)benzene) were synthesized with 3,3′,5,5′-azobenzenetetracarboxylic acid and flexible, semi-flexible and semi-flexible substituted bis(imidazole) linkers. They were characterized by IR spectroscopy, elemental analysis, single-crystal X-ray diffraction, powder X-ray diffractions (PXRD) and thermal analyses (TG/DTA). Complexes 1–3 exhibited structural diversities depending on flexible, semi-flexible and semi-flexible substituted bis(imidazole) ligands. Complex 1 was 2D structure with 3,6L18 topology. Complex 2 had a 3D pillar-layered framework with the raremore » sqc27 topology. When semi-flexible substituted bis(imidazole) linker was used, 3D framework of complex 3 was obtained with the paddlewheel Cd{sub 2}(CO{sub 2}){sub 4}-type binuclear SBU. Moreover, thermal and photoluminescence properties of the complexes were determined in detailed. - Graphical abstract: In this study, three novel Cd(II)-coordination polymers were synthesized with 3,3′,5,5′-azobenzenetetracarboxylic acid and flexible, semi-flexible and semi-flexible substituted bis(imidazole) linkers. They were characterized by IR spectroscopy, elemental analysis, single-crystal X-ray diffraction, powder X-ray diffractions (PXRD) and thermal analyses (TG/DTA). Complexes 1–3 exhibited structural diversities depending on flexible, semi-flexible and semi-flexible substituted bis(imidazole) ligands. Complex 1 was 2D structure with 3,6L18 topology. Complex 2 had a 3D pillar-layered framework with the rare sqc27 topology

Stabilization of peroxisome proliferator-activated receptor alpha by the ligand.

PubMed

Hirotani, M; Tsukamoto, T; Bourdeaux, J; Sadano, H; Osumi, T

2001-10-19

Peroxisome proliferator-activated receptor (PPAR) constitutes a subfamily among a large group of ligand-activated transcription factors, the nuclear receptor superfamily. We studied the effects of ligand on the intracellular behaviors of PPARalpha. Although nuclear localization of PPARalpha was not affected by a selective ligand, Wy14643, we observed that exogenously expressed PPARalpha was rapidly degraded in HeLa cells, and the ligand significantly stabilized the protein. The stability of PPARalpha was also improved by coexpression of the heterodimer partner retinoid X receptor (RXR) alpha, and further stabilization was not observed with the ligand. These results indicate that PPARalpha is stabilized through heterodimerization with RXR, and the excess protein unpaired with RXR is rapidly turned over, if not bound by an appropriate ligand. These observations on PPARalpha are in sharp contrast to the ligand-stimulated degradation reported on PPARgamma. The ligand-dependent stabilization would have physiological significance when the synthesis of PPARalpha is elevated exceeding the available level of RXR. Copyright 2001 Academic Press.

Synthesis and investigation of Pd(I) carbonyl complexes with heteroorganic ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamberov, A.A.; Polovnyak, V.K.; Akhmetov, N.S.

1987-09-10

Pd(I) carbonyl complexes are attracting attention because they have been shown to have catalytic properties in a series of organic syntheses. The stability and catalytic properties of these compounds are determined by the nature of the phosphine ligand and the bridge coordination of the carbonylgroup. Through the partial replacement of carbonyl and acido ligands by heteroorganic ligands in carbonyl halogenide and carbonyl acetate Pd(I) complexes, new stable Pd(I) complexes were obtained: (PdLX)/sub 2/CO, where L = PPh/sub 3/, X = OAc; L = AsPh/sub 3/, X = Cl, Br, OAc; L = SbPh/sub 3/, X = Cl Br, OAc; Lmore » = Ph/sub 2/PCH/sub 2/PPh/sub 2/, Ph/sub 2/AsCH/sub 2/AsPh/sub 2/, X = OAc. Atoms of the heteroorganic and acido ligands are equivalently coordinated to the palladium atoms. The carbonyl group in the complexes has bridge coordination to palladium atoms in the Pd(CO)Pd fragment; in complexes with bidentate heteroorganic ligands the covalent bond between palladium atoms is absent.« less

Global structure-activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors.

PubMed

Cunningham, Albert R; Carrasquer, C Alex; Qamar, Shahid; Maguire, Jon M; Cunningham, Suzanne L; Trent, John O

2012-10-01

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby's structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity.

Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Jing; Akwabi-Ameyaw, Adwoa; Britton, Jonathan E.

2009-06-24

A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ER{alpha} and ER{beta} binding affinity ranging from micromolar to low nanomolar.

High-throughput screening of dye-ligands for chromatography.

PubMed

Kumar, Sunil; Punekar, Narayan S

2014-01-01

Dye-ligand-based chromatography has become popular after Cibacron Blue, the first reactive textile dye, found application for protein purification. Many other textile dyes have since been successfully used to purify a number of proteins and enzymes. While the exact nature of their interaction with target proteins is often unclear, dye-ligands are thought to mimic the structural features of their corresponding substrates, cofactors, etc. The dye-ligand affinity matrices are therefore considered pseudo-affinity matrices. In addition, dye-ligands may simply bind with proteins due to electrostatic, hydrophobic, and hydrogen-bonding interactions. Because of their low cost, ready availability, and structural stability, dye-ligand affinity matrices have gained much popularity. Choice of a large number of dye structures offers a range of matrices to be prepared and tested. When presented in the high-throughput screening mode, these dye-ligand matrices provide a formidable tool for protein purification. One could pick from the list of dye-ligands already available or build a systematic library of such structures for use. A high-throughput screen may be set up to choose best dye-ligand matrix as well as ideal conditions for binding and elution, for a given protein. The mode of operation could be either manual or automated. The technology is available to test the performance of dye-ligand matrices in small volumes in an automated liquid-handling workstation. Screening a systematic library of dye-ligand structures can help establish a structure-activity relationship. While the origins of dye-ligand chromatography lay in exploiting pseudo-affinity, it is now possible to design very specific biomimetic dye structures. High-throughput screening will be of value in this endeavor as well.

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

NASA Astrophysics Data System (ADS)

Létourneau, Danny; Bédard, Mikaël; Cabana, Jérôme; Lefebvre, Andrée; Lehoux, Jean-Guy; Lavigne, Pierre

2016-06-01

START domain proteins are conserved α/β helix-grip fold that play a role in the non-vesicular and intracellular transport of lipids and sterols. The mechanism and conformational changes permitting the entry of the ligand into their buried binding sites is not well understood. Moreover, their functions and the identification of cognate ligands is still an active area of research. Here, we report the solution structure of STARD6 and the characterization of its backbone dynamics on multiple time-scales through 15N spin-relaxation and amide exchange studies. We reveal for the first time the presence of concerted fluctuations in the Ω1 loop and the C-terminal helix on the microsecond-millisecond time-scale that allows for the opening of the binding site and ligand entry. We also report that STARD6 binds specifically testosterone. Our work represents a milestone for the study of ligand binding mechanism by other START domains and the elucidation of the biological function of STARD6.

Analysis of the HIV-2 protease's adaptation to various ligands: characterization of backbone asymmetry using a structural alphabet.

PubMed

Triki, Dhoha; Cano Contreras, Mario Enrique; Flatters, Delphine; Visseaux, Benoit; Descamps, Diane; Camproux, Anne-Claude; Regad, Leslie

2018-01-15

The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We propose an exhaustive study of the local structural asymmetry between the two monomers of all available PR2 structures complexed with various inhibitors using a structural alphabet approach. On average, PR2 exhibits asymmetry in 31% of its positions-i.e., exhibiting different backbone local conformations in the two monomers. This asymmetry was observed all along its structure, particularly in the elbow and flap regions. We first differentiated structural asymmetry conserved in most PR2 structures from the one specific to some PR2. Then, we explored the origin of the detected asymmetry in PR2. We localized asymmetry that could be induced by PR2's flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. This latter could be important for the PR2's adaptation to diverse ligands. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity. This knowledge is critical for a better description of PR2's recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class.

Impact of human galectin-1 binding to saccharide ligands on dimer dissociation kinetics and structure.

PubMed

Romero, Juan M; Trujillo, Madia; Estrin, Darío A; Rabinovich, Gabriel A; Di Lella, Santiago

2016-12-01

Endogenous lectins can control critical biological responses, including cell communication, signaling, angiogenesis and immunity by decoding glycan-containing information on a variety of cellular receptors and the extracellular matrix. Galectin-1 (Gal-1), a prototype member of the galectin family, displays only one carbohydrate recognition domain and occurs in a subtle homodimerization equilibrium at physiologic concentrations. Such equilibrium critically governs the function of this lectin signaling by allowing tunable interactions with a preferential set of glycosylated receptors. Here, we used a combination of experimental and computational approaches to analyze the kinetics and mechanisms connecting Gal-1 ligand unbinding and dimer dissociation processes. Kinetic constants of both processes were found to differ by an order of magnitude. By means of steered molecular dynamics simulations, the ligand unbinding process was followed monitoring water occupancy changes. By determining the water sites in a carbohydrate binding place during the unbinding process, we found that rupture of ligand-protein interactions induces an increase in energy barrier while ligand unbinding process takes place, whereas the entry of water molecules to the binding groove and further occupation of their corresponding water sites contributes to lowering of the energy barrier. Moreover, our findings suggested local asymmetries between the two subunits in the dimer structure detected at a nanosecond timescale. Thus, integration of experimental and computational data allowed a more complete understanding of lectin ligand binding and dimerization processes, suggesting new insights into the relationship between Gal-1 structure and function and renewing the discussion on the biophysics and biochemistry of lectin-ligand lattices. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

High-Temperature Magnetism as a Probe for Structural and Compositional Uniformity in Ligand-Capped Magnetite Nanoparticles

PubMed Central

2015-01-01

To investigate magnetostructural relationships in colloidal magnetite (Fe3O4) nanoparticles (NPs) at high temperature (300–900 K), we measured the temperature dependence of magnetization (M) of oleate-capped magnetite NPs ca. 20 nm in size. Magnetometry revealed an unusual irreversible high-temperature dependence of M for these NPs, with dip and loop features observed during heating–cooling cycles. Detailed characterizations of as-synthesized and annealed Fe3O4 NPs as well as reference ligand-free Fe3O4 NPs indicate that both types of features in M(T) are related to thermal decomposition of the capping ligands. The ligand decomposition upon the initial heating induces a reduction of Fe3+ to Fe2+ and the associated dip in M, leading to more structurally and compositionally uniform magnetite NPs. Having lost the protective ligands, the NPs continually sinter during subsequent heating cycles, resulting in divergent M curves featuring loops. The increase in M with sintering proceeds not only through elimination of a magnetically dead layer on the particle surface, as a result of a decrease in specific surface area with increasing size, but also through an uncommonly invoked effect resulting from a significant change in Fe3+/Fe2+ ratio with heat treatment. The interpretation of irreversible features in M(T) indicates that reversible M(T) behavior, conversely, can be expected only for ligand-free, structurally and compositionally uniform magnetite NPs, suggesting a general applicability of high-temperature M(T) measurements as an analytical method for probing the structure and composition of magnetic nanomaterials. PMID:25506407

Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

PubMed

Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

2013-01-01

Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

Insights into an Original Pocket-Ligand Pair Classification: A Promising Tool for Ligand Profile Prediction

PubMed Central

Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A.; Villoutreix, Bruno O.; Camproux, Anne-Claude

2013-01-01

Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

Titanium, aluminum and zinc complexes containing diamine-bis(benzotriazole phenolate) ligands: Synthesis, structural characterization and catalytic studies for ring-opening polymerization of ε-caprolactone

NASA Astrophysics Data System (ADS)

Liu, Zheng-Tang; Li, Chen-Yu; Chen, Jhy-Der; Liu, Wan-Ling; Tsai, Chen-Yen; Ko, Bao-Tsan

2017-04-01

Structurally diverse metal complexes bearing diamine-bis(benzotriazole phenolate) (DiBTP) ligands have been synthesized and fully characterized by single crystal X-ray crystallography. The reaction of Ti(OiPr)4 with C8MEADiBTP-H2 or C8BEADiBTP-H2 (1.0 mol equiv.) generated the monomeric titanium alkoxy complexes [(C8MEADiBTP)Ti(OiPr)2] (1) and [(C8BEADiBTP)Ti(OiPr)2] (2), respectively. Moreover, C8BEADiBTP-H2 reacted with 2.0 molar equiv. of AlMe3 to give the tetra-coordinated di-aluminum complex [(C8BEADiBTP)Al2Me4] (3). Zinc complex [(C8BEADiBTP)Zn2Et2] (4) could be obtained by the alkane elimination of ZnEt2 (2.0 equiv.) with C8BEADiBTP-H2 as the pro-ligand under similar synthetic methods in good yield. Single-crystal X-ray diffraction indicates that 3 is a bimetallic aluminum dimethyl complex with a tetradentate C8BEADiBTP moiety chelating two metal atoms, whereas complex 4 displays the dinuclear feature containing both tetra- and penta-coordinated zinc atoms bonded by one ONNON-pentadentate C8BEADiBTP ligand. Catalytic studies for ring-opening polymerization of ε-caprolactone of complex 1-4 were systematic explored; the comparative studies of such polymerization were also discussed.

Structural basis for the ligand-binding specificity of fatty acid-binding proteins (pFABP4 and pFABP5) in gentoo penguin.

PubMed

Lee, Chang Woo; Kim, Jung Eun; Do, Hackwon; Kim, Ryeo-Ok; Lee, Sung Gu; Park, Hyun Ho; Chang, Jeong Ho; Yim, Joung Han; Park, Hyun; Kim, Il-Chan; Lee, Jun Hyuck

2015-09-11

Fatty acid-binding proteins (FABPs) are involved in transporting hydrophobic fatty acids between various aqueous compartments of the cell by directly binding ligands inside their β-barrel cavities. Here, we report the crystal structures of ligand-unbound pFABP4, linoleate-bound pFABP4, and palmitate-bound pFABP5, obtained from gentoo penguin (Pygoscelis papua), at a resolution of 2.1 Å, 2.2 Å, and 2.3 Å, respectively. The pFABP4 and pFABP5 proteins have a canonical β-barrel structure with two short α-helices that form a cap region and fatty acid ligand binding sites in the hydrophobic cavity within the β-barrel structure. Linoleate-bound pFABP4 and palmitate-bound pFABP5 possess different ligand-binding modes and a unique ligand-binding pocket due to several sequence dissimilarities (A76/L78, T30/M32, underlining indicates pFABP4 residues) between the two proteins. Structural comparison revealed significantly different conformational changes in the β3-β4 loop region (residues 57-62) as well as the flipped Phe60 residue of pFABP5 than that in pFABP4 (the corresponding residue is Phe58). A ligand-binding study using fluorophore displacement assays shows that pFABP4 has a relatively strong affinity for linoleate as compared to pFABP5. In contrast, pFABP5 exhibits higher affinity for palmitate than that for pFABP4. In conclusion, our high-resolution structures and ligand-binding studies provide useful insights into the ligand-binding preferences of pFABPs based on key protein-ligand interactions. Copyright © 2015 Elsevier Inc. All rights reserved.

Ligand exchange synthesis of organometallic Rh nanoparticles and application in explosive sensing

NASA Astrophysics Data System (ADS)

Srivastav, Amit K.; Agrawal, Bhavesh; Swami, Bhavya; Agrawal, Yadvendra K.; Maity, Prasenjit

2017-06-01

Alkyne {phenyl acetylene (PA) and 9-ethynylphenanthrene (EPT)}-ligated Rh nanoparticles ( 1 and 2, respectively) with mean diameter of 1.5 ± 0.2 nm were synthesized via a facile and high-yield biphasic ligand exchange protocol using similar sized ethylene glycol (EG)-stabilized Rh nanoparticles as precursors (EG:Rh). The synthesized organometallic Rh nanoparticles were convincingly characterized using several spectroscopic and microscopic techniques, e.g., Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), optical absorption spectroscopy (UV-Vis), photoluminescence spectroscopy (PL), powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscope (TEM). We propose that the syntheses mechanism relies on catalytic acetylenic (≡C-H, carbon-hydrogen) bond breaking by EG:Rh followed by strong metal-carbon bond formation with a vinyldiene (>C═C═M) motif. The obtained 1 and 2 showed luminescence property, which arises from ligand structure through intraparticle conjugation. Electron-rich phenanthrene-ligated Rh nanoparticles ( 2) showed good sensing performance for detection of electron deficient nitro-aromatic explosive molecules (NA) in solution phase through luminescence quenching method.

Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.

PubMed

Istyastono, Enade P; Nijmeijer, Saskia; Lim, Herman D; van de Stolpe, Andrea; Roumen, Luc; Kooistra, Albert J; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

2011-12-08

The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

A combination of spin diffusion methods for the determination of protein-ligand complex structural ensembles.

PubMed

Pilger, Jens; Mazur, Adam; Monecke, Peter; Schreuder, Herman; Elshorst, Bettina; Bartoschek, Stefan; Langer, Thomas; Schiffer, Alexander; Krimm, Isabelle; Wegstroth, Melanie; Lee, Donghan; Hessler, Gerhard; Wendt, K-Ulrich; Becker, Stefan; Griesinger, Christian

2015-05-26

Structure-based drug design (SBDD) is a powerful and widely used approach to optimize affinity of drug candidates. With the recently introduced INPHARMA method, the binding mode of small molecules to their protein target can be characterized even if no spectroscopic information about the protein is known. Here, we show that the combination of the spin-diffusion-based NMR methods INPHARMA, trNOE, and STD results in an accurate scoring function for docking modes and therefore determination of protein-ligand complex structures. Applications are shown on the model system protein kinase A and the drug targets glycogen phosphorylase and soluble epoxide hydrolase (sEH). Multiplexing of several ligands improves the reliability of the scoring function further. The new score allows in the case of sEH detecting two binding modes of the ligand in its binding site, which was corroborated by X-ray analysis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Four unprecedented cobalt(II) and cadmium(II) metal-organic frameworks based on a rigid tricarboxylate ligand: Synthesis, crystal structures, magnetic and fluorescence properties

NASA Astrophysics Data System (ADS)

Liu, Yaru; Liu, Lan; Zhang, Xiao; Wu, Jie

2018-03-01

A Co(II) MOF {[Co3(L)2(H2O)4](DMF)2}n (1) and three Cd(II) MOFs [Cd3(L)2(H2O)7]n (2), [Cd3(L)2(H2O)11]n (3) and [Cd3(L)2(DMF)2(H2O)]n (4) are synthesized based on the promising multifunctional tricarboxylate ligand 6-(3, 5-dicarboxyl phenyl) nicotinic acid (H3L). 1 exhibits a 3D framework with 1D channels which contains opposite-handedness helical chains based on the trinuclear Co(II) clusters. 2-4 are obtained depend on different reaction conditions. 2 displays a 3D framework, which is composed of two kinds of 2D layers linked with each other. 3 shows a rare tongue-and-groove-type bilayer structure. And 4 is an interesting 3D framework containing infinite 1D inorganic Cdsbnd Osbnd Cd chains. In these MOFs, the H3L ligand shows the versatile coordination modes and strong coordination ability. Furthermore, the magnetic and solid-state luminescent properties of the MOFs have been investigated.

Structural features of cytochromes P450 and ligands that affect drug metabolism as revealed by X-ray crystallography and NMR.

PubMed

Gay, Sean C; Roberts, Arthur G; Halpert, James R

2010-09-01

Cytochromes P450 (P450s) play a major role in the clearance of drugs, toxins, and environmental pollutants. Additionally, metabolism by P450s can result in toxic or carcinogenic products. The metabolism of pharmaceuticals by P450s is a major concern during the design of new drug candidates. Determining the interactions between P450s and compounds of very diverse structures is complicated by the variability in P450-ligand interactions. Understanding the protein structural elements and the chemical attributes of ligands that dictate their orientation in the P450 active site will aid in the development of effective and safe therapeutic agents. The goal of this review is to describe P450-ligand interactions from two perspectives. The first is the various structural elements that microsomal P450s have at their disposal to assume the different conformations observed in X-ray crystal structures. The second is P450-ligand dynamics analyzed by NMR relaxation studies.

Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors

PubMed Central

Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper L.; Gloriam, David E.

2013-01-01

Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands. PMID:24244317

Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.

PubMed

Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper L; Gloriam, David E

2013-01-01

Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

Structural Diversity of Ligand-Binding Androgen Receptors Revealed by Microsecond Long Molecular Dynamics Simulations and Enhanced Sampling.

PubMed

Duan, Mojie; Liu, Na; Zhou, Wenfang; Li, Dan; Yang, Minghui; Hou, Tingjun

2016-09-13

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa). The antagonistic drugs, which suppress the activity of AR, are widely used in the treatment of PCa. However, the molecular mechanism of antagonism about how ligands affect the structures of AR remains elusive. To better understand the conformational variability of ARs bound with agonists or antagonists, we performed long time unbiased molecular dynamics (MD) simulations and enhanced sampling simulations for the ligand binding domain of AR (AR-LBD) in complex with various ligands. Based on the simulation results, we proposed an allosteric pathway linking ligands and helix 12 (H12) of AR-LBD, which involves the interactions among the ligands and the residues W741, H874, and I899. The interaction pathway provides an atomistic explanation of how ligands affect the structure of AR-LBD. A repositioning of H12 was observed, but it is facilitated by the C-terminal of H12, instead of by the loop between helix 11 (H11) and H12. The bias-exchange metadynamics simulations further demonstrated the above observations. More importantly, the free energy profiles constructed by the enhanced sampling simulations revealed the transition process between the antagonistic form and agonistic form of AR-LBD. Our results would be helpful for the design of more efficient antagonists of AR to combat PCa.

Synthesis,and structural characterization of [(CH3(C5H4N))Ga(SCH2(CO)O)]-[(4-MepyH)]+, a novel Ga(III) five coordinate complex.

NASA Technical Reports Server (NTRS)

Banger, Kulbinder K.; Duraj, Stan A.; Fanwic, Phillp E.; Hepp, Aloysius F.; Martuch, Robert A.

2003-01-01

The synthesis and structural characterization of a novel ionic Ga(III) five coordinate complex [{CH3(C5H4N)}Ga(SCH2(CO)O)2]-[(4-MepyH)]+, (4-Mepy = CH3(C5H5N)) from the reaction between Ga2Cl4 with sodium mercapto-acetic acid in 4-methylpyridine is described. Under basic reaction conditions the mercapto ligand is found to behave as a 2e- bidentate ligand. Single crystal X-ray diffraction studies show the complex to have a distorted square pyramidal geometry with the [(-SCH2(CO)CO-)] ligands in a trans conformation. The compound crystallizes in the P2(sub 1)/c (No. 14) space group with a = 7.7413(6) A, b = 16.744(2) A, c = 14.459(2) A, V = 1987.1(6) A(sup 3), R(F) = 0.032 and R(sub w) = 0.038.

Ligand-hole localization in oxides with unusual valence Fe

PubMed Central

Chen, Wei-Tin; Saito, Takashi; Hayashi, Naoaki; Takano, Mikio; Shimakawa, Yuichi

2012-01-01

Unusual high-valence states of iron are stabilized in a few oxides. A-site-ordered perovskite-structure oxides contain such iron cations and exhibit distinct electronic behaviors at low temperatures, e.g. charge disproportionation (4Fe4+ → 2Fe3+ + 2Fe5+) in CaCu3Fe4O12 and intersite charge transfer (3Cu2+ + 4Fe3.75+ → 3Cu3+ + 4Fe3+) in LaCu3Fe4O12. Here we report the synthesis of solid solutions of CaCu3Fe4O12 and LaCu3Fe4O12 and explain how the instabilities of their unusual valence states of iron are relieved. Although these behaviors look completely different from each other in simple ionic models, they can both be explained by the localization of ligand holes, which are produced by the strong hybridization of iron d and oxygen p orbitals in oxides. The localization behavior in the charge disproportionation of CaCu3Fe4O12 is regarded as charge ordering of the ligand holes, and that in the intersite charge transfer of LaCu3Fe4O12 is regarded as a Mott transition of the ligand holes. PMID:22690318

Performance evaluation of structure based and ligand based virtual screening methods on ten selected anti-cancer targets.

PubMed

Ramasamy, Thilagavathi; Selvam, Chelliah

2015-10-15

Virtual screening has become an important tool in drug discovery process. Structure based and ligand based approaches are generally used in virtual screening process. To date, several benchmark sets for evaluating the performance of the virtual screening tool are available. In this study, our aim is to compare the performance of both structure based and ligand based virtual screening methods. Ten anti-cancer targets and their corresponding benchmark sets from 'Demanding Evaluation Kits for Objective In silico Screening' (DEKOIS) library were selected. X-ray crystal structures of protein-ligand complexes were selected based on their resolution. Openeye tools such as FRED, vROCS were used and the results were carefully analyzed. At EF1%, vROCS produced better results but at EF5% and EF10%, both FRED and ROCS produced almost similar results. It was noticed that the enrichment factor values were decreased while going from EF1% to EF5% and EF10% in many cases. Published by Elsevier Ltd.

[Ligands of cholinesterases of ephedrine and pseudoephedrine structure].

PubMed

Basova, N E; Kormilitsin, B N; Perchenok, A Yu; Rozengatt, E V; Saakov, V S; Suvorov, A A

2013-01-01

The paper is a review of literature data on interaction of the mammalian erythrocyte acetylcholinesterase and blood serum butyrylcholinesterase with a group of isomer complex ester derivatives (acetates, propionates, butyrates, valerates, and isobutyrates) of bases and iodomethylates of ephedrine and its enantiomer pseudoephedrine. For 20 alkaloid monoesters, parameters of enzymatic hydrolysis are determined and their certain specificity toward acetylcholinesterase is revealed, whereas 5 diesters of iodomethylates of pseudoephedrine were hydrolyzed only by butyrylcholinesterase. The studied 20 aklaloid diesters and 10 trimethylammonium derivatives turned out to be non-competitive reversible inhibitors of acetylcholinesterase and competitive inhibitors of butyrylcholinesterase. The performed for the first time isomer and enantiomer analysis "structure-efficiency" has shown that in most cases it is possible to state the greater comlementarity of the catalytical surface of enzymes for ligands of the pseudoephedrine structure, such differentiation being realized more often at the reversible inhibition of enzymes. pseudoephedrine.

Mononuclear nickel (II) and copper (II) coordination complexes supported by bispicen ligand derivatives: Experimental and computational studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Nirupama; Niklas, Jens; Poluektov, Oleg

2017-01-01

The synthesis, characterization and density functional theory calculations of mononuclear Ni and Cu complexes supported by the N,N’-Dimethyl-N,N’-bis-(pyridine-2-ylmethyl)-1,2-diaminoethane ligand and its derivatives are reported. The complexes were characterized by X-ray crystallography as well as by UV-visible absorption spectroscopy and EPR spectroscopy. The solid state structure of these coordination complexes revealed that the geometry of the complex depended on the identity of the metal center. Solution phase characterization data are in accord with the solid phase structure, indicating minimal structural changes in solution. Optical spectroscopy revealed that all of the complexes exhibit color owing to d-d transition bands in the visiblemore » region. Magnetic parameters obtained from EPR spectroscopy with other structural data suggest that the Ni(II) complexes are in pseudo-octahedral geometry and Cu(II) complexes are in a distorted square pyramidal geometry. In order to understand in detail how ligand sterics and electronics affect complex topology detailed computational studies were performed. The series of complexes reported in this article will add significant value in the field of coordination chemistry as Ni(II) and Cu(II) complexes supported by tetradentate pyridyl based ligands are rather scarce.« less

Synthesis and photoluminescence properties of silver(I) complexes based on N-benzoyl-L-glutamic acid and N-donor ligands with different flexibility

NASA Astrophysics Data System (ADS)

Yan, Ming-Jie; Feng, Qi; Song, Hui-Hua

2016-05-01

By changing the N-donor ancillary ligand, three novel silver (I) complexes {[Ag(HbzgluO) (4,4‧-bipy)]·H2O}n (1), {[Ag2(HbzgluO)2 (bpe)2]·2H2O}n (2) and {[Ag(HbzgluO)(bpp)]·2H2O}n (3) (H2bzgluO = N-benzoyl-L-glutamic acid, 4,4‧-bipy = 4,4ˊ-bipyridine, bpe = 1,2-di(4-pyridyl)ethane, bpp = 1,3-di(4-pyridyl)propane) were synthesized. Their structures have been determined by single-crystal X-ray diffraction analyses and further characterized by elemental analyses, IR spectra, powder X-ray diffraction (PXRD), and thermogravimetric analyses (TGA). In this study, the N-donor ligands are changed from rigidity (4,4‧-bipy), quasi-flexibility (bpe) to flexibility (bpp), the structures of complexes also change. Complex 1 features a 1D chain structure which is further linked together to construct a 2D supramolecular structure through hydrogen bonds. Complex 2 is a 1D double-chains configuration which eventually forms a 3D supramolecular network via hydrogen bonding interactions. Whereas, complex 3 exhibits a 2D pleated grid structure which is linked by hydrogen bonding interactions into a 3D supramolecular network. The present observations demonstrate that the modulation of coordination polymers with different structures can accomplish by changing the spacer length of N-donor ligands. In addition, the solid-state circular dichroism (CD) spectra indicated that compound 2 exhibited negative cotton effect which originated from the chiral ligands H2bzgluO and the solid-state fluorescence spectra of the three complexes demonstrated the auxiliary ligands have influence on the photoluminescence properties of the complexes.

Electronic structural dependence of the photophysical properties of fluorescent heteroditopic ligands - implications in designing molecular fluorescent indicators.

PubMed

Younes, Ali H; Zhang, Lu; Clark, Ronald J; Davidson, Michael W; Zhu, Lei

2010-12-07

Two fluorescent heteroditopic ligands (2a and 2b) for zinc ion were synthesized and studied. The efficiencies of two photophysical processes, intramolecular charge transfer (ICT) and photoinduced electron transfer (PET), determine the magnitudes of emission bathochromic shift and enhancement, respectively, when a heteroditopic ligand forms mono- or dizinc complexes. The electron-rich 2b is characterized by a high degree of ICT in the excited state with little propensity for PET, which is manifested in a large bathochromic shift of emission upon Zn(2+) coordination without enhancement in fluorescence quantum yield. The electron-poor 2a displays the opposite photophysical consequence where Zn(2+) binding results in greatly enhanced emission without significant spectral shift. The electronic structural effects on the relative efficiencies of ICT and PET in 2a and 2b as well as the impact of Zn(2+)-coordination are probed using experimental and computational approaches. This study reveals that the delicate balance between various photophysical pathways (e.g. ICT and PET) engineered in a heteroditopic ligand is sensitively dependent on the electronic structure of the ligand, i.e. whether the fluorophore is electron-rich or poor, whether it possesses a donor-acceptor type of structure, and where the metal binding occurs.

AutoSite: an automated approach for pseudo-ligands prediction—from ligand-binding sites identification to predicting key ligand atoms

PubMed Central

Ravindranath, Pradeep Anand; Sanner, Michel F.

2016-01-01

Motivation: The identification of ligand-binding sites from a protein structure facilitates computational drug design and optimization, and protein function assignment. We introduce AutoSite: an efficient software tool for identifying ligand-binding sites and predicting pseudo ligand corresponding to each binding site identified. Binding sites are reported as clusters of 3D points called fills in which every point is labelled as hydrophobic or as hydrogen bond donor or acceptor. From these fills AutoSite derives feature points: a set of putative positions of hydrophobic-, and hydrogen-bond forming ligand atoms. Results: We show that AutoSite identifies ligand-binding sites with higher accuracy than other leading methods, and produces fills that better matches the ligand shape and properties, than the fills obtained with a software program with similar capabilities, AutoLigand. In addition, we demonstrate that for the Astex Diverse Set, the feature points identify 79% of hydrophobic ligand atoms, and 81% and 62% of the hydrogen acceptor and donor hydrogen ligand atoms interacting with the receptor, and predict 81.2% of water molecules mediating interactions between ligand and receptor. Finally, we illustrate potential uses of the predicted feature points in the context of lead optimization in drug discovery projects. Availability and Implementation: http://adfr.scripps.edu/AutoDockFR/autosite.html Contact: sanner@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27354702

Structural study of biologically significant ligands with major birch pollen allergen Betv1 by docking and molecular dynamics simulation

PubMed Central

Kundu, Sangeeta; Roy, Debjani

2010-01-01

The major birch pollen allergen, Betv1 of Betula verrucosa is the main causative agent of birch pollen allergy in humans. Betv1 is capable of binding several physiological ligands including fatty acids, flavones, cytokinins and sterols. Until now, no structural information from crystallography or NMR is available regarding binding mode of any of these ligands into the binding pocket of Betv1. In the present study thirteen ligands have been successfully docked into the hydrophobic cavity of Betv1 and binding free energies of the complexes have been calculated using AutoDock 3.0.5. A linear relationship with correlation coefficient (R2) of 0.6 is obtained between ΔGbs values plotted against their corresponding IC50 values. The complex formed between Betv1 and the best docking pose for each ligand has been optimized by molecular dynamics simulation. Here, we describe the ligand binding of Betv1, which provides insight into the biological function of this protein. This knowledge is required for structural alteration or inhibition of some of these ligands in order to modify the allergenic properties of this protein. PMID:20978606

Syntheses, crystal structures, and properties of four complexes based on polycarboxylate and imidazole ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiao, Rui; Chen, Shui-Sheng, E-mail: chenss@fync.edu.cn; Coordination Chemistry Institute, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093

2015-08-15

Four metal–organic coordination polymers [Zn(HL)(H{sub 2}O)]·4H{sub 2}O (1), [Zn(HL)(L{sub 1})]·4H{sub 2}O (2), [Cu(HL)(H{sub 2}O)]·3H{sub 2}O (3) and [Cu(HL)(L{sub 1})]·5H{sub 2}O (4) were synthesized by reactions of the corresponding metal(II) salts with semirigid polycarboxylate ligand (5-((4-carboxypiperidin-1-yl)methyl)isophthalic acid hydrochloride, H{sub 3}L·HCl) or auxiliary ligand (1,4-di(1H-imidazol-4-yl)benzene, L{sub 1}). The structures of the compounds were characterized by elemental analysis, FT-IR spectroscopy and single-crystal X-ray diffraction. The use of auxiliary ligand L{sub 1} has great influence on the structures of two pairs of complexes 1, 2 and 3, 4. Complex 1 is a uninodal 3-connected rare 2-fold interpenetrating ZnSc net with a Point (Schlafli) symbolmore » of (10{sup 3}) while 2 is a one-dimensional (1D) ladder structure. Compound 3 features a two-dimensional (2D) honeycomb network with typical 6{sup 3}-hcb topology, while 4 is 2D network with (4, 4) sql topology based on binuclear Cu{sup II} subunits. The non-covalent bonding interactions such as hydrogen bonds, π···π stacking and C–H···π exist in complexes 1–4, which contributes to stabilize crystal structure and extend the low-dimensional entities into high-dimensional frameworks. And the photoluminescent property of 1 and 2 and gas sorption property of 4 have been investigated. - Graphical abstract: Four new coordination polymers have been obtained and their photoluminescent and gas sorption properties have also been investigated. - Highlights: • Two pairs of Zn{sup II}/ Cu{sup II} compounds have been synthesized. • Auxiliary ligand-controlled assembly of the complexes is reported. • The luminescent properties of complexes 1–2 were investigated. • The gas sorption property of 4 has been investigated.« less

CYPSI: a structure-based interface for cytochrome P450s and ligands in Arabidopsis thaliana

PubMed Central

2012-01-01

Background The cytochrome P450 (CYP) superfamily enables terrestrial plants to adapt to harsh environments. CYPs are key enzymes involved in a wide range of metabolic pathways. It is particularly useful to be able to analyse the three-dimensional (3D) structure when investigating the interactions between CYPs and their substrates. However, only two plant CYP structures have been resolved. In addition, no currently available databases contain structural information on plant CYPs and ligands. Fortunately, the 3D structure of CYPs is highly conserved and this has made it possible to obtain structural information from template-based modelling (TBM). Description The CYP Structure Interface (CYPSI) is a platform for CYP studies. CYPSI integrated the 3D structures for 266 A. thaliana CYPs predicted by three TBM methods: BMCD, which we developed specifically for CYP TBM; and two well-known web-servers, MUSTER and I-TASSER. After careful template selection and optimization, the models built by BMCD were accurate enough for practical application, which we demonstrated using a docking example aimed at searching for the CYPs responsible for ABA 8′-hydroxylation. CYPSI also provides extensive resources for A. thaliana CYP structure and function studies, including 400 PDB entries for solved CYPs, 48 metabolic pathways associated with A. thaliana CYPs, 232 reported CYP ligands and 18 A. thaliana CYPs docked with ligands (61 complexes in total). In addition, CYPSI also includes the ability to search for similar sequences and chemicals. Conclusions CYPSI provides comprehensive structure and function information for A. thaliana CYPs, which should facilitate investigations into the interactions between CYPs and their substrates. CYPSI has a user-friendly interface, which is available at http://bioinfo.cau.edu.cn/CYPSI. PMID:23256889

Ligand Recognition by A-Class Eph Receptors: Crystal Structures of the EphA2 Ligand-Binding Domain and the EphA2/ephrin-A1 Complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Himanen, J.; Goldgur, Y; Miao, H

2009-01-01

Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B-class receptors. Here, we present the crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2. Although these structures are similar overall to their B-class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules.more » This model is supported by structure-based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell-based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2-specific homotypic cell adhesion interactions.« less

Synthesis and studies on Cu(II), Co(II), Ni(II) complexes of Knoevenagel β-diketone ligands.

PubMed

Sumathi, S; Tharmaraj, P; Sheela, C D; Anitha, C

2012-11-01

Transition metal complexes of various acetylacetone based ligands of the type ML [where M=Cu(II), Ni(II), Co(II); L=3-(aryl)-pentane-2,4-dione] have been synthesized. The structural features have been derived from their elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, (1)H NMR, Mass and ESR spectral studies. Conductivity measurements reveal that all the complexes are non-electrolytic in nature. Spectroscopic and other analytical data of the complexes suggest octahedral geometry for other metal(II) complexes. The redox behavior of the copper(II) complexes have been studied by cyclic voltammetry. The free ligands and their metal complexes have been screened for their in vitro biological activities against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus as well as the fungus Candida albicans by well diffusion method. The zone of inhibition value indicates that the most of the metal(II) complexes are found to possess increased activities compared to those of the free ligands. All synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation (SHG) efficiency of the ligands (L1-L3) was found to be considerable effect than that of urea and KDP (potassium dihydrogen phosphate). Copyright © 2012 Elsevier B.V. All rights reserved.

Synthesis and studies on Cu(II), Co(II), Ni(II) complexes of Knoevenagel β-diketone ligands

NASA Astrophysics Data System (ADS)

Sumathi, S.; Tharmaraj, P.; Sheela, C. D.; Anitha, C.

2012-11-01

Transition metal complexes of various acetylacetone based ligands of the type ML [where M = Cu(II), Ni(II), Co(II); L = 3-(aryl)-pentane-2,4-dione] have been synthesized. The structural features have been derived from their elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, 1H NMR, Mass and ESR spectral studies. Conductivity measurements reveal that all the complexes are non-electrolytic in nature. Spectroscopic and other analytical data of the complexes suggest octahedral geometry for other metal(II) complexes. The redox behavior of the copper(II) complexes have been studied by cyclic voltammetry. The free ligands and their metal complexes have been screened for their in vitro biological activities against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus as well as the fungus Candida albicans by well diffusion method. The zone of inhibition value indicates that the most of the metal(II) complexes are found to possess increased activities compared to those of the free ligands. All synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation (SHG) efficiency of the ligands (L1-L3) was found to be considerable effect than that of urea and KDP (potassium dihydrogen phosphate).

Synthesis, molecular properties estimations, and dual dopamine D2 and D3 receptor activities of Benzthiazole-based ligands.

NASA Astrophysics Data System (ADS)

Schübler, Moritz; Sadek, Bassem; Kottke, Tim; Weizel, Lilia; Stark, Holger

2017-09-01

Neurleptic drugs, e.g. aripiprazole, targeting the dopamine D2s and D3 receptors (D2sR and D3R) in the central nervous system are widely used in the treatment of several psychotic and neurodegenerative diseases. Therefore, a new series of benz[d]thiazole-based ligands (1-18) was synthesized by applying the bioisosteric approach derived from the selective D3Rs ligand BP-897 and its structurally related benz[d]imidazole derivatives. Herein, introduction of the benz[d]thiazole moiety was well tolerated by D2sR and D3R binding sites leading to antagonist affinities in the low nanomolar concentration range at both receptor subtypes. Further exploration of different substitution patterns at the benz[d]thiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D2sR and D3R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D2sR binding affinity as compared to the parent ligand BP-897, and improved physicochemical and drug-likeness properties of ligands 1-9. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogues (10-18). Accordingly, compound 7 showed in addition to high dual affinity at the D2sR and D3R (Ki (hD2SR) = 2.8 ± 0.8 nM; Ki (hD3R) = 3.0 ± 1.6 nM), promising clogS, clogP, LE (hD2sR, hD3R), LipE (hD2sR, hD3R), and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (4.4, 4.3), and 0.7, respectively. Also, the deaminated analogue 8 (Ki (hD2SR) = 3.2 ± 0.4 nM; Ki (hD3R) = 8.5 ± 2.2 nM) revealed clogS, clogP, LE (hD2sR, hD3R), LipE (hD2sR, hD3R) and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (3.9, 3.5), and 0.4, respectively. The results observed for the newly developed benz[d]thiazole-based ligands 1-18 provide clues for the diversity in structure activity relationships (SARs) at the D2sR and D3R subtypes.

Synthesis and photoluminescence properties of novel Schiff base type polymer-rare earth complexes containing furfural-based bidentate Schiff base ligands

NASA Astrophysics Data System (ADS)

Gao, Baojiao; Zhang, Dandan; Li, Yanbin

2018-03-01

Luminescent polymer-rare earth complexes are an important class of photoluminescence and electroluminescence materials. Via molecular design, two furfural-based bidentate Schiff base ligands, furfural-aniline (FA) type ligand and furfural-cyclohexylamine (FC) type ligand, were bonded on the side chains of polysulfone (PSF), respectively, forming two functionalized macromolecules, PSF-FA and PSF-FC. And then through respective coordination reactions of the two functionalized macromolecules with Eu(Ⅲ) ion and Tb(Ⅲ) ion, novel luminescent binary and ternary (with 1,10-phenanthroline as the second ligand) polymer-rare earth complexes were synthesized. For these complexes, on basis of the characterization of their chemical structures, they photoluminescence properties were main researched, and the relationship between their luminescent properties and structures was explored. The experimental results show that the complexes coming from PSF-FA and Eu(Ⅲ) ion including binary and ternary complexes emit strong red luminescence, indicating that the bonded bidentate Schiff base ligand FA can sensitize the fluorescence emission of Eu(III) ion. While the complexes coming from PSF-FC and Tb(Ⅲ) ion produce green luminescence, displaying that the bonded bidentate Schiff base ligand FC can sensitize the fluorescence emission of Tb(Ⅲ) ion. The fluorescence emission intensities of the ternary complexes were stronger than that of binary complexes, reflecting the important effect of the second ligand. The fluorescence emission of the solid film of complexes is much stronger than that of the solutions of complexes. Besides, by comparison, it is found that the furfural (as a heteroaromatic compound)-based Schiff base type polymer-rare earth complexes have stronger fluorescence emission and higher energy transfer efficiency than salicylaldehyde (as a common aromatic compound)-based Schiff base type polymer-rare earth complexes.

Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

PubMed Central

Sauguet, Ludovic; Howard, Rebecca J.; Malherbe, Laurie; Lee, Ui S.; Corringer, Pierre-Jean; Harris, R. Adron; Delarue, Marc

2014-01-01

Ethanol alters nerve signalling by interacting with proteins in the central nervous system, particularly pentameric ligand-gated ion channels. A recent series of mutagenesis experiments on Gloeobacter violaceus ligand-gated ion channel, a prokaryotic member of this family, identified a single-site variant that is potentiated by pharmacologically relevant concentrations of ethanol. Here we determine crystal structures of the ethanol-sensitized variant in the absence and presence of ethanol and related modulators, which bind in a transmembrane cavity between channel subunits and may stabilize the open form of the channel. Structural and mutagenesis studies defined overlapping mechanisms of potentiation by alcohols and anaesthetics via the inter-subunit cavity. Furthermore, homology modelling show this cavity to be conserved in human ethanol-sensitive glycine and GABA(A) receptors, and to involve residues previously shown to influence alcohol and anaesthetic action on these proteins. These results suggest a common structural basis for ethanol potentiation of an important class of targets for neurological actions of ethanol. PMID:23591864

Structural Sensitivity of a Prokaryotic Pentameric Ligand-gated Ion Channel to Its Membrane Environment*

PubMed Central

Labriola, Jonathan M.; Pandhare, Akash; Jansen, Michaela; Blanton, Michael P.; Corringer, Pierre-Jean; Baenziger, John E.

2013-01-01

Although the activity of the nicotinic acetylcholine receptor (nAChR) is exquisitely sensitive to its membrane environment, the underlying mechanisms remain poorly defined. The homologous prokaryotic pentameric ligand-gated ion channel, Gloebacter ligand-gated ion channel (GLIC), represents an excellent model for probing the molecular basis of nAChR sensitivity because of its high structural homology, relative ease of expression, and amenability to crystallographic analysis. We show here that membrane-reconstituted GLIC exhibits structural and biophysical properties similar to those of the membrane-reconstituted nAChR, although GLIC is substantially more thermally stable. GLIC, however, does not possess the same exquisite lipid sensitivity. In particular, GLIC does not exhibit the same propensity to adopt an uncoupled conformation where agonist binding is uncoupled from channel gating. Structural comparisons provide insight into the chemical features that may predispose the nAChR to the formation of an uncoupled state. PMID:23463505

What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?

PubMed Central

Michino, Mayako; Beuming, Thijs; Donthamsetti, Prashant; Newman, Amy Hauck; Javitch, Jonathan A.

2015-01-01

G protein–coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy. PMID:25527701

Assembly of 4-, 6- and 8-connected Cd(II) pseudo-polymorphic coordination polymers: Synthesis, solvent-dependent structural variation and properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zhao-Hao; Xue, Li-Ping, E-mail: lpxue@163.com; Miao, Shao-Bin

2016-08-15

The reaction of Cd(NO{sub 3}){sub 2}·4H{sub 2}O, 2,5-thiophenedicarboxylic acid (H{sub 2}tdc) and 1,2-bis(imidazol-1′-yl)methane (bimm) by modulating solvent systems yielded three highly connected pseudo-polymorphic coordination polymers based on different dinuclear [Cd{sub 2}(CO{sub 2}){sub 2}] subunits bridged by carboxylate groups. Single crystal structural analyses reveal structural variation from 4-connected 2D sql layer, 6-connected 2-fold interpenetrated 3D pcu to 8-connected 3D bcu-type network in compounds 1–3. The structural dissimilarity in the structures dependent on the coordination environments of Cd(II) ions and linking modes of mixed ligand influenced by different solvent systems during the synthesis process. Moreover, thermogravimetric and photoluminescence behaviors of 1–3 weremore » also investigated for the first time, and all the complexes emit blue luminescence in the solid state. - Graphical abstract: Key Topic. Different solvent systems modulated three Cd(II) pseudo-polymorphic coordination polymers based on thiophene-2,5-dicarboxylate and 1,2-bis(imidazol-1′-yl)methane mixed ligands. Display Omitted - Highlights: • Three solvent-dependent Cd(II) pseudo-polymorphic coordination polymers have been synthesized. • Structural variation from 4-connected 2D layer, 6-connected 2-fold interpenetrated 3D net to 8-connected 3D net. • All complexes emit blue luminescence.« less

Syntheses, crystal structures, and properties of four complexes based on polycarboxylate and imidazole ligands

NASA Astrophysics Data System (ADS)

Qiao, Rui; Chen, Shui-Sheng; Sheng, Liang-Quan; Yang, Song; Li, Wei-Dong

2015-08-01

Four metal-organic coordination polymers [Zn(HL)(H2O)]·4H2O (1), [Zn(HL)(L1)]·4H2O (2), [Cu(HL)(H2O)]·3H2O (3) and [Cu(HL)(L1)]·5H2O (4) were synthesized by reactions of the corresponding metal(II) salts with semirigid polycarboxylate ligand (5-((4-carboxypiperidin-1-yl)methyl)isophthalic acid hydrochloride, H3L·HCl) or auxiliary ligand (1,4-di(1H-imidazol-4-yl)benzene, L1). The structures of the compounds were characterized by elemental analysis, FT-IR spectroscopy and single-crystal X-ray diffraction. The use of auxiliary ligand L1 has great influence on the structures of two pairs of complexes 1, 2 and 3, 4. Complex 1 is a uninodal 3-connected rare 2-fold interpenetrating ZnSc net with a Point (Schlafli) symbol of (103) while 2 is a one-dimensional (1D) ladder structure. Compound 3 features a two-dimensional (2D) honeycomb network with typical 63-hcb topology, while 4 is 2D network with (4, 4) sql topology based on binuclear CuII subunits. The non-covalent bonding interactions such as hydrogen bonds, π···π stacking and C-H···π exist in complexes 1-4, which contributes to stabilize crystal structure and extend the low-dimensional entities into high-dimensional frameworks. And the photoluminescent property of 1 and 2 and gas sorption property of 4 have been investigated.

High Valent Manganese and Cobalt Complexes of Oxidatively Robust Nitrogen and Oxygen Donor Ligands.

NASA Astrophysics Data System (ADS)

Gordon-Wylie, Scott Wallace

1995-01-01

The focus of this thesis is to extend the range of ligands that satisfy the Collins criteria through a program of organic synthesis, and to apply the resulting high valent metal ligand complexes to the solution of current problems in structural inorganic chemistry, solid state chemistry (with a particular emphasis on magnetic interactions in solids) and to homogeneous and heterogeneous catalysis. Notable achievements along these directions to date are: (i) A streamlined synthesis of diamide dialkoxide and diamide diphenoxide acyclic ligands which allows for a wide range of both electron withdrawing and electron donating substituents to be incorporated into the ligand framework. (ii) The first example of a LMn(V)O species stable enough to be crystallographically characterized was obtained, utilizing the acyclic ligands of (i). (iii) Catalytic O-atom transfer oxidations utilizing acyclic ligands from (i) have been performed. Planar Co(III) complexes of these ligands can catalyze O-atom transfers, ^1 with 30-50 turnovers, including enantioselective ones,^2 implicating that the ligands remain at least partially intact during the catalytic process. (iv) Unusual magnetic ordering has been observed in an infinite linear chain of S = 2 LMn(III) centers, in collaboration with Edmund P. Day. (v) Ferromagnetic exchange has been obtained in a ((LCo(III)) _3Co(II)) ^{-} complex^4 Magnetic model building in collaboration with Gordon Yee and Emile Bominaar has led to an understanding of the magnetic data suitable for publication.^5 (vi) Adaptation of a range of electronic substituents (see (i)) into a macrocyclic framework^7 allows for the preparation of hydrolytically and oxidatively stable high valent metal complexes. The presence of a range of electronic substituents further allows redox potentials for a single (LM) ^{rm n+}/(LM) ^{(rm n+1)+ } oxidation process to be tuned over a range that spans ca. 1 V. (vii) Initial linear syntheses for these macrocycles involved the use of

Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.

PubMed

Männel, Barbara; Jaiteh, Mariama; Zeifman, Alexey; Randakova, Alena; Möller, Dorothee; Hübner, Harald; Gmeiner, Peter; Carlsson, Jens

2017-10-20

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D 2 dopamine receptor (D 2 R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D 2 R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D 2 R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D 2 R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and β-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated β-arrestin recruitment (EC 50 = 320 nM, E max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

PubMed

Duffy, Bryan C; Liu, Shuang; Martin, Gregory S; Wang, Ruifang; Hsia, Ming Min; Zhao, He; Guo, Cheng; Ellis, Michael; Quinn, John F; Kharenko, Olesya A; Norek, Karen; Gesner, Emily M; Young, Peter R; McLure, Kevin G; Wagner, Gregory S; Lakshminarasimhan, Damodharan; White, Andre; Suto, Robert K; Hansen, Henrik C; Kitchen, Douglas B

2015-07-15

Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1). Copyright © 2015 Elsevier Ltd. All rights reserved.

Ligand induced structural isomerism in phosphine coordinated gold clusters revealed by ion mobility mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ligare, Marshall R.; Baker, Erin S.; Laskin, Julia

Structural isomerism in ligated gold clusters is revealed using electrospray ionization ion mobility spectrometry mass spectrometry. Phosphine ligated Au8 clusters are shown to adopt more “extended” type structures with increasing exchange of methyldiphenylphosphine (MePPh2) for triphenylphosphine (PPh3). These ligand-dependant structure-property relationships are critical to applications of clusters in catalysis.

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

NASA Astrophysics Data System (ADS)

Evensen, Erik; Joseph-McCarthy, Diane; Weiss, Gregory A.; Schreiber, Stuart L.; Karplus, Martin

2007-07-01

Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these "random" methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.

Synthesis of di-functional ligand and fluorescently labeling SiO2 microspheres

NASA Astrophysics Data System (ADS)

Chen, Kexu; Kang, Ming; Liu, Min; Shen, Simin; Sun, Rong

2018-05-01

In order to complete the fluorescent labeling of SiO2 microspheres, a kind of di-functional ligand was synthesized and purified, which could not only coordinate rare earth ions but also react with the active groups to bond host materials with an alkoxysilane groups. Fourier transform infrared spectroscopy (FT-IR), 1H NMR spectra, MS spectra, field emission scanning electron microscope (FESEM), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS) and luminescence spectrophotometer were used to study the structure of di-functional ligand and properties of fluorescent coupling agent and fluorescent labeled SiO2 microspheres. The optimal experiment conditions were acquired as follows: molar ratio as 1: 4 (MDBM: MICPTES), reaction time at 6 h and reaction temperature as 65 °C (yield up to 40%) through the orthogonal experiment and purification process. The results indicated that fluorescent coupling agent presented red photoluminesence of Eu3+ ions at 610 nm, and the absolute quantum yield was 11%. On the other hand, the hydrolysis of the coupling agent reacted on the surface of SiO2 microspheres and presented fluorescent labeling homogeneously.

Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics.

PubMed

Howard, Rebecca J; Trudell, James R; Harris, R Adron

2014-01-01

Alcohols and other anesthetic agents dramatically alter neurologic function in a wide range of organisms, yet their molecular sites of action remain poorly characterized. Pentameric ligand-gated ion channels, long implicated in important direct effects of alcohol and anesthetic binding, have recently been illuminated in renewed detail thanks to the determination of atomic-resolution structures of several family members from lower organisms. These structures provide valuable models for understanding and developing anesthetic agents and for allosteric modulation in general. This review surveys progress in this field from function to structure and back again, outlining early evidence for relevant modulation of pentameric ligand-gated ion channels and the development of early structural models for ion channel function and modulation. We highlight insights and challenges provided by recent crystal structures and resulting simulations, as well as opportunities for translation of these newly detailed models back to behavior and therapy.

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

PubMed Central

Trudell, James R.; Harris, R. Adron

2014-01-01

Alcohols and other anesthetic agents dramatically alter neurologic function in a wide range of organisms, yet their molecular sites of action remain poorly characterized. Pentameric ligand-gated ion channels, long implicated in important direct effects of alcohol and anesthetic binding, have recently been illuminated in renewed detail thanks to the determination of atomic-resolution structures of several family members from lower organisms. These structures provide valuable models for understanding and developing anesthetic agents and for allosteric modulation in general. This review surveys progress in this field from function to structure and back again, outlining early evidence for relevant modulation of pentameric ligand-gated ion channels and the development of early structural models for ion channel function and modulation. We highlight insights and challenges provided by recent crystal structures and resulting simulations, as well as opportunities for translation of these newly detailed models back to behavior and therapy. PMID:24515646

Theoretical studies of molecular structure, electronic structure, spectroscopic properties and the ancillary ligand effect: a comparison of tris-chelate ML3-type and ML2X-type species for gallium(III) complexes with N,O-donor phenolic ligand, 2-(2-hydroxyphenyl)benzothiazole.

PubMed

Tong, Yi-Ping; Lin, Yan-Wen

2011-02-01

Two Ga(III) complexes with main ligand, 2-(2-hydroxyphenyl)benzothiazole (HL'), namely mixed-ligand ML2X-type [GaL'2X'] (1) (HX'=acetic acid, as ancillary ligand) and the meridianal tris-chelate [GaL'3] (2) have been investigated by the density functional theory (DFT/TDDFT) level calculations. Both 1 and 2 can be presented as a similar "mixed-ligand ML2X-type" species. The molecular geometries, electronic structures, metal-ligand bonding property of Ga-O (N) (main ligand), Ga-O (N) (ancillary ligand) interactions, and the ancillary ligand effect on their HOMO-LUMO gap, their absorption/emission property, and their absorption/emission wavelengths/colors for them have been discussed in detail based on the orbital interactions, the partial density of states (PDOS), and so on. The current investigation also indicates that it is quite probable that by introduction of different ancillary ligands, a series of new mixed-ligand ML2X-type complexes for group 13 metals can be designed with their absorption/emission property and the absorption/emission wavelengths and colors being tuned. Copyright © 2011 Elsevier B.V. All rights reserved.

Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein.

PubMed Central

Bain, L J; McLachlan, J B; LeBlanc, G A

1997-01-01

The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increased efflux of the compounds by P-glycoprotein (P-gp) or related transporters. An extensive xenobiotic database, consisting primarily of pesticides, was utilized in this study to identify molecular characteristics that render a xenobiotic susceptible to transport by or inhibition of P-gp. Transport substrates were differentiated by several molecular size/shape parameters, lipophilicity, and hydrogen bonding potential. Electrostatic features differentiated inhibitory ligands from compounds not catagorized as transport substrates and that did no interact with P-gp. A two-tiered system was developed using the derived structure-activity relationships to identify P-gp transport substrates and inhibitory ligands. Prediction accuracy of the approach was 82%. We then validated the system using six additional pesticides of which tow were predicted to be P-gp inhibitors and four were predicted to be noninteractors, based upon the structure-activity analyses. Experimental determinations using cells transfected with the human MDR1 gene demonstrated that five of the six pesticides were properly catagorized by the structure-activity analyses (83% accuracy). Finally, structure-activity analyses revealed that among P-gp inhibitors, relative inhibitory potency can be predicted based upon the surface area or volume of the compound. These results demonstrate that P-gp transport substrates and inhibitory ligands can be distinguished using molecular characteristics. Molecular characteristics of transport substrates suggest that P-gp may function in the elimination of hydroxylated metabolites of xenobiotics. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 1. E Figure 1. F Figure 1. G Figure 1. H Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 3. A Figure 3. B PMID:9347896

Biocatalyzed Regioselective Synthesis in Undergraduate Organic Laboratories: Multistep Synthesis of 2-Arachidonoylglycerol

ERIC Educational Resources Information Center

Johnston, Meghan R.; Makriyannis, Alexandros; Whitten, Kyle M.; Drew, Olivia C.; Best, Fiona A.

2016-01-01

In order to introduce the concepts of biocatalysis and its utility in synthesis to organic chemistry students, a multistep synthesis of endogenous cannabinergic ligand 2-arachidonoylglycerol (2-AG) was tailored for use as a laboratory exercise. Over four weeks, students successfully produced 2-AG, purifying and characterizing products at each…

Coordination polymers with the chiral ligand N-p-tolylsulfonyl-L-glutamic acid: Influence of metal ions and different bipyridine ligands on structural chirality

DOE Office of Scientific and Technical Information (OSTI.GOV)

He Rong; Song Huihua, E-mail: songhuihua@mail.hebtu.edu.c; Wei Zhen

2010-09-15

Four new polymers, namely [Ni(-tsgluO)(2,4'-bipy){sub 2}(H{sub 2}O){sub 2}]{sub n}.5nH{sub 2}O (1), [Co(-tsgluO)(2,4'-bipy){sub 2}(H{sub 2}O){sub 2}]{sub n}.5nH{sub 2}O (2), [Ni(-tsgluO)(4,4'-bipy)]{sub n}.0.5nH{sub 2}O (3), and [Co(-tsgluO)(4,4'-bipy)]{sub n}.0.5nH{sub 2}O (4), where tsgluO{sup 2-}=(+)-N-p-tolylsulfonyl-L-glutamate dianion, 2,4'-bipy=2,4'-bipyridine, and 4,4'-bipy=4,4'-bipyridine, have been prepared and structurally characterized. Compounds 1 and 2 are isostructural and mononuclear, and crystallize in the acentric monoclinic space group Cc, forming 1D chain structures. Compound 3 is also mononuclear, but crystallizes in the chiral space group P2{sub 1}, forming a homochiral 2D architecture. In contrast to the other complexes, compound 4 crystallizes in the space group P-1 and is composed of binuclear [Co{submore » 2}O{sub 6}N{sub 2}]{sub n}{sup 4-} units, which give rise to a 2D bilayer framework. Moreover, compounds 1, 2, and 4 self-assemble to form 3D supramolecular structures through {pi}-{pi} stacking and hydrogen-bonding interactions, while compound 3 is further hydrogen-bonded to form 3D frameworks. We have demonstrated the influence of the central metal and bipyridine ligands on the framework chirality of the coordination complexes. - Graphical abstract: Four novel polymers based on a chiral ligand were prepared and structurally characterized; it represents the first series of investigations about the effect of central metals and bipyridine ligands on framework chirality.« less

PLI: a web-based tool for the comparison of protein-ligand interactions observed on PDB structures.

PubMed

Gallina, Anna Maria; Bisignano, Paola; Bergamino, Maurizio; Bordo, Domenico

2013-02-01

A large fraction of the entries contained in the Protein Data Bank describe proteins in complex with low molecular weight molecules such as physiological compounds or synthetic drugs. In many cases, the same molecule is found in distinct protein-ligand complexes. There is an increasing interest in Medicinal Chemistry in comparing protein binding sites to get insight on interactions that modulate the binding specificity, as this structural information can be correlated with other experimental data of biochemical or physiological nature and may help in rational drug design. The web service protein-ligand interaction presented here provides a tool to analyse and compare the binding pockets of homologous proteins in complex with a selected ligand. The information is deduced from protein-ligand complexes present in the Protein Data Bank and stored in the underlying database. Freely accessible at http://bioinformatics.istge.it/pli/.

In situ ligand synthesis with the UO22+ cation under hydrothermal conditions

NASA Astrophysics Data System (ADS)

Frisch, Mark; Cahill, Christopher L.

2007-09-01

A novel uranium (VI) coordination polymer, (UO 2) 2(C 2O 4)(C 5H 6NO 3) 2 ( 1), has been prepared under the hydrothermal reaction of uranium nitrate hexahydrate and L-pyroglutamic acid. Compound 1 (monoclinic, C2/ c, a=22.541(6) Å, b=5.7428(15) Å, c=15.815(4) Å, β=119.112(4)°, Z=4, R1=0.0237, w R2=0.0367) consists of uranium pentagonal bipyramids linked via L-pyroglutamate and oxalate anions to form an overall two-dimensional (2D) structure. With the absence of oxalic acid within the starting materials, the oxalate anions are hypothesized to form in situ whereby decarboxylation of L-pyroglutamic acid occurs followed by coupling of CO 2 to form the oxalate linkages as observed in the crystal structure. Addition of copper (II) to this system appears to promote oxalate formation in that synthetic moolooite (Cu(C 2O 4)· nH 2O; 0⩽ n⩽1) and a known uranyl oxalate [(UO 2) 2(C 2O 4)(OH) 2(H 2O) 2·H 2O], co-crystallize in significant quantity. Compound 1 exhibits the characteristic uranyl emission spectrum upon either direct uranyl excitation or ligand excitation, the latter of which shows an increase in relative intensity. This subsequent increase in the intensity indicates an energy transfer from the ligand to the uranyl cations thus illustrating an example of the antenna effect in the solid state.

Synthesis, crystal structure and cytotoxic activity of ruthenium(II) piano-stool complex with N,N-chelating ligand

NASA Astrophysics Data System (ADS)

Rogala, Patrycja; Jabłońska-Wawrzycka, Agnieszka; Kazimierczuk, Katarzyna; Borek, Agnieszka; Błażejczyk, Agnieszka; Wietrzyk, Joanna; Barszcz, Barbara

2016-12-01

A mononuclear compound of the general formula [(η6-p-cymene)RuIICl(2,2‧-PyBIm)]PF6 has been synthesized from a bidentate N,N-donor ligand, viz. 2,-(2‧-pyridyl)benzimidazole (2,2‧-PyBIm) and the corresponding chloro-complex [(η6-p-cymene)Ru(μ-Cl)Cl]2 (precursor). The isolated coordination compound was characterized by IR, UV-vis and 1H, 13C NMR spectroscopies. The single crystal X-ray analysis of the complex reveals that the asymmetric part of the unit cell consists of two symmetrically independent, [(η6-p-cymene)RuCl(2,2‧-PyBIm)]+ cationic complexes. Each cation exhibits a pseudo-octahedral three-legged piano-stool geometry, in which three "legs" are occupied by one chloride ion and two nitrogen donor atoms of the chelating ligand 2,2‧-PyBIm. The Hirshfeld surface analysis of obtained complex was determined, too. The ionic nature of the compound is identified by a strong band at around 830 cm-1 due to the νP-F stretching mode of the PF6- counter ion. The electronic spectrum of this monomeric complex displays high intensity bands in the ultraviolet region assignable to π→π*/n→π* transitions, as well as a band attributable to the metal-to-ligand charge transfer (MLCT) dπ(Ru)→π*(L) transition. Additionally, the complex has been screened for its cytotoxicity against three human cancer lines: non-small cell lung carcinoma (A549), colon adenocarcinoma (HT29) and breast adenocarcinoma (MCF-7) as well as normal mice fibroblast cells (BALB/3T3). The complex demonstrated a moderate antiproliferative activity against the cell lines tested.

An in vitro and in vivo investigation of bivalent ligands that display preferential binding and functional activity for different melanocortin receptor homodimers

PubMed Central

Lensing, Cody J.; Freeman, Katie T.; Schnell, Sathya M.; Adank, Danielle N.; Speth, Robert C.; Haskell-Luevano, Carrie

2017-01-01

Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 (CJL-1-140) possessed a functional profile that was unique from its monovalent counterparts providing evidence of the discrete effects of bivalent ligands. Lead compound 7 (CJL-1-87) significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects. PMID:26959173

New multirate sampled-data control law structure and synthesis algorithm

NASA Technical Reports Server (NTRS)

Berg, Martin C.; Mason, Gregory S.; Yang, Gen-Sheng

1992-01-01

A new multirate sampled-data control law structure is defined and a new parameter-optimization-based synthesis algorithm for that structure is introduced. The synthesis algorithm can be applied to multirate, multiple-input/multiple-output, sampled-data control laws having a prescribed dynamic order and structure, and a priori specified sampling/update rates for all sensors, processor states, and control inputs. The synthesis algorithm is applied to design two-input, two-output tip position controllers of various dynamic orders for a sixth-order, two-link robot arm model.

Indole synthesis by conjugate addition of anilines to activated acetylenes and an unusual ligand-free copper(II)-mediated intramolecular cross-coupling.

PubMed

Gao, Detian; Back, Thomas G

2012-11-12

A versatile new synthesis of indoles was achieved by the conjugate addition of N-formyl-2-haloanilines to acetylenic sulfones, ketones, and esters followed by a copper-catalyzed intramolecular C-arylation. The conjugate addition step was conducted under exceptionally mild conditions at room temperature in basic, aqueous DMF. Surprisingly, the C-arylation was performed most effectively by employing copper(II) acetate as the catalyst in the absence of external ligands, without the need for protection from air or water. An unusual feature of this process, for the case of acetylenic ketones, is the ability of the initial conjugate-addition product to serve as a ligand for the catalyst, which enables it to participate in the catalysis of its further transformation to the final indole product. Mechanistic studies, including EPR experiments, indicated that copper(II) is reduced to the active copper(I) species by the formate ion that is produced by the base-catalyzed hydrolysis of DMF. This process also served to recycle any copper(II) that was produced by the adventitious oxidation of copper(I), thereby preventing deactivation of the catalyst. Several examples of reactions involving acetylenic sulfones attached to a modified Merrifield resin demonstrated the feasibility of solid-phase synthesis of indoles by using this protocol, and tricyclic products were obtained in one pot by employing acetylenic sulfones that contain chloroalkyl substituents. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Molecular mechanism of ligand recognition by membrane transport protein, Mhp1

PubMed Central

Simmons, Katie J; Jackson, Scott M; Brueckner, Florian; Patching, Simon G; Beckstein, Oliver; Ivanova, Ekaterina; Geng, Tian; Weyand, Simone; Drew, David; Lanigan, Joseph; Sharples, David J; Sansom, Mark SP; Iwata, So; Fishwick, Colin WG; Johnson, A Peter; Cameron, Alexander D; Henderson, Peter JF

2014-01-01

The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5-helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1. PMID:24952894

Importance of ligand reorganization free energy in protein-ligand binding-affinity prediction.

PubMed

Yang, Chao-Yie; Sun, Haiying; Chen, Jianyong; Nikolovska-Coleska, Zaneta; Wang, Shaomeng

2009-09-30

Accurate prediction of the binding affinities of small-molecule ligands to their biological targets is fundamental for structure-based drug design but remains a very challenging task. In this paper, we have performed computational studies to predict the binding models of 31 small-molecule Smac (the second mitochondria-derived activator of caspase) mimetics to their target, the XIAP (X-linked inhibitor of apoptosis) protein, and their binding affinities. Our results showed that computational docking was able to reliably predict the binding models, as confirmed by experimentally determined crystal structures of some Smac mimetics complexed with XIAP. However, all the computational methods we have tested, including an empirical scoring function, two knowledge-based scoring functions, and MM-GBSA (molecular mechanics and generalized Born surface area), yield poor to modest prediction for binding affinities. The linear correlation coefficient (r(2)) value between the predicted affinities and the experimentally determined affinities was found to be between 0.21 and 0.36. Inclusion of ensemble protein-ligand conformations obtained from molecular dynamic simulations did not significantly improve the prediction. However, major improvement was achieved when the free-energy change for ligands between their free- and bound-states, or "ligand-reorganization free energy", was included in the MM-GBSA calculation, and the r(2) value increased from 0.36 to 0.66. The prediction was validated using 10 additional Smac mimetics designed and evaluated by an independent group. This study demonstrates that ligand reorganization free energy plays an important role in the overall binding free energy between Smac mimetics and XIAP. This term should be evaluated for other ligand-protein systems and included in the development of new scoring functions. To our best knowledge, this is the first computational study to demonstrate the importance of ligand reorganization free energy for the

Glucagon-Like Peptide-1 Receptor Ligand Interactions: Structural Cross Talk between Ligands and the Extracellular Domain

PubMed Central

West, Graham M.; Willard, Francis S.; Sloop, Kyle W.; Showalter, Aaron D.; Pascal, Bruce D.; Griffin, Patrick R.

2014-01-01

Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands. PMID:25180755

Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni

2014-07-01

To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL{sub 2}(H{sub 2}O){sub 2}]{sub n}·2nH{sub 2}O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H{sub 2}adbc), terephthalic acid (H{sub 2}tpa), thiophene-2,5-dicarboxylic acid (H{sub 2}tdc) and 1,4-benzenedithioacetic acid (H{sub 2}bdtc), four 3D structures [Co{sub 2}L{sub 2}(adbc)]{sub n}·nH{sub 2}O (2), [Co{sub 2}L{sub 2}(tpa)]{sub n}more » (3), [Co{sub 2}L{sub 2}(tdc)]{sub n} (4), [Co{sub 2}L{sub 2}(bdtc)(H{sub 2}O)]{sub n} (5) were obtained, respectively. It can be observed from the architectures of 1–5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated. - Graphical abstract: The structural differences show that the ancillary ligands have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. - Highlights: • Five new Co(II) coordination polymers have been synthesized by solvothermal reactions based on 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL). • The long-flexible ligand (HL) is a good candidate to produce interpenetrating architectures. • The secondary dicarboxylic acid ligands play important roles in the spatial connective fashions and the formation of various dimensional compounds. • The magnetism studies show that both 2 and 5 exhibit antiferromagnetic interactions.« less

Scanning the potential energy surface for synthesis of dendrimer-wrapped gold clusters: design rules for true single-molecule nanostructures.

PubMed

Thompson, Damien; Hermes, Jens P; Quinn, Aidan J; Mayor, Marcel

2012-04-24

The formation of true single-molecule complexes between organic ligands and nanoparticles is challenging and requires careful design of molecules with size, shape, and chemical properties tailored for the specific nanoparticle. Here we use computer simulations to describe the atomic-scale structure, dynamics, and energetics of ligand-mediated synthesis and interlinking of 1 nm gold clusters. The models help explain recent experimental results and provide insight into how multidentate thioether dendrimers can be employed for synthesis of true single-ligand-nanoparticle complexes and also nanoparticle-molecule-nanoparticle "dumbbell" nanostructures. Electronic structure calculations reveal the individually weak thioether-gold bonds (325 ± 36 meV), which act collectively through the multivalent (multisite) anchoring to stabilize the ligand-nanoparticle complex (∼7 eV total binding energy) and offset the conformational and solvation penalties involved in this "wrapping" process. Molecular dynamics simulations show that the dendrimer is sufficiently flexible to tolerate the strained conformations and desolvation penalties involved in fully wrapping the particle, quantifying the subtle balance between covalent anchoring and noncovalent wrapping in the assembly of ligand-nanoparticle complexes. The computed preference for binding of a single dendrimer to the cluster reveals the prohibitively high dendrimer desolvation barrier (1.5 ± 0.5 eV) to form the alternative double-dendrimer structure. Finally, the models show formation of an additional electron transfer channel between nitrogen and gold for ligands with a central pyridine unit, which gives a stiff binding orientation and explains the recently measured larger interparticle distances for particles synthesized and interlinked using linear ligands with a central pyridine rather than a benzene moiety. The findings stress the importance of organic-inorganic interactions, the control of which is central to the

Synthesis and structural study of N-isopropenylbenzimidazolone

NASA Astrophysics Data System (ADS)

Mondieig, D.; Negrier, Ph.; Leger, J. M.; Lakhrissi, L.; El Assyry, A.; Lakhrissi, B.; Essassi, E. M.; Benali, B.; Boucetta, A.

2015-05-01

The synthesis and the crystal structure of the N-isopropenylbenzimidazolone (C10H10N2O) are presented. The synthesis was performed by Meth-Cohen method by reaction of o-phenylenediamine with ethyl acetoacetate in refluxed xylene. The single crystal structure was determined at room temperature by means of X-rays diffraction. The crystal system is monoclinic, with space group C2/c and eight molecules per unit cell. The unit cell dimensions are: a = 15.978(1) Å, b = 6.100(2) Å, c = 18.222(2) Å, β = 90.16(1)° and V = 1776.0(6) Å3.

Synthesis of a zinc(II) complex with hexadentate N4S2 donor thioether ligand: X-ray structure, DNA binding study and DFT computation

NASA Astrophysics Data System (ADS)

Mondal, Apurba Sau; Jana, Mahendra Sekhar; Manna, Chandan Kumar; Naskar, Rahul; Mondal, Tapan Kumar

2018-07-01

A new zinc(II) complex, [Zn(L)](ClO4) with hexadentate N4S2 donor azo-thioether ligand (HL) was synthesized and characterized by several spectroscopic techniques. The structure was confirmed by single crystal X-ray analysis. The interaction of the complex with CT DNA was investigated by UV-vis method and binding constant is found to be 6.6 × 104 M-1. Competitive binding titration with ethidium bromide (EB) by fluorescence titration method reveals that the complex efficiently displaces EB from EB-DNA system and the Stern-Volmer dynamic quenching constant, Ksv is found to be 2.6 × 104 M-1. DFT and TDDFT calculations were carried out to interpret the electronic structure and electronic spectra of the complex.

One- and two-dimensional divalent copper coordination polymers based on kinked organodiimine and long flexible aliphatic dicarboxylate ligands

NASA Astrophysics Data System (ADS)

Mallika Krishnan, Subhashree; Supkowski, Ronald M.; LaDuca, Robert L.

2008-11-01

Hydrothermal synthesis under acidic conditions has afforded a pair of divalent copper coordination polymers containing the kinked dipodal tethering organodiimine 4,4'-dipyridylamine (dpa) and flexible long-chain aliphatic dicarboxylate ligands. The new materials were characterized by single crystal X-ray structure determination, infrared spectroscopy, and thermogravimetric analysis. [CuCl(suberate) 0.5(dpa)] ( 1) manifests 1-D ladder-like motifs aggregated into 3-D through hydrogen bonding and copper-mediated supramolecular interactions. Extension of the aliphatic chain within the dicarboxylate ligand by one methylene unit resulted in {[Cu(azelate)(dpa)(H 2O)] · 3H 2O} ( 2), a (4,4) rhomboid grid 2-D coordination polymer encapsulating acyclic water molecule trimers.

Synthesis, characterization and biological investigations of novel Schiff base ligands containing imidazoline moiety and their Co(II) and Cu(II) complexes

NASA Astrophysics Data System (ADS)

Radha, V. P.; Jone Kirubavathy, S.; Chitra, S.

2018-08-01

Novel imidazoline based Schiff base ligands L1 and L2 were synthesized from o-phenylenediamine/o-aminophenol with creatinine. The ligands were complexed with Co(II) and Cu(II) by direct reaction with metal salts. The synthesized ligands and the metal complexes were characterized by elemental analysis, FT-IR, 1H NMR, mass, electronic, thermal analyses, conductivity and magnetic susceptibility measurements. The conductivity measurements showed the non-electrolytic nature of the complexes. The thermogravimetric analyses confirmed the presence of lattice and coordinated water molecules in the complexes. The DFT calculations were carried out at B3LYP/6-31G(d,p) level for the determination of the optimized structure of the ligands. The synthesized ligands and the metal complexes were screened for their antimicrobial activity against two gram positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger and Candida albicans). The outcomes revealed that the metal complexes showed pronounced activity than the ligands.

Flexible ligand docking using a genetic algorithm

NASA Astrophysics Data System (ADS)

Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

1995-04-01

Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

NMR structure calculation for all small molecule ligands and non-standard residues from the PDB Chemical Component Dictionary.

PubMed

Yilmaz, Emel Maden; Güntert, Peter

2015-09-01

An algorithm, CYLIB, is presented for converting molecular topology descriptions from the PDB Chemical Component Dictionary into CYANA residue library entries. The CYANA structure calculation algorithm uses torsion angle molecular dynamics for the efficient computation of three-dimensional structures from NMR-derived restraints. For this, the molecules have to be represented in torsion angle space with rotations around covalent single bonds as the only degrees of freedom. The molecule must be given a tree structure of torsion angles connecting rigid units composed of one or several atoms with fixed relative positions. Setting up CYANA residue library entries therefore involves, besides straightforward format conversion, the non-trivial step of defining a suitable tree structure of torsion angles, and to re-order the atoms in a way that is compatible with this tree structure. This can be done manually for small numbers of ligands but the process is time-consuming and error-prone. An automated method is necessary in order to handle the large number of different potential ligand molecules to be studied in drug design projects. Here, we present an algorithm for this purpose, and show that CYANA structure calculations can be performed with almost all small molecule ligands and non-standard amino acid residues in the PDB Chemical Component Dictionary.

Three 3D metal coordination polymers based on triazol-functionalized rigid ligand: Synthesis, topological structure and properties

NASA Astrophysics Data System (ADS)

Meng, Lingkun; Liu, Kang; Liang, Chen; Guo, Xiaolei; Han, Xu; Ren, Siyuan; Ma, Dingxuan; Li, Guanghua; Shi, Zhan; Feng, Shouhua

2018-02-01

By using a triazol-functionalized tricarboxylate, three novel metal coordination polymers, namely, [Zn2L(OH)]·0.5H2O (1), [Co2L(OH)(H2O)]·5.5H2O (2), [Cu2(HL)] (3) L = ［5-(3-(4-carboxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl)isophthalate］ were synthesized under hydrothermal reactions. All the compounds were characterized by element analysis, IR spectroscopy, thermogravimetric analysis, power X-ray diffrcation and single-crystal X-ray diffrcation. Structural analysis reveals that compounds 1 and 2 have 3D networks with flu topologies where rigid trizaol-functionalized ligands as 4-connected nodes and Zn4(COO)6 or Co4(COO)6 clusters serves as 8-connected secondary building units. Compound 3 has 3D network with pcu topology where Cu4(COO)4 clusters serve as 6-connected secondary building units. Gas adsorption studies reveal that desolvated compoud 1 exhibits high H2 absorption capacity at 77 K and highly selective separation abilities of CO2 and C3H8 over CH4 at room temperature. The results suggest that 1 has potential application in gas storage and separation. In addition, the magnetic properties of compound 2 were also investigated.

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands.

PubMed

Hubin, Timothy J; Amoyaw, Prince N-A; Roewe, Kimberly D; Simpson, Natalie C; Maples, Randall D; Carder Freeman, TaRynn N; Cain, Amy N; Le, Justin G; Archibald, Stephen J; Khan, Shabana I; Tekwani, Babu L; Khan, M O Faruk

2014-07-01

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development. Published by Elsevier Ltd.

How Does Amino Acid Ligand Modulate Au Core Structure and Characteristics in Peptide Coated Au Nanocluster?

PubMed

Li, Nan; Li, Xu; Zhao, Hongkang; Zhao, Lina

2018-03-01

The atomic structures and the corresponding physicochemical properties of peptide coated Au nanoclusters determine their distinctive biological targeting applications. To learn the modulation of amino acid ligand on the atomic structure and electronic characteristics of coated Au core is the fundamental knowledge for peptide coated Au nanocluster design and construction. Based on our recent coated Au nanocluster configuration study (Nanoscale, 2016, 8, 11454), we built the typically simplified Au13(Cys-Au-Cys) system to more clearly learn the basic modulation information of amino acid ligand on Au core by the density functional theory (DFT) calculations. There are two isomers as ligand adjacent bonding (Iso1) and diagonal bonding (Iso2) to Au13 cores. The geometry optimizations indicate the adjacent bonding Iso1 is more stable than Iso2. More important, the Au13 core of Iso1 distorts much more significantly than that of Iso2 by Cys-Au-Cys bonding through the root-mean-square deviation (RMSD) analysis, which modulate their electronic characteristics in different ways. In addition, the frontier molecular orbital results of Au13(Cys-Au-Cys) isomers confirm that the Au cores mainly determine the blue shifts of Au13(Cys-Au-Cys) systems versus the original Au13 core in their UV-visible absorption spectrum studies. The configuration of Au13 core performs deformation under Cys-Au-Cys ligand modulation to reach new stability with distinct atomic structure and electronic properties, which could be the theory basis for peptide coated AuNCs design and construction.

Synthesis for Structure Rewriting Systems

NASA Astrophysics Data System (ADS)

Kaiser, Łukasz

The description of a single state of a modelled system is often complex in practice, but few procedures for synthesis address this problem in depth. We study systems in which a state is described by an arbitrary finite structure, and changes of the state are represented by structure rewriting rules, a generalisation of term and graph rewriting. Both the environment and the controller are allowed to change the structure in this way, and the question we ask is how a strategy for the controller that ensures a given property can be synthesised.

Synthesis, characterization, spectroscopic and theoretical studies of new zinc(II), copper(II) and nickel(II) complexes based on imine ligand containing 2-aminothiophenol moiety

NASA Astrophysics Data System (ADS)

Shafaatian, Bita; Mousavi, S. Sedighe; Afshari, Sadegh

2016-11-01

New dimer complexes of zinc(II), copper(II) and nickel(II) were synthesized using the Schiff base ligand which was formed by the condensation of 2-aminothiophenol and 2-hydroxy-5-methyl benzaldehyde. This tridentate Schiff base ligand was coordinated to the metal ions through the NSO donor atoms. In order to prevent the oxidation of the thiole group during the formation of Schiff base and its complexes, all of the reactions were carried out under an inert atmosphere of argon. The X-ray structure of the Schiff base ligand showed that in the crystalline form the SH groups were oxidized to produce a disulfide Schiff base as a new double Schiff base ligand. The molar conductivity values of the complexes in dichloromethane implied the presence of non-electrolyte species. The fluorescence properties of the Schiff base ligand and its complexes were also studied in dichloromethane. The products were characterized by FT-IR, 1H NMR, UV/Vis spectroscopies, elemental analysis, and conductometry. The crystal structure of the double Schiff base was determined by single crystal X-ray diffraction. Furthermore, the density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d,p) level of theory for the determination of the optimized structures of Schiff base complexes.

Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures.

PubMed

Silvaroli, Josie A; Arne, Jason M; Chelstowska, Sylwia; Kiser, Philip D; Banerjee, Surajit; Golczak, Marcin

2016-04-15

Important in regulating the uptake, storage, and metabolism of retinoids, cellular retinol-binding protein 1 (CRBP1) is essential for trafficking vitamin A through the cytoplasm. However, the molecular details of ligand uptake and targeted release by CRBP1 remain unclear. Here we report the first structure of CRBP1 in a ligand-free form as well as ultra-high resolution structures of this protein bound to either all-trans-retinol or retinylamine, the latter a therapeutic retinoid that prevents light-induced retinal degeneration. Superpositioning of human apo- and holo-CRBP1 revealed major differences within segments surrounding the entrance to the retinoid-binding site. These included α-helix II and hairpin turns between β-strands βC-βD and βE-βF as well as several side chains, such as Phe-57, Tyr-60, and Ile-77, that change their orientations to accommodate the ligand. Additionally, we mapped hydrogen bond networks inside the retinoid-binding cavity and demonstrated their significance for the ligand affinity. Analyses of the crystallographic B-factors indicated several regions with higher backbone mobility in the apoprotein that became more rigid upon retinoid binding. This conformational flexibility of human apo-CRBP1 facilitates interaction with the ligands, whereas the more rigid holoprotein structure protects the labile retinoid moiety during vitamin A transport. These findings suggest a mechanism of induced fit upon ligand binding by mammalian cellular retinol-binding proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Synthesis, Characterization and the Corrosion Inhibition Study of Two Schiff Base Ligands Derived From Urea and Thiourea and Their Complexes with Cu(II) and Hg(II) Ions

NASA Astrophysics Data System (ADS)

Alwan, Wasan Mohammed

2018-05-01

The research includes synthesis of [L1] and [L2] Schiff base ligands by the reaction of vanillin with urea and thiourea respectively in 2:1 mol ratio. The two ligands were reacted with CuII ion in 1:2 mol ratio and HgII ion in 1:1 mol ratio. The prepared compounds have been identified by FTIR, U.V-Vis, 1H-NMR (L1, L2 and HgII complex) spectroscopies, microelemental analysis (C.H.N.S), magnetic susceptibility measurements, atomic absorption, chloride content along with conductivity and melting point measurements. According to applied characterization methods, the proposed general formulas of CuII and HgII complexes were [Cu2LnCl4] and [HgLnCl]Cl, respectively, (where n = 1, 2). The ability of corrosion inhibition with two ligands and their cupper complexes has been studied in diluted hydrochloric acid media.

Synthesis, structural characterization and DFT calculation on a square-planar Ni(II) complex of a compartmental Schiff base ligand

NASA Astrophysics Data System (ADS)

Biswas, Surajit; Dolai, Malay; Dutta, Arpan; Ali, Mahammad

2016-12-01

Reaction of a symmetric compartmental Schiff-base ligand, (H2L) with nickel(II) perchlorate hexahydrate in 1:1 M ratio in methanol gives rise to a mononuclear nickel(II) compound, NiL (1). The compound has been characterized by C, H, N microanalyses and UV-Vis spectra. The single crystal X-ray diffraction studies reveal a square planar geometry around the Ni(II) center. The compound crystallizes in monoclinic system with space group C2/c with a = 21.6425(6), b = 9.9481(3), c = 13.1958(4) Å, β = 107.728(2)°, V = 2706.16(14) Å3 and Z = 4. Ground state DFT optimization and TDDFT calculations on the ligand and complex were performed to get their UV-Vis spectral pattern.

Synthesis and structure of the heterobimetallic Yb(II) complex of composition L2Yb2LiI3 supported with the β-diketiminato ligand [L=Et2NCH2CH2NC(Me)CHC(Me)NCH2CH2NEt2

NASA Astrophysics Data System (ADS)

Nikiforov, Grigori B.; Roesky, Herbert W.; Vidovic, Denis; Magull, Jörg

2003-08-01

The heterobimetallic Yb(II) mixed ligand complex L2Yb2LiI31 has been prepared by the reaction of the lithium salt of the ligand L with the ytterbium diiodide. Compound 1 is characterized by single crystal X-ray structural analysis, multinuclear NMR and mass spectrometry. Complex 1 consists of LYbI and LLi units connected with the central Yb(1) atom. The latter is surrounded by the LYbI and LLi moieties in a sandwich like structure including two bridging iodine atoms. The NCCCN unsaturated system of the ligand in each of the units is almost planar and π coordinated to the Yb(1) atom. These two planar units are tilted to each other and the pendant arms of the β-diketiminato ligand in each moiety are bent. The metal atoms are located out of the NCCCN plane of the ligands and the three metal atoms in complex 1 form almost a straight line.

Synthesis and structural characterization of dioxomolybdenum and dioxotungsten hydroxamato complexes and their function in the protection of radiation induced DNA damage.

PubMed

Paul, Shiv Shankar; Selim, Md; Saha, Abhijit; Mukherjea, Kalyan K

2014-02-21

The synthesis and structural characterization of two novel dioxomolybdenum(VI) (1) and dioxotungsten(VI) (2) complexes with 2-phenylacetylhydroxamic acid (PAHH) [M(O)2(PAH)2] [M = Mo, W] have been accomplished. The dioxomolybdenum(VI) and dioxotungsten(VI) moiety is coordinated by the hydroxamate group (-CONHO(-)) of the 2-phenylacetylhydroxamate (PAH) ligand in a bi-dentate fashion. In both the complexes the PAHH ligand is coordinated through oxygen atoms forming a five membered chelate. The hydrogen atom of N-H of the hydroxamate group is engaged in intermolecular H-bonding with the carbonyl oxygen of another coordinated hydroxamate ligand, thereby forming an extended 1D chain. The ligand as well as both the complexes exhibit the ability to protect from radiation induced damage both in CTDNA as well as in pUC19 plasmid DNA. As the damage to DNA is caused by the radicals generated during radiolysis, its scavenging imparts protection from the damage to DNA. To understand the mechanism of protection, binding affinities of the ligand and the complex with DNA were determined using absorption and emission spectral studies and viscosity measurements, whereby the results indicate that both the complexes and the hydroxamate ligand interact with calf thymus DNA in the minor groove. The intrinsic binding constants, obtained from UV-vis studies, are 7.2 × 10(3) M(-1), 5.2 × 10(4) M(-1) and 1.2 × 10(4) M(-1) for the ligand and complexes 1 and 2 respectively. The Stern-Volmer quenching constants obtained from a luminescence study for both the complexes are 5.6 × 10(4) M(-1) and 1.6 × 10(4) M(-1) respectively. The dioxomolybdenum(VI) complex is found to be a more potent radioprotector compared to the dioxotungsten(VI) complex and the ligand. Radical scavenging chemical studies suggest that the complexes have a greater ability to scavenge both the hydroxyl as well as the superoxide radicals compared to the ligand. The free radical scavenging ability of the ligand and the

Crystallization of bi-functional ligand protein complexes.

PubMed

Antoni, Claudia; Vera, Laura; Devel, Laurent; Catalani, Maria Pia; Czarny, Bertrand; Cassar-Lajeunesse, Evelyn; Nuti, Elisa; Rossello, Armando; Dive, Vincent; Stura, Enrico Adriano

2013-06-01

Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects. Copyright © 2013 Elsevier Inc. All rights reserved.

Hydrothermal synthesis, crystal structures, and enantioselective adsorption property of bis(L-histidinato)nickel(II) monohydrate

NASA Astrophysics Data System (ADS)

Ramos, Christian Paul L.; Conato, Marlon T.

2018-05-01

Despite the numerous researches in metal-organic frameworks (MOFs), there are only few reports on biologically important amino acids, histidine in particular, on its use as bridging ligand in the construction of open-framework architectures. In this work, hydrothermal synthesis was used to prepare a compound based on Ni2+ and histidine. The coordination assembly of imidazole side chain of histidine with divalent nickel ions in aqueous condition yielded purple prismatic solids. Single crystal X-ray diffraction (XRD) analysis of the product revealed structure for Ni(C6H8N3O2)2 • H2O that has a monoclinic (C2) structure with lattice parameters, a = 29.41, b = 8.27, c = 6.31 Å, β = 90.01 ˚. Circular dichroism - optical rotatory dispersion (CD-ORD), Powder X-ray diffraction (PXRD) and Fourier transform - infrared spectroscopy (FT-IR) analyses are conducted to further characterize the crystals. Enantioselective adsorption analysis using racemic mixture of 2-butanol confirmed bis(L-histidinato)nickel(II) monohydrate MOF crystal's enantioselective property preferentially favoring the adsorption of (S)-2-butanol isomer.

Synthesis, crystal structure and characterization of chiral, three-dimensional anhydrous potassium tris(oxalato)ferrate(III)

NASA Astrophysics Data System (ADS)

Saritha, A.; Raju, B.; Ramachary, M.; Raghavaiah, P.; Hussain, K. A.

2012-11-01

The synthesis, crystal structure and physical properties of chiral, three-dimensional anhydrous potassium tris(oxalato)ferrate(III) [K3Fe(C2O4)3] are described. X-ray analysis reveals that the compound crystallized in the chiral space group P4132 of cubic system with a=b=c=13.5970(2), Z=4. The structure of the complex consists of infinite anionic [Fe(C2O4)3]3- units with distorted octahedral environment of iron surrounded by six oxygen atoms of three oxalato groups. The anionic units are interlinked through K+ ions of three different coordination environments of distorted octahedral, bicapped trigonal prismatic and trigonal prismatic yielding a three-dimensional motif. The two broad absorption bands at 644 and 924 nm from UV-vis-NIR transmittance spectra were ascribed to a ligand-to-metal charge transfer. The room temperature crystalline EPR spectra indicate the high-spin (S=5/2) of Fe(III) ion. The vibrating sample magnetometer measurement shows the paramagnetic nature at room temperature. Thermal studies of the compound confirm the absence of water molecule.

Virtual screening applications: a study of ligand-based methods and different structure representations in four different scenarios.

PubMed

Hristozov, Dimitar P; Oprea, Tudor I; Gasteiger, Johann

2007-01-01

Four different ligand-based virtual screening scenarios are studied: (1) prioritizing compounds for subsequent high-throughput screening (HTS); (2) selecting a predefined (small) number of potentially active compounds from a large chemical database; (3) assessing the probability that a given structure will exhibit a given activity; (4) selecting the most active structure(s) for a biological assay. Each of the four scenarios is exemplified by performing retrospective ligand-based virtual screening for eight different biological targets using two large databases--MDDR and WOMBAT. A comparison between the chemical spaces covered by these two databases is presented. The performance of two techniques for ligand--based virtual screening--similarity search with subsequent data fusion (SSDF) and novelty detection with Self-Organizing Maps (ndSOM) is investigated. Three different structure representations--2,048-dimensional Daylight fingerprints, topological autocorrelation weighted by atomic physicochemical properties (sigma electronegativity, polarizability, partial charge, and identity) and radial distribution functions weighted by the same atomic physicochemical properties--are compared. Both methods were found applicable in scenario one. The similarity search was found to perform slightly better in scenario two while the SOM novelty detection is preferred in scenario three. No method/descriptor combination achieved significant success in scenario four.

Manganese-Vanadate Hybrids: Impact of Organic Ligands on Their Structures, Thermal Stabilities, Optical Properties, and Photocatalytic Activities.

PubMed

Luo, Lan; Zeng, Yuhan; Li, Le; Luo, Zhixiang; Smirnova, Tatyana I; Maggard, Paul A

2015-08-03

Manganese(II)-vanadate(V)/organic hybrids were prepared in high purity using four different N-donor organic ligands (2,6:2',2″-terpyridine = terpy, 2,2'-bipyrimidine = bpym, o-phenanthroline = o-phen, and 4,4'-bipyridine = 4,4'-bpy), and their crystalline structures, thermal stabilities, optical properties, photocatalytic activities and electronic structures were investigated as a function of the organic ligand. Hydrothermal reactions were employed that targeted a 1:2 molar ratio of Mn(II)/V(V), yielding four hybrid solids with the compositions of Mn(terpy)V2O6·H2O (I), Mn2(bpym)V4O12·0.6H2O (II), Mn(H2O)(o-phen)V2O6 (III), and Mn(4,4'-bpy)V2O6·1.16H2O (IV). The inorganic component within these hybrid compounds, that is, [MnV2O6], forms infinite chains in I and layers in II, III, and IV. In each case, the organic ligand preferentially coordinates to the Mn(II) cations within their respective structures, either as chelating and three-coordinate (mer isomer in I) or two-coordinate (cis isomers in II and III), or as bridging and two coordinate (trans isomer in IV). The terminating ligands in I (terpy) and III (o-phen) yield nonbridged "MnV2O6" chains and layers, respectively, while the bridging ligands in II (bpym) and IV (4,4'-bpy) result in three-dimensional, pillared hybrid networks. The coordination number of the ligand, that is, two- or three-coordinate, has the predominant effect on the dimensionality of the inorganic component, while the connectivity of the combined metal-oxide/organic network is determined by the chelating versus bridging ligand coordination modes. Each hybrid compound decomposes into crystalline MnV2O6 upon heating in air with specific surface areas from ∼7 m(2)/g for III to ∼41 m(2)/g for IV, depending on the extent of structural collapse as the lattice water is removed. All hybrid compounds exhibit visible-light bandgap sizes from ∼1.7 to ∼2.0 eV, decreasing with the increased dimensionality of the [MnV2O6] network in the order

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

DOE Office of Scientific and Technical Information (OSTI.GOV)

Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada

As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. In this paper, we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer boundmore » by a single CD4 without the typical antigenic hallmarks of CD4 induction. Finally, antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.« less

Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

DOE PAGES

Do Kwon, Young; Pancera, Marie; Acharya, Priyamvada; ...

2015-06-22

As the sole viral antigen on the HIV-1–virion surface, trimeric Env is a focus of vaccine efforts. In this paper, we present the structure of the ligand-free HIV-1–Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer boundmore » by a single CD4 without the typical antigenic hallmarks of CD4 induction. Finally, antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.« less

Crystal structure, magnetism, and luminescent properties of two isostructural pcu MOFs based on a triangular ligand

NASA Astrophysics Data System (ADS)

Yan, Pen-Ji; Yao, Xiao-Qiang; Xie, Hua; Xiao, Guo-Bin; Liu, Jia-Cheng; Xu, Xin-Jian

2018-05-01

Two isomorphous metal-organic frameworks, {[M(TIPA) (btec)½]H2O}n, [M = Co (1) or Zn (2)] were synthesized hydrothermally based on a semi-rigid N-center triangular ligand TIPA, where TIPA = tris(4-(1H-imidazol-1-yl)-phenyl)amine, H4btec = 1,2,4,5-benzenetetracarboxylic acid. Single crystal structural analyses show that complexes 1 and 2 are isostructural and both feature a twofold interpenetrated pcu topology. In 1 and 2, the btec4- ligand adopting μ2-η2:η1 and μ1-η1:η0 coordination modes connect adjacent dinuclear Co/Zn units to form a 1D straight polymeric chain. Then these chains arranged in parallel/parallel fashion were further extended to a 3D network by exo-tridentate ligand TIPA with μ2-κ2N:N‧ coordination mode. The magnetic property of 1 and the luminescent property of 2 were investigated. Furthermore, the structure and spectroscopic property of 2 were further investigated by DFT and TD-DFT calculations.

pH-specific synthesis and spectroscopic, structural, and magnetic studies of a chromium(III)-citrate species. Aqueous solution speciation of the binary chromium(III)-citrate system.

PubMed

Gabriel, C; Raptopoulou, C P; Terzis, A; Tangoulis, V; Mateescu, C; Salifoglou, A

2007-04-16

In an attempt to understand the aqueous interactions of Cr(III) with the low-molecular-mass physiological ligand citric acid, the pH-specific synthesis in the binary Cr(III)-citrate system was explored, leading to the complex (NH4)4[Cr(C6H4O7)(C6H5O7)].3H2O (1). 1 crystallizes in the monoclinic space group I2/a, with a = 19.260(10) A, b = 10.006(6) A, c = 23.400(10) A, beta = 100.73(2) degrees , V = 4431(4) A3, and Z = 8. 1 was characterized by elemental analysis and spectroscopic, structural, thermal, and magnetic susceptibility studies. Detailed aqueous speciation studies in the Cr(III)-citrate system suggest the presence of a number of species, among which is the mononuclear [Cr(C6H4O7)(C6H5O7)]4- complex, optimally present around pH approximately 5.5. The structure of 1 reveals a mononuclear octahedral complex of Cr(III) with two citrate ligands bound to it. The two citrate ligands have different deprotonation states, thus signifying the importance of the mixed deprotonation state in the coordination sphere of the Cr(III) species in aqueous speciation. The latter reveals the distribution of numerous species, including 1, for which the collective structural, spectroscopic, and magnetic data point out its physicochemical profile in the solid state and in solution. The importance of the synthetic efforts linked to 1 and the potential ramifications of Cr(III) reactivity toward both low- and high-molecular-mass biotargets are discussed in light of (a) the quest for well-characterized soluble Cr(III) species that could be detected and identified in biologically relevant fluids, (b) ongoing efforts to delineate the aqueous speciation of the Cr(III)-citrate system and its link to biotoxic Cr(III) manifestations, and (c) the synthetic utility of convenient Cr(III) precursors in the synthesis of advanced materials.

Lateral cis-1,3,5,7-tetraazadecalin podands and their complexes: synthesis, structure, and strong binding with Pb(II) and other heavy metal ions.

PubMed

Reany, Ofer; Fuchs, Benzion

2013-02-18

The chemistry and complexation behavior of diaminal podands based on cis-1,3,5,7-tetraazadecalin (cis-TAD) were elaborated, reassessed, and extended. The synthesis of 2,6-bis(hydroxymethylene)-cis-TAD (9) and 2,6-bis(α,α'-dimethyl-β- hydroxyethyl)-cis-TAD (10) as well as of suitably substituted 2,6-diaryl-cis-TAD podands is laid out. For the latter, the effect of electron donating or withdrawing substituents on the benzaldehyde reagents was examined while 9 and 10 were probed and showed considerable propensity for heavy metal-ion chelation. The [Cd(II)·(9)] and [Pb(II)·(9)] complexes stood out indeed, and their structure and properties show a particularly interesting 5-amino-1,3-diazane chelation type and strong ligand-ion binding mode, with intramolecular donor exchange in solution, all strongly influenced by the anomeric effect in the ligand.

Ligand-induced folding of the thiM TPP riboswitch investigated by a structure-based fluorescence spectroscopic approach

PubMed Central

Lang, Kathrin; Rieder, Renate; Micura, Ronald

2007-01-01

Riboswitches are genetic control elements within non-coding regions of mRNA. They consist of a metabolite-sensitive aptamer and an adjoining expression platform. Here, we describe ligand-induced folding of a thiamine pyrophosphate (TPP) responsive riboswitch from Escherichia coli thiM mRNA, using chemically labeled variants. Referring to a recent structure determination of the TPP/aptamer complex, each variant was synthesized with a single 2-aminopurine (AP) nucleobase replacement that was selected to monitor formation of tertiary interactions of a particular region during ligand binding in real time by fluorescence experiments. We have determined the rate constants for conformational adjustment of the individual AP sensors. From the 7-fold differentiation of these constants, it can be deduced that tertiary contacts between the two parallel helical domains (P2/J3-2/P3/L3 and P4/P5/L5) that grip the ligand's ends in two separate pockets, form significantly faster than the function-critical three-way junction with stem P1 fully developed. Based on these data, we characterize the process of ligand binding by an induced fit of the RNA and propose a folding model of the TPP riboswitch aptamer. For the full-length riboswitch domain and for shorter constructs that represent transcriptional intermediates, we have additionally evaluated ligand-induced folding via AP-modified variants and provide insights into the sequential folding pathway that involves a finely balanced equilibrium of secondary structures. PMID:17693433

Structural evolution and properties of small-size thiol-protected gold nanoclusters

NASA Astrophysics Data System (ADS)

Ma, Miaomiao; Liu, Liren; Zhu, Hengjiang; Lu, Junzhe; Tan, Guiping

2018-07-01

Ligand-protected gold clusters are widely used in biosensors and catalysis. Understanding the structural evolution of these kinds of nanoclusters is important for experimental synthesis. Herein, based on the particle swarm optimisation algorithm and density functional theory method, we use [Au1(SH)2]n, [Au2(SH)3]n, [Au3(SH)4]n (n = 1-3) as basic units to research the structural evolution relationships from building blocks to the final whole structures. Results show that there is a 'line-ring-core' structural evolution pattern in the growth process of the nanoclusters. The core structures of the ligand-protected gold clusters consist of Au3, Au4, Au6 and Au7 atoms. The electronics and optics analysis reflects that stability and optical properties gradually enhance with increase in size. These results can be used to understand the initial growth stage and design new ligand-protected nanoclusters.

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

PubMed Central

Cordier, Christopher; Morton, Daniel; Murrison, Sarah; O'Leary-Steele, Catherine

2008-01-01

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed. PMID:18663392

Synthesis and spectroscopic behavior of highly luminescent Eu 3+-dibenzoylmethanate (DBM) complexes with sulfoxide ligands

NASA Astrophysics Data System (ADS)

Niyama, E.; Brito, H. F.; Cremona, M.; Teotonio, E. E. S.; Reyes, R.; Brito, G. E. S.; Felinto, M. C. F. C.

2005-09-01

In this paper the synthesis, characterization and photoluminescent behavior of the [RE(DBM) 3L 2] complexes (RE = Gd and Eu) with a variety of sulfoxide ligands; L = benzyl sulfoxide (DBSO), methyl sulfoxide (DMSO), phenyl sulfoxide (DPSO) and p-tolyl sulfoxide (PTSO) have been investigated in solid state. The emission spectra of the Eu 3+-β-diketonate complexes show characteristics narrow bands arising from the 5D 0 → 7F J ( J = 0-4) transitions, which are split according to the selection rule for C n, C nv or C s site symmetries. The experimental Judd-Ofelt intensity parameters ( Ω2 and Ω4), radiative ( Arad) and non-radiative ( Anrad) decay rates, and R02 for the europium complexes have been determined and compared. The highest value of Ω2 (61.9 × 10 -20 cm 2) was obtained to the complex with PTSO ligand, indicating that Eu 3+ ion is in the highly polarizable chemical environment. The higher values of the experimental quantum yield ( q) and emission quantum efficiency of the emitter 5D 0 level ( η) for the Eu-complexes with DMSO, DBSO and PTSO sulfoxides suggest that these complexes are promising Light Conversion Molecular Devices (LCMDs). The lower value of quantum yield ( q = 1%), for the hydrated complex [Eu(DBM) 3(H 2O)], indicates that the luminescence quenching occurs via multiphonon relaxation by coupling with the OH-oscillators from water molecule coordinated to rare earth ion. The pure red emission of the Eu-complexes has been confirmed by ( x, y) color coordinates.

On the structural features of hairpin triloops in rRNA: from nucleotide to global conformational change upon ligand binding.

PubMed

Mitrasinovic, Petar M

2006-03-01

RNA structure can be viewed as both a construct composed of various structural motifs and a flexible polymer that is substantially influenced by its environment. In this light, the present paper represents an attempt to reconcile the two standpoints. By using the 3D structures both of four (16S and 23S) portions of unbound 50S, H50S, and T30S ribosomal subunits and of 38 large ribonucleoligand complexes as the starting point, the behavior, which is induced by ligand binding, of 73 hairpin triloops with closing g-c and c-g base pairs was investigated using root-mean-square deviation (RMSD) approach and pseudotorsional (eta,theta) convention at the nucleotide-by-nucleotide level. Triloops were annotated in accordance with a recent proposal of geometric nomenclature. A simple measure for the determination of the strain of a triloop is introduced. It is believed that a possible classification of the interior triloops, based on the 2D eta-theta unique path, will aid to conceive their local behavior upon ligand binding. All rRNA residues in contact with ligands as well as regions of considerable conformational changes upon complex formation were identified. The analysis offers the answer to: how proximal to and how far from the actual ligand-binding sites the structural changes occur?

Radical anionic versus neutral 2,2'-bipyridyl coordination in uranium complexes supported by amide and ketimide ligands.

PubMed

Diaconescu, Paula L; Cummins, Christopher C

2015-02-14

The synthesis and characterization of (bipy)(2)U(N[t-Bu]Ar)(2) (1-(bipy)(2), bipy = 2,2'-bipyridyl, Ar = 3,5-C(6)H(3)Me(2)), (bipy)U(N[(1)Ad]Ar)(3) (2-bipy), (bipy)(2)U(NC[t-Bu]Mes)(3) (3-(bipy)(2), Mes = 2,4,6-C(6)H(2)Me(3)), and IU(bipy)(NC[t-Bu]Mes)(3) (3-I-bipy) are reported. X-ray crystallography studies indicate that bipy coordinates as a radical anion in 1-(bipy)(2) and 2-bipy, and as a neutral ligand in 3-I-bipy. In 3-(bipy)(2), one of the bipy ligands is best viewed as a radical anion, the other as a neutral ligand. The electronic structure assignments are supported by NMR spectroscopy studies of exchange experiments with 4,4'-dimethyl-2,2'-bipyridyl and also by optical spectroscopy. In all complexes, uranium was assigned a +4 formal oxidation state.

Cationic Gold Clusters Ligated with Differently Substituted Phosphines: Effect of Substitution on Ligand Reactivity and Binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Grant E.; Olivares, Astrid M.; Hill, David E.

2015-01-01

We present a systematic study of the effect of the number of methyl (Me) and cyclohexyl (Cy) functional groups in monodentate phosphine ligands on the solution-phase synthesis of ligated sub-nanometer gold clusters and their gas-phase fragmentation pathways. Small mixed ligand cationic gold clusters were synthesized using ligand exchange reactions between pre-formed triphenylphosphine ligated (PPh3) gold clusters and monodentate Me- and Cy-substituted ligands in solution and characterized using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation (CID) experiments. Under the same experimental conditions, larger gold-PPh3 clusters undergo efficient exchange of unsubstituted PPh3 ligands for singly Me- and Cy-substituted PPh2Me and PPh2Cymore » ligands. The efficiency of ligand exchange decreases with an increasing number of Me or Cy groups in the substituted phosphine ligands. CID experiments performed for a series of ligand-exchanged gold clusters indicate that loss of a neutral Me-substituted ligand is preferred over loss of a neutral PPh¬3 ligand while the opposite trend is observed for Cy-substituted ligands. The branching ratio of the competing ligand loss channels is strongly correlated with the electron donating ability of the phosphorous lone pair as determined by the relative proton affinity of the ligand. The results indicate that the relative ligand binding energies increase in the order PMe3 < PPhMe2 < PPh2Me < PPh3< PPh2Cy < PPhCy2< PCy3. Furthermore, the difference in relative ligand binding energies increases with the number of substituted PPh3-mMem or PPh3-mCym ligands (L) exchanged onto each cluster. This study provides the first experimental determination of the relative binding energies of ligated gold clusters containing differently substituted monophosphine ligands, which are important to controlling their synthesis and reactivity in solution. The results also indicate that ligand substitution is an important

Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure

PubMed Central

Suddala, Krishna C.; Rinaldi, Arlie J.; Feng, Jun; Mustoe, Anthony M.; Eichhorn, Catherine D.; Liberman, Joseph A.; Wedekind, Joseph E.; Al-Hashimi, Hashim M.; Brooks, Charles L.; Walter, Nils G.

2013-01-01

Riboswitches are structural elements in the 5′ untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 (7-aminomethyl-7-deazaguanine) riboswitch family comprises some of the smallest metabolite sensing RNAs found in nature. Once ligand-bound, the transcriptional Bacillus subtilis and translational Thermoanaerobacter tengcongensis preQ1 riboswitch aptamers are structurally similar RNA pseudoknots; yet, prior structural studies have characterized their ligand-free conformations as largely unfolded and folded, respectively. In contrast, through single molecule observation, we now show that, at near-physiological Mg2+ concentration and pH, both ligand-free aptamers adopt similar pre-folded state ensembles that differ in their ligand-mediated folding. Structure-based Gō-model simulations of the two aptamers suggest that the ligand binds late (Bacillus subtilis) and early (Thermoanaerobacter tengcongensis) relative to pseudoknot folding, leading to the proposal that the principal distinction between the two riboswitches lies in their relative tendencies to fold via mechanisms of conformational selection and induced fit, respectively. These mechanistic insights are put to the test by rationally designing a single nucleotide swap distal from the ligand binding pocket that we find to predictably control the aptamers′ pre-folded states and their ligand binding affinities. PMID:24003028

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms.

PubMed

Bonati, Laura; Corrada, Dario; Tagliabue, Sara Giani; Motta, Stefano

2017-02-01

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

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.

Synthesis and characterization of a new zinc(II) complex with tetradentate azo-thioether ligand: X-ray structure, DNA binding study and DFT calculation

NASA Astrophysics Data System (ADS)

Mondal, Apurba Sau; Pramanik, Ajoy Kumar; Patra, Lakshman; Manna, Chandan Kumar; Mondal, Tapan Kumar

2017-10-01

A new zinc(II) complex, [Zn(L)(H2O)](ClO4) (1) with azo-thioether containing NSNO donor ligand, 3-(2-(2-((pyridin-2-ylmethyl)thio)phenyl)hydrazono)pentane-2,4-dione (HL) is synthesized and characterized by several spectroscopic techniques. The distorted square based pyramidal (DSBP) geometry is confirmed by single crystal X-ray structure. The ability of the complex to bind with CT DNA is investigated by UV-vis method and the binding constant is found to be 4.16 × 104 M-1. Competitive binding study with ethidium bromide (EB) by fluorescence method suggests that the zinc(II) complex efficiently displaces EB from EB-DNA. The Stern-Volmer dynamic quenching constant, Ksv is found to be 1.2 × 104 M-1. Theoretical calculations by DFT and TDDFT/CPCM methods are used to interpret the electronic structure and UV-vis spectrum of the complex.

Synthesis and characterisation of luminescent rhenium tricarbonyl complexes with axially coordinated 1,2,3-triazole ligands.

PubMed

Uppal, Baljinder S; Booth, Rebecca K; Ali, Noreen; Lockwood, Cindy; Rice, Craig R; Elliott, Paul I P

2011-08-07

A series of 1-alkyl-4-aryl-1,2,3-triazoles (1-methyl-4-phenyl-1,2,3-triazole (1a); 1-propyl-4-phenyl-1,2,3-triazole (1b); 1-benzyl-4-phenyl-1,2,3-triazole (1c); 1-propyl-4-p-tolyl-1,2,3-triazole (1d)) have been prepared through a one-pot procedure involving in situ generation of the alkyl azide from a halide precursor followed by copper catalysed alkyne/azide cycloaddition (CuAAC) with the appropriate aryl alkyne. Cationic Re(I) complexes [Re(bpy)(CO)(3)(1a-d)]PF(6) (2a-d) were then prepared by stirring [Re(bpy)(CO)(3)Cl] with AgPF(6) in dichloromethane in the presence of ligands 1a-d. X-ray crystal structures were obtained for 2a and 2b. In the solid state, 2a adopts a highly distorted geometry, which is not seen for 2b, in which the plane of the triazole ligand tilts by 13° with respect to the Re-N bond as a result of a π-stacking interaction between the Ph substituent and one of the rings of the bpy ligand. This π-stacking interaction also results in severe twisting of the bpy ligand. Infrared spectra of 2a-d exhibit ν(CO) bands at ∼2035 and ∼1926 cm(-1) suggesting that these ligands are marginally better donors than pyridine (ν(CO) = 2037, 1932 cm(-1)). The complexes are luminescent in aerated dichloromethane at room temperature with emission maxima at 542 to 552 nm comparable to that of the pyridine analogue (549 nm) and blue shifted relative to the parent chloride complex. Long luminescent lifetimes are observed for the triazole complexes (475 to 513 ns) in aerated dichloromethane solutions at room temperature.

Syntheses and structural characterization of Co(II) and Cd(II) coordination polymers with 1,4-bis(imidazolyl)butane ligand

NASA Astrophysics Data System (ADS)

Lalegani, Arash; Khalaj, Mehdi; Sedaghat, Sajjad; Łyczko, Krzysztof; Lipkowski, Janusz

2017-11-01

Two new coordination polymers, {[Co(bib)3](PF6)2}n (1) and [Cd (bib) Cl2]n (2), were prepared at room temperature by the reaction of appropriate salts of cobalt (II) and cadmium (II) with the flexible linker ligands 1,4-bis(imidazolyl) butane (bib). The compounds were characterized by elemental analyses, IR spectroscopy and single crystal X-ray diffraction. In the polymeric structure of 1, the Co(II) ion lies on an inversion centre and adopts the CoN6 octahedral geometry, while in the structure of 2, the Cd(II) ions adopt the CdN2Cl4 pseudo-octahedral geometry. In compound 1, six bib ligands are coordinated to one central cobalt (II) to form an open 3D 2-fold interpenetrating framework of the α-polonium (pcu) type topology, while in compound 2 two bib ligands are coordinated to one central cadmium (II) to form 2D network structure.

Synthesis and binding properties of new selective ligands for the nucleobase opposite the AP site.

PubMed

Abe, Yukiko; Nakagawa, Osamu; Yamaguchi, Rie; Sasaki, Shigeki

2012-06-01

DNA is continuously damaged by endogenous and exogenous factors such as oxidative stress or DNA alkylating agents. These damaged nucleobases are removed by DNA N-glycosylase and form apurinic/apyrimidinic sites (AP sites) as intermediates in the base excision repair (BER) pathway. AP sites are also representative DNA damages formed by spontaneous hydrolysis. The AP sites block DNA polymerase and a mismatch nucleobase is inserted opposite the AP sites by polymerization to cause acute toxicities and mutations. Thus, AP site specific compounds have attracted much attention for therapeutic and diagnostic purposes. In this study, we have developed nucleobase-polyamine conjugates as the AP site binding ligand by expecting that the nucleobase part would play a role in the specific recognition of the nucleobase opposite the AP site by the Watson-Crick base pair formation and that the polyamine part should contribute to the access of the ligand to the AP site by a non-specific interaction to the DNA phosphate backbone. The nucleobase conjugated with 3,3'-diaminodipropylamine (A-ligand, G-ligand, C-ligand, T-ligand and U-ligand) showed a specific stabilization of the duplex containing the AP site depending on the complementary combination with the nucleobase opposite the AP site; that is A-ligand to T, G-ligand to C, C-ligand to G, T- and U-ligand to A. The thermodynamic binding parameters clearly indicated that the specific stabilization is due to specific binding of the ligands to the complementary AP site. These results have suggested that the complementary base pairs of the Watson-Crick type are formed at the AP site. Copyright © 2012 Elsevier Ltd. All rights reserved.

Versatile synthesis of cationic N-heterocyclic carbene-gold(i) complexes containing a second ancillary ligand. Design of heterobimetallic ruthenium-gold anticancer agents.

PubMed

Fernández-Gallardo, Jacob; Elie, Benelita T; Sanaú, Mercedes; Contel, María

2016-02-21

We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest for the synthesis of compounds with potential catalytic and medicinal applications. The general synthetic strategy has been applied in the preparation of novel cationic heterobimetallic ruthenium(ii)-gold(i) complexes that are highly cytotoxic to renal cancer Caki-1 and colon cancer HCT 116 cell lines while showing a synergistic effect and being more selective than their monometallic counterparts.

Diarylethene-containing cyclometalated platinum(II) complexes: tunable photochromism via metal coordination and rational ligand design.

PubMed

Chan, Jacky Chi-Hung; Lam, Wai Han; Wong, Hok-Lai; Zhu, Nianyong; Wong, Wing-Tak; Yam, Vivian Wing-Wah

2011-08-17

The synthesis, characterization, electrochemistry, photophysics and photochromic behavior of a new class of cyclometalated platinum(II) complexes [Pt(C(∧)N)(O(∧)O)] (1a-5a and 1b-5b), where C(∧)N is a cyclometalating 2-(2'-thienyl)pyridyl (thpy) or 2-(2'-thienothienyl)pyridyl (tthpy) ligand containing the photochromic dithienylethene (DTE) unit and O(∧)O is a β-diketonato ligand of acetylacetonato (acac) or hexafluoroacetylacetonato (hfac), have been reported. The X-ray crystal structures of five of the complexes have also been determined. The electrochemical studies reveal that the first quasi-reversible reduction couple, and hence the nature of lowest unoccupied molecular orbital (LUMO) of the complexes, is sensitive to the nature of the ancillary O(∧)O ligands. Upon photoexcitation, complexes 1a-3a and 1b-3b exhibit drastic color changes, ascribed to the reversible photochromic behavior, which is found to be sensitive to the substituents on the pyridyl ring and the extent of π-conjugation of the C(∧)N ligand as well as the nature of the ancillary ligand. The thermal bleaching kinetics of complex 1a has been studied in toluene at various temperatures, and the activation barrier for the thermal cycloreversion of the complex has been determined. Density functional theory (DFT) calculations have been performed to provide an insight into the electrochemical, photophysical and photochromic properties.

Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.

PubMed

Kaczor, Agnieszka A; Silva, Andrea G; Loza, María I; Kolb, Peter; Castro, Marián; Poso, Antti

2016-04-05

Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mapping of ligand-binding cavities in proteins.

PubMed

Andersson, C David; Chen, Brian Y; Linusson, Anna

2010-05-01

The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterize and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity, and charge). This approach can provide valuable information on the similarities and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterization and mapping of "orphan structures", selection of protein structures for docking studies in structure-based design, and identification of proteins for selectivity screens in drug design programs. 2009 Wiley-Liss, Inc.

Characterization of Colloidal Quantum Dot Ligand Exchange by X-ray Photoelectron Spectroscopy

NASA Astrophysics Data System (ADS)

Atewologun, Ayomide; Ge, Wangyao; Stiff-Roberts, Adrienne D.

2013-05-01

Colloidal quantum dots (CQDs) are chemically synthesized semiconductor nanoparticles with size-dependent wavelength tunability. Chemical synthesis of CQDs involves the attachment of long organic surface ligands to prevent aggregation; however, these ligands also impede charge transport. Therefore, it is beneficial to exchange longer surface ligands for shorter ones for optoelectronic devices. Typical characterization techniques used to analyze surface ligand exchange include Fourier-transform infrared spectroscopy, x-ray diffraction, transmission electron microscopy, and nuclear magnetic resonance spectroscopy, yet these techniques do not provide a simultaneously direct, quantitative, and sensitive method for evaluating surface ligands on CQDs. In contrast, x-ray photoelectron spectroscopy (XPS) can provide nanoscale sensitivity for quantitative analysis of CQD surface ligand exchange. A unique aspect of this work is that a fingerprint is identified for shorter surface ligands by resolving the regional XPS spectrum corresponding to different types of carbon bonds. In addition, a deposition technique known as resonant infrared matrix-assisted pulsed laser evaporation is used to improve the CQD film uniformity such that stronger XPS signals are obtained, enabling more accurate analysis of the ligand exchange process.

Mixed-Ligand Uranyl Polyrotaxanes Incorporating a Sulfate/Oxalate Coligand: Achieving Structural Diversity via pH-Dependent Competitive Effect.

PubMed

Xie, Zhen-Ni; Mei, Lei; Hu, Kong-Qiu; Xia, Liang-Shu; Chai, Zhi-Fang; Shi, Wei-Qun

2017-03-20

A mixed-ligand system provides an alternative route to tune the structures and properties of metal-organic compounds by introducing functional organic or inorganic coligands. In this work, five new uranyl-based polyrotaxane compounds incorporating a sulfate or oxalate coligand have been hydrothermally synthesized via a mixed-ligand method. Based on C6BPCA@CB6 (C6BPCA = 1,1'-(hexane-1,6-diyl)bis(4-(carbonyl)pyridin-1-ium), CB6 = cucurbit[6]uril) ligand, UPS1 (UO 2 (L) 0.5 (SO 4 )(H 2 O)·2H 2 O, L = C6BPCA@CB6) is formed by the alteration of initial aqueous solution pH to a higher acidity. The resulting 2D uranyl polyrotaxane sheet structure of UPS1 is based on uranyl-sulfate ribbons connected by the C6BPCA@CB6 pseudorotaxane linkers. By using oxalate ligand instead of sulfate, four oxalate-containing uranyl polyrotaxane compounds, UPO1-UPO4, have been acquired by tuning reaction pH and ligand concentration: UPO1 (UO 2 (L) 0.5 (C 2 O 4 ) 0.5 (NO 3 )·3H 2 O) in one-dimensional chain was obtained at a low pH value range (1.47-1.89) and UPO2 (UO 2 (L)(C 2 O 4 )(H 2 O)·7H 2 O)obtained at a higher pH value range (4.31-7.21). By lowering the amount of oxalate, another two uranyl polyrotaxane network UPO3 ((UO 2 ) 2 (L) 0.5 (C 2 O 4 ) 2 (H 2 O)) and UPO4 ((UO 2 ) 2 O(OH)(L) 0.5 (C 2 O 4 ) 0.5 (H 2 O)) could be acquired at a low pH value of 1.98 and a higher pH value over 6, respectively. The UPO1-UPO4 compounds, which display structural diversity via pH-dependent competitive effect of oxalate, represent the first series of mixed-ligand uranyl polyrotaxanes with organic ligand as the coligand. Moreover, the self-assembly process and its internal mechanism concerning pH-dependent competitive effect and other related factors such as concentration of the reagents and coordination behaviors of the coligands were discussed in detail.

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

NASA Astrophysics Data System (ADS)

Zhang, Xianjun; Zhao, Fei; Wu, Yiran; Yang, Jun; Han, Gye Won; Zhao, Suwen; Ishchenko, Andrii; Ye, Lintao; Lin, Xi; Ding, Kang; Dharmarajan, Venkatasubramanian; Griffin, Patrick R.; Gati, Cornelius; Nelson, Garrett; Hunter, Mark S.; Hanson, Michael A.; Cherezov, Vadim; Stevens, Raymond C.; Tan, Wenfu; Tao, Houchao; Xu, Fei