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Sample records for base ligands derived

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

    PubMed Central

    Abou-Hussein, Azza A.; Linert, Wolfgang

    2014-01-01

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

  2. 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.

  3. Theoretical studies of organotin(IV) complexes derived from ONO-donor type schiff base ligands.

    PubMed

    Şirikci, Gökhan; Ancın, Nilgün Ataünal; Öztaş, Selma Gül

    2015-09-01

    In this work a molecular modeling study was carried out based on a series of organotin(IV) derivatives which were complexed with ONO-Donor type Schiff base ligands to build up a statistical data pool for researchers. For this purpose, various properties of the selected complexes such as energies, band gaps, chemical reactivity descriptors, polarizabilities, geometric parameters, (1)H-NMR, (13)C-NMR chemical shifting values were obtained through density functional theory using B3LYP, CAM-B3LYP, TPSSTPSS, TPSSh, HCTH, wB97XD, and MN12SX functionals. Empirical dispersion corrections were incorporated for some functionals and solvent effects were also taken into account through applying polarizable continuum model (PCM). (1)H-NMR, (13)C-NMR chemical shifts were calculated via linear regression analysis using either gauge invariant atomic orbital (GIAO) or continuous set of gauge transformations (CSGT) methods. While structural properties were being explored, quantitative effects of utilized functionals and empirical dispersion corrections over calculated properties were shown in detail. PMID:26245450

  4. Ligand based validated comparative chemometric modeling and pharmacophore mapping of aurone derivatives as antimalarial agents.

    PubMed

    Adhikari, Nilanjan; Halder, Amit Kumar; Mondal, Chanchal; Jha, Tarun

    2013-09-01

    Chloroquine resistance is nowadays a great problem. Aurone derivatives are effective against chloroquine resistant parasite. Ligand based validated comparative chemometric modeling through 2D-QSAR and kNN-MFA 3DQSAR studies as well as common feature 3D pharmacophore mapping were done on thirtyfive aurone derivatives having antimalarial activity. Statistically significant 2D-QSAR models were generated on unsplitted as well as splitted dataset by MLR and PLS technique. The MLR model of the unsplitted method was validated by two-deep cross validation and 10 fold cross validation for determining the predictive ability. The PLS technique of the unsplitted method was done to compare the significance of these methods. In the splitted method, model was developed on the training set by Y-based ranking method by using the same descriptors and was validated on fifty pairs of the test and the training sets by k-MCA technique. These models generated by using the same descriptors were well validated irrespective of MLR as well as PLS analysis of unsplitted as well as splitted methods and are showing similar results. Therefore, these descriptors and model generated were reliable and robust. The kNN-MFA 3D-QSAR models were generated by three variable selection methods: genetic algorithm, simulated annealing and stepwise regression. The kNN-MFA 3D-QSAR results support the 2D QSAR data and in turn validate the earlier observed SAR results. Common feature 3D-pharmacophore generation was performed on these compounds to validate both 2D and 3D-QSAR studies as well as the earlier observed SAR data. The work highlights the required structural features for the higher antimalarial activity. PMID:24010937

  5. Ligand Field Affected Single-Molecule Magnet Behavior of Lanthanide(III) Dinuclear Complexes with an 8-Hydroxyquinoline Schiff Base Derivative as Bridging Ligand.

    PubMed

    Wang, Wen-Min; Zhang, Hong-Xia; Wang, Shi-Yu; Shen, Hai-Yun; Gao, Hong-Ling; Cui, Jian-Zhong; Zhao, Bin

    2015-11-16

    New dinuclear lanthanide(III) complexes based on an 8-hydroxyquinoline Schiff base derivative and β-diketonate ligands, [Ln2(hfac)4(L)2] (Ln(III) = Gd (1), Tb (2), Dy (3), Ho (4), Er (5)), [Ln2(tfac)4(L)2] (Ln(III) = Gd (6), Tb (7), Dy (8), Ho (9)), and [Dy(bfac)4(L)2·C7H16] (10) (L = 2-[[(4-fluorophenyl)imino] methyl]-8-hydroxyquinoline, hfac = hexafluoroacetylacetonate, tfac = trifluoroacetylacetonate, and bfac = benzoyltrifluoroacetone), have been synthesized. The single-crystal X-ray diffraction data show that complexes 1-10 are phenoxo-O-bridged dinuclear complexes; each eight-coordinated center Ln(III) ion is in a slightly distorted dodecahedral geometry with two bidentate β-diketonate coligands and two μ2-O bridging 8-hydroxyquinoline Schiff base derivative ligands. The magnetic study reveals that 1 and 6 display cryogenic magnetic refrigeration properties, whereas complexes 3, 8, and 10 show different SMM behaviors with energy barriers of 6.77 K for 3, 19.83 K for 8, and 25.65 K for 10. Meanwhile, slow magnetic relaxation was observed in 7, while no out-of-phase alternating-current signals were found for 2. The different dynamic magnetic behaviors of two Tb2 complexes and the three Dy2 complexes mainly derive from the tiny crystal structure changes around the Ln(III) ions. It is also proved that the β-diketonate coligands can play an important role in modulating magnetic dynamics of the lanthanide 8-hydroxyquinoline Schiff base derivative system. PMID:26516660

  6. Structural diversity in mercury(II) coordination complexes with asymmetrical hydrazone-based ligands derived from pyridine

    NASA Astrophysics Data System (ADS)

    Masoumi, Asad; Servati Gargari, Masoumeh; Mahmoudi, Ghodrat; Miroslaw, Barbara; Therrien, Bruno; Abedi, Marjan; Hazendonk, Paul

    2015-05-01

    Three novel Hg(II) complexes 1-3 of asymmetrical hydrazone-pyridine based ligands, L1-L3, with distinct coordination structures have been prepared and characterized by a single crystal X-ray diffraction, elemental and thermal analysis, and IR spectroscopy. The complexes form either discrete units with one (1) or two (2) organic ligands, or one-dimensional polymers (3). Hence the ligands can be regarded as chelating (1), mono-dentate (2) or bridging (3) agents. The mercury center is essentially neutralized in each complex by two iodide anions. The coordination in complexes 2 and 3 adopts deformed tetrahedral shapes. In contrast the Hg(II) cation in complex 1 binds three coplanar ligating atoms (O,N,N) and, as with pincer ligands, its coordination polyhedron is supplemented with two I- anions in apical positions. The structural diversity in these complexes is strongly influenced by the position of N atom in pyridine derived moieties. The crystal structure is stabilized by N/O-H⋯N/O/I hydrogen bonds and π⋯π interactions.

  7. A Selective G-Quadruplex DNA-Stabilizing Ligand Based on a Cyclic Naphthalene Diimide Derivative.

    PubMed

    Islam, Md Monirul; Fujii, Satoshi; Sato, Shinobu; Okauchi, Tatsuo; Takenaka, Shigeori

    2015-01-01

    A cyclic naphthalene diimide (cyclic NDI, 1), carrying a benzene moiety as linker chain, was synthesized and its interaction with G-quadruplex DNAs of a-core and a-coreTT as a human telomeric DNA, c-kit and c-myc as DNA sequence at promoter region, or thrombin-binding aptamer (TBA) studied based on UV-VIS and circular dichroism (CD) spectroscopic techniques, thermal melting temperature measurement, and FRET-melting assay. The circular dichroism spectra showed that 1 induced the formation of different types of G-quadruplex DNA structure. Compound 1 bound to these G-quadruplexes with affinities in the range of 106-107 M-1 order and a 2:1 stoichiometry. Compound 1 showed 270-fold higher selectivity for a-core than dsDNA with a preferable a-core binding than a-coreTT, c-kit, c-myc and TBA in the presence of K+, which is supported by thermal melting studies. The FRET-melting assay also showed that 1 bound preferentially to human telomeric DNA. Compound 1 showed potent inhibition against telomerase activity with an IC50 value of 0.9 μM and preferable binding to G-quadruplexes DNA than our previously published cyclic NDI derivative 3 carrying a benzene moiety as longer linker chain. PMID:26076114

  8. Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents.

    PubMed

    Jorge, Salomão Dória; Palace-Berl, Fanny; Mesquita Pasqualoto, Kerly Fernanda; Ishii, Marina; Ferreira, Adilson Kleber; Berra, Carolina Maria; Bosch, Rosemary Viola; Maria, Durvanei Augusto; Tavares, Leoberto Costa

    2013-06-01

    A set of substituted-[N'-(benzofuroxan-5-yl)methylene]benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R(2) = 0.90 and Q(2) = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R(2) = 0.98, Q(2) = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred(2) = 0.91) and 3D-QSAR (Rpred(2) = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 μM). PMID:23644203

  9. A C2-symmetric, basic Fe(III) carboxylate complex derived from a novel triptycene-based chelating carboxylate ligand.

    PubMed

    Li, Yang; Wilson, Justin J; Do, Loi H; Apfel, Ulf-Peter; Lippard, Stephen J

    2012-08-21

    A triptycene-based bis(benzoxazole) diacid ligand H(2)L2(Ph4) bearing sterically encumbering groups was synthesized. Treatment of H(2)L2(Ph4) with Fe(OTf)(3) afforded a C(2)-symmetric trinuclear iron(III) complex, [NaFe(3)(L2(Ph4))(2)(μ(3)-O)(μ-O(2)CCPh(3))(2)(H(2)O)(3)](OTf)(2) (8). The triiron core of this complex adopts the well known "basic iron acetate" structure where the heteroleptic carboxylates, comprising two Ph(3)CCO(2)(-) and two (L2(Ph4))(2-) ligands, donate the six carboxylate bridges. The (L2(Ph4))(2-) ligand undergoes only minor conformational changes upon formation of the complex. PMID:22751622

  10. A C2-Symmetric, Basic Fe(III) Carboxylate Complex Derived from a Novel Triptycene-Based Chelating Carboxylate Ligand

    PubMed Central

    Li, Yang; Wilson, Justin J.; Do, Loi H.; Apfel, Ulf-Peter; Lippard, Stephen J.

    2012-01-01

    A triptycene-based bis(benzoxazole) diacid ligand H2L2Ph4 bearing sterically encumbering groups was synthesized. Treatment of H2L2Ph4 with Fe(OTf)3 afforded a C2-symmetric trinuclear iron(III) complex, [NaFe3(L2Ph4)2(μ3-O)(μ-O2CCPh3)2(H2O)3](OTf)2 (8). The triiron core of this complex adopts the well known “basic iron acetate” structure where the heteroleptic carboxylates, comprising two dianionic ligands (L2Ph4)2− and two Ph3CCO2−, donate the six carboxylate bridges. The (L2Ph4)2− ligand undergoes only minor conformational changes upon formation of the complex. PMID:22751622

  11. On the conditions for enhanced transport through molecular junctions based on metal centres ligated by pairs of pyridazino-derived ligands

    SciTech Connect

    Ding, Bei; Washington, Victoria; Dunietz, Barry D

    2010-10-10

    Transport properties of a Ni bis-η{sup 2} complex ligated by a pair of bi-pyridazino derivative are considered. This complex provides the opportunity to avoid perpendicular alignment of the ligand π planes. We study the effects of π-bonding and of intramolecular hydrogen bonding between the ligands as mediated by the metal centre on electron transport. The complicated effect of the electronic structure equilibration with the electrodes on the transport is discussed. The analysis at the electronic structure level provides guidelines to design a molecular bridge that is based on metal complexation with effective electronic transport.

  12. Synthesis, spectroscopic characterization and DNA nuclease activity of Cu(II) complexes derived from pyrazolone based NSO-donor Schiff base ligands

    NASA Astrophysics Data System (ADS)

    Vyas, Komal M.; Joshi, Rushikesh G.; Jadeja, R. N.; Ratna Prabha, C.; Gupta, Vivek K.

    2011-12-01

    Two neutral mononuclear Cu(II) complexes have been prepared in EtOH using Schiff bases derived from 4-toluoyl pyrazolone and thiosemicarbazide. Both the ligands have been characterized on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass spectral data. The molecular geometry of one of these ligands has been determined by single crystal X-ray study. It reveals that these ligands exist in amine-one tautomeric form in the solid state. Microanalytical data, Cu-estimation, molar conductivity, magnetic measurements, IR, UV-Visible, FAB-Mass, TG-DTA data and ESR spectral studies were used to confirm the structures of the complexes. Electronic absorption and IR spectra of the complexes suggest a square-planar geometry around the central metal ion. The interaction of complexes with pET30a plasmid DNA was investigated by spectroscopic measurements. Results suggest that the copper complexes bind to DNA via an intercalative mode and can quench the fluorescence intensity of EB bound to DNA. The interaction between the complexes and DNA has also been investigated by agarose gel electrophoresis, interestingly, we found that the copper(II) complexes can cleave circular plasmid DNA to nicked and linear forms.

  13. Synthesis of a series of new platinum organometallic complexes derived from bidentate Schiff-base ligands and their catalytic activity in the hydrosilylation and dehydrosilylation of styrene.

    PubMed

    Lachachi, M Belhadj; Benabdallah, Tayeb; Aguiar, Pedro M; Youcef, M Hadj; Whitwood, Adrian C; Lynam, Jason M

    2015-07-14

    The synthesis and properties of a novel class of platinum complexes containing Schiff bases as O,N-bidentate ligands is described as are the solution and solid state properties of the uncomplexed ligands. The platinum complexes were prepared from [PtBr2(COD)] (COD = 1,5-cyclooctadiene) and N-(2-hydroxy-1-naphthalidene)aniline derivatives in the presence of base (NaOBu(t)). Instead of a substitution reaction to afford cationic species, the addition of the Schiff base ligands results in both the formal loss of two equivalents of bromide and addition of hydroxide to the COD ligand of the complexes. It is proposed that this reaction proceeds through a cationic platinum complex [Pt(N-O)(COD)]Br which then undergoes addition of water and loss of HBr. An example of a dinuclear platinum complex in which two cyclo-octene ligands are bridged by an ether linkage is also reported. The platinum complexes were evaluated as catalysts for the hydrogenative and dehydrogenative silylation of styrene, the resulting behaviour is substituent, time and temperature dependent. PMID:26061657

  14. Palladium(II) and zinc(II) complexes of neutral [N2O2] donor Schiff bases derived from furfuraldehyde: synthesis, characterization, fluorescence and corrosion inhibitors of ligands.

    PubMed

    Ali, Omyma A M

    2014-11-11

    Metal complexes of Schiff bases derived from furfuraldehyde and 4,5-dimethyl-1,2-phenylendiamine (L1) or 4,5-dichloro-1,2-phenylendiamine (L2) have been reported and characterized based on elemental analyses, IR, 1H NMR, UV-Vis, magnetic moment, molar conductance and thermal analysis. The complexes are found to have the formulae [PdL1-2]Cl2 and [ZnL1-2](AcO)2·H2O. The molar conductance data reveal that Pd(II) and Zn(II) chelates are ionic in nature and are of the type 2:1 electrolytes. The spectral data are consistent with a square planar and tetrahedral geometry around Pd(II) and Zn(II), respectively, in which the ligands act as tetradentate ligands. The thermal behavior of some chelates is studied and the activation thermodynamic parameters are calculated using Coats-Redfern method. The corrosion inhibition of stainless steel types 410 and 304 in 1 M HCl using the synthesized Schiff bases as inhibitors have been studied by weight loss method. The obtained data considered these ligands as efficient corrosion inhibitors. The ligands and their metal complexes exhibited considerable antibacterial activity against Staphylococcusaureus, and Escherichiacoli and antifungal activity against Candida albicans. PMID:24858346

  15. Palladium(II) and zinc(II) complexes of neutral [N2O2] donor Schiff bases derived from furfuraldehyde: Synthesis, characterization, fluorescence and corrosion inhibitors of ligands

    NASA Astrophysics Data System (ADS)

    Ali, Omyma A. M.

    2014-11-01

    Metal complexes of Schiff bases derived from furfuraldehyde and 4,5-dimethyl-1,2-phenylendiamine (L1) or 4,5-dichloro-1,2-phenylendiamine (L2) have been reported and characterized based on elemental analyses, IR, 1H NMR, UV-Vis, magnetic moment, molar conductance and thermal analysis. The complexes are found to have the formulae [PdL1-2]Cl2 and [ZnL1-2](AcO)2·H2O. The molar conductance data reveal that Pd(II) and Zn(II) chelates are ionic in nature and are of the type 2:1 electrolytes. The spectral data are consistent with a square planar and tetrahedral geometry around Pd(II) and Zn(II), respectively, in which the ligands act as tetradentate ligands. The thermal behavior of some chelates is studied and the activation thermodynamic parameters are calculated using Coats-Redfern method. The corrosion inhibition of stainless steel types 410 and 304 in 1 M HCl using the synthesized Schiff bases as inhibitors have been studied by weight loss method. The obtained data considered these ligands as efficient corrosion inhibitors. The ligands and their metal complexes exhibited considerable antibacterial activity against Staphylococcusaureus, and Escherichiacoli and antifungal activity against Candida albicans.

  16. 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.

  17. Seven phenoxido-bridged complexes encapsulated by 8-hydroxyquinoline Schiff base derivatives and β-diketone ligands: single-molecule magnet, magnetic refrigeration and luminescence properties.

    PubMed

    Wang, Shi-Yu; Wang, Wen-Min; Zhang, Hong-Xia; Shen, Hai-Yun; Jiang, Li; Cui, Jian-Zhong; Gao, Hong-Ling

    2016-02-28

    Seven dinuclear complexes based on 8-hydroxyquinoline Schiff base derivatives and β-diketone ligands, [RE2(hfac)4L2] (RE = Y (1), Gd (2), Tb (3), Dy (4), Ho (5), Er (6) and Lu (7); hfac(-) = hexafluoroacetylacetonate; HL = 2-[(4-chloro-phenylimino)-methyl]-8-hydroxyquinoline), have been synthesized, and structurally and magnetically characterized. Complexes 1-7 have similar dinuclear structures, in which each RE(III) ion is eight coordinated by two L(-) and two hfac(-) ligands in a distorted dodecahedron geometry. The luminescence spectra indicate that complex 3 exhibits characteristic Tb(III) ion luminescence, while 1 and 7 show HL ligand luminescence. The magnetic studies reveal that 2 features a magnetocaloric effect with the magnetic entropy change of -ΔSm = 16.83 J kg(-1) K(-1) at 2 K for ΔH = 8 T, and 4 displays slow magnetic relaxation behavior with the anisotropic barrier of 6.7 K and pre-exponential factor τ0 = 5.3 × 10(-6) s. PMID:26792239

  18. Synthesis and characterization of a nickel(II) complex of 9-methoxy-2,3-dihydro-1,4-benzoxyzepine derived from a Schiff base ligand and its ligand substitution reaction

    NASA Astrophysics Data System (ADS)

    Saha, Sudeshna; Kottalanka, Ravi K.; Bhowmik, Prasanta; Jana, Subrata; Harms, Klaus; Panda, Tarun K.; Chattopadhyay, Shouvik; Nayek, Hari Pada

    2014-03-01

    A Schiff base ligand (2-{(E)-[2-bromoethyl)imino]methyl}-6-methoxy phenol (LH) has been synthesized and characterized by NMR, IR spectroscopy and elemental analysis. The reaction of LH with nickel acetate tetrahydrate results in the formation of a nickel(II) complex (1). The ligand (LH) has been converted into a heterocyclic moiety, 9-methoxy-2,3-dihydro-1,4-benzoxyzepine (L) in 1 and coordinated to nickel(II) ion. Ligand substitution reaction of 1 with 3-aminopyridine leads to the formation of 3-aminopyridine derivative of complex 1, [{3-(NH2-Py)}4Ni(H2O)2]Br2ṡ2(CH2Cl2) (2). Complexes 1 and 2 were characterized by using standard analytical techniques and their solid-state structures were confirmed by single crystal X-ray diffraction studies. Complex 1 crystallizes in orthorhombic space group Pccn with cell dimensions of a = 7.8483(10) Å, b = 30.662(3) Å, c = 9.3872(11) Å, Z = 4 and complex 2 crystallizes in orthorhombic space group Fddd with cell dimensions of a = 8.8108(4) Å, b = 21.0583(11) Å, c = 34.1913(17) Å, Z = 8. The optical properties and thermogravimetric analyses of complexes 1 and 2 are also reported.

  19. Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators.

    PubMed

    Tomašić, Tihomir; Hartzoulakis, Basil; Zidar, Nace; Chan, Fiona; Kirby, Robert W; Madge, David J; Peigneur, Steve; Tytgat, Jan; Kikelj, Danijel

    2013-12-23

    Voltage-gated sodium channels (VGSC) are attractive targets for drug discovery because of the broad therapeutic potential of their modulators. On the basis of the structure of marine alkaloid clathrodin, we have recently discovered novel subtype-selective VGSC modulators I and II that were used as starting points for two different ligand-based virtual screening approaches for discovery of novel VGSC modulators. Similarity searching in the ZINC database of drug-like compounds based on compound I resulted in five state-dependent Na(v)1.3 and Na(v)1.7 modulators with improved activity compared to I (IC₅₀ < 20 μM). Compounds 2 and 16 that blocked sodium permeation in Na(v)1.7 with IC₅₀ values of 7 and 9 μM, respectively, are among the most potent clathrodin analogs discovered so far. In the case of compound II, 3D similarity searching in the same database was followed by docking of an enriched compound library into our human Na(v)1.4 open-pore homology model. Although some of the selected compounds, e.g., 31 and 32 displayed 21% and 22% inactivated state I(peak) block of Na(v)1.4 at 10 μM, respectively, none showed better Na(v)1.4 modulatory activity than compound II. Taken together, virtual screening yielded compounds 2 and 16, which represent novel scaffolds for the discovery of human Na(v)1.7 modulators. PMID:24215100

  20. New insights into the selectivity of four 1,10-phenanthroline-derived ligands toward the separation of trivalent actinides and lanthanides: a DFT based comparison study.

    PubMed

    Wu, Han; Wu, Qun-Yan; Wang, Cong-Zhi; Lan, Jian-Hui; Liu, Zhi-Rong; Chai, Zhi-Fang; Shi, Wei-Qun

    2016-05-10

    Although many heterocyclic N-donor ligands have shown excellent competence for separating actinides from lanthanides, an explanation for why some ligands work whereas others fail is very fundamental but greatly needs to be addressed for designing novel and efficient extractants. In this work, we systematically investigated four phenanthroline-derived ligands, DHDIPhen, BQPhen, Ph2-BTPhen and CyMe4-BTPhen, and their coordination geometrical properties and formation reactions with Am(iii) and Eu(iii) ions by quasi-relativistic density functional theory. The calculated hardness of ligands, which may help to determine their selectivity toward actinides and lanthanides, yielded an order, from the softest to the hardest, as follows: Ph2-BTPhen < CyMe4-BTPhen < BQPhen < DHDIPhen. It shows that the intramolecular hydrogen bonds and size of a ligand cavity are two dominant factors for metal-ion complexation. Natural population analysis (NPA) reveals that the 5d/6d orbitals of Eu/Am accept significantly more electrons than other orbitals, but partial density of states and molecular orbital analysis prove that the d orbitals with more accepted electrons have little contribution to the metal-ligand bonds. The thermodynamic results suggest that ligand protonation does have a great influence on the complexation of ligands with metal ions but does not change the selectivity of ligands toward metal ions. This work can help in-depth understanding the differences of selectivity of various structurally similar ligands and provide more theoretical insights for designing more innovative ligands for Ln/An separation. PMID:27086653

  1. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.

    PubMed

    Vucicevic, Jelica; Srdic-Rajic, Tatjana; Pieroni, Marco; Laurila, Jonne M M; Perovic, Vladimir; Tassini, Sabrina; Azzali, Elisa; Costantino, Gabriele; Glisic, Sanja; Agbaba, Danica; Scheinin, Mika; Nikolic, Katarina; Radi, Marco; Veljkovic, Nevena

    2016-07-15

    The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. PMID:27265687

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

    PubMed

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

    2012-04-23

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

  3. Synthesis, Characterization, Antimicrobial, DNA Cleavage, and In Vitro Cytotoxic Studies of Some Metal Complexes of Schiff Base Ligand Derived from Thiazole and Quinoline Moiety

    PubMed Central

    Yernale, Nagesh Gunvanthrao; Bennikallu Hire Mathada, Mruthyunjayaswamy

    2014-01-01

    A novel Schiff base ligand N-(4-phenylthiazol-2yl)-2-((2-thiaxo-1,2-dihydroquinolin-3-yl)methylene)hydrazinecarboxamide (L) obtained by the condensation of N-(4-phenylthiazol-2-yl)hydrazinecarboxamide with 2-thioxo-1,2-dihydroquinoline-3-carbaldehyde and its newly synthesized Cu(II), Co(II), Ni(II), and Zn(II) complexes have been characterized by elemental analysis and various spectral studies like FT-IR, 1H NMR, ESI mass, UV-Visible, ESR, TGA/DTA, and powder X-ray diffraction studies. The Schiff base ligand (L) behaves as tridentate ONS donor and forms the complexes of type [ML(Cl)2] with square pyramidal geometry. The Schiff base ligand (L) and its metal complexes have been screened in vitro for their antibacterial and antifungal activities by minimum inhibitory concentration (MIC) method. The DNA cleavage activity of ligand and its metal complexes were studied using plasmid DNA pBR322 as a target molecule by gel electrophoresis method. The brine shrimp bioassay was also carried out to study the in vitro cytotoxicity properties for the ligand and its metal complexes against Artemia salina. The results showed that the biological activities of the ligand were found to be increased on complexation. PMID:24729778

  4. New L-Serine Derivative Ligands as Cocatalysts for Diels-Alder Reaction

    PubMed Central

    Sousa, Carlos A. D.; Rodríguez-Borges, José E.; Freire, Cristina

    2013-01-01

    New L-serine derivative ligands were prepared and tested as cocatalyst in the Diels-Alder reactions between cyclopentadiene (CPD) and methyl acrylate, in the presence of several Lewis acids. The catalytic potential of the in situ formed complexes was evaluated based on the reaction yield. Bidentate serine ligands showed good ability to coordinate medium strength Lewis acids, thus boosting their catalytic activity. The synthesis of the L-serine ligands proved to be highly efficient and straightforward. PMID:24383009

  5. Coordination behavior of new bis Schiff base ligand derived from 2-furan carboxaldehyde and propane-1,3-diamine. Spectroscopic, thermal, anticancer and antibacterial activity studies

    NASA Astrophysics Data System (ADS)

    Mohamed, Gehad G.; Zayed, Ehab M.; Hindy, Ahmed M. M.

    2015-06-01

    Novel bis Schiff base ligand, [N1,N3-bis(furan-2-ylmethylene)propane-1,3-diamine], was prepared by the condensation of furan-2-carboxaldehyde with propane-1,3-diamine. Its conformational changes on complexation with transition metal ions [Co(II), Ni(II), Cu(II), Mn(II), Cd(II), Zn(II) and Fe(III)] have been studied on the basis of elemental analysis, conductivity measurements, spectral (infrared, 1H NMR, electronic), magnetic and thermogravimetric studies. The conductance data of the complexes revealed their electrolytic nature suggesting them as 1:2 (for bivalent metal ions) and 1:3 (for Fe(III) ion) electrolytes. The complexes were found to have octahedral geometry based on magnetic moment and solid reflectance measurements. Thermal analysis data revealed the decomposition of the complexes in successive steps with the removal of anions, coordinated water and bis Schiff base ligand. The thermodynamic parameters were calculated using Coats-Redfern equation. The Anticancer screening studies were performed on human colorectal cancer (HCT), hepatic cancer (HepG2) and breast cancer (MCF-7) cell lines. The antimicrobial activity of all the compounds was studied against Gram negative (Escherichia coli and Proteus vulgaris) and Gram positive (Bacillus vulgaris and Staphylococcus pyogones) bacteria. It was observed that the coordination of metal ion has a pronounced effect on the microbial activities of the bis Schiff base ligand. All the metal complexes have shown higher antimicrobial effect than the free bis Schiff base ligand.

  6. Synthesis and spectroscopic studies of binuclear metal complexes of a tetradentate N 2O 2 Schiff base ligand derived from 4,6-diacetylresorcinol and benzylamine

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy

    2008-09-01

    A tetradentate N 2O 2 donor Schiff base ligand, H 2L, was synthesized by the condensation of 4,6-diacetylresorcinol with benzylamine. The structure of the ligand was elucidated by elemental analyses, IR, 1H NMR, electronic and mass spectra. Reaction of the Schiff base ligand with nickel(II), cobalt(II), iron(III), cerium(III), vanadyl(IV) and uranyl(VI) ions in 1:2 molar ratio afforded binuclear metal complexes. Also, reaction of the ligand with several copper(II) salts, including Cl -, NO 3-, AcO -, ClO 4- and SO 42- afforded different metal complexes that reflect the non-coordinating or weakly coordinating power of the ClO 4- anion as compared to the strongly coordinating power of SO 42- and Cl - anions. Characterization and structure elucidation of the prepared complexes were achieved by elemental and thermal analyses, IR, 1H NMR, electronic, mass and ESR spectra as well as magnetic susceptibility measurements. The metal complexes exhibited different geometrical arrangements such as square planar, octahedral, square pyramidal and pentagonal bipyramidal arrangements. The variety in the geometrical arrangements depends on the nature of both the anion and the metal ion.

  7. Coordination behavior of new bis Schiff base ligand derived from 2-furan carboxaldehyde and propane-1,3-diamine. Spectroscopic, thermal, anticancer and antibacterial activity studies.

    PubMed

    Mohamed, Gehad G; Zayed, Ehab M; Hindy, Ahmed M M

    2015-06-15

    Novel bis Schiff base ligand, [N1,N3-bis(furan-2-ylmethylene)propane-1,3-diamine], was prepared by the condensation of furan-2-carboxaldehyde with propane-1,3-diamine. Its conformational changes on complexation with transition metal ions [Co(II), Ni(II), Cu(II), Mn(II), Cd(II), Zn(II) and Fe(III)] have been studied on the basis of elemental analysis, conductivity measurements, spectral (infrared, (1)H NMR, electronic), magnetic and thermogravimetric studies. The conductance data of the complexes revealed their electrolytic nature suggesting them as 1:2 (for bivalent metal ions) and 1:3 (for Fe(III) ion) electrolytes. The complexes were found to have octahedral geometry based on magnetic moment and solid reflectance measurements. Thermal analysis data revealed the decomposition of the complexes in successive steps with the removal of anions, coordinated water and bis Schiff base ligand. The thermodynamic parameters were calculated using Coats-Redfern equation. The Anticancer screening studies were performed on human colorectal cancer (HCT), hepatic cancer (HepG2) and breast cancer (MCF-7) cell lines. The antimicrobial activity of all the compounds was studied against Gram negative (Escherichia coli and Proteus vulgaris) and Gram positive (Bacillus vulgaris and Staphylococcus pyogones) bacteria. It was observed that the coordination of metal ion has a pronounced effect on the microbial activities of the bis Schiff base ligand. All the metal complexes have shown higher antimicrobial effect than the free bis Schiff base ligand. PMID:25767990

  8. Synthesis of Phthalimide Derivatives as Potential PPAR-γ Ligands

    PubMed Central

    Eom, So Hyeon; Liu, Sen; Su, Mingzhi; Noh, Tae Hwan; Hong, Jongki; Kim, Nam Deuk; Chung, Hae Young; Yang, Min Hye; Jung, Jee H.

    2016-01-01

    Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma) in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships) study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γ agonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-γ activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes. PMID:27338418

  9. Synthesis, characterization and biological relevance of some metal (II) complexes with oxygen, nitrogen and oxygen (ONO) donor Schiff base ligand derived from thiazole and 2-hydroxy-1-naphthaldehyde

    NASA Astrophysics Data System (ADS)

    Nagesh, G. Y.; Mruthyunjayaswamy, B. H. M.

    2015-04-01

    The novel Schiff base ligand 2-((2-hydroxynaphthalen-1-yl)methylene)-N-(4-phenylthiazol-2-yl)hydrazinecarboxamide (L) obtained by the condensation of N-(4-phenylthiazol-2-yl)hydrazinecarboxamide with 2-hydroxy-1-naphthaldehyde and its newly synthesized Cu(II), Co(II), Ni(II), Zn(II) and Cd(II) complexes have been characterized by microanalysis, molar conductance, IR, 1H NMR, ESI-mass, UV-Visible, TGA/DTA, ESR and powder X-ray diffraction data to explicate their structures. The IR results confirmed the tridentate binding of the ligand involving oxygen atom of amide carbonyl, azomethine nitrogen and naphthol oxygen. 1H NMR spectral data of the ligand (L) and its Zn(II) complex agreed well with the proposed structures. Thermogravimetric studies for Cu(II) and Ni(II) complexes indicated the presence of coordinated water molecules and the final product is the metal oxide. In order to appraise the effect of antimicrobial activity of metal ions upon chelation, the newly synthesized ligand and its metal complexes were screened for their antimicrobial activity by minimum inhibitory concentration (MIC) method. The DNA cleavage activities were studied using plasmid DNA pBR322 (Bangal re Genei, Bengaluru, Cat. No 105850) as a target molecule by agarose gel electrophoresis method. The brine shrimp bioassay was also carried out to study the in vitro cytotoxicity properties against Artemia salina. Furthermore, the antioxidant activity were determined in vitro by reduction of 1,1-diphenyl-2-picryl hydrazyl (DPPH). The ligand exhibited better in vitro-antioxidant activity than its metal complexes.

  10. Ligating behaviour of Schiff base ligands derived from heterocyclic β-diketone and ethanol or propanol amine with oxovanadium (IV) metal ion

    NASA Astrophysics Data System (ADS)

    Thaker, B. T.; Barvalia, R. S.

    2009-12-01

    Synthesis and evaluation of six new oxovanadium (IV) complexes, formed by the interaction of vanadyl sulphate pentahydrate and the Schiff base, viz.; (HL 1)-(HL 3) and (HL 4)-(HL 6) such as 5-hydroxy-3-methyl-1(2-chloro)phenyl-1H-pyrazolone-4-carbaldehyde (I), 5-hydroxy-3-methyl-1(3-chloro)phenyl-1H-pyrazolone-4-carbaldehyde (II) and 5-hydroxy-3-methyl-1(3-sulphoamido)phenyl-1H-pyrazolone-4-carbaldehyde (III) with ethanol amine and propanol amine, respectively, in aqueous ethanol medium. The ligands and their Schiff base ligands have been characterized by elemental analyses, IR and 1H NMR. The resulting complexes have been characterized by elemental analyses, IR, 1H NMR, mass, electronic, electron spin resonance spectra, magnetic susceptibility measurement, molar conductance and thermal studies. The IR spectral data suggest that the ligand behaves as a dibasic bidentate with ON donor sequence towards metal ion. The molar conductivity data show them to be non-electrolytes. From the electronic, magnetic and ESR spectral data suggest that all the oxovanadium (IV) complexes have distorted octahedral geometry.

  11. EPR, magnetic and spectral studies of copper(II) and nickel(II) complexes of schiff base macrocyclic ligand derived from thiosemicarbazide and glyoxal

    NASA Astrophysics Data System (ADS)

    Chandra, Sulekh; Sangeetika, X.

    2004-01-01

    A new macrocylic Schiff base 1,2,5,6,8,11-hexaazacyclododeca-7,12-dithione-2,4,8,10-tetraene(H 2L 4) containing thiosemicarbazone moiety is readily prepared and characterized for the first time with fairly good yield. Macrocylic ligand (H 2L 4) is prepared from the mesocyle 6-ethoxy-4-thio-2,3,5-triazine(H 2L 3) in ethanol with copper chloride acting as template using high dilution technique. The complexes of macrocylic ligand with a general composition M(H 2L 4)X 2 [where M=Cu(II) or Ni(II); H 2L 4=1,2,5,6,8,11-hexaazacyclo dodeca-7,12-dithione-2,4,8,10-tetraene; X= Cl -, NO 3-, 1/ 2SO 42-] and ML 4 (where metal salt used to synthesize complex is copper acetate and nickel thiocyanate) have been synthesized. The complexes were characterized on the basis of elemental analysis, molar conductance, magnetic susceptibility, IR, electronic, 1H NMR, mass and EPR spectral studies. The complexes from H 2L 4 show different stoichiometry ratio and with a variable grade of deprotonation in the ligand, depending upon the salt used and working conditions.

  12. Synthesis and characterization of a copper(II) complex of a ONN donor Schiff base ligand derived from pyridoxal and 2-(pyrid-2-yl)ethylamine - A novel pyridoxal based fluorescent probe

    NASA Astrophysics Data System (ADS)

    Mandal, Senjuti; Modak, Ritwik; Goswami, Sanchita

    2013-04-01

    The title complex, Cu(LH)Cl2 is the first copper(II) complex with a Schiff base derived from pyridoxal and 2-(pyrid-2-yl)ethylamine. The central metal lies in a distorted square pyramidal environment with basal plane occupied by the tridentate ONN donor ligand and a Cl atom. The apical position is occupied by another Cl atom. The existence of two different kinds of H-bonds stabilize the network that propagates as parallel layers along crystallographic b axis. The compound exhibits an irreversible CuII/CuI couple in DMF. As pyridoxal containing moieties are fluorescent in nature, its potential as a fluorescent probe is cultivated. Copper(II) ion effectively quenches the fluorescence of HL and the association constant for Cu(II) was estimated to be 10.8 × 104 M-1 in methanol by the linear Benesi-Hildebrand equation.

  13. A New Ligand-Based Method for Purifying Active Human Plasma-Derived Ficolin-3 Complexes Supports the Phenomenon of Crosstalk between Pattern-Recognition Molecules and Immunoglobulins.

    PubMed

    Man-Kupisinska, Aleksandra; Michalski, Mateusz; Maciejewska, Anna; Swierzko, Anna S; Cedzynski, Maciej; Lugowski, Czeslaw; Lukasiewicz, Jolanta

    2016-01-01

    Despite recombinant protein technology development, proteins isolated from natural sources remain important for structure and activity determination. Ficolins represent a class of proteins that are difficult to isolate. To date, three methods for purifying ficolin-3 from plasma/serum have been proposed, defined by most critical step: (i) hydroxyapatite absorption chromatography (ii) N-acetylated human serum albumin affinity chromatography and (iii) anti-ficolin-3 monoclonal antibody-based affinity chromatography. We present a new protocol for purifying ficolin-3 complexes from human plasma that is based on an exclusive ligand: the O-specific polysaccharide of Hafnia alvei PCM 1200 LPS (O-PS 1200). The protocol includes (i) poly(ethylene glycol) precipitation; (ii) yeast and l-fucose incubation, for depletion of mannose-binding lectin; (iii) affinity chromatography using O-PS 1200-Sepharose; (iv) size-exclusion chromatography. Application of this protocol yielded average 2.2 mg of ficolin-3 preparation free of mannose-binding lectin (MBL), ficolin-1 and -2 from 500 ml of plasma. The protein was complexed with MBL-associated serine proteases (MASPs) and was able to activate the complement in vitro. In-process monitoring of MBL, ficolins, and total protein content revealed the presence of difficult-to-remove immunoglobulin G, M and A, in some extent in agreement with recent findings suggesting crosstalk between IgG and ficolin-3. We demonstrated that recombinant ficolin-3 interacts with IgG and IgM in a concentration-dependent manner. Although this association does not appear to influence ficolin-3-ligand interactions in vitro, it may have numerous consequences in vivo. Thus our purification procedure provides Ig-ficolin-3/MASP complexes that might be useful for gaining further insight into the crosstalk and biological activity of ficolin-3. PMID:27232184

  14. A New Ligand-Based Method for Purifying Active Human Plasma-Derived Ficolin-3 Complexes Supports the Phenomenon of Crosstalk between Pattern-Recognition Molecules and Immunoglobulins

    PubMed Central

    Man-Kupisinska, Aleksandra; Michalski, Mateusz; Maciejewska, Anna; Swierzko, Anna S.; Cedzynski, Maciej; Lugowski, Czeslaw; Lukasiewicz, Jolanta

    2016-01-01

    Despite recombinant protein technology development, proteins isolated from natural sources remain important for structure and activity determination. Ficolins represent a class of proteins that are difficult to isolate. To date, three methods for purifying ficolin-3 from plasma/serum have been proposed, defined by most critical step: (i) hydroxyapatite absorption chromatography (ii) N-acetylated human serum albumin affinity chromatography and (iii) anti-ficolin-3 monoclonal antibody-based affinity chromatography. We present a new protocol for purifying ficolin-3 complexes from human plasma that is based on an exclusive ligand: the O-specific polysaccharide of Hafnia alvei PCM 1200 LPS (O-PS 1200). The protocol includes (i) poly(ethylene glycol) precipitation; (ii) yeast and l-fucose incubation, for depletion of mannose-binding lectin; (iii) affinity chromatography using O-PS 1200-Sepharose; (iv) size-exclusion chromatography. Application of this protocol yielded average 2.2 mg of ficolin-3 preparation free of mannose-binding lectin (MBL), ficolin-1 and -2 from 500 ml of plasma. The protein was complexed with MBL-associated serine proteases (MASPs) and was able to activate the complement in vitro. In-process monitoring of MBL, ficolins, and total protein content revealed the presence of difficult-to-remove immunoglobulin G, M and A, in some extent in agreement with recent findings suggesting crosstalk between IgG and ficolin-3. We demonstrated that recombinant ficolin-3 interacts with IgG and IgM in a concentration-dependent manner. Although this association does not appear to influence ficolin-3-ligand interactions in vitro, it may have numerous consequences in vivo. Thus our purification procedure provides Ig-ficolin-3/MASP complexes that might be useful for gaining further insight into the crosstalk and biological activity of ficolin-3. PMID:27232184

  15. Syntheses, Structures, and Photochemistry of Manganese Nitrosyls Derived from Designed Schiff Base Ligands: Potential NO Donors that can be Activated by Near-Infrared Light

    PubMed Central

    Hoffman-Luca, C. Gianna; Eroy-Reveles, Aura A.; Alvarenga, Jose

    2016-01-01

    Two manganese nitrosyls, namely [Mn(SBPy3)(NO)](ClO4)2 (1) and [Mn(SBPy2Q)(NO)](ClO4)2 (2) have been synthesized by using designed pentadentate Schiff base ligands N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-aldimine (SBPy3) and N,N-bis(2-pyridyl methyl)amine-N-ethyl-2-quinoline-2-aldimine (SBPy2Q). Reaction of NO(g) with [Mn(SBPy3)(MeOH)](ClO4)2 and [Mn(SBPy2Q)(EtOH)](ClO4)2 in MeCN affords 1 and 2 respectively in good yields. Narrow-width peaks in the 1H NMR spectra and strong νNO at 1773 cm-1 (of 1) and 1759 cm-1 (of 2) confirm a strongly-coupled {low-spin Mn(II)-NO• }formulation for both these {Mn-NO}6 nitrosyls. In MeCN, 1 exhibits two strong absorption bands with λmax at 500 and 720 nm. These bands red shifts to 550 and 785 nm in case of 2 due to substitution of the pyridyl-imine moiety of SBPy3 with quinolyl-imine moiety in the SBPy2Q ligand frame. Exposure of solutions 1 and 2 to near-infrared (NIR) light (780 nm, 5 mW) results in rapid bleaching of the orange and fuchsia solutions and free NO is detected in the solutions by an NO-sensitive electrode. The high quantum yield values (Φ) of 1 (0.580 ± 0.010, λirr = 550 nm, MeCN) and 2 (0.434 ± 0.010, λirr = 550 nm, MeCN) and in particular their sensitivity to NIR light of 800-950 nm range strongly suggest that these designed manganese nitrosyls could be used as NIR light-triggered NO donors. PMID:19722518

  16. Dicynamide bridged two new zig-zag 1-D Zn(II) coordination polymers of pyrimidine derived Schiff base ligands: Synthesis, crystal structures and fluorescence studies

    NASA Astrophysics Data System (ADS)

    Konar, Saugata

    2015-07-01

    Two new zigzag 1-D polymeric Zn(II) coordination polymers {[Zn(L1)(μ1,5-dca)](H2O)}n (1), {[Zn(L2)(μ1,5-dca)](ClO4)}n (2) of two potentially tridentate NNO-, NNN-, donor Schiff base ligands [2-(2-(4,6-dimethylpyrimidin-2-yl)hydrazono)methyl)phenol] (L1), [1-(4,6-dimethylpyrimidin-2-yl)-2-(dipyridin-2ylmethylene)hydrazine] (L2) have been synthesized and characterized by elemental analyses, IR and 1H NMR, fluorescence spectroscopy and single crystal X-ray crystallography. The dicyanamide ions act as linkers (μ1,5 mode) in the formation of these coordination polymers. Both the complexes 1 and 2 have same distorted square pyramidal geometry around the Zn(II) centres. The weak forces like π⋯π, Csbnd H⋯π, anion⋯π interactions lead to various supramolecular architectures. Complex 1 shows high chelation enhanced fluorescence compared to that of 2. The fluorescence spectral changes observed high selectivity towards Zn(II) over other metal ions such as Mn(II), Co(II), Ni(II), Cu(II).

  17. Synthesis, spectral and magnetic studies of mono- and bi-nuclear metal complexes of a new bis(tridentate NO2) Schiff base ligand derived from 4,6-diacetylresorcinol and ethanolamine

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy

    2009-07-01

    A new bis(tridentate NO2) Schiff base ligand, H4L, was prepared by the reaction of the bifunctional carbonyl compound; 4,6-diacetylresorcinol (DAR) with ethanolamine. The ligand reacted with iron(III), cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II), cerium(III) and uranyl(VI) ions, in absence and in presence of LiOH, to yield mono- and bi-nuclear complexes with different coordinating sites. The ligand and its metal complexes were characterized by elemental analyses, IR, 1H NMR, electronic, ESR and mass spectra, conductivity and magnetic susceptibility measurements as well as thermal analyses. In absence of LiOH, mononuclear complexes (2, 3 and 5-9) as well as binuclear complexes (1 and 4) were obtained. In mononuclear complexes, the ligand acted as a neutral, mono- and di-basic/bi- and tetra-dentate ligand while in binuclear complexes (1 and 4), the ligand acted as a bis(mono- or di-basic/tridentate) ligand. On the other hand, in presence of LiOH, only binuclear complexes (10-15) were obtained in which the ligand acted as a bis(dibasic tridentate) ligand. The metal complexes exhibited different geometrical arrangements such as octahedral, tetrahedral, square planar, square pyramidal and pentagonal bipyramidal arrangements.

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

    SciTech Connect

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

    2014-01-01

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

  19. 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. PMID:26874044

  20. Electronic communication across diamagnetic metal bridges: a homoleptic gallium(III) complex of a redox-active diarylamido-based ligand and its oxidized derivatives

    PubMed Central

    Liddle, Brendan J.; Wanniarachchi, Sarath; Hewage, Jeewantha S.; Lindeman, Sergey V.; Bennett, Brian; Gardinier, James R.

    2012-01-01

    Complexes with cations of the type [Ga(L)2]n+ where L = bis(4-methyl-2-(1H-pyrazol-1-yl)phenyl)amido and n = 1, 2, 3 have been prepared and structurally characterized. The electronic properties of each were probed by electrochemical and spectroscopic means and were interpreted with the aid of DFT calculations. The dication, best described as [Ga(L−)(L0)]2+, and is a Robin-Day class II mixed-valence species. As such, a broad, weak, solvent-dependent intervalence charge transfer (IVCT) band was found in the NIR spectrum in the range 6390 to 6925 cm−1, depending on solvent. Band shape analyses and the use of Hush and Marcus relations revealed a modest electronic coupling, Hab of about 200 cm−1, and a large rate constant for electron transfer, ket, on the order of 1010 s−1 between redox active ligands. The di-oxidized complex [Ga(L0)2]3+ shows a half-field ΔMs = 2 transition in its solid-state X-Band EPR spectrum at 5 K which indicates that the triplet state is thermally populated. DFT calculations (M06/Def2-SV(P)) suggest that the singlet state is 21.7 cm−1 lower in energy than the triplet state. PMID:23163736

  1. Container molecules based on imine type ligands.

    PubMed

    Schulze, A Carina; Oppel, Iris M

    2012-01-01

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

  2. Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands

    DOEpatents

    Jones, Alun G.; Lister-James, John; Davison, Alan

    1988-05-24

    A bisamide-bisthiol ligand containing fatty acid substituted thiol useful for producing Tc-labelled radiodiagnostic imaging agents is described. The ligand forms a complex with the radionuclide .sup.99m Tc suitable for administration as a radiopharmaceutical to obtain images of the heart for diagnosis of myocardial disfunction.

  3. Stable coordination of the inhibitory Ca2+ ion at MIDAS in integrin CD11b/CD18 by an antibody-derived ligand aspartate: Implications for integrin regulation and structure-based drug design

    PubMed Central

    Mahalingam, Bhuvaneshwari; Ajroud, Kaouther; Alonso, Jose Luis; Anand, Saurabh; Adair, Brian; Horenstein, Alberto L; Malavasi, Fabio; Xiong, Jian-Ping; Arnaout, M. Amin

    2011-01-01

    A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg2+ ion hexacoordinated at the metal-ion-dependent-adhesion site (MIDAS) in the integrin A-domain. This interaction stabilizes the A-domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A-domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking monoclonal antibody (mAb) 107 binds MIDAS of integrin CD11b/CD18 A-domain (CD11bA), but in contrast, it favors the inhibitory Ca2+ ion over Mg2+ at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of Ca2+ at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca2+. Binding of Fab 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that denticity of the ligand Asp/Glu can modify divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca2+ ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists. PMID:22095715

  4. Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.

    PubMed

    Deekonda, Srinivas; Wugalter, Lauren; Rankin, David; Largent-Milnes, Tally M; Davis, Peg; Wang, Yue; Bassirirad, Neemah M; Lai, Josephine; Kulkarni, Vinod; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J

    2015-10-15

    We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required. PMID:26323872

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

    PubMed Central

    2015-01-01

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

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

    PubMed

    Marsh, Lorraine

    2015-01-01

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

  7. Increasing the CO2 /N2 Selectivity with a Higher Surface Density of Pyridinic Lewis Basic Sites in Porous Carbon Derived from a Pyridyl-Ligand-Based Metal-Organic Framework.

    PubMed

    Li, Liangjun; Wang, Ying; Gu, Xin; Yang, Qipeng; Zhao, Xuebo

    2016-07-01

    The development of functional porous carbon with high CO2 /N2 selectivity is of great importance for CO2 capture. In this paper, a type of porous carbon with doped pyridinic sites (termed MOFC) was prepared from the carbonization of a pyridyl-ligand based MOF. Four MOFCs derived from different carbonizing temperatures were prepared. Structural studies revealed high contents of pyridinic-N groups and nearly the same pore-size distributions for these MOFCs. Gas-sorption studies revealed outstanding CO2 uptake at low pressures and room temperature. Owing to the high content of pyridinic-N groups, the CO2 /N2 selectivity on these MOFCs exhibits values of about 40-50, which are among the top values in carbon materials. Further correlation studies demonstrated that the CO2 /N2 selectivities show a positive linear relationship with the surface density of pyridinic-N groups, thus validating the synergistic effect of the doped pyridinic-N groups on CO2 adsorption selectivity. PMID:27146096

  8. Heterobridged dinuclear, tetranuclear, dinuclear-based 1-d, and heptanuclear-based 1-D complexes of copper(II) derived from a dinucleating ligand: syntheses, structures, magnetochemistry, spectroscopy, and catecholase activity.

    PubMed

    Majumder, Samit; Sarkar, Sohini; Sasmal, Sujit; Sañudo, E Carolina; Mohanta, Sasankasekhar

    2011-08-15

    The work in this paper presents syntheses, characterization, crystal structures, variable-temperature/field magnetic properties, catecholase activity, and electrospray ionization mass spectroscopic (ESI-MS positive) study of five copper(II) complexes of composition [Cu(II)(2)L(μ(1,1)-NO(3))(H(2)O)(NO(3))](NO(3)) (1), [{Cu(II)(2)L(μ-OH)(H(2)O)}(μ-ClO(4))](n)(ClO(4))(n) (2), [{Cu(II)(2)L(NCS)(2)}(μ(1,3)-NCS)](n) (3), [{Cu(II)(2)L(μ(1,1)-N(3))(ClO(4))}(2)(μ(1,3)-N(3))(2)] (4), and [{Cu(II)(2)L(μ-OH)}{Cu(II)(2)L(μ(1,1)-N(3))}{Cu(II)(μ(1,1)-N(3))(4)(dmf)}{Cu(II)(2)(μ(1,1)-N(3))(2)(N(3))(4)}](n)·ndmf (5), derived from a new compartmental ligand 2,6-bis[N-(2-pyridylethyl)formidoyl]-4-ethylphenol, which is the 1:2 condensation product of 4-ethyl-2,6-diformylphenol and 2-(2-aminoethyl)pyridine. The title compounds are either of the following nuclearities/topologies: dinuclear (1), dinuclear-based one-dimensional (2 and 3), tetranuclear (4), and heptanuclear-based one-dimensional (5). The bridging moieties in 1-5 are as follows: μ-phenoxo-μ(1,1)-nitrate (1), μ-phenoxo-μ-hydroxo and μ-perchlorate (2), μ-phenoxo and μ(1,3)-thiocyanate (3), μ-phenoxo-μ(1,1)-azide and μ(1,3)-azide (4), μ-phenoxo-μ-hydroxo, μ-phenoxo-μ(1,1)-azide, and μ(1,1)-azide (5). All the five compounds exhibit overall antiferromagnetic interaction. The J values in 1-4 have been determined (-135 cm(-1) for 1, -298 cm(-1) for 2, -105 cm(-1) for 3, -119.5 cm(-1) for 4). The pairwise interactions in 5 have been evaluated qualitatively to result in S(T) = 3/2 spin ground state, which has been verified by magnetization experiment. Utilizing 3,5-di-tert-butyl catechol (3,5-DTBCH(2)) as the substrate, catecholase activity of all the five complexes have been checked. While 1 and 3 are inactive, complexes 2, 4, and 5 show catecholase activity with turn over numbers 39 h(-1) (for 2), 40 h(-1) (for 4), and 48 h(-1) (for 5) in dmf and 167 h(-1) (for 2) and 215 h(-1) (for 4) in acetonitrile

  9. Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

    PubMed Central

    Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

    2013-01-01

    The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

  10. Adapting Document Similarity Measures for Ligand-Based Virtual Screening.

    PubMed

    Himmat, Mubarak; Salim, Naomie; Al-Dabbagh, Mohammed Mumtaz; Saeed, Faisal; Ahmed, Ali

    2016-01-01

    Quantifying the similarity of molecules is considered one of the major tasks in virtual screening. There are many similarity measures that have been proposed for this purpose, some of which have been derived from document and text retrieving areas as most often these similarity methods give good results in document retrieval and can achieve good results in virtual screening. In this work, we propose a similarity measure for ligand-based virtual screening, which has been derived from a text processing similarity measure. It has been adopted to be suitable for virtual screening; we called this proposed measure the Adapted Similarity Measure of Text Processing (ASMTP). For evaluating and testing the proposed ASMTP we conducted several experiments on two different benchmark datasets: the Maximum Unbiased Validation (MUV) and the MDL Drug Data Report (MDDR). The experiments have been conducted by choosing 10 reference structures from each class randomly as queries and evaluate them in the recall of cut-offs at 1% and 5%. The overall obtained results are compared with some similarity methods including the Tanimoto coefficient, which are considered to be the conventional and standard similarity coefficients for fingerprint-based similarity calculations. The achieved results show that the performance of ligand-based virtual screening is better and outperforms the Tanimoto coefficients and other methods. PMID:27089312

  11. Metal-Ligand Cooperativity in a Methandiide-Derived Iridium Carbene Complex.

    PubMed

    Weismann, Julia; Waterman, Rory; Gessner, Viktoria H

    2016-03-01

    The synthesis, electronic structure, and reactivity of the first Group 9 carbene complex, [Cp*IrL] [L=C(Ph2 PS)(SO2 Ph)] (2), based on a dilithio methandiide are reported. Spectroscopic as well as computational studies have shown that, despite using a late transition-metal precursor, sufficient charge transfer occurred from the methandiide to the metal, resulting in a stable, nucleophilic carbene species with pronounced metal-carbon double-bond character. The potential of this iridium complex in the activation of a series of E-H bonds by means of metal-ligand cooperation has been tested. These studies have revealed distinct differences in the reactivity of 2 compared to a previously reported ruthenium analogue. Whereas attempts to activate the O-H bond in different phenol derivatives resulted in ligand cleavage, H-H and Si-H activation as well as dehydrogenation of isopropanol have been accomplished. These reactions are driven by the transformation of the carbene to an alkyl ligand. Contrary to a previously reported ruthenium carbene system, the dihydrogen activation has been found to proceed by a stepwise mechanism, with the activation first taking place solely at the metal. The activated products further reacted to afford a cyclometalated complex through liberation of the activated substrates. In the case of triphenylsilane, cyclometalation could thus be induced by a substoichiometric (i.e., catalytic) amount of silane. PMID:26748420

  12. Synthesis, characterization, X-ray crystal structures and antibacterial activities of Schiff base ligands derived from allylamine and their vanadium(IV), cobalt(III), nickel(II), copper(II), zinc(II) and palladium(II) complexes

    NASA Astrophysics Data System (ADS)

    Amiri Rudbari, Hadi; Iravani, Mohammad Reza; Moazam, Vahid; Askari, Banafshe; Khorshidifard, Mahsa; Habibi, Neda; Bruno, Giuseppe

    2016-12-01

    A new Schiff base ligand, HL2, and four new Schiff base complexes, NiL12, PdL12, NiL22 and ZnL22, have been prepared and characterized by elemental analysis (CHN), FT-IR and UV-Vis spectroscopy. 1H and 13C NMR techniques were employed for characterization of the ligand (HL2) and the diamagnetic complexes (PdL12 and ZnL22). The molecular structures of PdL12, NiL22 and ZnL22 complexes were determined by the single crystal X-ray diffraction technique. The crystallographic data reveal that in these complexes the metal centers are four-coordinated by two phenolate oxygen and two imine nitrogen atoms of two Schiff base ligands. The geometry around the metal center in the PdL12 and NiL22 complexes is square-planar and for ZnL22 it is a distorted tetrahedral.In the end, five new (HL2, NiL12, PdL12, NiL22 and ZnL22) and six reported (HL1, VOL12, CoL13, CuL12, ZnL12 and Zn2L14) Schiff base compounds were tested for their in vitro antimicrobial activity against Staphylococcus aureus and Escherichia coli as examples of Gram-positive and Gram-negative bacterial strains, respectively, by disc diffusion method.

  13. Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints.

    PubMed

    Sirci, Francesco; Istyastono, Enade P; Vischer, Henry F; Kooistra, Albert J; Nijmeijer, Saskia; Kuijer, Martien; Wijtmans, Maikel; Mannhold, Raimund; Leurs, Rob; de Esch, Iwan J P; de Graaf, Chris

    2012-12-21

    Virtual fragment screening (VFS) is a promising new method that uses computer models to identify small, fragment-like biologically active molecules as useful starting points for fragment-based drug discovery (FBDD). Training sets of true active and inactive fragment-like molecules to construct and validate target customized VFS methods are however lacking. We have for the first time explored the possibilities and challenges of VFS using molecular fingerprints derived from a unique set of fragment affinity data for the histamine H(3) receptor (H(3)R), a pharmaceutically relevant G protein-coupled receptor (GPCR). Optimized FLAP (Fingerprints of Ligands and Proteins) models containing essential molecular interaction fields that discriminate known H(3)R binders from inactive molecules were successfully used for the identification of new H(3)R ligands. Prospective virtual screening of 156,090 molecules yielded a high hit rate of 62% (18 of the 29 tested) experimentally confirmed novel fragment-like H(3)R ligands that offer new potential starting points for the design of H(3)R targeting drugs. The first construction and application of customized FLAP models for the discovery of fragment-like biologically active molecules demonstrates that VFS is an efficient way to explore protein-fragment interaction space in silico. PMID:23140085

  14. Organometallic Ru(II) Photosensitizers Derived from π-Expansive Cyclometalating Ligands: Surprising Theranostic PDT Effects.

    PubMed

    Sainuddin, Tariq; McCain, Julia; Pinto, Mitch; Yin, Huimin; Gibson, Jordan; Hetu, Marc; McFarland, Sherri A

    2016-01-01

    The purpose of the present study was to investigate the influence of π-expansive cyclometalating ligands on the photophysical and photobiological properties of organometallic Ru(II) compounds. Four compounds with increasing π conjugation on the cyclometalating ligand were prepared, and their structures were confirmed by HPLC, 1D and 2D (1)H NMR, and mass spectrometry. The properties of these compounds differed substantially from their Ru(II) polypyridyl counterparts. Namely, they were characterized by red-shifted absorption, very weak to no room temperature phosphorescence, extremely short phosphorescence state lifetimes (<10 ns), low singlet oxygen quantum yields (0.5-8%), and efficient ligand-centered fluorescence. Three of the metal complexes were very cytotoxic to cancer cells in the dark (EC50 values = 1-2 μM), in agreement with what has traditionally been observed for Ru(II) compounds derived from small C^N ligands. Surprisingly, the complex derived from the most π-expansive cyclometalating ligand exhibited no cytotoxicity in the dark (EC50 > 300 μM) but was phototoxic to cells in the nanomolar regime. Exceptionally large phototherapeutic margins, exceeding 3 orders of magnitude in some cases, were accompanied by bright ligand-centered intracellular fluorescence in cancer cells. Thus, Ru(II) organometallic systems derived from π-expansive cyclometalating ligands, such 4,9,16-triazadibenzo[a,c]napthacene (pbpn), represent the first class of potent light-responsive Ru(II) cyclometalating agents with theranostic potential. PMID:26672769

  15. Spectroscopic studies and biological evaluation of some transition metal complexes of azo Schiff-base ligand derived from (1-phenyl-2,3-dimethyl-4-aminopyrazol-5-one) and 5-((4-chlorophenyl)diazenyl)-2-hydroxybenzaldehyde

    NASA Astrophysics Data System (ADS)

    Anitha, C.; Sheela, C. D.; Tharmaraj, P.; Sumathi, S.

    2012-10-01

    A series of metal(II) complexes of VO(II), Co(II), Ni(II), Cu(II) and Zn(II) have been synthesized from the azo Schiff base ligand 4-((E)-4-((E)-(4-chlorophenyl)diazenyl)-2-hydroxybenzylideneamino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (CDHBAP) and characterized by elemental analysis, spectral (IR, UV-Vis, 1H NMR, ESR and EI-mass), magnetic moment measurements, molar conductance, DNA, SEM, X-ray crystallography and fluorescence studies. The electronic absorption spectra and magnetic susceptibility measurements of the complexes indicate square pyramidal geometry for VO(II) and octahedral geometry for all the other complexes. The important infrared (IR) spectral bands corresponding to the active groups in the ligand and the solid complexes under investigation were studied and implies that CDHBAP is coordinated to the metal ions in a neutral tridentate manner. The redox behavior of copper(II) and vanadyl(II) complexes have been studied by cyclic voltammetry. The nuclease activity of the above metal(II) complexes shows that the complexes cleave DNA. All the synthesized complexes can serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The antibacterial and antifungal activities of the synthesized ligand and its metal complexes were screened against bacterial species (Staphylococcus aureus, Salmonella typhi, Escherichia coli, Bacillus subtilis, Shigella sonnie) and fungi (Candida albicans, Aspergillus niger, Rhizoctonia bataicola). Amikacin and Ketoconozole were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with the parent Schiff base ligand against bacterial and fungal species. The second harmonic generation (SHG) efficiency of the ligand was measured and the NLO (non-linear optical) properties of the ligand are expected to result in the realization of advanced optical devices in optical fiber

  16. Spectral, magnetic, biocidal screening, DNA binding and photocleavage studies of mononuclear Cu(II) and Zn(II) metal complexes of tricoordinate heterocyclic Schiff base ligands of pyrazolone and semicarbazide/thiosemicarbazide based derivatives

    NASA Astrophysics Data System (ADS)

    Raman, N.; Selvan, A.; Manisankar, P.

    2010-07-01

    We depict the synthesis and characterization of copper(II) and zinc(II) coordination compounds of 4-(3',4'-dimethoxybenzaldehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-semicarbazone ( 1a), 4-(3',4'-dimethoxybenzaldehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-thiosemicarbazone ( 1b), 4-(3'-hydroxy-4'-nitrobenzaldehydene)2-3-dimeth yl-1-phenyl-3-pyrazolin-5-semicarbazone ( 1c) and 4-(3'-hydroxy-4'-nitrobenzal dehydene)2-3-dimethyl-1-phenyl-3-pyrazolin-5-thiosemicarbazone ( 1d). All the remote compounds have the general composition [ML 2] (M = Cu(II) and Zn(II)); L = Schiff base ( 1a- 1d). All the complexes were characterized by elemental analysis, molar conductivity, IR, 1H NMR, UV-vis, ESI-Mass, magnetic susceptibility measurements, cyclic voltammetric measurements, and EPR spectral studies. It has been originated that the Schiff bases with Cu(II) and Zn(II) ions form mononuclear complexes on 1:2 (metal:ligand) stoichiometry. Distorted octahedral environment is suggested for the metal complexes. The conductivity data confirm the non-electrolytic nature of the complexes. The interaction of CuL 21a- 1d complexes with CT DNA was investigated by spectroscopic, electrochemical and viscosity measurements. Results suggest that the copper complexes bind to DNA via an intercalative mode. Moreover, the complexes have been found to promote the photocleavage of plasmid DNA pBR322 under irradiation at 365 nm. The Schiff bases and their metal complexes were screened for their antifungal and antibacterial activities against different species of pathogenic fungi and bacteria and their biopotency has been discussed.

  17. Synthesis, XAFS and X-ray structural studies of mono- and binuclear metal-chelates of N,O,O(N,O,S) tridentate Schiff base pyrazole derived ligands

    NASA Astrophysics Data System (ADS)

    Burlov, Anatolii S.; Uraev, Ali I.; Garnovskii, Dmitrii A.; Lyssenko, Konstantin A.; Vlasenko, Valery G.; Zubavichus, Yan V.; Murzin, Vadim Yu.; Korshunova, Eugenie V.; Borodkin, Gennadii S.; Levchenkov, Sergey I.; Vasilchenko, Igor S.; Minkin, Vladimir I.

    2014-05-01

    The syntheses of a series of novel N,O,O and N,O,S donor tridentate Schiff base ligands H2L1 and H2L2via the condensation of 1-phenyl-3-methyl-4-formylpyrazol-5-ol(thiol) with 2-hydroxymethylaniline and their Co(II), Ni(II), Cu(II), Fe(III), and Mn(II) complexes are reported. The compounds are characterized by the C, H, N, S, metal elemental analysis, IR spectroscopy; 1H NMR data for ligands, low-temperature magnetic measurements, X-ray absorption spectroscopy. The crystal structures for Ni(II) and Cu(II) coordination compounds with the compositions NiL21 and CuL21 are established by X-ray crystallography.

  18. Binding affinity prediction of novel estrogen receptor ligands using receptor-based 3-D QSAR methods.

    PubMed

    Sippl, Wolfgang

    2002-12-01

    We have recently reported the development of a 3-D QSAR model for estrogen receptor ligands showing a significant correlation between calculated molecular interaction fields and experimentally measured binding affinity. The ligand alignment obtained from docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection procedure, a significant and robust model was obtained (q(2)(LOO)=0.921, SDEP=0.345). To further analyze the robustness and the predictivity of the established model several recently developed estrogen receptor ligands were selected as external test set. An excellent agreement between predicted and experimental binding data was obtained indicated by an external SDEP of 0.531. Two other traditionally used prediction techniques were applied in order to check the performance of the receptor-based 3-D QSAR procedure. The interaction energies calculated on the basis of receptor-ligand complexes were correlated with experimentally observed affinities. Also ligand-based 3-D QSAR models were generated using program FlexS. The interaction energy-based model, as well as the ligand-based 3-D QSAR models yielded models with lower predictivity. The comparison with the interaction energy-based model and with the ligand-based 3-D QSAR models, respectively, indicates that the combination of receptor-based and 3-D QSAR methods is able to improve the quality of prediction. PMID:12413831

  19. Bisaryldiketene derivatives: A new class of selective ligands for c-myc G-quadruplex DNA.

    PubMed

    Peng, Dan; Tan, Jia-Heng; Chen, Shuo-Bin; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu

    2010-12-01

    A series of bisaryldiketene derivatives were designed and synthesized as a new class of specific G-quadruplex ligands. The ligand-quadruplex interactions were further evaluated by FRET, ITC, and PCR stop assay. In contrast to most of the G-quadruplex ligands reported so far, which comprise an extended aromatic ring, these compounds are neither polycyclic nor macrocyclic, but have a non-aromatic and relative flexible linker between two quinoline moieties enabling the conformation of compounds to be flexible. Our results showed that these bisaryldiketene derivatives could selectively recognize G-quadruplex DNA rather than binding to duplex DNA. Moreover, they showed promising discrimination between different G-quadruplex DNA. The primary binding affinity of ligand M2 for c-myc G-quadruplex DNA was over 200 times larger than that for telomere G-quadruplex DNA. PMID:21036049

  20. Syntheses, crystal structure, spectroscopic and photoluminescence studies of mononuclear copper(II), manganese(II), cadmium(II), and a 1D polymeric Cu(II) complexes with a pyrimidine derived Schiff base ligand

    NASA Astrophysics Data System (ADS)

    Ray, Sangita; Konar, Saugata; Jana, Atanu; Das, Kinsuk; Dhara, Anamika; Chatterjee, Sudipta; Kar, Susanta Kumar

    2014-01-01

    The complexation behaviour of Schiff base ligand 2-((2-(4,6-dimethylpyrimidin-2-yl)hydrazono)methyl)phenol [HL] towards different metal centres is reported by the syntheses and characterization of three mononuclear Cu(II), Mn(II) and Cd(II) complexes, [Cu(L)(H2O)2](NO3)(H2O) (1), [Mn(L)2](CH3OH) (2), [Cd(L)2](CH3OH) (3) and a 1D polymeric Cu(II) complex, [Cu(L)(ClO4)(C2N2O2H)]n(CH3OH) (4) respectively. In the complexes 1-4 the deprotonated uninegative tridentate ligand serves as NNO donor where one pyrimidine ring N, the azomethine N and the salicyl hydroxyl oxygen atoms are coordinatively active. The complex 1 has almost square pyramidal geometry [τ = 0.2081] whereas the metal centres maintain distorted octahedral geometry in the remaining three complexes 2-4. All the complexes are characterized by X-ray crystallography. The Cd(II) complex has considerable fluorescence while the rest of the complexes and the ligand molecule are fluorescent silent.

  1. Cd(II) and Zn(II) complexes of two new hexadentate Schiff base ligands derived from different aldehydes and ethanol amine; X-ray crystal structure, IR and NMR spectroscopy studies

    NASA Astrophysics Data System (ADS)

    Golbedaghi, Reza; Rezaeivala, Majid; Albeheshti, Leila

    2014-11-01

    Four new [Cd(H2L1)(NO3)]ClO4 (1), [Zn(H2L1)](ClO4)2 (2), [Cd(H2L2)(NO3)]ClO4 (3), and [Zn(H2L2)](ClO4)2 (4), complexes were prepared by the reaction of two new Schiff base ligands and Cd(II) and Zn(II) metal ions in equimolar ratios. The ligands H2L1 and H2L2 were synthesized by reaction of 2-[2-(2-formyl phenoxy)ethoxy]benzaldehyde and/or 2-[2-(3-formyl phenoxy)propoxy]benzaldehyde and ethanol amine and characterized by IR, 1H and 13C NMR spectroscopy. All complexes were characterized by IR, 1H and 13C NMR, COSY, and elemental analysis. Also, the complex 1 was characterized by X-ray in addition to the above methods. The X-ray crystal structure of compound 1 showed that all nitrogen and oxygen atoms of ligand (N2O4) and a molecule of nitrate with two donor oxygen atom have been coordinated to the metal ion and the Cd(II) ion is in an eight-coordinate environment that is best described as a distorted dodecahedron geometry.

  2. A new trinuclear zinc(II) complex and a heptacoordinated mononuclear cadmium(II) complex with a pyrimidine derived Schiff base ligand: Syntheses, crystal structures, photoluminescence and DFT calculations

    NASA Astrophysics Data System (ADS)

    Das, Kinsuk; Jana, Atanu; Konar, Saugata; Chatterjee, Sudipta; Mondal, Tapan Kumar; Barik, Anil Kumar; Kar, Susanta Kumar

    2013-09-01

    The new N6 donor hexadentate Schiff base 2,4-bis [2-(pyridine-2-ylmethylidene) hydrazinyl] pyrimidine (L), its trinuclear Zn(II) complex, [Zn3(L)2Cl6] (1) and mononuclear heptacoordinate Cd(II) complex [Cd(L)(H2O)2](ClO4)2 (2) have been synthesised and characterised by crystallographically and spectroscopically. Complex 1 is featured by the triangular arrangement of three zinc atoms where the neighbouring Zn atoms are linked via half portion (N3 chromophore) of the same ligand molecule. In 1, the ligand molecules behave as hexadentate ones (employing both pyrimidine nitrogen atoms as active donor centres) to create the octahedral environment around Zn(II). The central and terminal Zn(II) atom has N6 and N3Cl3 chromophores respectively. In 2 the same ligand (L) behaves as pentadentate one (ignoring one pyrimidine nitrogen in the coordination process) to produce a pentagonal bipyramidal geometry with two apical water molecules. The geometries of both complexes were optimised in the singlet state by DFT method. The TDDFT calculations have been done on the optimised geometries to understand the electronic structure and spectral transition in the complexes. Complex 1 exhibits intraligand 1(π → π*) fluorescence in aqueous methanol solvent at room temperature.

  3. The first scorpionate ligand based on diazaphosphole.

    PubMed

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

    2015-12-14

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

  4. Mixed ligand complexes of bis(phenylimine) Schiff base ligands incorporating pyridinium moiety. Synthesis, characterization and antibacterial activity

    NASA Astrophysics Data System (ADS)

    Mohamed, Gehad G.; El-Wahab, Zeinab H. Abd

    2005-04-01

    The synthesis and structural characterization of mixed ligand complexes derived from 2,6-pyridinedicarboxaldehydebis( o-hydroxyphenylimine), 2,6-pyridinedicarboxaldehydebis( p-hydroxyphenylimine) (1 ry ligands) and 2-aminopyridne (2 ry ligand) are reported. The ligands and their transition metal complexes were characterized on the bases of their elemental analyses, IR, solid reflectance, magnetic moment, molar conductance and thermal analysis (TGA). The mixed ligand complexes are formed in the 1:1:1 (M:L 1 or L 2:L') ratio as found from the elemental analyses and found to have the formulae [MX 2(L 1 or L 2)(L')]· nH 2O where M = Co(II), Ni(II), Cu(II) and Zn(II), L 1 = 2,6-pyridinedicarboxaldehydebis( p-hydroxyphenylimine), L 2 = 2,6-pyridine dicarboxaldehydebis( o-hydroxyphenylimine), L' = 2-aminopyridine, X = Cl - in case of Cu(II) complex and Br - in case of Co(II), Ni(II) and Zn(II) complexes and y = 0-3. The molar conductance data reveal that the chelates are non-electrolytes. IR spectra show that the Schiff bases are coordinated to the metal ions in a terdentate manner with NNN donor sites of the pyridine- N and two azomethine- N. While 2-aminopyridine coordinated to the metal ions via its pyridine- N. Magnetic and solid reflectance spectra are used to infer the coordinating capacity of the ligand and the geometrical structure of these complexes are found to be octahedral. The thermal behaviour of these chelates shows that the hydrated water molecules and the anions are removed in a successive two steps followed immediately by decomposition of the ligands (L 1, L 2 and L') in the subsequent steps. The activation thermodynamic parameters, such as, E*, Δ H*, Δ S* and Δ G* are calculated from the TG curves and discussed. The ligands and their metal chelates have been screened for their antimicrobial activities and the findings have been reported, explained and compared with some known antibiotics.

  5. Mixed ligand complexes of bis(phenylimine) Schiff base ligands incorporating pyridinium moiety Synthesis, characterization and antibacterial activity.

    PubMed

    Mohamed, Gehad G; Abd El-Wahab, Zeinab H

    2005-04-01

    The synthesis and structural characterization of mixed ligand complexes derived from 2,6-pyridinedicarboxaldehydebis(o-hydroxyphenylimine), 2,6-pyridinedicarboxaldehydebis(p-hydroxyphenylimine) (1(ry) ligands) and 2-aminopyridne (2(ry) ligand) are reported. The ligands and their transition metal complexes were characterized on the bases of their elemental analyses, IR, solid reflectance, magnetic moment, molar conductance and thermal analysis (TGA). The mixed ligand complexes are formed in the 1:1:1 (M:L(1) or L(2):L') ratio as found from the elemental analyses and found to have the formulae [MX(2)(L(1) or L(2))(L')].nH(2)O where M = Co(II), Ni(II), Cu(II) and Zn(II), L(1) = 2,6-pyridinedicarboxaldehydebis(p-hydroxyphenylimine), L(2) = 2,6-pyridine dicarboxaldehydebis(o-hydroxyphenylimine), L' = 2-aminopyridine, X = Cl(-) in case of Cu(II) complex and Br(-) in case of Co(II), Ni(II) and Zn(II) complexes and y = 0-3. The molar conductance data reveal that the chelates are non-electrolytes. IR spectra show that the Schiff bases are coordinated to the metal ions in a terdentate manner with NNN donor sites of the pyridine-N and two azomethine-N. While 2-aminopyridine coordinated to the metal ions via its pyridine-N. Magnetic and solid reflectance spectra are used to infer the coordinating capacity of the ligand and the geometrical structure of these complexes are found to be octahedral. The thermal behaviour of these chelates shows that the hydrated water molecules and the anions are removed in a successive two steps followed immediately by decomposition of the ligands (L(1), L(2) and L') in the subsequent steps. The activation thermodynamic parameters, such as, E*, DeltaH*, DeltaS* and DeltaG* are calculated from the TG curves and discussed. The ligands and their metal chelates have been screened for their antimicrobial activities and the findings have been reported, explained and compared with some known antibiotics. PMID:15741103

  6. Synthesis and spectroscopic studies of homo-binuclear, alkoxo bridged homo- and hetero-tetranuclear metal complexes of a bis-N 2O 4 Schiff base ligand derived from ethanolamine and macroacyclic tetranaphthaldehyde

    NASA Astrophysics Data System (ADS)

    Karaoğlu, Kaan; Baran, Talat; Değirmencioğlu, İsmail; Serbest, Kerim

    2011-09-01

    Three new homo-binuclear Ni(II), Cu(II), Zn(II) complexes ( 2-4), homo-tetranuclear Cu(II) complex ( 5), and hetero-tetranuclear Cu(II)-Ni(II) complex ( 6) of a macroacyclic potentially bis-hexadentate N 2O 4 Schiff base have been synthesized. The imino-alcohol ligand, H 4L was obtained by the condensation of ethanolamine with 2,2'-[2,3-bis(1-formyl-2-naphthyloxymethyl)-but-2-ene-1,4-diyldioxy]bis(naphthalene-1-carbaldehyde). The structures of both the Schiff base and its complexes have been proposed by elemental analyses, spectroscopic data i.e. IR, 1H and 13C NMR, UV-vis, electrospray ionisation mass spectra, molar conductivities and magnetic susceptibility measurements. The ligand has two similar compartments to bind first primary two metal ions, and acts bi- or tetra-negative, bis-tetradentate forming five membered chelate ring. However, secondary two metal ions (either Cu 2+ or Ni 2+) are ligated with dianionic oxygen atoms of the alcohol groups and are linked to the 1,10-phenanthroline-nitrogen atoms in the tetranuclear complexes ( 5 and 6).

  7. Synthesis and spectroscopic studies of some chromium and molybdenum derivatives of bis-(acetylacetone)ethylenediimine ligand

    NASA Astrophysics Data System (ADS)

    Ramadan, Ramadan M.; Abdel-Rahman, Laila H.; Ismael, Mohamed; Youssef, Teraze A.; Ali, Saadia A.

    2013-10-01

    Interaction of [Cr(CO)6] with bis-(acetylacetone)ethylenediimine Schiff base, H2acacen, under reduced pressure resulted in the formation of [Cr(CO)3(H2acacen)] derivative. The Schiff base acted as a tridentate and coordinated the metal through the nitrogen of the azomethine groups and one hydroxyl group. Reaction of [Mo(CO)6] with H2acacen under sunlight irradiation in presence of air gave the oxo derivative [Mo2O6(H2acacen)2]. The ligand acted as a bidentate and coordinated the metal through the two imine groups. In presence of 2,2'-bipyridine (bpy), the reaction of [Mo(CO)6] with H2acacen gave [Mo2O6(bpy)(H2acacec)]. The structures of the reported complexes were proposed on the basis of spectroscopic studies. The proposed structures were also verified by theoretical calculations based on accurate DFT approximations. Moreover, the relative reactivity was estimated using chemical descriptors analysis.

  8. Steric and electronic effects of 1,3-disubstituted cyclopentadienyl ligands on metallocene derivatives of Cerium, Titanium, Manganese, and Iron

    SciTech Connect

    Sofield, C.D.

    2000-05-19

    Sterically demanding 1,3-disubstituted cyclopentadienyl ligands were used to modify the physical properties of the corresponding metallocenes. Sterically demanding ligands provided kinetic stabilization for trivalent cerium compounds. Tris(di-t-butylcyclopentadienyl)cerium was prepared and anion competition between halides and cyclopentadienyl groups which had complicated synthesis of the tris(cyclopentadienyl)compound was qualitatively examined. Bis(di-t-butylcyclopentadienyl)cerium methyl was prepared and its rate of decomposition, by ligand redistribution, to tris(di-t-butylcyclopentadienyl)cerium was shown to be slower than the corresponding rate for less sterically demanding ligands. Asymmetrically substituted ligands provided a symmetry label for examination of chemical exchange processes. Tris[trimethylsilyl(t-butyl)cyclopentadienyl]cerium was prepared and the rate of interconversion between the C1 and C3 isomers was examined. The enthalpy difference between the two distereomers is 7.0 kJ/mol. The sterically demanding cyclopentadienyl ligands ansa-di-t-butylcyclopentadiene (Me2Si[(Me3C)2C5H3]2), ansa-bis(trimethylsilyl)cyclopentadiene (Me2Si[(Me3Si)2C5H3]2) and tetra-t-butylfulvalene and metallocene derivatives of the ligands were prepared and their structures were examined by single crystal X-ray crystallography. The effect that substituents on the cyclopentadienyl ring have on the pi-electron system of the ligand was examined through interaction between ligand and metal orbitals. A series of 1,3-disubstituted manganocenes was prepared and their electronic states were determined by solid-state magnetic susceptibility, electron paramagnetic resonance, X-ray crystallography, and variable temperature UV-vis spectroscopy. Spin-equilibria in [(Me3C)2C5H3]2Mn and [(Me3C)(Me3Si)C5H3]2Mn were examined and indicate an enthalpy difference of 15 kJ/mol between the high-spin and low-spin forms. Cyclopentadienyl groups resistant to intramolecular oxidative addition

  9. Synthesis, characterization, and tyrosinase biomimetic catalytic activity of copper(II) complexes with schiff base ligands derived from α-diketones with 2-methyl-3-amino-(3 H)-quinazolin-4-one

    NASA Astrophysics Data System (ADS)

    Ramadan, Abd El-Motaleb M.; Ibrahim, Mohamed M.; Shaban, Shaban Y.

    2011-12-01

    A template condensation of α-diketones (biacetyl, benzile and 2,3-pentanedione) with 2-methyl-3-amino-(3 H)-quinazolin-4-one (AMQ) in the presence of CuX 2 (X = Cl -, Br -, NO3- or ClO4-) resulted in the formation of tetradentate Schiff base copper(II) complexes of the type [CuLX]X and [CuL]X 2. Structural characterization of the complex species was achieved by several physicochemical methods, namely elemental analysis, electronic spectra, IR, ESR, molar conductivity, thermal analysis (TAG & DTG), and magnetic moment measurements. The stereochemistry, the nature of the metal chelates, and the catalytic reactivity are markedly dependent upon the type of counter anions and the ligand substituent within the carbonyl moiety. A square planar monomeric structure is proposed for the perchlorate, nitrate, and bromide complexes, in which the counter anions are loosely bonded to copper(II) ion. For the chloride complexes, the molar conductivities and the spectral data indicated that they have square-pyramidal environments around copper(II) center. The reported copper(II) complexes exhibit promising tyrosinase catalytic activity towards the hydroxylation of phenol followed by the aerobic oxidation of the resulting catechol. A linear correlation almost exists between the catalytic reactivity and the Lewis-acidity of the central copper(II) ion created by the donating properties of the parent ligand. The steric considerations could be accounted to clarify the difference in the catalytic activity of these functional models.

  10. Asymmetric ligand-exchange reaction of biphenol derivatives and chiral bis(oxazolinyl)phenyl-rhodium complex.

    PubMed

    Inoue, Hiroko; Ito, Jun-ichi; Kikuchi, Makoto; Nishiyama, Hisao

    2008-09-01

    Chiral bis(oxazolinyl)phenyl-rhodium acetate complex can enantioselectively capture 1,1'-binaphthol derivatives by ligand-exchange reaction. The structure of the bis(oxazolinyl)phenyl-rhodium biphenol and binaphthol complexes were confirmed by X-ray analysis. PMID:18496824

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

    PubMed Central

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

    2013-01-01

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

  12. Multifunctional Transmembrane Protein Ligands for Cell-Specific Targeting of Plasma Membrane-Derived Vesicles.

    PubMed

    Zhao, Chi; Busch, David J; Vershel, Connor P; Stachowiak, Jeanne C

    2016-07-01

    Liposomes and nanoparticles that bind selectively to cell-surface receptors can target specific populations of cells. However, chemical conjugation of ligands to these particles is difficult to control, frequently limiting ligand uniformity and complexity. In contrast, the surfaces of living cells are decorated with highly uniform populations of sophisticated transmembrane proteins. Toward harnessing cellular capabilities, here it is demonstrated that plasma membrane vesicles (PMVs) derived from donor cells can display engineered transmembrane protein ligands that precisely target cells on the basis of receptor expression. These multifunctional targeting proteins incorporate (i) a protein ligand, (ii) an intrinsically disordered protein spacer to make the ligand sterically accessible, and (iii) a fluorescent protein domain that enables quantification of the ligand density on the PMV surface. PMVs that display targeting proteins with affinity for the epidermal growth factor receptor (EGFR) bind at increasing concentrations to breast cancer cells that express increasing levels of EGFR. Further, as an example of the generality of this approach, PMVs expressing a single-domain antibody against green fluorescence protein (eGFP) bind to cells expressing eGFP-tagged receptors with a selectivity of ≈50:1. The results demonstrate the versatility of PMVs as cell targeting systems, suggesting diverse applications from drug delivery to tissue engineering. PMID:27294846

  13. Porphyrin-based design of bioinspired multitarget quadruplex ligands.

    PubMed

    Laguerre, Aurélien; Desbois, Nicolas; Stefan, Loic; Richard, Philippe; Gros, Claude P; Monchaud, David

    2014-09-01

    Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, (PNA)PorphySQ, are reported, where peptidic nucleic acid guanine ((PNA)G) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged (PNA)G residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making (PNA)PorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of (PNA)PorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands. PMID:24678052

  14. Bidentate coordinating behaviour of chalcone based ligands towards oxocations: VO(IV) and Mo(V)

    NASA Astrophysics Data System (ADS)

    Thaker, B. T.; Barvalia, R. S.

    2013-08-01

    We synthesized and studied the coordinating behaviour of chalcone based ligands derived from DHA and n-alkoxy benzaldehyde and their complexes of VO(IV) and MoO(V). The chalcone ligands are characterized by elemental analyses, UV-visible, IR, 1H NMR, and mass spectra. The resulting oxocation complexes are also characterized by elemental analyses, IR, 1H NMR, electronic, electron spin resonance spectra, magnetic susceptibility measurement and molar conductance studies. The IR and 1H NMR spectral data suggest that the chalcone ligands behave as a monobasic bidentate with O:O donor sequence towards metal ion. The molar conductivity data show them to be non-electrolytes. From the electronic, magnetic and ESR spectral data suggest that all the chalcone ligand complexes of VO(IV) and MoO(V) have distorted octahedral geometry.

  15. The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

    PubMed

    Savall, Brad M; Meduna, Steven P; Venable, Jennifer; Wei, Jianmei; Smith, Russell C; Hack, Michael D; Thurmond, Robin L; McGovern, Patricia; Edwards, James P

    2014-12-01

    During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists. PMID:25455490

  16. Polymer light-emitting diodes based on cationic iridium(III) complexes with a 1,10-phenanthroline derivative containing a bipolar carbazole-oxadiazole unit as the auxiliary ligand

    NASA Astrophysics Data System (ADS)

    Tang, Huaijun; Wei, Liying; Meng, Guoyun; Li, Yanhu; Wang, Guanze; Yang, Furui; Wu, Hongbin; Yang, Wei; Cao, Yong

    2014-11-01

    A 1,10-phenanthroline derivative (co-phen) containing a bipolar carbazole-oxadiazole unit was synthesized and used as the auxiliary ligand in cationic iridium(III) complexes [(ppy)2Ir(co-phen)]PF6 (ppy: 2-phenylpyridine) and [(npy)2Ir(co-phen)]PF6 (npy: 2-(naphthalen-1-yl)pyridine). Two complexes have high thermal stability with the glass-transition temperatures (Tg) of 207 °C and 241 °C, and the same 5% weight-reduction temperatures (ΔT5%) of 402 °C. Both of them were used as phosphorescent dopants in solution-processed polymer light-emitting diodes (PLEDs): ITO/PEDOT: PSS/PVK: PBD: complex (mass ratios 100: 40: x, x = 1.0, 2.0, and 4.0)/CsF/Al. The maximum luminances of the PLEDs using [(ppy)2Ir(co-phen)]PF6 and [(npy)2Ir(co-phen)]PF6 were 12567 cd m-2 and 11032 cd m-2, the maximum luminance efficiencies were 17.3 cd A-1 and 20.4 cd A-1, the maximum power efficiencies were 9.8 lm W-1 and 10.3 lm W-1, and the maximum external quantum efficiencies were 9.3% and 11.4% respectively. The CIE color coordinates were around (0.37, 0.57) and (0.44, 0.54) respectively, corresponding to the yellow green region.

  17. Pharmacophore-based discovery of ligands for drug transporters

    PubMed Central

    Chang, Cheng; Ekins, Sean; Bahadduri, Praveen; Swaan, Peter W.

    2006-01-01

    The ability to identify ligands for drug transporters is an important step in drug discovery and development. It can both improve accurate profiling of lead pharmacokinetic properties and assist in the discovery of new chemical entities targeting transporters. In silico approaches, especially pharmacophore-based database screening methods have great potential in improving the throughput of current transporter ligand identification assays, leading to a higher hit rate by focusing in vitro testing to the most promising hits. In this review, the potential of different in silico methods in transporter ligand identification studies are compared and summarized with an emphasis on pharmacophore modeling. Various implementations of pharmacophore model generation, database compilation and flexible screening algorithms are also introduced. Recent successful utilization of database searching with pharmacophores to identify novel ligands for the pharmaceutically significant transporters hPepT1, P-gp, BCRP, MRP1 and DAT are reviewed and challenges encountered with current approaches are discussed. PMID:17097188

  18. Synthesis, spectral characterization, structural investigation and antimicrobial studies of mononuclear Cu(II), Ni(II), Co(II), Zn(II) and Cd(II) complexes of a new potentially hexadentate N2O4 Schiff base ligand derived from salicylaldehyde

    NASA Astrophysics Data System (ADS)

    Keypour, Hassan; Shayesteh, Maryam; Rezaeivala, Majid; Chalabian, Firoozeh; Elerman, Yalcin; Buyukgungor, Orhan

    2013-01-01

    A new potentially hexadentate N2O4 Schiff base ligand, H2L derived from condensation reaction of an aromatic diamine and salicylaldehyde, and its metal complexes were characterized by elemental analyses, IR, UV-Vis, EI-MS, 1H and 13C NMR spectra, as well as conductance measurements. It has been originated that the Schiff base ligand with Cu(II), Ni(II), Co(II), Cd(II) and Zn(II) ions form mononuclear complexes on 1:1 (metal:ligand) stoichiometry. The conductivity data confirm the non-electrolytic nature of the complexes. Also the crystal structures of the complexes [ZnL] and [CoL] have also been determined by using X-ray crystallographic technique. The Zn(II) and Co(II) complexes show a tetrahedral configuration. Electronic absorption spectra of the Cu(II) and Ni(II) complexes suggest a square-planar geometry around the central metal ion. The synthesized compounds have antibacterial activity against the three Gram-positive bacteria: Bacillus cereus, Enterococcus faecalis and Listeria monocytogenes and also against the three Gram-negative bacteria: Salmonella paraB, Citrobacter freundii and Enterobacter aerogenes. The results showed that in some cases the antibacterial activity of complexes were more than nalidixic acid and amoxicillin as standards.

  19. Kidney branching morphogenesis under the control of a ligand-receptor-based Turing mechanism

    NASA Astrophysics Data System (ADS)

    Menshykau, Denis; Iber, Dagmar

    2013-08-01

    The main signalling proteins that control early kidney branching have been defined. Yet the underlying mechanism is still elusive. We have previously shown that a Schnakenberg-type Turing mechanism can recapitulate the branching and protein expression patterns in wild-type and mutant lungs, but it is unclear whether this mechanism would extend to other branched organs that are regulated by other proteins. Here, we show that the glial cell line-derived neurotrophic factor-RET regulatory interaction gives rise to a Schnakenberg-type Turing model that reproduces the observed budding of the ureteric bud from the Wolffian duct, its invasion into the mesenchyme and the observed branching pattern. The model also recapitulates all relevant protein expression patterns in wild-type and mutant mice. The lung and kidney models are both based on a particular receptor-ligand interaction and require (1) cooperative binding of ligand and receptor, (2) a lower diffusion coefficient for the receptor than for the ligand and (3) an increase in the receptor concentration in response to receptor-ligand binding (by enhanced transcription, more recycling or similar). These conditions are met also by other receptor-ligand systems. We propose that ligand-receptor-based Turing patterns represent a general mechanism to control branching morphogenesis and other developmental processes.

  20. Antispermatogenic Activity of the Benzothiazoline Ligand and Corresponding Organoantimony(V) Derivative in Male Albino Rats

    PubMed Central

    Sharma, Pankaj K.; Rehwani, H.; Rai, A. K.; Gupta, R. S.; Singh, Y. P.

    2006-01-01

    Triphenylantimony(V) derivative, Ph3Sb(OPri) [SC6H4N : C(CH3)CH2C(O)CH3], 1b, and the corresponding benzothiazoline ligand [1, 2], HNC6H4SC⎴(CH3)CH2C(O)CH3, 1a, have been tested for their effects on the reproductive system of male albino rats. The oral administration of both 1a and 1b at the dose level of 10 mg/rat/day produced significant reduction in the weights of testes, epididymides, seminal vesicles, and ventral prostate. Significant decrease in sperm motility as well as in sperm density resulted in 100% sterility. Significant (P < .01) alterations were also found in biochemical parameters of reproductive organs in treated male rats as compared to the control group. Production of preleptotene, pachytene, and secondary spermatocytes was decreased by 42%, 43%, 39%, and by 44%, 49%, 55% in the ligand, 1a, and organoantimony(V) derivative, 1b, treated rats, respectively. These results indicate that both compounds 1a and 1b are antispermatogenic in nature and on oral administration in male rats, and finally caused sterility. A comparison indicates that the organoantimony(V) derivative 1b is more effective pertaining to its antispermatogenic activity than the corresponding ligand 1a. PMID:17496999

  1. Electronic Structure Determination of Pyridine N-Heterocyclic Carbene Iron Dinitrogen Complexes and Neutral Ligand Derivatives

    PubMed Central

    2015-01-01

    The electronic structures of pyridine N-heterocyclic dicarbene (iPrCNC) iron complexes have been studied by a combination of spectroscopic and computational methods. The goal of these studies was to determine if this chelate engages in radical chemistry in reduced base metal compounds. The iron dinitrogen example (iPrCNC)Fe(N2)2 and the related pyridine derivative (iPrCNC)Fe(DMAP)(N2) were studied by NMR, Mössbauer, and X-ray absorption spectroscopy and are best described as redox non-innocent compounds with the iPrCNC chelate functioning as a classical π acceptor and the iron being viewed as a hybrid between low-spin Fe(0) and Fe(II) oxidation states. This electronic description has been supported by spectroscopic data and DFT calculations. Addition of N,N-diallyl-tert-butylamine to (iPrCNC)Fe(N2)2 yielded the corresponding iron diene complex. Elucidation of the electronic structure again revealed the CNC chelate acting as a π acceptor with no evidence for ligand-centered radicals. This ground state is in contrast with the case for the analogous bis(imino)pyridine iron complexes and may account for the lack of catalytic [2π + 2π] cycloaddition reactivity. PMID:25328270

  2. Synthesis and Characterization of Metal Complexes with Schiff Base Ligands

    ERIC Educational Resources Information Center

    Wilkinson, Shane M.; Sheedy, Timothy M.; New, Elizabeth J.

    2016-01-01

    In order for undergraduate laboratory experiments to reflect modern research practice, it is essential that they include a range of elements, and that synthetic tasks are accompanied by characterization and analysis. This intermediate general chemistry laboratory exercise runs over 2 weeks, and involves the preparation of a Schiff base ligand and…

  3. 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

  4. Novel Chalcone-Based Fluorescent Human Histamine H3 Receptor Ligands as Pharmacological Tools

    PubMed Central

    Tomasch, Miriam; Schwed, J. Stephan; Weizel, Lilia; Stark, Holger

    2012-01-01

    Novel fluorescent chalcone-based ligands at human histamine H3 receptors (hH3R) have been designed, synthesized, and characterized. Compounds described are non-imidazole analogs of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH3R in the same concentration range like the reference antagonist ciproxifan (hH3R pKi value of 7.2). Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be used to visualize hH3R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues. PMID:22470321

  5. N6-benzyladenosine derivatives as novel N-donor ligands of platinum(II) dichlorido complexes.

    PubMed

    Starha, Pavel; Popa, Igor; Trávníček, Zdeněk; Vančo, Ján

    2013-01-01

    The platinum(II) complexes trans-[PtCl₂(Ln)₂]∙xSolv 1-13 (Solv = H₂O or CH3OH), involving N6-benzyladenosine-based N-donor ligands, were synthesized; L(n) stands for N6-(2-methoxybenzyl)adenosine (L₁, involved in complex 1), N6-(4-methoxy-benzyl)adenosine (L₂, 2), N6-(2-chlorobenzyl)adenosine (L₃, 3), N6-(4-chlorobenzyl)-adenosine (L₄, 4), N6-(2-hydroxybenzyl)adenosine (L₅, 5), N6-(3-hydroxybenzyl)-adenosine (L₆, 6), N6-(2-hydroxy-3-methoxybenzyl)adenosine (L₇, 7), N6-(4-fluoro-benzyl)adenosine (L₈, 8), N6-(4-methylbenzyl)adenosine (L₉, 9), 2-chloro-N6-(3-hydroxy-benzyl)adenosine (L₁₀, 10), 2-chloro-N6-(4-hydroxybenzyl)adenosine (L₁₁, 11), 2-chloro-N6-(2-hydroxy-3-methoxybenzyl)adenosine (L₁₂, 12) and 2-chloro-N6-(2-hydroxy-5-methylbenzyl)adenosine (L₁₃, 13). The compounds were characterized by elemental analysis, mass spectrometry, IR and multinuclear (¹H-, ¹³C-, ¹⁹⁵Pt- and ¹⁵N-) and two-dimensional NMR spectroscopy, which proved the N7-coordination mode of the appropriate N6-benzyladenosine derivative and trans-geometry of the title complexes. The complexes 1-13 were found to be non-toxic in vitro against two selected human cancer cell lines (HOS and MCF7; with IC₅₀ > 50.0 µM). However, they were found (by ESI-MS study) to be able to interact with the physiological levels of the sulfur-containing biogenic biomolecule L-methionine by a relatively simple 1:1 exchange mechanism (one L(n) molecule was replaced by one L-methionine molecule), thus forming a mixed-nitrogen/sulfur-ligand dichlorido-platinum(II) coordination species. PMID:23771060

  6. Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands.

    PubMed

    Łażewska, Dorota; Jończyk, Jakub; Bajda, Marek; Szałaj, Natalia; Więckowska, Anna; Panek, Dawid; Moore, Caitlin; Kuder, Kamil; Malawska, Barbara; Kieć-Kononowicz, Katarzyna

    2016-08-15

    In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93μM and EqBuChE IC50=1.64μM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases. PMID:27445168

  7. Metal complexes of ONO donor Schiff base ligand as a new class of bioactive compounds; Synthesis, characterization and biological evolution

    NASA Astrophysics Data System (ADS)

    Kumar Naik, K. H.; Selvaraj, S.; Naik, Nagaraja

    2014-10-01

    Present work reviews that, the synthesis of (E)-N";-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide [L] ligand and their metal complexes. The colored complexes were prepared of type [M2+L]X2, where M2+ = Mn, Co, Ni, Cu, Sr and Cd, L = (7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)benzohydrazide, X = Cl-. Ligand derived from the condensation of 8-formyl-7-hydroxy-4-methylcoumarin and benzohydrazide in the molar ratio 1:1 and in the molar ratio 1:2 for metal complexes have been prepared. The chelation of the ligand to metal ions occurs through the both oxygen groups, as well as the nitrogen atoms of the azomethine group of the ligand. Reactions of the Schiff base ligand with Manganese(II), Cobalt(II), Nickel(II), Copper(II), Strontium(II), and Cadmium(II) afforded the corresponding metal complexes. The structures of the obtained ligand and their respective metal complexes were elucidated by infra-red, elemental analysis, Double beam UV-visible spectra, conductometric measurements, magnetic susceptibility measurements and also thermochemical studies. The metal complex exhibits octahedral coordination geometrical arrangement. Schiff base ligand and their metal complexes were tested against antioxidants, antidiabetic and antimicrobial activities have been studied. The Schiff base metal complexes emerges effective α-glucosidase inhibitory activity than free Schiff base ligand.

  8. Coordination chemistry of a new rigid, hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand.

    PubMed

    Bleiholder, Christian; Börzel, Heidi; Comba, Peter; Ferrari, Rosana; Heydt, Matthias; Kerscher, Marion; Kuwata, Shigemasa; Laurenczy, Gabor; Lawrance, Geoffrey A; Lienke, Achim; Martin, Bodo; Merz, Michael; Nuber, Bernd; Pritzkow, Hans

    2005-10-31

    The hexadentate bispidine-based ligand 2,4-bis(2-pyridyl)-3,7-bis(2-methylenepyridine)-3,7-diazabicyclo[3.3.1]nonane-9-on-1,5-bis(carbonic acid methyl ester), L(6m), with four pyridine and two tertiary amine donors, based on a very rigid diazaadamantane-derived backbone, is coordinated to a range of metal ions. On the basis of experimental and computed structural data, the ligand is predicted to form very stable complexes. Force field calculations indicate that short metal-donor distances lead to a buildup of strain in the ligand; that is, the coordination of large metal ions is preferred. This is confirmed by experimentally determined stability constants, which indicate that, in general, stabilities comparable to those with macrocyclic ligands are obtained with the relative order Cu(2+) > Zn(2+) > Ni(2+) < Co(2+), which is not the typical Irving-Williams behavior. The preference for large M-N distances also emerges from relatively high redox potentials (the higher oxidation states, that is, the smaller metal ions, are destabilized) and from relatively weak ligand fields (dd-transition, high-spin electronic ground states). The potentiometric titrations confirm the efficient encapsulation of the metal ions since only 1:1 complexes are observed, and, over a large pH range, ML is generally the only species present in solution. PMID:16241165

  9. Synthesis of novel Schiff base ligands from gluco- and galactochloraloses for the Cu(II) catalyzed asymmetric Henry reaction.

    PubMed

    Alkan, Sevda; Telli, Fatma Ç; Salman, Yeşim; Astley, Stephen T

    2015-04-30

    A series of chiral Schiff base ligands has been prepared using aminochloralose derivatives of glucose and galactose. These ligands were used as catalysts in the asymmetric Henry reaction in the presence of Cu(II) ions giving yields of up to 95%. An interesting solvent dependency on enantiomeric control was observed with the best enantiomeric excesses (up to 91%) being obtained in the presence of water. PMID:25742867

  10. HybridDock: A Hybrid Protein-Ligand Docking Protocol Integrating Protein- and Ligand-Based Approaches.

    PubMed

    Huang, Sheng-You; Li, Min; Wang, Jianxin; Pan, Yi

    2016-06-27

    Structure-based molecular docking and ligand-based similarity search are two commonly used computational methods in computer-aided drug design. Structure-based docking tries to utilize the structural information on a drug target like protein, and ligand-based screening takes advantage of the information on known ligands for a target. Given their different advantages, it would be desirable to use both protein- and ligand-based approaches in drug discovery when information for both the protein and known ligands is available. Here, we have presented a general hybrid docking protocol, referred to as HybridDock, to utilize both the protein structures and known ligands by combining the molecular docking program MDock and the ligand-based similarity search method SHAFTS, and evaluated our hybrid docking protocol on the CSAR 2013 and 2014 exercises. The results showed that overall our hybrid docking protocol significantly improved the performance in both binding affinity and binding mode predictions, compared to the sole MDock program. The efficacy of the hybrid docking protocol was further confirmed using the combination of DOCK and SHAFTS, suggesting an alternative docking approach for modern drug design/discovery. PMID:26317502

  11. Stereochemical influences upon the opioid ligand activities of 4-alkyl-4-arylpiperidine derivatives.

    PubMed

    Casy, A F; Dewar, G H; al Deeb, O A

    1989-01-01

    The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative. PMID:2561991

  12. Optimal ligand descriptor for pocket recognition based on the Beta-shape.

    PubMed

    Kim, Jae-Kwan; Won, Chung-In; Cha, Jehyun; Lee, Kichun; Kim, Deok-Soo

    2015-01-01

    Structure-based virtual screening is one of the most important and common computational methods for the identification of predicted hit at the beginning of drug discovery. Pocket recognition and definition is frequently a prerequisite of structure-based virtual screening, reducing the search space of the predicted protein-ligand complex. In this paper, we present an optimal ligand shape descriptor for a pocket recognition algorithm based on the beta-shape, which is a derivative structure of the Voronoi diagram of atoms. We investigate six candidates for a shape descriptor for a ligand using statistical analysis: the minimum enclosing sphere, three measures from the principal component analysis of atoms, the van der Waals volume, and the beta-shape volume. Among them, the van der Waals volume of a ligand is the optimal shape descriptor for pocket recognition and best tunes the pocket recognition algorithm based on the beta-shape for efficient virtual screening. The performance of the proposed algorithm is verified by a benchmark test. PMID:25835497

  13. Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

    PubMed Central

    2013-01-01

    The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested. PMID:23517011

  14. Prospects for three-electron donor boronyl (BO) ligands and dioxodiborene (B2O2) ligands as bridging groups in binuclear iron carbonyl derivatives.

    PubMed

    Chang, Yu; Li, Qian-Shu; Xie, Yaoming; King, R Bruce

    2012-08-20

    Recent experimental work (2010) on (Cy(3)P)(2)Pt(BO)Br indicates that the oxygen atom of the boronyl (BO) ligand is more basic than that in the ubiquitous CO ligand. This suggests that bridging BO ligands in unsaturated binuclear metal carbonyl derivatives should readily function as three-electron donor bridging ligands involving both the oxygen and the boron atoms. In this connection, density functional theory shows that three of the four lowest energy singlet Fe(2)(BO)(2)(CO)(7) structures have such a bridging η(2)-μ-BO group as well as a formal Fe-Fe single bond. In addition, all four of the lowest energy singlet Fe(2)(BO)(2)(CO)(6) structures have two bridging η(2)-μ-BO groups and formal Fe-Fe single bonds. Other Fe(2)(BO)(2)(CO)(n) (n = 7, 6) structures are found in which the two BO groups have coupled to form a bridging dioxodiborene (B(2)O(2)) ligand with B-B bonding distances of ~1.84 Å. All of these Fe(2)(μ-B(2)O(2))(CO)(n) structures have long Fe···Fe distances indicating a lack of direct iron-iron bonding. One of the singlet Fe(2)(BO)(2)(CO)(7) structures has such a bridging dioxodiborene ligand with cis stereochemistry functioning as a six-electron donor to the pair of iron atoms. In addition, the lowest energy triplet structures for both Fe(2)(BO)(2)(CO)(7) and Fe(2)(BO)(2)(CO)(6) have bridging dioxodiborene ligands with trans stereochemistry functioning as a four-electron donor to the pair of iron atoms. PMID:22862812

  15. Molecular Fingerprint-based Artificial Neural Networks QSAR for Ligand Biological Activity Predictions

    PubMed Central

    Myint, Kyaw-Zeyar; Wang, Lirong; Tong, Qin; Xie, Xiang-Qun

    2012-01-01

    In this manuscript, we have reported a novel 2D fingerprint-based artificial neural network QSAR (FANN-QSAR) method in order to effectively predict biological activities of structurally diverse chemical ligands. Three different types of fingerprints, namely ECFP6, FP2 and MACCS, were used in FANN-QSAR algorithm development, and FANN-QSAR models were compared to known 3D and 2D QSAR methods using five data sets previously reported. In addition, the derived models were used to predict GPCR cannabinoid ligand binding affinities using our manually curated cannabinoid ligand database containing 1699 structurally diverse compounds with reported cannabinoid receptor subtype CB2 activities. To demonstrate its useful applications, the established FANN-QSAR algorithm was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds and we have discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. To the best of our knowledge, this is the first report for a fingerprint-based neural network approach validated with a successful virtual screening application in identifying lead compounds. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID:22937990

  16. Receptor-based 3D QSAR analysis of estrogen receptor ligands--merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods.

    PubMed

    Sippl, W

    2000-08-01

    One of the major challenges in computational approaches to drug design is the accurate prediction of binding affinity of biomolecules. In the present study several prediction methods for a published set of estrogen receptor ligands are investigated and compared. The binding modes of 30 ligands were determined using the docking program AutoDock and were compared with available X-ray structures of estrogen receptor-ligand complexes. On the basis of the docking results an interaction energy-based model, which uses the information of the whole ligand-receptor complex, was generated. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities and calculated ligand-receptor interaction energies. The highest correlation coefficient (r2 = 0.617, q2Loo = 0.570) was obtained considering protein flexibility during the interaction energy evaluation. The second prediction method uses a combination of receptor-based and 3D quantitative structure-activity relationships (3D QSAR) methods. The ligand alignment obtained from the docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection, a significant and robust model was obtained (r2 = 0.991, q2LOO = 0.921). The predictive ability of the established model was further evaluated by using a test set of six additional compounds. The comparison with the generated interaction energy-based model and with a traditional CoMFA model obtained using a ligand-based alignment (r2 = 0.951, q2L00 = 0.796) indicates that the combination of receptor-based and 3D QSAR methods is able to improve the quality of the underlying model. PMID:10921772

  17. Computational insights into the photophysical and electroluminescence properties of homoleptic fac-Ir(C^N)3 complexes employing different phenyl-derivative-featuring phenylimidazole-based ligands for promising phosphors in OLEDs.

    PubMed

    Li, Jieqiong; Wang, Li; Sun, Kenan; Zhang, Jinglai

    2016-02-21

    The electronic structures and photophysical properties of three homoleptic iridium(iii) complexes IrL3 with C^N ligands, including 2a (L = 1-(2,6-diisopropylphenyl)-2-phenyl-1H-imidazole), 5a (L = 1-(2,6-dimethylphenyl)-2-phenyl-1H-imidazole), and 6a (L = 1-(3,5-diisopropylbiphenyl-4-yl)-2-phenyl-1H-imidazole), are investigated by means of the density functional method. Furthermore, seven new complexes are theoretically designed, including 1a (L = 1,2-diphenyl-1H-imidazole), 3a (L = 1-(2,6-dimethoxyphenyl)-2-phenyl-1H-imidazol), 4a (L = 2-(2-phenyl-1H-imidazol-1-yl)isophthalaldehyde), 1b (L = 2-(biphenyl-3-yl)-1H-imidazole), 2b (L = 2-(2',6'-diisopropylbiphenyl-3-yl)-1H-imidazole), 3b (L = 2-(2',6'-dimethoxybiphenyl-3-yl)-1H-imidazole), and 4b (L = 3'-(1H-imidazol-2-yl)biphenyl-2,6-dicarbaldehyde), to explore the influence of different substituents and different substituted positions on the electronic structures, phosphorescence properties, and organic light-emitting diode (OLED) performance. The HOMO-LUMO energy gap is greatly decreased by introduction of the -CHO group into the phenyl ring (4a and 4b see -sketched structures for all the investigated Ir(iii) complexes). As a result, their absorption and emission spectra present red-shifting leading them to be potential red-emitting phosphors. Other complexes are all blue-emitting materials, indicating that the effect of the substituted position on the emitting color is negligible. However, the addition of the substituent on the para-position of the phenyl ring in the phenylimidazole ligand would increase the quantum yield and electroluminescence (EL) performance compared with that on the imidazole ring. PMID:26763190

  18. Coordination polymers from a highly flexible alkyldiamine-derived ligand: structure, magnetism and gas adsorption studies.

    PubMed

    Hawes, Chris S; Chilton, Nicholas F; Moubaraki, Boujemaa; Knowles, Gregory P; Chaffee, Alan L; Murray, Keith S; Batten, Stuart R; Turner, David R

    2015-10-28

    The synthesis and structural, magnetic and gas adsorption properties of a series of coordination polymer materials prepared from a new, highly flexible and internally functional tetrakis-carboxybenzyl ligand H4L derived from 1,2-diaminoethane have been examined. The compound poly-[Ni3(HL)2(OH2)4]·2DMF·2H2O 1, a two-dimensional coordination polymer, contains aqua- and carboxylato-bridged trinuclear Ni(II) clusters, the magnetic behaviour of which can be well described through experimental fitting and ab initio modelling to a ferromagnetically coupled trimer with a positive axial zero-field splitting parameter D. Compound poly-[Zn2L]·2DMF·3H2O 2, a three-dimensional coordination polymer displaying frl topology, contains large and well-defined solvent channels, which are shown to collapse on solvent exchange or drying. Compound poly-[Zn2(L)(DMSO)4]·3DMSO·3H2O 3, a highly solvated two-dimensional coordination polymer, displayed poor stability characteristics, however a structurally related material poly-[Zn2(L)(bpe)(DMSO)2]·DMSO·3H2O 4 was prepared under similar synthetic conditions by including the 1,2-bis(4-pyridyl)ethylene bpe co-ligand. Compound 4, containing small one-dimensional solvent channels, shows excellent structural resilience to solvent exchange and evacuation, and the evacuated material displays selective adsorption of CO2 over N2 at 273 K in the pressure range 0-1 atm. Each of the coordination polymers displays subtle differences in the conformation and binding mode of the ligand species, with switching between two distinct conformers (X-shaped and H-shaped), as well as a variable protonation state of the central core, with significant effects on the resulting network structures and physical properties of the materials. PMID:26223788

  19. Studies on the binding sites of IgG2 monoclonal antibodies recognized by terpyridine-based affinity ligands.

    PubMed

    Lin, Chih-Pei; Boysen, Reinhard I; Campi, Eva M; Saito, Kei; Hearn, Milton T W

    2016-07-01

    This investigation has examined the origin of the molecular recognition associated with the interaction of monoclonal IgG2's with terpyridine-based ligands immobilized onto agarose-derived chromatographic adsorbents. Isothermal titration calorimetric (ITC) methods have been employed to acquire thermodynamic data associated with the IgG2-ligand binding. These ITC investigations have documented that different enthalpic and entropic processes are involved depending on the nature of the chemical substituents in the core structure of the terpyridinyl moiety. In addition, molecular docking studies have been carried out with IgG2 structures with the objective to identify possible ligand binding sites and key interacting amino acid residues. These molecular docking experiments with the different terpyridine-based ligands have shown that all of the examined ligands can potentially undergo favorable interactions with a site located within the Fab region of the IgG2. However, another favorable binding site was also identified from the docking poses to exist within the Fc region of the IgG2 for some, but not all, of the ligands studied. These investigations have provided a basis to elucidate the unique binding properties and chromatographic behaviors shown by several substituted terpyridine ligands in their interaction with IgGs of different isotype. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26842829

  20. Optimal assignment methods for ligand-based virtual screening

    PubMed Central

    2009-01-01

    Background Ligand-based virtual screening experiments are an important task in the early drug discovery stage. An ambitious aim in each experiment is to disclose active structures based on new scaffolds. To perform these "scaffold-hoppings" for individual problems and targets, a plethora of different similarity methods based on diverse techniques were published in the last years. The optimal assignment approach on molecular graphs, a successful method in the field of quantitative structure-activity relationships, has not been tested as a ligand-based virtual screening method so far. Results We evaluated two already published and two new optimal assignment methods on various data sets. To emphasize the "scaffold-hopping" ability, we used the information of chemotype clustering analyses in our evaluation metrics. Comparisons with literature results show an improved early recognition performance and comparable results over the complete data set. A new method based on two different assignment steps shows an increased "scaffold-hopping" behavior together with a good early recognition performance. Conclusion The presented methods show a good combination of chemotype discovery and enrichment of active structures. Additionally, the optimal assignment on molecular graphs has the advantage to investigate and interpret the mappings, allowing precise modifications of internal parameters of the similarity measure for specific targets. All methods have low computation times which make them applicable to screen large data sets. PMID:20150995

  1. Redox, thermodynamic and spectroscopic of some transition metal complexes containing heterocyclic Schiff base ligands

    NASA Astrophysics Data System (ADS)

    Abu-Hussen, Azza A. A.; Linert, Wolfgang

    2009-09-01

    Complexes of two series of Schiff base ligands, H 2L a and H 2L b derived from the reaction of 2,6-diacetyl pyridine with semicarbazide, H 2L a and thiosemicarbazide, H 2L b, with the metal ions, Co(II), Ni(II), Cu(II), VO(IV) and UO 2(VI) have been prepared. The ligands are characterized by elemental analysis, IR, UV-vis and 1H NMR. The structures of the complexes are investigated with the IR, UV-vis, X-band ESR spectra, 1H NMR and thermal gravimetric analysis as well as conductivity and magnetic moment measurements. The IR-spectra reveal the presence of variable modes of chelation for the investigated ligands. A variety of binuclear or mononuclear complexes were obtained with the two ligands in tri-, tetra or pentadentate forms. The bonding sites are the pyridine nitrogen, two azomethine nitrogen atoms and ketonic oxygen in case of H 2L a or sulphur atoms in case of H 2L b. The Coats-Redfern equation has been used to calculate the kinetic and thermodynamic parameters for the different thermal decomposition steps of some complexes. Cyclic voltammograms of Co(II) and Ni(II) show quasi-reversible peaks. The redox properties and the nature of the electro-active species of the complexes have been characterized.

  2. A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly

    SciTech Connect

    Mugridge, Jeffrey; Fiedler, Dorothea; Raymond, Kenneth

    2010-02-04

    A ferrocene-based biscatecholamide ligand was prepared and investigated for the formation of metal-ligand supramolecular assemblies with different metals. Reaction with Ge(IV) resulted in the formation of a variety of Ge{sub n}L{sub m} coordination complexes, including [Ge{sub 2}L{sub 3}]{sup 4-} and [Ge{sub 2}L{sub 2}({mu}-OMe){sub 2}]{sup 2-}. The ligand's ability to swivel about the ferrocenyl linker and adopt different conformations accounts for formation of many different Ge{sub n}L{sub m} species. This study demonstrates why conformational ligand rigidity is essential in the rational design and directed self-assembly of supramolecular complexes.

  3. Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation.

    PubMed

    Gioiello, Antimo; Cerra, Bruno; Mostarda, Serena; Guercini, Chiara; Pellicciari, Roberto; Macchiarulo, Antonio

    2014-01-01

    Bile acids are a peculiar class of steroidal compounds that never cease to amaze. From being simple detergents with a primary role in aiding the absorption of fats and fat-soluble vitamins, bile acids are now widely considered as crucial hormones endowed with genomic and non-genomic functions that are mediated by their interaction with several proteins including the nuclear receptor Farnesoid X Receptor (FXR). Taking advantages of the peculiar properties of bile acids in interacting with the FXR receptor, several biliary derivatives have been synthesized and tested as FXR ligands. The availability of these compounds has contributed to characterize the receptor from a structural, patho-physiological and therapeutic standpoint. Among these, obeticholic acid is a first-in-class FXR agonist that is demonstrating hepatoprotective effects upon FXR activation in patients with liver diseases such as primary biliary cirrhosis and nonalcoholic steatohepatitis. This review provides an historical overview of the rationale behind the discovery of obeticholic acid and chemical tools generated to depict the molecular features and bio-pharmacological relevance of the FXR receptor, as well as to summarize structure-activity relationships of bile acid-based FXR ligands so far reported. PMID:25388535

  4. Ligand Biological Activity Predictions Using Fingerprint-Based Artificial Neural Networks (FANN-QSAR)

    PubMed Central

    Myint, Kyaw Z.; Xie, Xiang-Qun

    2015-01-01

    This chapter focuses on the fingerprint-based artificial neural networks QSAR (FANN-QSAR) approach to predict biological activities of structurally diverse compounds. Three types of fingerprints, namely ECFP6, FP2, and MACCS, were used as inputs to train the FANN-QSAR models. The results were benchmarked against known 2D and 3D QSAR methods, and the derived models were used to predict cannabinoid (CB) ligand binding activities as a case study. In addition, the FANN-QSAR model was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds. We discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID:25502380

  5. Synthesis and structural characterization of zinc(II) and cobalt(II) complexes based on multidentate hydrazone ligands

    NASA Astrophysics Data System (ADS)

    Li, Li; Zhang, Yuan Zhuo; Liu, E.; Yang, Chengxiong; Golen, James A.; Rheingold, Arnold L.; Zhang, Guoqi

    2016-04-01

    Two multidentate Schiff base ligands containing a hydrazone unit have been synthesized and investigated for zinc(II) and cobalt(II) coordination chemistry. The reactions of the 4-pyridyl derived hydrazone ligand HL1 with zinc(II) or cobalt(II) salts gave three mononuclear complexes that were structurally characterized by X-ray diffraction analysis. The results revealed that the ligand could adopt different coordination modes when various counter anions were employed. While in the case that zinc dichloride was used as a metal salt a neutral mononuclear mono-ligand complex was formed, the deprotonation of hydrazone occurred when zinc(II) or cobalt(II) nitrate were present and two new isostructural mononuclear bis-ligand complexes were isolated. Modification of the hydrazone ligand with oxygen donors was found to have a significant impact on the ligand reactivity, and a similar reaction of H2L2 with cobalt(II) nitrate gave a protonated product of H2L2 without the incorporation of cobalt(II), which features a one-dimensional hydrogen-bonded network in the solid state.

  6. Emissive bis-salicylaldiminato Schiff base ligands and their zinc(II) complexes: Synthesis, photophysical properties, mesomorphism and DFT studies

    NASA Astrophysics Data System (ADS)

    Paul, Manoj Kr.; Dilipkumar Singh, Y.; Bedamani Singh, N.; Sarkar, Utpal

    2015-02-01

    Bis-salicylaldiminato Schiff base ligands and their Zn(II) complexes derived from 2,3-Diaminomaleonitrile (DAMN) were synthesized. Their molecular structures, photophysical properties and mesogenic behaviors were investigated. The ligands and their Zn(II) complexes were characterized by using elemental analysis, FT-IR, 1H NMR and molar conductivity measurements. Photophysical properties of ligands and their Zn(II) complexes were investigated in different polar solvents by using UV-visible and fluorescence spectroscopic studies. Ligands emit green light whereas complexes emit orange light upon irradiation with UV-visible light. The liquid crystalline phases of ligands and their Zn(II) complexes were characterized by polarizing optical microscopy and differential scanning calorimetry. The ligand having longer 4-n-octadecyloxy chain (n = 18) displays columnar phase whereas the lower homologues (n = 16, 12) did not show mesophase. The Zn(II) complexes having 4-n-octadecyloxy end chain display smectic B like phase whereas other lower homologues are non mesogenic in nature. The thermal stability of the compounds were studied by using thermo gravimetric analysis. The density functional theory was carried out to obtain the stable molecular conformation, dipole moment, molecular orbitals and polarizability of the ligands and their Zn(II) complexes.

  7. New biphenol-based, fine-tunable monodentate phosphoramidite ligands for catalytic asymmetric transformations

    PubMed Central

    Hua, Zihao; Vassar, Victor C.; Choi, Hojae; Ojima, Iwao

    2004-01-01

    Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6′-dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare and flexible for modifications. The fine-tuning capability of these ligands plays a significant role in achieving high enantioselectivity in the asymmetric hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to cycloalkenones. PMID:15020764

  8. Mechanistic insight into gramicidin-based detection of protein-ligand interactions via sensitized photoinactivation

    NASA Astrophysics Data System (ADS)

    Rokitskaya, Tatyana I.; Macrae, Michael X.; Blake, Steven; Egorova, Natalya S.; Kotova, Elena A.; Yang, Jerry; Antonenko, Yuri N.

    2010-11-01

    Among the many challenges for the development of ion channel-based sensors is the poor understanding of how to engineer modified transmembrane pores with tailored functionality that can respond to external stimuli. Here, we use the method of sensitized photoinactivation of gramicidin A (gA) channels in planar bilayer lipid membranes to help elucidate the underlying mechanistic details for changes in macroscopic transmembrane ionic current observed upon interaction of C-terminally attached gA ligands with specific proteins in solution. Three different systems were studied: (i) carbonic anhydrase (CA) and gA-sulfonamide, (ii) PSD-95 protein (belonging to the 'PDZ domain-containing protein') and a gA analog carrying the KGGHRRSARYLESSV peptide sequence at the C-terminus, and (iii) an anti-biotin antibody and gA-biotin. The results challenge a previously proposed mechanistic hypothesis suggesting that protein-induced current suppression is due to steric blockage of the ion passage through gA channels, while they reveal new insight for consideration in alternative mechanistic models. Additionally, we demonstrate that the length of a linker between the ligand and the gA channel may be less important for gramicidin-based detection of monovalent compared to multivalent protein-ligand interactions. These studies collectively shed new light on the mechanism of protein-induced current alterations in bilayer recordings of gA derivatives, which may be important in the design of new gramicidin-based sensors.

  9. Mechanistic insight into gramicidin-based detection of protein-ligand interactions via sensitized photoinactivation.

    PubMed

    Rokitskaya, Tatyana I; Macrae, Michael X; Blake, Steven; Egorova, Natalya S; Kotova, Elena A; Yang, Jerry; Antonenko, Yuri N

    2010-11-17

    Among the many challenges for the development of ion channel-based sensors is the poor understanding of how to engineer modified transmembrane pores with tailored functionality that can respond to external stimuli. Here, we use the method of sensitized photoinactivation of gramicidin A (gA) channels in planar bilayer lipid membranes to help elucidate the underlying mechanistic details for changes in macroscopic transmembrane ionic current observed upon interaction of C-terminally attached gA ligands with specific proteins in solution. Three different systems were studied: (i) carbonic anhydrase (CA) and gA-sulfonamide, (ii) PSD-95 protein (belonging to the 'PDZ domain-containing protein') and a gA analog carrying the KGGHRRSARYLESSV peptide sequence at the C-terminus, and (iii) an anti-biotin antibody and gA-biotin. The results challenge a previously proposed mechanistic hypothesis suggesting that protein-induced current suppression is due to steric blockage of the ion passage through gA channels, while they reveal new insight for consideration in alternative mechanistic models. Additionally, we demonstrate that the length of a linker between the ligand and the gA channel may be less important for gramicidin-based detection of monovalent compared to multivalent protein-ligand interactions. These studies collectively shed new light on the mechanism of protein-induced current alterations in bilayer recordings of gA derivatives, which may be important in the design of new gramicidin-based sensors. PMID:21339605

  10. Coordination Chemistry and Structural Dynamics of a Long and Flexible Piperazine-Derived Ligand.

    PubMed

    Hawes, Chris S; Hamilton, Sophie E; Hicks, Jamie; Knowles, Gregory P; Chaffee, Alan L; Turner, David R; Batten, Stuart R

    2016-07-01

    A long and highly flexible internally functionalized dipyridyl ligand α,α'-p-xylylenebis(1-(4-pyridylmethylene)-piper-4-azine), L, has been employed in the synthesis of a series of coordination polymer materials with Co(II), Cd(II), and Ag(I) ions. In poly-[Cd(L)(TPA)] 1 and poly-[Co(L)(IPA)], 2, (TPA = terephthalate, IPA = isophthalate) the ligand adopts a similar linear conformation to that seen in the structure of the unbound molecule and provides a long (2.6 nm) metal-metal bridging distance. Due to the mismatch of edge lengths with that provided by the carboxylate coligands, geometric distortions from the regular dia and (4,4) network geometries for 1 and 2, respectively, are observed. In poly-[Ag2(CF3SO3)2(L)], 3, the ligand coordinates through both pyridine groups and two of the four piperazine nitrogen donors, forming a high-connectivity 2-dimensional network. The compound poly-[Ag2(L)](BF4)2·2MeCN, 4, a porous 3-dimensional cds network, undergoes a fascinating and rapid single-crystal-to-single-crystal rearrangement on exchange of the acetonitrile guests for water in ambient air, forming a nonporous hydrated network poly-[Ag2(L)](BF4)2·2H2O, 5, in which the well-ordered guest water molecules mediate the rearrangement of the tetrafluoroborate anions and the framework itself through hydrogen bonding. The dynamics of the system are examined in greater detail through the preparation of a kinetic product, the dioxane-solvated species poly-[Ag2(L)](BF4)2·2C4H8O2, 6, which undergoes a slow conversion to 5 over the course of approximately 16 h, a transition which can be monitored in real time. The reverse transformation can also be observed on immersing the hydrate 5 in dioxane. The structural features and physical properties of each of the materials can be rationalized based on the flexible and multifunctional nature of the ligand molecule, as well as the coordination behavior of the chosen metal ions. PMID:27328206

  11. Highly symmetric organic ligand-capped Lindqvist structures derived from 3d-elements.

    PubMed

    Seisenbaeva, Gulaim A; Mallah, Talal; Kessler, Vadim G

    2010-09-01

    Interaction of M(acac)(2) with Ti(OEt)(4) associated with hydrolysis or thermolysis provides with high yields, through the decomposition of the initially formed M(2)Ti(2)(acac)(4)(OEt)(8), M = Ni (1), Co (2), poorly soluble Lindqvist-type products with the formula M(5)TiO(acac)(6)(OEt)(6), M = Ni (3), Co (4), Mg (5). The compounds 3-5 are isostructural and display a perfect statistical disorder between the OEt groups and 1/2 of the beta-diketonate, acac, ligand. The metal atoms constitute a regular octahedron, centered by the oxo-oxygen atom. There is only one symmetrically independent metal site, which imposes it to contain 1/6 of titanium and 5/6 of the divalent metal atom. The oxygen atoms on the surface of the octahedron are doubly bridging and are located above the twelve edges of the octahedron, as is usual for the Lindqvist-type structures. The coordination of the metal atoms is completed by a single terminal oxygen atom. The complexes 3-5 are volatile with decomposition, releasing only homometallic products into the gas phase in the case of 3 and 4, but with a considerable contribution of molecular evaporation in the case of 5. The intermediates 1 and 2 belong to the tetramolybdate, M(4)O(16), structure type. Highly soluble 1 and 2 can be considered as attractive molecular precursors for the incorporation of 3 and 4 into porous matrices for the preparation of combustion catalysts. Application of the same synthetic approach to n-propoxide complexes offers in a Co-Ti system a derivative with a different composition and resolved metal and ligand disorder, Co(4)Ti(2)O(acac)(4)(O(n)Pr)(10) (6), which, however, still follows the Lindquist type and displays high (tetragonal) symmetry for both the molecule and the crystal structure. PMID:20648394

  12. Ruthenium nitrosyls derived from polypyridine ligands with carboxamide or imine nitrogen donor(s): isoelectronic complexes with different NO photolability.

    PubMed

    Rose, Michael J; Patra, Apurba K; Alcid, Eric A; Olmstead, Marylin M; Mascharak, Pradip K

    2007-03-19

    As part of our search for photoactive ruthenium nitrosyls, a set of {RuNO}6 nitrosyls has been synthesized and structurally characterized. In this set, the first nitrosyl [(SBPy3)Ru(NO)](BF4)3 (1) is derived from a polypyridine Schiff base ligand SBPy3, while the remaining three nitrosyls are derived from analogous polypyridine ligands containing either one ([(PaPy3)Ru(NO)](BF4)2 (2)) or two ([(Py3P)Ru(NO)]BF4 (3) and [(Py3P)Ru(NO)(Cl)] (4)) carboxamide group(s). The coordination structures of 1 and 2 are very similar except that in 2, a carboxamido nitrogen is coordinated to the ruthenium center in place of an imine nitrogen in case of 1. In 3 and 4, the ruthenium center is coordinated to two carboxamido nitrogens in the equatorial plane and the bound NO is trans to a pyridine nitrogen (in 3) and chloride (in 4), respectively. Complexes 1-3 contain N6 donor set, and the NO stretching frequencies (nuNO) correlate well with the N-O bond distances. All four diamagnetic {RuNO}(6) nitrosyls are photoactive and release NO rapidly upon illumination with low-intensity (5-10 mW) UV light. Interestingly, photolysis of 1 generates the diamagnetic Ru(II) photoproduct [(SBPy3)Ru(MeCN)](2+) while 2-4 afford paramagnetic Ru(III) species in MeCN solution. The quantum yield values of NO release under UV illumination (lambda(max) = 302 nm) lie in the range 0.06-0.17. Complexes 3 and 4 also exhibit considerable photoactivity under visible light. The efficiency of NO release increases in the order 2 < 3 < 4, indicating that photorelease of NO is facilitated by (a) the increase in the number of coordinated carboxamido nitrogen(s) and (b) the presence of negatively charged ligands (like chloride) trans to the bound NO. PMID:17315866

  13. A 3-fold-symmetric ligand based on 2-hydroxypyridine: regulation of ligand binding by hydrogen bonding.

    PubMed

    Moore, Cameron M; Quist, David A; Kampf, Jeff W; Szymczak, Nathaniel K

    2014-04-01

    A tripodal ligand based on 2-hydroxypyridine is presented. Cu-Cl adducts of H3thpa with Cu(I) and Cu(II) provide complexes featuring highly directed, intramolecular hydrogen-bonding interactions. An upper limit for the hydrogen-bonding free energy to Cu(I)-Cl was estimated at ∼18 kcal/mol. PMID:24654846

  14. Systemic immunomodulation of autoimmune disease using MHC-derived recombinant TCR ligands.

    PubMed

    Burrows, Gregory G

    2005-04-01

    Human autoimmune disease involves local activation of antigen-specific CD4(+) T cells that produce inflammatory Th1 cytokines leading to the further recruitment and activation of lymphocytes and monocytes, resulting ultimately in the destruction of target tissue. Antigen presenting cells (APCs) initiate activation of CD4(+) T cells in a multistep process that minimally involves co-ligation of the TCR and CD4 by the MHC class II/peptide complex and costimulation through additional T cell surface molecules such as CD28. Disruption of this highly orchestrated series of events can result in the direct modulation of CD4(+) T cell behavior. The interaction between MHC and TCR holds unique promise as a focal point for therapeutic intervention in the pathology of CD4(+) T cell-mediated diseases, and MHC class II-derived Recombinant TCR Ligands ("RTLs") have emerged as a new class of therapeutics with potent clinical efficacy in a diverse set of animal models for multiple sclerosis. Here I review the systemic effect that RTL therapy has on the intact immune system and present an overview of a molecular mechanism by which RTL therapy could induce these systemic changes. PMID:15853741

  15. Synthesis and pharmacological evaluation of new biphenylic derivatives as CB2 receptor ligands.

    PubMed

    Bertini, Simone; Chicca, Andrea; Arena, Chiara; Chicca, Stefano; Saccomanni, Giuseppe; Gertsch, Jürg; Manera, Clementina; Macchia, Marco

    2016-06-30

    Targeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer. Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor. In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4' and 5 of the biphenyl scaffold. Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4', with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists. This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays. PMID:27078864

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

    NASA Astrophysics Data System (ADS)

    Köse, Muhammet; Akgün, Eyup; Ceyhan, Gökhan

    2015-12-01

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

  17. Effects of the Hydroxyl Group on Phenyl Based Ligand/ERRγ Protein Binding

    PubMed Central

    2015-01-01

    Bisphenol-A (4,4′-dihydroxy-2,2-diphenylpropane, BPA, or BPA-A) and its derivatives, when exposed to humans, may affect functions of multiple organs by specific binding to the human estrogen-related receptor γ (ERRγ). We carried out atomistic molecular dynamics (MD) simulations of three ligand compounds including BPA-A, 4-α-cumylphenol (BPA-C), and 2,2-diphenylpropane (BPA-D) binding to the ligand binding domain (LBD) of a human ERRγ to study the structures and energies associated with the binding. We used the implicit Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method to estimate the free energies of binding for the phenyl based compound/ERRγ systems. The addition of hydroxyl groups to the aromatic ring had only a minor effect on binding structures and a significant effect on ligand/protein binding energy in an aqueous solution. Free binding energies of BPA-D to the ERRγ were found to be considerably less than those of BPA-A and BPA-C to the ERRγ. These results are well correlated with those from experiments where no binding affinities were determined in the BPA-D/ERRγ complex. No conformational change was observed for the helix 12 (H-12) of ERRγ upon binding of these compounds preserving an active transcriptional conformation state. PMID:25098505

  18. Recent developments in the synthesis and utilization of chiral β-aminophosphine derivatives as catalysts or ligands.

    PubMed

    Li, Wenbo; Zhang, Junliang

    2016-03-14

    In the last few years, the research area of chiral β-aminophosphines capable of promoting a wide range of diverse organic transformations has attracted more attention. Their derivatives constitute attractive reagents towards this end, due to their stability, low toxicity and ease of handling. These novel β-aminophosphine derivatives are potentially useful as organocatalysts and ligands in metal-catalysed reactions. In particular, chiral β-aminophosphines have recently emerged as powerful phosphine catalysts in asymmetric synthesis and catalysis. The asymmetric transformations to which metal complexes of these ligands have been applied include palladium-catalysed allylic substitutions and copper-catalysed 1,4-additions to enones among others. This review summarizes the most significant developments in the area of synthesis and application of chiral β-aminophosphine derivatives, providing a detailed overview of the current state of the art and including future aspects. PMID:26776280

  19. Synthesis and Evaluation of Quinazolone Derivatives as a New Class of c-KIT G-Quadruplex Binding Ligands.

    PubMed

    Wang, Xiaoxiao; Zhou, Chen-Xi; Yan, Jin-Wu; Hou, Jin-Qiang; Chen, Shuo-Bin; Ou, Tian-Miao; Gu, Lian-Quan; Huang, Zhi-Shu; Tan, Jia-Heng

    2013-10-10

    The c-KIT G-quadruplex structures are a novel class of attractive targets for the treatment of gastrointestinal stromal tumor (GIST). Herein, a series of new quinazolone derivatives with the expansion of unfused aromatic ring system were designed and synthesized. Subsequent biophysical studies demonstrated that the derivatives with adaptive scaffold could effectively bind to and stabilize c-KIT G-quadruplexes with good selectivity against duplex DNA. More importantly, these ligands further inhibited the transcription and expression of c-KIT gene and exhibited significant cytotoxicity on the GIST cell line HGC-27. Overall, these quinazolone derivatives represent a new class of promising c-KIT G-quadruplex ligands. The experimental results have also reinforced the idea of inhibition of c-KIT expression through targeting c-KIT G-quadruplex DNA. PMID:24900584

  20. DNA-Based Nanostructures: Changes of Mechanical Properties of DNA upon Ligand Binding

    NASA Astrophysics Data System (ADS)

    Nechipurenko, Yury; Grokhovsky, Sergey; Gursky, Georgy; Nechipurenko, Dmitry; Polozov, Robert

    The formation of DNA-based nanostructures involves the binding of different kinds of ligands to DNA as well as the interaction of DNA molecules with each other. Complex formation between ligand and DNA can alter physicochemical properties of the DNA molecule. In the present work, the accessibility of DNA-ligand complexes to cleavage by DNase I are considered, and the exact algorithms for analysis of diagrams of DNase I footprinting for ligand-DNA complexes are obtained. Changes of mechanical properties of the DNA upon ligand binding are also demonstrated by the cleavage patterns generated upon ultrasound irradiation of cis-platin-DNA complexes. Propagation of the mechanical perturbations along DNA in the presence of bound ligands is considered in terms of a string model with a heterogeneity corresponding to the position of a bound ligand on DNA. This model can reproduce qualitatively the cleavage patterns obtained upon ultrasound irradiation of cis-platin-DNA complexes.

  1. Pharmacological Role of Anions (Sulphate, Nitrate, Oxalate and Acetate) on the Antibacterial Activity of Cobalt(II), Copper(II) and Nickel(II) Complexes With Nicotinoylhydrazine-Derived ONO, NNO and SNO Ligands.

    PubMed

    Chohan, Z H; Rauf, A

    1996-01-01

    Mixed ligands biologically active complexes of cobalt(II), copper(II) and nickel(II) with nicotinoylhydrazine-derived ONO, NNO and SNO donor schiff-base ligands having the same metal ion but different anions such as sulphate, nitrate, oxalate and acetate have been synthesised and characterised on the basis of their physical, analytical and spectral data. In order to evaluate the role of anions on their bioability, these ligands and their synthesised metal complexes with various anions have been screened against bacterial species such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus and the title studies have proved a definative role of anions in increasing the biological activity. PMID:18472896

  2. Pharmacological Role of Anions (Sulphate, Nitrate, Oxalate and Acetate) on the Antibacterial Activity of Cobalt(II), Copper(II) and Nickel(II) Complexes With Nicotinoylhydrazine-Derived ONO, NNO and SNO Ligands

    PubMed Central

    Rauf, Abdur

    1996-01-01

    Mixed ligands biologically active complexes of cobalt(II), copper(II) and nickel(II) with nicotinoylhydrazine-derived ONO, NNO and SNO donor schiff-base ligands having the same metal ion but different anions such as sulphate, nitrate, oxalate and acetate have been synthesised and characterised on the basis of their physical, analytical and spectral data. In order to evaluate the role of anions on their bioability, these ligands and their synthesised metal complexes with various anions have been screened against bacterial species such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus and the title studies have proved a definative role of anions in increasing the biological activity PMID:18472896

  3. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    SciTech Connect

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

    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} (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.

  4. Herbo-mineral based Schiff base ligand and its metal complexes: Synthesis, characterization, catalytic potential and biological applications.

    PubMed

    Kareem, Abdul; Laxmi; Arshad, Mohammad; Nami, Shahab A A; Nishat, Nahid

    2016-07-01

    Schiff base ligand, (L), derived from condensation reaction of 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, (curcumin), with pyridine-3-carboxamide, (nicotinamide), and its complexes of Co(II), Ni(II) and Cu(II) ions, containing 1,10-phenanthroline as auxiliary ligand were synthesized and characterized by various physico-chemical techniques. From the micro analytical data, the stoichiometry of the complexes 1:1 (metal: ligand) was ascertained. The Co(II) and Cu(II) forms octahedral complexes, while the geometric structure around Ni(II) atom can be described as square planar. The catalytic potential of the metal complexes have been evaluated by recording the rate of decomposition of hydrogen peroxide. The results reveal that the percent decomposition of H2O2increases with time and the highest value (50.50%) was recorded for Co(II) complex. The ligand and its complexes were also screened for their in vitro antibacterial activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes and Pseudomonas aeruginosa. The relative order of antibacterial activity against S. Pyogenes, S. aureus and E. coli is Cu(II)>Ni(II)>Co(II)>(L); while with P. aeruginosa, K. pneumoniae the order of activity is Cu(II)>Co(II)>Ni(II)>(L). The anthelmintic screening was performed using Pheretima posthuma. The order of anthelmintic activity of ligand and its complexes is [(Phen)CuLCl2]>[(Phen)CoLCl2]>[(Phen)NiL]Cl2>(L). PMID:27107703

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

    PubMed

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

    2007-12-10

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

  6. Highly Active Multidentate Ligand-Based Alkyne Metathesis Catalysts.

    PubMed

    Du, Ya; Yang, Haishen; Zhu, Chengpu; Ortiz, Michael; Okochi, Kenji D; Shoemaker, Richard; Jin, Yinghua; Zhang, Wei

    2016-06-01

    Alkyne metathesis catalysts composed of molybdenum(VI) propylidyne and multidentate tris(2-hydroxylbenzyl)methane ligands have been developed, which exhibit excellent stability (remains active in solution for months at room temperature), high activity, and broad functional-group tolerance. The homodimerization and cyclooligomerization of monopropynyl or dipropynyl substrates, including challenging heterocycle substrates (e.g., pyridine), proceed efficiently at 40-55 °C in a closed system. The ligand structure and catalytic activity relationship has been investigated, which shows that the ortho groups of the multidentate phenol ligands are critical to the stability and activity of such a catalyst system. PMID:27113640

  7. Polyethylene glycol-based homologated ligands for nicotinic acetylcholine receptors☆

    PubMed Central

    Scates, Bradley A.; Lashbrook, Bethany L.; Chastain, Benjamin C.; Tominaga, Kaoru; Elliott, Brandon T.; Theising, Nicholas J.; Baker, Thomas A.; Fitch, Richard W.

    2010-01-01

    A homologous series of polyethylene glycol (PEG) monomethyl ethers were conjugated with three ligand series for nicotinic acetylcholine receptors. Conjugates of acetylaminocholine, the cyclic analog 1-acetyl-4,4-dimethylpiperazinium, and pyridyl ether A-84543 were prepared. Each series was found to retain significant affinity at nicotinic receptors in rat cerebral cortex with tethers of up to six PEG units. Such compounds are hydrophilic ligands which may serve as models for fluorescent/affinity probes and multivalent ligands for nAChR. PMID:19006672

  8. Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

    PubMed Central

    Apps, Michael G.; Johnson, Ben W.; Sutcliffe, Oliver B.; Brown, Sarah D.; Wheate, Nial J.

    2014-01-01

    Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand. PMID:24893964

  9. Towards targeting anticancer drugs: ruthenium(ii)-arene complexes with biologically active naphthoquinone-derived ligand systems.

    PubMed

    Kubanik, Mario; Kandioller, Wolfgang; Kim, Kunwoo; Anderson, Robert F; Klapproth, Erik; Jakupec, Michael A; Roller, Alexander; Söhnel, Tilo; Keppler, Bernhard K; Hartinger, Christian G

    2016-08-16

    Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays. PMID:27214822

  10. 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

  11. Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands.

    PubMed

    Zheng, Yu; Harms, Klaus; Zhang, Lilu; Meggers, Eric

    2016-08-16

    Chiral rhodium(III) complexes containing two cyclometalating 2-phenyl-5,6-(S,S)-pinenopyridine ligands and two additional acetonitriles are introduced as excellent catalysts for the highly enantioselective alkynylation of 2-trifluoroacetyl imidazoles. Whereas the ligand-based chirality permits the straightforward synthesis of the complexes in a diastereomerically and enantiomerically pure fashion, the metal-centered chirality is responsible for the asymmetric induction over the course of the catalysis. For comparison, the analogous iridium congeners provide only low enantioselectivity, and previously reported benzoxazole- and benzothiazole-based catalysts do not show any catalytic activity for this reaction under standard reaction conditions. PMID:27312941

  12. Ligand-based virtual screening interface between PyMOL and LiSiCA.

    PubMed

    Dilip, Athira; Lešnik, Samo; Štular, Tanja; Janežič, Dušanka; Konc, Janez

    2016-01-01

    Ligand-based virtual screening of large small-molecule databases is an important step in the early stages of drug development. It is based on the similarity principle and is used to reduce the chemical space of large databases to a manageable size where chosen ligands can be experimentally tested. Ligand-based virtual screening can also be used to identify bioactive molecules with different basic scaffolds compared to already known bioactive molecules, thus having the potential to increase the structural variability of compounds. Here, we present an interface between the popular molecular graphics system PyMOL and the ligand-based virtual screening software LiSiCA available at http://insilab.org/lisica-plugin and demonstrate how this interface can be used in the early stages of drug discovery process.Graphical AbstractLigand-based virtual screening interface between PyMOL and LiSiCA. PMID:27606012

  13. Three novel indium MOFs derived from dicarboxylate ligands: Syntheses, structures and photoluminescent properties

    SciTech Connect

    Wang Liping; Song Tianyou; Li Chao; Xia Jing; Wang Shengyan; Wang Li; Xu Jianing

    2012-06-15

    The self-assembly of InCl{sub 3} with 1,4-phenylenediacetic acid (1,4-H{sub 2}pda), 1,3-benzendicarboxylic acid (1,3-H{sub 2}bdc) and 1,4-cyclohexanedicarboxylic acid (1,4- H{sub 2}chdc) generates three new In(III) MOFs, (Me{sub 2}NH{sub 2})[In(cis-1,4-pda){sub 2}] (1), HIn(1,3-bdc){sub 2}{center_dot}2DMF (2) and In(OH)(trans-1,4-chdc) (3) (Me{sub 2}NH=dimethylamine, DMF=N, N'-dimethylformamide). Compound 1 displays a novel 1D no-planar double chain. Although a mixture of cis- and trans-1,4-H{sub 2}pda was used, the product of compound 1 is a single phase with only cis-pda{sup 2-} ligands. Compound 2 possesses a 2D square lattice with sql topology. Interestingly, in compound 2, the 4-connected building unit containing InO{sub 6} octahedron is firstly occurred in In-MOFs. Compound 3 is built up from the infinite metal-oxide chains cross-linked by trans-1,4-chdc{sup 2-} to form 3D framework with rhombus-shaped channels. Furthermore, compounds 1-3 present intense solid-state fluorescent emissions at room temperature. - Graphical abstract: Three new In-MOFs based on different dicaboxylate acids display 1D chain, 2D layer and 3D open-framework, respectively and show strong luminescence emissions at room temperature. Highlights: Black-Right-Pointing-Pointer Three new indium metal-organic frameworks have been solvothermal synthesized. Black-Right-Pointing-Pointer The structural variation is attributed to the diverse coordination modes of ligands. Black-Right-Pointing-Pointer Compounds 1-3 exhibit 1D double chain, 2D layer and 3D open-framework, respectively. Black-Right-Pointing-Pointer These compounds exhibit strong solid-state luminescence emission at room temperature.

  14. Paired Ig-Like Type 2 Receptor-Derived Agonist Ligands Ameliorate Inflammatory Reactions by Downregulating β1 Integrin Activity

    PubMed Central

    Lee, Kyoung-Jin; Lim, Dongyoung; Yoo, Yeon Ho; Park, Eun-Ji; Lee, Sun-Hee; Yadav, Birendra Kumar; Lee, Yong-Ki; Park, Jeong Hyun; Kim, Daejoong; Park, Kyeong Han; Hahn, Jang-Hee

    2016-01-01

    The paired immunoglobulin-like type 2 receptor (PILR) family consists of two functionally opposite members, inhibitory PILRα and activating PILRβ receptors. PILRs are widely expressed in various immune cells and interact with their ligands, especially CD99 expressed on activated T cells, to participate in immune responses. Here we investigated whether PILR-derived agonists inhibit β1 integrin activity as ligands for CD99. PILR-derived peptides as well as PILR-Fc fusion proteins prevented cell adhesion to fibronectin through the regulation of β1 integrin activity. Especially, PILRpep3, a representative 3-mer peptide covering the conserved motifs of the PILR extracellular domain, prevented the clustering and activation of β1 integrin by dephosphorylating FAK and vinculin, which are major components of focal adhesion. In addition, PILRpep3 inhibited transendothelial migration of monocytes as well as endothelial cell tube formation. Furthermore, upon intraperitoneal injection of PILRpep3 into mice with collagen-induced arthritis, the inflammatory response of rheumatoid arthritis was strongly suppressed. Taken together, these results suggest that PILR-derived agonist ligands may prevent the inflammatory reactions of rheumatoid arthritis by activating CD99. PMID:27306643

  15. Identification of Novel Smoothened Ligands Using Structure-Based Docking

    PubMed Central

    Torosyan, Hayarpi; Parathaman, Pranavan; Irwin, John J.; Shoichet, Brian K.

    2016-01-01

    The seven transmembrane protein Smoothened is required for Hedgehog signaling during embryonic development and adult tissue homeostasis. Inappropriate activation of the Hedgehog signalling pathway leads to cancers such as basal cell carcinoma and medulloblastoma, and Smoothened inhibitors are now available clinically to treat these diseases. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of Smoothened crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In this study, we docked 3.2 million available, lead-like molecules against Smoothened, looking for those with high physical complementarity to its structure; this represents the first such campaign against the class Frizzled G-protein coupled receptor family. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize Smoothened with IC50 values better than 50 μM. A screen for analogs revealed another six molecules, with IC50 values in the low micromolar range. Importantly, one of the most active of the new antagonists continued to be efficacious at the D473H mutant of Smoothened, which confers clinical resistance to the antagonist vismodegib in cancer treatment. PMID:27490099

  16. Identification of Novel Smoothened Ligands Using Structure-Based Docking.

    PubMed

    Lacroix, Celine; Fish, Inbar; Torosyan, Hayarpi; Parathaman, Pranavan; Irwin, John J; Shoichet, Brian K; Angers, Stephane

    2016-01-01

    The seven transmembrane protein Smoothened is required for Hedgehog signaling during embryonic development and adult tissue homeostasis. Inappropriate activation of the Hedgehog signalling pathway leads to cancers such as basal cell carcinoma and medulloblastoma, and Smoothened inhibitors are now available clinically to treat these diseases. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of Smoothened crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In this study, we docked 3.2 million available, lead-like molecules against Smoothened, looking for those with high physical complementarity to its structure; this represents the first such campaign against the class Frizzled G-protein coupled receptor family. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize Smoothened with IC50 values better than 50 μM. A screen for analogs revealed another six molecules, with IC50 values in the low micromolar range. Importantly, one of the most active of the new antagonists continued to be efficacious at the D473H mutant of Smoothened, which confers clinical resistance to the antagonist vismodegib in cancer treatment. PMID:27490099

  17. Novel, efficient alkene-phosphinite hybrid ligand based on D-glucose.

    PubMed

    Minuth, Tobias; Boysen, Mike M K

    2009-09-17

    A commercially available 2,3-unsaturated pyranoside, derived from d-glucose, was converted into a new type of olefin phosphorus chelate ligand in only three steps. Application in rhodium catalyzed conjugate additions of phenylboronic acid to enones led to excellent levels of stereoinduction for several cyclic substrates. The easy preparation and the high efficiency of this ligand make it an interesting and promising alternative to established systems. PMID:19691311

  18. Derivation of ligands for the complement C3a receptor from the C-terminus of C5a

    PubMed Central

    Halai, Reena; Bellows-Peterson, Meghan L; Branchett, Will; Smadbeck, James; Kieslich, Chris A; Croker, Daniel E; Cooper, Matthew A; Morikis, Dimitrios; Woodruff, Trent M; Floudas, Christodoulos A; Monk, Peter N

    2014-01-01

    The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena. PMID:25446428

  19. Protein-specific force field derived from the fragment molecular orbital method can improve protein-ligand binding interactions.

    PubMed

    Chang, Le; Ishikawa, Takeshi; Kuwata, Kazuo; Takada, Shoji

    2013-05-30

    Accurate computational estimate of the protein-ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein-ligand simulations, we use a protein-specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO-RESP method to two proteins, dodecin, and lysozyme, we found that protein-specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO-RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. PMID:23420697

  20. Electron-Donating Para-Methoxy Converts a Benzamide-Isoquinoline Derivative into a Highly Sigma-2 Receptor Selective Ligand

    PubMed Central

    Hajipour, Abdol R.; Guo, Lian-Wang; Pal, Arindam; Mavlyutov, Timur; Ruoho, Arnold E.

    2011-01-01

    The sigma-2 (σ2) receptor has been suggested to be a promising target for pharmacological interventions to curb tumor progression. Development of σ2-specific ligands, however, has been hindered by lack of understanding of molecular determinants that underlie selective ligand-σ2 interactions. Here we have explored effects of electron donating and withdrawing groups on ligand selectivity for the σ2 versus σ1 receptor using new benzamide-isoquinoline derivatives. The electron-donating methoxy group increased but the electron-withdrawing nitro group decreased σ2 affinity. In particular, an extra methoxy added to the para-position (5e) of the benzamide phenyl ring of 5f dramatically improved (631 fold) the σ2 selectivity relative to the σ1 receptor. This para-position provided a sensitive site for effective manipulation of the sigma receptor subtype selectivity using either the methoxy or nitro substituent. Our study provides a useful guide for further improving the σ2-over-σ1 selectivity of new ligands. PMID:22055714

  1. Triptycene-Based Chiral and meso-N-Heterocyclic Carbene Ligands and Metal Complexes.

    PubMed

    Savka, Roman; Bergmann, Marvin; Kanai, Yuki; Foro, Sabine; Plenio, Herbert

    2016-07-01

    Based on 1-amino-4-hydroxy-triptycene, new saturated and unsaturated triptycene-NHC (N-heterocyclic carbene) ligands were synthesized from glyoxal-derived diimines. The respective carbenes were converted into metal complexes [(NHC)MX] (M=Cu, Ag, Au; X=Cl, Br) and [(NHC)MCl(cod)] (M=Rh, Ir; cod=1,5-cyclooctadiene) in good yields. The new azolium salts and metal complexes suffer from limited solubility in common organic solvents. Consequently, the introduction of solubilizing groups (such as 2-ethylhexyl or 1-hexyl by O-alkylation) is essential to render the complexes soluble. The triptycene unit infers special steric properties onto the metal complexes that enable the steric shielding of selected areas close to the metal center. Next, chiral and meso-triptycene based N-heterocyclic carbene ligands were prepared. The key step in the synthesis of the chiral ligand is the Buchwald-Hartwig amination of 1-bromo-4-butoxy-triptycene with (1S,2S)-1,2-diphenyl-1,2-diaminoethane, followed by cyclization to the azolinium salt with HC(OEt)3 . The analogous reaction with meso-1,2-diphenyl-1,2-diaminoethane provides the respective meso-azolinium salt. Both the chiral and meso-azolinium salts were converted into metal complexes including [(NHC)AuCl], [(NHC)RhCl(cod)], [(NHC)IrCl(cod)], and [(NHC)PdCl(allyl)]. An in situ prepared chiral copper complex was tested in the enantioselective borylation of α,β-unsaturated esters and found to give an excellent enantiomeric ratio (er close to 90:10). PMID:27295113

  2. Small antibody-like proteins with prescribed ligand specificities derived from the lipocalin fold

    PubMed Central

    Beste, Gerald; Schmidt, Frank S.; Stibora, Thomas; Skerra, Arne

    1999-01-01

    We demonstrate that the ligand pocket of a lipocalin from Pieris brassicae, the bilin-binding protein (BBP), can be reshaped by combinatorial protein design such that it recognizes fluorescein, an established immunological hapten. For this purpose 16 residues at the center of the binding site, which is formed by four loops on top of an eight-stranded β-barrel, were subjected to random mutagenesis. Fluorescein-binding BBP variants were then selected from the mutant library by bacterial phage display. Three variants were identified that complex fluorescein with high affinity, exhibiting dissociation constants as low as 35.2 nM. Notably, one of these variants effects almost complete quenching of the ligand fluorescence, similarly as an anti-fluorescein antibody. Detailed ligand-binding studies and site-directed mutagenesis experiments indicated (i) that the molecular recognition of fluorescein is specific and (ii) that charged residues at the center of the pocket are responsible for tight complex formation. Sequence comparison of the BBP variants directed against fluorescein with the wild-type protein and with further variants that were selected against several other ligands revealed that all of the randomized amino acid positions are variable. Hence, a lipocalin can be used for generating molecular pockets with a diversity of shapes. We term this class of engineered proteins “anticalins.” Their one-domain scaffold makes them a promising alternative to antibodies to create a stable receptor protein for a ligand of choice. PMID:10051566

  3. Spectral, electrochemical and molecular orbital studies on solvatochromic mixed ligand copper(II) complexes of malonate and diamine derivatives

    NASA Astrophysics Data System (ADS)

    Taha, Ali

    2003-04-01

    Solvatochromic mixed ligand complexes of copper(II) with malonate and diamine derivatives, Cu n(RMal)(diam) nXm (where n=1 or 2, m=1-4, RMal, malonic acid (H 2Mal), diethylmalonate (HDEtMal) or diethylethoxyethylenemalonate (DEtEMal), and diam, ethylenediamine (en), 1,3-propylenediamine (1,3-pn), N, N, N'-trimethylethylenediamine (Me 3en), N, N, N'-triethylethylenediamine (Et 3en), N, N, N', N'-tetramethylethylenediamine (Me 4en), N, N, N', N'-tetramethylpropylenediamine (Me 4pn), or N-methyl-1,4-diazacycloheptane (medach); and X=ClO 4- or Cl -), has been synthesized and characterized by spectroscopic, magnetic, molar conductance and electrochemical measurements. The mass spectra along with the analytical data of the complexes show peaks with m/ e corresponding to a bridged binuclear structure for the chloride complexes, while perchlorate complexes showed either mononuclear structure for DEtMal and DEtEMal or bridged binuclear structure for Mal complexes. These results correspond to IR spectral data, which indicated that the modes of ester and carboxylato coordination sites are mono- and/or bidentate. The d-d absorption bands in weak donor solvents suggest square-planar and distorted square pyramidal-trigonal bipyramid geometries for the perchlorate and chloride complexes; respectively. On the other hand, an octahedral structure is identified for complexes in strong donor solvents. Perchlorate complexes show a drastic color change from violet to green as the donation ability of solvent increases, whereas chloride complexes are highly affected by the acceptor properties of the solvent. Cyclic voltammetric measurements on the complexes, proposed a quasi-reversible or irreversible and mainly diffusion controlled reduction process. Such behavior has been explained according to the ECE mechanism. A linear correlation has been found between the Cu(II) reduction potential and the spectral data. Molecular orbital calculations were performed for the ligands on the bases of

  4. A new cyclic supramolecular Zn(II) complex derived from a N2O2 oxime chelate ligand with luminescence mechanochromism.

    PubMed

    Zhang, Shou-Ting; Li, Tian-Rong; Wang, Bao-Dui; Yang, Zheng-Yin; Liu, Jian; Wang, Zhi-Yi; Dong, Wen-Kui

    2014-02-21

    A new Zn(II) complex was synthesized based on a new Salen-type tetradentate N2O2 bisoxime chelate ligand (H2L) derived from 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone (PMBP) and 1,2-bis(aminooxy)ethane. Single-crystal X-ray diffraction analysis reveals that the structure of the Zn(II) complex features a three-dimensional (3D) cyclic supramolecular system via intermolecular hydrogen bonds. Moreover, the solid-state photoluminescent properties demonstrate that the Zn(II) complex exhibits unusual luminescence mechanochromism tuned by CH3OH. PMID:24352216

  5. Synthesis and Characterization of a New TRIPHOS Ligand Derivative and the Corresponding Pd(II) Complexes

    SciTech Connect

    Miller, Deanna L.; Boro, Brian J.; Grubel, Katarzyna; Helm, Monte L.; Appel, Aaron M.

    2015-12-01

    The synthesis of the new bis(2-(diphenylphosphino)ethyl)methylhydroxyphosphine tridentate phosphine ligand, LCH2OH/Ph, is reported. The ligand reacts with [Pd(Cl)2(PhCN)2 to form [Pd(LCH2OH/Ph)Cl]Cl. Exchange of the chloride ions for triflate (OTf–) using AgOTf yielded pure [Pd(LCH2OH/Ph)OTf]OTf. In addition to spectral characterization the free ligand, LCH2OH/Ph, and Pd(II) complex, [Pd(LCH2OH/Ph)OTf]OTf, are structurally characterized. This research was supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Biosciences, and Geosciences. Pacific Northwest National Laboratory is a multiprogram national laboratory operated by Battelle for DOE.

  6. Ruthenium Nitrosyls Derived from Tetradentate Ligands Containing Carboxamido-N and Phenolato-O Donors: Syntheses, Structures, Photolability and Time Dependent Density Functional Theory Studies

    PubMed Central

    Fry, Nicole L.; Rose, Michael J.; Rogow, David L.; Nyitray, Crystal; Kaur, Manpreet; Mascharak, Pradip K.

    2010-01-01

    Ruthenium nitrosyls derived from ligands containing carboxamido-N and phenolato-O donors release NO upon exposure to low power UV light. Results of theoretical calculations on a set of such nitrosyls indicate strong interactions between the ligand MOs and MOs encompassing the Ru-NO moiety that dictate the parameters of NO photolability. PMID:20063858

  7. Design, synthesis and biological evaluation of 4-anilinoquinazoline derivatives as new c-myc G-quadruplex ligands.

    PubMed

    Jiang, Yin; Chen, Ai-Chun; Kuang, Guo-Tao; Wang, Shi-Ke; Ou, Tian-Miao; Tan, Jia-Heng; Li, Ding; Huang, Zhi-Shu

    2016-10-21

    A series of 4-anilinoquinazoline derivatives were designed and synthesized as novel c-myc promoter G-quadruplex binding ligands. Subsequent biophysical and biochemical evaluation demonstrated that the introduction of aniline group at 4-position of quinazoline ring and two side chains with terminal amino group improved their binding affinity and stabilizing ability to G-quadruplex DNA. RT-PCR assay and Western blot showed that compound 7a could down-regulate transcription and expression of c-myc gene in Hela cells, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene. More importantly, RTCA and colony formation assays indicated that 7a obviously inhibited Hela cells proliferation, without influence on normal primary cultured mouse mesangial cells. Flow cytometric assays suggested that 7a induced Hela cells to arrest in G0/G1 phase both in a time-dependent and dose-dependent manner. PMID:27372288

  8. Anthranilic acid derivatives as nuclear receptor modulators--development of novel PPAR selective and dual PPAR/FXR ligands.

    PubMed

    Merk, Daniel; Lamers, Christina; Weber, Julia; Flesch, Daniel; Gabler, Matthias; Proschak, Ewgenij; Schubert-Zsilavecz, Manfred

    2015-02-01

    Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism. PMID:25583100

  9. SERS Activity of Silver Nanoparticles Functionalized with A Desferrioxamine B Derived Ligand for FE(III) Binding and Sensing

    NASA Astrophysics Data System (ADS)

    Galinetto, P.; Taglietti, A.; Pasotti, L.; Pallavicini, P.; Dacarro, G.; Giulotto, E.; Grandi, M. S.

    2016-01-01

    We report the SERS activity of colloidal silver nanoparticles functionalized with a ligand, derived from the siderophore desferrioxamine B (desferal, DFO), an iron chelator widely used in biological and medical applications. The ligand was equipped with a sulfur-containing moiety to ensure optimal binding with silver surfaces. By means of Raman and SERS effects we monitored the route of material preparation from the modified DFO-S molecule to the colloidal aggregates. The results indicate that the functionalization of the chelating agent does not affect its binding ability towards Fe(III). The resulting functionalized silver nanoparticles are a promising SERS tag for operation in biological environments. The Fe-O stretching signature, arising when DFO-S grafted to silver nanoparticles binds Fe(III), could provide a tool for cation sensing in solution.

  10. 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

  11. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  13. Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

    NASA Astrophysics Data System (ADS)

    Liu, Shuang

    Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

  14. Syntheses, characterizations and structures of NO donor Schiff base ligands and nickel(II) and copper(II) complexes

    NASA Astrophysics Data System (ADS)

    Şenol, Cemal; Hayvali, Zeliha; Dal, Hakan; Hökelek, Tuncer

    2011-06-01

    New Schiff base derivatives ( L 1 and L 2) were prepared by the condensation of 2-hydroxy-3-methoxybenzaldehyde ( o-vanillin) and 3-hydroxy-4-methoxybenzaldehyde ( iso-vanillin) with 5-methylfurfurylamine. Two new complexes [Ni(L 1) 2] and [Cu(L 1) 2] have been synthesized with bidentate NO donor Schiff base ligand ( L 1). The Ni(II) and Cu(II) atoms in each complex are four coordinated in a square planar geometry. Schiff bases ( L 1 and L 2) and complexes [Ni(L 1) 2] and [Cu(L 1) 2] were characterized by elemental analyses, FT-IR, UV-vis, mass and 1H, 13C NMR spectroscopies. The crystal structures of the ligand ( L 2) and complexes [Ni(L 1) 2] and [Cu(L 1) 2] have also been determined by using X-ray crystallographic technique.

  15. Modulating structural dimensionality of cadmium(II) coordination polymers by means of pyrazole, tetrazole and pyrimidine derivative ligands

    NASA Astrophysics Data System (ADS)

    Seco, Jose Manuel; Calahorro, Antonio; Cepeda, Javier; Rodríguez-Diéguez, Antonio

    2015-06-01

    Six new compounds with functionalized pyrazole, tetrazole, and pyrimidine ligands, namely [Cd(μ-4-Hampz)(μ-Cl)2]n(1), [Cd(μ3-pzdc)(μ-H2O)(H2O)]n(2), [Cd(μ-5-amtz)2(eda)]n(3), {[Cd9(μ4-5-amtz)8(μ-Cl)10(H2O)2]ṡxH2O}n(4), {[Cd2(μ-dm2-pmc)2Cl2(H2O)2]ṡH2O}n(5), and [Cd2(μ-Br2-pmc)(μ-Cl)3(H2O)2]n(6) (where 4-Hampz = 4-aminopyrazole, pzdc = 3,5-pyrazoledicarboxylate, 5-amtz = 5-aminotetrazolate, eda = ethylenediamine, dm2-pmc = 4,6-dimethoxy-2-pyrimidinecarboxylate, Br2-pmc = 5-bromopyrimidine-2-carboxylate) have been synthesized under hydrothermal conditions and structurally characterized by single crystal X-ray diffraction. Compounds 1 and 2 share the structural feature of being constructed from dinuclear building units that are further connected through the pyrazole based ligands, rendering a compact and a potentially open 3D frameworks, respectively. On the other hand, 5-amtz ligand exhibits two different coordination modes in compounds 3 and 4 as a result of the presence or absence of an additional blocking ligand. In this way, the μ-κ4N,N‧,N″,N‴ mode in 4 affords robust clusters that are joined in a topologically novel 3D open architecture containing two types of channels, whereas a simple bidentate bridging mode is limited for 5-amtz in 3 due to the presence of the chelating eda ligand. 1D and 3D structures are obtained with pyrimidine ligands in compounds 5 and 6 according to the steric hindrance of the substituents.

  16. 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

    2016-04-01

    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. PMID:26990027

  17. Current trends in virtual high throughput screening using ligand-based and structure-based methods.

    PubMed

    Sukumar, Nagamani; Das, Sourav

    2011-12-01

    High throughput in silico methods have offered the tantalizing potential to drastically accelerate the drug discovery process. Yet despite significant efforts expended by academia, national labs and industry over the years, many of these methods have not lived up to their initial promise of reducing the time and costs associated with the drug discovery enterprise, a process that can typically take over a decade and cost hundreds of millions of dollars from conception to final approval and marketing of a drug. Nevertheless structure-based modeling has become a mainstay of computational biology and medicinal chemistry, helping to leverage our knowledge of the biological target and the chemistry of protein-ligand interactions. While ligand-based methods utilize the chemistry of molecules that are known to bind to the biological target, structure-based drug design methods rely on knowledge of the three-dimensional structure of the target, as obtained through crystallographic, spectroscopic or bioinformatics techniques. Here we review recent developments in the methodology and applications of structure-based and ligand-based methods and target-based chemogenomics in Virtual High Throughput Screening (VHTS), highlighting some case studies of recent applications, as well as current research in further development of these methods. The limitations of these approaches will also be discussed, to give the reader an indication of what might be expected in years to come. PMID:21843144

  18. Structure-activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout.

    PubMed

    Karaki, Fumika; Ohgane, Kenji; Fukuda, Hiromitsu; Nakamura, Masahiko; Dodo, Kosuke; Hashimoto, Yuichi

    2014-07-15

    Niemann-Pick type C1-like 1 (NPC1L1) is an intestinal cholesterol transporter that is known to be the target of the cholesterol absorption inhibitor ezetimibe. We previously discovered steroidal NPC1L1 ligands by using a novel cell-based assay that employs pharmacological chaperone effect as a readout. Those steroid derivatives bound to a site different from both the sterol-binding domain and the ezetimibe-binding site, implying that they may be a novel class of NPC1L1 inhibitors with a distinct mode of action. As an extension of that work, we aimed here to find non-steroidal NPC1L1 ligands, which may be better candidates for clinical application than steroidal ligands, by using the same assay to screen our focused library of ligands for liver X receptor (LXR), a nuclear receptor that recognizes oxysterols as endogenous ligands. Here we describe identification of a novel class of NPC1L1 ligands with a ring-fused quinolinone scaffold, and an analysis of the structure-activity relationships of their derivatives as NPC1L1 ligands. PMID:24906511

  19. Synthesis and spectroscopic studies on the Schiff base ligand derived from condensation of 2-furaldehyde and 3,3'-diaminobenzidene, L and its complexes with Co(II), Ni(II), Cu(II) and Zn(II): Comparative DNA binding studies of L and its Cu(II) and Zn(II) complexes

    NASA Astrophysics Data System (ADS)

    Shakir, Mohammad; Abbasi, Ambreen; Khan, Asad U.; Khan, Shahper N.

    2011-01-01

    The Schiff base ligand, N,N'-bis-(2-furancarboxaldimine)-3,3'-diaminobenzidene (L) obtained by condensation of 2-furaldehyde and 3,3'-diaminobenzidene, was used to synthesize the mononuclear complexes of the type, [M(L)](NO 3) 2 [M = Co(II), Ni(II), Cu(II) and Zn(II)]. The newly synthesized ligand, (L) and its complexes have been characterized on the basis of the results of the elemental analysis, molar conductance, magnetic susceptibility measurements and spectroscopic studies viz, FT-IR, 1H and 13C NMR, mass, UV-vis and EPR. EPR, UV-vis and magnetic moment data revealed a square planar geometry for the complexes with distortion in Cu(II) complex and conductivity data show a 1:2 electrolytic nature of the complexes. Absorption and fluorescence spectroscopic studies support that Schiff base ligand, L and its Cu(II) and Zn(II) complex exhibit significant binding to calf thymus DNA. The highest binding affinity in case of L may be due to the more open structure as compared to the metal coordinated complexes.

  20. Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

    NASA Astrophysics Data System (ADS)

    Liu, Shuang

    Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

  1. Synthesis and Fluorescence Properties of Eu(3+), Tb(3+) Complexes with Schiff Base Derivatives.

    PubMed

    Liu, Yanhong; Kong, Weihua; Yang, Zehui; Dai, Ming; Shi, Ling; Guo, Dongcai

    2016-03-01

    Novel Schiff base ligands derived from N'-benzylidene-benzohydrazide (substituted by -H, -CH3, -OCH3, -Cl) and 2-chloro-N-phenylacetamide were synthesized. The solid complexes of rare earth (Eu, Tb) nitrate with these Schiff base ligands were synthesized and characterized by elemental analysis, EDTA titrimetric analysis, thermal analysis, infrared spectra and UV-Vis spectra analysis. The fluorescence properties of rare earth (Eu, Tb) complexes in solid were studied. Under the excitation of ultraviolet light, these complexes exhibited characteristic emission of europium and terbium ions. The results showed that the ligand favored energy transfer to the emitting energy of Eu and Tb ions. Effects of different ligands on the fluorescence intensity of rare earth (Eu, Tb) complexes had been discussed. The electrochemical properties of rare earth (Eu, Tb) complexes were also investigated. PMID:26658796

  2. Are superhalogens without halogen ligand capable of transcending traditional halogen-based superhalogens? Ab initio case study of binuclear anions based on pseudohalogen ligand

    SciTech Connect

    Li, Jin-Feng; Sun, Yin-Yin; Li, Miao-Miao; Li, Jian-Li; Yin, Bing; Bai, Hongcun

    2015-06-15

    The superhalogen properties of polynuclear structures without halogen ligand are theoretically explored here for several [M{sub 2}(CN){sub 5}]{sup −1} (M =  Ca, Be) clusters. At CCSD(T) level, these clusters have been confirmed to be superhalogens due to their high vertical electron detachment energies (VDE). The largest one is 9.70 eV for [Ca{sub 2}(CN){sub 5}]{sup −1} which is even higher than those of corresponding traditional structures based on fluorine or chlorine ligands. Therefore the superhalogens stronger than the traditional halogen-based structures could be realized by ligands other than halogen atoms. Compared with CCSD(T), outer valence Green’s function (OVGF) method either overestimates or underestimates the VDEs for different structures while MP2 results are generally consistent in the aspect of relative values. The extra electrons of the highest VDE anions here aggregate on the bridging CN units with non-negligible distribution occurring on other CN units too. These two features lower both the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to the detachment of cyanide ligand were also investigated. The sum of these results identifies the potential of polynuclear structures with pseudohalogen ligand as suitable candidates with enhanced superhalogens properties.

  3. Reviewing Ligand-Based Rational Drug Design: The Search for an ATP Synthase Inhibitor

    PubMed Central

    Lee, Chia-Hsien; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2011-01-01

    Following major advances in the field of medicinal chemistry, novel drugs can now be designed systematically, instead of relying on old trial and error approaches. Current drug design strategies can be classified as being either ligand- or structure-based depending on the design process. In this paper, by describing the search for an ATP synthase inhibitor, we review two frequently used approaches in ligand-based drug design: The pharmacophore model and the quantitative structure-activity relationship (QSAR) method. Moreover, since ATP synthase ligands are potentially useful drugs in cancer therapy, pharmacophore models were constructed to pave the way for novel inhibitor designs. PMID:21954360

  4. Gold(I)-triphenylphosphine complexes with hypoxanthine-derived ligands: in vitro evaluations of anticancer and anti-inflammatory activities.

    PubMed

    Křikavová, Radka; Hošek, Jan; Vančo, Ján; Hutyra, Jakub; Dvořák, Zdeněk; Trávníček, Zdeněk

    2014-01-01

    A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1-9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4-6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4-6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1-30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study. PMID:25226034

  5. Gold(I)-Triphenylphosphine Complexes with Hypoxanthine-Derived Ligands: In Vitro Evaluations of Anticancer and Anti-Inflammatory Activities

    PubMed Central

    Křikavová, Radka; Hošek, Jan; Vančo, Ján; Hutyra, Jakub; Dvořák, Zdeněk; Trávníček, Zdeněk

    2014-01-01

    A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1–9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4–6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4–6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1–30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study. PMID:25226034

  6. Hsp90 Inhibitors, Part 2: Combining Ligand-Based and Structure-Based Approaches for Virtual Screening Application

    PubMed Central

    2015-01-01

    Hsp90 continues to be an important target for pharmaceutical discovery. In this project, virtual screening (VS) for novel Hsp90 inhibitors was performed using a combination of Autodock and Surflex-Sim (LB) scoring functions with the predictive ability of 3-D QSAR models, previously generated with the 3-D QSAutogrid/R procedure. Extensive validation of both structure-based (SB) and ligand-based (LB), through realignments and cross-alignments, allowed the definition of LB and SB alignment rules. The mixed LB/SB protocol was applied to virtually screen potential Hsp90 inhibitors from the NCI Diversity Set composed of 1785 compounds. A selected ensemble of 80 compounds were biologically tested. Among these molecules, preliminary data yielded four derivatives exhibiting IC50 values ranging between 18 and 63 μM as hits for a subsequent medicinal chemistry optimization procedure. PMID:24555544

  7. Guanosine and its modified derivatives are endogenous ligands for TLR7.

    PubMed

    Shibata, Takuma; Ohto, Umeharu; Nomura, Shosaku; Kibata, Kayoko; Motoi, Yuji; Zhang, Yan; Murakami, Yusuke; Fukui, Ryutaro; Ishimoto, Tatsushi; Sano, Shigetoshi; Ito, Tomoki; Shimizu, Toshiyuki; Miyake, Kensuke

    2016-05-01

    Toll-like receptor (TLR) 7and 8 were considered to recognize single-strand RNA (ssRNA) from viruses. Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. In the structure of human TLR8 (huTLR8) with ssRNA, there are two ligand-binding sites: one binds a uridine and the other binds an oligoribonucleotide (ORN). This finding demonstrates that huTLR8 recognizes degradation products of ssRNA, suggesting the presence of natural small ligands. We here show that TLR7 works as the sensor for guanosine (G)/2'-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7-methylguanosine, 8-hydroxyguanosine (8-OHG) and 8-hydroxydeoxyguanosine (8-OHdG) activated TLR7 with ORNs. Importantly, 8-OHdG-a well-known oxidative DNA damage marker with unknown function-induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Although 8-OHdG bound TLR7/ORN with lower affinity than dG did in isothermal titration calorimetry, administered 8-OHdG was metabolically more stable than dG in the serum, indicating that 8-OHdG acts on TLR7 as an endogenous ligand in vivo To address a role of G analogs in the disease state, we also examined macrophages from Unc93b1 (D34A/D34A) mice, which suffer from TLR7-dependent systemic inflammation, and found that Unc93b1 (D34A/D34A) macrophages showed significantly enhanced response to G alone or 8-OHdG with ORN. In conclusion, our results provide evidence that G, dG, 8-OHG and 8-OHdG are novel endogenous ligands for TLR7. PMID:26489884

  8. Discovering new agents active against methicillin-resistant Staphylococcus aureus with ligand-based approaches.

    PubMed

    Wang, Ling; Le, Xiu; Li, Long; Ju, Yingchen; Lin, Zhongxiang; Gu, Qiong; Xu, Jun

    2014-11-24

    To discover new agents active against methicillin-resistant Staphylococcus aureus (MRSA), in silico models derived from 5451 cell-based anti-MRSA assay data were developed using four machine learning methods, including naïve Bayesian, support vector machine (SVM), recursive partitioning (RP), and k-nearest neighbors (kNN). A total of 876 models have been constructed based on physicochemical descriptors and fingerprints. The overall predictive accuracies of the best models exceeded 80% for both training and test sets. The best model was employed for the virtual screening of anti-MRSA compounds, which were then validated by a cell-based assay using the broth microdilution method with three types of highly resistant MRSA strains (ST239, ST5, and 252). A total of 12 new anti-MRSA agents were confirmed, which had MIC values ranging from 4 to 64 mg/L. This work proves the capacity of combined multiple ligand-based approaches for the discovery of new agents active against MRSA with cell-based assays. We think this work may inspire other lead identification processes when cell-based assay data are available. PMID:25375651

  9. Key role of the Lewis base position in asymmetric bifunctional catalysis: design and evaluation of a new ligand for chiral polymetallic catalysts.

    PubMed

    Fujimori, Ikuo; Mita, Tsuyoshi; Maki, Keisuke; Shiro, Motoo; Sato, Akihiro; Furusho, Sanae; Kanai, Motomu; Shibasaki, Masakatsu

    2006-12-27

    New chiral ligands for asymmetric polymetallic catalysts were designed on the basis of the assumption that the higher-order assembly structure is stabilized by modifying the modular unit. The designed ligands 6 and 7 contained a scaffolding cyclohexane ring with a Lewis base phosphine oxide directly attached to the scaffold. A module in the polymetallic complex contains two metals per ligand, and a stable 6-, 5-, 5-membered fused chelation ring system should be generated. Synthesis of these ligands is simple and high yielding, using a catalytic dynamic kinetic resolution promoted by the Trost catalyst as a key step. Ligand function was assessed in a catalytic asymmetric ring-opening reaction of meso-aziridines with TMSCN, a useful reaction for the synthesis of optically active beta-amino acids. The Gd complex generated from Gd(OiPr)3 and the ligand was a highly active and enantioselective catalyst in this reaction. Enantioselectivity was reversed compared to the previously reported d-glucose-derived catalyst containing the same chirality of the individual module. ESI-MS analysis and X-ray crystallographic studies indicate that the assembly state of the modules in the polymetallic catalysts differs depending on the chiral ligand. The difference in the higher-order structure stems from a subtle change (one carbon) in the position of the Lewis base relative to the Gd metal. The change in the higher-order structure of the polymetallic complex led to a dramatic reversal of the enantioselectivity and increased catalyst activity. PMID:17177358

  10. PoLi: A Virtual Screening Pipeline Based On Template Pocket And Ligand Similarity

    PubMed Central

    Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey

    2015-01-01

    Often in pharmaceutical research, the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand binding pockets in proteins is small. PoLi identifies similar ligand binding pockets in a holo-template protein library, selectively copies relevant parts of template ligands and uses them for VS. In practice, PoLi is a hybrid structure and ligand based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6 respectively, in the top 1% of the screened library. In contrast, traditional docking based VS using AutoDock Vina and homology-based VS using FINDSITEfilt have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods. PMID:26225536

  11. New synthesis of a high molecular weight ligand derived from dota; thermodynamic stability of the MRI contrast agent formed with gadolinium.

    PubMed

    Pierrard, Jean-Claude; Rimbault, Jean; Aplincourt, Michel; Le Greneur, Soizic; Port, Marc

    2008-01-01

    The new total synthesis in four steps of the compound P1041 is reported. This compound is a high molecular mass ligand (MW 6.32 kDa) derived from dota in which the four substituents are hydroxylated and contain amidic groups. The attribution of the nine protonation constants of P1041 is based on the comparison with the behaviour of the precursor ligands dota and tced, a tetracarboxylated derivative of dota. From these results, the studies of the systems P1041/Na(+) and P1041/Gd(3+) lead to the determination of the stability constants corresponding to the three species Na(P1041)H(h) (h = 0, 2 or 4) and to the five complexes Gd(P1041)H(h) (h = 0, 2, 3, 4 or 5). The complexing ability of P1041 towards Gd(3+) is compared with those of dota and tced. At physiological pH = 7.4, the very stable species Gd(P1041)H(4) (-) (currently named P792 in the literature) of this rapid clearance blood pool agent is predominant. PMID:19072772

  12. Protein-ligand docking using fitness learning-based artificial bee colony with proximity stimuli.

    PubMed

    Uehara, Shota; Fujimoto, Kazuhiro J; Tanaka, Shigenori

    2015-07-01

    Protein-ligand docking is an optimization problem, which aims to identify the binding pose of a ligand with the lowest energy in the active site of a target protein. In this study, we employed a novel optimization algorithm called fitness learning-based artificial bee colony with proximity stimuli (FlABCps) for docking. Simulation results revealed that FlABCps improved the success rate of docking, compared to four state-of-the-art algorithms. The present results also showed superior docking performance of FlABCps, in particular for dealing with highly flexible ligands and proteins with a wide and shallow binding pocket. PMID:26050878

  13. Substituted phenylhydrazono derivatives of curcumin as new ligands, a theoretical study

    NASA Astrophysics Data System (ADS)

    Arrue, Lily; Zarate, Ximena; Schott-Verdugo, Stephan; Schott, Eduardo

    2015-03-01

    A family of phenylhydrazono curcumin ligands was studied to see the influence of the substituents over the composition of the molecular orbitals, electronic transitions and reactivity by means of DFT and TDDFT calculations. The substituents varied between electron-donor groups (EDG) to electron-withdrawing groups (EWG). The geometrical parameters remain almost unchanged when the character of the substituent was changed. On the other hand the HOMO, LUMO and HOMO-LUMO gap (HLG) energies changed dramatically. TDDFT calculations were performed in order to propose the main absorption bands of this family of compounds. All the obtained showed a good correlation with a Hammett correlation.

  14. Pyridazine based scorpionate ligand in a copper boratrane compound.

    PubMed

    Nuss, Gernot; Saischek, Gerald; Harum, Bastian N; Volpe, Manuel; Belaj, Ferdinand; Mösch-Zanetti, Nadia C

    2011-12-19

    Reaction of potassium tris(mercapto-tert-butylpyridazinyl)borate K[Tn(tBu)] with copper(II) chloride in dichloromethane at room temperature led to the diamagnetic copper boratrane compound [Cu{B(Pn(tBu))(3)}Cl] (Pn = pyridazine-3-thionyl) (1) under activation of the B-H bond and formation of a Cu-B dative bond. In contrast to this, stirring of the same ligand with copper(I) chloride in tetrahydrofuran (THF) gave the dimeric compound [Cu{Tn(tBu)}](2) (2) where one copper atom is coordinated by two sulfur atoms and one hydrogen atom of one ligand and one sulfur of the other ligand. Hereby, no activation of the B-H bond occurred but a 3-center-2-electron B-H···Cu bond is formed. The reaction of copper(II) chloride with K[Tn(tBu)] in water gave the same product 2, but a formal reduction of the metal center from Cu(II) to Cu(I) occurred. When adding tricyclohexyl phosphine to the reaction mixture of K[Tn(R)] (R = tBu, Me) and copper(I) chloride in MeOH, the distorted tetrahedral Cu complexes [Cu{Tn(R)}(PCy(3))] (R = tBu 3, Me 4) were formed. Compound 4 is exhibiting an "inverted" κ(3)-H,S,S, coordination mode. The copper boratrane 1 was further investigated by density functional theory (DFT) calculations for a better understanding of the M→B interaction involving the d(8) electron configuration of Cu. PMID:22092010

  15. Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone.

    PubMed

    Takeo, Makoto; Hale, Christopher S; Ito, Mayumi

    2016-07-01

    Clinically, many nail disorders accompany bone deformities, but whether the two defects are causally related is under debate. To investigate the potential interactions between the two tissue types, we analyzed epithelial-specific β-catenin-deficient mice, in which nail differentiation is abrogated. These mice showed regression of not only the nail plate but also of the underlying digit bone. Characterization of these bone defects revealed active bone resorption, which is suppressed by Wnt activation in osteoblast and osteoclast precursors. Furthermore, we found that Wntless expression, essential for Wnt ligand secretion, was lacking in the β-catenin-deficient nail epithelium and that genetic deletion of Wntless (Wls) in the nail epithelium led to the lack of Wnt activation in osteoblast and osteoclast precursors and subsequently led to defective regression of the underlying digit bone. Together, these data show that epithelial Wnt ligands can ultimately regulate Wnt signaling in osteoblast and osteoclast precursors, known to regulate bone homeostasis. These results reveal a critical role for the nail epithelium on the digit bone during homeostatic regeneration and show that Wnt/β-catenin signaling is critical for this interaction. PMID:27021406

  16. Nickel Complexes of a Binucleating Ligand Derived from an SCS Pincer

    SciTech Connect

    Peterson, Sonja M.; Helm, Monte L.; Appel, Aaron M.

    2015-01-01

    A binucleating ligand has been prepared that contains an SCS pincer and three oxygen donor ligands in a partial crown ether loop. To enable metalation with Ni0, a bromoarene precursor was used and resulted in the formation of a nickel-bromide complex in the SCS pincer. Reaction of the nickel complex with a lithium salt yielded a heterobimetallic complex with bromide bridging the two metal centers. The solid-state structures were determined for this heterobimetallic complex and the nickel-bromide precursor, and the two complexes were characterized electrochemically to determine the influence of coordinating the second metal. This research was supported by the US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences. MLH was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science. Pacific Northwest National Laboratory (PNNL) is a multiprogram national laboratory operated for DOE by Battelle.

  17. Improved ligand binding energies derived from molecular dynamics: replicate sampling enhances the search of conformational space.

    PubMed

    Adler, Marc; Beroza, Paul

    2013-08-26

    Does a single molecular trajectory provide an adequate sample conformational space? Our calculations indicate that for Molecular Mechanics--Poisson-Boltzmann Surface Area (MM-PBSA) measurement of protein ligand binding, a single molecular dynamics trajectory does not provide a representative sampling of phase space. For a single trajectory, the binding energy obtained by averaging over a number of molecular dynamics frames in an equilibrated system will converge after an adequate simulation time. A separate trajectory with nearly identical starting coordinates (1% randomly perturbed by 0.001 Å), however, can lead to a significantly different calculated binding energy. Thus, even though the calculated energy converges for a single molecular dynamics run, the variation across separate runs implies that a single run inadequately samples the system. The divergence in the trajectories is reflected in the individual energy components, such as the van der Waals and the electrostatics terms. These results indicate that the trajectories sample different conformations that are not in rapid exchange. Extending the length of the dynamics simulation does not resolve the energy differences observed between different trajectories. By averaging over multiple simulations, each with a nearly equivalent starting structure, we find the standard deviation in the calculated binding energy to be ∼1.3 kcal/mol. The work presented here indicates that combining MM-PBSA with multiple samples of the initial starting coordinates will produce more precise and accurate estimates of protein/ligand affinity. PMID:23845109

  18. Manganese clusters derived from a 2,6-diacetylpyridine dioximato ligand: structure and magnetic study.

    PubMed

    Escuer, Albert; Cordero, Beatriz; Font-Bardia, Mercé; Calvet, Teresa; Roubeau, Olivier; Teat, Simon J; Fedi, Serena; Fabrizi de Biani, Fabrizia

    2010-05-28

    Reactions of 2,6-diacetylpyridine dioxime (dapdoH₂) with Mn(NO₃)₂ or Mn(SO₃CF₃)₂ under a variety of conditions or co-ligands yield compounds with the formula [Mn₆O₂(OMe)₂(dapdo)₂(dapdoH)₄](X)₂ in which X = NO₃⁻ (1) or SO₃CF₃⁻ (2), [Mn₈O₂(dapdo)₆(NO₃)₂]·H₂O (3) and [Mn(dapdoH₂)(N₃)₂](n) (4). Compounds 1, 3 and 4 were structurally characterized and equivalent structures for 1 and 2 were inferred from spectroscopic and analytical results. Compounds 1 and 2 consist of hexanuclear Mn₂(II)Mn₄(III) complexes whereas 3 consists of an octanuclear Mn₆(II)Mn₂(III) cluster in which the manganese atoms exhibit a rare bicapped elongated octahedral topology. Compound 4 consists of a 1D system bridged by double end-on azido ligands. Variable temperature magnetic studies were performed between 2-300 K, confirming the ground state S = 5 for 1 and 2, S = 0 for 3 and ferromagnetic response for 4. PMID:21491694

  19. An approach to rational ligand-design based on a thermodynamic analysis.

    PubMed

    Ui, Mihoko; Tsumoto, Kouhei

    2010-11-01

    Thermodynamic analysis is an effective tool in screening of lead-compounds for development of potential drug candidates. In most cases, a ligand achieve high affinity and specificity to a target protein by means of both favorable enthalpy and entropy terms, which can be reflected in binding profiles of Isothermal Titration Calorimetry (ITC). A favorable enthalpy change suggests the contribution of noncovalent contacts such as hydrogen bonding and van der Waals interaction between a ligand and its target protein. In general, optimization of binding enthalpy is more difficult than that of entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its binding enthalpic gain. In this paper, we demonstrate the utility of thermodynamic approach to ligand screening using anti-ciguatoxin antibody 10C9 as a model of a target protein which possesses a large hydrophobic pocket. As a result of this screening, we have identified three compounds that could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. Comparison of their structure with the proper antigen ciguatoxin CTX3C revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. ITC measurement might be useful and powerful for a rational ligand screening and the optimization of the ligand; the enthalpic gain is an effective index for ligand-design studies. PMID:21171955

  20. Self-assembly of metallosupramolecular rhombi from chiral concave 9,9’-spirobifluorene-derived bis(pyridine) ligands

    PubMed Central

    Hovorka, Rainer; Hytteballe, Sophie; Piehler, Torsten; Meyer-Eppler, Georg; Topić, Filip; Rissanen, Kari; Engeser, Marianne

    2014-01-01

    Summary Two new 9,9’-spirobifluorene-based bis(4-pyridines) were synthesised in enantiopure and one also in racemic form. These ligands act as concave templates and form metallosupramolecular [(dppp)2M2L2] rhombi with cis-protected [(dppp)Pd]2+ and [(dppp)Pt]2+ ions. The self-assembly process of the racemic ligand preferably occurs in a narcissistic self-recognising manner. Hence, a mixture of all three possible stereoisomers [(dppp)2M2{(R)-L}2](OTf)4, [(dppp)2M2{(S)-L}2](OTf)4, and [(dppp)2M2{(R)-L}{(S)-L}](OTf)4 was obtained in an approximate 1.5:1.5:1 ratio which corresponds to an amplification of the homochiral assemblies by a factor of approximately three as evidenced by NMR spectroscopy and mass spectrometry. The racemic homochiral assemblies could also be characterised by single crystal X-ray diffraction. PMID:24605163

  1. Electrocatalytic Hydrogen Production by an Aluminum(III) Complex: Ligand-Based Proton and Electron Transfer.

    PubMed

    Thompson, Emily J; Berben, Louise A

    2015-09-28

    Environmentally sustainable hydrogen-evolving electrocatalysts are key in a renewable fuel economy, and ligand-based proton and electron transfer could circumvent the need for precious metal ions in electrocatalytic H2 production. Herein, we show that electrocatalytic generation of H2 by a redox-active ligand complex of Al(3+) occurs at -1.16 V vs. SCE (500 mV overpotential). PMID:26249108

  2. Syntheses, crystal structures, anticancer activities of three reduce Schiff base ligand based transition metal complexes

    NASA Astrophysics Data System (ADS)

    Chang, Hui-Qin; Jia, Lei; Xu, Jun; Zhu, Tao-Feng; Xu, Zhou-Qing; Chen, Ru-Hua; Ma, Tie-Liang; Wang, Yuan; Wu, Wei-Na

    2016-02-01

    Three nickel(II) complexes, [Ni2(L1)2(tren)2(H2O)](ClO4)3 (1), [NiL2(tren)2](ClO4)·2.5H2O (2), [NiL2(tren)2]I·1.5H2O·CH3OH (3) based on amino acid reduced Schiff ligands are synthesized and characterized by physico-chemical and spectroscopic methods. The results show that in all complexes, the amino acid ligand is deprotonated and acts as an anionic ligand. In the dinuclear complex 1, each Ni(II) atom has a distorted octahedron geometry while with different coordination environment. However, the complexes 2 and 3 are mononuclear, almost with the same coordination environment. Furthermore, in vitro experiments are carried out, including MTT assay, Annexin V/PI flow cytometry and western blotting, to assess whether the complexes have antitumor effect. And the results show that all the three complexes have moderate anticancer activity towards human hepatic cancer (HepG2), human cervical cancer (HeLa) and human prostate (PC3) cell lines, in a concentration dependent way. The complex 1 exhibit higher cytotoxicity than the other two complexes and can induce human hepatic cancer cell (HepG2) to cell apoptosis by activating caspase 3.

  3. Graphlet signature-based scoring method to estimate protein–ligand binding affinity

    PubMed Central

    Singh, Omkar; Sawariya, Kunal; Aparoy, Polamarasetty

    2014-01-01

    Over the years, various computational methodologies have been developed to understand and quantify receptor–ligand interactions. Protein–ligand interactions can also be explained in the form of a network and its properties. The ligand binding at the protein-active site is stabilized by formation of new interactions like hydrogen bond, hydrophobic and ionic. These non-covalent interactions when considered as links cause non-isomorphic sub-graphs in the residue interaction network. This study aims to investigate the relationship between these induced sub-graphs and ligand activity. Graphlet signature-based analysis of networks has been applied in various biological problems; the focus of this work is to analyse protein–ligand interactions in terms of neighbourhood connectivity and to develop a method in which the information from residue interaction networks, i.e. graphlet signatures, can be applied to quantify ligand affinity. A scoring method was developed, which depicts the variability in signatures adopted by different amino acids during inhibitor binding, and was termed as GSUS (graphlet signature uniqueness score). The score is specific for every individual inhibitor. Two well-known drug targets, COX-2 and CA-II and their inhibitors, were considered to assess the method. Residue interaction networks of COX-2 and CA-II with their respective inhibitors were used. Only hydrogen bond network was considered to calculate GSUS and quantify protein–ligand interaction in terms of graphlet signatures. The correlation of the GSUS with pIC50 was consistent in both proteins and better in comparison to the Autodock results. The GSUS scoring method was better in activity prediction of molecules with similar structure and diverse activity and vice versa. This study can be a major platform in developing approaches that can be used alone or together with existing methods to predict ligand affinity from protein–ligand complexes. PMID:26064572

  4. Spectral, redox and catalytic studies of triphenylphosphine/triphenylarsine complexes of Ru(III) with N, O donor ligands derived from 2-hydroxy-1-naphthaldehyde and primary amines.

    PubMed

    Mahalingam, V; Karvembu, R; Chinnusamy, V; Natarajan, K

    2006-07-01

    A series of new mixed ligand hexacoordinated ruthenium(III) Schiff base complexes of the type [RuX(2)(EPh(3))(2)(LL')] (X=Cl, E=P; X=Cl or Br, E=As and LL'=anion of the Schiff bases derived from the condensation of 2-hydroxy-1-naphthaldehyde with aniline, 4-chloroaniline, 2-methyl aniline and 4-methoxy aniline) are reported. All the complexes have been characterized by analytical and spectral (IR, electronic and EPR) data. The redox behavior of the complexes has also been studied. The complexes exhibit catalytic activity in the oxidation of benzyl alcohol to benzaldehyde in the presence of N-methyl morpholine-N-oxide (NMO). An octahedral structure has been proposed for all of the complexes. PMID:16330248

  5. PatchSurfers: Two methods for local molecular property-based binding ligand prediction.

    PubMed

    Shin, Woong-Hee; Bures, Mark Gregory; Kihara, Daisuke

    2016-01-15

    Protein function prediction is an active area of research in computational biology. Function prediction can help biologists make hypotheses for characterization of genes and help interpret biological assays, and thus is a productive area for collaboration between experimental and computational biologists. Among various function prediction methods, predicting binding ligand molecules for a target protein is an important class because ligand binding events for a protein are usually closely intertwined with the proteins' biological function, and also because predicted binding ligands can often be directly tested by biochemical assays. Binding ligand prediction methods can be classified into two types: those which are based on protein-protein (or pocket-pocket) comparison, and those that compare a target pocket directly to ligands. Recently, our group proposed two computational binding ligand prediction methods, Patch-Surfer, which is a pocket-pocket comparison method, and PL-PatchSurfer, which compares a pocket to ligand molecules. The two programs apply surface patch-based descriptions to calculate similarity or complementarity between molecules. A surface patch is characterized by physicochemical properties such as shape, hydrophobicity, and electrostatic potentials. These properties on the surface are represented using three-dimensional Zernike descriptors (3DZD), which are based on a series expansion of a 3 dimensional function. Utilizing 3DZD for describing the physicochemical properties has two main advantages: (1) rotational invariance and (2) fast comparison. Here, we introduce Patch-Surfer and PL-PatchSurfer with an emphasis on PL-PatchSurfer, which is more recently developed. Illustrative examples of PL-PatchSurfer performance on binding ligand prediction as well as virtual drug screening are also provided. PMID:26427548

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

    SciTech Connect

    Yang, Xiao-Le; Shangguan, Yi-Qing; Hu, Huai-Ming Xu, Bing; Wang, Bao-Cheng; Xie, Juan; Yuan, Fei; Yang, Meng-Lin; Dong, Fa-Xin; Xue, Gang-Lin

    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 a 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

  7. Impaired ergosterol biosynthesis mediated fungicidal activity of Co(II) complex with ligand derived from cinnamaldehyde.

    PubMed

    Shreaz, Sheikh; Shiekh, Rayees A; Raja, Vaseem; Wani, Waseem A; Behbehani, Jawad M

    2016-03-01

    In this study, we have used aldehyde function of cinnamaldehyde to synthesize N, N'-Bis (cinnamaldehyde) ethylenediimine [C20H20N2] and Co(II) complex of the type [Co(C40H40N4)Cl2]. The structures of the synthesized compounds were determined on the basis of physiochemical analysis and spectroscopic data ((1)H NMR, FTIR, UV-visible and mass spectra) along with molar conductivity measurements. Anticandidal activity of cinnamaldehyde its ligand [L] and Co(II) complex was investigated by determining MIC80, time-kill kinetics, disc diffusion assay and ergosterol extraction and estimation assay. Ligand [L] and Co(II) complex are found to be 4.55 and 21.0 folds more efficient than cinnamaldehyde in a liquid medium. MIC80 of Co(II) complex correlated well with ergosterol inhibition suggesting ergosterol biosynthesis to be the primary site of action. In comparison to fluconazole, the test compounds showed limited toxicity against H9c2 rat cardiac myoblasts. In confocal microscopy propidium iodide (PI) penetrates the yeast cells when treated with MIC of metal complex, indicating a disruption of cell membrane that results in imbibition of dye. TEM analysis of metal complex treated cells exhibited notable alterations or damage to the cell membrane and the cell wall. The structural disorganization within the cell cytoplasm was noted. It was concluded that fungicidal activity of Co(II) complex originated from loss of membrane integrity and a decrease in ergosterol content is only one consequence of this. PMID:26806515

  8. Catalytic hydrogenation using complexes of base metals with tridentate ligands

    DOEpatents

    Vasudevan, Kalyan V.; Zhang, Guoqi; Hanson, Susan K.

    2016-09-06

    Complexes of cobalt and nickel with tridentate ligand PNHP.sup.R are effective for hydrogenation of unsaturated compounds. Cobalt complex [(PNHP.sup.Cy)Co(CH.sub.2SiMe.sub.3)]BAr.sup.F.sub.4 (PNHP.sup.Cy=bis[2-(dicyclohexylphosphino)ethyl]amine, BAr.sup.F.sub.4=B(3,5-(CF.sub.3).sub.2C.sub.6H.sub.3).sub.4)) was prepared and used with hydrogen for hydrogenation of alkenes, aldehydes, ketones, and imines under mild conditions (25-60.degree. C., 1-4 atm H.sub.2). Nickel complex [(PNHP.sup.Cy)Ni(H)]BPh.sub.4 was used for hydrogenation of styrene and 1-octene under mild conditions. (PNP.sup.Cy)Ni(H) was used for hydrogenating alkenes.

  9. Controlling the Atomic Structure of Au30 Nanoclusters by a Ligand-Based Strategy.

    PubMed

    Higaki, Tatsuya; Liu, Chong; Zeng, Chenjie; Jin, Renxi; Chen, Yuxiang; Rosi, Nathaniel L; Jin, Rongchao

    2016-06-01

    We report the X-ray structure of a gold nanocluster with 30 gold atoms protected by 18 1-adamantanethiolate ligands (formulated as Au30 (S-Adm)18 ). This nanocluster exhibits a threefold rotationally symmetrical, hexagonal-close-packed (HCP) Au18 kernel protected by six dimeric Au2 (SR)3 staple motifs. This new structure is distinctly different from the previously reported Au30 S(S-(t) Bu)18 nanocluster protected by 18 tert-butylthiolate ligands and one sulfido ligand with a face-centered cubic (FCC) Au22 kernel. The Au30 (S-Adm)18 nanocluster has an anomalous solubility (it is only soluble in benzene but not in other common solvents). This work demonstrates a ligand-based strategy for controlling nanocluster structure and also provides a method for the discovery of possibly overlooked clusters because of their anomalous solubility. PMID:27099989

  10. A Fluid Membrane-Based Soluble Ligand Display System for Live CellAssays

    SciTech Connect

    Nam, Jwa-Min; Nair, Pradeep N.; Neve, Richard M.; Gray, Joe W.; Groves, Jay T.

    2005-10-14

    Cell communication modulates numerous biological processes including proliferation, apoptosis, motility, invasion and differentiation. Correspondingly, there has been significant interest in the development of surface display strategies for the presentation of signaling molecules to living cells. This effort has primarily focused on naturally surface-bound ligands, such as extracellular matrix components and cell membranes. Soluble ligands (e.g. growth factors and cytokines) play an important role in intercellular communications, and their display in a surface-bound format would be of great utility in the design of array-based live cell assays. Recently, several cell microarray systems that display cDNA, RNAi, or small molecules in a surface array format were proven to be useful in accelerating high-throughput functional genetic studies and screening therapeutic agents. These surface display methods provide a flexible platform for the systematic, combinatorial investigation of genes and small molecules affecting cellular processes and phenotypes of interest. In an analogous sense, it would be an important advance if one could display soluble signaling ligands in a surface assay format that allows for systematic, patterned presentation of soluble ligands to live cells. Such a technique would make it possible to examine cellular phenotypes of interest in a parallel format with soluble signaling ligands as one of the display parameters. Herein we report a ligand-modified fluid supported lipid bilayer (SLB) assay system that can be used to functionally display soluble ligands to cells in situ (Figure 1A). By displaying soluble ligands on a SLB surface, both solution behavior (the ability to become locally enriched by reaction-diffusion processes) and solid behavior (the ability to control the spatial location of the ligands in an open system) could be combined. The method reported herein benefits from the naturally fluid state of the supported membrane, which allows

  11. Synthesis, characterization, and stability of iron (III) complex ions possessing phenanthroline-based ligands

    PubMed Central

    Rios, Andrew; Frias, Elma; Eichler, Jack F.

    2014-01-01

    It has previously been demonstrated that phenanthroline-based ligands used to make gold metallotherapuetics have the ability to exhibit cytotoxicity when not coordinated to the metal center. In an effort to help assess the mechanism by which these ligands may cause tumor cell death, iron binding and removal experiments have been considered. The close linkage between cell proliferation and intracellular iron concentrations suggest that iron deprivation strategies may be a mechanism involved in inhibiting tumor cell growth. With the creation of iron (III) phen complexes, the iron binding abilities of three polypyridal ligands [1,10-phenanthroline (phen), 2,9-dimethyl-1, 10-phenanthroline (methylphen), and 2,9-di-sec-butyl-1, 10-phenanthroline (sec-butylphen)] can be tested via a competition reaction with a known iron chelator. Therefore, iron (III) complexes possessing all three ligands were synthesized. Initial mass spectrometric and infrared absorption data indicate that iron (III) tetrachloride complex ions with protonated phen ligands (RphenH+) were formed: [phenH][FeCl4], [methylphenH][FeCl4], [sec-butylphenH][FeCl4]. UV-Vis spectroscopy was used to monitor the stability of the complex ions, and it was found that the sec-butylpheniron complex was more stable than the phen and methylphen analogues. This was based on the observation that free ligand was observed immediately upon the addition of EDTA to the [phenH][FeCl4] and [methylphenH] [FeCl4] complex ions. PMID:25379358

  12. Synthesis and structural features of U VI and V IV chelate complexes with (hhmmbH)Cl·H 2O [hhmmb = {3-hydroxyl-5-(hydroxymethyl)-2-methylpyridine-4-yl-methylene}benzohydrazide], a new Schiff base ligand derived from vitamin B6

    NASA Astrophysics Data System (ADS)

    Back, Davi Fernando; Ballin, Marco Aurélio; de Oliveira, Gelson Manzoni

    2009-10-01

    The Schiff base ligand {3-hydroxyl-5-(hydroxymethyl)-2-methylpyridine-4-yl-methylene}benzohydrazide hydrochloride monohydrated {(hhmmbH)Cl·H 2O} ( 1) was prepared by reaction of pyridoxine hydrochloride with benzoic acid hydrazide. The reaction of 1 with [VO(acac) 2] and triethylamine yields the neutral vanadium IV complex [VO 2(hhmmb)]·Py ( 2), with a distorted quadratic pyramidal configuration. The Schiff base 1 reacts also with UO 2(NO 3) 2·6H 2O and triethylamine under deprotonation giving the uranium VI cationic complexes [UO 2(hhmmb)(H 2O)Cl] + ( 3) and [UO 2(hhmmb)(CH 3OH)Cl] + ( 4), both showing the classical pentagonal bipyrimidal geometry of UO22+ complexes. The structural features of all compounds are discussed.

  13. Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position

    PubMed Central

    Savino, Salvatore; Denora, Nunzio; Iacobazzi, Rosa Maria; Porcelli, Letizia; Azzariti, Amalia; Natile, Giovanni; Margiotta, Nicola

    2016-01-01

    The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC50 = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC50 = 2.31 μM after 72 h treatment). PMID:27347942

  14. 6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand.

    PubMed

    Williams, Dwight A; Zheng, Yi; David, Bethany G; Yuan, Yunyun; Zaidi, Saheem A; Stevens, David L; Scoggins, Krista L; Selley, Dana E; Dewey, William L; Akbarali, Hamid I; Zhang, Yan

    2016-08-17

    The 6β-N-heterocyclic naltrexamine derivative, NAP, has been demonstrated to be a peripherally selective mu opioid receptor modulator. To further improve peripheral selectivity of this highly potent ligand, its pyridal ring was quaterinized with benzyl bromide to produce BNAP. In radioligand binding assay, the Ki of BNAP for MOR was 0.76 ± 0.09 nM and was >900-fold more selective for MOR than DOR. The Ki for KOR was 3.46 ± 0.05 nM. In [(35)S]GTPγS ligand stimulated assay, BNAP showed low agonist efficacy with 14.6% of the maximum response of DAMGO with an EC50 of 4.84 ± 0.6 nM. However, unlike its parent compound NAP, BNAP displayed partial agonist activity at KOR with % maximum response at 45.9 ± 1.7% of U50,488H. BNAP did not reverse morphine-induced antinociception when administered subcutaneously but did antagonize when administered intracerebroventricularly. BNAP antagonized morphine-induced contractions of the circular muscle in mice colon. BNAP inhibition of field-stimulated contractions in longitudinal muscle strips for the guinea-pig ileum were also blocked by nor-BNI, a kappa opioid receptor antagonist. BNAP induced inhibition of acetic acid induced abdominal stretching in chronic morphine treated mice. These findings suggest that BNAP is a dual MOR antagonist/KOR agonist and may have functional use in irritable bowel patients. PMID:27269866

  15. Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position.

    PubMed

    Savino, Salvatore; Denora, Nunzio; Iacobazzi, Rosa Maria; Porcelli, Letizia; Azzariti, Amalia; Natile, Giovanni; Margiotta, Nicola

    2016-01-01

    The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC50 = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC50 = 2.31 μM after 72 h treatment). PMID:27347942

  16. Facile ligand oxidation and ring nitration in ruthenium complexes derived from a ligand with dicarboxamide-N and phosphine-P donors.

    PubMed

    Fry, Nicole L; Rose, Michael J; Nyitray, Crystal; Mascharak, Pradip K

    2008-12-15

    The reaction of the tetradentate dicarboxamide ligand 1,2-bis-N-[2'(diphenylphosphanyl)benzoyl]diaminobenzene (dppbH(2)) with RuCl(3) in DMF or ethanol results in metal-mediated ligand oxidation and formation of the diamagnetic Ru(II) complex [(dppQ)Ru(Cl)(2)] (1) with N(2)P(2) chromophore. The o-phenylenedicarboxamide portion of the dppb(2-) ligand is oxidized to a o-benzoquinonediimine (bqdi) moiety in [(dppQ)Ru(Cl)(2)]. Presence of oxygen accelerates the ligand oxidation process. Unlike other tetradentate dicarboxamide ligands with pyridine-N, phenolato-O, or thiolato-S donors, dppb(2-) provides stability to the +2 oxidation state of ruthenium and facilitates oxidation of the coordinated ligand frame. Results of spectroscopic and redox studies strongly support the +2 oxidation state of Ru in 1. Exposure of 1 to NO(g) does not lead to formation of any metal nitrosyl; instead, the bqdi ring is nitrated to afford [(NO(2)dppQ)Ru(Cl)(2)] (2). PMID:19006289

  17. Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors.

    PubMed Central

    Nocka, K; Buck, J; Levi, E; Besmer, P

    1990-01-01

    The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor for an unidentified ligand and is allelic with the murine white-spotting locus (W). W mutations affect melanogenesis, gametogenesis and hematopoiesis during development and in adult life. Cellular targets of W mutations in hematopoiesis include distinct cell populations in the erythroid and mast cell lineages as well as stem cells. In the absence of interleukin-3 (IL-3) mast cells derived from normal mice but not from W mutant mice can be maintained by co-culture with 3T3 fibroblasts. Based on the defective proliferative response of W mast cells in the 3T3 fibroblast co-culture system it had been proposed that fibroblasts produce the c-kit ligand. We have used a mast cell proliferation assay to purify a 30 kd protein, designated KL, from conditioned medium of Balb/3T3 fibroblasts to apparent homogeneity. KL stimulates the proliferation of normal bone marrow derived mast cells but not mast cells from W mice, although both normal and mutant mast cells respond similarly to IL-3. Connective tissue-type mast cells derived from the peritoneal cavity of normal mice were found to express a high level of c-kit protein on their surface and to proliferate in response to KL. The effect of KL on erythroid progenitor cells was investigated as well. In combination with erythropoietin, KL was found to stimulate early erythroid progenitors (BFU-E) from fetal liver and spleen cells but not from bone marrow cells of adult mice and from fetal liver cells of W/W mice.(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 1. Fig. 3. Fig. 5. Fig. 7. PMID:1698611

  18. Development of the Knowledge-based & Empirical Combined Scoring Algorithm (KECSA) to Score Protein-Ligand Interactions

    PubMed Central

    Zheng, Zheng

    2013-01-01

    We describe a novel knowledge-based protein-ligand scoring function that employs a new definition for the reference state, allowing us to relate a statistical potential to a Lennard-Jones (LJ) potential. In this way, the LJ potential parameters were generated from protein-ligand complex structural data contained in the PDB. Forty-nine types of atomic pairwise interactions were derived using this method, which we call the knowledge-based and empirical combined scoring algorithm (KECSA). Two validation benchmarks were introduced to test the performance of KECSA. The first validation benchmark included two test sets that address the training-set and enthalpy/entropy of KECSA The second validation benchmark suite included two large-scale and five small-scale test sets to compare the reproducibility of KECSA with respect to two empirical score functions previously developed in our laboratory (LISA and LISA+), as well as to other well-known scoring methods. Validation results illustrate that KECSA shows improved performance in all test sets when compared with other scoring methods especially in its ability to minimize the RMSE. LISA and LISA+ displayed similar performance using the correlation coefficient and Kendall τ as the metric of quality for some of the small test sets. Further pathways for improvement are discussed which would KECSA more sensitive to subtle changes in ligand structure. PMID:23560465

  19. Modern spectroscopic technique in the characterization of biosensitive macrocyclic Schiff base ligand and its complexes: Inhibitory activity against plantpathogenic fungi

    NASA Astrophysics Data System (ADS)

    Tyagi, Monika; Chandra, Sulekh; Akhtar, Jameel; Chand, Dinesh

    2014-01-01

    Complexes of the type [M(L)Cl2], where M = Co(II), Ni(II) and Cu(II) have been synthesized with a macrocyclic Schiff base ligand (1,4,5,7,10,11,12,15-octaaza,5,11,16,18-tetraphenyl, 3,4,12,13-tetramethyl cyclo-octadecane) derived from Schiff base (obtained by the condensation of 4-aminoantipyrine and dibenzoyl methane) and ethylenediamine. The ligand was characterized on the basis of elemental analysis, IR, 1H NMR, EI Mass and molecular modeling studies while the complexes were characterized by elemental analysis, molar conductance measurements, magnetic susceptibility measurements, IR, electronic and EPR spectral studies. All the complexes are non-electrolyte in nature. The covalency factor (β) and coefficient factor (α) suggest the covalent nature of the complexes. The ligand and its metal complexes have shown antifungal activity with their LD50 values determined by probit analysis against two economically important fungal plant pathogens i.e. Macrophomina phaseolina and Fusarium solani.

  20. Structural insights into human 5-lipoxygenase inhibition: combined ligand-based and target-based approach.

    PubMed

    Charlier, Caroline; Hénichart, Jean-Pierre; Durant, François; Wouters, Johan

    2006-01-12

    The human 5-LOX enzyme and its interaction with competitive inhibitors were investigated by means of a combined ligand-based and target-based approach. First, a pharmacophore model was generated for 16 non redox 5-LOX inhibitors with Catalyst (HipHop module). It includes two hydrophobic groups, an aromatic ring, and two hydrogen bond acceptors. The 3D structure of human 5-LOX was then modeled based on the crystal structure of rabbit 15-LOX, and the binding modes of representative ligands were studied by molecular docking. Confrontation of the docking results with the pharmacophore model allowed the weighting of the pharmacophoric features and the integration of structural information. This led to the proposal of an interaction model inside the 5-LOX active site, consisting of four major and two secondary interaction points: on one hand, two hydrophobic groups, an aromatic ring, and a hydrogen bond acceptor, and, on the other hand, an acidic moiety and an additional hydrogen bond acceptor. PMID:16392803

  1. Ligand-target interaction-based weighting of substructures for virtual screening.

    PubMed

    Crisman, Thomas J; Sisay, Mihiret T; Bajorath, Jürgen

    2008-10-01

    A methodology is introduced to assign energy-based scores to two-dimensional (2D) structural features based on three-dimensional (3D) ligand-target interaction information and utilize interaction-annotated features in virtual screening. Database molecules containing such fragments are assigned cumulative scores that serve as a measure of similarity to active reference compounds. The Interaction Annotated Structural Features (IASF) method is applied to mine five high-throughput screening (HTS) data sets and often identifies more hits than conventional fragment-based similarity searching or ligand-protein docking. PMID:18821751

  2. Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter

    PubMed Central

    Li, Junfeng; Zhang, Xiang; Zhang, Zhanbin; Padakanti, Prashanth K.; Jin, Hongjun; Cui, Jinquan; Li, Aixiao; Zeng, Dexing; Rath, Nigam P.; Flores, Hubert; Perlmutter, Joel S.; Parsons, Stanley M.; Tu, Zhude

    2013-01-01

    To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALog D values between 0.53-3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k and 24a-b) displayed high affinity for VAChT (Ki = 0.93 – 18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44 – 4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 for VAChT, 900-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain. PMID:23802889

  3. Derivation of GFDM Based on OFDM Principles

    SciTech Connect

    Hussein Moradi; Behrouz Farhang-Boroujeny

    2015-06-01

    This paper starts with discussing the principle based on which the celebrated orthogonal frequency division multiplexing (OFDM) signals are constructed. It then extends the same principle to construct the newly introduced generalized frequency division multiplexing (GFDM) signals. This novel derivation sheds light on some interesting properties of GFDM. In particular, our derivation seamlessly leads to an implementation of GFDM transmitter which has significantly lower complexity than what has been reported so far. Our derivation also facilitates a trivial understanding of how GFDM (similar to OFDM) can be applied in MIMO channels.

  4. Cyclopentadienyl-ruthenium(II) and iron(II) organometallic compounds with carbohydrate derivative ligands as good colorectal anticancer agents.

    PubMed

    Florindo, Pedro R; Pereira, Diane M; Borralho, Pedro M; Rodrigues, Cecília M P; Piedade, M F M; Fernandes, Ana C

    2015-05-28

    New ruthenium(II) and iron(II) organometallic compounds of general formula [(η(5)-C5H5)M(PP)Lc][PF6], bearing carbohydrate derivative ligands (Lc), were prepared and fully characterized and the crystal structures of five of those compounds were determined by X-ray diffraction studies. Cell viability of colon cancer HCT116 cell line was determined for a total of 23 organometallic compounds and SAR's data analysis within this library showed an interesting dependency of the cytotoxic activity on the carbohydrate moiety, linker, phosphane coligands, and metal center. More importantly, two compounds, 14Ru and 18Ru, matched oxaliplatin IC50 (0.45 μM), the standard metallodrug used in CC chemotherapeutics, and our leading compound 14Ru was shown to be significantly more cytotoxic than oxaliplatin to HCT116 cells, triggering higher levels of caspase-3 and -7 activity and apoptosis in a dose-dependent manner. PMID:25923600

  5. Effects of active immunisation with myelin basic protein and myelin-derived altered peptide ligand on pain hypersensitivity and neuroinflammation.

    PubMed

    Perera, Chamini J; Lees, Justin G; Duffy, Samuel S; Makker, Preet G S; Fivelman, Brett; Apostolopoulos, Vasso; Moalem-Taylor, Gila

    2015-09-15

    Neuropathic pain is a debilitating condition in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Specific myelin basic protein (MBP) peptides are encephalitogenic, and myelin-derived altered peptide ligands (APLs) are capable of preventing and ameliorating EAE. We investigated the effects of active immunisation with a weakly encephalitogenic epitope of MBP (MBP87-99) and its mutant APL (Cyclo-87-99[A(91),A(96)]MBP87-99) on pain hypersensitivity and neuroinflammation in Lewis rats. MBP-treated rats exhibited significant mechanical and thermal pain hypersensitivity associated with infiltration of T cells, MHC class II expression and microglia activation in the spinal cord, without developing clinical signs of paralysis. Co-immunisation with APL significantly decreased pain hypersensitivity and neuroinflammation emphasising the important role of neuroimmune crosstalk in neuropathic pain. PMID:26298325

  6. Affinity ligands for glycoprotein purification based on the multi-component Ugi reaction.

    PubMed

    Chen, Chen; Khoury, Graziella El; Lowe, Christopher R

    2014-10-15

    One challenge facing the purification of therapeutic glycoproteins by affinity chromatography is creating ligands specific for the glycan moiety. Affinity chromatography of glycoproteins is currently conducted with immobilized lectins or boronates, although biomimetic ligands could present a more desirable option. This work describes the rational design and combinatorial synthesis of carbohydrate-binding ligands based on the solid phase multi-component Ugi reaction. An aldehyde-functionalized Sepharose™ solid support constitutes one component (aldehyde) in the four-component reaction, while the other three components (a primary/secondary amine, a carboxylic acid and an isocyanide) are varied in a combinatorial fashion to generate a tri-substituted Ugi scaffold which provides a degree of rigidity and is functionally suitable for interacting with the glycan moiety of glycoproteins. An Ugi library containing 48 ligands was initially screened against glucose oxidase (GOx) as the model glycoprotein to identify a candidate ligand, A13C24I8, which showed affinity to GOx through its carbohydrate moiety. Immobilized ligand A13C24I8 demonstrated a static binding capacity of 16.7mg GOx/ml resin and an apparent dissociation constant (Kd) of 1.45×10(-6)M at pH 7.4. The adsorbent can also bind 8.1mg AGP/ml resin and displays an apparent affinity constant Kd=1.44×10(-5)M. The ligand has a sugar specificity in the following sequence: sorbitol>fructose>mannitol>ribose>arabinose>xylose>galactose>mannose>glucose>fructose; however, it did not display any specificity for sialic acid or methyl α-D-glycosides. A control ligand, generated by substitution of C24 (3-carboxyphenylboronic acid) with C7 (4-hydroxyphenyl acetic acid), failed to show affinity to the carbohydrate moiety, supporting the importance of the role that boronic acid group plays in sugar binding. GOx spiked E. coli samples were loaded onto immobilized ligand A13C24I8, 3-aminophenylboronic acid (APBA) and

  7. Influences of pH and ligand type on the performance of inorganic aqueous precursor-derived ZnO thin film transistors.

    PubMed

    Jun, Taehwan; Jung, Yangho; Song, Keunkyu; Moon, Jooho

    2011-03-01

    The aqueous precursor-derived ZnO semiconductor is a promising alternative to organic semiconductors and amorphous silicon materials in applications requiring transparent thin-film transistors at low temperatures. The pH in the aqueous solution is an important factor in determining the device performance of ZnO-TFTs. Using a basic aqueous solution, the ZnO transistor annealed at 150 °C exhibited a high field-effect mobility (0.42 cm(2) V(-1) s(-1)) and an excellent on/off ratio (10(6)). In contrast, the ZnO layer annealed at 150 °C prepared from an acidic solution was inactive. Chemical and structural analyses confirmed that the variation of the device characteristics originates from the existing state difference of Zn in solution. The hydroxyo ligand is stable in basic conditions, which involves a lower energy pathway for the solution-to-solid conversion, whereas the hydrated zinc cation undergoes more complex reactions that occur at a higher temperature. Our results suggest that the pH and ligand type play critical roles in the preparation of aqueous precursor-based ZnO-TFTs which demonstrate high performance at low temperatures. PMID:21366236

  8. Synthesis, characterization and antibacterial activity of new Ln(III) complexes with an unsymmetrical schiff base ligand

    NASA Astrophysics Data System (ADS)

    Caifeng, Bi; Liangliang, Yan; Yuhua, Fan; Xia, Zhang; Aidong, Wang

    2006-07-01

    A new unsymmetrical Schiff base ligand (H2LLi) was synthesized using L-lysine, salicyladehyde and 2-hydroxy-1-naphthaldehyde. Three solid metal complexes of this ligand [Ln(H2L)(NO3)] NO3·2H2O (Ln=La, Sm, Ho) have been prepared and characterized by elemental analyses, IR spectra, UV spectra, TG-DTG and molar conductance. The antibacterial activities of the ligand and its complexes are also studied. The antibacterial experiments indicate that the ligand and its complexes possess antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis and that the complexes have higher activity than those of the ligand.

  9. Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.

    PubMed

    Łażewska, Dorota; Więcek, Małgorzata; Ner, Joanna; Kamińska, Katarzyna; Kottke, Tim; Schwed, J Stephan; Zygmunt, Małgorzata; Karcz, Tadeusz; Olejarz, Agnieszka; Kuder, Kamil; Latacz, Gniewomir; Grosicki, Marek; Sapa, Jacek; Karolak-Wojciechowska, Janina; Stark, Holger; Kieć-Kononowicz, Katarzyna

    2014-08-18

    A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken. PMID:24996140

  10. Multi-tasking Schiff base ligand: a new concept of AuNPs synthesis.

    PubMed

    Abad, Jose Maria; Bravo, Iria; Pariente, Felix; Lorenzo, Encarnación

    2016-03-01

    Multi-tasking 3,4-dihydroxysalophen Schiff base tetradentate ligand (3,4-DHS) as reductant, stabilizer, and catalyst in a new concept of gold nanoparticles (AuNPs) synthesis is demonstrated. 3,4-DHS is able to reduce HAuCl4 in water, acting also as capping agent for the generation of stable colloidal suspensions of Schiff base ligand-AuNPs assemblies of controlled size by providing a robust coating to AuNPs, within a unique reaction step. Once deposited on carbon electrodes, 3,4-DHS-AuNPs assemblies show a potent electrocatalytic effect towards hydrazine oxidation and hydrogen peroxide oxidation/reduction. PMID:26922338

  11. A novel photoaffinity ligand for the dopamine transporter based on pyrovalerone

    PubMed Central

    Lapinsky, David J.; Aggarwal, Shaili; Huang, Yurong; Surratt, Christopher K.; Lever, John R.; Foster, James D.; Vaughan, Roxanne A.

    2009-01-01

    Non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored in contrast to tropane-based compounds such as cocaine. In order to fill this knowledge gap, a ligand was synthesized in which the aromatic ring of pyrovalerone was substituted with a photoreactive azido group. The analog 1-(4-azido-3-iodophenyl)-2-pyrrolidin-1-yl-pentan-1-one demonstrated appreciable binding affinity for the DAT (Ki = 78 ± 18 nM), suggesting the potential utility of a radioiodinated version in structure-function studies of this protein. PMID:19442525

  12. Ligand-based reactivity of a platinum bisdithiolene: double diene addition yields a new C2-chiral chelate ligand.

    PubMed

    Kerr, Mitchell J; Harrison, Daniel J; Lough, Alan J; Fekl, Ulrich

    2009-10-01

    The reaction of Pt(tfd)(2) [tfd = S(2)C(2)(CF(3))(2)] with excess 2,3-dimethyl-1,3-butadiene initially yields the expected 1:1 adduct, in which the diene has added across two sulfur atoms on separate tfd ligands. However, within 1 day at 50 degrees C, this kinetic product quantitatively converts into a thermodynamic product where two dienes have added to one tfd ligand via unprecedented addition across the dithiolene CS bonds. The new reaction is highly selective for the C(2)-symmetric diastereomer. A new chiral bisthioether chelate ligand has formed in the product, which has been characterized crystallographically. PMID:19634863

  13. Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas.

    PubMed

    Chauhan, Kanchan; Arun, Ashutosh; Singh, Saurabh; Manohar, Murli; Chuttani, Krishna; Konwar, Rituraj; Dwivedi, Anila; Soni, Ravi; Singh, Ajai Kumar; Mishra, Anil K; Datta, Anupama

    2016-04-20

    The synthesis of estradiol based bivalent ligand [(EST)2DT] is reported and its potential for targeted imaging and therapy of ER(+) tumors has been evaluated. For the purpose, ethinylestradiol was functionalized with an azidoethylamine moiety via click chemistry. The resultant derivative was reacted in a bivalent mode with DTPA-dianhydride to form the multicoordinate chelating agent, (EST)2DT which displayed capability to bind (99m)Tc. The radiolabeled complex, (99m)Tc-(EST)2DT was obtained in >99% radiochemical purity and 20-48 GBq/μmol of specific activity. RBA assay revealed ∼15% binding with estrogen receptor. Evaluation of ligand on ER(+)-cell line (MCF-7) suggested enhanced and ER-mediated uptake. In vivo assays displayed early tracer accumulation in MCF-7 xenografts with tumor to muscle ratio ∼6 in 2 h and negligible uptakes in nontargeted organs. MTT assay performed on ER(+) and ER(-) cell lines displayed selective inhibition of ER(+) cancer cell growth with IC50 = 14.3 μM which was comparable to tamoxifen. The anticancer activity of the ligand is possibly due to the increase in ERβ and suppression of ERα protein levels in gene transcription. The studies reveal the potential of (EST)2DT as diagnostic imaging agent with the additional benefits in therapy. PMID:26999669

  14. Zn(II), Ni(II), Cu(II) and Pb(II) complexes of tridentate asymmetrical Schiff base ligands: Synthesis, characterization, properties and biological activity

    NASA Astrophysics Data System (ADS)

    Şahin, Mustafa; Koçak, Nuriye; Erdenay, Damla; Arslan, Uğur

    2013-02-01

    New asymmetrical tridentate Schiff base ligands were synthesized using 1,2-phenylenediamine, 4-methyl-1,2-phenylenediamine, 2-hydroxy-1-napthaldehyde, 9-anthracenecarboxaldehyde. Schiff base ligands and their metal complexes were synthesised and characterized by using FT-IR, 1H NMR, 13C NMR, UV-Vis, XRD, ESR, elemental analysis and fluorescence studies. The antimicrobial activity of the ligands and their metal complexes were studied against Staphylococcus aureus ATCC 29213, S. aureus ATCC 25923, Streptococcus mutans RSHM 676, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853. The determination of the antibacterial activity was done using the broth microdilution methods. In general, it has been determined that the studied compounds have MIC values similar to Gram-positive and Gram-negative bacteria. It has been found that Ni, Pb, Zn derivatives of HL1A and ZnL2A has lower MIC values than ampicillin for P. aeruginosa ATCC 27853 strain.

  15. Development of a quantitative fluorescence-based ligand-binding assay

    PubMed Central

    Breen, Conor J.; Raverdeau, Mathilde; Voorheis, H. Paul

    2016-01-01

    A major goal of biology is to develop a quantitative ligand-binding assay that does not involve the use of radioactivity. Existing fluorescence-based assays have a serious drawback due to fluorescence quenching that accompanies the binding of fluorescently-labeled ligands to their receptors. This limitation of existing fluorescence-based assays prevents the number of cellular receptors under investigation from being accurately measured. We have developed a method where FITC-labeled proteins bound to a cell surface are proteolyzed extensively to eliminate fluorescence quenching and then the fluorescence of the resulting sample is compared to that of a known concentration of the proteolyzed FITC-protein employed. This step enables the number of cellular receptors to be measured quantitatively. We expect that this method will provide researchers with a viable alternative to the use of radioactivity in ligand binding assays. PMID:27161290

  16. Development of a quantitative fluorescence-based ligand-binding assay.

    PubMed

    Breen, Conor J; Raverdeau, Mathilde; Voorheis, H Paul

    2016-01-01

    A major goal of biology is to develop a quantitative ligand-binding assay that does not involve the use of radioactivity. Existing fluorescence-based assays have a serious drawback due to fluorescence quenching that accompanies the binding of fluorescently-labeled ligands to their receptors. This limitation of existing fluorescence-based assays prevents the number of cellular receptors under investigation from being accurately measured. We have developed a method where FITC-labeled proteins bound to a cell surface are proteolyzed extensively to eliminate fluorescence quenching and then the fluorescence of the resulting sample is compared to that of a known concentration of the proteolyzed FITC-protein employed. This step enables the number of cellular receptors to be measured quantitatively. We expect that this method will provide researchers with a viable alternative to the use of radioactivity in ligand binding assays. PMID:27161290

  17. Screening of Peptide Ligands for Pyrroloquinoline Quinone Glucose Dehydrogenase Using Antagonistic Template-Based Biopanning

    PubMed Central

    Abe, Koichi; Yoshida, Wataru; Terada, Kotaro; Yagi-Ishii, Yukiko; Ferri, Stefano; Ikebukuro, Kazunori; Sode, Koji

    2013-01-01

    We have developed a novel method, antagonistic template-based biopanning, for screening peptide ligands specifically recognizing local tertiary protein structures. We chose water-soluble pyrroloquinoline quinone (PQQ) glucose dehydrogenase (GDH-B) as a model enzyme for this screening. Two GDH-B mutants were constructed as antagonistic templates; these have some point mutations to induce disruption of local tertiary structures within the loop regions that are located at near glucose-binding pocket. Using phage display, we selected 12-mer peptides that specifically bound to wild-type GDH-B but not to the antagonistic templates. Consequently, a peptide ligand showing inhibitory activity against GDH-B was obtained. These results demonstrate that the antagonistic template-based biopanning is useful for screening peptide ligands recognizing the specific local tertiary structure of proteins. PMID:24287902

  18. Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins

    DOE PAGESBeta

    Ng, Simon; Lin, Edith; Kitov, Pavel I.; Tjhung, Katrina F.; Gerlits, Oksana O.; Deng, Lu; Kasper, Brian; Sood, Amika; Paschal, Beth M.; Zhang, Ping; et al

    2015-04-10

    Here we describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based-discovery (GE-FBD) uses selection of phagedisplayed glycopeptides to dock a glycan fragment at the CRD and guide selection of Synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 108 glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40 50-fold enhancement in affinity over methyl α-D-mannopyranoside (MeMan). Lectin array Suggested specificity: Man-WYD derivative bound only to 3 outmore » of 17 proteins-ConA, LcH, and PSA-that bind to Man. An X-ray structure of ConA.:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking; but their extra-CRD binding modes are significantly. different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry :of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.« less

  19. Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins

    SciTech Connect

    Ng, Simon; Lin, Edith; Kitov, Pavel I.; Tjhung, Katrina F.; Gerlits, Oksana O.; Deng, Lu; Kasper, Brian; Sood, Amika; Paschal, Beth M.; Zhang, Ping; Ling, Chang-Chun; Klassen, John S.; Noren, Christopher J.; Mahal, Lara K.; Woods, Robert J.; Coates, Leighton; Derda, Ratmir

    2015-04-10

    Here we describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based-discovery (GE-FBD) uses selection of phagedisplayed glycopeptides to dock a glycan fragment at the CRD and guide selection of Synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 108 glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40 50-fold enhancement in affinity over methyl α-D-mannopyranoside (MeMan). Lectin array Suggested specificity: Man-WYD derivative bound only to 3 out of 17 proteins-ConA, LcH, and PSA-that bind to Man. An X-ray structure of ConA.:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking; but their extra-CRD binding modes are significantly. different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry :of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.

  20. Synthesis of BODIPY derivatives substituted with various bioconjugatable linker groups: a construction kit for fluorescent labeling of receptor ligands.

    PubMed

    Heisig, Fabian; Gollos, Sabrina; Freudenthal, Sven J; El-Tayeb, Ali; Iqbal, Jamshed; Müller, Christa E

    2014-01-01

    The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one-pot procedure starting from 2,4-dimethylpyrrole and ω-bromoalkylcarboxylic acid chlorides was used to obtain new ω-bromoalkyl-substituted BODIPY fluorophores (1a-1f) connected via alkyl spacers of different length to the 8-position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The ω-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a-1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water-soluble derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioadenosine was alkylated with bromoethyl-BODIPY 1b. The resulting fluorescent 2-substituted adenosine derivative 15 displayed selectivity for the A3 adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes. PMID:24052460

  1. A new series of heteroleptic oxidovanadium(IV) compounds with phenanthroline-derived co-ligands: selective Trypanosoma cruzi growth inhibitors.

    PubMed

    Fernández, Mariana; Varela, Javier; Correia, Isabel; Birriel, Estefanía; Castiglioni, Jorge; Moreno, Virtudes; Costa Pessoa, Joao; Cerecetto, Hugo; González, Mercedes; Gambino, Dinorah

    2013-09-01

    Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(IV) complexes, [V(IV)O(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative (L1-L5) and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial-equatorial mode. The stability of the complexes in solution was investigated by EPR and (51)V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [V(IV)O(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure-activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by (1)H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the

  2. Design, engineering, and production of human recombinant t cell receptor ligands derived from human leukocyte antigen DR2.

    PubMed

    Chang, J W; Mechling, D E; Bächinger, H P; Burrows, G G

    2001-06-29

    Major histocompatibility complex (MHC) class II molecules are membrane-anchored heterodimers on the surface of antigen-presenting cells that bind the T cell receptor, initiating a cascade of interactions that results in antigen-specific activation of clonal populations of T cells. Susceptibility to multiple sclerosis is associated with certain MHC class II haplotypes, including human leukocyte antigen (HLA) DR2. Two DRB chains, DRB5*0101 and DRB1*1501, are co-expressed in the HLA-DR2 haplotype, resulting in the formation of two functional cell surface heterodimers, HLA-DR2a (DRA*0101, DRB5*0101) and HLA-DR2b (DRA*0101, DRB1*1501). Both isotypes can present an immunodominant peptide of myelin basic protein (MBP-(84-102)) to MBP-specific T cells from multiple sclerosis patients. We have previously demonstrated that the peptide binding/T cell recognition domains of rat MHC class II (alpha1 and beta1 domains) could be expressed as a single exon for structural and functional characterization; Burrows, G. G., Chang, J. W., Bächinger, H.-P., Bourdette, D. N., Wegmann, K. W., Offner, H., and Vandenbark A. A. (1999) Protein Eng. 12, 771-778; Burrows, G. G., Adlard, K. L., Bebo, B. F., Jr., Chang, J. W., Tenditnyy, K., Vandenbark, A. A., and Offner, H. (2000) J. Immunol. 164, 6366-6371). Single-chain human recombinant T cell receptor ligands (RTLs) of approximately 200 amino acid residues derived from HLA-DR2b were designed using the same principles and have been produced in Escherichia coli with and without amino-terminal extensions containing antigenic peptides. Structural characterization using circular dichroism predicted that these molecules retained the antiparallel beta-sheet platform and antiparallel alpha-helices observed in the native HLA-DR2 heterodimer. The proteins exhibited a cooperative two-state thermal unfolding transition, and DR2-derived RTLs with a covalently linked MBP peptide (MBP-(85-99)) showed increased stability to thermal unfolding relative to the

  3. Tuning of the spin distribution between ligand- and metal-based spin: electron paramagnetic resonance of mixed-ligand molybdenum tris(dithiolene) complex anions.

    PubMed

    Fekl, Ulrich; Sarkar, Biprajit; Kaim, Wolfgang; Zimmer-De Iuliis, Marco; Nguyen, Neilson

    2011-09-19

    Electron paramagnetic resonance spectra of homoleptic and mixed-ligand molybdenum tris(dithiolene) complex anions [Mo(tfd)(m)(bdt)(n)](-) (n + m = 3; bdt = S(2)C(6)H(4); tfd = S(2)C(2)(CF(3))(2)) reveal that the spin density has mixed metal-ligand character with more ligand-based spin for [Mo(tfd)(3)](-) and a higher degree of metal-based spin for [Mo(bdt)(3)](-): the magnitude of the isotropic (95,97)Mo hyperfine interaction increases continuously, by a factor of 2.5, on going from the former to the latter. The mixed complexes fall in between, and the metal character of the spin increases with the bdt content. The experiments were corroborated by density functional theory computations, which reproduce this steady increase in metal-based character. PMID:21853970

  4. Effect of doping of calcium fluoride nanoparticles on the photoluminescence properties of europium complexes with benzoic acid derivatives as secondary ligands and 2-aminopyridine as primary ligand

    NASA Astrophysics Data System (ADS)

    Sharma, Garima; Narula, Anudeep Kumar

    2015-08-01

    The present article reports the synthesis of three Eu(III) complexes [Eu(BA)3(2-ap)] (1), [Eu(HBA)3(2-ap)] (2) and [Eu(ABA)3(2-ap)] (3) (BA = benzoic acid, HBA = 2-hydroxy benzoic acid, ABA = 2-amino benzoic acid and 2-ap = 2-aminopyridine) carried out in ethanol solution. The complexes were further doped with CaF2 nanoparticles and a change in the photoluminescence properties was observed. The compositions and structural investigation of the complexes were determined by elemental analysis and Fourier transform infrared spectroscopy (FTIR) which suggest the coordination of ligands with the central Eu(III) ion. The optical properties of the complexes were studied by Ultraviolet Visible absorption spectroscopy (UV-Vis) and photoluminescence studies (PL). The relative PL intensity was enhanced in the Eu(III) complexes doped with CaF2 nanoparticles as compared to the pure Eu(III) complexes, however the increase in intensity varied in the order of ligands ABA > HBA > BA. The photoluminescence lifetime decay curves also revealed the longer lifetime (τ) and higher quantum efficiency (η) for europium complexes with ABA ligands suggesting the efficient energy transfer and better sensitizing ability of the ligand to europium ion. The morphology of the synthesized compounds were studied by Scanning Electron Microscopy (SEM) revealing spherical morphology with agglomeration of the nanoparticles.

  5. Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling.

    PubMed

    Cappel, Daniel; Dixon, Steven L; Sherman, Woody; Duan, Jianxin

    2015-02-01

    3-D ligand conformations are required for most ligand-based drug design methods, such as pharmacophore modeling, shape-based screening, and 3-D QSAR model building. Many studies of conformational search methods have focused on the reproduction of crystal structures (i.e. bioactive conformations); however, for ligand-based modeling the key question is how to generate a ligand alignment that produces the best results for a given query molecule. In this work, we study different conformation generation modes of ConfGen and the impact on virtual screening (Shape Screening and e-Pharmacophore) and QSAR predictions (atom-based and field-based). In addition, we develop a new search method, called common scaffold alignment, that automatically detects the maximum common scaffold between each screening molecule and the query to ensure identical coordinates of the common core, thereby minimizing the noise introduced by analogous parts of the molecules. In general, we find that virtual screening results are relatively insensitive to the conformational search protocol; hence, a conformational search method that generates fewer conformations could be considered "better" because it is more computationally efficient for screening. However, for 3-D QSAR modeling we find that more thorough conformational sampling tends to produce better QSAR predictions. In addition, significant improvements in QSAR predictions are obtained with the common scaffold alignment protocol developed in this work, which focuses conformational sampling on parts of the molecules that are not part of the common scaffold. PMID:25408244

  6. Ruthenium(II) complexes containing quinone based ligands: Synthesis, characterization, catalytic applications and DNA interaction

    NASA Astrophysics Data System (ADS)

    Anitha, P.; Manikandan, R.; Endo, A.; Hashimoto, T.; Viswanathamurthi, P.

    2012-12-01

    1,2-Naphthaquinone reacts with amines such as semicarbazide, isonicotinylhydrazide and thiosemicarbazide in high yield procedure with the formation of tridentate ligands HLn (n = 1-3). By reaction of ruthenium(II) starting complexes and quinone based ligands HLn (n = 1-3), a series of ruthenium complexes were synthesized and characterized by elemental and spectroscopic methods (FT-IR, electronic, 1H, 13C, 31P NMR and ESI-MS). The ligands were coordinated to ruthenium through quinone oxygen, imine nitrogen and enolate oxygen/thiolato sulfur. On the basis of spectral studies an octahedral geometry may be assigned for all the complexes. Further, the catalytic oxidation of primary, secondary alcohol and transfer hydrogenation of ketone was carried out. The DNA cleavage efficiency of new complexes has also been tested.

  7. Near-Infrared Phosphorescent Iridium(III) Benzonorrole Complexes Possessing Pyridine-based Axial Ligands.

    PubMed

    Maurya, Yogesh Kumar; Ishikawa, Takahiro; Kawabe, Yasunori; Ishida, Masatoshi; Toganoh, Motoki; Mori, Shigeki; Yasutake, Yuhsuke; Fukatsu, Susumu; Furuta, Hiroyuki

    2016-06-20

    Novel near-infrared phosphorescent iridium(III) complexes based on benzo-annulated N-linked corrole analogue (termed as benzonorrole) were synthesized. The structures of the complexes revealed octahedral coordination geometries involving an organometallic iridium-carbon bond with two external axial ligands. Interestingly, the iridium(III) complex exhibits near-infrared phosphorescence at room temperature at wavelengths beyond 900 nm. The significant redshift of the emission, as compared to the corrole congener, is originated from the ligand-centered triplet character. The fine-tuning of the photophysical properties of the complexes was achieved by introducing electron-donating and electron-withdrawing substituents on the axial pyridine ligands. PMID:27249778

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

    PubMed

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

    2004-08-20

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

  9. The effect of ligand-based tautomer and protomer prediction on structure-based virtual screening.

    PubMed

    Kalliokoski, Tuomo; Salo, Heikki S; Lahtela-Kakkonen, Maija; Poso, Antti

    2009-12-01

    As tautomerism and ionization may significantly change the interaction possibilities between a ligand and a target protein, these phenomena could have an effect on structure-based virtual screening. Tautomeric- and protonation-state enumeration ensures that the state with optimal interaction possibilities is included in the screening process, as the predicted state may not always be the optimal binder. However, there is very little information published if tautomer and protomer enumeration actually improves the enrichment of active molecules compared to the alternative of using a predicted form of each molecule. In this study, a retrospective virtual screening was performed using AutoDock on 19 drug targets with a publicly available data set. It is proposed that tautomer and protomer prediction can significantly save computing resources and can yield similar results to enumeration. PMID:19928753

  10. A Ferrocenyl-Backboned Unsymmetric O,C-Coordinating Ligand and Its Tin Derivatives.

    PubMed

    Janssen, Bastian; Lutter, Michael; Alnasr, Hazem; Krossing, Ingo; Jurkschat, Klaus

    2016-08-01

    The syntheses of the phosphonyl-substituted ferrocenyl stannane Fe[{η (5)-C5H3-1-SnPh3-2-P(O)(O-iPr)2}{η (5)-C5H4P(O)(O-iPr)2}] (1) and its iodine derivative Fe[{η (5)-C5H3-1-SnPh2I-2-P(O)(O-iPr)2}{η (5)-C5H4P(O)(O-iPr)2}] (2) are reported. The syntheses of the corresponding salts Fe[{η (5)-C5H3-1-SnPh2-2-P(O)(O-iPr)2}{η (5)-C5H4P(O)(O-iPr)2}]X (3, X=Al{OC(CF3)3}4, 4, X=ClO4, 5, X=HgI3), respectively, are also described. The compounds are characterized by elemental analyses, (1)H, (13)C, (31)P, (119)Sn NMR and IR spectroscopy, electrospray ionization mass spectrometry, and, except for 4 and 5, single-crystal X-ray diffraction analyses. PMID:27547641

  11. A Ferrocenyl‐Backboned Unsymmetric O,C‐Coordinating Ligand and Its Tin Derivatives

    PubMed Central

    Janssen, Bastian; Lutter, Michael; Alnasr, Hazem; Krossing, Ingo

    2016-01-01

    Abstract The syntheses of the phosphonyl‐substituted ferrocenyl stannane Fe[{η 5‐C5H3‐1‐SnPh3‐2‐P(O)(O‐iPr)2}{η 5‐C5H4P(O)(O‐iPr)2}] (1) and its iodine derivative Fe[{η 5‐C5H3‐1‐SnPh2I‐2‐P(O)(O‐iPr)2}{η 5‐C5H4P(O)(O‐iPr)2}] (2) are reported. The syntheses of the corresponding salts Fe[{η 5‐C5H3‐1‐SnPh2‐2‐P(O)(O‐iPr)2}{η 5‐C5H4P(O)(O‐iPr)2}]X (3, X=Al{OC(CF3)3}4, 4, X=ClO4, 5, X=HgI3), respectively, are also described. The compounds are characterized by elemental analyses, 1H, 13C, 31P, 119Sn NMR and IR spectroscopy, electrospray ionization mass spectrometry, and, except for 4 and 5, single‐crystal X‐ray diffraction analyses. PMID:27547641

  12. SPOT-Ligand: Fast and effective structure-based virtual screening by binding homology search according to ligand and receptor similarity.

    PubMed

    Yang, Yuedong; Zhan, Jian; Zhou, Yaoqi

    2016-07-01

    Structure-based virtual screening usually involves docking of a library of chemical compounds onto the functional pocket of the target receptor so as to discover novel classes of ligands. However, the overall success rate remains low and screening a large library is computationally intensive. An alternative to this "ab initio" approach is virtual screening by binding homology search. In this approach, potential ligands are predicted based on similar interaction pairs (similarity in receptors and ligands). SPOT-Ligand is an approach that integrates ligand similarity by Tanimoto coefficient and receptor similarity by protein structure alignment program SPalign. The method was found to yield a consistent performance in DUD and DUD-E docking benchmarks even if model structures were employed. It improves over docking methods (DOCK6 and AUTODOCK Vina) and has a performance comparable to or better than other binding-homology methods (FINDsite and PoLi) with higher computational efficiency. The server is available at http://sparks-lab.org. © 2016 Wiley Periodicals, Inc. PMID:27074979

  13. Ligand-to-Ligand Charge Transfer within Metal-Organic Frameworks Based on Manganese Coordination Polymers with Tetrathiafulvalene-Bicarboxylate and Bipyridine Ligands.

    PubMed

    Huo, Peng; Chen, Ting; Hou, Jin-Le; Yu, Lei; Zhu, Qin-Yu; Dai, Jie

    2016-07-01

    A systematic study on ligand-to-ligand charge-transfer (LLCT) properties of three closely related metal-organic frameworks (MOFs) is presented. These compounds are formulated as [MnL(4,4'-bpy)(H2O)]n·nCH3CN (1), [MnL(bpe)0.5(DMF)]n·2nH2O (2), and [MnL(bpa)(H2O)]n·2nH2O (3) (L = dimethylthio-tetrathiafulvalene-bicarboxylate, 4,4'-bpy = 4,4'-bipyridine, bpe = 1,2-bis(4-pyridyl)ethene, bpa = 1,2-bis(4-pyridyl)ethane). The X-ray single-crystal diffractions show that complexes 1-3 are all two-dimensional (2-D) coordination polymers with different frameworks in crystal lattices. Charge-transfer (CT) interactions within these MOFs are visually apparent in colors and vary according to the conjugated states of the bipyridine ligands (4,4'-bpy, bpe, and bpa). Theoretical calculations show that the charge transfer occurs from ligand L to bipyridine. The intensity of the LLCT is in the order of 2 > 1 > 3 investigated by theoretical calculations and ESR, which indicates that the intensity of CT is related to the bipyridyl conjugated state. Photocurrent responses of these compounds are consequently studied, and the results are in agreement with the intensity of charge transfer and linearly related to the LLCT energy. PMID:27285178

  14. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    NASA Astrophysics Data System (ADS)

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

    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 [CoL2(H2O)2]n·2nH2O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H2adbc), terephthalic acid (H2tpa), thiophene-2,5-dicarboxylic acid (H2tdc) and 1,4-benzenedithioacetic acid (H2bdtc), four 3D structures [Co2L2(adbc)]n·nH2O (2), [Co2L2(tpa)]n (3), [Co2L2(tdc)]n (4), [Co2L2(bdtc)(H2O)]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.

  15. Metal Complexes of Macrocyclic Schiff-Base Ligand: Preparation, Characterisation, and Biological Activity

    PubMed Central

    Ahmed, Riyadh M.; Yousif, Enaam I.; Hasan, Hasan A.; Al-Jeboori, Mohamad J.

    2013-01-01

    A new macrocyclic multidentate Schiff-base ligand Na4L consisting of two submacrocyclic units (10,21-bis-iminomethyl-3,6,14,17-tricyclo[17.3.1.18,12]tetracosa-1(23),2,6,8,10,12(24),13,17,19,21,-decaene-23,24-disodium) and its tetranuclear metal complexes with Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) are reported. Na4L was prepared via a template approach, which is based on the condensation reaction of sodium 2,4,6-triformyl phenolate with ethylenediamine in mole ratios of 2 : 3. The tetranuclear macrocyclic-based complexes were prepared from the reaction of the corresponding metal chloride with the ligand. The mode of bonding and overall geometry of the compounds were determined through physicochemical and spectroscopic methods. These studies revealed tetrahedral geometries about Mn, Co, and Zn atoms. However, square planar geometries have been suggested for NiII and CuII complexes. Biological activity of the ligand and its metal complexes against Gram positive bacterial strain Staphylococcus aureus and Gram negative bacteria Escherichia coli revealed that the metal complexes become more potentially resistive to the microbial activities as compared to the free ligand. However, these metal complexes do not exhibit any effects on the activity of Pseudomonas aeruginosa bacteria. There is therefore no inhibition zone. PMID:23935414

  16. Dopaminergic receptor-ligand binding assays based on molecularly imprinted polymers on quartz crystal microbalance sensors.

    PubMed

    Naklua, Wanpen; Suedee, Roongnapa; Lieberzeit, Peter A

    2016-07-15

    Molecularly imprinted polymers (MIPs) have been successfully applied as selective materials for assessing the binding activity of agonist and antagonist of dopamine D1 receptor (D1R) by using quartz crystal microbalance (QCM). In this study, D1R derived from rat hypothalamus was used as a template and thus self-organized on stamps. Those were pressed into an oligomer film consisting of acrylic acid: N-vinylpyrrolidone: N,N'-(1,2-dihydroxyethylene) bis-acrylamide in a ratio of 2:3:12 spin coated onto a dual electrode QCM. Such we obtained one D1R-MIP-QCM electrode, whereas the other electrode carried the non-imprinted control polymer (NIP) that had remained untreated. Successful imprinting of D1R was confirmed by AFM. The polymer can re-incorporate D1R leading to frequency responses of 100-1200Hz in a concentration range of 5.9-47.2µM. In a further step such frequency changes proved inherently useful for examining the binding properties of test ligands to D1R. The resulting mass-sensitive measurements revealed Kd of dopamine∙HCl, haloperidol, and (+)-SCH23390 at 0.874, 25.6, and 0.004nM, respectively. These results correlate well with the values determined in radio ligand binding assays. Our experiments revealed that D1R-MIP sensors are useful for estimating the strength of ligand binding to the active single site. Therefore, we have developed a biomimetic surface imprinting strategy for QCM studies of D1R-ligand binding and presented a new method to ligand binding assay for D1R. PMID:26926593

  17. Homology Model and Docking-Based Virtual Screening for Ligands of the σ1 Receptor

    PubMed Central

    2011-01-01

    This study presents for the first time the 3D model of the σ1 receptor protein as obtained from homology modeling techniques, shows the applicability of this structure to docking-based virtual screening, defines a computational strategy to optimize the results based on a combination of 3D pharmacophore-based docking and MM/PBSA free energy of binding scoring, and provides evidence that these in silico models and recipes are powerful tools on which virtual screening of new σ1 ligands can be based. In particular, the validation of the applicability of docking-based virtual screening to homology models is of utmost importance, since no crystal structure is available to date for the σ1 receptor, and this missing information still constitutes a major hurdle for a rational ligand design for this important protein target. PMID:24900272

  18. Role of ligand-based drug design methodologies toward the discovery of new anti- Alzheimer agents: futures perspectives in Fragment-Based Ligand Design.

    PubMed

    Speck-Planche, A; Luan, F; Cordeiro, M N D S

    2012-01-01

    Alzheimer's disease (AD), a degenerative disease affecting the brain, is the single most common source of dementia in adults. The cause and the progression of AD still remains a mystery among medical experts. As a result, a cure has not yet been discovered, even after decade's worth of research that started since 1906, when the disease was first identified. Despite the efforts of the scientific community, several of the biological receptors associated with AD have not been sufficiently studied to date, limiting in turn the design of new and more potent anti-AD agents. Thus, the search for new drug candidates as inhibitors of different targets associated with AD constitutes an essential part towards the discovery of new and more efficient anti-AD therapies. The present work is focused on the role of the Ligand-Based Drug Design (LBDD) methodologies which have been applied for the elucidation of new molecular entities with high inhibitory activity against targets related with AD. Particular emphasis is given also to the current state of fragment-based ligand approaches as alternatives of the Fragment-Based Drug Discovery (FBDD) methodologies. Finally, several guidelines are offered to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with AD. PMID:22376033

  19. Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity.

    PubMed

    Labani-Motlagh, Alireza; Israelsson, Pernilla; Ottander, Ulrika; Lundin, Eva; Nagaev, Ivan; Nagaeva, Olga; Dehlin, Eva; Baranov, Vladimir; Mincheva-Nilsson, Lucia

    2016-04-01

    Cancers constitutively produce and secrete into the blood and other biofluids 30-150 nm-sized endosomal vehicles called exosomes. Cancer-derived exosomes exhibit powerful influence on a variety of biological mechanisms to the benefit of the tumors that produce them. We studied the immunosuppressive ability of epithelial ovarian cancer (EOC) exosomes on two cytotoxic pathways of importance for anticancer immunity-the NKG2D receptor-ligand pathway and the DNAM-1-PVR/nectin-2 pathway. Using exosomes, isolated from EOC tumor explant and EOC cell-line culture supernatants, and ascitic fluid from EOC patients, we studied the expression of NKG2D and DNAM-1 ligands on EOC exosomes and their ability to downregulate the cognate receptors. Our results show that EOC exosomes differentially and constitutively express NKG2D ligands from both MICA/B and ULBP families on their surface, while DNAM-1 ligands are more seldom expressed and not associated with the exosomal membrane surface. Consequently, the NKG2D ligand-bearing EOC exosomes significantly downregulated the NKG2D receptor expression on peripheral blood mononuclear cells (PBMC) while the DNAM-1 receptor was unaffected. The downregulation of NKG2D receptor expression was coupled to inhibition of NKG2D receptor-ligand-mediated degranulation and cytotoxicity measured in vitro with OVCAR-3 and K562 cells as targets. The EOC exosomes acted as a decoy impairing the NKG2D mediated cytotoxicity while the DNAM-1 receptor-ligand system remained unchanged. Taken together, our results support and explain the mechanism behind the recently reported finding that in EOC, NK-cell recognition and killing of tumor cells was mainly dependent on DNAM-1 signaling while the contribution of the NKG2D receptor-ligand pathway was complementary and uncertain. PMID:26563374

  20. A Fluorescence Displacement Assay for Antidepressant Drug Discovery Based on Ligand-Conjugated Quantum Dots

    SciTech Connect

    Chang, Jerry; Tomlinson, Ian; Warnement, Michael; Iwamoto, Hideki

    2011-01-01

    The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) protein plays a central role in terminating 5-HT neurotransmission and is the most important therapeutic target for the treatment of major depression and anxiety disorders. We report an innovative, versatile, and target-selective quantum dot (QD) labeling approach for SERT in single Xenopus oocytes that can be adopted as a drug-screening platform. Our labeling approach employs a custom-made, QD-tagged indoleamine derivative ligand, IDT318, that is structurally similar to 5-HT and accesses the primary binding site with enhanced human SERT selectivity. Incubating QD-labeled oocytes with paroxetine (Paxil), a high-affinity SERT-specific inhibitor, showed a concentration- and time-dependent decrease in QD fluorescence, demonstrating the utility of our approach for the identification of SERT modulators. Furthermore, with the development of ligands aimed at other pharmacologically relevant targets, our approach may potentially form the basis for a multitarget drug discovery platform.

  1. Enhanced association for C70 over C60 with a metal complex with corannulene derivate ligands.

    PubMed

    Álvarez, Celedonio M; García-Escudero, Luis A; García-Rodríguez, Raúl; Martín-Álvarez, Jose M; Miguel, Daniel; Rayón, Víctor M

    2014-11-14

    The geometry imposed by the coordination sphere around the metal, together with the choice of the "arms" can be advantageously used to build corannulene-based molecular tweezers, which show great affinities for C60 and C70, as revealed by NMR titration experiments, mass spectroscopy, DFT calculations and the single crystal X-ray structural analysis of the compound C60 ⊂1. PMID:25181755

  2. Imidazolin-2-iminato Ligand-Supported Titanium Complexes as Catalysts for the Synthesis of Urea Derivatives.

    PubMed

    Naktode, Kishor; Das, Suman; Bhattacharjee, Jayeeta; Nayek, Hari Pada; Panda, Tarun K

    2016-02-01

    The reactions of tetrakis(dimethylamido)titanium(IV) [Ti(NMe2)4] with three different imidazolin-2-imines (Im(R)NH; R = tert-butyl (tBu), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp)) afforded the corresponding titanium imidazolin-2-iminato complexes [(Im(R)N)Ti(NMe2)3] (R = tBu, 1a; R = Mes, 1b; R = Dipp, 1c). Treatment of complex 1a with two different carbodiimides [R'N═C═NR'; R' = cyclohexyl (Cy) and isopropyl (iPr)] resulted in the formation of imidazolin-2-iminato titanium mono(guanidinate) complex of the type [(Im(R)N)Ti(R'NC(NMe2)NR') (NMe2)2 (R' = iPr; R = tBu (2a), R = Dipp (2c); R' = Cy, R = tBu (3a)], as yellow solid in 94% yield. However, a similar reaction of 1b and 1c with 2 equiv of phenyl isocyanates at ambient temperature resulted in the formation of corresponding titanium bis(ureate) complexes [(Im(R)N)Ti{κ(2)-OC(NMe2)NPh}2(NMe2)] (R = Mes, 4b and R = Dipp, 4c). Three equivalents of phenyl isothiocyanate reacted with complex 1c to afford respective titanium tris(thioureate) complex [(Im(Dipp)N)Ti{κ(2)-SC(NMe2)NPh}2{κ(1)-SC(NMe2)NPh}] (6c). The molecular structures of 1a-c, 2a, 2c, 3a, 4c, and 6c were established by X-ray diffraction analyses, and, from the solid-state structures of 1a-c, 2a, 2c, 3a, 4c, and 6c, it was confirmed that the imidazolin-2-iminato titanium bond in each case is very short and possesses a multiple-bonding character. The imidazolin-2-iminato titanium complex 1c was utilized as a precatalyst for the addition of amine N-H bond to phenyl isocyanate. High yields of the corresponding urea derivatives were achieved under mild conditions. The mechanistic study of the aforementioned catalytic reaction was performed, and the active catalyst complex 7b was isolated using 2 equiv of iminopyrrole [2-(2,6-iPr2C6H3N═CH)C4H3NH] and the complex 4b. The molecular structure of 7b was thereafter established. PMID:26789927

  3. Computational ligand-based rational design: Role of conformational sampling and force fields in model development.

    PubMed

    Shim, Jihyun; Mackerell, Alexander D

    2011-05-01

    A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more

  4. Computational ligand-based rational design: Role of conformational sampling and force fields in model development

    PubMed Central

    Shim, Jihyun; MacKerell, Alexander D.

    2011-01-01

    A significant number of drug discovery efforts are based on natural products or high throughput screens from which compounds showing potential therapeutic effects are identified without knowledge of the target molecule or its 3D structure. In such cases computational ligand-based drug design (LBDD) can accelerate the drug discovery processes. LBDD is a general approach to elucidate the relationship of a compound's structure and physicochemical attributes to its biological activity. The resulting structure-activity relationship (SAR) may then act as the basis for the prediction of compounds with improved biological attributes. LBDD methods range from pharmacophore models identifying essential features of ligands responsible for their activity, quantitative structure-activity relationships (QSAR) yielding quantitative estimates of activities based on physiochemical properties, and to similarity searching, which explores compounds with similar properties as well as various combinations of the above. A number of recent LBDD approaches involve the use of multiple conformations of the ligands being studied. One of the basic components to generate multiple conformations in LBDD is molecular mechanics (MM), which apply an empirical energy function to relate conformation to energies and forces. The collection of conformations for ligands is then combined with functional data using methods ranging from regression analysis to neural networks, from which the SAR is determined. Accordingly, for effective application of LBDD for SAR determinations it is important that the compounds be accurately modelled such that the appropriate range of conformations accessible to the ligands is identified. Such accurate modelling is largely based on use of the appropriate empirical force field for the molecules being investigated and the approaches used to generate the conformations. The present chapter includes a brief overview of currently used SAR methods in LBDD followed by a more

  5. Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors

    PubMed Central

    Gruber, Christian W.; Muttenthaler, Markus; Freissmuth, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30–50%). Closer scrutiny, however, shows that only a modest fraction of (~60) GPCRs are, in fact, exploited as drug targets, only ~20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the “orthosteric site”). These additional sites include (i) binding sites for ligands (referred to as “allosteric ligands”) that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points. PMID:20687879

  6. Synthesis, spectroscopic, thermal and antimicrobial studies of neodymium(III) and samarium(III) complexes derived from tetradentate ligands containing N and S donor atoms.

    PubMed

    Ain, Qurratul; Pandey, S K; Pandey, O P; Sengupta, S K

    2015-04-01

    Trivalent lanthanide complexes of the type [Ln(L)Cl(H2O)2] (where Ln=Nd(III) or Sm(III) and LH2=Schiff bases derived by the condensation of 3-(phenyl/substitutedphenyl)-4-amino-5-mercapto-1,2,4-triazole with diacetyl/benzil) have been synthesized by the reactions of anhydrous lanthanide(III) chloride with Schiff bases in methanol. The structures of the complexes have been proposed on the basis of elemental analysis, electrical conductance, magnetic moment, spectroscopic measurements (IR, 1H, 13C NMR and UV-vis spectra) and X-ray diffraction studies. The spectral data reveal that the Schiff base ligands behave as dibasic tetradentate chelating agents having coordination sites at two thiol sulfur atoms and two azomethine nitrogen atoms. The presence of coordinated water in metal complexes was confirmed by thermal and IR data of the complexes. All the Schiff bases and their metal complexes have also been screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus and antifungal activities against Aspergillus niger, Curvularia pallescens and Colletotrichum capsici. PMID:25579799

  7. Synthesis, spectroscopic, thermal and antimicrobial studies of neodymium(III) and samarium(III) complexes derived from tetradentate ligands containing N and S donor atoms

    NASA Astrophysics Data System (ADS)

    Ain, Qurratul; Pandey, S. K.; Pandey, O. P.; Sengupta, S. K.

    2015-04-01

    Trivalent lanthanide complexes of the type [Ln(L)Cl(H2O)2] (where Ln = Nd(III) or Sm(III) and LH2 = Schiff bases derived by the condensation of 3-(phenyl/substitutedphenyl)-4-amino-5-mercapto-1,2,4-triazole with diacetyl/benzil) have been synthesized by the reactions of anhydrous lanthanide(III) chloride with Schiff bases in methanol. The structures of the complexes have been proposed on the basis of elemental analysis, electrical conductance, magnetic moment, spectroscopic measurements (IR, 1H, 13C NMR and UV-vis spectra) and X-ray diffraction studies. The spectral data reveal that the Schiff base ligands behave as dibasic tetradentate chelating agents having coordination sites at two thiol sulfur atoms and two azomethine nitrogen atoms. The presence of coordinated water in metal complexes was confirmed by thermal and IR data of the complexes. All the Schiff bases and their metal complexes have also been screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus and antifungal activities against Aspergillus niger, Curvularia pallescens and Colletotrichum capsici.

  8. Recent Advances in Ligand-Based Drug Design: Relevance and Utility of the Conformationally Sampled Pharmacophore Approach

    PubMed Central

    Acharya, Chayan; Coop, Andrew; Polli, James E.; MacKerell, Alexander D.

    2010-01-01

    In the absence of three-dimensional (3D) structures of potential drug targets, ligand-based drug design is one of the popular approaches for drug discovery and lead optimization. 3D structure-activity relationships (3D QSAR) and pharmacophore modeling are the most important and widely used tools in ligand-based drug design that can provide crucial insights into the nature of the interactions between drug target and ligand molecule and provide predictive models suitable for lead compound optimization. This review article will briefly discuss the features and potential application of recent advances in ligand-based drug design, with emphasis on a detailed description of a novel 3D QSAR method based on the conformationally sample pharmacophore (CSP) approach (denoted CSP-SAR). In addition, data from a published study is used to compare the CSP-SAR approach to the Catalyst method, emphasizing the utility of the CSP approach for ligand-based model development. PMID:20807187

  9. PBSA_E: A PBSA-Based Free Energy Estimator for Protein-Ligand Binding Affinity.

    PubMed

    Liu, Xiao; Liu, Jinfeng; Zhu, Tong; Zhang, Lujia; He, Xiao; Zhang, John Z H

    2016-05-23

    Improving the accuracy of scoring functions for estimating protein-ligand binding affinity is of significant interest as well as practical utility in drug discovery. In this work, PBSA_E, a new free energy estimator based on the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) descriptors, has been developed. This free energy estimator was optimized using high-quality experimental data from a training set consisting of 145 protein-ligand complexes. The method was validated on two separate test sets containing 121 and 130 complexes. Comparison of the binding affinities predicted using the present method with those obtained using three popular scoring functions, i.e., GlideXP, GlideSP, and SYBYL_F, demonstrated that the PBSA_E method is more accurate. This new energy estimator requires a MM/PBSA calculation of the protein-ligand binding energy for a single complex configuration, which is typically obtained by optimizing the crystal structure. The present study shows that PBSA_E has the potential to become a robust tool for more reliable estimation of protein-ligand binding affinity in structure-based drug design. PMID:27088302

  10. Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation

    PubMed Central

    Fukunishi, Yoshifumi; Nakamura, Haruki

    2012-01-01

    We have developed a method for estimating protein-ligand binding free energy (ΔG) based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the ΔG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA) and dihedral angles of the protein-ligand complex system as the entropy terms of the ΔG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated ΔG values was 0.81, and the average error of ΔG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation. PMID:24281257