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Sample records for 2-mercapto benzothiazolate ligand

  1. Exchange of Alkyl and Tris(2-mercapto-1-t-butylimidazolyl)hydroborato Ligands Between Zinc, Cadmium and Mercury‡

    PubMed Central

    Kreider-Mueller, Ava; Quinlivan, Patrick J.; Rong, Yi

    2015-01-01

    The tris(2-mercaptoimidazolyl)hydroborato ligand, [TmBut], has been used to investigate the exchange of alkyl and sulfur donor ligands between the Group 12 metals, Zn, Cd and Hg. For example, [TmBut]2Zn reacts with Me2Zn to yield [TmBut]ZnMe, while [TmBut]CdMe is obtained readily upon reaction of [TmBut]2Cd with Me2Cd. Ligand exchange is also observed between different metal centers. For example, [TmBut]CdMe reacts with Me2Zn to afford [TmBut]ZnMe and Me2Cd. Likewise, [TmBut]HgMe reacts with Me2Zn to afford [TmBut]ZnMe and Me2Hg. However, whereas the [TmBut] ligand transfers from mercury to zinc in the methyl system, [TmBut]HgMe/Me2Zn, transfer of the [TmBut] ligand from zinc to mercury is observed upon treatment of [TmBut]2Zn with HgI2 to afford [TmBut]HgI and [TmBut]ZnI. These observations demonstrate that the phenomenological preference for the [TmBut] ligand to bind one metal rather than another is strongly influenced by the nature of the co-ligands. PMID:26273109

  2. Characterization and electrochemical studies of Mn(II), Co(II), Ni(II) and Cu(II) complexes with 2-mercapto-3-substituted-quinazolin-4-one and 1,10-phenanthroline or ethylenediamine as ligands

    NASA Astrophysics Data System (ADS)

    Sawant, V. A.; Gotpagar, S. N.; Yamgar, B. A.; Sawant, S. K.; Kankariya, R. D.; Chavan, S. S.

    2009-04-01

    Some mixed ligand complexes of the type [M(L 1 or L 2)( phen or en)(H 2O)Cl], where M = Mn(II), Co(II), Ni(II) and Cu(II); HL 1 = 2-mercapto-quinazolin-4-one; HL 2 = 2-mercapto-3-phenyl-quinazolin-4-one; phen = 1,10-phenanthroline; en = ethylenediamine have been prepared. All complexes were characterized on the basis of elemental analysis, molar conductance, magnetic susceptibility measurements, IR, UV-vis, ESR and powder X-ray diffraction studies. IR spectra of these complexes reveal that the complex formation occurred through both nitrogen and sulphur atoms. On the basis of electronic spectral data and magnetic susceptibility measurement octahedral geometry has been proposed for the complexes. The ESR spectral data of the Cu(II) complexes showed that the metal-ligand bonds have considerable covalent character. X-ray diffraction studies of Cu(II) complexes are used to elucidate the crystal structure. The electrochemical behaviour of mixed ligand Ni(II) complexes was studied which showed that complexes of phen appear at more positive potential as compared to those for corresponding en complexes.

  3. Characterization and electrochemical studies of Mn(II), Co(II), Ni(II) and Cu(II) complexes with 2-mercapto-3-substituted-quinazolin-4-one and 1,10-phenanthroline or ethylenediamine as ligands.

    PubMed

    Sawant, V A; Gotpagar, S N; Yamgar, B A; Sawant, S K; Kankariya, R D; Chavan, S S

    2009-04-01

    Some mixed ligand complexes of the type [M(L(1) or L(2))(phen or en)(H(2)O)Cl], where M=Mn(II), Co(II), Ni(II) and Cu(II); HL(1)=2-mercapto-quinazolin-4-one; HL(2)=2-mercapto-3-phenyl-quinazolin-4-one; phen=1,10-phenanthroline; en=ethylenediamine have been prepared. All complexes were characterized on the basis of elemental analysis, molar conductance, magnetic susceptibility measurements, IR, UV-vis, ESR and powder X-ray diffraction studies. IR spectra of these complexes reveal that the complex formation occurred through both nitrogen and sulphur atoms. On the basis of electronic spectral data and magnetic susceptibility measurement octahedral geometry has been proposed for the complexes. The ESR spectral data of the Cu(II) complexes showed that the metal-ligand bonds have considerable covalent character. X-ray diffraction studies of Cu(II) complexes are used to elucidate the crystal structure. The electrochemical behaviour of mixed ligand Ni(II) complexes was studied which showed that complexes of phen appear at more positive potential as compared to those for corresponding en complexes.

  4. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  5. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  6. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  7. Inhibition of Brass Corrosion by 2-Mercapto-1-methylimidazole in Weakly Alkaline Solution

    NASA Astrophysics Data System (ADS)

    Radovanovic, Milan B.; Antonijevic, Milan M.

    2016-03-01

    The electrochemical behavior of brass and anticorrosion effect of 2-mercapto-1-methylimidazole (2-MMI) in weakly alkaline solution with and without presence of chloride ions was investigated using electrochemical techniques in addition to SEM-EDS analysis. Results show that inhibition efficiency depended on inhibitor concentration and immersion time of brass electrode in inhibitor solution. Inhibition mechanism of 2-mercapto-1-methylimidazole includes adsorption of inhibitor on active sites on electrode surface which was confirmed by SEM-EDS analysis of the brass. Adsorption of the 2-MMI in sodium tetraborate solution obeys Flory-Huggins adsorption isotherm, while in the presence of chloride, ions adsorption of inhibitor obeys Langmuir adsorption isotherm.

  8. A trinuclear palladium(II) complex containing N,S-coordinating 2-(benzylsulfanyl)anilinide and 1,3-benzothiazole-2-thiolate ligands with a central square-planar PdN4 motif.

    PubMed

    Cross, Edward D; MacDonald, Kristen L; McDonald, Robert; Bierenstiel, Matthias

    2014-01-01

    The reaction of dichlorido(cod)palladium(II) (cod = 1,5-cyclooctadiene) with 2-(benzylsulfanyl)aniline followed by heating in N,N-dimethylformamide (DMF) produces the linear trinuclear Pd3 complex bis(μ2-1,3-benzothiazole-2-thiolato)bis[μ2-2-(benzylsulfanyl)anilinido]dichloridotripalladium(II) N,N-dimethylformamide disolvate, [Pd3(C7H4NS2)2(C13H12NS)2Cl2]·2C3H7NO. The molecule has -1 symmetry and a Pd...Pd separation of 3.2012 (4) Å. The outer Pd(II) atoms have a square-planar geometry formed by an N,S-chelating 2-(benzylsulfanyl)anilinide ligand, a chloride ligand and the thiolate S atom of a bridging 1,3-benzothiazole-2-thiolate ligand, while the central Pd(II) core shows an all N-coordinated square-planar geometry. The geometry is perfectly planar within the PdN4 core and the N-Pd-N bond angles differ significantly [84.72 (15)° for the N atoms of ligands coordinated to the same outer Pd atom and 95.28 (15)° for the N atoms of ligands coordinated to different outer Pd atoms]. This trinuclear Pd3 complex is the first example of one in which 1,3-benzothiazole-2-thiolate ligands are only N-coordinated to one Pd centre. The 1,3-benzothiazole-2-thiolate ligands were formed in situ from 2-(benzylsulfanyl)aniline.

  9. Electronic Structures and Spectroscopic Properties of a Novel Iridium (III) Complex with an Ancillary Ligand 2-(4-Trifluoromethyl -2-Hydroxylphenyl) Benzothiazole

    NASA Astrophysics Data System (ADS)

    Lei, Li-Ping; Hao, Yu-Ying; Fan, Wen-Hao; Xu, Bing-She

    2011-06-01

    Iridium (III) complexes with 2-phenylpyridine (ppy) have been demonstrated as a type of promising phosphorescence dopant in emitting layers of organic light emitting diodes (OLEDs). In most iridium (III) complexes, there exist the strong spin-orbit coupling between π-orbitals of cyclometalated ligands and 5d orbitals of the centric iridium. We study a novel iridium (III) complex (ppy)2Ir(4-TfmBTZ) with ppy as cyclometalated ligands and 2-(4-trifluoromethyl-2-hydroxylphenyl)benzothiazole (4-TfmBTZ) as an ancillary ligand using the Gaussian 03 program. The geometries, electronic structures and spectroscopic properties of this iridium (III) complex are investigated by density functional theory (DFT) and time-dependent density functional theory (TD-DFT). The results show that the spin-orbit coupling occurs not only between ppy and iridium atom but also between 4-TfmBTZ and iridium atom in this complex. The highest occupied molecular orbital is dominantly localized on the Ir atom and 4-TfmBTZ ligand, while the lowest unoccupied molecular orbital on 4-TfmBTZ ligand. The triplet lowest-lying transition is attributed to the Ir-to-4-TfmBTZ charge-transfer (3MLCT) transition while the sub-low-lying transitions are assigned to the 3MLCT transitions of Ir(ppy)2. The nature of the lowest unoccupied orbital changes from ppy-localized to 4-TfmBTZ-localized and reveals that phosphorescent color of Ir(III) complex can be controlled by the ancillary ligand and substituent.

  10. DNA interaction, antimicrobial studies of newly synthesized copper (II) complexes with 2-amino-6-(trifluoromethoxy)benzothiazole Schiff base ligands.

    PubMed

    Rambabu, Aveli; Pradeep Kumar, Marri; Tejaswi, Somapangu; Vamsikrishna, Narendrula; Shivaraj

    2016-12-01

    Four novel Schiff base ligands, L(1) (1-((E)-(6-(trifluoromethoxy)benzo[d]thiazol-2-ylimino)methyl)naphthalen-2-ol, C19H11F3N2O2S), L(2) (3-((E)-(6-(trifluoromethoxy)benzo[d]thiazol-2-ylimino)methyl)benzene-1,2-diol, C15H9F3N2O3S), L(3) (2-((E)-(6-(trifluoromethoxy)benzo[d]thiazol-2-ylimino)methyl)-5-methoxyphenol, C16H11F3N2O3S) and L(4) (2-((E)-(6-(trifluoromethoxy)benzo[d]thiazol-2-ylimino)methyl)-4-bromophenol, C15H8BrF3N2O2S) and their binary copper(II) complexes 1 [Cu(L(1))2], 2 [Cu(L(2))2], 3 [Cu(L(3))2] and 4 [Cu(L(4))2] have been synthesized and characterized by elemental analysis, (1)H NMR, (13)C NMR, ESI mass, FT-IR, ESR, UV-Visible, magnetic susceptibility, TGA, SEM and powder XRD studies. Based on spectral and analytical data, a square planar geometry is assigned for all Cu(II) complexes. The ligands and their Cu(II) complexes have been screened for antimicrobial activity against bacterial species E. coli, P. aeruginosa, B. amyloliquefaciens and S. aureus and fungal species S. rolfsii and M. phaseolina and it is observed that all Cu(II) complexes are more potent than corresponding ligands. DNA binding (UV absorption, fluorescence and viscosity titrations) and cleavage (oxidative and photo cleavage) studies of Cu(II) complexes have also been investigated against calf thymus DNA (CT-DNA) and supercoiled pBR322 DNA respectively. From the experimental results, it is found that the complexes bound effectively to CT-DNA through an intercalative mode and also cleaved pBR322 DNA in an efficient manner. The DNA binding and cleavage affinities of newly synthesized Cu(II) complexes are in the order of 2>1>3>4.

  11. Synthesis and antitumor activity evaluation of new 2-(4-aminophenyl)benzothiazole derivatives bearing different heterocyclic rings.

    PubMed

    Yurttaş, Leyla; Tay, Funda; Demirayak, Şeref

    2015-06-01

    Twenty-five new N-[4-(benzothiazole-2-yl)phenyl]acetamide derivatives bearing different heterocyclic ring systems were synthesized using 2-(4-aminophenyl)benzothiazole structure as a pharmacophoric group. Final compounds were screened for their potential antitumor activity in vitro against approximately 60 human tumor cell lines derived from nine neoplastic diseases at National Cancer Institute, USA. 2-(4-Aminophenyl)benzothiazole structure was prepared by the reaction of 4-aminobenzoic acid and 2-aminothiophenol in polyphosphoric acid using microwave irradiation. After acetylation reaction, amide compounds 2a and 2b were obtained, which were then reacted with 2-mercapto(benz)imidazole/benzothiazole/benzoxazole derivatives in acetone with the presence of potassium carbonate to gain final compounds (3-27). Among all tested compounds, compound 10, namely N-[4-(benzothiazole-2-yl)-3-chlorophenyl]-2-[(benzimidazole-2-yl)thio]acetamide, and compound 16, namely N-[4-(benzothiazole-2-yl)phenyl]-2-[(1,5-diphenyl-1H-imidazole-2-yl)thio]acetamide, were found to be of considerable anticancer activity against some cancer cell lines.

  12. Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives.

    PubMed

    Chugunova, Elena; Boga, Carla; Sazykin, Ivan; Cino, Silvia; Micheletti, Gabriele; Mazzanti, Andrea; Sazykina, Marina; Burilov, Alexander; Khmelevtsova, Ludmila; Kostina, Natalia

    2015-03-26

    New compounds containing both benzofuroxan and benzothiazole scaffolds were synthesized through electrophile/nucleophile combination of nitrobenzofuroxan derivatives and 2-mercapto- or 2-aminobenzothiazole derivatives and their biological effect on the natural strain Vibrio genus and different bacterial lux-biosensors was studied. Among all the compounds synthesized, that obtained from 2-mercaptobenzothiazole and 7-chloro-4,6-dinitrobenzofuroxan was toxic for bacterial cells, and also able to activated the 1st type Quorum Sensing system. The reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminobenzothiazole derivatives gave two products, one bearing the benzofuroxan moiety linked to the exocyclic amino nitrogen, and the second derived from the attack of two molecules of electrophile to both the nitrogen atoms of the benzothiazole reagent. Their relative ratio is modifiable by tuning the reagents ratio and the reaction time.

  13. Theoretical studies of molecular structure, electronic structure, spectroscopic properties and the ancillary ligand effect: A comparison of tris-chelate ML 3-type and ML 2X-type species for gallium(III) complexes with N, O-donor phenolic ligand, 2-(2-hydroxyphenyl)benzothiazole

    NASA Astrophysics Data System (ADS)

    Tong, Yi-Ping; Lin, Yan-Wen

    2011-02-01

    Two Ga(III) complexes with main ligand, 2-(2-hydroxyphenyl)benzothiazole (HL'), namely mixed-ligand ML 2X-type [GaL' 2X'] ( 1) (HX' = acetic acid, as ancillary ligand) and the meridianal tris-chelate [GaL' 3] ( 2) have been investigated by the density functional theory (DFT/TDDFT) level calculations. Both 1 and 2 can be presented as a similar "mixed-ligand ML 2X-type" species. The molecular geometries, electronic structures, metal-ligand bonding property of Ga-O (N) (main ligand), Ga-O (N) (ancillary ligand) interactions, and the ancillary ligand effect on their HOMO-LUMO gap, their absorption/emission property, and their absorption/emission wavelengths/colors for them have been discussed in detail based on the orbital interactions, the partial density of states (PDOS), and so on. The current investigation also indicates that it is quite probable that by introduction of different ancillary ligands, a series of new mixed-ligand ML 2X-type complexes for group 13 metals can be designed with their absorption/emission property and the absorption/emission wavelengths and colors being tuned.

  14. Theoretical studies of molecular structure, electronic structure, spectroscopic properties and the ancillary ligand effect: a comparison of tris-chelate ML3-type and ML2X-type species for gallium(III) complexes with N,O-donor phenolic ligand, 2-(2-hydroxyphenyl)benzothiazole.

    PubMed

    Tong, Yi-Ping; Lin, Yan-Wen

    2011-02-01

    Two Ga(III) complexes with main ligand, 2-(2-hydroxyphenyl)benzothiazole (HL'), namely mixed-ligand ML2X-type [GaL'2X'] (1) (HX'=acetic acid, as ancillary ligand) and the meridianal tris-chelate [GaL'3] (2) have been investigated by the density functional theory (DFT/TDDFT) level calculations. Both 1 and 2 can be presented as a similar "mixed-ligand ML2X-type" species. The molecular geometries, electronic structures, metal-ligand bonding property of Ga-O (N) (main ligand), Ga-O (N) (ancillary ligand) interactions, and the ancillary ligand effect on their HOMO-LUMO gap, their absorption/emission property, and their absorption/emission wavelengths/colors for them have been discussed in detail based on the orbital interactions, the partial density of states (PDOS), and so on. The current investigation also indicates that it is quite probable that by introduction of different ancillary ligands, a series of new mixed-ligand ML2X-type complexes for group 13 metals can be designed with their absorption/emission property and the absorption/emission wavelengths and colors being tuned.

  15. Efficient purification of lysozyme from egg white by 2-mercapto-5-benzimidazolesulfonic acid modified Fe3O4/Au nanoparticles.

    PubMed

    Zhu, Xinjun; Zhang, Lianying; Fu, Aiyun; Yuan, Hao

    2016-02-01

    2-Mercapto-5-benzimidazolesulfonic acid (MBISA) modified Fe3O4/Au nanoparticles were synthesized in aqueous solution and characterized by photo correlation spectroscopy (PCS) and vibrating sample magnetometer (VSM). The so-obtained Fe3O4/Au-MBISA nanoparticles were capable of specific adsorbing lysozyme. The maximum amount of lysozyme adsorbed on 1.0mg Fe3O4/Au-MBISA nanoparticles was 346μg. The lysozyme desorption behavior was studied and the lysozyme recovery from Fe3O4/Au-MBISA nanoparticles approached 100% under optimal conditions, and the reusability studies showed that the nanoparticles could maintain about 91% of the initial lysozyme adsorption capacity after 7 repeated adsorption-elution cycles. The Fe3O4/Au-MBISA nanoparticles were used in the purification of lysozyme from chicken egg white, which was verified by a single SDS-PAGE band. Therefore, the obtained Fe3O4/Au-MBISA nanoparticles exhibited excellent performance in the direct purification of lysozyme from egg white.

  16. Bioactive thiazole and benzothiazole derivatives.

    PubMed

    Rouf, Abdul; Tanyeli, Cihangir

    2015-06-05

    The heterocycles are the versatile compounds existing in almost all natural products and synthetic organic compounds, usually associated with one or the other biological activity. Among the heterocycles the thiazoles and benzothiazoles occupy a prominent position. They possess a broad range of biological activities and are found in many potent biologically active molecules and drugs such as vitamin thiamine, sulfathiazol (antimicrobial drug), ritonavir (antiretroviral drug), abafungin (antifungal drug) and tiazofurin (antineoplastic drug). The thiazole moiety is abundantly found in natural products while benzothiazole moiety is rare. In this review we disclose the literature reports of thiazoles and benzothiazoles possessing different biological activities.

  17. Electroanalytical studies on Cu (II) ion-selective sensor of coated pyrolytic graphite electrodes based on N2S2O2 and N2S2O3 heterocyclic benzothiazol ligands.

    PubMed

    Singh, A K; Sahani, Manoj Kumar; Bandi, Koteswara Rao; Jain, A K

    2014-08-01

    Benzothiazol based chelating ionophores such as 1,3-bis[2-(1,3-benzothiazol-2-yl)-phenoxy]propane (L1) and 1,2'-bis[2-(1,3-benzothiazol-2-yl)-phenoxy]2-ethoxyethane(L2) were synthesized and explored as neutral ionophores in the fabrication of Cu(2+) ion-selective electrodes. Variety of PVC-based electrodes i.e., polymeric membrane electrodes (PME), coated graphite electrodes (CGE) and coated pyrolytic graphite electrodes (CPGE) were prepared. The membranes having composition L1:PVC:1-CN:NaTPB≡5:38:55:2 (w/w; mg) and L2:PVC:1-CN:NaTPB in the ratio of 6:39:53:2 are found to be exhibit the best potentiometric characteristics. The comparative studies of PME, CGE and CPGE based on L2 reveals that the CPGE is superior in terms of low detection limit of 6.30×10(-9) mol L(-1) with a Nernstian slope of 29.5 mV decade(-1) of activity between pH2.0 to 8.5 with a fast response time of 9s and could be used over a period of 5 months without any significant divergence in its potentiometric characteristics. The sensor has been employed for the estimation of Cu(2+) ion in real samples viz., water, soil and herbal medicinal plants and besides this, the sensor was also used as an indicator electrode in the potentiometric determination of Cu(2+) with EDTA.

  18. Synthesis and evaluation of 18F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease.

    PubMed

    Neumaier, B; Deisenhofer, S; Sommer, C; Solbach, C; Reske, S N; Mottaghy, F

    2010-06-01

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [(11)C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of (11)C, longer lived (18)F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [(18)F]fluoroethoxy-substituted benzothiazole derivatives ([(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [(18)F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [(18)F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [(18)F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [(18)F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  19. Synthesis and structures of photoactive manganese-carbonyl complexes derived from 2-(pyridin-2-yl)-1,3-benzothiazole and 2-(quinolin-2-yl)-1,3-benzothiazole.

    PubMed

    Stenger-Smith, Jenny; Chakraborty, Indranil; Carrington, Samantha; Mascharak, Pradip

    2017-04-01

    PhotoCORMs (photo-active CO-releasing molecules) have emerged as a class of CO donors where the CO release process can be triggered upon illumination with light of appropriate wavelength. We have recently reported an Mn-based photoCORM, namely [MnBr(pbt)(CO)3] [pbt is 2-(pyridin-2-yl)-1,3-benzothiazole], where the CO release event can be tracked within cellular milieu by virtue of the emergence of strong blue fluorescence. In pursuit of developing more such trackable photoCORMs, we report herein the syntheses and structural characterization of two Mn(I)-carbonyl complexes, namely fac-tricarbonylchlorido[2-(pyridin-2-yl)-1,3-benzothiazole-κ(2)N,N']manganese(I), [MnCl(C12H8N2S)(CO)3], (1), and fac-tricarbonylchlorido[2-(quinolin-2-yl)-1,3-benzothiazole-κ(2)N,N']manganese(I), [MnCl(C16H10N2S)(CO)3], (2). In both complexes, the Mn(I) center resides in a distorted octahedral coordination environment. Weak intermolecular C-H...Cl contacts in complex (1) and Cl...S contacts in complex (2) consolidate their extended structures. These complexes also exhibit CO release upon exposure to low-power broadband visible light. The apparent CO release rates for the two complexes have been measured to compare their CO donating capacity. The fluorogenic 2-(pyridin-2-yl)-1,3-benzothiazole and 2-(quinolin-2-yl)-1,3-benzothiazole ligands provide a convenient way to track the CO release event through the `turn-ON' fluorescence which results upon de-ligation of the ligands from their respective metal centers following CO photorelease.

  20. Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif.

    PubMed

    Buchholz, Ina; Karg, Beatrice; Dickerhoff, Jonathan; Sievers-Engler, Adrian; Lämmerhofer, Michael; Weisz, Klaus

    2017-03-09

    A benzothiazole derivative was identified as potent ligand for DNA G-quadruplex structures. Fluorescence titrations revealed selective binding to quadruplexes of different topologies including parallel, antiparallel and (3+1) hybrid structures. The parallel c-MYC sequence was found to constitute the preferred target with dissociation constants in the micromolar range. Binding of the benzothiazole-based ligand to c-MYC was structurally and thermodynamically characterized in detail by employing a comprehensive set of spectroscopic and calorimetric techniques. Job plot analyses and mass spectral data indicate non-cooperative ligand binding to form 1:1 and 2:1 complex stoichiometries. Whereas stacking interactions are suggested by optical methods, NMR chemical shift perturbations also indicate significant rearrangements of both 5'- and 3'-flanking sequences upon ligand binding. Additional isothermal calorimetry studies yield a thermodynamic profile of the ligand-quadruplex association and reveal enthalpic contributions to be the major driving force for binding. The structural and thermodynamic information obtained in the present work provides the basis for the rational development of benzothiazole derivatives as promising quadruplex binding agents.

  1. Au-Ag-Au double shell nanoparticles-based localized surface plasmon resonance and surface-enhanced Raman scattering biosensor for sensitive detection of 2-mercapto-1-methylimidazole.

    PubMed

    Liao, Xue; Chen, Yanhua; Qin, Meihong; Chen, Yang; Yang, Lei; Zhang, Hanqi; Tian, Yuan

    2013-12-15

    In this paper, Au-Ag-Au double shell nanoparticles were prepared based on the reduction of the metal salts HAuCl4 and AgNO3 at the surface of seed particles. Due to the synergistic effect between Au and Ag, the hybrid nanoparticles are particularly stable and show excellent performances on the detection of 2-mercapto-1-methylimidazole (methimazole). The binding of target molecule at the surface of Au-Ag-Au double shell nanoparticles was demonstrated based on both localized surface plasmon resonance (LSPR) and surface-enhanced Raman scattering (SERS) spectra. The LSPR intensity is directly proportional to the methimazole concentration in the range of 0.10-3.00×10(-7) mol L(-1). The SERS spectrum can be applied in identification of methimazole molecule. The LSPR coupled with SERS based on the Au-Ag-Au double shell nanoparticles would be very attractive for the quantitative determination and qualitative analysis of the analytes in medicines.

  2. Antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives.

    PubMed

    Li, Pei; Shi, Li; Gao, Man-Ni; Yang, Xia; Xue, Wei; Jin, Lin-Hong; Hu, De-Yu; Song, Bao-An

    2015-02-01

    In this study, a series of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives were synthesized and evaluated for their antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt caused by Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the turbidimeter test in vitro. Antibacterial bioassays indicated that most compounds demonstrated appreciable antibacterial bioactivities against Xoo and R. solanacearum. Among the title compounds, compound 4i demonstrated the best inhibitory effect against Xoo and R. solanacearum with half-maximal effective concentration (EC50) values of 14.69 and 15.14μg/mL, respectively, which were even better than those of commercial agents Bismerthiazol and Thiodiazole Copper. In vivo antibacterial activities tests under greenhouse conditions revealed that the control efficiency of compound 4i against rice bacterial leaf blight and tobacco bacterial wilt were better than those of Bismerthiazol and Thiodiazole Copper. Meanwhile, field trials also indicated that compound 4i demonstrated appreciable control efficiency against rice bacterial leaf blight and tomato bacterial wilt.

  3. Synthesis, structural characterization, thermal and electrochemical studies of Mn(II), Co(II), Ni(II) and Cu(II) complexes containing thiazolylazo ligands

    NASA Astrophysics Data System (ADS)

    Chavan, S. S.; Sawant, V. A.

    2010-02-01

    Some thiazolylazo derivatives and their metal complexes of the type [M(L)(H 2O)Cl]; M = Mn(II), Co(II), Ni(II), Cu(II) and L = 6-(2'-thiazolylazo)-2-mercapto-quinazolin-4-one (HL 1), 6-(4'-phenyl-2'-thiazolylazo)-2-mercapto-quinazolin-4-one (HL 2), 6-(2'-thiazolylazo)-2-mercapto-3-( m-tolyl)-quinazolin-4-one (HL 3) and 6-(4'-phenyl-2'-thiazolylazo)-2-mercapto-3-( m-tolyl)-quinazolin-4-one (HL 4) have been prepared. All the complexes were characterized on the basis of elemental analysis, molar conductance, magnetic moment, IR, UV-vis, ESR, TG-DTA and powder X-ray diffraction studies. IR spectra of these complexes reveal that the complex formation occurred through thiazole nitrogen, azo nitrogen, imino nitrogen and sulfur atom of the ligands. On the basis of electronic spectral data and magnetic susceptibility measurement octahedral geometry has been proposed for the Mn(II), Co(II) and Ni(II) complexes and distorted octahedral geometry for the Cu(II) complexes. Electrochemical behavior of Ni(II) complexes exhibit quasireversible oxidation corresponding to Ni(III)/Ni(II) couple along with ligand reduction. X-ray diffraction study is used to elucidate the crystal structure of the complexes.

  4. Synthesis, molecular structures and phase transition studies on benzothiazole-cored Schiff bases with their Cu(II) and Pd(II) complexes: Crystal structure of (E)-6-methoxy-2-(4-octyloxy-2-hydroxybenzylideneamino)benzothiazole

    NASA Astrophysics Data System (ADS)

    Yeap, Guan-Yeow; Heng, Boon-Teck; Faradiana, Nur; Zulkifly, Raihana; Ito, Masato M.; Tanabe, Makoto; Takeuchi, Daisuke

    2012-03-01

    Two new homologous series of Cu(II) and Pd(II) complexes with benzothiazole-cored Schiff bases have been synthesised with the aim to study the mesomorphic and thermal properties of ligands upon formation of metal complexes. The molecular structure of title compounds were elucidated with the employment of FT-IR, 1D and 2D FT-NMR spectroscopic techniques. Mesomorphic and thermal behaviour of title compounds have been investigated by differential scanning calorimetry and polarising optical microscope. All the ligands are nematogenic but the corresponding Cu(II) and Pd(II) complexes crystallised in ordinary solid. The conformation of 6-methoxy-2-(4-octyloxy-2-hydroxy-benzylideneamino)benzothiazole was determined by single crystal X-ray diffraction analysis of which the title compound favours more stable (E)-6-methoxy-2-(4-octyloxy-2-hydroxybenzylideneamino)benzothiazole. Crystal structure of the title compound also revealed that the bond length of Cdbnd N (1.303 Å) in the benzothiazole rings very close to that in the exocyclic Cdbnd N linkage (1.298 Å).

  5. Discovery of benzothiazole guanidines as novel inhibitors of thrombin and trypsin IV.

    PubMed

    Karle, Michael; Knecht, Wolfgang; Xue, Yafeng

    2012-07-15

    In a project to find novel neutral P1 fragments for the synthesis of thrombin inhibitors with improved pharmacokinetic properties, fragments containing a benzothiazole guanidine scaffold were identified as weak thrombin inhibitors. WaterLOGSY (Water-Ligand Observed via Gradient SpectroscopY) NMR was used to detect fragments binding to thrombin and these fragments were followed up by Biacore A100 affinity measurements and enzyme assays. A crystal structure of the most potent compound with thrombin was obtained and revealed an unexpected binding mode as well as the key interactions of the fragment with the protein. Based on these results, the structure-based design and synthesis of a small series of optimized novel substituted benzothiazole guanidines with comparatively low pK(a) values was accomplished. Testing of these compounds against human trypsin I and human trypsin IV revealed unexpected inhibitory activity and selectivity of some of the compounds, making them attractive starting points for selective trypsin inhibitors.

  6. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    PubMed

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  7. Synthesis and X-ray diffraction study of palladium(II) 1,3-diphenyl-5-(benzothiazol-2-yl)formazanate

    NASA Astrophysics Data System (ADS)

    Zaĭdman, A. V.; Pervova, I. G.; Rezinskikh, Z. G.; Lipunov, I. N.; Slepukhin, P. A.

    2010-05-01

    The behavior of 1,3-diphenyl-5-(benzothiazol-2-yl)formazan as a bidentate ligand in the synthesis of the mononuclear palladium complex was investigated using slow diffusion. According to the X-ray diffraction study, the PdN4 coordination unit has a distorted square structure. The ligands form two six-membered chelate rings formed through the N1 and N4 atoms of the formazan fragment.

  8. Medicinal significance of benzothiazole scaffold: an insight view.

    PubMed

    Sharma, Prabodh Chander; Sinhmar, Alka; Sharma, Archana; Rajak, Harish; Pathak, Dharam Pal

    2013-04-01

    Heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core structure of a number of biologically interesting compounds. Benzothiazole, a group of xenobiotic compounds containing a benzene ring fused with a thiazole ring, are used worldwide for a variety of therapeutic applications. Benzothiazole and their heterocyclic derivatives represent an important class of compounds possessing a wide spectrum of biological activities. The myriad spectrum of medicinal properties associated with benzothiazole related drugs has encouraged the medicinal chemists to synthesize a large number of novel therapeutic agents. Several analogues containing benzothiazole ring system exhibit significant antitumour, antimicrobial, antidiabetic, anti-inflammatory, anticonvulsant, antiviral, antioxidant, antitubercular, antimalarial, antiasthmatic, anthelmintic, photosensitizing, diuretic, analgesic and other activities. This article is an attempt to present the research work reported in recent scientific literature on different pharmacological activities of benzothiazole compounds.

  9. Functional roles of benzothiazole motif in antiepileptic drug research.

    PubMed

    Amir, Mohammad; Hassan, Mohd Zaheen

    2013-12-01

    Benzothiazoles are promising candidates for the design of novel antiepileptic drugs. The endocyclic sulphur and nitrogen functions present in this heterocyclic nucleus have been shown to be critical for the anticonvulsant activity. The present review outlines the rational design and anticonvulsant potential of promising benzothiazole lead molecules. Particular focus has been placed on the structure activity relationship of different benzothiazole derivatives giving selected examples of molecules with significant activity being that these molecules may serve as prototypes for the development of more active antiepileptic drugs.

  10. Anticonvulsant and neurological profile of benzothiazoles: a mini-review.

    PubMed

    Gagoria, Jagbir; Verma, Prabhakar Kumar; Khatkar, Anurag

    2015-01-01

    From last few years research work on heterocyclic compound and their derivatives has been increasing. Benzothiazole molecule has a heterocyclic structure, basic in nature with wide variety of active sites. As a small molecule, it contains electronegative atoms due to which it is feasible for other moieties to form conjugates. Referring to the bioorganic and medicinal chemistry, the moiety has potential to give active pharmacophores to develop new therapeutically important compounds. Benzothiazole derivatives were found to exhibit efficacy against some very serious diseases like cancer, neurodegeneration, neuropathic pain, infectious diseases, epilepsy etc. In the present review, antiepileptic profile of benzothiazole derivatives is emphasized.

  11. [Degradation of benzothiazole in electro-assisted microbial reactor].

    PubMed

    Liu, Chun-Miao; Ding, Jie; Liu, Xian-Shu; Cheng, Wang-Bin

    2014-11-01

    The oxidative degradation of benzothiazole (BTH) in a single-chamber electro-assisted microbial reactor was investigated. The effects of applied voltage and COD/BTH ratio on the performance of degrading benzothiazole were studied. The research showed that BTH was oxidized to 2-hydroxy-benzothiazole (OHBT), then thiazole ring scission, and BTH translated into 2-methylsulfonylaniline eventually. The degrading of benzothiazole was in conformity with the pseudo first-order kinetic model, and the pseudo first-order kinetic constant can be increased by raising the applied voltage and co-metabolism. When the applied voltage was 0.7 V and COD/BTH ratio was 30, the degradation rate was 96% in 48 h, achieving the detoxification of BTH, and that is advantageous to the biochemical treatment.

  12. Enantioselective Dearomative [3+2] Cycloaddition Reactions of Benzothiazoles.

    PubMed

    Wang, Dong-Chao; Xie, Ming-Sheng; Guo, Hai-Ming; Qu, Gui-Rong; Zhang, Meng-Cheng; You, Shu-Li

    2016-11-02

    A highly enantioselective dearomative [3+2] cycloaddition of benzothiazole has been successfully developed. A wide range of benzothiazoles and cyclopropane-1,1-dicarboxylates are suitable substrates for this reaction. The desired hydropyrrolo[2,1-b]thiazole compounds were obtained in excellent enantioselectivity and yields (up to 97 % ee and 97 % yield). With the same catalytic system, a highly efficient kinetic resolution of 2-substituted cyclopropane-1,1-dicarboxylates was also realized.

  13. Benzothiazoles: how relevant in cancer drug design strategy?

    PubMed

    Singh, Meenakshi; Singh, Sushil K

    2014-01-01

    Heterocyclic compounds, analogs and derivatives have attracted attention due to their diverse biological and pharmacological properties. Benzoheterocycles such as benzothiazoles, benzimidazoles and benzoxazoles are constituents of many bioactive heterocyclic compounds, having wider range of applications. They have been extensively studied for their biological activities, and can serve as unique and versatile scaffolds for drug design. The benzothiazole, in the family of heterocyclic compounds has assumed special significance in synthetic chemistry, pharmaceutical chemistry as well as in clinical applications because of its anti-tumor properties. This review is organized in the following ways. It begins with brief introduction on the chemical diversity of synthetic analogs of benzothiazole. After this, drug design strategy and mechanisms of action through its diverse biological targets in which benzothiazole and its derivatives display their anticancer activity are discussed. It ends with the metabolism pattern of benzothiazole and its analogs. Analysis of the structure-activity relationships (SAR), quantitative structure-activity relationships (QSAR) as well as on docking studies of this family of compounds highlights the potential that may lead to the development of novel anticancer agents. Such relationships will definitely create lot of interest among the researchers to synthesize optimized variety of benzothiazole derivatives and to screen them for their anticancer activity.

  14. cis-Bis[2-(1,3-benzothia-zol-2-yl)-1-(4-fluoro-phen-yl)ethen-yl](pentane-2,4-dionato-κO,O')iridium(III).

    PubMed

    Xiao, Guo-Yong; Lei, Peng; Chi, Hai-Jun; Hu, Zhi-Zhi; Li, Xiao

    2009-03-25

    In the title compound, [Ir(C(15)H(9)FNS)(2)(C(5)H(7)O(2))], the Ir atom is hexa-coordinated by three chelating ligands, with two cyclo-metalated 2-(1,3-benzothia-zol-2-yl)-1-(4-fluoro-phen-yl)ethenyl ligands showing N,C-bidentate coordination and an O,O'-bidenate pentane-2,4-dionate anion, thereby forming a distorted octa-hedral enviroment.

  15. Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system.

    PubMed

    Husain, Asif; Madhesia, Diwakar; Rashid, Mohd; Ahmad, Aftab; Khan, Shah Alam

    2016-12-01

    A series of new 6-substituted-N-[3-{2-(substituted phenyl)-ethenyl} quinoxaline-2(1H)-ylidene]-1,3-benzothiazole-2-amine (4a-f) were designed and synthesized by condensing 2-amino-benzothiazole-6-sulfonic acid amide (1) with chalcones of quinoxaline-2-one (3a-f) in a hope to obtain promising and a new class of diuretic agents. Structures of all the newly synthesized compounds were characterized by spectral data and elemental analysis. The pharmacological studies in experimental rats indicates that compound 4c possesses excellent in vivo diuretic activity of 1.13 and appears to be a better diuretic agent than the reference drugs, acetazolamide (1.0) and urea (0.88). Insight of the binding mode of the synthesized compounds (ligand) into the binding sites of carbonic anhydrase enzyme (PDF code: 4KUV) was provided by docking studies, performed with the help of Maestro 9.0 docking software. Further pharmacokinetic and toxicological studies are needed to confirm the safety of compound 4c which emerged as a lead diuretic compound.

  16. Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules.

    PubMed

    Rothweiler, Ulli; Stensen, Wenche; Brandsdal, Bjørn Olav; Isaksson, Johan; Leeson, Frederick Alan; Engh, Richard Alan; Svendsen, John S Mjøen

    2016-11-10

    DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.

  17. The thermodynamic properties of benzothiazole and benzoxazole

    NASA Astrophysics Data System (ADS)

    Steele, W. V.; Chirico, R. D.; Knipmeyer, S. E.; Nguyen, A.

    1991-08-01

    This research program, funded by the Department of Energy, Office of Fossil Energy, Advanced Extraction and Process Technology, provides accurate experimental thermochemical and thermophysical properties for key organic diheteroatom-containing compounds present in heavy petroleum feedstocks, and applies the experimental information to thermodynamic analyses of key hydrodesulfurization, hydrodenitrogenation, and hydrodeoxygenation reaction networks. Thermodynamic analyses, based on accurate information, provide insights for the design of cost-effective methods of heteroatom removal. The results reported here, and in a companion report to be completed, will point the way to the development of new methods of heteroatom removal from heavy petroleum. Measurements leading to the calculation of the ideal-gas thermodynamic properties are reported for benzothiazole and benzoxazole. Experimental methods included combustion calorimetry, adiabatic heat-capacity calorimetry, comparative ebulliometry, inclinded-piston gauge manometry, and differential-scanning calorimetry (d.s.c). Critical property estimates are made for both compounds. Entropies, enthalpies, and Gibbs energies of formation were derived for the ideal gas for both compounds for selected temperatures between 280 K and near 650 K. The Gibbs energies of formation will be used in a subsequent report in thermodynamic calculations to study the reaction pathways for the removal of the heteratoms by hydrogenolysis. The results obtained in this research are compared with values present in the literature. The failure of a previous adiabatic heat capacity study to see the phase transition in benzothiazole is noted. Literature vibrational frequency assignments were used to calculate ideal gas entropies in the temperature range reported here for both compounds. Resulting large deviations show the need for a revision of those assignments.

  18. The thermodynamic properties of benzothiazole and benzoxazole

    SciTech Connect

    Steele, W.V.; Chirico, R.D.; Knipmeyer, S.E.; Nguyen, A.

    1991-08-01

    This research program, funded by the Department of Energy, Office of Fossil Energy, Advanced Extraction and Process Technology, provides accurate experimental thermochemical and thermophysical properties for key'' organic diheteroatom-containing compounds present in heavy petroleum feedstocks, and applies the experimental information to thermodynamic analyses of key hydrodesulfurization, hydrodenitrogenation, and hydrodeoxygenation reaction networks. Thermodynamic analyses, based on accurate information, provide insights for the design of cost-effective methods of heteroatom removal. The results reported here, and in a companion report to be completed, will point the way to the development of new methods of heteroatom removal from heavy petroleum. Measurements leading to the calculation of the ideal-gas thermodynamic properties are reported for benzothiazole and benzoxazole. Experimental methods included combustion calorimetry, adiabatic heat-capacity calorimetry, comparative ebulliometry, inclinded-piston gauge manometry, and differential-scanning calorimetry (d.s.c). Critical property estimates are made for both compounds. Entropies, enthalpies, and Gibbs energies of formation were derived for the ideal gas for both compounds for selected temperatures between 280 K and near 650 K. The Gibbs energies of formation will be used in a subsequent report in thermodynamic calculations to study the reaction pathways for the removal of the heteratoms by hydrogenolysis. The results obtained in this research are compared with values present in the literature. The failure of a previous adiabatic heat capacity study to see the phase transition in benzothiazole is noted. Literature vibrational frequency assignments were used to calculate ideal gas entropies in the temperature range reported here for both compounds. Resulting large deviations show the need for a revision of those assignments. 68 refs., 6 figs., 15 tabs.

  19. Ferroelectric nanofibers with an embedded optically nonlinear benzothiazole derivative

    NASA Astrophysics Data System (ADS)

    Baptista, Rosa M. F.; Isakov, Dmitry; Raposo, M. Manuela M.; Belsley, Michael; Bdikin, Igor; Kholkin, Andrei L.; Costa, Susana P. G.; de Matos Gomes, Etelvina

    2014-07-01

    We report measurements of the molecular first hyperpolarizability, thermal stability, photophysical, piezoelectric, and ferroelectric properties of a benzothiazole derivative bearing an arylthiophene π-conjugated bridge both in solution and when embedded into a poly ( l-lactic acid) matrix in the form of electrospun fibers with an average diameter of roughly 500 nm. The embedded nanocrystalline phenylthienyl-benzothiazole with crystal sizes of about 1.4 nm resulted in a good piezoelectric response from these functionalized electrospun fibers, indicative of a polar crystalline structure.

  20. Cytotoxic activities of some benzothiazole-piperazine derivatives.

    PubMed

    Gurdal, Enise Ece; Durmaz, Irem; Cetin-Atalay, Rengul; Yarim, Mine

    2015-01-01

    Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Compound 1d is highly cytotoxic against all tested cancer cell lines. Further investigation of compound 1d by Hoechst Staining and Fluorescence-Activated Cell Sorting Analysis (FACS) revealed that this compound causes apoptosis by cell cycle arrest at subG1 phase.

  1. New potent calcimimetics: II. Discovery of benzothiazole trisubstituted ureas.

    PubMed

    Deprez, Pierre; Temal, Taoues; Jary, Hélène; Auberval, Marielle; Lively, Sarah; Guédin, Denis; Vevert, Jean-Paul

    2013-04-15

    Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50=20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.

  2. Synthesis and anticancer activity of (E)-2-benzothiazole hydrazones.

    PubMed

    Lindgren, Eric B; de Brito, Monique A; Vasconcelos, Thatyana R A; de Moraes, Manuel O; Montenegro, Raquel C; Yoneda, Julliane D; Leal, Kátia Z

    2014-10-30

    Benzothiazole hydrazones have been synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). The good cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3o and 3p pointed them as promising lead molecules for anticancer drug design.

  3. Synthesis, Characterization and Antibacterial Studies of N-(Benzothiazol-2-yl)-4-chlorobenzenesulphonamide and Its Neodymium(III) and Thallium(III) Complexes.

    PubMed

    Obasi, Lawrence Nnamdi; Oruma, Uchechukwu Susan; Al-Swaidan, Ibrahim Abdulrazak; Ramasami, Ponnadurai; Ezeorah, Chigozie Julius; Ochonogor, Alfred Ezinna

    2017-02-22

    N-(Benzothiazol-2-yl)-4-chlorobenzenesulphonamide (NBTCS) was synthesized by condensation reaction of 4-chlorobenzenesulphonyl chloride and 2-aminobenzothiazole in acetone under reflux. Neodymium(III) and thallium(III) complexes of the ligand were also synthesized. Both ligand and metal complexes were characterized using UV-Vis, IR, ¹H- and (13)C-NMR spectroscopies, elemental analysis and molar conductance measurement. IR studies revealed that the ligand is tridentate and coordinates to the metal ions through nitrogen and oxygen atoms of the sulphonamide group and nitrogen atom attached to benzothiazole ring. The neodymium(III) complex displays a coordination number of eight while thallium(III) complex displays a coordination number of six. The ligand and its complexes were screened in vitro for their antibacterial activities against Escherichia coli strains (E. coli 6 and E. coli 13), Proteus species, Staphylococcus aureus and Pseudomonas aeruginosa using the agar well diffusion technique. The synthesized compounds were found to be more active against the microorganisms screened relative to ciprofloxacin, gentamicin and co-trimoxazole.

  4. Synthesis, structure and photophysical properties of a 2-(1'-hydroxypyrenyl)benzothiazole.

    PubMed

    Wang, Kangnan; Lv, Qiang; Chen, Ying; Chen, Hongyu; Liu, Zhiqiang; Cao, Duxia; Fang, Qi

    2016-01-15

    A pyrene-based 2-aryl-benzothiazole derivative, 2-(1'-hydroxypyrenyl)benzothiazole (1H2PBT), was synthesized. Its crystal structure and photophysical properties were investigated. In comparison with the generally studied parent compound, 2-(2'-hydroxyphenyl)benzothiazole (HBT), 1H2PBT exhibited red-shifted absorption and emission in solution, as well as impressive solid state emission with high efficiency (0.35).

  5. Synthesis, structure and photophysical properties of a 2-(1‧-hydroxypyrenyl)benzothiazole

    NASA Astrophysics Data System (ADS)

    Wang, Kangnan; Lv, Qiang; Chen, Ying; Chen, Hongyu; Liu, Zhiqiang; Cao, Duxia; Fang, Qi

    2016-01-01

    A pyrene-based 2-aryl-benzothiazole derivative, 2-(1‧-hydroxypyrenyl)benzothiazole (1H2PBT), was synthesized. Its crystal structure and photophysical properties were investigated. In comparison with the generally studied parent compound, 2-(2‧-hydroxyphenyl)benzothiazole (HBT), 1H2PBT exhibited red-shifted absorption and emission in solution, as well as impressive solid state emission with high efficiency (0.35).

  6. Proteomic profile of the Bradysia odoriphaga in response to the microbial secondary metabolite benzothiazole.

    PubMed

    Zhao, Yunhe; Cui, Kaidi; Xu, Chunmei; Wang, Qiuhong; Wang, Yao; Zhang, Zhengqun; Liu, Feng; Mu, Wei

    2016-11-24

    Benzothiazole, a microbial secondary metabolite, has been demonstrated to possess fumigant activity against Sclerotinia sclerotiorum, Ditylenchus destructor and Bradysia odoriphaga. However, to facilitate the development of novel microbial pesticides, the mode of action of benzothiazole needs to be elucidated. Here, we employed iTRAQ-based quantitative proteomics analysis to investigate the effects of benzothiazole on the proteomic expression of B. odoriphaga. In response to benzothiazole, 92 of 863 identified proteins in B. odoriphaga exhibited altered levels of expression, among which 14 proteins were related to the action mechanism of benzothiazole, 11 proteins were involved in stress responses, and 67 proteins were associated with the adaptation of B. odoriphaga to benzothiazole. Further bioinformatics analysis indicated that the reduction in energy metabolism, inhibition of the detoxification process and interference with DNA and RNA synthesis were potentially associated with the mode of action of benzothiazole. The myosin heavy chain, succinyl-CoA synthetase and Ca(+)-transporting ATPase proteins may be related to the stress response. Increased expression of proteins involved in carbohydrate metabolism, energy production and conversion pathways was responsible for the adaptive response of B. odoriphaga. The results of this study provide novel insight into the molecular mechanisms of benzothiazole at a large-scale translation level and will facilitate the elucidation of the mechanism of action of benzothiazole.

  7. Proteomic profile of the Bradysia odoriphaga in response to the microbial secondary metabolite benzothiazole

    PubMed Central

    Zhao, Yunhe; Cui, Kaidi; Xu, Chunmei; Wang, Qiuhong; Wang, Yao; Zhang, Zhengqun; Liu, Feng; Mu, Wei

    2016-01-01

    Benzothiazole, a microbial secondary metabolite, has been demonstrated to possess fumigant activity against Sclerotinia sclerotiorum, Ditylenchus destructor and Bradysia odoriphaga. However, to facilitate the development of novel microbial pesticides, the mode of action of benzothiazole needs to be elucidated. Here, we employed iTRAQ-based quantitative proteomics analysis to investigate the effects of benzothiazole on the proteomic expression of B. odoriphaga. In response to benzothiazole, 92 of 863 identified proteins in B. odoriphaga exhibited altered levels of expression, among which 14 proteins were related to the action mechanism of benzothiazole, 11 proteins were involved in stress responses, and 67 proteins were associated with the adaptation of B. odoriphaga to benzothiazole. Further bioinformatics analysis indicated that the reduction in energy metabolism, inhibition of the detoxification process and interference with DNA and RNA synthesis were potentially associated with the mode of action of benzothiazole. The myosin heavy chain, succinyl-CoA synthetase and Ca+-transporting ATPase proteins may be related to the stress response. Increased expression of proteins involved in carbohydrate metabolism, energy production and conversion pathways was responsible for the adaptive response of B. odoriphaga. The results of this study provide novel insight into the molecular mechanisms of benzothiazole at a large-scale translation level and will facilitate the elucidation of the mechanism of action of benzothiazole. PMID:27883048

  8. Antimicrobial Applications of Transition Metal Complexes of Benzothiazole Based Terpolymer: Synthesis, Characterization, and Effect on Bacterial and Fungal Strains

    PubMed Central

    Riswan Ahamed, Mohamed A.; Azarudeen, Raja S.; Kani, N. Mujafar

    2014-01-01

    Terpolymer of 2-amino-6-nitro-benzothiazole-ethylenediamine-formaldehyde (BEF) has been synthesized and characterized by elemental analysis and various spectral techniques like FTIR, UV-Visible, and 1H and 13C-NMR. The terpolymer metal complexes were prepared with Cu2+, Ni2+, and Zn2+ metal ions using BEF terpolymer as a ligand. The complexes have been characterized by elemental analysis and IR, UV-Visible, ESR, 1H-NMR, and 13C-NMR spectral studies. Gel permeation chromatography was used to determine the molecular weight of the ligand. The surface features and crystalline behavior of the ligand and its complexes were analyzed by scanning electron microscope and X-ray diffraction methods. Thermogravimetric analysis was used to analyze the thermal stability of the ligand and its metal complexes. Kinetic parameters such as activation energy (Ea) and order of reaction (n) and thermodynamic parameters, namely, ΔS, ΔF, S*, and Z, were calculated using Freeman-Carroll (FC), Sharp-Wentworth (SW), and Phadnis-Deshpande (PD) methods. Thermal degradation model of the terpolymer and its metal complexes was also proposed using PD method. Biological activities of the ligand and its complexes were tested against Shigella sonnei, Escherichia coli, Klebsiella species, Staphylococcus aureus, Bacillus subtilis, and Salmonella typhimurium bacteria and Aspergillus flavus, Aspergillus niger, Penicillium species, Candida albicans, Cryptococcus neoformans, Mucor species fungi. PMID:25298760

  9. Novel Ru(III) Complexes with Some Benzothiazole Derivatives: Synthesis, Physicochemical and Pharmacological Investigations.

    PubMed

    Nikolova, A; Momekov, G; Bakalova, A; Nikolova, K; Ivanov, D

    2015-06-01

    In this work we present 3 new complexes of Ruthenium (III) with a general formula HL[Ru(L)2Cl4], where L=benzothiazole, 2-methylbenzothiazole and 2-mercaptobenzothiazole. The syntheses were carried out in polar medium under argon. The compounds obtained were characterised by IR-, (1)H-NMR- (13)C-NMR-, UV-VIS-spectroscopy and conductivity measurements. The ligands behaved as monodentate, bounding Ru(III) through the nitrogen atoms from the heterocycle. The cytotoxicity of the new complexes was tested against 2 human leukemic cell lines (K-562 and KE-37), using the MTT-dye reduction assay. The Ru(III) coordination compound with 2-methylbenzothiazole displayed superior activity compared to the other novel complexes. Its IC50 values were comparable to that of the reference cytotoxic drug cisplatin. In general, the ligands displayed only marginal inhibitory effects on the human leukemic cell lines. Moreover, the ability of the complexes to trigger apoptosis was evaluated using a commercially available DNA-fragmentation ELISA kit and the obtained data indicated that their proapoptotic effects well correlate to the MTT-bioassay data.

  10. Dermal, Eye and Oral Toxicological Evaluations. Phase II. Acute Oral LD Determinations of Benzothiazole, Dithiane, and Oxathiane.

    DTIC Science & Technology

    1986-09-03

    Dose - Response Curve for Males-Benzothiazole .............. 14 2. Dose - Response Curve for...Females-Benzothiazole .......... 15 3. Dose - Response Curve for Combined Sexes-Benzothiazole... 16 4. Dose - Response Curve for Males-Dithiane...29 5. Dose - Response Curve for Females-Dithiane ................. 30 6. Dose - Response Curve for Combined Sexes-Dithiane ........ 31 7. Dose

  11. 5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

    PubMed

    Arasappan, Ashok; Bennett, Frank; Girijavallabhan, Vinay; Huang, Yuhua; Huelgas, Regina; Alvarez, Carmen; Chen, Lei; Gavalas, Stephen; Kim, Seong-Heon; Kosinski, Aneta; Pinto, Patrick; Rizvi, Razia; Rossman, Randall; Shankar, Bandarpalle; Tong, Ling; Velazquez, Francisco; Venkatraman, Srikanth; Verma, Vishal A; Kozlowski, Joseph; Shih, Neng-Yang; Piwinski, John J; MacCoss, Malcolm; Kwong, Cecil D; Clark, Jeremy L; Fowler, Anita T; Geng, Feng; Kezar, Hollis S; Roychowdhury, Abhijit; Reynolds, Robert C; Maddry, Joseph A; Ananthan, Subramaniam; Secrist, John A; Li, Cheng; Chase, Robert; Curry, Stephanie; Huang, Hsueh-Cheng; Tong, Xiao; Njoroge, F George

    2012-05-01

    Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.

  12. Structure-activity relationships of benzothiazole GPR35 antagonists.

    PubMed

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  13. Structure-activity relationships of benzothiazole GPR35 antagonists

    PubMed Central

    Abdalhameed, Manahil M.; Zhao, Pingwei; Hurst, Dow P.; Reggio, Patricia H.; Abood, Mary E.; Croatt, Mitchell P.

    2017-01-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound. PMID:27989666

  14. Fluorescent Properties of Manganese Halide Benzothiazole Inorganic-Organic Hybrids.

    PubMed

    Yu, Hui; Mei, YingXuan; Wei, ZhenHong; Mei, GuangQuan; Cai, Hu

    2016-11-01

    The reaction of manganese (II) halides MnX2 and benzothiazole (btz) in the concentrated acids HX (X = Cl, Br) at 80 °C resulted in the formation of two inorganic-organic hybrid complexes: [(btz)2(MnX4)]·2H2O (X = Cl, 1; X = Br, 2). Both compounds showed green luminescence and exhibited moderate quantum yields of 43.17 % for 1 and 26.18 % for 2, which were directly originated from the tetrahedral coordination of Mn(2+) ion. Two organic - inorganic hybrids [(btz)2(MnX4)]·2H2O based on MnCl2, benzothiazole and halide acids emitted green light with the moderate quantum efficiencies when excited by 365 nm light. Graphical abstract Two organic-inorganic hybrids [(btz)2(MnX4)]·2H2O based on MnCl2, benzothiazole and halide acids emitted green light with the moderate quantum efficiencies when excited by 365 nm light.

  15. A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles.

    PubMed

    Seth, Sonakshi

    2015-01-01

    Heterocyclic analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. Benzothiazole is a class of heterocyclic compounds having 2 hetero atoms namely, sulphur and nitrogen. The analogues of benzothiazoles and its derivatives have a significant role in research area especially in synthetic, medicinal and pharmaceutical chemistry because of their biological and pharmacological activity. These compounds have special significance in the field of Medicinal chemistry due to their remarkable pharmacological potentialities. Benzothiazole is an organosulfur heterocyclic compound, weakly basic in nature. They are widely found in bioorganic and medicinal chemistry with wide application in drug discovery. Benzothiazoles are fused membered rings, which contain the heterocycles bearing thiazole as central moiety. A large number of therapeutic agents are synthesized with the help of benzothiazoles nucleus. In addition, benzothiazoles act as core nucleus in various drugs due to their various activities e.g. pramipexole, probenazole, lubeluzole, zopolrestat, ethoxazolamide and bentaluron etc. and their derivatives have attracted a great deal of interest due to their wide range of biological activities such as anticancer, antimicrobial, antitubercular, anti-HIV, cardiovascular, local anaesthetic, anti-inflammatory, anticonvulsant and anti-diabetic. The therapeutic properties of the heterocycles have encouraged the medicinal chemist to synthesize a large number of novel chemotherapeutic agents. This review is mainly an attempt to present the research work reported in the recent scientific literature focusing on different biological activities of benzothiazoles compounds.

  16. A fluorescent benzothiazole probe with efficient two-photon absorption

    NASA Astrophysics Data System (ADS)

    Echevarria, Lorenzo; Moreno, Iván; Camacho, José; Salazar, Mary Carmen; Hernández, Antonio

    2012-11-01

    In this work, we report the two-photon absorption of 2-[4-(dimethylamino)phenyl]-1,3-benzothiazole-6-carbonitrile (DBC) in DMSO solution pumping at 779 nm with a 10 ns pulse laser-Nd:YAG system. The obtained two-photon absorption cross-section in DBC (407 ± 18 GM) is considerably high. Because DBC is a novel compound and have high values of fluorescence quantum yield, this result is expected to have an impact in biomolecules detection, diagnosis and treatment of cancer. Similar structures have previously been reported to show remarkable antitumour effects.

  17. Synthesis and Properties of Rigid-Rod Benzobisazole Polymers Containing Benzothiazole Pendent Groups

    DTIC Science & Technology

    1990-11-16

    WRDC-TR-90-4092 SYNTHESIS AND PROPERTIES OF RIGID-ROD BENZOBISAZOLE POLYMERS CONTAINING BENZOTHIAZOLE PENDENT GROUPS Tsu-Tzu Tsai and Fred E. Arnold...Polymers Containing Benzothiazole Pendent Groups 12. PERSONAL AUTHOR(S) T. T. Tsai and F. E. Arnold 13a. TYPE OF REPORT 113b. TIME COVERED 14. DATE OF REPORT...on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP Rigid-Rod Polymers, Benzothiazole Pendent Groups 19. ABSTRACT (Continue on

  18. Synthesis and Structures of Cadmium Carboxylate and Thiocarboxylate Compounds with a Sulfur-Rich Coordination Environment: Carboxylate Exchange Kinetics Involving Tris(2-mercapto-1-t-butylimidazolyl)hydroborato Cadmium Complexes, [TmBut]Cd(O2CR)

    PubMed Central

    2016-01-01

    A series of cadmium carboxylate compounds in a sulfur-rich environment provided by the tris(2-tert-butylmercaptoimidazolyl)hydroborato ligand, namely, [TmBut]CdO2CR, has been synthesized via the reactions of the cadmium methyl derivative [TmBut]CdMe with RCO2H. Such compounds mimic aspects of cadmium-substituted zinc enzymes and also the surface atoms of cadmium chalcogenide crystals, and have therefore been employed to model relevant ligand exchange processes. Significantly, both 1H and 19F NMR spectroscopy demonstrate that the exchange of carboxylate groups between [TmBut]Cd(κ2-O2CR) and the carboxylic acid RCO2H is facile on the NMR time scale, even at low temperature. Analysis of the rate of exchange as a function of concentration of RCO2H indicates that reaction occurs via an associative rather than dissociative pathway. In addition to carboxylate compounds, the thiocarboxylate derivative [TmBut]Cd[κ1-SC(O)Ph] has also been synthesized via the reaction of [TmBut]CdMe with thiobenzoic acid. The molecular structure of [TmBut]Cd[κ1-SC(O)Ph] has been determined by X-ray diffraction, and an interesting feature is that, in contrast to the carboxylate derivatives [TmBut]Cd(κ2-O2CR), the thiocarboxylate ligand binds in a κ1 manner via only the sulfur atom. PMID:25826184

  19. [Design, synthesis and activities of novel benzothiazole derivatives containing arylpiperazine].

    PubMed

    Liu, Wen-Hu; Chang, Jin-Xia; Liu, Yi; Luo, Jie-Wei; Zhang, Jian-Wu

    2013-08-01

    Twenty-four novel benzothiazole derivatives containing arylpiperazine were designed and synthesized by bioisosterism principle. Anti-proliferative effect of these synthesized compounds against four cancer cell and two normal cell lines were evaluated in vitro by the standard MTT assay. Pharmacological test showed that most of the compounds exhibited potent antitumor activity. Some of the compounds (II2, II3, II6, II7) showed strong anti-proliferation activities against HepG2 and HeLa229 cell lines with the IC 50 values of 1.6-4.5 micromol x L(-1) and 2.5-5.3 micromol x L(-1), respectively, and compounds having cyan in p-substituted benzene ring (I4, I8, I12, II4, II8 and II12) were found to have better antitumor activities against AsPC-1 cell lines with the IC50 values of 5.2-11.3 micromol x L(-1). The structure-activity relationship of benzothiazole derivatives containing arylpiperazine was also discussed preliminarily.

  20. Coumarin benzothiazole derivatives as chemosensors for cyanide anions.

    PubMed

    Wang, Kangnan; Liu, Zhiqiang; Guan, Ruifang; Cao, Duxia; Chen, Hongyu; Shan, Yanyan; Wu, Qianqian; Xu, Yongxiao

    2015-06-05

    Four coumarin benzothiazole derivatives, N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (1), (Z)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide (2), 7-(diethylamino)-N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (3) and (Z)-7-(diethylamino)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide) (4), have been synthesized. Their crystal structures, photophysical properties in acetonitrile and recognition properties for cyanide anions have been investigated. All the compounds are generally planar, especially compound 1 exhibits perfect planarity with dihedral angle between benzothiazolyl group and coumarin group being only 3.63°. Coumarin benzothiazole compounds 1 and 3 can recognize cyanide anions by Michael addition reaction and compound 3 exhibits color change from yellow to colorless and green fluorescence was quenched completely, which can be observed by naked eye. Coumarin benzothiazolyliden compound 4 can recognize cyanide anions with fluorescence turn-on response based on the copper complex ensemble displacement mechanism.

  1. Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors.

    PubMed

    Gjorgjieva, Marina; Tomašič, Tihomir; Barančokova, Michaela; Katsamakas, Sotirios; Ilaš, Janez; Tammela, Päivi; Peterlin Mašič, Lucija; Kikelj, Danijel

    2016-10-13

    Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization toward dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

  2. Coumarin benzothiazole derivatives as chemosensors for cyanide anions

    NASA Astrophysics Data System (ADS)

    Wang, Kangnan; Liu, Zhiqiang; Guan, Ruifang; Cao, Duxia; Chen, Hongyu; Shan, Yanyan; Wu, Qianqian; Xu, Yongxiao

    2015-06-01

    Four coumarin benzothiazole derivatives, N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (1), (Z)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide (2), 7-(diethylamino)-N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (3) and (Z)-7-(diethylamino)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide) (4), have been synthesized. Their crystal structures, photophysical properties in acetonitrile and recognition properties for cyanide anions have been investigated. All the compounds are generally planar, especially compound 1 exhibits perfect planarity with dihedral angle between benzothiazolyl group and coumarin group being only 3.63°. Coumarin benzothiazole compounds 1 and 3 can recognize cyanide anions by Michael addition reaction and compound 3 exhibits color change from yellow to colorless and green fluorescence was quenched completely, which can be observed by naked eye. Coumarin benzothiazolyliden compound 4 can recognize cyanide anions with fluorescence turn-on response based on the copper complex ensemble displacement mechanism.

  3. Synthesis and antileishmanial activity of (1,3-benzothiazol-2-yl) amino-9-(10H)-acridinone derivatives.

    PubMed

    Delmas, Florence; Avellaneda, Antonio; Di Giorgio, Carole; Robin, Maxime; De Clercq, Erik; Timon-David, Pierre; Galy, Jean-Pierre

    2004-08-01

    (1,3-Benzothiazol-2-yl) amino-9-(10H)-acridinone derivatives were synthesized via a procedure based on the Ullman reaction and were assessed for their in vitro antileishmanial and anti-HIV activities. Two derivatives, 4-(6-nitro-benzothiazol-2-ylamino)-10H-acridin-9-one and 1-(6-amino-benzothiazol-2-ylamino)-10H-acridin-9-one, revealed a selective antileishmanial activity, mainly due to amastigote-specific toxicity. Results suggested that:the addition of a benzothiazole group on a parent amino-9-(10H)-acridinone ring could enhance antileishmanial abilities, the presence of a 6-amino-benzothiazole group on position 2 amino chain or a 6-nitro-benzothiazole group on position 4 amino chain was essential for specific anti-amastigote properties.

  4. Benzothiazole derivatives as novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

    PubMed

    Su, Xiangdong; Vicker, Nigel; Ganeshapillai, Dharshini; Smith, Andrew; Purohit, Atul; Reed, Michael J; Potter, Barry V L

    2006-03-27

    Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here, we report the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11beta-HSD1 from human hepatic microsomes measured using a radioimmunoassay (RIA) method. The benzothiazole derivatives 1 and 2 showed greater than 80% inhibition for 11beta-HSD1 at 10 microM and exhibited IC50 values in the low micromolar range. The preliminary SAR study suggested the introduction of a chlorine substituent at the 4 position of the benzothiazole ring greatly enhanced the inhibitory activities. Docking studies with the benzothiazole derivative 1 into the crystal structure of human 11beta-HSD1 revealed how the molecule may interact with the enzyme and cofactor.

  5. The Synthesis and Evaluation of Third-Order Optical Nonlinearities of Model Compounds Containing Benzothiazole, Benzimidazole and Benzoxazole Moieties.

    DTIC Science & Technology

    1991-02-01

    AD-A235 622 WL-TR-91-4015 THE SYNTHESIS AND EVALUATION OF THIRD-ORDER OPTICAL NONLINEARITIES OF MODEL COMPOUNDS CONTAINING BENZOTHIAZOLE ...Nonlinearities of Model Compounds Containing Benzothiazole , Benzimidazole, and Benzoxazole Moieties 12 PERSONAL AUTHOR(S) Bruce A. Reinhardt, Marilyn R...necessary and identify by block number) FIELD GROUP SUB-GROUP nonlinear optical properties benzothiazole u/ 03 degenerate four-wave mixing benzimidazole 21

  6. Synthesis and in vitro antitumor activity of new series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives.

    PubMed

    Gabr, Moustafa T; El-Gohary, Nadia S; El-Bendary, Eman R; El-Kerdawy, Mohamed M

    2014-10-06

    New series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives were synthesized and characterized by analytical and spectrometrical methods (IR, HRMS, (1)H and (13)C NMR). Nineteen of the synthesized compounds were selected by the National Cancer Institute (NCI), USA, to be screened for their antitumor activity at a single dose (10 μM) against a panel of 60 cancer cell lines. The most active compounds, 4, 6, 10, 14, 17 and 20 were selected for further evaluation at five dose level screening. Compounds 17 (GI50 = 0.44 μM, TGI = 1.2 μM and LC50 MG-MID = 6.6 μM) and 4 (GI50 = 0.77 μM, TGI = 2.08 μM and LC50 MG-MID = 11.74 μM) were proved to be the most active members in this study. 3D and 2D pharmacophoric maps for the structural features of both compounds were studied.

  7. Inhibition of TNF-{alpha}-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes

    SciTech Connect

    Lee, Young-Rae; Jin, Guo Hua; Lee, Sang-Myeong; Park, Jin-Woo; Ryu, Jae-Ha; Jeon, Raok; Park, Byung-Hyun

    2011-05-20

    Highlights: {yields} We synthesized SPA0537, a benzothiazole analog. {yields} SPA0537 is a potent NF-{kappa}B inhibitor. {yields} SPA0537 suppresses the production of proinflammatory mediators in human rheumatoid fibroblast-like synoviocytes. {yields} SPA0537 is effective at suppressing osteoclast differentiation. -- Abstract: The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-{kappa}B. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-{kappa}B activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-{kappa}B subunits, which correlated with the inhibitory effects on IKK phosphorylation and I{kappa}B{alpha} degradation in TNF-{alpha}-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-{alpha}-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-{kappa}B ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-{kappa}B pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis.

  8. Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases

    PubMed Central

    Stokes, Neil R.; Thomaides-Brears, Helena B.; Barker, Stephanie; Bennett, James M.; Berry, Joanne; Collins, Ian; Czaplewski, Lloyd G.; Gamble, Vicki; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J.; Peasley, Hilary; Pommier, Stéphanie; Price, Daniel; Smee, Carol

    2013-01-01

    The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10−10 with compound A and <5.8 × 10−11 with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%. PMID:24041906

  9. Effects of the microbial secondary metabolite benzothiazole on the nutritional physiology and enzyme activities of Bradysia odoriphaga (Diptera: Sciaridae).

    PubMed

    Zhao, Yunhe; Xu, Chunmei; Wang, Qiuhong; Wei, Yan; Liu, Feng; Xu, Shuangyu; Zhang, Zhengqun; Mu, Wei

    2016-05-01

    Bradysia odoriphaga (Diptera: Sciaridae) is the major pest that damages Chinese chive production. As a volatile compound derived from microbial secondary metabolites, benzothiazole has been determined to possess fumigant activity against B. odoriphaga. However, the mechanism of action of benzothiazole is not well understood. In the present study, fourth-instar larvae of B. odoriphaga were exposed to LC10 and LC30 of benzothiazole. Sublethal concentrations (LC10 and LC30) of benzothiazole significantly reduced the food consumption of the larvae on the second day after treatment (2 DAT). However, there were no significant changes in pupal weight among the different treatments. We also measured the protein, lipid, carbohydrate, and trehalose contents and the digestive enzyme activities of the larvae, and the results suggest that benzothiazole reduced the nutrient accumulation and decreased the digestive enzyme activities of B. odoriphaga. In addition, the activity of glutathione S-transferase was significantly decreased at 6h after treatment with benzothiazole, whereas general esterase activities were significantly increased at 6 and 24h after treatment. The results of this study indicate that benzothiazole interferes in the normal food consumption and digestion process by decreasing the activities of digestive enzymes. These results provide valuable information for understanding the toxicity of benzothiazole and for exploring volatile compound for the control of this pest.

  10. Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis-inducing agents against cervical cancer.

    PubMed

    Singh, Meenakshi; Modi, Arusha; Narayan, Gopeshwar; Singh, Sushil K

    2016-07-01

    Cervical cancer is a major cause of morbidity and mortality in women worldwide. In recent years, benzothiazole analogues have attracted considerable attention in anticancer research. Therefore, in this study, the earlier reported amide series of benzothiazole derivatives were investigated for their antiproliferative activity. The activity of amide derivatives was evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometric analysis, apoptosis assay, and DNA fragmentation on two human cervical cancer cell lines: SiHa and C33-A. The data reported from this investigation indicated that benzothiazole derivatives show pronounced cytotoxicity in the HPV16-positive SiHa cells compared with HPV-negative C-33A cells. The in-vitro cytotoxicity of the compounds on the HEK-293 noncancer cell line was evaluated to establish selectivity. Cells treated with benzothiazole derivatives showed prominent morphological features as evidenced by cell shrinkage, membrane blebbing, apoptotic nuclei, and DNA fragmentation. The benzothiazole derivatives show accumulation of cells in the sub-G1 and S-phase of the cell cycle in SiHa and C33-A, respectively. In addition, these derivatives exert their beneficial effect by inducing apoptosis, in the chemoprevention of cervical cancer cells, and were further ascertained using a DNA fragmentation assay. The compounds studied showed potent cytotoxic and apoptotic properties against SiHa and C33-A cancer cell lines and thus represent an excellent starting point for further optimization of therapeutically effective anticancer drugs.

  11. Degradation of benzotriazole and benzothiazole in treatment wetlands and by artificial sunlight.

    PubMed

    Felis, Ewa; Sochacki, Adam; Magiera, Sylwia

    2016-11-01

    Laboratory-scale experiments were performed using unsaturated subsurface-flow treatment wetlands and artificial sunlight (with and without TiO2) to study the efficiency of benzotriazole and benzothiazole removal and possible integration of these treatment methods. Transformation products in the effluent from the treatment wetlands and the artificial sunlight reactor were identified by high performance liquid chromatography coupled with tandem mass spectrometry. The removal of benzothiazole in the vegetated treatment wetlands was 99.7%, whereas the removal of benzotriazole was 82.8%. The vegetation positively affected only the removal of benzothiazole. The major transformation products in the effluents from the treatment wetlands were methylated and hydroxylated derivatives of benzotriazole, and hydroxylated derivatives of benzothiazole. Hydroxylation was found to be the main process governing the transformation pathway for both compounds in the artificial sunlight experiment (with and without TiO2). Benzotriazole was not found to be susceptible to photodegradation in the absence of TiO2. The integration of the sunlight-induced processes (with TiO2) with subsurface-flow treatment wetlands caused further elimination of the compounds (42% for benzotriazole and 58% for benzothiazole). This was especially significant for the elimination of benzotriazole, because the removal of this compound was 96% in the coupled processes.

  12. New synthesis and biological evaluation of benzothiazole derivates as antifungal agents.

    PubMed

    Herrera Cano, Natividad; Ballari, María S; López, Abel G; Santiago, Ana N

    2015-04-15

    In search of new antifungal agrochemicals that could replace commercially available, aryl-2-mercaptobenzothiazoles were synthesized. They were prepared by two methodologies, using both photostimulated reaction and microwave assisted reaction. These reactions took place without the use of metallic catalyst by a one-pot procedure with excellent yields (70-98%). Synthesized compounds were evaluated for fungal growth inhibition against Botrytis cinerea. Most of the compounds have an excellent antifungal activity, and three of these showed a superior inhibitory effect to commercial fungicide Triadimefon. IC50 values observed for 2-(phenylthio)benzothiazole, 2-(2-chlorophenylthio)benzothiazole, and 2-(3-chlorophenyl thio)benzothiazole were 0.75, 0.69, and 0.65 μg mL(-1), respectively.

  13. Hydroxylamine as an oxygen nucleophile: substitution of sulfonamide by a hydroxyl group in benzothiazole-2-sulfonamides.

    PubMed

    Kamps, Jos J A G; Belle, Roman; Mecinović, Jasmin

    2013-02-21

    Benzothiazole-2-sulfonamides react with an excess of hydroxylamine in aqueous solutions to form 2-hydroxybenzothiazole, sulfur dioxide, and the corresponding amine. Mechanistic studies that employ a combination of structure-reactivity relationships, oxygen labeling experiments, and (in)direct detection of intermediates and products reveal that the reaction proceeds via oxygen attack, and that oxygen incorporated in the 2-hydroxybenzothiazole product derives from hydroxylamine. The reaction, which is performed under mild conditions, can be used as a deprotection method for cleavage of benzothiazole-2-sulfonyl-protected amino acids.

  14. Synthesis, antimicrobial and cytotoxic activities of pyrimidinyl benzoxazole, benzothiazole and benzimidazole.

    PubMed

    Seenaiah, D; Reddy, P Ramachandra; Reddy, G Mallikarjuna; Padmaja, A; Padmavathi, V; Krishna, N Siva

    2014-04-22

    A variety of pyrimidinyl benzoxazoles, benzothiazoles and benzimidazoles linked by thio, methylthio and amino moieties were prepared and studied their antimicrobial and cytotoxic activities. The compound pyrimidinyl bis methylthio benzimidazole 22 was a potent antimicrobial agent particularly against Staphylococcus aureus (29 mm, MIC 12.5 μg/mL) and Penicillium chrysogenum (38 mm, MIC 12.5 μg/mL). The amino linked pyrimidinyl bis benzothiazole 24 exhibited cytotoxic activity on A549 cells with IC50 value of 10.5 μM.

  15. Chrysin-benzothiazole conjugates as antioxidant and anticancer agents.

    PubMed

    Mistry, Bhupendra M; Patel, Rahul V; Keum, Young-Soo; Kim, Doo Hwan

    2015-12-01

    7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2-aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS(+) scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono-fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis.

  16. Benzothiazole-Based Neutral Ratiometric Fluorescence Sensor for Amyloid Fibrils.

    PubMed

    Mora, Aruna K; Murudkar, Sushant; Alamelu, A; Singh, Prabhat K; Chattopadhyay, Subrata; Nath, Sukhendu

    2016-11-07

    Early detection of amyloid fibrils is very important for the timely diagnosis of several neurological diseases. Thioflavin-T (ThT) is a gold standard fluorescent probe for amyloid fibrils and has been used for the last few decades. However, due to its positive charge, ThT is incapable of crossing the blood-brain barrier and cannot be used for in vivo imaging of fibrils. In the present work, we synthesized a neutral ThT derivative, 2-[2'-Me,4'-(dimethylamino)phenyl]benzothiazole (2Me-DABT), which showed a strong affinity towards the amyloid fibrils. On association with the amyloid fibrils, 2Me-DABT not only showed a large increase in its emission intensity, but also, unlike ThT, a large blueshift in its emission spectrum was observed. Thus, unlike ThT, 2Me-DABT is a potential candidate for the ratiometric sensor of the amyloid fibrils. Detailed photophysical properties of 2Me-DABT in amyloid fibrils and different solvent media were studied to understand its sensory activity. Fluorescence resonance energy transfer (FRET) studies suggested that the sites of localization for ThT and 2Me-DABT in amyloid fibrils are not same and their average distance of separation in amyloid fibrils was determined. The experimental data was nicely supported by molecular docking studies, which confirmed the binding of 2Me-DABT in the inner core of the amyloid fibrils.

  17. Reactivity of cyclopentadienyl transition metal(ii) complexes with borate ligands: structural characterization of the toluene-activated molybdenum complex [Cp*Mo(CO)2(η(3)-CH2C6H5)].

    PubMed

    Ramalakshmi, Rongala; Maheswari, K; Sharmila, Dudekula; Paul, Anamika; Roisnel, Thierry; Halet, Jean-François; Ghosh, Sundargopal

    2016-10-18

    Reactions of cyclopentadienyl transition-metal halide complexes [Cp*Mo(CO)3Cl], 1, and [CpFe(CO)2I], 2, (Cp = C5H5; Cp* = η(5)-C5Me5) with borate ligands are reported. Treatment of 1 with [NaBt2] (Bt2 = dihydrobis(2-mercapto-benzothiazolyl)borate) in toluene yielded [Cp*Mo(CO)2(C7H4S2N)], 3, and [Cp*Mo(CO)2(η(3)-CH2C6H5)], 4, with a selective binding of toluene through C-H activation followed by orthometallation. Note that compound 4 is a structurally characterized toluene-activated molecule in which the metal is in η(3)-coordination mode. Under similar reaction conditions, [NaPy2] (Py2 = dihydrobis(2-mercaptopyridyl)borate) produced only the mercaptopyridyl molybdenum complex [Cp*Mo(CO)2(C5H4SN)], 5, in good yield. On the other hand, when compound 2 was treated individually with [NaBt] (Bt = trihydro(2-mercapto-benzothiazolyl)borate) and [NaPy2] in THF, formation of the η(1)-coordinated complexes [CpFe(CO)2(C7H4S2N)], 6, and [CpFe(CO)2(C5H4SN)], 7, was observed. The solid-state molecular structures of compounds 3, 4, 6, and 7 have been established by single-crystal X-ray crystallographic analyses.

  18. Chlorination of benzothiazoles and benzotriazoles and transformation products identification by LC-HR-MS/MS.

    PubMed

    Nika, Maria-Christina; Bletsou, Anna A; Koumaki, Elena; Noutsopoulos, Constantinos; Mamais, Daniel; Stasinakis, Athanasios S; Thomaidis, Nikolaos S

    2017-02-05

    The fate of four benzotriazoles [1-H-benzotriazole (1-H-BTRi), tolyltriazole (TTRi), xylyltriazole (XTRi) and 1-hydroxy-benzotriazole (1-OH-BTRi)] and three benzothiazoles [benzothiazole (BTH), 2-hydroxy-benzothiazole (2-OH-BTH) and 2-amino-benzothiazole (2-amino-BTH)], during chlorination batch experiments was investigated. In the first step, their degradation under different experimental conditions (applied molar ratio of NaOCl and the target contaminant (m.r.), reaction's contact time, pH value of the reaction's solution and the influence of total suspended solids (TSS) presence) was investigated and their removal kinetics parameters (kobs and t1/2) were determined. In the second step, LC-QTOFMS/MS was used for the detection and identification of transformation products (TPs) formed during chlorination, through the application of suspect and non-target screening approaches. Four and five TPs of XTRi and 2-amino-BTH, respectively, were detected and tentatively identified, while 1-H-BTRi was proven to be formed by the chlorination of 1-OH-BTRi. Moreover, since the identified TPs were also detected in spiked wastewater samples, after lab-scale chlorination experiments, toxicity assessment was carried out by ECOSAR calculations for the environmental relevance of their occurrence. The proposed chlorinated TPs were proven to be more toxic than their parent compounds.

  19. In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles

    EPA Science Inventory

    As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of six benzothiazoles to affect endpoints related to thyroid hormone ...

  20. Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

    PubMed Central

    Sarkar, Souvik; Siddiqui, Asim A.; Saha, Shubhra J.; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S.; Nag, Shiladitya; Adhikari, Susanta

    2016-01-01

    We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [3H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. PMID:27139466

  1. In Vitro, Ex Vivo, and In Vivo Determination of Thyroid Hormone Modulating Activity of Benzothiazoles.

    PubMed

    Hornung, Michael W; Kosian, Patricia A; Haselman, Jonathan T; Korte, Joseph J; Challis, Katie; Macherla, Chitralekha; Nevalainen, Erica; Degitz, Sigmund J

    2015-08-01

    As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of 6 benzothiazoles to affect endpoints related to thyroid hormone synthesis inhibition were assessed using in vitro, ex vivo, and in vivo assays. Inhibition of thyroid peroxidase (TPO) derived from pig thyroid glands was determined for benzothiazole (BTZ), 2-mercaptobenzothiazole (MBT), 5-chloro-2-mercaptobenzothiazole (CMBT), 2-aminobenzothiazole (ABT), 2-hydroxybenzothiazole (HBT), and 2-methylthiobenzothiazole (MTBT). Their rank order potency for TPO inhibition was MBT=CMBT>ABT>BTZ, whereas HBT and MTBT exhibited no inhibitory activity. The benzothiazoles were tested further in a Xenopus laevis thyroid gland explant culture assay in which inhibition of thyroxine (T4) release was the measured endpoint. In this assay all 6 benzothiazoles inhibited T4 release. The activity of the benzothiazoles for disrupting thyroid hormone activity was verified in vivo using X. laevis tadpoles in a 7-day assay. The 2 most potent chemicals for TPO inhibition, MBT and CMBT, produced responses in vivo indicative of T4 synthesis inhibition including induction of sodium iodide symporter mRNA and decreases in glandular and circulating thyroid hormones. The capability to measure thyroid hormone levels in the glands and blood by ultrahigh performance LC-MS/MS methods optimized for small tissue samples was critical for effects interpretation. These results indicate that inhibition of TPO activity in vitro was a good indicator of a chemical's potential for thyroid hormone disruption in vivo and may be useful for prioritizing chemicals for further investigation.

  2. The washout effect during laundry on benzothiazole, benzotriazole, quinoline, and their derivatives in clothing textiles.

    PubMed

    Luongo, Giovanna; Avagyan, Rozanna; Hongyu, Ren; Östman, Conny

    2016-02-01

    In two previous papers, the authors have shown that benzothiazole, benzotriazole, quinoline, and several of their derivatives are widespread in clothing textile articles. A number of these compounds exhibit allergenic and irritating properties and, due to their octanol-water partition coefficient, are prone to be absorbed by the skin. Moreover, they are slightly soluble in water, which could make washing of clothes a route of emission into the environment. In the present study, the washout effect of benzothiazole, benzotriazole, quinoline, and some of their derivatives has been investigated. Twenty-seven textile samples were analyzed before, as well as after five and ten times of washing. The most abundant analyte was found to be benzothiazole, which was detected in 85 % of the samples with an average concentration of 0.53 μg/g (median 0.44 μg/g), followed by quinoline, detected in 81 % of the samples with an average concentration of 2.42 μg/g (median 0.21 μg/g). The average decrease in concentration for benzothiazoles was 50 % after ten times washing, while it was around 20 % for quinolines. The average emission to household wastewater of benzothiazoles and quinolines during one washing (5 kg of clothes made from polyester materials) was calculated to 0.5 and 0.24 g, respectively. These results strongly indicate that laundering of clothing textiles can be an important source of release of these compounds to household wastewater and in the end to aquatic environments. It also demonstrates a potential source of human exposure to these chemicals since considerable amounts of the compounds remain in the clothes even after ten times of washing.

  3. Efficient and economical access to substituted benzothiazoles: copper-catalyzed coupling of 2-haloanilides with metal sulfides and subsequent condensation.

    PubMed

    Ma, Dawei; Xie, Siwei; Xue, Peng; Zhang, Xiaojing; Dong, Jinhua; Jiang, Yongwen

    2009-01-01

    Don't tell azole: The first metal-catalyzed direct coupling of metal sulfides with aryl halides and subsequent intramolecular condensation provided substituted benzothiazoles (see scheme). A wide range of functional groups are tolerated under the reaction conditions.

  4. Synthesis, conjugation and relaxation studies of gadolinium(III)-4-benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent.

    PubMed

    Saini, Nisha; Varshney, Raunak; Tiwari, Anjani K; Kaul, Ankur; Allard, Michele; Ishar, M P S; Mishra, Anil K

    2013-04-14

    Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r1 = 4.18 mM(-1) s(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pKa1 = 9.91, pKa2 = 8.22, pKa3 = 5.01) and the stability constant of the complex formed between Gd(III), Eu(III) and Ca(II) and ligand DO3A-BT (log βGdL = 18.4, log βEuL = 18.3, log βZn2L = 7.1, log βCa2L = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10(-5) s(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H2O and D2O solutions to determine the coordination state of this complex. The in vivo biodistribution of (99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo

  5. Water networks contribute to enthalpy/entropy compensation in protein-ligand binding.

    PubMed

    Breiten, Benjamin; Lockett, Matthew R; Sherman, Woody; Fujita, Shuji; Al-Sayah, Mohammad; Lange, Heiko; Bowers, Carleen M; Heroux, Annie; Krilov, Goran; Whitesides, George M

    2013-10-16

    The mechanism (or mechanisms) of enthalpy-entropy (H/S) compensation in protein-ligand binding remains controversial, and there are still no predictive models (theoretical or experimental) in which hypotheses of ligand binding can be readily tested. Here we describe a particularly well-defined system of protein and ligands--human carbonic anhydrase (HCA) and a series of benzothiazole sulfonamide ligands with different patterns of fluorination--that we use to define enthalpy/entropy (H/S) compensation in this system thermodynamically and structurally. The binding affinities of these ligands (with the exception of one ligand, in which the deviation is understood) to HCA are, despite differences in fluorination pattern, indistinguishable; they nonetheless reflect significant and compensating changes in enthalpy and entropy of binding. Analysis reveals that differences in the structure and thermodynamic properties of the waters surrounding the bound ligands are an important contributor to the observed H/S compensation. These results support the hypothesis that the molecules of water filling the active site of a protein, and surrounding the ligand, are as important as the contact interactions between the protein and the ligand for biomolecular recognition, and in determining the thermodynamics of binding.

  6. Synthesis, characterization and carbonic anhydrase inhibitory activity of novel benzothiazole derivatives.

    PubMed

    Küçükbay, F Zehra; Buğday, Nesrin; Küçükbay, Hasan; Tanc, Muhammet; Supuran, Claudiu T

    2016-12-01

    N-protected amino acids were reacted with substituted benzothiazoles to give the corresponding N-protected amino acid-benzothiazole conjugates (60-89%). Their structures were confirmed by proton nuclear magnetic resonance ((1)H NMR), carbon-13 nuclear magnetic resonance ((13)C NMR), IR and elemental analysis. Their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activities were determined against two cytosolic human isoforms (hCA I and hCA II), one membrane-associated (hCA IV) and one transmembrane (hCA XII) enzyme by a stopped-flow CO2 hydrase assay method. The new compounds showed rather weak, micromolar inhibitory activity against most of these enzymes.

  7. A benzothiazole-based fluorescent probe for distinguishing and bioimaging of Hg(2+) and Cu(2).

    PubMed

    Gu, Biao; Huang, Liyan; Su, Wei; Duan, Xiaoli; Li, Haitao; Yao, Shouzhuo

    2017-02-15

    A new benzothiazole-based fluorescent probe 2-(benzo[d]thiazol-2-yl)-4-(1,3- dithian-2-yl)phenol (BT) with two different reaction sites, a thioacetal group (site 1 for Hg(2+)), and O and N atoms of the benzothiazole dye (site 2 for Cu(2+)), was designed and synthesized. The probe BT showed ratiometric fluorescent response to Hg(2+) and fluorescence quenching behavior to Cu(2+), which induces naked-eye fluorescent color changes from green to blue and colorless, respectively. Moreover, it displayed highly sensitivity and selectivity toward Hg(2+) and Cu(2+) without interference from other metal ions. The sensing mechanisms were also confirmed by (1)H NMR titration, mass spectrum and Job's plot analyses. Finally, probe BT was successfully used for fluorescent imaging of Hg(2+) and Cu(2+) in living cells, demonstrating its potential applications in biological science.

  8. Synthesis and anticancer activity evaluation of some benzothiazole-piperazine derivatives.

    PubMed

    Gurdal, Enise Ece; Buclulgan, Ebru; Durmaz, Irem; Cetin-Atalay, Rengul; Yarim, Mine

    2015-01-01

    Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Aroyl substituted compounds 1h and 1j were found to be the most active derivatives. In addition, further investigation of compounds 1h and 1j by Hoechst staining and FACS revealed that these compounds cause apoptosis by cell cycle arrest at subG1 phase.

  9. Benzothiazole derivatives: novel inhibitors of methylglyoxal mediated glycation of proteins in vitro.

    PubMed

    Abbasi, Sanaullah; Mirza, Salma; Rasheed, Saima; Hussain, Shafqat; Khan, Jalaluddin A J; Khan, Khalid Mohammed; Perveen, Shahnaz; Choudhary, Muhammad Iqbal

    2014-01-01

    This manuscript describes the protein anti-glycation activity of thirty-three (33) benzothiazoles, out of which twenty-seven were the newly synthesized benzothiazoles. Compound 1 (IC50= 187 ± 2.6 µM) was found to be the most active, while compounds 2 (IC50= 219 ± 3.6 µM), 3 (IC50= 224 ± 1.9 µM), 4 (IC50= 223 ± 3.3 µM), 5 (IC50= 238 ± 2.2 µM), 7 (IC50= 266 ± 5.4 µM), 17 (IC50= 226 ± 1.6 µM) and 18 (IC50= 274 ± 2.4 µM) were significantly active, when compared with the standard rutin (IC50= 294 ± 1.5 µM). This study identified potential inhibitors of methylglyoxal mediated glycation of proteins, which is the pathophysiology of late diabetic complications.

  10. Structural and spectral comparisons between isomeric benzisothiazole and benzothiazole based aromatic heterocyclic dyes

    NASA Astrophysics Data System (ADS)

    Wang, Yin-Ge; Wang, Yue-Hua; Tao, Tao; Qian, Hui-Fen; Huang, Wei

    2015-09-01

    A pair of isomeric heterocyclic compounds, namely 3-amino-5-nitro-[2,1]-benzisothiazole and 2-amino-6-nitrobenzothiazole, are used as the diazonium components to couple with two N-substituted 4-aminobenzene derivatives. As a result, two pairs of isomeric aromatic heterocyclic azo dyes have been produced and they are structurally and spectrally characterized and compared including single-crystal structures, electronic spectra, solvatochromism and reversible acid-base discoloration, thermal stability and theoretically calculations. It is concluded that both benzisothiazole and benzothiazole based dyes show planar molecular structures and offset π-π stacking interactions, solvatochromism and reversible acid-base discoloration. Furthermore, benzisothiazole based aromatic heterocyclic dyes exhibit higher thermal stability, larger solvatochromic effects and maximum absorption wavelengths than corresponding benzothiazole based ones, which can be explained successfully by the differences of their calculated isomerization energy, dipole moment and molecular band gaps.

  11. Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

    PubMed

    Oanh, Dao Thi Kim; Hai, Hoang Van; Park, Sang Ho; Kim, Hyun-Jung; Han, Byung-Woo; Kim, Hyung-Sook; Hong, Jin-Tae; Han, Sang-Bae; Hue, Van Thi My; Nam, Nguyen-Hai

    2011-12-15

    Data from clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of our ongoing effort to identify novel small molecules to target these important enzymes, we have prepared two series of benzothiazole-containing analogues of SAHA. It was found that several compounds with 6C-bridge linking benzothiazole moiety and hydroxamic functional groups showed good inhibition against HDAC3 and 4 at as low as 1 μg/ml and exhibited potent cytotoxicity against five cancer cell lines with average IC(50) values of as low as 0.81 μg/ml, almost equipotent to SAHA.

  12. Synthesis, DNA cleavage and antimicrobial activity of 4-thiazolidinones-benzothiazole conjugates.

    PubMed

    Singh, Meenakshi; Gangwar, Mayank; Nath, Gopal; Singh, Sushil K

    2014-11-01

    Antimicrobial screening of several novel 4-thiazolidinones with benzothiazole moiety has been performed. These compounds were evaluated for antimicrobial activity against a panel of bacterial and fungal strains. The strains were treated with these benzothiazole derivatives at varying concentrations, and MIC's were calculated. Structures of these compounds have been determined by spectroscopic studies viz., FT-IR, 1H NMR, 13C NMR and elemental analysis. Significant antimicrobial activity was observed for some members of the series, and compounds viz. 3-(4-(benzo[d]thiazol-2-yl) phenyl-2-(4-methoxyphenyl)thiazolidin-4-one and 3-(4-(benzo[d]thiazol-2-yl)phenyl)-2-(4-hydroxy phenyl)thiazolidin-4-one were found to be the most active against E.coli and C. albicans with MIC values in the range of 15.6-125 microg/ml. Preliminary study of the structure-activity relationship revealed that electron donating groups associated with thiazolidine bearing benzothiazole rings had a great effect on the antimicrobial activity of these compounds and contributes positively for the action. DNA cleavage experiments gave valuable hints with supporting evidence for describing the mechanism of action and hence showed a good correlation between their calculated MIC's and its lethality.

  13. [Synthesis and antitumor activity of 5-substituted-2-(pyridyl)benzothiazole compounds].

    PubMed

    Liu, Wen-Hu; Chang, Jin-Xia; Liu, Yi

    2013-01-01

    Fifteen novel 5-substituted-2-(pyridyl)benzothiazole compounds were designed and synthesized by simple hydrolization and condensation reaction of the 2-amino-5-substituent benzothiazole. Activities of these synthesized compounds were evaluated on Bcap-37, HCT-15 and HepG2 tumor cells in vitro by standard MTT assay. 5-Fluorouracil (5-FU) was used as the positive control. The results revealed that most of the new compounds had potent effects on Bcap-37, HCT-15 and HepG2 tumor cells, and had no or less effect on 293T and L02 normal cells. Particularly, compounds 1c and 2e exhibited better activities on HCT-15 and HepG2 cells with IC50 values of 41.59 and 38.65 micromol x L(-1), and 1i showed excellent activities on Bcap-37 and HepG2 cells with IC50 values of 46.63 and 23.51 micromol x L(-1), respectively. The structure-activity relationship of 5-substituted-2-(pyridyl)benzothiazole compounds were also discussed preliminarily.

  14. Preparation, thermo-optic property and simulation of optical switch based on azo benzothiazole polymer

    NASA Astrophysics Data System (ADS)

    Cao, Zhijuan; Qiu, Fengxian; Wang, Qing; Cao, Guorong; Guan, Yijun; Zhuang, Lin; Xu, Xiaolong; Wang, Jie; Chen, Qian; Yang, Dongya

    2013-04-01

    An azo chromophore molecule 4-[(benzothiazole-2-yl)diazenyl]phenyl-1,3-diamine (BTPD) was prepared with 2-amino benzothiazole and m-phenylenediamine by diazo-coupling reaction. Then, the chromophore molecule BTPD was polymerized with NJ-210 and isophorone diisocyanate (IPDI) to obtain novel azo benzothiazole polymer (BTPU). The structures of BTPD and BTPU were characterized using the Fourier transform infrared, UV-visible spectroscopy, DSC and TGA. The physical properties of the obtained BTPU were investigated. The refractive index ( n) of BTPU was demonstrated at different temperature and wavelength (532, 650 and 850 nm) using attenuated total reflection technique. The transmission loss and dispersion characteristic of BTPU film were investigated using the CCD digital imaging devices and Sellmeyer equation. A Y-branch and 2 × 2 Mach-Zehnder interferometer (MZI) polymeric thermo-optic switches based on the thermo-optic effect of prepared BTPU were proposed and the performance of switches was simulated. The results indicated that the power consumption of the Y-branch thermo-optic switch could be only 0.6 mW. The Y-branch and MZI switching rising and falling times obtained were 8.0 and 1.8 ms.

  15. Benzothiazole Amphiphiles Ameliorate Amyloid β-Related Cell Toxicity and Oxidative Stress.

    PubMed

    Cifelli, Jessica L; Chung, Tim S; Liu, Haiyan; Prangkio, Panchika; Mayer, Michael; Yang, Jerry

    2016-06-15

    Oxidative stress from the increase of reactive oxygen species in cells is a common part of the normal aging process and is accelerated in patients with Alzheimer's disease (AD). Herein, we report the evaluation of three benzothiazole amphiphiles (BAMs) that exhibit improved biocompatibility without loss of biological activity against amyloid-β induced cell damage compared to a previously reported hexa(ethylene glycol) derivative of benzothiazole aniline (BTA-EG6). The reduced toxicity of these BAM agents compared to BTA-EG6 corresponded with their reduced propensity to induce membrane lysis. In addition, all of the new BAMs were capable of protecting differentiated SH-SY5Y neuroblastoma cells from toxicity and concomitant oxidative stress induced by AD-related aggregated Aβ (1-42) peptides. Binding and microscopy studies support that these BAM agents target Aβ and inhibit the interactions of catalase with Aβ in cells, which, in turn, can account for an observed inhibition of Aβ-induced increases in hydrogen peroxide in cells treated with these compounds. These results support that this family of benzothiazole amphiphiles may have therapeutic potential for treating cellular damage associated with AD and other Aβ-related neurologic diseases.

  16. Tautomeric conversion, vibrational spectra, and density functional studies on peripheral sulfur derivatives of benzothiazole and benzothiazoline isomers

    NASA Astrophysics Data System (ADS)

    Altun, Ahmet; Kuliyev, Eziz; Aghatabay, Naz M.

    2016-01-01

    The room temperature structural (tautomerism, dimerization, conformational preference, geometry parameters) and vibrational spectral (IR and Raman) analyses have been performed on benzothiazoline (benzothiazoline-2-thione, 3-methyl-benzothiazoline-2-thione) and benzothiazole [2-mercaptobenzothiazole, 2-methylthiobenzothiazole, and bis(benzothiazole-2-ylthio)ethane] derivatives at the B3LYP/6-311++G∗∗ level of theory. Although the keto to enol transition barriers are too high over the most stable benzothiazoline isomers, vibrational spectral analyses reveal some major bands of benzothiazole isomers in the present room temperature experimental FT-IR and FT-Raman specta. Therefore, benzothiazole isomers exist at rare amounts in the powdered samples that are mainly composed of benzothiazoline isomers. The benzothiazole isomers have two stable conformations due to the orientation of their SH and SCH3 moieties. The energetic and vibrational spectral analyses suggest that the benzothiazoline-2-thione molecules can be stabilized further through the NH⋯S intermolecular hydrogen bonds in solid phase. All observed fundamental vibrational bands of the molecules have been assigned based on the calculated mode frequencies and IR/Raman intensities. The mode assignments have been expressed in terms of internal coordinates and their percent potential energy distributions. The effects of substitution at the nitrogen and peripheral sulfur atoms have been analyzed for the geometries and vibrational bands of the molecules.

  17. Tautomeric conversion, vibrational spectra, and density functional studies on peripheral sulfur derivatives of benzothiazole and benzothiazoline isomers.

    PubMed

    Altun, Ahmet; Kuliyev, Eziz; Aghatabay, Naz M

    2016-01-05

    The room temperature structural (tautomerism, dimerization, conformational preference, geometry parameters) and vibrational spectral (IR and Raman) analyses have been performed on benzothiazoline (benzothiazoline-2-thione, 3-methyl-benzothiazoline-2-thione) and benzothiazole [2-mercaptobenzothiazole, 2-methylthiobenzothiazole, and bis(benzothiazole-2-ylthio)ethane] derivatives at the B3LYP/6-311++G(∗∗) level of theory. Although the keto to enol transition barriers are too high over the most stable benzothiazoline isomers, vibrational spectral analyses reveal some major bands of benzothiazole isomers in the present room temperature experimental FT-IR and FT-Raman specta. Therefore, benzothiazole isomers exist at rare amounts in the powdered samples that are mainly composed of benzothiazoline isomers. The benzothiazole isomers have two stable conformations due to the orientation of their SH and SCH3 moieties. The energetic and vibrational spectral analyses suggest that the benzothiazoline-2-thione molecules can be stabilized further through the NH⋯S intermolecular hydrogen bonds in solid phase. All observed fundamental vibrational bands of the molecules have been assigned based on the calculated mode frequencies and IR/Raman intensities. The mode assignments have been expressed in terms of internal coordinates and their percent potential energy distributions. The effects of substitution at the nitrogen and peripheral sulfur atoms have been analyzed for the geometries and vibrational bands of the molecules.

  18. EGFR tyrosine kinase targeted compounds: in vitro antitumor activity and molecular modeling studies of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives.

    PubMed

    Gabr, Moustafa T; El-Gohary, Nadia S; El-Bendary, Eman R; El-Kerdawy, Mohamed M

    2014-01-01

    In this study, we illustrate computer aided drug design of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors. Compounds 1-5 were screened at NCI, USA, for antitumor activity against non-small cell lung cancer (NCI-H522), colon cancer (HCT-116, HCT-15 and HT29) and breast cancer (MDA-MB-468 and MDA-MB-231/ATCC) cell lines in which EGFR is overexpressed in varying levels. Results indicated that these compounds are more potent antitumor agents compared to erlotinib against HT29 and MDA-MB-231/ATCC cell lines. Compound 3 showed GI50 value of 22.3 nM against NCI-H522 cell line, while erlotinib exhibited GI50 value of 1 µM against the same cell line. In addition, these compounds were studied for their EGFR tyrosine kinase inhibitory activity. Virtual screening utilizing molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for antitumor activity. Docking the designed compounds into the ATP binding site of EGFR-TK domain was done to predict the analogous binding mode of these compounds to the EGFR-TK inhibitors.

  19. EGFR tyrosine kinase targeted compounds: in vitro antitumor activity and molecular modeling studies of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives

    PubMed Central

    Gabr, Moustafa T.; El-Gohary, Nadia S; El-Bendary, Eman R.; El-Kerdawy, Mohamed M.

    2014-01-01

    In this study, we illustrate computer aided drug design of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors. Compounds 1-5 were screened at NCI, USA, for antitumor activity against non-small cell lung cancer (NCI-H522), colon cancer (HCT-116, HCT-15 and HT29) and breast cancer (MDA-MB-468 and MDA-MB-231/ATCC) cell lines in which EGFR is overexpressed in varying levels. Results indicated that these compounds are more potent antitumor agents compared to erlotinib against HT29 and MDA-MB-231/ATCC cell lines. Compound 3 showed GI50 value of 22.3 nM against NCI-H522 cell line, while erlotinib exhibited GI50 value of 1 µM against the same cell line. In addition, these compounds were studied for their EGFR tyrosine kinase inhibitory activity. Virtual screening utilizing molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for antitumor activity. Docking the designed compounds into the ATP binding site of EGFR-TK domain was done to predict the analogous binding mode of these compounds to the EGFR-TK inhibitors. PMID:26417284

  20. Correlation between electronic parameters and corrosion inhibition of benzothiazole derivatives- NMR parameters as important and neglected descriptors

    NASA Astrophysics Data System (ADS)

    Behzadi, Hadi; Forghani, Ali

    2017-03-01

    The relation between electronic properties and corrosion inhibitive performance of three benzothiazole derivatives 1,3-benzothiazol-2-amine (BTA), 6-methyl-1,3-benzothiazol-2-amine (MBTA) and 2-amino-1,3-benzthiazole-6-thiol (TBTA) has been investigated by density functional theory. The electronic properties including EHOMO, ELUMO and related parameters were calculated at the B3LYP/6-311++G(d,p) level. The chemical shielding CS tensors were introduced as important and neglected descriptors to evaluate inhibitive efficiency of corrosion inhibitors. Nuclear independent chemical shift (NICS) components, as an aromaticity criterion, were also investigated as local descriptor. Polarizability and CS descriptors, as second rank tensors, show the best correlations with inhibition efficiencies of studied inhibitors.

  1. Determination of total sulfur compounds and benzothiazole in asphalt fume samples by gas chromatography with sulfur chemiluminescence detection.

    PubMed

    Jaycox, L B; Olsen, L D

    2000-09-01

    As part of a collaborative project between the National Institute for Occupational Safety and Health and the Federal Highway Administration to evaluate asphalt pavers' exposures to asphalt fume and their potential health effects, a method was developed for the determination of total sulfur compounds and benzothiazole in asphalt fume samples. Asphalt fume samples were collected from asphalt mixtures with and without the addition of ground-up rubber tires. The asphalt fume samples were collected with sampling trains that consisted of a Teflon membrane filter and an XAD-2 adsorbent tube. Filter and sampling tube media were extracted with hexane and subsequently analyzed by gas chromatography with a sulfur chemiluminescence detector. Separation was achieved with a 100 percent dimethyl polysiloxane fused silica column. Typical calibration curves had linear correlation coefficients of 0.99 or better with a relative standard deviation (RSD) of 5 percent. Benzothiazole desorption efficiency (DE) determined using spiked sampling tubes ranged from 96.5 percent at 5.0 micrograms to 89.4 percent at 40 micrograms with RSD values from 0.9 to 4.0 percent. Benzothiazole storage recovery determined using sampling tubes spiked at 20 micrograms and refrigerated for 30 days at 4 degrees C was 89.8 percent when corrected for the DE with an RSD of 1.1 percent. The limit of detection for the method determined using spiked sampling tubes was 0.30 microgram. Quantitation for total sulfur compounds and benzothiazole was against benzothiazole standards in hexane. Because of detector selectivity, sample preparation consisted of a simple hexane extraction even when samples had a high background due to hydrocarbon overload. Detector sensitivity provided quantitation in the sub-microgram region. Because of the sample preparation step and because benzothiazole was determined during the same analysis run, this method is straightforward and analytically efficient. The method has been used to

  2. Discovery and in vivo evaluation of alcohol-containing benzothiazoles as potent dual-targeting bacterial DNA supercoiling inhibitors.

    PubMed

    Palmer, James T; Axford, Lorraine C; Barker, Stephanie; Bennett, James M; Blair, Michael; Collins, Ian; Davies, David T; Ford, Leigh; Gannon, Carlie T; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J; Morton, Craig J; Offermann, Daniel A; Pitt, Gary R W; Rao, B Narasinga; Singh, Amit K; Shukla, Tarun; Srivastava, Anil; Stokes, Neil R; Thomaides-Brears, Helena B; Yadav, Anju; Haydon, David J

    2014-09-01

    A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.

  3. Copper-catalyzed thiolation annulations of 1,4-dihalides with sulfides leading to 2-trifluoromethyl benzothiophenes and benzothiazoles.

    PubMed

    Li, Chun-Lin; Zhang, Xing-Guo; Tang, Ri-Yuan; Zhong, Ping; Li, Jin-Heng

    2010-10-15

    Copper-catalyzed double thiolation reaction of 1,4-dihalides with sulfides has been developed for selectively synthesizing 2-trifluoromethyl benzothiophenes and benzothiazoles. In the presence of CuI, a variety of 2-halo-1-(2-haloaryl)-3,3,3-trifluoropropylenes smoothly underwent the thiolation annulation with Na(2)S to afford 2-trifluoromethyl benzothiophenes in moderate to good yields. Moreover, the conditions are compatible with N-(2-haloaryl)trifluoroacetimidoyl chlorides in the presence of NaHS and K(3)PO(4), leading to 2-trifluoromethyl benzothiazoles.

  4. Occurrence, phase distribution, and mass loadings of benzothiazoles in riverine runoff of the Pearl River Delta, China.

    PubMed

    Ni, Hong-Gang; Lu, Feng-Hui; Luo, Xian-lin; Tian, Hui-Yu; Zeng, Eddy Y

    2008-03-15

    A set of six benzothiazoles was determined in riverine runoff samples of the Pearl River Delta (PRD) collected monthly from March 2005 to February 2006. The concentrations of total benzothiazoles ranged from 220 to 611 ng/L, with benzothiazole (BT) being the most prominent (82%), followed by 2-methylthiobenzothiazole (MBT),thianaphthene (TN), and triphenylene (TP). The annual fluxes ofTN, BT, MBT, dibenzothiophene (DBT), 2-(4-morpholinyl)benzothiazole (24MoBT), and TP from the PRD to the coastal ocean were 1.94, 65.1, 10.1,0.63, 0.18, and 0.89 tons/yr, summing to yield an annual flux of 79 tons/yr for total benzothiazoles. In the PRD, approximately 1.1 x 10(5) tons of rubber are estimated to be released into the environment each year. This corresponds to the annual fluxes of 13 tons/yr for BT and 0.4 tons/yr for 24MoBT from tire particles. The annual fluxes of BT from scrap tires from Japan, Korea, Brazil, the European Union, the United States, and China were 99, 21, 36, 270, 328, and 120 tons/yr, respectively. The fluxes of 24MoBT from the same countries were 3.0, 0.5, 1.1, 8.4, 10.3, and 3.8 tons/ yr, respectively. These results indicated that tire-wear particles and scrap tires are the dominant sources of benzothiazoles in the environment. By comparison, Asia may be the major contributor to the global input of benzothiazoles from auto tires in the coming years. Overall, the six benzothiazoles under investigation appeared to be suitable tracers of pollutant inputs to surface runoff within the PRD aquatic system. In addition, 24MoBT seemed more appropriate than BT to trace tire rubber residues and therefore can be a good indicator of economic development and urbanization in a specific region.

  5. Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles induce CYP1A1 expression, become metabolized, and bind to macromolecules in sensitive human cancer cells.

    PubMed

    Brantley, Eileen; Trapani, Valentina; Alley, Michael C; Hose, Curtis D; Bradshaw, Tracey D; Stevens, Malcolm F G; Sausville, Edward A; Stinson, Sherman F

    2004-12-01

    Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In "sensitive" cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochromes P450 (CYP1A1, CYP1A2, or CYP1B1) to clarify the basis for fluorinated benzothiazole metabolism. 5F 203 induced CYP1A1 and CYP1B1 mRNA expression in sensitive breast and renal cancer cells, whereas 5F 203 induced CYP1A1 mRNA but not CYP1B1 mRNA expression in sensitive ovarian cancer cells. 5F 203 did not induce CYP1A1 or CYP1B1 mRNA expression in any "resistant" cancer cells. The fluorinated benzothiazoles induced CYP1A1 protein expression exclusively in sensitive cells. [14C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells.

  6. Synthesis, physical properties and simulation of thermo-optic switch based on azo benzothiazole heterocyclic polymer

    NASA Astrophysics Data System (ADS)

    Qiu, Fengxian; Chen, Caihong; Zhou, Qiaolan; Cao, Zhijuan; Cao, Guorong; Guan, Yijun; Yang, Dongya

    2014-05-01

    A chromophore molecule 4-[(benzothiazole-2-yl)diazenyl]phenyl-1,3-diamine (BTPD) was prepared with 2-amino benzothiazole and m-phenylenediamine by diazo-coupling reaction. Then, the BTPD was polymerized with polyether polyol (NJ-220) and isophorone diisocyanate (IPDI) to obtain novel azo benzothiazole polyurethane-urea (BTPUU). The chemical structures of BTPD and BTPUU were characterized by FT-IR and UV-visible spectroscopy. The thermal and mechanical properties of BTPUU film were investigated. The refractive index and transmission loss of BTPUU film were measured at different temperatures and different laser wavelengths (532 nm, 650 nm and 850 nm) by an attenuated total reflection (ATR) technique and CCD digital imaging devices. The thermo-optic coefficients of BTPUU are -4.7086 × 10-4 °C-1 (532 nm), -6.5257 × 10-4 °C-1 (650 nm) and -5.1029 × 10-4 °C-1 (850 nm), respectively. A Y-branch switch and Mach-Zehnder interferometer (MZI) thermo-optic switches based on thermo-optic effect were proposed and the performances of the switches were simulated, respectively. The results show that the power consumption of the Y-branch thermo-optic switch is only 3.28 mW. The response times of Y-branch and MZI switches are 8.0 ms and 2.0 ms, respectively. The results indicate that the prepared BTPUU has high potential for the applications of the Y-branch digital optical switch (DOS), MZI thermo-optic switch, directional coupler (DC) switch and optical modulators.

  7. Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.

    PubMed

    Collier, Philip N; Martinez-Botella, Gabriel; Cornebise, Mark; Cottrell, Kevin M; Doran, John D; Griffith, James P; Mahajan, Sudipta; Maltais, François; Moody, Cameron S; Huck, Emilie Porter; Wang, Tiansheng; Aronov, Alex M

    2015-01-08

    Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.

  8. Novel cycloalkylthiophene-imine derivatives bearing benzothiazole scaffold: synthesis, characterization and antiviral activity evaluation.

    PubMed

    Ke, Shaoyong; Wei, Yanhong; Yang, Ziwen; Wang, Kaimei; Liang, Ying; Shi, Liqiao

    2013-09-15

    A series of novel cycloalkylthiophene-imine derivatives containing benzothiazole unit were designed, synthesized and evaluated for their anti-viral activities. The bio-evaluation results indicated that some of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on CVB5, ADV7 and EV71 viruses, however, these compounds did not have inhibition activity against H1N1 virus. Especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a new and efficient approach to evolve novel multi-functional antiviral agents by rational integration of active pharmacophores.

  9. X-ray diffraction investigation of 1-phenyl-3-isopropyl-5-(benzothiazol-2-yl)formazan

    NASA Astrophysics Data System (ADS)

    Slepukhin, P. A.; Pervova, I. G.; Rezinskikh, Z. G.; Lipunova, G. N.; Gorbatenko, Yu. A.; Lipunov, I. N.

    2008-01-01

    The crystal structure of 1-phenyl-3-isopropyl-5-(benzothiazol-2-yl)formazan is investigated using X-ray diffraction. The compound crystallizes in the form of two crystallographically independent molecules ( A and B) in identical conformations that are stabilized by intermolecular hydrogen bonds. The intermolecular hydrogen bonds N-H…N (N…N, 2.892 and 2.939 Å) link molecules into AB dimers. Both molecules have a flattened structure, except for the isopropyl fragment. The bonds in the formazan chains are delocalized. Molecules A and B have close geometric characteristics.

  10. 2-(1,3-Benzothia-zol-2-ylsulfan-yl)-1-phenyl-ethanone.

    PubMed

    Loghmani-Khouzani, Hossein; Hajiheidari, Dariush; Robinson, Ward T; Abdul Rahman, Noorsaadah; Kia, Reza

    2009-09-12

    In the mol-ecule of the title compound, C(15)H(11)NOS(2), the 1,3-benzothia-zole ring is oriented at a dihedral angle of 6.61 (6)° with respect to the phenyl ring. In the crystal structure, inter-molecular C-H⋯O inter-actions link the mol-ecules in a herring-bone arrangement along the b axis and π-π contacts between the thia-zole and phenyl rings [centroid-centroid distance = 3.851 (1) Å] may further stabilize the structure.

  11. Synthesis and herbicidal evaluation of novel benzothiazole derivatives as potential inhibitors of D1 protease.

    PubMed

    Huang, Tonghui; Sun, Jie; An, Lin; Zhang, Lixian; Han, Cuiping

    2016-04-01

    D1 protease is a C-terminal processing protease that has been predicted to be an ideal herbicidal target. Three novel series of benzothiazole derivatives were synthesized and evaluated for their herbicidal activities against Brassica napus (rape) and Echinochloa crusgalli (barnyard grass). The preliminary bioassay indicated that most of the synthesized compounds possess promising D1 protease inhibitory activities and considerable herbicidal activities. Molecular docking was performed to position representative compounds into the active site of D1 protease to determine a probable binding model.

  12. Synthesis, photophysical and electrochemical properties of a carbazole dimer-based derivative with benzothiazole units

    NASA Astrophysics Data System (ADS)

    Shi, He-ping; Dai, Jian-xin; Shi, Li-wen; Xu, Lei; Zhou, Zhao-bin; Zhang, Yan; Zhou, Wen; Dong, Chuan

    A novel A-π-D-π-D-π-A type compound, containing two benzothiazole rings as electron acceptors and two N-ethylcarbazole groups as electron donors, (E)-1,2-bis(3-(benzothiazol-2-yl)-9-ethylcarbazol-6-yl)ethene (BBECE), was synthesized and characterized by elemental analysis, NMR, MS and thermogravimetric analysis. Electrochemical property of compound BBECE was studied by cyclic voltammetry analysis. The absorption and emission spectra of BBECE was experimentally determined in several solvents and simultaneously computed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The calculated absorption and emission wavelengths are coincident with the measured data. The lowest-lying absorption spectra can be mainly attributed to intramolecular charge transfer (ICT), and the fluorescence spectra can be mainly described as originating from an excited state with intramolecular charge transfer (ICT) character. The molecular orbitals (HOMO and LUMO), the ionization potential (IP), the electron affinity (EA) and reorganization energy of compound BBECE were also investigated using density functional theory (DFT). The results show that compound BBECE exhibited excellent thermal stability and electrochemical stability as well as high fluorescence quantum yield, indicating its potential applications as an excellent optoelectronic material in optical fields.

  13. Studies of benzothiazole and benzoselenazole squaraines as fluorescent probes for albumins detection.

    PubMed

    Volkova, Kateryna D; Kovalska, Vladyslava B; Losytskyy, Mykhaylo Yu; Bento, Artur; Reis, Lucinda V; Santos, Paulo F; Almeida, Paulo; Yarmoluk, Sergiy M

    2008-09-01

    Series of squaraine benzothiazole and benzoselenazole dyes were studied as possible fluorescent probes for the detection of proteins, particularly albumins. It was shown that majority of the studied squaraines give significant fluorescent response on the human serum albumin (HSA) and bovine serum albumin presence. For squaraine dyes with N-hexyl pendent groups (P-1, P-2, P-3, P-5) about 100-540-fold fluorescence intensity increase upon albumins addition was observed. At the same time in presence of other proteins, namely insulin, avidin from hen egg white, immunoglobulin G (IgG), carbonic anhydrase fluorescence enhancement values were considerably lower -up to 43 times in IgG presence. It was noted that generally, squaraines with long N-hexyl pendent groups demonstrate higher emission increase values upon proteins addition comparing with their analogues with short N-ethyl tails. It was shown that fluorescence intensity enhancement for benzothiazole squaraine dye P-3, relates linearly to the HSA concentration over the wide range-from 0.2 to 500 microg/ml. Together with noticeable selectivity of this dye to albumins, existence of wide dynamic range gives possibility to propose P-3 dye as probe for HSA quantification.

  14. Synthesis and in vitro antiproliferative evaluation of some B-norcholesteryl Benzimidazole and Benzothiazole derivatives.

    PubMed

    Cui, Jianguo; Qi, Binbin; Gan, Chunfang; Liu, Zhipin; Huang, Hu; Lin, Qifu; Zhao, Dandan; Huang, Yanmin

    2015-04-22

    Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3β'-Acetoxy-5β'-hydroxy-6'-B-norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.

  15. Benzothiazole, benzotriazole, and their derivates in clothing textiles--a potential source of environmental pollutants and human exposure.

    PubMed

    Avagyan, Rozanna; Luongo, Giovanna; Thorsén, Gunnar; Östman, Conny

    2015-04-01

    Textiles play an important role in our daily life, and textile production is one of the oldest industries. In the manufacturing chain from natural and/or synthetic fibers to the final clothing products, the use of many different chemicals is ubiquitous. A lot of research has focused on chemicals in textile wastewater, but the knowledge of the actual content of harmful chemicals in clothes sold on the retail market is limited. In this paper, we have focused on eight benzothiazole and benzotriazole derivatives, compounds rated as high production volume chemicals. Twenty-six clothing samples of various textile materials and colors manufactured in 14 different countries were analyzed in textile clothing using liquid chromatography tandem mass spectrometry. Among the investigated textile products, 11 clothes were for babies, toddlers, and children. Eight of the 11 compounds included in the investigation were detected in the textiles. Benzothiazole was present in 23 of 26 investigated garments in concentrations ranging from 0.45 to 51 μg/g textile. The garment with the highest concentration of benzothiazole contained a total amount of 8.3 mg of the chemical. The third highest concentration of benzothiazole (22 μg/g) was detected in a baby body made from "organic cotton" equipped with the "Nordic Ecolabel" ("Svanenmärkt"). It was also found that concentrations of benzothiazoles in general were much higher than those for benzotriazoles. This study implicates that clothing textiles can be a possible route for human exposure to harmful chemicals by skin contact, as well as being a potential source of environmental pollutants via laundering and release to household wastewater.

  16. 2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity.

    PubMed Central

    Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schultz, R. J.; Paull, K. D.; Stevens, M. F.

    1998-01-01

    2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nM range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-aminophenyl)benzothiazoles; IC50 values > 30 microM were obtained. Potency and selectivity were confirmed when compounds were examined in the National Cancer Institute's Developmental Therapeutics screen; the spectrum of activity included specific ovarian, renal, colon as well as breast carcinoma cell lines. Moreover, comparing 6-day and 48-h incubations, the exposure time-dependent nature of the biphasic response was corroborated. Differential perturbation of cell cycle distribution followed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminophenyl)benzothiazoles. In MDA 468 populations only, accumulation of events in G2/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 microM), which exhibit cross-resistance to substituted benzothiazoles, but equal sensitivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel, benzothiazoles revealed unique profiles of growth inhibition, suggesting a mode(s) of action shared with no known clinically active class of chemotherapeutic agents. PMID:9514053

  17. 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor

    SciTech Connect

    Bazzi, Rana; Bradshaw, Tracey D.; Rowlands, J. Craig; Stevens, Malcolm F.G.; Bell, David R.

    2009-05-15

    2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and related compounds are a series of anti-cancer candidate pharmaceuticals, that have been shown to activate the AhR. We show that these compounds are high-affinity ligands for the rat AhR, but a quantitative assay for their ability to induce CYP1A1 RNA in H4IIEC3 cells, a measure of activation of the AhR, showed a poor relationship between affinity for the AhR and ability to induce CYP1A1 RNA. 5F 203, an agonist with low potency, was able to antagonise the induction of CYP1A1 RNA by TCDD, while IH 445, a potent agonist, did not antagonise the induction of CYP1A1 RNA by TCDD, and Schild analysis confirmed 5F 203 to be a potent antagonist of the induction of CYP1A1 RNA by TCDD in H4IIEC3 cells. In contrast, several benzothiazoles show potent induction of CYP1A1 RNA in human MCF-7 cells, and 5F 203 is unable to detectably antagonise the induction of CYP1A1 RNA in MCF-7 cells, showing a species difference in antagonism. Evaluation of the anti-proliferative activity of benzothiazoles showed that the ability to agonise the AhR correlated with growth inhibition both in H4IIEC3 cells for a variety of benzothiazoles, and between H4IIEC3 and MCF-7 cells for 5F 203, suggesting an important role of agonism of the AhR in the anti-proliferative activity of benzothiazoles.

  18. A SAR study of novel antiproliferative ruthenium and osmium complexes with quinoxalinone ligands in human cancer cell lines.

    PubMed

    Ginzinger, Werner; Mühlgassner, Gerhard; Arion, Vladimir B; Jakupec, Michael A; Roller, Alexander; Galanski, Markus; Reithofer, Michael; Berger, Walter; Keppler, Bernhard K

    2012-04-12

    A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.

  19. DFT study of conformational and vibrational characteristics of 2-(2-hydroxyphenyl)benzothiazole molecule

    NASA Astrophysics Data System (ADS)

    Pandey, Urmila; Srivastava, Mayuri; Singh, R. P.; Yadav, R. A.

    2014-08-01

    The conformational and IR and Raman spectral studies of 2-(2-hydroxyphenyl)benzothiazole have been carried out by using the DFT method at the B3LYP/6-311++G** level. The detailed vibrational assignments have been done on the basis of calculated potential energy distributions. Comparative studies of molecular geometries, atomic charges and vibrational fundamentals of all the conformers have been made. There are four possible conformers for this molecule. The optimized geometrical parameters obtained by B3LYP/6-311++G** method showed good agreement with the experimental X-ray data. The atomic polar tensor (APT) charges, Mulliken atomic charges, natural bond orbital (NBO) analysis and HOMO-LUMO energy gap of HBT and its conformers were also computed.

  20. Inhibition of carbonic anhydrase isoforms I, II, IX and XII with secondary sulfonamides incorporating benzothiazole scaffolds.

    PubMed

    Petrou, Anthi; Geronikaki, Athina; Terzi, Emine; Guler, Ozen Ozensoy; Tuccinardi, Tiziano; Supuran, Claudiu T

    2016-12-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of benzothiazole-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I and hCA II and the transmembrane hCA IX and hCA XII. Several of the investigated derivatives showed interesting inhibition activity and selectivities for inhibiting hCA IX and hCA XII over the off-target ones hCA I and hCA II. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

  1. Design of benzothiazole-1,3,4-thiadiazole conjugates: synthesis and anticonvulsant evaluation.

    PubMed

    Siddiqui, Nadeem; Ahuja, Priya; Malik, Sachin; Arya, Satish K

    2013-11-01

    Various 2-[(6-substituted-1,3-benzothiazol-2-yl)amino]-N-[5-substituted-phenyl-1,3,4-thiadiazol-2-yl]acetamides were synthesized with a prospective exploration of "lead hopping", using pharmacophoric elements for in vivo anticonvulsant activity. This yielded three potent candidates (5i, 5t, and 5u) in the preliminary screening employing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) test, showing minimal neurotoxicity. Their quantitative study indicated an increase of nearly 2-10 times for the MES test and 7- to 67-fold for the scPTZ test in the protective index, the keystone in drug discovery for anticonvulsant activity.

  2. [Synthesis and biological evaluation of 2-(3-butynoicamidophenyl) benzothiazole derivatives as antitumor agents].

    PubMed

    Yin, Gui-Lin; Li, Yan; Tang, Ke; Jin, Xiao-Feng; Chen, Xiao-Guang; Li, Li; Feng, Zhi-Qiang

    2014-06-01

    A series of 2-(3-butynoicamidophenyl)benzothiazole derivatives were synthesized starting from 4-fluoro-3-nitrobenzoic acid. Structures of all the synthesized compounds were confirmed by 1H NMR and HR-MS. Their antitumor activities against human tumor cells lines (HCT116, Mia-PaCa2, U87-MG, A549, NCI-H1975) were evaluated by MTT assay. The results revealed that most of the synthesized compounds showed potent activities against HCT116, Mia-PaCa2, U87-MG tumor cells lines. Particularly, compounds 14c and 14h exhibited better activity with IC50 values of 1 x 10(-8) mol x L(-1) against U87-MG and HCT116 respectively. The structure-activity relationship of compounds was also discussed preliminarily.

  3. Synthesis and anticancer potential of benzothiazole linked phenylpyridopyrimidinones and their diones as mitochondrial apoptotic inducers.

    PubMed

    Kamal, Ahmed; Ashraf, Md; Vishnu Vardhan, M V P S; Faazil, Shaikh; Nayak, V Lakshma

    2014-01-01

    A series of benzothiazole linked phenylpyridopyrimidinones (8a-g) and their diones (9a-g) have been designed, synthesized and evaluated for their anticancer activity. Among the series one of the conjugate 8b showed significant cytotoxicity against human cervical cancer cell line ME-180 with IC50 value of 4.01μM. This compound was tested on the cell cycle perturbations and DNA damage. Flow cytometry analysis revealed that the compound 8b showed drastic cell cycle perturbations due to concentration dependent increase in the sub-G0 phase in ME-180 cell line. DNA fragmentation and Hoechst staining reveals that this compound induced cell death by apoptosis. Further caspase-3 and loss of mitochondrial membrane potential suggested that the compound induces cell death by apoptosis.

  4. Hybrid benzothiazole analogs as antiurease agent: Synthesis and molecular docking studies.

    PubMed

    Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Wadood, Abdul; Rahim, Fazal; Khan, Khalid Muhammad; Riaz, Muhammad

    2016-06-01

    Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and (1)H NMR, and evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory potential varying from 1.4±0.10 to 34.43±2.10μM when compared with standard thiourea (IC50 19.46±1.20μM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20 with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity than compound 20 having 3-methoxy substituent. The binding interactions of these active analogs were confirmed through molecular docking.

  5. Benzothiazole-Pyimidine-Based BF2 Complex for Selective Detection of Cysteine.

    PubMed

    Liu, Qingsong; Zhang, Changli; Wang, Xiaoqing; Gong, Shuwen; He, Weijiang; Liu, Zhipeng

    2016-01-01

    Due to the similar structure and reactivity of cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), the simultaneous discrimination of Cys over Hcy and GSH by a single fluorescent sensor is still a great challenge. In this work, a benzothiazole-pyimidine-based boron difluoride complex (BPB) was developed as a new fluorescent sensor for Cys. The sensor exhibits a highly selective "turn-on" response to cysteine over Hcy, GSH and other amino acids in aqueous solution at physiological pH. The observed pseudo-first-order rate constant for the reaction of BPB with Cys was calculated to be about 0.062 min(-1) . The detection limit of this sensor for Cys was determined to be 332 nm, and bioimaging of exogenous Cys by this sensor was successfully applied in living cells, thus indicating that this sensor holds great potential for biological applications.

  6. Chiral separation of benzothiazole derivatives of amino acids using capillary zone electrophoresis.

    PubMed

    Nováková, Zuzana; Pejchal, Vladimír; Fischer, Jan; Česla, Petr

    2017-02-01

    A method for the separation of enantiomers of leucine and phenylalanine benzothiazole derivatives as potential antimicrobial agents was developed using capillary zone electrophoresis with a dual cyclodextrin (CD) system. The best resolution of enantiomers was achieved in 100 mmol/L phosphate background electrolyte (pH 3.5) with the dual CD system consisting of 10 mmol/L of β-CD with 10 mmol/L of 2-hydroxypropyl-β-cyclodextrin for leucine derivative and 10 mmol/L of 2-hydroxypropyl-γ-cyclodextrin for phenylalanine derivative, respectively. Under the optimal conditions, the highest enantioresolution of 1.25 was achieved in a noncoated-fused silica capillary at 17°C and 24 kV applied voltage.

  7. Methylsulfonyl benzothiazoles (MSBT) derivatives: Search for new potential antimicrobial and anticancer agents.

    PubMed

    Lad, Nitin P; Manohar, Yogesh; Mascarenhas, Malcolm; Pandit, Yashwant B; Kulkarni, Mahesh R; Sharma, Rajiv; Salkar, Kavita; Suthar, Ashish; Pandit, Shivaji S

    2017-03-01

    A series of novel 4 and 5-substituted methylsulfonyl benzothiazole (MSBT) compounds having amide, alkoxy, sulfonamide, nitro and amine functionality were synthesized from sequential reactions on 5-ethoxy-2-(methylsulfonyl)benzo[d]thiazole such as nitration, reduction, sulfonation, dealkylation, etc. All synthesized compounds were screened against antimicrobial and selected screened for anticancer activity. Antimicrobial activities studies reveled that among all compounds screened, out of MSBT-07, MSBT-11, MSBT-12, MSBT-14, MSBT-19, and MSBT-27 were found to have promising antimicrobial activity at MIC range of 4-50μg/ml against selected bacterial as well as fungal species. Compounds having good antimicrobial activity were screened for cervical cancer (HeLA cell lines). Of these MSBT-07 and MSBT-12 significantly reduced the cell growth. Consequently their calculated GI50 values were found to be 0.1 or <0.1μM.

  8. 2-(2{prime}-hydroxyphenyl)benzothiazoles, -benzoxazoles, and -benzimidazoles for plastic scintillation applications

    SciTech Connect

    Pla-Dalmau, A.

    1995-08-25

    A new series of fluorescent compounds has been tested as dopants for plastic scintillation applications. Several 2-(2{prime}-hydroxyphenyl)benzothiazole, -benzoxazole, and -benzimidazole derivatives have been prepared and studied in a polystyrene matrix. Each derivative has been added to a styrene solution which has been thermally polymerized. The transmittance, fluorescence, and light yield characteristics of these compounds in polystyrene have been determined. Their emission time distributions have also been measured, and the decay time constants have been calculated from these data. In addition, the doped polystyrene samples have been irradiated to a total dose of 10 Mrad, utilizing a {sup 60}Co source in order to evaluate their susceptibility to radiation-induced damage. 6 figs., 1 tab.

  9. Multistep divergent synthesis of benzimidazole linked benzoxazole/benzothiazole via copper catalyzed domino annulation.

    PubMed

    Liao, Jen-Yu; Selvaraju, Manikandan; Chen, Chih-Hau; Sun, Chung-Ming

    2013-04-21

    An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1.

  10. Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors.

    PubMed

    Axford, Lorraine C; Agarwal, Piyush K; Anderson, Kelly H; Andrau, Laura N; Atherall, John; Barker, Stephanie; Bennett, James M; Blair, Michael; Collins, Ian; Czaplewski, Lloyd G; Davies, David T; Gannon, Carlie T; Kumar, Dushyant; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J; Mitchell, Dale R; Offermann, Daniel A; Palmer, James T; Palmer, Nicholas; Pitt, Gary R W; Pommier, Stéphanie; Price, Daniel; Narasinga Rao, B; Saxena, Rashmi; Shukla, Tarun; Singh, Amit K; Singh, Mahipal; Srivastava, Anil; Steele, Christopher; Stokes, Neil R; Thomaides-Brears, Helena B; Tyndall, Edward M; Watson, David; Haydon, David J

    2013-12-15

    The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.

  11. 2-(Nitroaryl)benzothiazole and benzoxazole derivatives as fluorogenic substrates for the detection of nitroreductase activity in clinically important microorganisms.

    PubMed

    Cellier, Marie; Gignoux, Amandine; James, Arthur L; Orenga, Sylvain; Perry, John D; Robinson, Shaun N; Stanforth, Stephen P; Turnbull, Graeme

    2015-12-15

    A series of carboxy-substituted 2-(nitroaryl)benzothiazole derivatives and carboxy-substituted 2-(nitroaryl)benzoxazole derivatives were prepared and evaluated as potential nitroreductase substrates for the purpose of detecting clinically important microorganisms. Several of the substrates produced highly fluorescent colonies with the majority of a panel of 10 Gram-negative bacteria and also with two of a panel of 8 Gram-positive bacteria.

  12. Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

    PubMed

    MacKinnon, Colin H; Lau, Kevin; Burch, Jason D; Chen, Yuan; Dines, Jonathon; Ding, Xiao; Eigenbrot, Charles; Heifetz, Alexander; Jaochico, Allan; Johnson, Adam; Kraemer, Joachim; Kruger, Susanne; Krülle, Thomas M; Liimatta, Marya; Ly, Justin; Maghames, Rosemary; Montalbetti, Christian A G N; Ortwine, Daniel F; Pérez-Fuertes, Yolanda; Shia, Steven; Stein, Daniel B; Trani, Giancarlo; Vaidya, Darshan G; Wang, Xiaolu; Bromidge, Steven M; Wu, Lawren C; Pei, Zhonghua

    2013-12-01

    Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.

  13. A comparative study between para-aminophenyl and ortho-aminophenyl benzothiazoles using NMR and DFT calculations.

    PubMed

    Pierens, G K; Venkatachalam, T K; Reutens, D

    2014-08-01

    Ortho-substituted and para-substituted aminophenyl benzothiazoles were synthesised and characterised using NMR spectroscopy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for the NH protons indicating the presence of a hydrogen bond in all ortho-substituted compounds as compared to the para compounds. The presence of intramolecular hydrogen bond in the ortho amino substituted aminophenyl benzothiazole forces the molecule to be planar which may be an additional advantage in developing these compounds as Alzheimer's imaging agent because the binding to amyloid fibrils prefers planar compounds. The splitting pattern of the methylene proton next to the amino group also showed significant coupling to the amino proton consistent with the notion of the existence of slow exchange and hydrogen bond in the ortho-substituted compounds. This is further verified by density functional theory calculations which yielded a near planar low energy conformer for all the o-aminophenyl benzothiazoles and displayed a hydrogen bond from the amine proton to the nitrogen of the thiazole ring. A detailed analysis of the (1)H, (13)C and (15)N NMR chemical shifts and density functional theory calculated structures of the compounds are described.

  14. Structure, Spectra, and DFT Simulation of Nickel Benzazolate Complexes with Tris(2-aminoethyl)amine Ligand.

    PubMed

    Cerezo, Javier; Requena, Alberto; Zúñiga, José; Piernas, María José; Santana, M Dolores; Pérez, José; García, Luís

    2017-03-20

    Benzazolate complexes of Ni(II), [Ni(pbz)(tren)]ClO4 (pbz = 2-(2'-hydroxyphenyl)-benzimidazole (pbm), 1, 2-(2'-hydroxyphenyl)-benzoxazole (pbx), 2, 2-(2'-hydroxyphenyl)-benzothiazole (pbt), 3; tren = tris(2-aminoethyl)amine), are prepared by self-assembly reaction and structurally characterized. Theoretical DFT simulations are carried out to reproduce the features of their crystal structures and their spectroscopic and photophysic properties. The three complexes are moderately luminescent at room temperature both in acetonitrile solution and in the solid state. The simulations indicate that the absorption spectrum is dominated by two well-defined transitions, and the electronic density concentrates in three MOs around the benzazole ligands. The Stokes shifts of the emission spectra of complexes 1-3 are determined by optimizing the electronic excited state.

  15. Determination of benzothiazole and benzotriazole derivates in tire and clothing textile samples by high performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    PubMed

    Avagyan, Rozanna; Sadiktsis, Ioannis; Thorsén, Gunnar; Östman, Conny; Westerholm, Roger

    2013-09-13

    A high performance liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive and negative mode has been developed for the separation and detection of benzothiazole and benzotriazole derivates. Ultra-sonication assisted solvent extraction of these compounds has also been developed and the overall method demonstrated on a selected clothing textile and an automobile tire sample. Matrix effects and extraction recoveries, as well as linearity and limits of detection have been evaluated. The calibration curves spanned over more than two orders of magnitude with coefficients of correlation R(2)>0.99 and the limits of detection and the limits of quantification were in the range 1.7-58pg injected and 18-140pg/g, respectively. The extraction recoveries ranged between 69% and 102% and the matrix effects between 75% and 101%. Benzothiazole and benzotriazole derivates were determined in the textile sample and benzothiazole derivatives determined in the tire sample with good analytical performance.

  16. Study on the Synthesis and Spectra of a Novel Kind of Carbozole Benzothiazole Indole Styryl Cyanine Dye with a Carbazole Bridged Chain.

    PubMed

    Fei, Xuening; Hao, Yachao; Gu, Yingchun; Li, Chao; Yu, Lu

    2014-03-01

    Based on the frequently-used cyanine dye probe thiazole orange (TO) and Cy3, a novel kind of styryl cyanine dye was designed and synthesized. Carbazole was inserted into the structures of two cyanine dyes, TO and Cy3, to act as a bridge to link the benzothiazole and indole. This modification resulted in a novel kind of carbozole benzothiazole indole cyanine dye with a carbazole-bridged chain. The dyes were characterized by HNMR and MS. The spectra of the novel dyes were also studied and the results showed that the fluorescence wavelength of novel carbazole benzothiazole indole cyanine dye shifted red, the Stokes shift and Fluorescence quantum yields increased and the fluorescence intensity was enhanced compared to that of TO. These results indicated that the novel dye could be used as an excellent fluorescent probe in biological labeling.

  17. A novel water-soluble benzothiazole derivative BD926 triggers ROS-mediated B lymphoma cell apoptosis via mitochondrial and endoplasmic reticulum signaling pathways.

    PubMed

    Li, Min-Hui; Yang, Ping; Yang, Tai; Zhang, Kun; Liu, Yang; Liu, Jin; Li, Li-Mei; Luo, Xing-Yan; Yang, Shu-Xia; Zou, Qiang; Zhang, Chong-Jie

    2016-11-01

    Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy have received considerable attention in recent years. However, the poor water solubility of most benzothiazole derivatives has limited their clinical application. We developed BD926, a novel water-soluble benzothiazole derivative and showed here that it could inhibit the proliferation and induce apoptosis of human Ramos B-lymphoma cells. We further showed that BD926 triggered apoptosis through both mitochondria and endoplasmic reticulum pathways. Moreover, BD926 caused cell cycle arrest at G0/G1 stage. Furthermore, accumulation of reactive oxygen species (ROS) were observed after BD926 treatment and ROS inhibitor was able to attenuate BD926-induced apoptosis, which suggested that BD926-induced apoptosis may be due to over-producing ROS. These results demonstrate the anticancer effects of BD926 in cell models and raise the possibility for the application of BD926 in cancer therapy.

  18. Addition Reactions of Me3 SiCN with Aldehydes Catalyzed by Aluminum Complexes Containing in their Coordination Sphere O, S, and N Ligands.

    PubMed

    Yang, Zhi; Yi, Yafei; Zhong, Mingdong; De, Sriman; Mondal, Totan; Koley, Debasis; Ma, Xiaoli; Zhang, Dongxiang; Roesky, Herbert W

    2016-05-10

    The reaction of one equivalent of LAlH2 (1; L=HC(CMeNAr)2 , Ar=2,6-iPr2 C6 H3 , β-diketiminate ligand) with two equivalents of 2-mercapto-4,6-dimethylpyrimidine hydrate resulted in LAl[(μ-S)(m-C4 N2 H)(CH2 )2 ]2 (2) in good yield. Similarly, when N-2-pyridylsalicylideneamine, N-(2,6-diisopropylphenyl)salicylaldimine, and ethyl 3-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate were used as starting materials, the corresponding products LAl[(μ-O)(o-C6 H4 )CN(C5 NH4 )]2 (3), LAlH[(μ-O)(o-C4 H4 )CN(2,6-iPr2 C6 H3 )] (4), and LAl[(μ-NH)(o-C8 SH8 )(COOC2 H5 )]2 (5) were isolated. Compounds 2-5 were characterized by (1) H and (13) C NMR spectroscopy as well as by single-crystal X-ray structural analysis. Surprisingly, compounds 2-5 exhibit good catalytic activity in addition reactions of aldehydes with trimethylsilyl cyanide (TMSCN).

  19. FeF(3) catalyzed cascade C-C and C-N bond formation: synthesis of differentially substituted triheterocyclic benzothiazole functionalities under solvent-free condition.

    PubMed

    Atar, Amol B; Jeong, Yeon Tae

    2014-05-01

    A series of diverse polyfunctionalized triheterocyclic benzothiazoles were easily prepared in excellent yields via the Biginelli reaction of 2-aminobenzothiazole with substituted benzaldehydes and α-methylene ketones using FeF(3) as an expeditious catalyst under solvent-free conditions. The protocol provides a practical and straightforward approach toward highly functionalized triheterocyclic benzothiazole derivatives in excellent yields. The reaction was conveniently promoted by FeF(3) and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom economy, operational simplicity, shorter reaction time, convergence, and facile automation.

  20. The Structure of Poly-2,5-Benzoxazole (ABPBO) and Poly-2,6-Benzothiazole (ABPBT) Fibers By X-Ray Diffraction

    DTIC Science & Technology

    1985-07-01

    AFWAL-TR-85-4097 ADA \\bC \\ Uq THE STRUCTURE OF POLY-2,5-BENZOXAZOLE (ABPBO) AND POLY-2,6-BENZOTHIAZOLE (ABPBT) FIBERS BY X-RAY DIFFRACTION Albert V...Classification) THE STRUCTURE OF POLY-2,5-BENZOXAZOLE (ABPBO) AND POLY-2,6-BENZOTHIAZOLE (ABPBT) FIBERS BY X-RAY DIFFRACTION 12. PERSONAL AUTHOR(S) W. Wade Adams...and identify by block number) FIELD GROUP SUB-GROUP Polybenzoxazole Unit Cell ABPBO Aromatic Heterocyclic 07 04 Polymer 11 04 19. ABSTRACT (Continue

  1. DFT simulation, quantum chemical electronic structure, spectroscopic and structure-activity investigations of 2-benzothiazole acetonitrile

    NASA Astrophysics Data System (ADS)

    Arjunan, V.; Thillai Govindaraja, S.; Jose, Sujin P.; Mohan, S.

    2014-07-01

    The Fourier transform infrared and FT-Raman spectra of 2-benzothiazole acetonitrile (BTAN) have been recorded in the range 4000-450 and 4000-100 cm-1 respectively. The conformational analysis of the compound has been carried out to obtain the stable geometry of the compound. The complete vibrational assignment and analysis of the fundamental modes of the compound are carried out using the experimental FTIR and FT-Raman data and quantum chemical studies. The experimental vibrational frequencies are compared with the wavenumbers derived theoretically by B3LYP gradient calculations employing the standard 6-31G**, high level 6-311++G** and cc-pVTZ basis sets. The structural parameters, thermodynamic properties and vibrational frequencies of the normal modes obtained from the B3LYP methods are in good agreement with the experimental data. The 1H (400 MHz; CDCl3) and 13C (100 MHz; CDCl3) nuclear magnetic resonance (NMR) spectra are also recorded. The electronic properties, the energies of the highest occupied and lowest unoccupied molecular orbitals are measured by DFT approach. The kinetic stability of the molecule has been determined from the frontier molecular orbital energy gap. The charges of the atoms and the structure-chemical reactivity relations of the compound are determined by its chemical potential, global hardness, global softness, electronegativity, electrophilicity and local reactivity descriptors by conceptual DFT methods. The non-linear optical properties of the compound have been discussed by measuring the polarisability and hyperpolarisability tensors.

  2. Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents.

    PubMed

    Kharbanda, Chetna; Alam, Mohammad Sarwar; Hamid, Hinna; Javed, Kalim; Bano, Sameena; Dhulap, Abhijeet; Ali, Yakub; Nazreen, Syed; Haider, Saqlain

    2014-11-01

    The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5 b, 5 c, 5 e, 5 g, 5 h, 6 b, 6 e and 6 f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-α assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5 d and 6 f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-α production without being either cytotoxic or ulcerogenic.

  3. Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines.

    PubMed

    Demir Özkay, Ümide; Can, Özgür Devrim; Sağlık, Begüm Nurpelin; Acar Çevik, Ulviye; Levent, Serkan; Özkay, Yusuf; Ilgın, Sinem; Atlı, Özlem

    2016-11-15

    In the current study, 14 new benzothiazole-piperazine compounds were designed to meet the structural requirements of acetylcholine esterase (AChE) inhibitors. The target compounds were synthesised in three steps. Structures of the newly synthesised compounds (7-20) were confirmed using IR, (1)H NMR, (13)C NMR, and HRMS methods. The inhibitory potential of the compounds on AChE (E.C.3.1.1.7, from electric eel) was then investigated. Among the compounds, 19 and 20 showed very good activity on AChE enzyme. Kinetics studies were performed to observe the effects of the most active compounds on the substrate-enzyme relationship. Cytotoxicity studies, genotoxicity studies, and theoretical calculation of pharmacokinetics properties were also carried out. The compounds 19 and 20 were found to be nontoxic in both of the toxicity assays. A good pharmacokinetics profile was predicted for the synthesised compounds. Molecular docking studies were performed for the most active compounds, 19 and 20, and interaction modes with enzyme active sites were determined. Docking studies indicated a strong interaction between the active sites of AChE enzyme and the analysed compounds.

  4. New benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents.

    PubMed

    Tung, Truong Thanh; Oanh, Dao Thi Kim; Dung, Phan Thi Phuong; Hue, Van Thi My; Park, Sang Ho; Han, Byung Woo; Kim, Youngsoo; Hong, Jin-Tae; Han, Sang-Bae; Nam, Nguyen-Hai

    2013-12-01

    Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza(®) (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N(1)-(6-chlorobenzo[d]thiazol-2-yl)-N(8)-hydroxyoctanediamide (3a), N(1)-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N(8)-hydroxyoctanediamide (3b) and N(1)-(thiazol-2-yl)-N(8)-hydroxyoctanediamide (6) were synthesized and evaluated for HDAC inhibition and cytotoxic activities. All three compounds showed very potent HDAC inhibitory effects. Docking revealed that both two compounds 3a, 3b showed higher affinities towards HDAC(8) compared to SAHA. In vitro, compound 3a exhibited cytotoxicity equipotent to SAHA against five human cancer cell lines. In term of in vivo activity, compound 3a demonstrated equivalent efficacy to SAHA in mouse xenograft model.

  5. An iminocoumarin benzothiazole-based fluorescent probe for imaging hydrogen sulfide in living cells.

    PubMed

    Zhang, Huatang; Xie, Yusheng; Wang, Ping; Chen, Ganchao; Liu, Ruochuan; Lam, Yun-Wah; Hu, Yi; Zhu, Qing; Sun, Hongyan

    2015-04-01

    Hydrogen sulfide (H2S) has recently been identified as the third gaseous signaling molecule that is involved in regulating many important cellular processes. We report herein a novel fluorescent probe for detecting H2S based on iminocoumarin benzothiazole scaffold. The probe displayed high sensitivity and around 80-fold increment in fluorescence signal after reacting with H2S under physiological condition. The fluorescent intensity of the probe was linearly related to H2S concentration in the range of 0-100 μM with a detection limit of 0.15 μM (3σ/slope). The probe also showed excellent selectivity towards H2S over other biologically relevant species, including ROS, RSS and RNS. Its selectivity for H2S is 32 folds higher than other reactive sulfur species. Furthermore, the probe has been applied for imaging H2S in living cells. Cell imaging experiments demonstrated that the probe is cell-permeable and can be used to monitor the alteration of H2S concentrations in living cells. We envisage that this probe can provide useful tools to further elucidate the biological roles of H2S.

  6. Synthesis, materials characterization and opto(electrical) properties of unsymmetrical azomethines with benzothiazole core

    NASA Astrophysics Data System (ADS)

    Iwan, Agnieszka; Palewicz, Marcin; Krompiec, Michal; Grucela-Zajac, Marzena; Schab-Balcerzak, Ewa; Sikora, Andrzej

    2012-11-01

    Optical (UV-vis and photoluminescence) properties of two soluble organic molecules based on azomethines with benzothiazole core (BTA1 and BTA2) were reported. The structures of both compounds are characterized by means FTIR, 1H NMR, and 13C NMR spectroscopy and elemental analysis; the results show an agreement with the proposed structure. The investigated compounds emitted blue light. Influence of excitation wavelength and concentration on maximum and intensity of emission of BTA1 and BTA2 was found. Electrochemical properties of the compounds were studied by differential pulse voltammetry. Introduction of fluorine moieties (BTA1) resulted in lower energy band gap (Eg) of approximately ˜0.5 eV, whereas BTA2 showed Eg of ˜2.8 eV. The devices comprised of BTA1 with P3HT:PCBM (1:1:1) showed an open circuit voltage (VOC) of 0.40 V, a short circuit current (JSC) of 1.19 mA/cm2, and a fill factor (FF) of 0.23, giving a power-conversion efficiency (PCE) of 0.10% under AM1.5G irradiation (100 mW/cm2).

  7. Experimental and theoretical study of three new benzothiazole-fused carbazole derivatives

    NASA Astrophysics Data System (ADS)

    Shi, He-ping; Xu, Lei; Cheng, Ying; He, Jing-yuan; Dai, Jian-xin; Xing, Li-wen; Chen, Bai-quan; Fang, Li

    2011-10-01

    Three new D-π-A type compounds, each containing one benzothiazole ring as an electron acceptor and one N-ethylcarbazole group as electron donor, were synthesized and characterized by elemental analysis, NMR, MS and thermogravimetric analysis. The absorption and emission spectra of three compounds were experimentally determined in several solvents and were simultaneously computed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The calculated reorganization energy for hole and electron indicates that three compounds are in favor of hole transport than electron transport. The calculated absorption and emission wavelengths are well coincident with the measured data. The calculated lowest-lying absorption spectra can be mainly attributed to intramolecular charge transfer (ICT). And the calculated fluorescence spectra can be mainly described as originating from an excited state with intramolecular charge transfer (ICT) character. The results show that three compounds exhibited excellent thermal stability and high fluorescence quantum yields, indicating their potential applications as excellent optoelectronic material in optical field.

  8. The Detoxification and Degradation of Benzothiazole from the Wastewater in Microbial Electrolysis Cells.

    PubMed

    Liu, Xianshu; Ding, Jie; Ren, Nanqi; Tong, Qingyue; Zhang, Luyan

    2016-12-20

    In this study, the high-production-volume chemical benzothiazole (BTH) from synthetic water was fully degraded into less toxic intermediates of simple organic acids using an up-flow internal circulation microbial electrolysis reactor (UICMER) under the hydraulic retention time (HRT) of 24 h. The bioelectrochemical system was operated at 25 ± 2 °C and continuous-flow mode. The BTH loading rate varied during experiments from 20 g·m(-3)·day(-1) to 110 g·m(-3)·day(-1). BTH and soluble COD (Chemical Oxygen Demand) removal efficiency reached 80% to 90% under all BTH loading rates. Bioluminescence based Shewanella oneidensis strain MR-1 ecotoxicity testing demonstrated that toxicity was largely decreased compared to the BTH wastewater influent and effluent of two control experiments. The results indicated that MEC (Microbial Electrolysis Cell) was useful and reliable for improving BTH wastewater treatment efficiency, enabling the microbiological reactor to more easily respond to the requirements of higher loading rate, which is meaningful for economic and efficient operation in future scale-up.

  9. A novel acidic pH fluorescent probe based on a benzothiazole derivative.

    PubMed

    Ma, Qiujuan; Li, Xian; Feng, Suxiang; Liang, Beibei; Zhou, Tiqiang; Xu, Min; Ma, Zhuoyi

    2017-04-15

    A novel acidic pH fluorescent probe 1 based on a benzothiazole derivative has been designed, synthesized and developed. The linear response range covers the acidic pH range from 3.44 to 6.46, which is valuable for pH researches in acidic environment. The evaluated pKa value of the probe 1 is 4.23. The fluorescence enhancement of the studied probe 1 with an increase in hydrogen ions concentration is based on the hindering of enhanced photo-induced electron transfer (PET) process. Moreover, the pH sensor possesses a highly selective response to H(+) in the presence of metal ions, anions and other bioactive small molecules which would be interfere with its fluorescent pH response. Furthermore, the probe 1 responds to acidic pH with short response time that was less than 1min. The probe 1 has been successfully applied to confocal fluorescence imaging in live HeLa cells and can selectively stain lysosomes. All of such good properties prove it can be used to monitoring pH fluctuations in acidic environment with high sensitivity, pH dependence and short response time.

  10. Photophysical properties and photostability of novel benzothiazole-based D- π- A- π- D systems

    NASA Astrophysics Data System (ADS)

    Cigáň, Marek; Gáplovský, Anton; Gajdoš, Peter; Magdolen, Peter; Zahradník, Pavol; Vetríková, Zuzana

    2010-12-01

    The photophysical properties and photochemical stability of two novel D- π- A- π- D systems based on a benzothiazole core and terminal N, N-dimethylaminophenyl and N, N-diphenylaminophenyl groups were investigated. The quantum yield of photoreactions ( Φ) was determined for various oxygen concentrations in the solvent (CH 2Cl 2) and various irradiation wavelengths. Trans- cis photoisomerization is proposed as a photobleaching mechanism during irradiation at longer wavelength due to charge-transfer transitions. Solution deoxygenation led to an unusual decrease in the photostability of the compounds investigated, most likely because of cation radical formation. The population of higher excited states for short-wavelength irradiation opened another degradation pathway and the overall degradation percentage decreased in comparison with long-wavelength irradiation. We assume that photoisomerization of the second double bond and electron transfer to CH 2Cl 2 (and subsequent oxidation reactions) contribute to this slower degradation branch. Singlet oxygen contributes significantly, albeit to the smallest values of Φ, to the overall photodegradation for both types of irradiation.

  11. Synthesis and cytotoxic activity of certain benzothiazole derivatives against human MCF-7 cancer cell line.

    PubMed

    Mohamed, Lamia W; Taher, Azza T; Rady, Ghada S; Ali, Mamdouh M; Mahmoud, Abeer E

    2016-10-04

    A new series of benzothiazole has been synthesized as cytotoxic agents. The new derivatives were tested for their cytotoxic activity toward the human breast cancer MCF-7 cell line against cisplatin as the reference drug. Many derivatives revealed good cytotoxic effect, whereas four of them, 4, 5c, 5d, and 6b, were more potent than cisplatin, with IC50 values being 8.64, 7.39, 7.56, and 5.15 μm compared to 13.33 μm of cisplatin. The four derivatives' cytotoxic activity was accompanied by regulating free radicals production, by increasing the activity of superoxide dismutase and depletion of intracellular reduced glutathione, catalase, and glutathione peroxidase activities, accordingly, the high production of hydrogen peroxide, nitric oxide, and other free radicals causing tumor cell death as monitored by reduction in the synthesis of protein and nucleic acids. Most of the tested compounds showed potent to moderate growth inhibitory activity; in particular, compound 6b exhibited the highest activity suggesting it is a lead compound in cytotoxic activity.

  12. Widespread Occurrence of Benzotriazoles and Benzothiazoles in Tap Water: Influencing Factors and Contribution to Human Exposure.

    PubMed

    Wang, Lei; Zhang, Junjie; Sun, Hongwen; Zhou, Qixing

    2016-03-01

    Despite the frequent detection of benzotriazoles (BTRs) and benzothiazoles (BTHs) in groundwater and surface-water environments, knowledge on their occurrence and profile in tap water is still scarce. This study demonstrates widespread occurrence of these compounds in tap water from 51 major cities in China, which have ranges of

  13. Advanced treatment of benzothiazole contaminated waters: comparison of O3, AC, and O3/AC processes.

    PubMed

    Valdés, H; Zaror, C A

    2005-01-01

    Benzothiazole (BT) is a toxic and poorly biodegradable contaminant, usually found in wastewater from rubber related applications. This compound could be effectively eliminated using advanced treatment processes. This paper compares experimental results on detoxification systems based on ozone oxidation, activated carbon adsorption, and simultaneous adsorption-oxidation using ozone in the presence of activated carbon. The effect of pH (2-11), and the presence of radical scavengers (tert-butyl alcohol and sodium carbonate) on process rates and removal efficiencies are assessed at laboratory scale. The experimental system consisted of a 1 L differential circular flow reactor and an ozone generator rated at 5 g O3/h. Results show that ozone oxidation combined with activated carbon adsorption increases the overall BT oxidation rate with respect to the ozonation process and activated carbon adsorption. In the presence of free radical scavenger, only a 44% reduction in BT removal rate is observed in the simultaneous treatment, as compared with 72% when ozonation treatment is used, suggesting that BT oxidation reactions mainly take place on the activated carbon surface.

  14. A novel acidic pH fluorescent probe based on a benzothiazole derivative

    NASA Astrophysics Data System (ADS)

    Ma, Qiujuan; Li, Xian; Feng, Suxiang; Liang, Beibei; Zhou, Tiqiang; Xu, Min; Ma, Zhuoyi

    2017-04-01

    A novel acidic pH fluorescent probe 1 based on a benzothiazole derivative has been designed, synthesized and developed. The linear response range covers the acidic pH range from 3.44 to 6.46, which is valuable for pH researches in acidic environment. The evaluated pKa value of the probe 1 is 4.23. The fluorescence enhancement of the studied probe 1 with an increase in hydrogen ions concentration is based on the hindering of enhanced photo-induced electron transfer (PET) process. Moreover, the pH sensor possesses a highly selective response to H+ in the presence of metal ions, anions and other bioactive small molecules which would be interfere with its fluorescent pH response. Furthermore, the probe 1 responds to acidic pH with short response time that was less than 1 min. The probe 1 has been successfully applied to confocal fluorescence imaging in live HeLa cells and can selectively stain lysosomes. All of such good properties prove it can be used to monitoring pH fluctuations in acidic environment with high sensitivity, pH dependence and short response time.

  15. Hybrid Moving Bed Biofilm Reactor for the biodegradation of benzotriazoles and hydroxy-benzothiazole in wastewater.

    PubMed

    Mazioti, Aikaterini A; Stasinakis, Athanasios S; Psoma, Aikaterini K; Thomaidis, Nikolaos S; Andersen, Henrik R

    2017-02-05

    A laboratory scale Hybrid Moving Bed Biofilm Reactor (HMBBR) was used to study the removal of five benzotriazoles and one benzothiazole from municipal wastewater. The HMBBR system consisted of two serially connected fully aerated bioreactors that contained activated sludge (AS) and K3-biocarriers and a settling tank. The average removal of target compounds ranged between 41% (4-methyl-1H-benzotriazole; 4TTR) and 88% (2-hydroxybenzothiazole; OHBTH). Except for 4TTR, degradation mainly occurred in the first bioreactor. Calculation of biodegradation constants in batch experiments and application of a model for describing micropollutants removal in the examined system showed that AS is mainly involved in biodegradation of OHBTH, 1H-benzotriazole (BTR) and xylytriazole (XTR), carriers contribute significantly on 4TTR biodegradation, while both types of biomass participate on elimination of 5-chlorobenzotriazole (CBTR) and 5-methyl-1H-benzotriazole (5TTR). Comparison of the HMBBR system with MBBR or AS systems from literature showed that the HMBBR system was more efficient for the biodegradation of the investigated chemicals. Biotransformation products of target compounds were identified using ultra high-performance liquid chromatography, coupled with a quadrupole-time-of-flight high-resolution mass spectrometer (UHPLC-QToF-MS). Twenty two biotransformation products were tentatively identified, while retention time denoted the formation of more polar transformation products than the parent compounds.

  16. 6,6 '-Disubstituted benzothiazole trimethine cyanines - new fluorescent dyes for DNA detection

    NASA Astrophysics Data System (ADS)

    Kovalska, Vladyslava B.; Volkova, Kateryna D.; Losytskyy, Mykhaylo Yu.; Tolmachev, Olexiy I.; Balanda, Anatoliy O.; Yarmoluk, Sergiy M.

    2006-10-01

    The influence of methyl-, 2-hydroxyethyl-, dimethyl-, diethyl- and benzoyl-amino substituents in the 6,6'-positions of benzothiazole heterocycle of trimethine cyanines on their spectral-luminescent properties and behavior in presence of DNA, RNA and BSA was studied. It was shown that incorporation of 6,6'-substituents generally leads to the increase in dyes tendency to aggregation, resulting in the considerable decrease in the emission intensity of the disubstituted dyes as compared to the unsubstituted ones. Emission of the studied 6,6'-disubstited dyes in DNA presence is considerably more intensive than in presence of RNA, that points on the existing of DNA binding preference for the mentioned dyes. Insertion of benzoyl-amino groups into the 6,6'-positions permitted us to design the DNA-sensitive dyes on the basis of symmetric trimethine cyanines with unsubstituted polymethine chain, while typically such dyes slightly respond on the presence of biopolymers. 6,6'-Benzoyl-amino-disubstituted trimethine cyanines are proposed as efficient dyes for DNA detection.

  17. 6,6'-Disubstituted benzothiazole trimethine cyanines--new fluorescent dyes for DNA detection.

    PubMed

    Kovalska, Vladyslava B; Volkova, Kateryna D; Losytskyy, Mykhaylo Yu; Tolmachev, Olexiy I; Balanda, Anatoliy O; Yarmoluk, Sergiy M

    2006-10-01

    The influence of methyl-, 2-hydroxyethyl-, dimethyl-, diethyl- and benzoyl-amino substituents in the 6,6'-positions of benzothiazole heterocycle of trimethine cyanines on their spectral-luminescent properties and behavior in presence of DNA, RNA and BSA was studied. It was shown that incorporation of 6,6'-substituents generally leads to the increase in dyes tendency to aggregation, resulting in the considerable decrease in the emission intensity of the disubstituted dyes as compared to the unsubstituted ones. Emission of the studied 6,6'-disubstited dyes in DNA presence is considerably more intensive than in presence of RNA, that points on the existing of DNA binding preference for the mentioned dyes. Insertion of benzoyl-amino groups into the 6,6'-positions permitted us to design the DNA-sensitive dyes on the basis of symmetric trimethine cyanines with unsubstituted polymethine chain, while typically such dyes slightly respond on the presence of biopolymers. 6,6'-Benzoyl-amino-disubstituted trimethine cyanines are proposed as efficient dyes for DNA detection.

  18. The Detoxification and Degradation of Benzothiazole from the Wastewater in Microbial Electrolysis Cells

    PubMed Central

    Liu, Xianshu; Ding, Jie; Ren, Nanqi; Tong, Qingyue; Zhang, Luyan

    2016-01-01

    In this study, the high-production-volume chemical benzothiazole (BTH) from synthetic water was fully degraded into less toxic intermediates of simple organic acids using an up-flow internal circulation microbial electrolysis reactor (UICMER) under the hydraulic retention time (HRT) of 24 h. The bioelectrochemical system was operated at 25 ± 2 °C and continuous-flow mode. The BTH loading rate varied during experiments from 20 g·m−3·day−1 to 110 g·m−3·day−1. BTH and soluble COD (Chemical Oxygen Demand) removal efficiency reached 80% to 90% under all BTH loading rates. Bioluminescence based Shewanella oneidensis strain MR-1 ecotoxicity testing demonstrated that toxicity was largely decreased compared to the BTH wastewater influent and effluent of two control experiments. The results indicated that MEC (Microbial Electrolysis Cell) was useful and reliable for improving BTH wastewater treatment efficiency, enabling the microbiological reactor to more easily respond to the requirements of higher loading rate, which is meaningful for economic and efficient operation in future scale-up. PMID:27999421

  19. A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry.

    PubMed

    Keri, Rangappa S; Patil, Mahadeo R; Patil, Siddappa A; Budagumpi, Srinivasa

    2015-01-07

    Benzothiazole (BTA) and its derivatives are the most important heterocyclic compounds, which are common and integral feature of a variety of natural products and pharmaceutical agents. BTA shows a variety of pharmacological properties, and its analogs offer a high degree of structural diversity that has proven useful for the search of new therapeutic agents. The broad spectrum of pharmacological activity in individual BTA derivative indicates that, this series of compounds is of an undoubted interest. The related research and developments in BTA-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous BTA-based compounds as clinical drugs have been extensively used in practice to treat various types of diseases with high therapeutic potency. This work systematically gives a comprehensive review in current developments of BTA-based compounds in the whole range of medicinal chemistry as anticancer, antibacterial, antifungal, antiinflammatory, analgesic, anti-HIV, antioxidant, anticonvulsant, antitubercular, antidiabetic, antileishmanial, antihistaminic, antimalarial and other medicinal agents. It is believed that, this review article is helpful for new thoughts in the quest for rational designs of more active and less toxic BTA-based drugs, as well as more effective diagnostic agents and pathologic probes.

  20. Synergistic Inhibition Effect of Zinc Acetylacetonate and Benzothiazole in Epoxy Coating on the Corrosion of Mild Steel

    NASA Astrophysics Data System (ADS)

    Amoozadeh, S. M.; Mahdavian, M.

    2015-06-01

    The corrosion inhibition effect of zinc acetylacetonate (ZAA) and benzothiazole (BTH) mixture was evaluated for mild steel in 3.5% NaCl solution. To this end, ZAA:BTH mixtures ranged from 6:1 to 1:6 mol ratios were examined by weight loss and open circuit potential to obtain optimal mole ratio. The optimal mixture of ZAA:BTH at 1:5 mol ratio showed a significant corrosion inhibition efficiency proved by electrochemical impedance spectroscopy and polarization studies. The addition of the optimal mixture of ZAA:BTH to epoxy coating showed a considerable increase of corrosion protection evaluated by salt spray exposure.

  1. The influence of the various central metals on photophysical and photochemical properties of benzothiazole-substituted phthalocyanines

    NASA Astrophysics Data System (ADS)

    Nas, Asiye; Dilber, Gülsev; Durmuş, Mahmut; Kantekin, Halit

    2015-01-01

    The photophysical (fluorescence quantum yields and lifetimes, fluorescence quenching studies by 1,4-benzoquinone (BQ)) and photochemical (singlet oxygen quantum yields and photodegradation studies under light irradiation) properties of tetra-benzothiazole substituted metal-free (H2Pc, 1), lead (II) (PbPc, 2) and zinc(II) (ZnPc, 3) phthalocyanine compounds were investigated in tetrahydrofuran (THF) solution. All of these compounds did not show any aggregation and they produced good singlet oxygen (especially ZnPc). The influence of the various central metal ions (zinc, lead or without metal) on the photophysical and photochemical parameters was also investigated and compared.

  2. PMHS-mediated couplings of alkynes or benzothiazoles with various electrophiles: application to the synthesis of (-)-akolactone A.

    PubMed

    Gallagher, William P; Maleczka, Robert E

    2003-08-22

    Polymethylhydrosiloxane (PMHS) in combination with CsF facilitates the cross-coupling of alkynes or benzothiazoles with an array of vinyl, styryl, and aryl halides or nonaflates as well as acid chlorides. Experimental and spectroscopic evidence indicates that these reactions involve the in situ generation of a siloxyl intermediate. These cross-couplings proceed relatively quickly at room temperature and under amine-free conditions. To demonstrate the applicability of the method, a total synthesis of the cyctotoxic butanolide (-)-akolactone A was carried out.

  3. The influence of the various central metals on photophysical and photochemical properties of benzothiazole-substituted phthalocyanines.

    PubMed

    Nas, Asiye; Dilber, Gülsev; Durmuş, Mahmut; Kantekin, Halit

    2015-01-25

    The photophysical (fluorescence quantum yields and lifetimes, fluorescence quenching studies by 1,4-benzoquinone (BQ)) and photochemical (singlet oxygen quantum yields and photodegradation studies under light irradiation) properties of tetra-benzothiazole substituted metal-free (H2Pc, 1), lead (II) (PbPc, 2) and zinc(II) (ZnPc, 3) phthalocyanine compounds were investigated in tetrahydrofuran (THF) solution. All of these compounds did not show any aggregation and they produced good singlet oxygen (especially ZnPc). The influence of the various central metal ions (zinc, lead or without metal) on the photophysical and photochemical parameters was also investigated and compared.

  4. Differential encapsulation of trans-2-[4-(dimethylamino)styryl] benzothiazole in cyclodextrin hosts: Application towards nanotubular suprastructure formation

    NASA Astrophysics Data System (ADS)

    Purkayastha, Pradipta; Das, Debasmita; Syed Jaffer, S.

    2008-12-01

    The guest size dependent extent of encapsulation by cyclodextrins (CDs) of different sizes ( viz., α-, β-, and γ-) has been studied using cyclic voltammetry and fluorescence spectroscopy. Electrochemical and chemical oxidation methods have been used to understand the extent to which trans-2-[4-(dimethylamino)styryl]benzothiazole (DMASBT) gets encapsulated in the cyclodextrin cavities. The guest molecule can induce the formation of nanocapsules with cyclodextrin hosts due to hydrophobic interaction leading to the formation of nanotubes followed by suprastructures. The electrochemically obtained results were confirmed using chemical method. The differential encapsulation of DMASBT in the CDs may define the architecture of the nanotubes.

  5. Piezochromic luminescence behaviors of two new benzothiazole-enamido boron difluoride complexes: intra- and inter-molecular effects induced by hydrostatic compression.

    PubMed

    Wang, Xiaoqing; Liu, Qingsong; Yan, Hui; Liu, Zhipeng; Yao, Mingguang; Zhang, Qingfu; Gong, Shuwen; He, Weijiang

    2015-05-01

    Two new propeller-shaped benzothiazole-enamide boron difluoride complexes exhibiting piezochromic luminescence upon mechanical grinding or hydrostatic compression were prepared. The two analogues displayed the red shift in luminescence under high pressure, while compound 2 with ICT effects showed a more sensitive piezochromic response at low pressure (<1.5 GPa). The different piezochromic luminescence behaviors of these compounds were investigated.

  6. Anchoring of Cu(II) onto surface of porous metal-organic framework through post-synthesis modification for the synthesis of benzimidazoles and benzothiazoles

    SciTech Connect

    Kardanpour, Reihaneh; Tangestaninejad, Shahram Mirkhani, Valiollah Moghadam, Majid Mohammadpoor-Baltork, Iraj; Zadehahmadi, Farnaz

    2016-03-15

    Efficient synthesis of various benzimidazoles and benzothiazoles under mild conditions catalyzed by Cu(II) anchored onto UiO-66–NH{sub 2} metal organic framework is reported. In this manner, first, the aminated UiO-66 was modified with thiophene-2-carbaldehyde and then the prepared Schiff base was reacted with CuCl{sub 2}. The prepared catalyst was characterized by FT-IR, UV–vis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N{sub 2} adsorption, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). The UiO-66–NH{sub 2}–TC–Cu was applied as a highly efficient catalyst for synthesis of benzimidazole and benzothiazole derivatives by the reaction of aldehydes with 1,2-diaminobenzene or 2-aminothiophenol. The Cu(II)-containing MOF was reused several times without any appreciable loss of its efficiency. - Graphical abstract: Efficient synthesis of benzimidazoles and benzothiazoles catalyzed by Cu(II) anchored onto UiO-66–NH{sub 2} metal organic framework is reported. - Highlights: • A copper Schiff base was immobilized on UiO-66 via postsynthetic modification. • The modified MOFs were fully characterized by a variety of methods. • The catalyst was used for the preparation of benzimidazoles and benzothiazoles. • In comparison of other catalysts, our catalyst was more efficient and forceful.

  7. Copper-catalyzed double C-S bonds formation via different paths: synthesis of benzothiazoles from N-benzyl-2-iodoaniline and potassium sulfide.

    PubMed

    Zhang, Xiaoyun; Zeng, Weilan; Yang, Yuan; Huang, Hui; Liang, Yun

    2014-02-07

    A new, highly efficient procedure for the synthesis of benzothiazoles from easily available N-benzyl-2-iodoaniline and potassium sulfide has been developed. The results show copper-catalyzed double C-S bond formation via a traditional cross-coupling reaction and an oxidative cross-coupling reaction.

  8. Properties, theoretical study and crystal structure of 3-benzothiazole-9-ethyl carbazole.

    PubMed

    Gu, Yingchun; Lin, Dayong; Fei, Xuening; Wang, Cuihong; Li, Ling; Tang, Yalin; Zhou, Jianguo

    2016-09-01

    The title compound of 3-benzothiazole-9-ethyl carbazole was synthesized by the reaction of 3-aldehyde-9-ethyl carbazole and 2-aminothiophenol. The compound was characterized by (1) H nuclear magnetic resonance (NMR) and mass spectrometry (MS). Its crystal structure was obtained and determined by single crystal X-ray diffraction. The results showed that the crystal belongs to the orthorhombic crystal system and the cell parameters of space group P2(1)2(1)2(1) were a = 5.6626 (12) Å, b = 12.606 (3) Å, c = 22.639 (5) Å, α = 90°, β = 90°, γ = 90°, V = 1616.0 (6) Å(3) , Z = 4, Dc = 1.350 mg/m(3) . The UV-vis and fluorescence spectra were also studied preliminarily. The fluorescence spectra of the title compound with bovine serum albumin (BSA) showed that BSA could be marked with the compound and the stability constant between them was 0.82 × 10(7)  M(-1) . Meanwhile, the crystal and molecule were theoretically surveyed by density functional tight-binding (DFTB). The results showed that there was an orbital overlap for lowest unoccupied molecular orbital (LUMO) between the neighbouring molecules for the crystal, which is different from the molecule structure. It was also showed that the crystal structure is a non-conductor. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Red hair benzothiazines and benzothiazoles: mutation-inspired chemistry in the quest for functionality.

    PubMed

    Napolitano, Alessandra; Panzella, Lucia; Leone, Loredana; d'Ischia, Marco

    2013-02-19

    Nature provides a primary source of leads for the design of π-conjugated organic chromophores and other functional molecular systems useful for molecular recognition, light harvesting, photoconversion, and other technological applications. In this Account, we draw attention to a unique group of naturally occurring heterocyclic compounds, the 2H-1,4-benzothiazines and related benzothiazole derivatives. Derived from tyrosine and cysteine, these molecules arise from a mutation-induced deviation of the melanin pathway to provide the core structure of the red human hair pigments pheomelanins. Since the elucidation of the biosynthetic pathway of pheomelanins in the 1960s, researchers have focused on 1,4-benzothiazines and red hair pigments. Not only do these molecules have interesting photochemical and molecular recognition properties, they also have compelling biomedical significance. Numerous studies have linked higher levels of pheomelanins and mutations in the pathways that produce these pigments in individuals with red hair and fair skin with an increased sensitivity to UV light and a higher susceptibility to melanoma and other skin cancers. Prompted by new data about the structure and photochemistry of the bibenzothiazine system, this Account highlights the chemistry of benzothiazines in red-haired individuals as a novel source of inspiration in the quest for innovative scaffolds and biomimetic functional systems. Model studies have gradually shed light on a number of remarkable physical and chemical properties of benzothiazine-based systems. Bibenzothiazine is a robust visible chromophore that combines photochromism and acidichromism. Benzothiazine-based polymers (synthetic pheomelanins) show remarkable photochemical, paramagnetic, and redox cycling properties. Biomimetic or synthetic manipulations of the benzothiazine systems, through decarboxylation pathways controlled by metal ions or unusually facile ring-contraction processes, can produce a diverse set of

  10. Heterogeneous and homogeneous catalytic ozonation of benzothiazole promoted by activated carbon: kinetic approach.

    PubMed

    Valdés, Héctor; Zaror, Claudio A

    2006-11-01

    Ozone oxidation combined with activated carbon adsorption (O(3)/AC) has recently started to be developed as a single process for water and wastewater treatment. While a number of aspects of aqueous ozone decomposition are well understood, the importance and relationship between aqueous ozone decomposition and organic contaminant degradation in the presence of activated carbon is still not clear. This study focuses on determining the contribution of homogeneous and heterogeneous reactions to organic contaminants removal in O(3)/AC system. Benzothiazole (BT) was selected as a target organic pollutant due to its environmental concern. A reactor system based on a differential circular flow reactor composed by a 19 cm(3) activated carbon fixed bed column and 1 dm(3) storage tank was used. Ozone was produced from pure and dry oxygen using an Ozocav ozone generator rated at 5 g O(3)h(-1). Experimental results show that BT removal rate was proportional to activated carbon dosage. Activated carbon surface contribution to BT oxidation reactions with ozone, increased with pH in absence of radical scavengers. The radical reaction contribution within the pH range 2-11 accounted for 67-83% for BT removal in O(3)/AC simultaneous treatment. Results suggest that at pH higher than the pH of the point of zero charge of the activated carbon dissociated acid groups such as carboxylic acid anhydrides and carboxylic acids present on activated carbon surface could be responsible for the observed increase in the ozone decomposition reaction rate. A simplified mechanism and a kinetic scheme representing the contribution of homogeneous and heterogeneous reactions on BT ozonation in the presence of activated carbon is proposed.

  11. Synthesis and biological evaluation of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases.

    PubMed

    Vicini, Paola; Geronikaki, Athina; Incerti, Matteo; Busonera, Bernadetta; Poni, Graziella; Cabras, Carla Alba; La Colla, Paolo

    2003-11-03

    Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole compounds showed a marked cytotoxicity (CC(50)=4-9 microM) against the human CD4(+) lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]isothiazole derivatives inhibited the growth of leukaemia cell lines, whereas only one of the above mentioned compounds (1e) showed antiproliferative activity against two solid tumor-derived cell lines.

  12. Benzotriazole, benzothiazole, and benzophenone compounds in indoor dust from the United States and East Asian countries.

    PubMed

    Wang, Lei; Asimakopoulos, Alexandros G; Moon, Hyo-Bang; Nakata, Haruhiko; Kannan, Kurunthachalam

    2013-05-07

    Organic corrosion inhibitors (OCIs), including ultraviolet light filters, are widely used in plastics, rubbers, colorants, and coatings to increase the performance of products. Derivatives of benzotriazole (BTR), benzothiazole (BTH), and benzophenone (BP) are high-production volume OCIs that have been detected in the environment and human tissues. However, knowledge of their occurrence in indoor environments, as well as human exposure to them, is still lacking. In this study, BTR, BTH, BP and their 12 derivatives were determined in indoor dust for the first time. All three groups of OCIs were found in all 158 indoor dust samples from the U.S. and three East Asian countries (China, Japan, and Korea). The geometric mean (GM) concentration of the sum of six BTRs (GM CΣBTRs) ranged from 20 to 90 ng/g among the four countries studied, with a maximum CΣBTRs of ∼2000 ng/g found in a dust sample from China. Tolyltriazole was the major derivative of BTR measured in dust. GM CΣBTHs in indoor dust from the four countries ranged from 600 to 2000 ng/g. 2-OH-BTH was the predominant BTH in dust from the U.S., Japan, and Korea. GM CΣBPs in dust ranged from 80 to 600 ng/g, with 2-OH-4-MeO-BP and 2,4-2OH-BP, contributing to the majority of ∑BP concentrations. Based on the concentrations of three types of OCIs in indoor dust, human exposure through dust ingestion was calculated. Daily intake of OCIs through dust ingestion was higher for people in the U.S., Japan, and Korea than in China; the residents in urban China are exposed to higher levels of OCIs via dust ingestion than are those in rural China.

  13. Identification of selected microorganisms from activated sludge capable of benzothiazole and benzotriazole transformation.

    PubMed

    Kowalska, Katarzyna; Felis, Ewa

    2015-01-01

    Benzothiazole (BT) and benzotriazole (BTA) are present in the environment - especially in urban and industrial areas, usually as anthropogenic micropollutants. BT and BTA have been found in the municipal and industrial wastewater, rivers, soil, groundwater, sediments and sludge. The origins of those substances' presence in the environment are various industry branches (food, chemical, metallurgical, electrical), households and surface runoff from industrial areas. Increasingly strict regulations on water quality and the fact that the discussed compounds are poorly biodegradable, make them a serious problem in the environment. Considering this, it is important to look for environmentally friendly and socially acceptable ways to remove BT and BTA. The aim of this study was to identify microorganisms capable of BT and BTA transformation or/and degradation in aquatic environment. Selected microorganisms were isolated from activated sludge. The identification of microorganisms capable of BT and BTA removal was possible using molecular biology techniques (PCR, DNA sequencing). Among isolated microorganisms of activated sludge are bacteria potentially capable of BT and BTA biotransformation and/or removal. The most common bacteria capable of BT and BTA transformation were Rhodococcus sp., Enterobacter sp., Arthrobacter sp. They can grow in a medium with BT and BTA as the only carbon source. Microorganisms previously adapted to the presence of the studied substances at a concentration of 10 mg/l, showed a greater rate of growth of colonies on media than microorganisms unconditioned to the presence of such compounds. Results of the biodegradation test suggest that BT was degraded to a greater extent than BTA, 98-100% and 11-19%, respectively.

  14. Ligand modeling and design

    SciTech Connect

    Hay, B.P.

    1997-10-01

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

  15. Identification of benzothiazole derivatives and polycyclic aromatic hydrocarbons as aryl hydrocarbon receptor agonists present in tire extracts.

    PubMed

    He, Guochun; Zhao, Bin; Denison, Michael S

    2011-08-01

    Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. The ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, but the responsible chemicals and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemicals were metabolically labile. The application of CALUX (chemical-activated luciferase gene expression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown.

  16. Quantitative investigations of cation complexation of photochromic 8-benzothiazole-substituted benzopyran: towards metal-ion sensors.

    PubMed

    Zakharova, Marianna I; Coudret, Christophe; Pimienta, Véronique; Micheau, Jean Claude; Delbaere, Stéphanie; Vermeersch, Gaston; Metelitsa, Anatoly V; Voloshin, Nikolai; Minkin, Vladimir I

    2010-02-01

    The photochromic, thermochromic and metallochromic behaviour of a series of three spiro[indoline-8-(benzothiazol-2-yl)-benzopyrans] has been investigated. The thermodynamic and kinetic parameters of their thermal equilibrium between the ring-closed (spiro) and ring-opened (merocyanine) isomeric forms have been determined using UV-Vis absorption and (1)H NMR spectroscopies. By adding Co(ii) and Ni(ii) ions in acetonitrile solution, 1 : 1 and 1 : 2 metal : merocyanine complexes are formed simultaneously. Using appropriate numerical methods, the kinetic analysis of the complexation allowed us to determine accurately key thermodynamic and spectroscopic parameters of the metal complexes. Results showed that the complexation strength is very sensitive to the size of the indoline nitrogen substituent. Complexation can be reversed by shining white light on the coloured complexes which regenerates the inactive spiropyran form, and releases the metallic ion; hence, these systems display fully reversible negative photochromism. The Zn(ii) complexes exhibit intense fluorescence in the 600-800 nm wavelength range. All these behaviours make these spiropyrans bearing benzothiazole heterocycles promising building blocks for the future construction of photodynamic chemosensors for transition metal ions.

  17. Identification of Benzothiazole Derivatives and Polycyclic Aromatic Hydrocarbons as Aryl Hydrocarbon Receptor Agonists Present in Tire Extracts

    PubMed Central

    He, Guochun; Zhao, Bin; Denison, Michael S.

    2012-01-01

    Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. While the ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, the responsible chemical(s) and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemical(s) was metabolically labile. The application of CALUX (Chemical-Activated LUciferase gene eXpression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons, but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. PMID:21590714

  18. Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis.

    PubMed

    Patrick, Donald A; Gillespie, J Robert; McQueen, Joshua; Hulverson, Matthew A; Ranade, Ranae M; Creason, Sharon A; Herbst, Zackary M; Gelb, Michael H; Buckner, Frederick S; Tidwell, Richard R

    2017-02-09

    A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24 , 2451 - 2465 ) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.

  19. Modulating the near-infrared luminescence of neodymium and ytterbium complexes with tridentate ligands based on benzoxazole-substituted 8-hydroxyquinolines.

    PubMed

    Shavaleev, Nail M; Scopelliti, Rosario; Gumy, Frédéric; Bünzli, Jean-Claude G

    2009-04-06

    An improved synthesis of 2-(2'-benzothiazole)- and 2-(2'-benzoxazole)-8-hydroxyquinoline ligands that combine a tridentate N,N,O-chelating unit for metal binding and extended chromophore for light harvesting is developed. The 2-(2'-benzoxazole)-8-hydroxyquinoline ligands form mononuclear nine-coordinate complexes with neodymium, [Nd(kappa(3)-ligand)(3)], and an eight-coordinate complex with ytterbium, [Yb(kappa(3)-ligand)(2) x (kappa(1)-ligand) x H(2)O], as verified by crystallographic characterization of five complexes with four different ligands. The chemical stability of the complexes increases when the ligand contains 5,7-dihalo-8-hydroxyquinoline versus an 8-hydroxyquinoline group. The complexes feature a ligand-centered visible absorption band with a maximum at 508-527 nm and an intensity of (7.5-9.6) x 10(3) M(-1) x cm(-1). Upon excitation with UV and visible light within ligand absorption transitions, the complexes display characteristic lanthanide luminescence in the near-infrared at 850-1450 nm with quantum yields and lifetimes in the solid state at room temperature as high as 0.33% and 1.88 micros, respectively. The lanthanide luminescence in the complexes is enhanced upon halogenation of the 5,7-positions in the 8-hydroxyquinoline group and upon the addition of electron-donating substituents to the benzoxazole ring. Facile modification of chromophore units in 2-(2'-benzoxazole)-8-hydroxyquinoline ligands provides means for controlling the luminescence properties of their lanthanide complexes.

  20. Conformational Analysis of Poly-2,5-Benzimidazole (ABPBI), Poly-2,5- Benzoxazole (ABPBO), and Poly-2,6-Benzothiazole (ABPBT) Dimers by the Modified Neglect of Diatomic Overlap (MNDO) and Austin Method 1 (AM1) Semiempirical Molecular Orbital Methods

    DTIC Science & Technology

    1987-07-01

    AFWAL-TR-87-4034 A\\) CONFORMATIONAL ANALYSIS OF POLY-2,5-BENZOIMIDAZOLE (ABPBI), POLY-2,5-BENZOXAZOLE (ABPBO), AND POLY-2,6- BENZOTHIAZOLE (ABPBT... benzothiazole Molecular Orbital 19. ABSTRACT (Continue on reverse if necessar and identif-y by block number) The two repeat unit analogs of three, aromatic...SECURITY CLASSIFICATION OF THIS PAGE 11. TITLE (Cont) Poly-2,5-benzoxazole (ABPBO), and Poly-2,6- benzothiazole (ABPBT) Dimers by the Modified Neglect

  1. Ligand modeling and design

    SciTech Connect

    Hay, B.

    1996-10-01

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

  2. Biodegradation of benzotriazoles and hydroxy-benzothiazole in wastewater by activated sludge and moving bed biofilm reactor systems.

    PubMed

    Mazioti, Aikaterini A; Stasinakis, Athanasios S; Pantazi, Ypapanti; Andersen, Henrik R

    2015-09-01

    Two laboratory scale fully aerated continuous flow wastewater treatment systems were used to compare the removal of five benzotriazoles and one benzothiazole by suspended and attached growth biomass. The activated sludge system was operated under low organic loading conditions. The moving bed biofilm reactor (MBBR) system consisted of two serially connected reactors filled with K3-biocarriers. It was either operated under low or high organic loading conditions. Target compounds were removed partially and with different rates in tested systems. For MBBR, increased loading resulted in significantly lower biodegradation for 4 out of 6 examined compounds. Calculation of specific removal rates (normalized to biomass) revealed that attached biomass had higher biodegradation potential for target compounds comparing to suspended biomass. Clear differences in the biodegradation ability of attached biomass grown in different bioreactors of MBBR systems were also observed. Batch experiments showed that micropollutants biodegradation by both types of biomass is co-metabolic.

  3. Kinetic study of the complex reaction between copper(II) and 2-(2'-hydroxy-3'-methoxyphenyl)benzothiazole

    NASA Astrophysics Data System (ADS)

    Freinbichler, Wolfhardt; Soliman, Ahmed; Jameson, Reginald F.; Jameson, Guy N. L.; Linert, Wolfgang

    2009-09-01

    2-(2'-Hydroxy-3'-methoxyphenyl)benzothiazole reacts with copper(II) in an ethanol/water mixture to form an O,S chelate which exhibits the remarkable property of changing the chelation site above a pH of ca. 5.0, to the O,N site. The detailed kinetics of this reaction in an ethanol/water mixture (3:1) at a temperature of 25 °C was investigated using a stopped-flow spectrophotometric technique employing a wavelength of 400 nm. The initial complex, Cu(O,S), is formed via a fast, reversible second-order complex formation step whereupon the formation of the Cu (O,N) follows first order kinetics. The Cu(O,N) complex is, however, unstable towards internal electron exchange and after the reaction is complete, a black polymeric material very slowly precipitates out of solution. Rate and equilibrium constants for the postulated reactions are presented and discussed.

  4. Synthesis and pharmacological properties of benzothiazole, 1,3-4-oxadiazole and 1,3,4-thiadiazole derivatives.

    PubMed

    Santagati, M; Modica, M; Santagati, A; Russo, F; Caruso, A; Cutuli, V; Di Pietro, E; Amico-Roxas, M

    1994-12-01

    The reaction of the 2-amino-substituted 1,3,4-oxadiazoles 9, 10 and the benzothiazoles 11, 12 with ethyl cyanoacetate is described. The obtained cyanoacetamide derivatives 13-16 gave the benzylidene derivatives 18-21 by condensation with benzaldehyde. 2-Phenyl-5-amino-1,3,4-oxadiazolo[3,2-a]pyrimidin-7-one (17) was also obtained. Moreover, the preparation of 6,7,8,9-tetraydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin++ +-5-thio-derivatives 22-25 and N-(1,3,4-thiadiazol-2-yl-5-substituted)-3,4-5,6-tetrahydro-anthran ilic acids 26-29 is also described. All above compounds and compounds, related to them, 1-8 were tested for their analgesic and antiinflammatory activities and the pharmacological screening results are reported and discussed.

  5. Anchoring of Cu(II) onto surface of porous metal-organic framework through post-synthesis modification for the synthesis of benzimidazoles and benzothiazoles

    NASA Astrophysics Data System (ADS)

    Kardanpour, Reihaneh; Tangestaninejad, Shahram; Mirkhani, Valiollah; Moghadam, Majid; Mohammadpoor-Baltork, Iraj; Zadehahmadi, Farnaz

    2016-03-01

    Efficient synthesis of various benzimidazoles and benzothiazoles under mild conditions catalyzed by Cu(II) anchored onto UiO-66-NH2 metal organic framework is reported. In this manner, first, the aminated UiO-66 was modified with thiophene-2-carbaldehyde and then the prepared Schiff base was reacted with CuCl2. The prepared catalyst was characterized by FT-IR, UV-vis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). The UiO-66-NH2-TC-Cu was applied as a highly efficient catalyst for synthesis of benzimidazole and benzothiazole derivatives by the reaction of aldehydes with 1,2-diaminobenzene or 2-aminothiophenol. The Cu(II)-containing MOF was reused several times without any appreciable loss of its efficiency.

  6. A p-Hydroxyphenacyl-Benzothiazole-Chlorambucil Conjugate as a Real-Time-Monitoring Drug-Delivery System Assisted by Excited-State Intramolecular Proton Transfer.

    PubMed

    Barman, Shrabani; Mukhopadhyay, Sourav K; Biswas, Sandipan; Nandi, Surajit; Gangopadhyay, Moumita; Dey, Satyahari; Anoop, Anakuthil; Pradeep Singh, N D

    2016-03-18

    Among the well-known phototriggers, the p-hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high-conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2-(2'-hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited-state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p-hydroxyphenacyl-benzothiazole-chlorambucil conjugate presents excellent properties, such as real-time monitoring, photoregulated drug delivery, and biocompatibility.

  7. Application of the SOS/umu test and high-content in vitro micronucleus test to determine genotoxicity and cytotoxicity of nine benzothiazoles.

    PubMed

    Ye, Yan; Weiwei, Jiang; Na, Li; Mei, Ma; Kaifeng, Rao; Zijian, Wang

    2014-12-01

    Benzothiazole and benzothiazole derivatives (BTs) have been detected in various environmental matrices as well as in human beings, but little is currently available regarding their toxicities. In our study, genotoxicities of nine BTs (benzothiazole [BT], 2-chlorobenzothiazole [CBT], 2-bromobenzothiazole [BrBT], 2-fluorobenzothiazole [FBT], 2-methylbenzothiazole [MeBT], 2-mercaptobenzothiazole [MBT], 2-aminobenzothiazole [ABT], 2-hydroxy-benzothiazole [OHBT] and 2-methythiobenzothiazole [MTBT]) are comprehensively evaluated by the SOS/umu test using the bacterial Salmonella typhimurium TA1535/pSK1002 for DNA-damaging effect and the high content in vitro micronucleus test using two human carcinoma cells (MGC-803 and A549) for chromosome-damaging effect. The cytotoxicity of BTs on both bacteria and two human cells was also evaluated. Except for the cytotoxic effect of MBT on MGC-803 and A549, the other tested BTs showed more than 50% cytotoxicity at their highest concentrations in a dose-dependent manner, and their LC50s ranged from 19 (MBT in bacteria) to 270 mg l(-1) (CBT in A549). Activation and inactivation were observed for specific BTs after metabolism. On the other hand, no evidence of genotoxicity was obtained for BT, FBT and MBT, and DNA damage was induced by ABT, OHBT, BrBT and MTBT in MGC-803, by MeBT in A549 and by CBT in both cells. Through quantitative structure-activity relationship analysis, two structure alerts for chemical genotoxicity, including heterocyclic amine and hacceptor-path3-hacceptor are present in ABT and OHBT respectively; however, the underlying mechanisms still need further evaluation.

  8. Ligand fitting with CCP4

    PubMed Central

    2017-01-01

    Crystal structures of protein–ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein–ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building in Coot (LO/Carb) and ligand-validation tools (FLEV), the release of the CCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation. PMID:28177312

  9. Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and its complexes.

    PubMed

    Shpakovsky, D B; Banti, C N; Beaulieu-Houle, G; Kourkoumelis, N; Manoli, M; Manos, M J; Tasiopoulos, A J; Hadjikakou, S K; Milaeva, E R; Charalabopoulos, K; Bakas, T; Butler, I S; Hadjiliadis, N

    2012-12-28

    Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride [(tert-Bu-)(2)(HO-Ph)](2)SnCl(2) (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)(2)(HO-Ph)](2)Sn(PMT)(2)} (2), {[(tert-Bu-)(2)(HO-Ph)](2)Sn(MPMT)(2)} (3), {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(PYT)} (4) and {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, (1)H-, (13)C-, (119)Sn-NMR, EPR, FT-IR, Raman and Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1–5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1–5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2)-configurations in 2. However, in the case of 4 and 5 complexes two carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement. Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one nitrogen atom in a unique coordination mode of thioamides toward the tin(IV) cation. Compounds 1–5 were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line. Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC(50) = 0.58 ± 0.1 μM).

  10. Synthesis and phase transition studies on non-symmetric liquid crystal dimers: N-(4-(n-(4-(benzothiazol-2-yl)phenoxy)alkyloxy)-benzylidene)-4-chloroanilines

    NASA Astrophysics Data System (ADS)

    Yeap, Guan-Yeow; Al-Taifi, Elham A.; Ong, Chin-Hin; Kamil Mahmood, Wan Ahmad; Takeuchi, Daisuke; Ito, Masato M.

    2012-06-01

    A new series of non-symmetric liquid crystal dimers N-(4-(n-(4-(benzothiazol-2-yl)phenoxy)alkyloxy)benzylidene)-4-chloroaniline containing benzothiazole and benzylideneimine units connected by a flexible alkyl spacer, -(CH2) n -, with n ranging from 4 to 12 in even parity have been prepared. All five members of this homologous series exhibit an enantiotropic nematic phase. The compounds with greater n of 8-12 exhibit both nematic and smectic phases upon cooling. A notable feature among this series is that for the member with n = 10, the smectic-nematic transition is also present. The nematic-isotropic transition temperatures and associated entropy changes with respect to all compounds in this series exhibit a dramatic dependence on the length of the flexible spacer. A comparison of the transitional properties of this series with those of α-(4-benzylidenechloroaniline-4‧-oxy)-ω-[4-(thiophene-2-carboxyl)benzylideneaniline-4‧-oxy]alkanes reveals that replacing benzothiazole moiety at one side of the flexible alkyl spacer reduces the nematic-isotropic transition temperature.

  11. LigandRNA: computational predictor of RNA-ligand interactions.

    PubMed

    Philips, Anna; Milanowska, Kaja; Lach, Grzegorz; Bujnicki, Janusz M

    2013-12-01

    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.

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

    DOEpatents

    Von Dreele, Robert B.

    2008-12-23

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

  13. EGF receptor ligands: recent advances

    PubMed Central

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

    2016-01-01

    Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR. PMID:27635238

  14. In vitro DNA binding, pBR322 plasmid cleavage and molecular modeling study of chiral benzothiazole Schiff-base-valine Cu(II) and Zn(II) complexes to evaluate their enantiomeric biological disposition for molecular target DNA

    NASA Astrophysics Data System (ADS)

    Alizadeh, Rahman; Afzal, Mohd; Arjmand, Farukh

    2014-10-01

    Bicyclic heterocyclic compounds viz. benzothiazoles are key components of deoxyribonucleic acid (DNA) molecules and participate directly in the encoding of genetic information. Benzothiazoles, therefore, represent a potent and selective class of antitumor compounds. The design and synthesis of chiral antitumor chemotherapeutic agents of Cu(II) and Zn(II), L- and -D benzothiazole Schiff base-valine complexes 1a &b and 2a &b, respectively were carried out and thoroughly characterized by spectroscopic and analytical techniques. Interaction of 1a and b and 2a and b with CT DNA by employing UV-vis, florescence, circular dichroic methods and cleavage studies of 1a with pBR322 plasmid, molecular docking were done in order to demonstrate their enantiomeric disposition toward the molecular drug target DNA. Interestingly, these studies unambiguously demonstrated the greater potency of L-enantiomer in comparison to D-enantiomer.

  15. In vitro DNA binding, pBR322 plasmid cleavage and molecular modeling study of chiral benzothiazole Schiff-base-valine Cu(II) and Zn(II) complexes to evaluate their enantiomeric biological disposition for molecular target DNA.

    PubMed

    Alizadeh, Rahman; Afzal, Mohd; Arjmand, Farukh

    2014-10-15

    Bicyclic heterocyclic compounds viz. benzothiazoles are key components of deoxyribonucleic acid (DNA) molecules and participate directly in the encoding of genetic information. Benzothiazoles, therefore, represent a potent and selective class of antitumor compounds. The design and synthesis of chiral antitumor chemotherapeutic agents of Cu(II) and Zn(II), L- and -D benzothiazole Schiff base-valine complexes 1a &b and 2a &b, respectively were carried out and thoroughly characterized by spectroscopic and analytical techniques. Interaction of 1a and b and 2a and b with CT DNA by employing UV-vis, florescence, circular dichroic methods and cleavage studies of 1a with pBR322 plasmid, molecular docking were done in order to demonstrate their enantiomeric disposition toward the molecular drug target DNA. Interestingly, these studies unambiguously demonstrated the greater potency of L-enantiomer in comparison to D-enantiomer.

  16. NMR screening of new carbocyanine dyes as ligands for affinity chromatography.

    PubMed

    Cruz, Carla; Boto, Renato E F; Drzazga, Anna K; Almeida, Paulo; Queiroz, João A

    2014-04-01

    Four new carbocyanines containing symmetric and asymmetric heterocyclic moieties and N-carboxyalkyl groups have been synthesized and characterized. The binding mechanism established between these cyanines and several proteins was evaluated using saturation transfer difference (STD) NMR. The results obtained for the different dyes revealed a specific interaction to the standard proteins lysozyme, α-chymotrypsin, ribonuclease (RNase), bovine serum albumin (BSA), and gamma globulin. For instance, the two un-substituted symmetrical dyes (cyanines 1 and 3) interacted preferentially through its benzopyrrole and dibenzopyrrole units with lysozyme, α-chymotrypsin, and RNase, whereas the symmetric disulfocyanine dye (cyanine 2) bound BSA and gamma globulin through its carboxyalkyl chains. On the other hand, the asymmetric dye (cyanine 4) interacts with lysozyme and α-chymotrypsin through benzothiazole moiety and with RNase through dibenzopyrrole unit. Thus, STD-NMR technique was successfully used to screen cyanine-protein interactions and determine potential binding sites of the cyanines for posterior use as ligands in affinity chromatography.

  17. Antitumor and antimetastatic activities of a novel benzothiazole-2-thiol derivative in a murine model of breast cancer.

    PubMed

    Hu, XiaoLin; Li, Sen; He, Yan; Ai, Ping; Wu, Shaoyong; Su, Yonglin; Li, Xiaolin; Cai, Lei; Peng, Xingchen

    2017-01-02

    The prognosis of metastatic breast cancer is always very poor. Thus, it is urgent to develop novel drugs with less toxicity against metastatic breast cancer. A new drug (XC-591) derived from benzothiazole-2-thiol was designed and synthesized in our lab. In this study, we tried to assess effects of XC-591 treatment on primary breast cancer and pulmonary metastasis in 4T1 mice model. Furthermore, we tried to discover its possible molecular mechanism of action. MTT experiment showed XC-591 had significant anti-cancer activity on diverse cancer cells. Furthermore, XC-591 significantly suppressed the proliferation of 4T1 cells by colony formation assay. The in vivo results displayed that XC-591 could inhibit the growth and metastasis in 4T1 model. Moreover, histological analysis revealed that XC-591 treatment increased apoptosis, inhibited proliferation and angiogenesis in vivo. In addition, XC-591 did not contribute to obvious drug associated toxicity during the whole study. Molecular mechanism showed XC-591 could inhibit RhoGDI, activate caspase-3 and decrease phosphorylated Akt. The present data may be important to further explore this kind of new small-molecule inhibitor.

  18. Common benzothiazole and benzoxazole fluorescent DNA intercalators for studying Alzheimer Aβ1-42 and prion amyloid peptides.

    PubMed

    Stefansson, Steingrimur; Adams, Daniel L; Tang, Cha-Mei

    2012-05-01

    Amyloids are fibrillar protein aggregates associated with a number of neurodegenerative pathologies including Alzheimer and Creutzfeldt-Jakob disease. The study of amyloids is usually based on fluorescence with the dye thioflavin-T. Although a number of amyloid binding compounds have been synthesized, many are nonfluorescent or not readily available for research use. Here we report on a class of commercial benzothiazole/benzoxazole containing fluorescent DNA intercalators from Invitrogen that possess the ability to bind amyloid Aβ1-42 peptide and hamster prion. These dyes fluoresce from 500-750 nm and are available as dimers or monomers. We demonstrate that these dyes can be used as acceptors for thioflavin-T fluorescence resonance energy transfer as well as reporter groups for binding studies with Congo red and chrysamine G. As more potential therapeutic compounds for these diseases are generated, there is a need for simple and inexpensive methods to monitor their interactions with amyloids. The fluorescent dyes reported here are readily available and can be used as tools for biochemical studies of amyloid structures and in vitro screening of potential therapeutics.

  19. Third-Order Optical Nonlinearities of Squarylium Dyes with Benzothiazole Donor Groups Measured Using the Picosecond Z-Scan Technique

    NASA Astrophysics Data System (ADS)

    Li, Zhong-Yu; Xu, Song; Chen, Zi-Hui; Zhang, Fu-Shi; Kasatani, Kazuo

    2011-08-01

    Third-order optical nonlinearities of two squarylium dyes with benzothiazole donor groups (BSQ1 and BSQ2) in chloroform solution are measured by a picosecond Z-scan technique at 532 nm. It is found that the two compounds show the saturation absorption and nonlinear self-focus refraction effect. The molecular second hyperpolarizabilities are calculated to be 7.46 × 10-31 esu and 5.01 × 10-30 esu for BSQ1 and BSQ2, respectively. The large optical nonlinearities of squarylium dyes can be attributed to their rigid and intramolecular charge transfer structure. The difference in γ values is attributed to the chloro group of benzene rings of BSQ2 and the one-photon resonance effect. It is found that the third-order nonlinear susceptibilities of two squarylium dyes are mainly determined by the real parts of χ(3), and the large optical nonlinearities of studied squarylium dyes can be attributed to the nonlinear refraction.

  20. TD-DFT Study of Absorption and Emission Spectra of 2-(2'-Aminophenyl)benzothiazole Derivatives in Water.

    PubMed

    Manojai, Natthaporn; Daengngern, Rathawat; Kerdpol, Khanittha; Kungwan, Nawee; Ngaojampa, Chanisorn

    2017-03-01

    Reduction of aromatic azides to amines is an important property of hydrogen sulphide (H2S) which is useful in fluorescence microscopy and H2S probing in cells. The aim of this work is to study the substituent effect on the absorption and emission spectra of 2-(2'-aminophenyl)benzothiazole (APBT) in order to design APBT derivatives for the use of H2S detection. Absorption and emission spectra of APBT derivatives in aqueous environment were calculated using density functional theory (DFT) and time-dependent DFT (TD-DFT) at B3LYP/6-311+G(d,p) level. The computed results favoured the substitution of strong electron-donating group on the phenyl ring opposite to the amino group for their large Stokes' shifts and emission wavelengths of over 600 nm. Also, three designed compounds were suggested as potential candidates for the fluorescent probes. Such generalised guideline learnt from this work can also be useful in further designs of other fluorescent probes of H2S in water.

  1. Synthesis and anticancer activity of novel benzimidazole and benzothiazole derivatives against HepG2 liver cancer cells.

    PubMed

    Youssef, Amal M; Malki, Ahmed; Badr, Mona H; Elbayaa, Rasha Y; Sultan, Ahmed S

    2012-03-01

    Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.

  2. Novel benzothiazole, benzimidazole and benzoxazole derivatives as potential antitumor agents: synthesis and preliminary in vitro biological evaluation.

    PubMed

    Xiang, Pu; Zhou, Tian; Wang, Liang; Sun, Chang-Yan; Hu, Jing; Zhao, Ying-Lan; Yang, Li

    2012-01-17

    In a previous hit-to-lead research program targeting anticancer agents, two promising lead compounds, 1a and 1b, were found. However, the poor solubility of 1a and 1b made difficult further in vivo studies. To solve this problem, a lead optimization was conducted through introducing N-methyl-piperazine groups at the 2-position and 6-position. To our delight, the optimized analogue 1d showed comparable antiproliferative activity in vitro with better solubility, compared with 1a. Based on this result, the replacement of the benzothiazole scaffold with benzimidazole and benzoxazole moieties afforded 1f and 1g, whose activities were fundamentally retained. In the preliminary in vitro biological evaluation, the immunofluorescence staining of HCT116 cells indicated that 1d, 1f and 1g led to cytosolic vacuolization which was not induced by 1a at low micromolecular concentrations. These results suggest that these optimized compounds might potentially constitute a novel class of anticancer agents, which merit further studies.

  3. Insight into the Amino-Type Excited-State Intramolecular Proton Transfer Cycle Using N-Tosyl Derivatives of 2-(2'-Aminophenyl)benzothiazole.

    PubMed

    Chen, Chi-Lin; Tseng, Huan-Wei; Chen, Yi-An; Liu, Jun-Qi; Chao, Chi-Min; Liu, Kuan-Miao; Lin, Tzu-Chieh; Hung, Cheng-Hsien; Chou, Yen-Lin; Lin, Ta-Chun; Chou, Pi-Tai

    2016-02-25

    Studies have been carried out to gain insight in to an overall excited-state proton transfer cycle for a series of N-tosyl derivatives of 2-(2'-aminophenyl)benzothiazole. The results indicate that followed by ultrafast (<150 fs) excited-state intramolecular proton transfer (ESIPT), the titled compounds undergo rotational isomerization along the C1-C1' bond. For the model compound 2-(2'-tosylaminophenyl)benzothiazole (PBT-NHTs) the subsequent cis-trans isomerization process in both triplet and ground states are probed by nanosecond transient absorption (TA) and two-step laser-induced fluorescence (TSLIF) spectroscopy. Both TA and TSLIF results indicate the existence of a long-lived trans-tautomer species in the ground state with a lifetime of few microseconds. The experimental results correlate well with the theoretical approach, which suggests that PBT-NHTs proton transfer tautomer generated in the excited state undergoes intramolecular C1-C1' rotation to ∼100° between benzothiazole and phenyl moieties in which the energetics for the S1 and T1 states are nearly identical. As a result, the intersystem crossing between S1 and T1 states serves as a fast deactivation pathway for the excited-state cis-tautomer to channel into both cis- and trans-tautomer in their respective T1 states, followed by the dominant T1-S0 radiationless deactivation to populate the trans-tautomer in the ground state. The trans-tautomer species in the S0 state proceeds with intermolecular double proton transfer to regenerate the cis-normal form. An overall proton-transfer cycle describing the amino-type ESIPT and the subsequent isomerization processes is thus depicted in detail.

  4. A rhodamine-benzothiazole conjugated sensor for colorimetric, ratiometric and sequential recognition of copper(II) and sulfide in aqueous media.

    PubMed

    Tang, Lijun; Dai, Xin; Wen, Xin; Wu, Di; Zhang, Qiang

    2015-03-15

    A new rhodamine-benzothiazole conjugated colorimetric sensor 1 that exhibits sequential recognition to Cu(2+) and S(2-) in CH3CN/HEPES buffer (v/v=1:1, HEPES 10mM, pH=7.0) solution has been developed. Sensor 1 displays highly selective and sensitive recognition to Cu(2+) with a ratiometric behavior, and the resultant 1-Cu(2+) complex can act as a highly selective S(2-) sensor via Cu(2+) displacement approach. The Cu(2+) and S(2-) recognition processes are rapid and reversible, and the Cu(2+) and S(2-) inputs can result in an INHIBIT logic gate.

  5. A rhodamine-benzothiazole conjugated sensor for colorimetric, ratiometric and sequential recognition of copper(II) and sulfide in aqueous media

    NASA Astrophysics Data System (ADS)

    Tang, Lijun; Dai, Xin; Wen, Xin; Wu, Di; Zhang, Qiang

    2015-03-01

    A new rhodamine-benzothiazole conjugated colorimetric sensor 1 that exhibits sequential recognition to Cu2+ and S2- in CH3CN/HEPES buffer (v/v = 1:1, HEPES 10 mM, pH = 7.0) solution has been developed. Sensor 1 displays highly selective and sensitive recognition to Cu2+ with a ratiometric behavior, and the resultant 1-Cu2+ complex can act as a highly selective S2- sensor via Cu2+ displacement approach. The Cu2+ and S2- recognition processes are rapid and reversible, and the Cu2+ and S2- inputs can result in an INHIBIT logic gate.

  6. Melatonin: functions and ligands.

    PubMed

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

  7. Bifunctional DTPA-type ligand

    SciTech Connect

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

    1990-03-26

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

  8. Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents.

    PubMed

    Xie, Lijun; Huang, Jie; Chen, Xiaoming; Yu, Hui; Li, Kualiang; Yang, Dan; Chen, Xiaqin; Ying, Jiayin; Pan, Fusheng; Lv, Youbing; Cheng, Yuanrong

    2016-01-01

    The immunosuppressant drug rapamycin, was firstly identified as a mammalian target of rapamycin (mTOR) allosteric inhibitor, and its derivatives have been successfully developed as anti-cancer drugs. Therefore, finding rapamycin derivatives with better anti-cancer activity has been proved to be an effective way to discover new targeted anti-cancer drugs. In this paper, structure modification was performed at the C-43 position of rapamycin using bioisosterism and a hybrid approach: a series of novel rapamycin-benzothiazole hybrids 4a-e, 5a-c, and 9a, b have been designed, synthesized and evaluated for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of these compounds (4a-e, 9a, b) displayed good to excellent potency against the Caski and SK-NEP-1 cell line as compared with rapamycin. Compound 9b as the most active compound showed IC50 values of 8.3 (Caski) and 9.6 μM (SK-NEP-1), respectively. In addition, research on the mechanism showed that 9b was able to cause G1 phase arrest and induce apoptosis in the Caski cell line. Most importantly, it significantly decreased the phosphorylation of S6 ribosomal protein, p70S6K1 and 4EBP1, which indicated that 9b inhibited the cancer cell growth by blocking the mTOR pathway and may have the potential to become a new mTOR inhibitor.

  9. A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumor activity in solid malignancies.

    PubMed

    Xuejiao, Song; Yong, Xia; Ningyu, Wang; Lidan, Zhang; Xuanhong, Shi; Youzhi, Xu; Tinghong, Ye; Yaojie, Shi; Yongxia, Zhu; Luoting, Yu

    2013-01-01

    Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67-positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy.

  10. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives.

    PubMed

    Okaniwa, Masanori; Hirose, Masaaki; Arita, Takeo; Yabuki, Masato; Nakamura, Akito; Takagi, Terufumi; Kawamoto, Tomohiro; Uchiyama, Noriko; Sumita, Akihiko; Tsutsumi, Shunichirou; Tottori, Tsuneaki; Inui, Yoshitaka; Sang, Bi-Ching; Yano, Jason; Aertgeerts, Kathleen; Yoshida, Sei; Ishikawa, Tomoyasu

    2013-08-22

    With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

  11. Validity of ligand efficiency metrics.

    PubMed

    Murray, Christopher W; Erlanson, Daniel A; Hopkins, Andrew L; Keserü, György M; Leeson, Paul D; Rees, David C; Reynolds, Charles H; Richmond, Nicola J

    2014-06-12

    A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.

  12. Ligand Identification Scoring Algorithm (LISA)

    PubMed Central

    Zheng, Zheng; Merz, Kenneth M.

    2011-01-01

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

  13. Ligand Identification Scoring Algorithm (LISA).

    PubMed

    Zheng, Zheng; Merz, Kenneth M

    2011-06-27

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

  14. Synthesis, DNA/HSA Interaction Spectroscopic Studies and In Vitro Cytotoxicity of a New Mixed Ligand Cu(II) Complex.

    PubMed

    Gan, Qian; Fu, Xiabing; Chen, Weijiang; Xiong, Yahong; Fu, Yinlian; Chen, Shi; Le, Xueyi

    2016-05-01

    A new mixed ligand copper(II)-dipeptide complex with 2-(2'-pyridyl)benzothiazole (pbt), [Cu(Gly-L-leu)(pbt)(H2O)]·ClO4 (Gly-L-leu = Glycyl-L-leucine anion) was synthesized and characterized by various physico-chemical means. The DNA binding and cleavage properties of the complex investigated by viscosity, agarose gel electrophoresis and multi-spectroscopic techniques (UV, circular dichroism (CD) and fluorescence) showed that the complex was bound to CT-DNA through intercalation mode with moderate binding constant (K b = 3.132 × 10(4) M(-1)), and cleaved pBR322 DNA efficiently (~ 5 μM) in the presence of Vc, probably via an oxidative mechanism induced by •OH. Additionally, the interaction of the complex with human serum albumin (HSA) was explored by UV-visible, CD, fluorescence, synchronous fluorescence and 3D fluorescence spectroscopy. The complex exhibits desired affinity to HSA through hydrophobic interaction. Moreover, the cytotoxicity of the complex against three human carcinoma cell lines (HeLa, HepG2 and A549) was evaluated by MTT assay, which showed that the complex had effective cytotoxicity and higher inhibition toward A549 cell lines with IC50 of 38.0 ± 3.2 μM.

  15. Why mercury prefers soft ligands

    SciTech Connect

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

    2013-01-01

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

  16. What are Nuclear Receptor Ligands?

    PubMed Central

    Sladek, Frances M.

    2010-01-01

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

  17. Molecular Recognition and Ligand Association

    NASA Astrophysics Data System (ADS)

    Baron, Riccardo; McCammon, J. Andrew

    2013-04-01

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

  18. Micro-Raman, Mid-IR, Far-IR and DFT studies on 2-[4-(4-Fluorobenzamido)phenyl]benzothiazole

    NASA Astrophysics Data System (ADS)

    Unsalan, O.; Sert, Y.; Ari, H.; Simão, A.; Yilmaz, A.; Boyukata, M.; Bolukbasi, O.; Bolelli, K.; Yalcin, I.

    Molecular structure of 2-[4-(4-Fluorobenzamido)phenyl]benzothiazole was determined by quantum chemical calculations. MidIR and FarIR spectra were recorded at room temperature, with 4 cm-1 resolution in the 4000-400 cm-1 and 700-30 cm-1 regions, respectively for the first time. Raman spectrum was recorded in the 4000-100 cm-1 range. Optimized molecular structure and vibrational wavenumbers of the compound in its ground state have been calculated by using Density Functional Theory using B3LYP functional with 6-311++G(d,p) basis set. Vibrational wavenumbers were seen to be in good agreement with the experimental IR data. Furthermore, assignments of each vibrational mode were interpreted in terms of potential energy distributions in detail.

  19. Designing, synthesis of selective and high-affinity chalcone-benzothiazole hybrids as Brugia malayi thymidylate kinase inhibitors: In vitro validation and docking studies.

    PubMed

    Sashidhara, Koneni V; Avula, Srinivasa Rao; Doharey, Pawan Kumar; Singh, L Ravithej; Balaramnavar, Vishal M; Gupta, Jyoti; Misra-Bhattacharya, Shailja; Rathaur, Sushma; Saxena, Anil K; Saxena, Jitendra Kumar

    2015-10-20

    In our continuing search for safe and efficacious antifilarials, a series of novel chalcone-benzothiazole hybrids have been synthesized and evaluated for their Brugia malayi thymidylate kinase (BmTMK) enzyme inhibition activity. Their selectivity towards BmTMK was studied and compared to the human TMK (HsTMK) by an in silico method. Out of seventeen derivatives, compounds 34 and 42 showed higher interactions with the BmTMK active site. MolDock docking model revealed the interactions of these two derivatives and the results corroborated well with their in vitro antifilarial activities. Our studies suggest that these hybrids are selective towards the BmTMK enzyme and may serve as potential therapeutic agents against filariasis.

  20. SKLB-163, a new benzothiazole-2-thiol derivative, exhibits potent anticancer activity by affecting RhoGDI/JNK-1 signaling pathway.

    PubMed

    Peng, X; Xie, G; Wang, Z; Lin, H; Zhou, T; Xiang, P; Jiang, Y; Yang, S; Wei, Y; Yu, L; Zhao, Y

    2014-03-27

    Small-molecule inhibitors are an attractive therapeutic approach for most types of human cancers. SKLB-163, a novel benzothiazole-2-thiol derivative, was developed via computer-aided drug design and de novo synthesis. MTT assay showed it had potent anti-proliferative activity on various human cancer cells. Treatment of cancer cells with SKLB-163 induced obvious apoptosis and inhibited proliferation in vitro. SKLB-163 administered p.o. showed a marked antitumor activity in vivo. Proteomic techniques were employed to identify possible drug target proteins. The data showed molecular mechanism of action might be involved in downregulation of RhoGDI, which finally contributed to increased apoptosis and inhibited proliferation. These findings provided the potential value of SKLB-163 as a novel candidate antitumor drug.

  1. Micro-Raman, mid-IR, far-IR and DFT studies on 2-[4-(4-fluorobenzamido)phenyl]benzothiazole.

    PubMed

    Unsalan, O; Sert, Y; Ari, H; Simão, A; Yilmaz, A; Boyukata, M; Bolukbasi, O; Bolelli, K; Yalcin, I

    2014-05-05

    Molecular structure of 2-[4-(4-Fluorobenzamido)phenyl]benzothiazole was determined by quantum chemical calculations. MidIR and FarIR spectra were recorded at room temperature, with 4 cm(-1) resolution in the 4000-400 cm(-1) and 700-30 cm(-1) regions, respectively for the first time. Raman spectrum was recorded in the 4000-100 cm(-1) range. Optimized molecular structure and vibrational wavenumbers of the compound in its ground state have been calculated by using Density Functional Theory using B3LYP functional with 6-311++G(d,p) basis set. Vibrational wavenumbers were seen to be in good agreement with the experimental IR data. Furthermore, assignments of each vibrational mode were interpreted in terms of potential energy distributions in detail.

  2. Synthesis and biological evaluation of a series of benzoxazole/benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants.

    PubMed

    Wang, Songlin; Chen, Yin; Zhao, Song; Xu, Xiangqing; Liu, Xin; Liu, Bi-Feng; Zhang, Guisen

    2014-04-01

    A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a-5d and 8a-8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki=17 nM) and 5-HT2A (Ki=0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.

  3. 4-Benzothiazole-7-hydroxyindolinyl diaryl ureas are potent P2Y1 antagonists with favorable pharmacokinetics: low clearance and small volume of distribution.

    PubMed

    Qiao, Jennifer X; Wang, Tammy C; Hiebert, Sheldon; Hu, Carol H; Schumacher, William A; Spronk, Steven A; Clark, Charles G; Han, Ying; Hua, Ji; Price, Laura A; Shen, Hong; Chacko, Silvi A; Everlof, Gerry; Bostwick, Jeffrey S; Steinbacher, Thomas E; Li, Yi-Xin; Huang, Christine S; Seiffert, Dietmar A; Rehfuss, Robert; Wexler, Ruth R; Lam, Patrick Y S

    2014-10-01

    Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.

  4. Photocatalysis by 3,6-disubstituted-s-tetrazine: visible-light driven metal-free green synthesis of 2-substituted benzimidazole and benzothiazole.

    PubMed

    Samanta, Suvendu; Das, Sudipto; Biswas, Papu

    2013-11-15

    s-Tetrazine based molecules were prepared for visible-light-driven organic transformations. The 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) derivative shows visible light absorption and reversible one-electron reduction behavior. In the presence of pytz and aerial oxygen, aldehyde reacts with o-phenylenediamine or o-aminothiophenol under visible light irradiation at ambient temperature to produce corresponding 2-substituted benzimidazoles and benzothiazoles, respectively. Pytz catalyst demonstrates excellent catalytic activity for alkyl, aryl, organo-metallic substituted aldehydes and reducing sugar. The reaction yield is high for both the electron-donating and electron withdrawing substituents in aromatic aldehydes. The use of a metal-free catalyst and visible light energy, along with the mild reaction conditions, makes this reaction an environmentally benign and energy-saving chemical process.

  5. Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants.

    PubMed

    Zhu, Xue Y; Etukala, Jagan R; Eyunni, Suresh V K; Setola, Vincent; Roth, Bryan L; Ablordeppey, Seth Y

    2012-07-01

    The synthesis and evaluation of several benzothiazole-based compounds are described in an attempt to identify novel dual-acting 5HT(1A) receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT(1A) receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT(1A) receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT(2C) receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side effects.

  6. Ligand-induced Epitope Masking

    PubMed Central

    Mould, A. Paul; Askari, Janet A.; Byron, Adam; Takada, Yoshikazu; Jowitt, Thomas A.; Humphries, Martin J.

    2016-01-01

    We previously demonstrated that Arg-Gly-Asp (RGD)-containing ligand-mimetic inhibitors of integrins are unable to dissociate pre-formed integrin-fibronectin complexes (IFCs). These observations suggested that amino acid residues involved in integrin-fibronectin binding become obscured in the ligand-occupied state. Because the epitopes of some function-blocking anti-integrin monoclonal antibodies (mAbs) lie near the ligand-binding pocket, it follows that the epitopes of these mAbs may become shielded in the ligand-occupied state. Here, we tested whether function-blocking mAbs directed against α5β1 can interact with the integrin after it forms a complex with an RGD-containing fragment of fibronectin. We showed that the anti-α5 subunit mAbs JBS5, SNAKA52, 16, and P1D6 failed to disrupt IFCs and hence appeared unable to bind to the ligand-occupied state. In contrast, the allosteric anti-β1 subunit mAbs 13, 4B4, and AIIB2 could dissociate IFCs and therefore were able to interact with the ligand-bound state. However, another class of function-blocking anti-β1 mAbs, exemplified by Lia1/2, could not disrupt IFCs. This second class of mAbs was also distinguished from 13, 4B4, and AIIB2 by their ability to induce homotypic cell aggregation. Although the epitope of Lia1/2 was closely overlapping with those of 13, 4B4, and AIIB2, it appeared to lie closer to the ligand-binding pocket. A new model of the α5β1-fibronectin complex supports our hypothesis that the epitopes of mAbs that fail to bind to the ligand-occupied state lie within, or very close to, the integrin-fibronectin interface. Importantly, our findings imply that the efficacy of some therapeutic anti-integrin mAbs could be limited by epitope masking. PMID:27484800

  7. Multifunctional Ligands in Transition Metal Catalysis

    SciTech Connect

    Crabtree, Robert H

    2011-01-01

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

  8. Benzothiazoles with tunable electron-withdrawing strength and reverse polarity: a route to triphenylamine-based chromophores with enhanced two-photon absorption.

    PubMed

    Hrobárik, Peter; Hrobáriková, Veronika; Sigmundová, Ivica; Zahradník, Pavol; Fakis, Mihalis; Polyzos, Ioannis; Persephonis, Peter

    2011-11-04

    A series of dipolar and octupolar triphenylamine-derived dyes containing a benzothiazole positioned in the matched or mismatched fashion have been designed and synthesized via palladium-catalyzed Sonogashira cross-coupling reactions. Linear and nonlinear optical properties of the designed molecules were tuned by an additional electron-withdrawing group (EWG) and by changing the relative positions of the donor and acceptor substituents on the heterocyclic ring. This allowed us to examine the effect of positional isomerism and extend the structure-property relationships useful in the engineering of novel heteroaromatic-based systems with enhanced two-photon absorption (TPA). The TPA cross-sections (δ(TPA)) in the target compounds dramatically increased with the branching of the triphenylamine core and with the strength of the auxiliary acceptor. In addition, a change from the commonly used polarity in push-pull benzothiazoles to a reverse one has been revealed as a particularly useful strategy (regioisomeric control) for enhancing TPA cross-sections and shifting the absorption and emission maxima to longer wavelengths. The maximum TPA cross-sections of the star-shaped three-branched triphenylamines are ∼500-2300 GM in the near-infrared region (740-810 nm); thereby the molecular weight normalized δ(TPA)/MW values of the best performing dyes within the series (2.0-2.4 GM·g(-1)·mol) are comparable to those of the most efficient TPA chromophores reported to date. The large TPA cross-sections combined with high emission quantum yields and large Stokes shifts make these compounds excellent candidates for various TPA applications, including two-photon fluorescence microscopy.

  9. Multicoordinate ligands for actinide/lanthanide separations.

    PubMed

    Dam, Henk H; Reinhoudt, David N; Verboom, Willem

    2007-02-01

    In nuclear waste treatment processes there is a need for improved ligands for the separation of actinides (An(III)) and lanthanides (Ln(III)). Several research groups are involved in the design and synthesis of new An(III) ligands and in the confinement of these and existing An(III) ligands onto molecular platforms giving multicoordinate ligands. The preorganization of ligands considerably improves the An(III) extraction properties, which are largely dependent on the solubility and rigidity of the platform. This tutorial review summarizes the most important An(III) ligands with emphasis on the preorganization strategy using (macrocyclic) platforms.

  10. Kinetics of ligand binding to nucleic acids.

    PubMed

    Arakelyan, V B; Babayan, S Y; Tairyan, V I; Arakelyan, A V; Parsadanyan, M A; Vardevanyan, P O

    2006-02-01

    Ligand binding to nucleic acids (NA) is considered as a stationary Markov process. It is shown that the probabilistic description of ligand-NA binding allows one to describe not only the kinetics of the change of number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. The general analysis of absorption isotherms and kinetics of ligand binding to NA make it possible to determine of rate constants of ligand-NA complex formation and dissociation.

  11. Spectroscopic study of 2-[2-(4-cyclaminophenyl)ethen-1-yl] benzothiazoles and their N-allylbenzothiazolium bromides. Solvent and substituent effects on their ultraviolet-visible and fluorescence spectra

    NASA Astrophysics Data System (ADS)

    Gáplovský, Anton; Donovalová, Jana; Magdolen, Peter; Toma, Štefan; Zahradník, Pavol

    2002-01-01

    UV-vis and fluorescence spectra of 2-[2-(4-cyclaminophenyl)ethen-1-yl] benzothiazoles 1 and their N-allylbenzothiazolium bromides 2 have been measured and interpreted. The substitution and solvent effects on electronic structure and spectra have been investigated. The benzothiazolium salts substituted with saturated cyclamines show strong push-pull character and can be used as potential NLO materials. Formation of aggregated structures was observed at higher concentrations of the benzothiazolium bromides.

  12. Glyconanomaterials: synthesis, characterization, and ligand presentation.

    PubMed

    Wang, Xin; Ramström, Olof; Yan, Mingdi

    2010-05-04

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

  13. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

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

  14. Ligand chain length conveys thermochromism.

    PubMed

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

    2014-08-14

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

  15. Presentation of Ligands on Hydroxylapatite

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  16. Tumor Targeting via Integrin Ligands

    PubMed Central

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

    2013-01-01

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

  17. Tools for ligand validation in Coot

    PubMed Central

    Emsley, Paul

    2017-01-01

    Coot is a molecular-graphics program primarily aimed at model building using X-ray data. Recently, tools for the manipulation and representation of ligands have been introduced. Here, these new tools for ligand validation and comparison are described. Ligands in the wwPDB have been scored by density-fit, distortion and atom-clash metrics. The distributions of these scores can be used to assess the relative merits of the particular ligand in the protein–ligand complex of interest by means of ‘sliders’ akin to those now available for each accession code on the wwPDB websites. PMID:28291755

  18. Ligand identification using electron-density mapcorrelations

    SciTech Connect

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

    2006-12-01

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

  19. NKG2D ligands as therapeutic targets

    PubMed Central

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

    2013-01-01

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

  20. Development of a solid-phase extraction liquid chromatography tandem mass spectrometry method for benzotriazoles and benzothiazoles in wastewater and recycled water.

    PubMed

    Loi, Clara H; Busetti, Francesco; Linge, Kathryn L; Joll, Cynthia A

    2013-07-19

    Two methods employing solid-phase extraction and liquid chromatography tandem mass spectrometry were developed for the analysis of benzotriazoles (BTs) and benzothiazoles (BThs), compounds which are commonly found in a large variety of commercial and household products. The first method was able to detect 7 BTs and 7 BThs, the largest suite of BTs and BThs analysed in a single method to-date, but could not distinguish between the isomers, 4-methylbenzotriazole (4-MeBT) and 5-methylbenzotriazole (5-MeBT). Therefore, a second method was developed to achieve the chromatographic separation of 4-MeBT and 5-MeBT. The methods were validated for ultrapure water and secondary wastewater, and method limits of detection (MLD) for BTs and BThs (for the primary method) ranged from 0.1 to 58ngL(-1) for ultrapure water, and 2 to 322ngL(-1) for secondary wastewater. For the secondary method, MLDs for 4- and 5-MeBT ranged from 8 to 12ngL(-1) for ultrapure water, and 388 to 406ngL(-1) for secondary wastewater. Analysis of secondary wastewater and reverse osmosis (RO) treated water from an advanced water recycling plant in Australia is presented, and represents the first reported data from the analysis of BTs and BThs in recycled water. Some of these compounds were found to persist through wastewater treatment and incompletely removed by RO treatment. Benzotriazole (BT), 4-MeBT, 5-MeBT and 2-(methylthio)benzothiazole were detected in secondary wastewater, however the latter compound was not quantifiable. Concentrations of BT and tolyltriazoles (TTs, i.e. sum of 4- and 5-MeBT, detected with the primary method) in secondary wastewater were 3.3 (±0.02) and 2.8 (±0.04)μgL(-1), respectively. These same compounds were also detected in the post-RO water samples at concentrations of 974 (±28)ngL(-1) for BT and 416(±34)ngL(-1) for TTs. 2-Hydroxybenzothiazole was also detected in the post-RO water samples, however it was not quantifiable. Removal efficiencies for RO treatment were

  1. The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies.

    PubMed

    Khan, Khalid Mohammed; Mesaik, Mohammad A; Abdalla, Omer M; Rahim, Fazal; Soomro, Samreen; Halim, Sobia A; Mustafa, Ghulam; Ambreen, Nida; Khalid, Ahmad Shukralla; Taha, Muhammad; Perveen, Shahnaz; Alam, Muhammad Tanveer; Hameed, Abdul; Ul-Haq, Zaheer; Ullah, Hayat; Rehman, Zia Ur; Siddiqui, Rafat Ali; Voelter, Wolfgang

    2016-02-01

    Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.

  2. Novel Ligands for a Purine Riboswitch Discovered by RNA-Ligand Docking

    PubMed Central

    Daldrop, Peter; Reyes, Francis E.; Robinson, David A.; Hammond, Colin M.; Lilley, David M.; Batey, Robert T.; Brenk, Ruth

    2011-01-01

    Summary The increasing number of RNA crystal structures enables a structure-based approach to the discovery of new RNA-binding ligands. To develop the poorly explored area of RNA-ligand docking, we have conducted a virtual screening exercise for a purine riboswitch to probe the strengths and weaknesses of RNA-ligand docking. Using a standard protein-ligand docking program with only minor modifications, four new ligands with binding affinities in the micromolar range were identified, including two compounds based on molecular scaffolds not resembling known ligands. RNA-ligand docking performed comparably to protein-ligand docking indicating that this approach is a promising option to explore the wealth of RNA structures for structure-based ligand design. PMID:21439477

  3. 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

  4. A universal rule for organic ligand exchange.

    PubMed

    You, Hongjun; Wang, Wenjin; Yang, Shengchun

    2014-11-12

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

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

    PubMed

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

    2013-01-01

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

  6. CB receptor ligands from plants.

    PubMed

    Woelkart, Karin; Salo-Ahen, Outi M H; Bauer, Rudolf

    2008-01-01

    Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

  7. Measurement of protein-ligand complex formation.

    PubMed

    Lowe, Peter N; Vaughan, Cara K; Daviter, Tina

    2013-01-01

    Experimental approaches to detect, measure, and quantify protein-ligand binding, along with their theoretical bases, are described. A range of methods for detection of protein-ligand interactions is summarized. Specific protocols are provided for a nonequilibrium procedure pull-down assay, for an equilibrium direct binding method and its modification into a competition-based measurement and for steady-state measurements based on the effects of ligands on enzyme catalysis.

  8. Assessment of 2-(4-morpholinyl) benzothiazole (24MoBT) and N-cyclohexyl-2-benzothiazolamine (NCBA) as traffic tracers in metropolitan cities of China and India

    NASA Astrophysics Data System (ADS)

    Pan, Suhong; Sun, Yali; Zhang, Gan; Li, Jun; Xie, Qilai; Chakraborty, Paromita

    2012-09-01

    2-(4-Morpholinyl) benzothiazole (24MoBT) and N-cyclohexyl-2-benzothiazolamine (NCBA), which are present in automobile tires, are impurities of the vulcanisation accelerators OBS and CBS, respectively, as defined by the Japan Industrial Standard. To assess 24MoBT and NCBA as markers to trace the usage patterns of OBS and CBS in developing countries, urban dusts were collected from five representative cities of China and India for the analysis of 24MoBT and NCBA. The concentrations in these dust samples were found to be within the range of 3.40-151 ng g-1 for 24MoBT and nd-56.9 ng g-1 for NCBA. The higher levels of 24MoBT may indicate that the traditional accelerator OBS is still used in vehicle tires, whereas the relatively lower contents of NCBA are mainly related to the lesser use of CBS tires. The individual fractions of 24MoBT and NCBA in BTs (24MoBT + NCBA) are compared among cities, and the results show that the fraction sequence is consistent with the number of vehicles and the cities' economic development. This study indicates not only that 24MoBT is presently more suitable for tracing tire wear emissions than NCBA in China but also that there is a potential to assess the impact of traffic sources on urban environments using BTs.

  9. Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers.

    PubMed

    Subba Rao, A V; Swapna, Konderu; Shaik, Siddiq Pasha; Lakshma Nayak, V; Srinivasa Reddy, T; Sunkari, Satish; Shaik, Thokhir Basha; Bagul, Chandrakant; Kamal, Ahmed

    2017-02-01

    A series of colchicine site binding tubulin inhibitors were synthesized by the modification of the combretastatin pharmacophore. The ring B was replaced by the pharmacologically relevant benzothiazole scaffolds, and the cis configuration of the olefinic bond was restricted by the incorporation of a triazole and tetrazole rings which is envisaged by the structural resemblance to a tubulin inhibitor like combretastatin (CA-4). These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (9a and 9b) demonstrated an antiproliferative effect comparable to that of CA-4. Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. Western blot analysis revealed that these compounds accumulate more tubulin in the soluble fraction. The colchicine competitive binding assay and the molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of CA-4. Moreover, the triggering of apoptotic cell death after mitotic arrest was investigated by studying their effect by Hoechst staining, Annexin-V-FITC assay, mitochondrial membrane potential, ROS generation and caspase-3 activation.

  10. Conformational structure of the unsymmetrical monomethine cyanine bearing 2-azaazulene and 2-benzothiazole residues as terminal groups: Experimental and quantum-chemical investigation

    NASA Astrophysics Data System (ADS)

    Ryabitskii, Aleksey B.; Bricks, Julia L.; Kachkovskii, Aleksey D.; Chernega, Alexander N.; Vlasenko, Yurii G.

    2010-10-01

    Conformational features of unsymmetrical monomethine cyanine dye 2-[(2-butyl-1,3-dimethylcyclohepta[ c]pyrrol-6(2 H)-ylidene)methyl]-3-ethyl-1,3-benzothiazol-3-ium iodide-perchlorate have been investigated in solution by means of NMR spectroscopy and in the solid state by X-ray diffraction. The possibility of molecule conformational transformations was proved by scanning of potential energy surface along torsion angels. The corresponding energy barriers values have been calculated by means of DFT (B3LYP and M05-2X) methods. A comparison of structural parameters obtained by means of both methods was reported. The isomerization process was investigated by dynamic NMR spectroscopy. A comparison of 1H NMR spectra recorded in different solvents was performed. It was shown that in solution, intramolecular rotation around the bond С(6) аzaazulene-С methyne decelerated in NMR time scale took place. The data on dynamic behavior of dye molecules have been compared with the experimental X-ray data. Quantum-chemical calculation results are in agreement with the experimental data.

  11. Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability.

    PubMed

    Ashraf, Md; Shaik, Thokhir B; Malik, M Shaheer; Syed, Riyaz; Mallipeddi, Prema L; Vardhan, M V P S Vishnu; Kamal, Ahmed

    2016-09-15

    A series of colchicine site binding tubulin inhibitors were designed and synthesized by the modification of the combretastatin A-4 (CA4) pharmacophore. The ring B was replaced by the pharmacologically relevant benzimidazole or benzothiazole scaffolds, and the cis-configuration of the olefinic bond was restricted by the incorporation of a pyridine ring which is envisaged by the structural resemblance to a tubulin inhibitor like E7010. These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (6c and 6l) demonstrated an antiproliferative effect comparable and superior to that of CA4 (GI50 up to 40nM). Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. The molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of combretastatin A-4.

  12. Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Bao, Guanglong; Wang, Limei; Li, Wanting; Xu, Boxuan; Du, Baoquan; Lv, Jie; Zhai, Xin; Gong, Ping

    2015-01-01

    Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization.

  13. A pressurised hot water extraction and liquid chromatography-high resolution mass spectrometry method to determine polar benzotriazole, benzothiazole and benzenesulfonamide derivates in sewage sludge.

    PubMed

    Herrero, P; Borrull, F; Marcé, R M; Pocurull, E

    2014-08-15

    Benzothiazole, benzotriazole and benzenesulfonamide derivates are well-known aquatic contaminants, although very few studies have been published about their occurrence in sewage sludge samples. In this paper, a pressurised hot water extraction (PHWE) method has been developed for the simultaneous determination of these families of compounds. The compounds were determined by LC-Orbitrap-HRMS and several clean-up strategies such as in-cell PHWE and solid-phase extraction (SPE) were tested to reduce the high matrix effect that occurs when sludge samples are analysed. Absolute recoveries using the whole method were above 80% and the matrix effect was under -20% for most of the compounds studied. Repeatability and reproducibility were usually under 10% (%RSD, 50 and 250ngg(-1) (d.w.), n=5), while LODs and LOQs were between 0.25 and 25ngg(-1) (d.w.) and 0.5 and 50ngg(-1) (d.w.), respectively. The PHWE/SPE/LC-HRMS method developed was used to analyse several sludge samples collected from five sewage treatment plants (STPs) in Catalonia that use different sewage treatments. The most frequently determined compounds were benzotriazole derivates and the most abundant compound found was 2-hydroxybenzothiazole.

  14. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

  15. Molecular, spectroscopic and thermal studies on catechol, 4,5-dibromocatechol, resorcinol, hydroquinone and 4-4‧-dihydroxybiphenyl derivatives armed with benzothiazole moieties

    NASA Astrophysics Data System (ADS)

    Alshargabi, Arwa; Yeap, Guan-Yeow; Mahmood, Wan Ahmad Kamil; Samikannu, Rakesh

    2013-05-01

    A new series of catechol, 4,5-dibromocatechol, resorcinol, hydroquinone and 4-4'-dihydroxybiphenyl derivatives possessing two benzothiazole moieties at respective positions of 1,2, 1,3, 1,4 and/or 4,4' has successfully been synthesized. The molecular structures were fully elucidated by spectroscopic techniques (1H NMR, 13C NMR and two dimensional COSY, HMBC, HMQC, DEPT-135 and DEPT-90). The connectivity study between the cause of using different core systems in the target compounds and the anisotropic behavior as inferred from phase transition temperature and relevant morphology studies has led to some unique features arising from this series. Compounds with ortho substituent exhibit enantiotropic N and SmA phases. The analogues containing resorcinol and 4,4'-disubstituentbiphenyl show enanotiotropic nematic behavior while the hydroquinone derivative induces the formation of monotropic nematogen. An extensive study to further substantiate the relationship between the stability of the nematic phase and associated transition temperatures due to different core systems is also reported.

  16. An electro-optical and electron injection study of benzothiazole-based squaraine dyes as efficient dye-sensitized solar cell materials: a first principles study.

    PubMed

    Al-Fahdan, Najat Saeed; Asiri, Abdullah M; Irfan, Ahmad; Basaif, Salem A; El-Shishtawy, Reda M

    2014-12-01

    Squaraine dyes have attracted significant attention in many areas of daily life from biomedical imaging to semiconducting materials. Moreover, these dyes are used as photoactive materials in the field of solar cells. In the present study, we investigated the structural, electronic, photophysical, and charge transport properties of six benzothiazole-based squaraine dyes (Cis-SQ1-Cis-SQ3 and Trans-SQ1-Trans-SQ3). The effect of electron donating (-OCH3) and electron withdrawing (-COOH) groups was investigated intensively. Ground state geometry and frequency calculations were performed by applying density functional theory (DFT) at B3LYP/6-31G** level of theory. Absorption spectra were computed in chloroform at the time-dependent DFT/B3LYP/6-31G** level of theory. The driving force of electron injection (ΔG (inject)), relative driving force of electron injection (ΔG r (inject)), electronic coupling constants (|VRP|) and light harvesting efficiency (LHE) of all six compounds were calculated and compared with previously studied sensitizers. The ΔG (inject), ΔG r (inject) and |VRP| of all six compounds revealed that these sensitizers would be efficient dye-sensitized solar cell materials. Cis/Trans-SQ3 exhibited superior LHE as compared to other derivatives. The Cis/Trans geometric effect was studied and discussed with regard to electro-optical and charge transport properties.

  17. Synthesis, photophysical and charge-transporting properties of a novel asymmetric indolo [3,2-b]carbazole derivative containing benzothiazole and diphenylamino moieties

    NASA Astrophysics Data System (ADS)

    Shi, Heping; Yuan, Jiandong; Dong, Xiuqing; Cheng, Fangqin

    2014-12-01

    A novel asymmetric donor-π-donor-π-acceptor compound, 2-benzothiazolyl-8-diphenylamino-5,11-dihexylindolo[3,2-b]carbazole (BDDAICZ), has been successfully synthesized by introducing a benzothiazole moiety (as an electron-acceptor) and a diphenylamino moiety (as an electron-donor) to 2-position and 8-position of indolo[3,2-b]carbazole moiety (as a skeleton and an electron-donor), and characterized by elemental analysis, 1H NMR, 13C NMR and MS. The thermal, electrochemical properties of BDDAICZ were characterized by thermogravimetric analysis combined with electrochemistry. The absorption and emission spectra of BDDAICZ was experimentally determined in several solvents and computed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The calculated absorption and emission wavelengths are coincident with the measured data. The ionization potential (IP), the electron affinity (EA) and reorganization energy of BDDAICZ were also investigated using density functional theory (DFT). Charge-transporting properties of BDDAICZ were characterized by OLEDs devices fabricated by using it as charge-transport layers. The results show that BDDAICZ has excellent thermal stability, electrochemical stability and hole-transporting properties, indicating its potential application as a hole-transporting material in OLEDs devices.

  18. 99mTc(CO)3-Labeled Benzothiazole Derivatives Preferentially Bind Cerebrovascular Amyloid: Potential Use as Imaging Agents for Cerebral Amyloid Angiopathy.

    PubMed

    Jia, Jianhua; Cui, Mengchao; Dai, Jiapei; Liu, Boli

    2015-08-03

    Cerebral amyloid angiopathy (CAA) is a disorder affecting the elderly that is characterized by amyloid-β (Aβ) deposition in blood vessel walls of the brain. A series of 99mTc(CO)3-labeled benzothiazole derivatives as potential SPECT imaging probes for cerebrovascular Aβ deposition is reported. Rhenium surrogate displayed high affinities to Aβ aggregates with Ki values ranging from 106 to 42 nM, and they strongly stained Aβ deposits in transgenic mice (Tg) and Alzheimer's disease (AD) patients. In vitro autoradiography on brain sections of Tg and AD patients confirmed that [99mTc]24 possessed sufficient affinity for Aβ plaques, and [99mTc]24 could only label Aβ deposition in blood vessels but not Aβ plaques in the parenchyma of the brain of AD patients. Moreover, [99mTc]24 possessed favorable initial uptake (1.21% ID/g) and fast blood washout (blood2 min/blood60 min=23) in normal mice. These preliminary results suggest that [99mTc]24 may be used as an Aβ imaging probe for the detection of CAA.

  19. Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/MEK/ERK-dependent pathway in MCF-7 cells.

    PubMed

    Kamal, Ahmed; Faazil, Shaikh; Ramaiah, M Janaki; Ashraf, Md; Balakrishna, M; Pushpavalli, S N C V L; Patel, Nibedita; Pal-Bhadra, Manika

    2013-10-15

    By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.

  20. Synthesis, photophysical and charge-transporting properties of a novel asymmetric indolo [3,2-b]carbazole derivative containing benzothiazole and diphenylamino moieties.

    PubMed

    Shi, Heping; Yuan, Jiandong; Dong, Xiuqing; Cheng, Fangqin

    2014-12-10

    A novel asymmetric donor-π-donor-π-acceptor compound, 2-benzothiazolyl-8-diphenylamino-5,11-dihexylindolo[3,2-b]carbazole (BDDAICZ), has been successfully synthesized by introducing a benzothiazole moiety (as an electron-acceptor) and a diphenylamino moiety (as an electron-donor) to 2-position and 8-position of indolo[3,2-b]carbazole moiety (as a skeleton and an electron-donor), and characterized by elemental analysis, (1)H NMR, (13)C NMR and MS. The thermal, electrochemical properties of BDDAICZ were characterized by thermogravimetric analysis combined with electrochemistry. The absorption and emission spectra of BDDAICZ was experimentally determined in several solvents and computed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The calculated absorption and emission wavelengths are coincident with the measured data. The ionization potential (IP), the electron affinity (EA) and reorganization energy of BDDAICZ were also investigated using density functional theory (DFT). Charge-transporting properties of BDDAICZ were characterized by OLEDs devices fabricated by using it as charge-transport layers. The results show that BDDAICZ has excellent thermal stability, electrochemical stability and hole-transporting properties, indicating its potential application as a hole-transporting material in OLEDs devices.

  1. Benzothiazole aniline tetra(ethylene glycol) and 3-amino-1,2,4-triazole inhibit neuroprotection against amyloid peptides by catalase overexpression in vitro.

    PubMed

    Chilumuri, Amrutha; Odell, Mark; Milton, Nathaniel G N

    2013-11-20

    Alzheimer's disease, Familial British dementia, Familial Danish dementia, Type 2 diabetes mellitus, plus Creutzfeldt-Jakob disease are associated with amyloid fibril deposition and oxidative stress. The antioxidant enzyme catalase is a neuroprotective amyloid binding protein. Herein the effects of catalase overexpression in SH-SY5Y neuronal cells on the toxicity of amyloid-β (Aβ), amyloid-Bri (ABri), amyloid-Dan (ADan), amylin (IAPP), and prion protein (PrP) peptides were determined. Results showed catalase overexpression was neuroprotective against Aβ, ABri, ADan, IAPP, and PrP peptides. The catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and catalase-amyloid interaction inhibitor benzothiazole aniline tetra(ethylene glycol) (BTA-EG4) significantly enhanced neurotoxicity of amyloid peptides in catalase overexpressing neuronal cells. This suggests catalase neuroprotection involves breakdown of hydrogen peroxide (H2O2) plus a direct binding interaction between catalase and the Aβ, ABri, ADan, IAPP, and PrP peptides. Kisspeptin 45-50 had additive neuroprotective actions against the Aβ peptide in catalase overexpressing cells. The effects of 3-AT had an intracellular site of action, while catalase-amyloid interactions had an extracellular component. These results suggest that the 3-AT and BTA-EG4 compounds may be able to inhibit endogenous catalase mediated neuroprotection. Use of BTA-EG4, or compounds that inhibit catalase binding to amyloid peptides, as potential therapeutics for Neurodegenerative diseases may therefore result in unwanted effects.

  2. Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies.

    PubMed

    Taha, Muhammad; Ismail, Nor Hadiani; Lalani, Salima; Fatmi, Muhammad Qaiser; Atia-Tul-Wahab; Siddiqui, Salman; Khan, Khalid Mohammed; Imran, Syahrul; Choudhary, Muhammad Iqbal

    2015-03-06

    In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds.

  3. Asymmetric catalysis with chiral ferrocene ligands.

    PubMed

    Dai, Li-Xin; Tu, Tao; You, Shu-Li; Deng, Wei-Ping; Hou, Xue-Long

    2003-09-01

    Chiral ferrocene ligands have been widely used in asymmetric catalysis. The advantages of using ferrocene as a scaffold for chiral ligands are described, particularly those regarding planar chirality, rigid bulkiness, and ease of derivatization. The role of planar chirality in 1,2- and 1,1'-disubstituted ferrocene systems is discussed. By using a bulky ferrocene fragment, novel ferrocene ligands were designed, and high enantioselectivity and regioselectivity were achieved in the allylic substitution reaction of monosubstituted allyl substrates. Using the tunable electronic properties of a diphosphine-oxazoline ferrocenyl ligand, the regioselectivity of the intermolecular asymmetric Heck reaction was also examined.

  4. Integrated ligand based pharmacophore model derived from diverse FAAH covalent ligand classes.

    PubMed

    Shen, Lingling; Huang, Hongwei; Makriyannis, Alexandros; Fisher, Luke S

    2012-12-01

    3D pharmacophore modeling is an important computational methodology for ligand-enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH.

  5. Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

    DTIC Science & Technology

    2013-10-01

    sub 10nM range efficacy. Our primary objective was to establish a series of compounds blocking the AR ligand-dependent and ligand-independent gene ...of AR driven genes to be more comprehensive and more in line with what is currently known about AR-driven signaling in prostate cancer. We have...developed a robust panel of genes for AR signaling that is reflective of the clinical findings in both ligand dependent and ligand-independent androgen

  6. Cis-interactions between Notch and its ligands block ligand-independent Notch activity

    PubMed Central

    Palmer, William Hunt; Jia, Dongyu; Deng, Wu-Min

    2014-01-01

    The Notch pathway is integrated into numerous developmental processes and therefore is fine-tuned on many levels, including receptor production, endocytosis, and degradation. Notch is further characterized by a twofold relationship with its Delta-Serrate (DSL) ligands, as ligands from opposing cells (trans-ligands) activate Notch, whereas ligands expressed in the same cell (cis-ligands) inhibit signaling. We show that cells without both cis- and trans-ligands can mediate Notch-dependent developmental events during Drosophila oogenesis, indicating ligand-independent Notch activity occurs when the receptor is free of cis- and trans-ligands. Furthermore, cis-ligands can reduce Notch activity in endogenous and genetically induced situations of elevated trans-ligand-independent Notch signaling. We conclude that cis-expressed ligands exert their repressive effect on Notch signaling in cases of trans-ligand-independent activation, and propose a new function of cis-inhibition which buffers cells against accidental Notch activity. DOI: http://dx.doi.org/10.7554/eLife.04415.001 PMID:25486593

  7. Ligand binding by PDZ domains.

    PubMed

    Chi, Celestine N; Bach, Anders; Strømgaard, Kristian; Gianni, Stefano; Jemth, Per

    2012-01-01

    The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common protein-protein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.

  8. A highly selective fluorescent 'turn-on' chemosensor for Zn(2+) based on a benzothiazole conjugate: their applicability in live cell imaging and use of the resultant complex as a secondary sensor of CN(-).

    PubMed

    Khairnar, Nilesh; Tayade, Kundan; Sahoo, Suban K; Bondhopadhyay, Banashree; Basu, Anupam; Singh, Jasminder; Singh, Narinder; Gite, Vikas; Kuwar, Anil

    2015-02-07

    A benzothiazole derivative linked "off-on" multi-responsive and selective chemosensor has been synthesized and evaluated for cation recognition properties. The receptor shows a high sensitivity and selectivity for Zn(2+) through a 'turn-on' fluorescence response over the other tested cations with a detection limit as low as 0.67 μM. The receptor was successfully applied for the detection of Zn(2+) in live HeLa cells. Then, the Zn(2+) complex of receptor was also used for cyanide detection and recognition.

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

    PubMed Central

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

    2014-01-01

    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 leverages prior knowledge from earlier structures to facilitate ligand placement in the current structure. PMID:24419386

  10. Flexible ligand docking using a genetic algorithm

    NASA Astrophysics Data System (ADS)

    Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

    1995-04-01

    Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

  11. Biomimetic affinity ligands for protein purification.

    PubMed

    Sousa, Isabel T; Taipa, M Angela

    2014-01-01

    The development of sophisticated molecular modeling software and new bioinformatic tools, as well as the emergence of data banks containing detailed information about a huge number of proteins, enabled the de novo intelligent design of synthetic affinity ligands. Such synthetic compounds can be tailored to mimic natural biological recognition motifs or to interact with key surface-exposed residues on target proteins and are designated as "biomimetic ligands." A well-established methodology for generating biomimetic or synthetic affinity ligands integrates rational design with combinatorial solid-phase synthesis and screening, using the triazine scaffold and analogues of amino acids side chains to create molecular diversity.Triazine-based synthetic ligands are nontoxic, low-cost, highly stable compounds that can replace advantageously natural biological ligands in the purification of proteins by affinity-based methodologies.

  12. Qualification of a free ligand assay in the presence of anti-ligand antibody Fab fragments.

    PubMed

    Hansen, Ryan J; Brown, Robin M; Lu, Jirong; Wroblewski, Victor J

    2013-01-01

    The aim of this work was to develop and characterize an ELISA to measure free ligand concentrations in rat serum in the presence of a Fab to the same ligand. A variety of experiments were conducted to understand optimal assay conditions and to verify that only free ligand was detected. The parameters explored included sample incubation time on plate, the initial concentrations of Fab and ligand, and the pre-incubation time required for the Fab-ligand complex concentrations to reach equilibrium. We found the optimal experimental conditions to include a 10-minute on-plate incubation of ligand-containing samples, with a 24-hour pre-incubation time for test samples of Fab and ligand to reach equilibrium. An alternative approach, involving removal of Fab-ligand complexes from the solution prior to measuring concentrations of the ligand, was also used to verify that the assay only measured free ligand. Rats were dosed subcutaneously with Fab and the assay was used to demonstrate dose-dependent suppression of endogenous free ligand levels in vivo.

  13. Efficient tandem solid-phase extraction and liquid chromatography-triple quadrupole mass spectrometry method to determine polar benzotriazole, benzothiazole and benzenesulfonamide contaminants in environmental water samples.

    PubMed

    Herrero, P; Borrull, F; Pocurull, E; Marcé, R M

    2013-09-27

    An analytical method has been developed that allows the simultaneous determination of five benzotriazole (BTRs), four benzothiazole (BTs) and five benzenesulfonamide (BSAs) derivates. The method is based on tandem solid-phase extraction (SPE) with Oasis HLB followed by a clean-up step with Florisil. The chromatographic analysis was performed in less than 15min and detection was carried out with a triple quadrupole mass analyser operating in multiple reaction monitoring (MRM) mode. A comparison was performed between Oasis HLB and Oasis MAX sorbents for the solid-phase extraction, with Oasis HLB being the sorbent that gave the highest recoveries, ranging between 75% and 106%, depending on the compound and the matrix analysed. The proposed clean-up with Florisil sorbent reduced the matrix effect to below 20%. The repeatability (%RSD, 50-3000ng/L, n=3) of the method was less than 15% for all of the compounds in all of the matrices. The limits of detection (LODs) achieved ranged from 1ng/L for BTR in river water up to 100ng/L for BT in influent sewage. All of the compounds were determined in environmental waters such as river water and sewage. The highest concentrations determined corresponded to influent sewage samples in which the sum of concentrations for all compounds were between 4.6μg/L and 8.0μg/L. These concentrations were slightly reduced in secondary effluent and tertiary effluent sewage. Moreover, samples from tertiary effluent sewage based on ultra-filtration membrane treatments were also analysed and preliminary results seem to indicate that these treatments may be most effective for removing BTR, BT and BSA derivates.

  14. Preconcentration and determination of trace silver ion using benzothiazole calix[4]arene modified silica by flow injection flame atomic absorption spectrometry.

    PubMed

    Waluvanaruk, Jitwilai; Aeungmaitrepirom, Wanlapa; Tuntulani, Thawatchai; Ngamukot, Passapol

    2014-01-01

    The silica gel modified with benzothiazole calix[4]arene (APS-L1) via Schiff's base reaction was applied as a sorbent in an online system for preconcentration and determination of silver ion by flame atomic absorption spectrometry (FAAS). APS-L1 was used as an effective sorbent for solid phase extraction (SPE) of silver(I) ion in both batch and column methods. The optimum experimental parameters such as pH, eluent type, sample flow rate, eluent volume and eluent flow rate including the effect of interfering ions were investigated. Silver(I) ion was determined at pH 6-7. The capacity of APS-L1 sorbent was found to be 12.2 mg/g of sorbent. The high affinity was obtained without interference from the interfering ions. The optimum conditions of the online flow injection preconcentration coupled with the FAAS (FI-FAAS system) were evaluated. The sample flow rate was 3.0 mL min(-1) using sample volume of 5-10 mL. Elution was performed with 250 μL of 0.1 mol L(-1) thiosulfate at the flow rate of 1.5 mL min(-1). The analytical characteristics and performance of the FI-FAAS system were studied under optimum conditions using a solution spiked with standard silver(I) ion at 20 and 50 μg L(-1). The detection limit of 0.44 μg L(-1) was obtained. The accuracy of the proposed method was evaluated and percentages of recovery at 20 and 50 μg L(-1) were 100.2 and 99.5%, respectively. The percent relative standard deviations (%RSD) at 20 and 50 μg L(-1) were 6.1 and 3.3%, respectively. The developed method was successfully applied to determine trace silver(I) ion in drinking and tap water samples.

  15. Chemistry of Marine Ligands and Siderophores

    NASA Astrophysics Data System (ADS)

    Vraspir, Julia M.; Butler, Alison

    2009-01-01

    Marine microorganisms are presented with unique challenges to obtain essential metal ions required to survive and thrive in the ocean. The production of organic ligands to complex transition metal ions is one strategy to both facilitate uptake of specific metals, such as iron, and to mitigate the potential toxic effects of other metal ions, such as copper. A number of important trace metal ions are complexed by organic ligands in seawater, including iron, cobalt, nickel, copper, zinc, and cadmium, thus defining the speciation of these metal ions in the ocean. In the case of iron, siderophores have been identified and structurally characterized. Siderophores are low molecular weight iron-binding ligands produced by marine bacteria. Although progress has been made toward the identity of in situ iron-binding ligands, few compounds have been identified that coordinate the other trace metals. Deciphering the chemical structures and production stimuli of naturally produced organic ligands and the organisms they come from is fundamental to understanding metal speciation and bioavailability. The current evidence for marine ligands, with an emphasis on siderophores, and discussion of the importance and implications of metal-binding ligands in controlling metal speciation and cycling within the world's oceans are presented.

  16. Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-Raf(V600E) and C-Raf kinase inhibitory activities.

    PubMed

    El-Damasy, Ashraf Kareem; Lee, Ju-Hyeon; Seo, Seon Hee; Cho, Nam-Chul; Pae, Ae Nim; Keum, Gyochang

    2016-06-10

    A new series of benzothiazole amide and urea derivatives tethered with the privileged pyridylamide moiety by ether linkage at the 6-position of benzothiazole (22 final compounds) has been designed and synthesized as potent anticancer sorafenib analogs. A selected group of twelve derivatives was appraised for its antiproliferative activity over a panel of 60 human cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Compounds 4b, 5a, 5b and 5d exhibited promising growth inhibitions and thus were further tested in advanced 5-dose testing assay to determine their GI50 values. The cellular based assay results revealed that 3,5-bis-trifluoromethylphenyl (5b) urea member is the best derivative with superior potency and efficacy compared to sorafenib as well as notable extended spectrum activity covering 57 human cancer cell lines. Kinase screening of compound 5b showed its kinase inhibitory effect against both B-Raf(V600E) and C-Raf. Moreover, the most potent derivatives in cells were investigated for their RAF inhibitory activities, and the results were rationalized with the molecular docking study. Profiling of CYP450 and hERG channel inhibitory effects for the active compounds revealed their low possibilities to exhibit undesirable drug-drug interactions and cardiac side effects.

  17. Influence of Exciplex formation on the electroluminescent properties of dimeric Zn (II) bis-2-(2'-hydroxyphenyl) benzoxazole complex and monomeric Zn (II) 2-(1'-hydroxynaphthyl) benzothiazole complex

    NASA Astrophysics Data System (ADS)

    Prakash, Sattey; Anand, R. S.; Manoharan, S. Sundar

    2011-10-01

    In this paper we present the factors affecting electroluminescent properties of Zinc complexes of oxazole & thiazole derivatives. Electroluminescent spectra of the Zinc (II) complex of bis-[2-(2'-hydroxyphenyl) benzoxazole], [Zn (HPBO)2]2 and 2-(1'-hydroxynaphthyl) benzothiazole [Zn (HNBT)2] show unusual broadening and shows structural and photophysical similarity with [Zn (HPBT)2]2, a dimeric complex. The [Zn (HPBO)2]2 complex as an emissive layer in the device structure ITO /PEDOT:PSS /TPD (30nm) /[Zn (HPBO)2]2 (60nm) /BCP (6nm) /Ca (3nm) /Al (200nm) shows a broad bluish green emission, with a full width at half maxima (FWHM1˜70nm). The EL spectra is much broader compared to the PL spectra because of exciplex formation at the interfacial region between the emissive layer (EML) & hole transport layer (HTL). We also show the device performance of Zinc 2-(1'-hydroxynaphthyl) benzothiazole [Zn (HNBT)2] complex as emissive layer. Distinctly this device shows a broad greenish yellow emission with a peak maxima at 535nm and 690nm, owing to the exciplex formation between electron transport layer (ETL) and emissive layer (EML), which is in sharp contrast to the exciplex formation across the HTL-EML interface observed for the [Zn (HPBO)2]2 complex.

  18. Development and application of an LC-MS method to determine possible migration of mercaptobenzothiazole, benzothiazole and related vulcanization residues from rubber used in contact with food and drink.

    PubMed

    Barnes, K A; Castle, L; Damant, A P; Read, W A; Speck, D R

    2003-02-01

    A method was developed for the analysis of food and drink for residues of specific vulcanization accelerators used to cross-link rubber. The method was applied to the analysis of 236 samples of selected retail foodstuffs that may have been in contact with rubber during their manufacture, transport and storage. The method of analysis involved extraction of the food using acidified solvent and analysis by liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry (LC-APcI-MS). The detection limit depended on the sample type and was in the range 0.005-0.043 mg kg(-1) for 2-mercaptobenzothiazole (MBT) and benzothiazole (BT). The average analytical recovery rate was 82% for MBT and 87% for BT. The analytical method was validated using a blind check sample exercise. For MBT and BT at seven different concentrations in the range 0.1-0.2 mg kg(-1), the laboratory found a mean of 91 and 90% of the expected concentrations, respectively. No trace of MBT or BT was found in any of the retail samples. It is also concluded that no sample contained significant 2-mercaptobenzothiazyl disulphide (MBTS) or N- cyclohexyl-2-benzothiazole sulphenamide (CBS). Both MBTS and CBS are important accelerators used to vulcanize rubber and they break down in foodstuffs to form MBT and BT. The absence of MBT and BT in the foodstuffs therefore also provides proof of the absence of MBTS and CBS.

  19. ProPose: steered virtual screening by simultaneous protein-ligand docking and ligand-ligand alignment.

    PubMed

    Seifert, Markus H J

    2005-01-01

    The 'model-free' screening engine ProPose implements a general method for performing simultaneous protein-ligand docking, ligand-ligand alignment, pharmacophore queries-and combinations thereof-in order to incorporate a priori information into screening protocols. In this manuscript we describe a case study on herpes simplex virus thymidine kinase, an important antiviral drug target, where we evaluate different approaches for handling a specific type of a priori information, i.e., multiple target structures. We demonstrate that a simultaneous alignment on two target structures--in conjunction with logic operations on interactions and docking constraints derived from protein structure--is an effective means of (i) improving the enrichment of chemical substructures that are compatible with the a priori known ligands, (ii) ensuring the steric fit into the target protein, and (iii) handling target flexibility. The combination of ligand- and receptor-based methods steers the virtual screening by ranking molecules according to the similarity of their interaction pattern with known ligands, thereby--to some extent--outweighing the deficiencies of simple scoring functions often used in initial virtual screening.

  20. Ligand engineering of nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton

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

  1. Automated design of ligands to polypharmacological profiles

    PubMed Central

    Besnard, Jérémy; Ruda, Gian Filippo; Setola, Vincent; Abecassis, Keren; Rodriguiz, Ramona M.; Huang, Xi-Ping; Norval, Suzanne; Sassano, Maria F.; Shin, Antony I.; Webster, Lauren A.; Simeons, Frederick R.C.; Stojanovski, Laste; Prat, Annik; Seidah, Nabil G.; Constam, Daniel B.; Bickerton, G. Richard; Read, Kevin D.; Wetsel, William C.; Gilbert, Ian H.; Roth, Bryan L.; Hopkins, Andrew L.

    2012-01-01

    The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery. We describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology. PMID:23235874

  2. Ligand inducible assembly of a DNA tetrahedron.

    PubMed

    Dohno, Chikara; Atsumi, Hiroshi; Nakatani, Kazuhiko

    2011-03-28

    Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron.

  3. Advanced Organic Ligands for Protecting Metal Nanoparticles

    NASA Astrophysics Data System (ADS)

    Yu, Jonathan Ka-Wing

    Organic monolayer protected metal nanoparticles have been utilized in many different fields such as catalysis, drug delivery, and sensor chemistry. However, these nanomaterials are prone to increase in size consequently losing its function at the nanoscale. The stability these nanoparticles have been a great interest of research. This thesis focuses on the synthesis of a novel cross-linkable ligand for the protection of metal nanoparticles. Chapter 1 reviews key concepts of nanoparticles, its usefulness in applications, some of the stabilizing strategies employed, and the scope of the thesis project. Chapter 2 describes the synthetic attempts and optimization of the novel cross-linkable ligand. In addition, its characterization data is also included. Section 2.8 also highlights another fully synthesized novel hydrophobic ligand. Chapter 3 contains the summary of the work and closing remarks. Future works is also included to describe the prospects of the synthesis of the novel ligand. Chapter 4 entails the experimental data and supplementary information.

  4. GW-501516 GlaxoSmithKline/Ligand.

    PubMed

    Pelton, Patricia

    2006-04-01

    GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.

  5. The Retinoid X Receptors and Their Ligands

    PubMed Central

    Dawson, Marcia I.; Xia, Zebin

    2014-01-01

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

  6. Affinity Electrophoresis Using Ligands Attached To Polymers

    NASA Technical Reports Server (NTRS)

    Van Alstine, James M.; Snyder, Robert S.; Harris, J. M.; Brooks, D. E.

    1990-01-01

    In new technique, reduction of electrophoretic mobilities by addition of polyethylene glycol to ligands increases electrophoretic separabilities. In immuno-affinity electrophoresis, modification of ligands extends specificity of electrophoretic separation to particles having surface electric-charge structures otherwise making them electrophoretically inseparable. Modification of antibodies by polyethylene glycol greatly reduces ability to aggregate while enhancing ability to affect electrophoretic mobilities of cells. In hydrophobic-affinity electrophoresis, addition of polyethylene glycol reduces tendency toward aggregation of cells or macromolecules.

  7. Semiconductor Quantum Dots with Photoresponsive Ligands.

    PubMed

    Sansalone, Lorenzo; Tang, Sicheng; Zhang, Yang; Thapaliya, Ek Raj; Raymo, Françisco M; Garcia-Amorós, Jaume

    2016-10-01

    Photochromic or photocaged ligands can be anchored to the outer shell of semiconductor quantum dots in order to control the photophysical properties of these inorganic nanocrystals with optical stimulations. One of the two interconvertible states of the photoresponsive ligands can be designed to accept either an electron or energy from the excited quantum dots and quench their luminescence. Under these conditions, the reversible transformations of photochromic ligands or the irreversible cleavage of photocaged counterparts translates into the possibility to switch luminescence with external control. As an alternative to regulating the photophysics of a quantum dot via the photochemistry of its ligands, the photochemistry of the latter can be controlled by relying on the photophysics of the former. The transfer of excitation energy from a quantum dot to a photocaged ligand populates the excited state of the species adsorbed on the nanocrystal to induce a photochemical reaction. This mechanism, in conjunction with the large two-photon absorption cross section of quantum dots, can be exploited to release nitric oxide or to generate singlet oxygen under near-infrared irradiation. Thus, the combination of semiconductor quantum dots and photoresponsive ligands offers the opportunity to assemble nanostructured constructs with specific functions on the basis of electron or energy transfer processes. The photoswitchable luminescence and ability to photoinduce the release of reactive chemicals, associated with the resulting systems, can be particularly valuable in biomedical research and can, ultimately, lead to the realization of imaging probes for diagnostic applications as well as to therapeutic agents for the treatment of cancer.

  8. New bifunctional ligands for radioimmunoimaging and radioimmunotherapy

    SciTech Connect

    Brechbiel, M.W.

    1988-01-01

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

  9. Interrupting autocrine ligand-receptor binding: comparison between receptor blockers and ligand decoys.

    PubMed Central

    Forsten, K E; Lauffenburger, D A

    1992-01-01

    Stimulation of cell behavioral functions by ligand/receptor binding can be accomplished in autocrine fashion, where cells secrete ligand capable of binding to receptors on their own surfaces. This proximal secretion of autocrine ligands near the surface receptors on the secreting cell suggests that control of these systems by inhibitors of receptor/ligand binding may be more difficult than for systems involving exogenous ligands. Hence, it is of interest to predict the conditions under which successful inhibition of cell receptor binding by the autocrine ligand can be expected. Previous theoretical work using a compartmentalized model for autocrine cells has elucidated the conditions under which addition of solution decoys for the autocrine ligand can interrupt cell receptor/ligand binding via competitive binding of the secreted molecules (Forsten, K. E., and D. A. Lauffenburger. 1992. Biophys. J. 61:1-12.) We now apply a similar modeling approach to examine the addition of solution blockers targeted against the cell receptor. Comparison of the two alternative inhibition strategies reveals that a significantly lower concentration of receptor blockers, compared to ligand decoys, will obtain a high degree of inhibition. The more direct interruption scheme characteristic of the receptor blockers may make them a preferred strategy when feasible. PMID:1330038

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

    PubMed Central

    DeLuca, Samuel; Khar, Karen; Meiler, Jens

    2015-01-01

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

  11. Time, the Forgotten Dimension of Ligand Binding Teaching

    ERIC Educational Resources Information Center

    Corzo, Javier

    2006-01-01

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

  12. Ligand clouds around protein clouds: a scenario of ligand binding with intrinsically disordered proteins.

    PubMed

    Jin, Fan; Yu, Chen; Lai, Luhua; Liu, Zhirong

    2013-01-01

    Intrinsically disordered proteins (IDPs) were found to be widely associated with human diseases and may serve as potential drug design targets. However, drug design targeting IDPs is still in the very early stages. Progress in drug design is usually achieved using experimental screening; however, the structural disorder of IDPs makes it difficult to characterize their interaction with ligands using experiments alone. To better understand the structure of IDPs and their interactions with small molecule ligands, we performed extensive simulations on the c-Myc₃₇₀₋₄₀₉ peptide and its binding to a reported small molecule inhibitor, ligand 10074-A4. We found that the conformational space of the apo c-Myc₃₇₀₋₄₀₉ peptide was rather dispersed and that the conformations of the peptide were stabilized mainly by charge interactions and hydrogen bonds. Under the binding of the ligand, c-Myc₃₇₀₋₄₀₉ remained disordered. The ligand was found to bind to c-Myc₃₇₀₋₄₀₉ at different sites along the chain and behaved like a 'ligand cloud'. In contrast to ligand binding to more rigid target proteins that usually results in a dominant bound structure, ligand binding to IDPs may better be described as ligand clouds around protein clouds. Nevertheless, the binding of the ligand and a non-ligand to the c-Myc₃₇₀₋₄₀₉ target could be clearly distinguished. The present study provides insights that will help improve rational drug design that targets IDPs.

  13. Posttranslational regulation of Fas ligand function

    PubMed Central

    Voss, Matthias; Lettau, Marcus; Paulsen, Maren; Janssen, Ottmar

    2008-01-01

    The TNF superfamily member Fas ligand acts as a prototypic death factor. Due to its ability to induce apoptosis in Fas (APO-1, CD95) expressing cells, Fas ligand participates in essential effector functions of the immune system. It is involved in natural killer cell- and T cell-mediated cytotoxicity, the establishment of immune privilege, and in termination of immune responses by induction of activation-induced cell death. In addition, Fas ligand-positive tumours may evade immune surveillance by killing Fas-positive tumour-infiltrating cells. Given these strong cytotoxic capabilities of Fas ligand, it is obvious that its function has to be strictly regulated to avoid uncontrolled damage. In hematopoietic cells, the death factor is stored in secretory lysosomes and is mobilised to the immunological synapse only upon activation. The selective sorting to and the release from this specific lysosomal compartment requires interactions of the Fas ligand cytosolic moiety, which mediates binding to various adapter proteins involved in trafficking and cytoskeletal reorganisation. In addition, Fas ligand surface expression is further regulated by posttranslational ectodomain shedding and subsequent regulated intramembrane proteolysis, releasing a soluble ectodomain cytokine into the extracellular space and an N-terminal fragment with a potential role in intracellular signalling processes. Moreover, other posttranslational modifications of the cytosolic domain, including phosphorylation and ubiquitylation, have been described to affect various aspects of Fas ligand biology. Since FasL is regarded as a potential target for immunotherapy, the further characterisation of its biological regulation and function will be of great importance for the development and evaluation of future therapeutic strategies. PMID:19114018

  14. Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

    PubMed

    Li, Huameng; Li, Chenglong

    2010-07-30

    Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively.

  15. Design of a Hole Trapping Ligand

    DOE PAGES

    La Croix, Andrew D.; O’Hara, Andrew; Reid, Kemar R.; ...

    2017-01-18

    A new ligand that covalently attaches to the surface of colloidal CdSe/ CdS nanorods and can simultaneously chelate a molecular metal center is described. The dithiocarbamate$-$bipyridine ligand system facilitates hole transfer through energetic overlap at the inorganic$-$organic interface and conjugation through the organic ligand to a chelated metal center. Density functional theory calculations show that the coordination of the free ligand to a CdS surface causes the formation of two hybridized molecular states that lie in the band gap of CdS. The further chelation of Fe(II) to the bipyridine moiety causes the presence of seven midgap states. Hole transfer frommore » the CdS valence band to the midgap states is dipole allowed and occurs at a faster rate than what is experimentally known for the CdSe/CdS band-edge radiative recombination. In the case of the ligand bound with iron, a two-step process emerges that places the hole on the iron, again at rates much faster than band gap recombination. The system was experimentally assembled and characterized via UV$-$vis absorbance spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence spectroscopy, and energy dispersive X-ray spectroscopy. Lastly, theoretically predicted red shifts in absorbance were observed experimentally, as well as the expected quench in photoluminescence and lifetimes in time-resolved photoluminescence« less

  16. Chelating ligands for nanocrystals' surface functionalization.

    PubMed

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

    2004-09-22

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

  17. Engineering death receptor ligands for cancer therapy.

    PubMed

    Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

    2013-05-28

    CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand-based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering.

  18. A screening cascade to identify ERβ ligands

    PubMed Central

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

    2014-01-01

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

  19. Surface Ligand Mediated Plasmon Driven Photochemical Reactions.

    PubMed

    Kafle, Bijesh; Poveda, Marisa; Habteyes, Terefe G

    2017-02-07

    Contrary to the general expectation that surface ligands reduce the reactivity of surfaces by blocking the active sites, we present experimental evidence that surface ligands can in fact increase reactivity and induce important reaction pathways in plasmon-driven surface photochemistry. The remarkable effect of surface ligands is demonstrated by comparing the photochemistry of p-aminothiophenol (PATP) on resonant plasmonic gold nanorods (AuNRs) in the presence of citrate, hexadecyltrimethylammonium bromide (CTAB), and no surface ligands under visible light irradiation. The use of AuNRs with citrate and no surface ligand results in the usual azo-coupling reaction. In contrast, CTAB coated AuNRs oxidize PATP primarily to p-nitrothiophenol (PNTP). Strong correlation has been observed between the N-O and Au-Br vibration band intensities, suggesting that CTAB influences the reaction pathway through the Br- counterions that can minimize electron-hole recombination rate by reacting with hole, and hence increasing the concentration of hot electrons that drive the oxidation reaction.

  20. Controlling Gold Nanoclusters by Diphospine Ligands

    SciTech Connect

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

    2014-01-08

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

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

    PubMed

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

    2015-09-09

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

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

    PubMed Central

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

    2014-01-01

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

  3. Cationic ruthenium alkylidene catalysts bearing phosphine ligands.

    PubMed

    Endo, Koji; Grubbs, Robert H

    2016-02-28

    The discovery of highly active catalysts and the success of ionic liquid immobilized systems have accelerated attention to a new class of cationic metathesis catalysts. We herein report the facile syntheses of cationic ruthenium catalysts bearing bulky phosphine ligands. Simple ligand exchange using silver(i) salts of non-coordinating or weakly coordinating anions provided either PPh3 or chelating Ph2P(CH2)nPPh2 (n = 2 or 3) ligated cationic catalysts. The structures of these newly reported catalysts feature unique geometries caused by ligation of the bulky phosphine ligands. Their activities and selectivities in standard metathesis reactions were also investigated. These cationic ruthenium alkylidene catalysts reported here showed moderate activity and very similar stereoselectivity when compared to the second generation ruthenium dichloride catalyst in ring-closing metathesis, cross metathesis, and ring-opening metathesis polymerization assays.

  4. Comparison of experimental and DFT-calculated NMR chemical shifts of 2-amino and 2-hydroxyl substituted phenyl benzimidazoles, benzoxazoles and benzothiazoles in four solvents using the IEF-PCM solvation model.

    PubMed

    Pierens, Gregory K; Venkatachalam, T K; Reutens, David C

    2016-04-01

    A comparative study of experimental and calculated NMR chemical shifts of six compounds comprising 2-amino and 2-hydroxy phenyl benzoxazoles/benzothiazoles/benzimidazoles in four solvents is reported. The benzimidazoles showed interesting spectral characteristics, which are discussed. The proton and carbon chemical shifts were similar for all solvents. The largest chemical shift deviations were observed in benzene. The chemical shifts were calculated with density functional theory using a suite of four functionals and basis set combinations. The calculated chemical shifts revealed a good match to the experimentally observed values in most of the solvents. The mean absolute error was used as the primary metric. The use of an additional metric is suggested, which is based on the order of chemical shifts. The DP4 probability measures were also used to compare the experimental and calculated chemical shifts for each compound in the four solvents. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Efficient chemoenzymatic synthesis of chiral pincer ligands.

    PubMed

    Felluga, Fulvia; Baratta, Walter; Fanfoni, Lidia; Pitacco, Giuliana; Rigo, Pierluigi; Benedetti, Fabio

    2009-05-01

    Chiral, nonracemic pincer ligands based on the 6-phenyl-2-aminomethylpyridine and 2-aminomethylbenzo[h]quinoline scaffolds were obtained by a chemoenzymatic approach starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the enantiodifferentiating step, secondary alcohols of opposite absolute configuration were obtained by a baker's yeast reduction of the ketones and by lipase-mediated dynamic kinetic resolution of the racemic alcohols. Their transformation into homochiral 1-methyl-1-heteroarylethanamines occurred without loss of optical purity, giving access to pincer ligands used in enantioselective catalysis.

  6. Ligand Intermediates in Metal-Catalyzed Reactions

    SciTech Connect

    Gladysz, John A.

    1999-07-31

    The longest-running goal of this project has been the synthesis, isolation, and physical chemical characterization of homogeneous transition metal complexes containing ligand types believed to be intermediates in the metal-catalyzed conversion of CO/H{sub 2}, CO{sub 2}, CH{sub 4}, and similar raw materials to organic fuels, feedstocks, etc. In the current project period, complexes that contain unusual new types of C{sub x}(carbide) and C{sub x}O{sub y} (carbon oxide) ligands have been emphasized. A new program in homogeneous fluorous phase catalysis has been launched as described in the final report.

  7. Assessment of automatic ligand building in ARP/wARP

    PubMed Central

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

    2007-01-01

    The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement. PMID:17164533

  8. Assessment of automatic ligand building in ARP/wARP.

    PubMed

    Evrard, Guillaume X; Langer, Gerrit G; Perrakis, Anastassis; Lamzin, Victor S

    2007-01-01

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

  9. Ligand expansion in ligand-based virtual screening using relevance feedback

    NASA Astrophysics Data System (ADS)

    Abdo, Ammar; Saeed, Faisal; Hamza, Hentabli; Ahmed, Ali; Salim, Naomie

    2012-03-01

    Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.

  10. CLiBE: a database of computed ligand binding energy for ligand-receptor complexes.

    PubMed

    Chen, X; Ji, Z L; Zhi, D G; Chen, Y Z

    2002-11-01

    Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.

  11. Fine tuning of emission color of iridium(III) complexes from yellow to red via substituent effect on 2-phenylbenzothiazole ligands: synthesis, photophysical, electrochemical and DFT study.

    PubMed

    Li, Ming; Zeng, Hui; Meng, Yanyan; Sun, Huiqin; Liu, Song; Lu, Zhiyun; Huang, Yan; Pu, Xuemei

    2011-07-21

    Four novel iridium(III) complexes bearing biphenyl (7a-7c) or fluorenyl (7d) modified benzothiazole cyclometallate ligands are synthesized. In comparison with the yellow parent complex, bis(2-phenylbenzothiozolato-N,C(2')) iridium(III) (acetylacetonate) [(pbt)(2)Ir(acac)] (λ(PLmax) = 557 nm, φ(PL) = 0.26), 7a-7d show 20-43 nm bathochromic shifted orange or red phosphorescence in solution, with maximum photoluminescence (PL) quantum yield of 0.62, and PL lifetime of 1.8-2.0 μs. Meanwhile, the resulting complexes also exhibit intense orange or red phosphorescence of λ(PLmax) = 588-611 nm in solid films. The complex 7c with two tert-butyl substituents possesses the highest phosphorescent efficiency both in dilute solution and thin solid films, therefore may be a prospective candidate for both doping and host emitting electrophosphorescent material. Furthermore, despite the observation of severe oxygen quenching for 7a-7d in solution, 7a and 7c even show efficient emission intensity quenching by oxygen in their solid state due to the existence of void channels in crystals; consequently, they are promising molecular oxygen sensor reagents. Electrochemical measurement and DFT calculation results suggest that all these chelates own declined LUMOs of 0.1 eV relative to that of (pbt)(2)Ir(acac) owing to the contribution of the phenyl substituents; whereas only 7d shows a more destabilized HOMO (∼0.1 eV) compared with the parent chelate.

  12. Optimizing electrostatic affinity in ligand-receptor binding: Theory, computation, and ligand properties

    NASA Astrophysics Data System (ADS)

    Kangas, Erik; Tidor, Bruce

    1998-11-01

    The design of a tight-binding molecular ligand involves a tradeoff between an unfavorable electrostatic desolvation penalty incurred when the ligand binds a receptor in aqueous solution and the generally favorable intermolecular interactions made in the bound state. Using continuum electrostatic models we have developed a theoretical framework for analyzing this problem and have shown that the ligand-charge distribution can be optimized to produce the most favorable balance of these opposing free energy contributions [L.-P. Lee and B. Tidor, J. Chem. Phys. 106, 8681 (1997)]. Herein the theoretical framework is extended and calculations are performed for a wide range of model receptors. We examine methods for computing optimal ligands (including cases where there is conformational change) and the resulting properties of optimized ligands. In particular, indicators are developed to aid in the determination of the deficiencies in a specific ligand or basis. A connection is established between the optimization problem here and a generalized image problem, from which an inverse-image basis set can be defined; this basis is shown to perform very well in optimization calculations. Furthermore, the optimized ligands are shown to have favorable electrostatic binding free energies (in contrast to many natural ligands), there is a strong correlation between the receptor desolvation penalty and the optimized binding free energy for fixed geometry, and the ligand and receptor cannot generally be mutually optimal. Additionally, we introduce the display of complementary desolvation and interaction potentials and the deviation of their relationship from ideal as a useful tool for judging effective complementarity. Scripts for computing and displaying these potentials with GRASP are available at http://mit.edu/tidor.

  13. [Kinetics of ligand binding to nucleic acids at random fillings].

    PubMed

    Arakelian, V B; Babaian, S Iu; Tairian, V I; Arakelian, A V; Parsadanian, M A; Vardevanian, P O

    2006-01-01

    Ligand binding with nucleic acids is described in frames of the theory of random processes. It is shown that the probabilistic description of binding of a ligand to nucleic acid allows one to describe not only the kinetics of changes in the number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. A general analysis of absorption isotherms and the kinetics of ligand binding with nucleic acids allows one to determine the rate constants of formation and decomposition of the ligand-nucleic acid complex. A comparison of the results obtained with the case of low fillings is conducted.

  14. Solar energy conversion through ligand photodissociation

    SciTech Connect

    Hoffman, B.M.; Sima, P.D.

    1983-04-06

    A new technique for photochemical conversion of solar energy based on ligand photodissociation from metal complexes is examined. The concept is illustrated with a photogalvanic cell in which voltages are generated by photodissociation of CO from carbonylferroheme and with a cell in which the illuminated electrode is coated with an iron tetraphenylporphyrin.

  15. Identification of ligands for bacterial sensor proteins.

    PubMed

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

    2016-02-01

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

  16. [Functional selectivity of opioid receptors ligands].

    PubMed

    Audet, Nicolas; Archer-Lahlou, Elodie; Richard-Lalonde, Mélissa; Piñeyro-Filpo, Graciela

    2010-01-01

    Opiates are the most effective analgesics available for the treatment of severe pain. However, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence and respiratory depression. The strategy to develop new opiates with reduced side effects has mainly focused on the study and production of ligands that specifically bind to different opiate receptors subtypes. However, this strategy has not allowed the production of novel therapeutic ligands with a better side effects profile. Thus, other research strategies need to be explored. One which is receiving increasing attention is the possibility of exploiting ligand ability to stabilize different receptor conformations with distinct signalling profiles. This newly described property, termed functional selectivity, provides a potential means of directing the stimulus generated by an activated receptor towards a specific cellular response. Here we summarize evidence supporting the existence of ligand-specific active conformations for two opioid receptors subtypes (delta and mu), and analyze how functional selectivity may contribute in the production of longer lasting, better tolerated opiate analgesics. double dagger.

  17. Cooperative Ligand Binding to Linear Chain Molecules

    ERIC Educational Resources Information Center

    Applequist, Jon

    1977-01-01

    Summarizes the Ising model of ligand binding as it applies to cooperative binding to long chain molecules. Also presents some illustrations which help to visualize the connection between the interaction parameters and the shape of the binding isotherm. (Author/MR)

  18. [Central effects of ORL1 receptor ligands].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L

    2003-01-01

    It has been discussed literature data on molecular structure of ORL1 receptor and its interaction with intracellular signal systems and neurotransmitters. Data on chemical structure of ORL1 receptor ligands and their central effects (nociception, locomotion, feeding, cognition) are presented.

  19. CXCR3 ligands in disease and therapy.

    PubMed

    Van Raemdonck, Katrien; Van den Steen, Philippe E; Liekens, Sandra; Van Damme, Jo; Struyf, Sofie

    2015-06-01

    Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines.

  20. Ligand iron catalysts for selective hydrogenation

    DOEpatents

    Casey, Charles P.; Guan, Hairong

    2010-11-16

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

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

    NASA Astrophysics Data System (ADS)

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

    2011-07-01

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

  2. Thermodynamic proton-ligand and metal-ligand stability constants of some drugs.

    PubMed

    Agrawal, Y K; Patel, D R

    1986-02-01

    The thermodynamic proton-ligand (pKa) and metal-ligand stability constants of clioquinol, clofibrate, nitrofurazone, and tetracycline with Cu2+, Zn2+, Mn2+, Mg2+, and Ca2+ have been determined at 35 degrees C in 50% ethanol-water media. An empirical pH correction for mixed-aqueous media has been applied. The metal-ligand stability constants were determined by following the Bjerrum Calvin titration technique as applied by Agrawal to mixed-aqueous solvents. The effect of the basicity of the ligand and the order of stability constants is discussed. The stability constants of the divalent metals follow the order: Cu2+ greater than Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+ with all the drugs.

  3. Dissociation of Multisubunit Protein-Ligand Complexes in the Gas Phase. Evidence for Ligand Migration

    NASA Astrophysics Data System (ADS)

    Zhang, Yixuan; Deng, Lu; Kitova, Elena N.; Klassen, John S.

    2013-10-01

    The results of collision-induced dissociation (CID) experiments performed on gaseous protonated and deprotonated ions of complexes of cholera toxin B subunit homopentamer (CTB5) with the pentasaccharide (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p (GM1)) and corresponding glycosphingolipid (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p-Cer (GM1-Cer)) ligands, and the homotetramer streptavidin (S4) with biotin (B) and 1,2-dipalmitoyl- sn-glycero-3-phosphoethanolamine-N-(biotinyl) (Btl), are reported. The protonated (CTB5 + 5GM1)n+ ions dissociated predominantly by the loss of a single subunit, with the concomitant migration of ligand to another subunit. The simultaneous loss of ligand and subunit was observed as a minor pathway. In contrast, the deprotonated (CTB5 + 5GM1)n- ions dissociated preferentially by the loss of deprotonated ligand; the loss of ligand-bound and ligand-free subunit were minor pathways. The presence of ceramide (Cer) promoted ligand migration and the loss of subunit. The main dissociation pathway for the protonated and deprotonated (S4 + 4B)n+/- ions, as well as for deprotonated (S4 + 4Btl)n- ions, was loss of the ligand. However, subunit loss from the (S4 + 4B)n+ ions was observed as a minor pathway. The (S4 + 4Btl)n+ ions dissociated predominantly by the loss of free and ligand-bound subunit. The charge state of the complex and the collision energy were found to have little effect on the relative contribution of the different dissociation channels. Thermally-driven ligand migration between subunits was captured in the results of molecular dynamics simulations performed on protonated (CTB5 + 5GM1)15+ ions (with a range of charge configurations) at 800 K. Notably, the migration pathway was found to be highly dependent on the charge configuration of the ion. The main conclusion of this study is that the dissociation pathways of multisubunit protein-ligand

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

    PubMed Central

    Kantardjiev, Alexander A.

    2012-01-01

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

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

    PubMed

    Kantardjiev, Alexander A

    2012-07-01

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

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

    DOE PAGES

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; ...

    2016-01-21

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

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

    PubMed

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

    2016-03-09

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

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

    SciTech Connect

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

    2016-01-21

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

  9. Affinity Regulates Spatial Range of EGF Receptor Autocrine Ligand Binding

    SciTech Connect

    Dewitt, Ann; Iida, Tomoko; Lam, Ho-Yan; Hill, Virginia; Wiley, H S.; Lauffenburger, Douglas A.

    2002-08-08

    Proper spatial localization of EGFR signaling activated by autocrine ligands represents a critical factor in embryonic development as well as tissue organization and function, and ligand/receptor binding affinity is among the molecular and cellular properties suggested to play a role in governing this localization. The authors employ a computational model to predict how receptor-binding affinity affects local capture of autocrine ligand vis-a-vis escape to distal regions, and provide experimental test by constructing cell lines expressing EGFR along with either wild-type EGF or a low-affinity mutant, EGF{sup L47M}. The model predicts local capture of a lower affinity autocrine ligand to be less efficient when the ligand production rate is small relative to receptor appearance rate. The experimental data confirm this prediction, demonstrating that cells can use ligand/receptor binding affinity to regulate ligand spatial distribution when autocrine ligand production is limiting for receptor signaling.

  10. Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility.

    PubMed

    Van Lehn, Reid C; Alexander-Katz, Alfredo

    2014-08-07

    Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature.

  11. Amino Acids in Nine Ligand-Prefer Ramachandran Regions.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    2016-01-01

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

  13. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    PubMed Central

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-01-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup. PMID:28256624

  14. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    NASA Astrophysics Data System (ADS)

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-03-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup.

  15. Diamine Ligands in Copper-Catalyzed Reactions

    PubMed Central

    Surry, David S.

    2012-01-01

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

  16. 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.

  17. galectin-3 ligand — EDRN Public Portal

    Cancer.gov

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

  18. Selective oxoanion separation using a tripodal ligand

    DOEpatents

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

    2016-02-16

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

  19. Gated escaping of ligand out of protein

    NASA Astrophysics Data System (ADS)

    Sheu, Sheh-Yi; Yang, Dah-Yen

    2000-01-01

    We construct a new gating model and develop a new theory to study the escaping process of a ligand out of a spherical cavity with a puncture (or gate) on the surface. The gate undulation can be regulated by any time-dependent function and the motion of the ligand inside the spherical cavity is mapped into a two-dimensional entropy potential surface. Hence the driving force of our model is entropy only. For a static gate, the escaping process corresponds to climbing a two-dimensional entropy barrier. When the gate open angle is small, the escaping rate is proportional to the square of the opening angle. The prefactor of the escaping rate constant depends on the curvature of the entropy potential surface. For coherent gating, the survival time depends not only on the gate undulation frequency but also on how the initial state is defined. On the escaping from protein, our escaping rate shows it is qualitatively consistent with the experimental result of ligand recombination in myoglobin.

  20. RAGE and its ligands in retinal disease.

    PubMed

    Barile, Gaetano R; Schmidt, Ann M

    2007-12-01

    RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

  1. Modeling of the Aryl Hydrocarbon Receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands

    PubMed Central

    Bisson, William; Koch, Daniel; O’Donnell, Edmond; Khalil, Sammy M.; Kerkvliet, Nancy; Tanguay, Robert; Abagyan, Ruben; Kolluri, Siva Kumar

    2012-01-01

    The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and inter-species differences in ligand binding using Molecular Docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes. PMID:19719119

  2. Assessment of automatic ligand building in ARP/wARP

    SciTech Connect

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

    2007-01-01

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

  3. The Recognition of Identical Ligands by Unrelated Proteins

    PubMed Central

    Barelier, Sarah; Sterling, Teague; O'Meara, Matthew J.; Shoichet, Brian K.

    2015-01-01

    The binding of drugs and reagents to off-targets is well-known. Whereas many off-targets are related to the primary target by sequence and fold, many ligands bind to unrelated pairs of proteins, and these are harder to anticipate. If the binding site in the off-target can be related to that of the primary target, this challenge resolves into aligning the two pockets. However, other cases are possible: the ligand might interact with entirely different residues and environments in the off-target, or wholly different ligand atoms may be implicated in the two complexes. To investigate these scenarios at atomic resolution, the structures of 59 ligands in 116 complexes (62 pairs in total), where the protein pairs were unrelated by fold but bound an identical ligand, were examined. In almost half of the pairs, the ligand interacted with unrelated residues in the two proteins (29 pairs), and in 14 of the pairs wholly different ligand moieties were implicated in each complex. Even in those 19 pairs of complexes that presented similar environments to the ligand, ligand superposition rarely resulted in the overlap of related residues. There appears to be no single pattern-matching “code” for identifying binding sites in unrelated proteins that bind identical ligands, though modeling suggests that there might be a limited number of different patterns that suffice to recognize different ligand functional groups. PMID:26421501

  4. Identification of Ligand-Receptor Interactions: Ligand Molecular Arrays, SPR and NMR Methodologies.

    PubMed

    Day, Christopher J; Hartley-Tassell, Lauren E; Korolik, Victoria

    2017-01-01

    Despite many years of research into bacterial chemotaxis, the only well characterized system to date is that of E. coli. Even for E. coli, the direct ligand binding had been fully characterized only for aspartate and serene receptors Tar and Tsr. In 30 years since, no other direct receptor-ligand interaction had been described for bacteria, until the characterization of the C. jejuni aspartate and multiligand receptors (Hartley-Tassell et al. Mol Microbiol 75:710-730, 2010). While signal transduction components of many sensory pathways have now been characterized, ligand-receptor interactions remain elusive due to paucity of high-throughput screening methods. Here, we describe the use of microarray screening we developed to identify ligands, surface plasmon resonance, and saturation transfer difference nuclear magnetic resonance (STD-NMR) we used to verify the hits and to determine the affinity constants of the interactions, allowing for more targeted verification of ligands with traditional chemotaxis and in vivo assays described in Chapter 13 .

  5. Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation.

    PubMed

    Hennig, Robert; Pollinger, Klaus; Veser, Anika; Breunig, Miriam; Goepferich, Achim

    2014-11-28

    The conjugation of receptor ligands to shielded nanoparticles is a widely used strategy to precisely control nanoparticle-cell interactions. However, it is often overlooked that a ligand's affinity can be severely impaired by its attachment to the polyethylene glycol (PEG) chains that are frequently used to protect colloids from serum protein adsorption. Using the model ligand EXP3174, a small-molecule antagonist for the angiotensin II receptor type 1 (AT1R), we investigated the ligand's affinity before and after its PEGylation and when attached to PEGylated nanoparticles. The PEGylated ligand displayed a 580-fold decreased receptor affinity compared to the native ligand. Due to their multivalency, the nanoparticles regained a low nanomolar receptor affinity, which is in the range of the affinity of the native ligand. Moreover, a four orders of magnitude higher concentration of free ligand was required to displace PEGylated nanoparticles carrying EXP3174 from the receptor. On average, one nanoparticle was decorated with 11.2 ligand molecules, which led to a multivalent enhancement factor of 22.5 compared to the monovalent PEGylated ligand. The targeted nanoparticles specifically bound the AT1R and showed no interaction to receptor negative cells. Our study shows that the attachment of a small-molecule ligand to a PEG chain can severely affect its receptor affinity. Concomitantly, when the ligand is tethered to nanoparticles, the immense avidity greatly increases the ligand-receptor interaction. Based on our results, we highly recommend the affinity testing of receptor ligands before and after PEGylation to identify potent molecules for active nanoparticle targeting.

  6. A chemogenomics view on protein-ligand spaces

    PubMed Central

    Strömbergsson, Helena; Kleywegt, Gerard J

    2009-01-01

    Background Chemogenomics is an emerging inter-disciplinary approach to drug discovery that combines traditional ligand-based approaches with biological information on drug targets and lies at the interface of chemistry, biology and informatics. The ultimate goal in chemogenomics is to understand molecular recognition between all possible ligands and all possible drug targets. Protein and ligand space have previously been studied as separate entities, but chemogenomics studies deal with large datasets that cover parts of the joint protein-ligand space. Since drug discovery has traditionally focused on ligand optimization, the chemical space has been studied extensively. The protein space has been studied to some extent, typically for the purpose of classification of proteins into functional and structural classes. Since chemogenomics deals not only with ligands but also with the macromolecules the ligands interact with, it is of interest to find means to explore, compare and visualize protein-ligand subspaces. Results Two chemogenomics protein-ligand interaction datasets were prepared for this study. The first dataset covers the known structural protein-ligand space, and includes all non-redundant protein-ligand interactions found in the worldwide Protein Data Bank (PDB). The second dataset contains all approved drugs and drug targets stored in the DrugBank database, and represents the approved drug-drug target space. To capture biological and physicochemical features of the chemogenomics datasets, sequence-based descriptors were computed for the proteins, and 0, 1 and 2 dimensional descriptors for the ligands. Principal component analysis (PCA) was used to analyze the multidimensional data and to create global models of protein-ligand space. The nearest neighbour method, computed using the principal components, was used to obtain a measure of overlap between the datasets. Conclusion In this study, we present an approach to visualize protein-ligand spaces from a

  7. Evaluation of small ligand-protein interaction by ligation reaction with DNA-modified ligand.

    PubMed

    Sugita, Rie; Mie, Masayasu; Funabashi, Hisakage; Kobatake, Eiry

    2010-01-01

    A method for the evaluation of interactions between protein and ligand using DNA-modified ligands, including signal enhancement of the DNA ligation reactions, is described. For proof of principle, a DNA probe modified by biotin was used. Two DNA probes were prepared with complementary sticky-ends. While one DNA probe was modified at the 5'-end of the sticky-end, the other was not modified. The probes could be ligated together by T4 DNA ligase along the strand without biotin modification. However, in the presence of streptavidin or anti-biotin Fab, the ligation reaction joining the two probes could not occur on either strand.

  8. Landscape of protein–small ligand binding modes

    PubMed Central

    Kinoshita, Kengo

    2016-01-01

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

  9. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status.

    PubMed

    van der Meel, Roy; Vehmeijer, Laurens J C; Kok, Robbert J; Storm, Gert; van Gaal, Ethlinn V B

    2013-10-01

    Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.

  10. (Ligand intermediates in metal-catalyzed reactions)

    SciTech Connect

    Not Available

    1992-01-01

    This report consists of sections on sigma bond complexes of alkenes, a new carbon-hydrogen bond activation reaction of alkene complexes, carbon-hydrogen bond migrations in alkylidene complexes, carbon- hydrogen bond migrations in alkyne complexes, synthesis, structure and reactivity of C{sub x} complexes, synthesis and reactivity of alcohol and ether complexes, new catalysts for the epimerization of secondary alcohols; carbon-hydrogen bond activation in alkoxide complexes, pi/sigma equilibria in metal/O=CXX' complexes, and other hydrocarbon ligands; miscellaneous.(WET)

  11. Transmutable nanoparticles with reconfigurable surface ligands

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

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

  12. Differential Effects of TR Ligands on Hormone Dissociation Rates: Evidence for Multiple Ligand Entry/Exit Pathways

    PubMed Central

    Lima, Suzana T. Cunha; Nguyen, Ngoc-Ha; Togashi, Marie; Apriletti, James W.; Nguyen, Phuong; Polikarpov, Igor; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

    2009-01-01

    Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself. This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here, we show that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T1/2 <2 hours) of radiolabeled T3 versus T3 (T1/2 ≈5–7 hours). We cannot discern relationships between this effect and ligand size, activity or affinity for TRβ. One ligand, GC-24, binds the TR LBC and (weakly) to the TRβ-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T3 dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T3 release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T3 release and that this effect enhances hormone dissociation. PMID:19729063

  13. Does the ligand-biopolymer equilibrium binding constant depend on the number of bound ligands?

    PubMed

    Beshnova, Daria A; Lantushenko, Anastasia O; Evstigneev, Maxim P

    2010-11-01

    Conventional methods, such as Scatchard or McGhee-von Hippel analyses, used to treat ligand-biopolymer interactions, indirectly make the assumption that the microscopic binding constant is independent of the number of ligands, i, already bound to the biopolymer. Recent results on the aggregation of aromatic molecules (Beshnova et al., J Chem Phys 2009, 130, 165105) indicated that the equilibrium constant of self-association depends intrinsically on the number of molecules in an aggregate due to loss of translational and rotational degrees of freedom on formation of the complex. The influence of these factors on the equilibrium binding constant for ligand-biopolymer complexation was analyzed in this work. It was shown that under the conditions of binding of "small" molecules, these factors can effectively be ignored and, hence, do not provide any hidden systematic error in such widely-used approaches, such as the Scatchard or McGhee-von Hippel methods for analyzing ligand-biopolymer complexation. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 932-935, 2010.

  14. SuperLigands – a database of ligand structures derived from the Protein Data Bank

    PubMed Central

    Michalsky, Elke; Dunkel, Mathias; Goede, Andrean; Preissner, Robert

    2005-01-01

    Background Currently, the PDB contains approximately 29,000 protein structures comprising over 70,000 experimentally determined three-dimensional structures of over 5,000 different low molecular weight compounds. Information about these PDB ligands can be very helpful in the field of molecular modelling and prediction, particularly for the prediction of protein binding sites and function. Description Here we present an Internet accessible database delivering PDB ligands in the MDL Mol file format which, in contrast to the PDB format, includes information about bond types. Structural similarity of the compounds can be detected by calculation of Tanimoto coefficients and by three-dimensional superposition. Topological similarity of PDB ligands to known drugs can be assessed via Tanimoto coefficients. Conclusion SuperLigands supplements the set of existing resources of information about small molecules bound to PDB structures. Allowing for three-dimensional comparison of the compounds as a novel feature, this database represents a valuable means of analysis and prediction in the field of biological and medical research. PMID:15943884

  15. DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade.

    PubMed

    Berdnikova, Daria V; Aliyeu, Tseimur M; Paululat, Thomas; Fedorov, Yuri V; Fedorova, Olga A; Ihmels, Heiko

    2015-03-21

    A supramolecular five-component cascade is presented that enables light-controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy.

  16. Phenotypic spandrel: absolute discrimination and ligand antagonism

    NASA Astrophysics Data System (ADS)

    François, Paul; Hemery, Mathieu; Johnson, Kyle A.; Saunders, Laura N.

    2016-12-01

    We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below the discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a ‘phenotypic spandrel’: a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from the detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCɛRIs, as well as endocrine signalling/disruption.

  17. Molecular modulators of benzodiazepine receptor ligand binding

    SciTech Connect

    Villar, H.O.; Loew, G.H. )

    1989-01-01

    Ten derivatives of {beta}-carbolines with known affinities to the GABA{sub A}/BDZ (benzodiazepine) receptor were studied using the Am 1 and MNDO/H Semiempirical techniques to identify and characterize molecular modulators of receptor recognition. Steric, lipophilic, and electrostatic properties of these compounds were calculated and examined for their possible role in recognition. Particular attention was paid to the regions around the two most favorable proton-accepting sites, the ON and the substituent at the C{sub 3} position, already implicated in recognition, as well as to the acidic N9H group that could be a proton donating center. To probe further the role of these three ligand sites in receptor interactions, a model of the receptor using three methanol molecules was made and optimum interactions of these three sites with them characterized. The results indicate some similarity in the shape of these ligands, which could reflect a steric requirement. The receptor affinity appears to be modulated to some extent by the ratio of lipophilic to hydrophilic surface, the negative potential at the {beta}N, provided there is also one at the C{sub 3} substituent confirming the importance of two accepting sites in recognition. The acidic N9H does not appear to be a modulator of affinity or does it form a stable H-bond with methanol as acceptor. The two proton donating molecules do form such a stable complex, and both are needed for high affinity.

  18. Continuous microfluidic assortment of interactive ligands (CMAIL)

    NASA Astrophysics Data System (ADS)

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-08-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display.

  19. Continuous microfluidic assortment of interactive ligands (CMAIL)

    PubMed Central

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-01-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display. PMID:27578501

  20. Activating Cell Death Ligand Signaling Through Proteasome Inhibition

    DTIC Science & Technology

    2009-05-01

    Activating Cell Death Ligand Signaling Through Proteasome Inhibition PRINCIPAL INVESTIGATOR: Steven R Schwarze...SUBTITLE Activating Cell Death Ligand Signaling Through 5a. CONTRACT NUMBER Proteasome Inhibition 5b. GRANT NUMBER W81XWH-08-1-0392 5c...proteasome inhibition can act as an anti-neoplastic agent in vivo by sensitizing cancer cells to cell death ligands in the tumor microenvironment

  1. Selective high affinity polydentate ligands and methods of making such

    DOEpatents

    DeNardo, Sally; DeNardo, Gerald; Balhorn, Rodney

    2010-02-16

    This invention provides novel polydentate selective high affinity ligands (SHALs) that can be used in a variety of applications in a manner analogous to the use of antibodies. SHALs typically comprise a multiplicity of ligands that each bind different region son the target molecule. The ligands are joined directly or through a linker thereby forming a polydentate moiety that typically binds the target molecule with high selectivity and avidity.

  2. Quasielastic neutron scattering study of POSS ligand dynamics

    SciTech Connect

    Jalarvo, Niina H; Tyagi, Madhusudan; Crawford, Michael

    2015-01-01

    Polyoligosilsesquioxanes are molecules having cage-like structures composed of silicon and oxygen. These molecules can have a wide variety of functional ligands attached to them. Depending on the nature of the ligand, interesting properties and applications are found. In this work we present results from quasielastic neutron scattering measurements of four different POSS molecules that illustrate the presence of strong coupling between the ligand dynamics and the POSS crystal structures.

  3. A quick, easy, cheap, effective, rugged and safe extraction method followed by liquid chromatography-(Orbitrap) high resolution mass spectrometry to determine benzotriazole, benzothiazole and benzenesulfonamide derivates in sewage sludge.

    PubMed

    Herrero, Pol; Borrull, Francesc; Pocurull, Eva; Marcé, Rosa M

    2014-04-25

    A Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) extraction method followed by liquid chromatography-(Orbitrap) high resolution mass spectrometry was developed for the simultaneous determination of five benzotriazole, four benzothiazole and five benzenesulfonamide derivates in sewage sludge. While the method was being developed, several buffers and dispersive solid-phase extraction clean-up (dSPE) sorbents were tested. Citrate buffer and Z-sep+ (zirconium-based sorbent) were the most effective extraction buffer and dSPE clean-up material. The absolute recoveries were higher than 80% for all compounds (100ng/g (d.w.)) and the matrix effect was less than -20% for most compounds. The limits of detection were between 0.5 and 10ng/g (d.w.) and the limits of quantification (LOQ) were between 1 and 25ng/g (d.w.). Repeatability and reproducibility were lower than 15% (%RSD, n=5). Several sludge samples from five sewage treatment plants in Catalonia were analysed and the most abundant compounds were 2-hydroxybenzothiazole (

  4. The characterization of electroplex generated from the interface between 2-(4-trifluoromethyl-2-hydroxyphenyl)benzothiazole] zinc and N,N'-diphenyl-N,N'- bis(1-naphthyl)-(1,1'-biphenyl)-4,4'-diamine

    NASA Astrophysics Data System (ADS)

    Zhang, Ye; Hao, Yuying; Meng, Weixin; Xu, Huixia; Wang, Hua; Xu, Bingshe

    2012-03-01

    The electroplex between (2-(4-trifluoromethyl-2-hydroxyphenyl)benzothiazole) zinc [Zn(4-TfmBTZ)2] as an electron-acceptor and N,N'-diphenyl-N,N'-bis(1-naphthyl)-(1,1'-biphenyl)-4,4'-diamine (NPB) as an electron-donor was characterized by bilayer, blend, and multilayer quantum-well (MQW) device, respectively. The blend composition and quantum-well number are effective parameters for tuning electroluminescence color. White light with high color purity and color rendering index (CRI) was observed from these devices based on Zn(4-TfmBTZ)2/NPB. Moreover, the blend and MQW devices all exhibit high operation stability, hence excellent color stability. For the device with 5 mol% NPB in blend layer, its Commission International Del'Eclairage (CIE) coordinate region is x=0.28-0.31, y=0.33-0.35 and CRI is 83.3-91.2 at 5-9 V. For MQW structure device with NPB of 60 nm thickness, its CIE coordinate region is x=0.29-0.32, y=0.31-0.34 and CRI=87.9-92.5 at 10-15 V. Such high color stability and purity and CRI, being close to ideal white light, are of current important for white OLED.

  5. Effects of tricyclazole (5-methyl-1,2,4-triazol[3,4] benzothiazole), a specific DHN-melanin inhibitor, on the morphology of Fonsecaea pedrosoi conidia and sclerotic cells.

    PubMed

    Franzen, Anderson J; Cunha, Marcel M L; Batista, Evander J O; Seabra, Sergio H; De Souza, Wanderley; Rozental, Sonia

    2006-09-01

    The influence of tricyclazole (5-methyl-1,2,4-triazol[3,4]benzothiazole), a specific DHN-melanin inhibitor, on the cell walls and intracellular structures of Fonsecaea pedrosoi conidia and sclerotic cells was analyzed by transmission electron microscopy (TEM), deep-etching, and field emission scanning electron microscopy. The treatment of the fungus with 16 microg mL(-1) of tricyclazole (TC) did not significantly affect fungal viability, but electron microscopy observations showed several important morphological differences between TC-treated and non-TC treated cells. Control sclerotic cells presented patched granules, with an average diameter of 47 nm, on the cell surface, which were absent in TC-treated cells. Also, TC-treated sclerotic cells showed an undulated relief. TC treatment leads to an accumulation of electron lucent vacuoles in the fungal cytoplasm of both conidia and sclerotic cells, and treated conidia observed by deep etching showed a relevant thickening of the fungal cell wall. Together, these observations support the previous data of our group that F. pedrosoi synthesizes melanin in intracellular organelles. In addition, we suggest that melanin is not only an extracellular constituent but could also be dispersing all over the cell walls and could have an effective role in cross-linking different cell wall compounds that help maintain the regular shape of the cell wall.

  6. Mixed Extracellular Matrix Ligands Synergistically Modulate Integrin Adhesion and Signaling

    PubMed Central

    Reyes, Catherine D.; Petrie, Timothy A.; García, Andrés J

    2008-01-01

    Cell adhesion to extracellular matrix (ECM) components through cell-surface integrin receptors is essential to the formation, maintenance and repair of numerous tissues, and therefore represents a central theme in the design of bioactive materials that successfully interface with the body. While the adhesive responses associated with a single ligand have been extensively analyzed, the effects of multiple integrin subtypes binding to multivalent ECM signals remain poorly understood. In the present study, we generated a high throughput platform of non-adhesive surfaces presenting well-defined, independent densities of two integrin-specific engineered ligands for the type I collagen (COL-I) receptor α2β1 and the fibronectin (FN) receptor α5β1 to evaluate the effects of integrin cross-talk on adhesive responses. Engineered surfaces displayed ligand density-dependent adhesive effects, and mixed ligand surfaces significantly enhanced cell adhesion strength and focal adhesion assembly compared to single FN and COL-I ligand surfaces. Moreover, surfaces presenting mixed COL-I/FN ligands synergistically enhanced FAK activation compared to the single ligand substrates. The enhanced adhesive activities of the mixed ligand surfaces also promoted elevated proliferation rates. Our results demonstrate interplay between multivalent ECM ligands in adhesive responses and downstream cellular signaling. PMID:18613064

  7. Superior serum half life of albumin tagged TNF ligands

    SciTech Connect

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-06-11

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  8. Biased ligands: pathway validation for novel GPCR therapeutics.

    PubMed

    Rominger, David H; Cowan, Conrad L; Gowen-MacDonald, William; Violin, Jonathan D

    2014-06-01

    G protein-coupled receptors (GPCRs), in recent years, have been shown to signal via multiple distinct pathways. Furthermore, biased ligands for some receptors can differentially stimulate or inhibit these pathways versus unbiased endogenous ligands or drugs. Biased ligands can be used to gain a deeper understanding of the molecular targets and cellular responses associated with a GPCR, and may be developed into therapeutics with improved efficacy, safety and/or tolerability. Here we review examples and approaches to pathway validation that establish the relevance and therapeutic potential of distinct pathways that can be selectively activated or blocked by biased ligands.

  9. ADAM Proteases: Ligand Processing and Modulation of the Notch Pathway

    PubMed Central

    Zolkiewska, Anna

    2009-01-01

    ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step of the regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. PMID:18344021

  10. Hysteresis of ligand binding in CNGA2 ion channels

    PubMed Central

    Nache, Vasilica; Eick, Thomas; Schulz, Eckhard; Schmauder, Ralf; Benndorf, Klaus

    2013-01-01

    Tetrameric cyclic nucleotide-gated (CNG) channels mediate receptor potentials in olfaction and vision. The channels are activated by the binding of cyclic nucleotides to a binding domain embedded in the C terminus of each subunit. Here using a fluorescent cGMP derivative (fcGMP), we show for homotetrameric CNGA2 channels that ligand unbinding is ~50 times faster at saturating than at subsaturating fcGMP. Analysis with complex Markovian models reveals two pathways for ligand unbinding; the partially liganded open channel unbinds its ligands from closed states only, whereas the fully liganded channel reaches a different open state from which it unbinds all four ligands rapidly. Consequently, the transition pathways for ligand binding and activation of a fully liganded CNGA2 channel differ from that of ligand unbinding and deactivation, resulting in pronounced hysteresis of the gating mechanism. This concentration-dependent gating mechanism allows the channels to respond to changes in the cyclic nucleotide concentration with different kinetics. PMID:24287615

  11. Riboswitch Structure: an Internal Residue Mimicking the Purine Ligand

    SciTech Connect

    Delfosse, V.; Bouchard, P; Bonneau, E; Dagenais, P; Lemay, J; Lafontaine, D; Legault, P

    2009-01-01

    The adenine and guanine riboswitches regulate gene expression in response to their purine ligand. X-ray structures of the aptamer moiety of these riboswitches are characterized by a compact fold in which the ligand forms a Watson-Crick base pair with residue 65. Phylogenetic analyses revealed a strict restriction at position 39 of the aptamer that prevents the G39-C65 and A39-U65 combinations, and mutational studies indicate that aptamers with these sequence combinations are impaired for ligand binding. In order to investigate the rationale for sequence conservation at residue 39, structural characterization of the U65C mutant from Bacillus subtilis pbuE adenine riboswitch aptamer was undertaken. NMR spectroscopy and X-ray crystallography studies demonstrate that the U65C mutant adopts a compact ligand-free structure, in which G39 occupies the ligand-binding site of purine riboswitch aptamers. These studies present a remarkable example of a mutant RNA aptamer that adopts a native-like fold by means of ligand mimicking and explain why this mutant is impaired for ligand binding. Furthermore, this work provides a specific insight into how the natural sequence has evolved through selection of nucleotide identities that contribute to formation of the ligand-bound state, but ensures that the ligand-free state remains in an active conformation.

  12. Dewetting-Controlled Binding of Ligands to Hydrophobic Pockets

    PubMed Central

    Setny, P.; Wang, Z.; Cheng, L.-T.; Li, B.; McCammon, J. A.; Dzubiella, J.

    2010-01-01

    We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting-dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semiquantitatively. PMID:19905832

  13. Design of targeting ligands in medicinal inorganic chemistry.

    PubMed

    Storr, Tim; Thompson, Katherine H; Orvig, Chris

    2006-06-01

    This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

  14. Ultrafast heme-ligand recombination in truncated hemoglobin HbO from Mycobacterium tuberculosis: A ligand cage

    NASA Astrophysics Data System (ADS)

    Jasaitis, Audrius; Ouellet, Hugues; Lambry, Jean-Christophe; Martin, Jean-Louis; Friedman, Joel M.; Guertin, Michel; Vos, Marten H.

    2012-03-01

    Truncated hemoglobin HbO from Mycobacterium tuberculosis displays very slow exchange of diatomic ligands with its environment. Using femtosecond spectroscopy, we show that upon photoexcitation, ligands rebind with unusual speed and efficiency. Only ˜1% O2 can escape from the heme pocket and less than 1% NO. Most remarkably, CO rebinding occurs for 95%, predominantly in 1.2 ns. The general CO rebinding properties are unexpectedly robust against changes in the interactions with close by aromatic residues Trp88 (G8) and Tyr36 (CD1). Molecular dynamics simulations of the CO complex suggest that interactions of the ligand with structural water molecules as well as its rotational freedom play a role in the high reactivity of the ligand and the heme. The slow exchange of ligands between heme and environment may result from a combination of hindered ligand access to the heme pocket by the network of distal aromatic residues, and low escape probability from the pocket.

  15. LibME-automatic extraction of 3D ligand-binding motifs for mechanistic analysis of protein-ligand recognition.

    PubMed

    He, Wei; Liang, Zhi; Teng, MaiKun; Niu, LiWen

    2016-12-01

    Identifying conserved binding motifs is an efficient way to study protein-ligand recognition. Most 3D binding motifs only contain information from the protein side, and so motifs that combine information from both protein and ligand sides are desired. Here, we propose an algorithm called LibME (Ligand-binding Motif Extractor), which automatically extracts 3D binding motifs composed of the target ligand and surrounding conserved residues. We show that the motifs extracted by LibME for ATP and its analogs are highly similar to well-known motifs reported by previous studies. The superiority of our method to handle flexible ligands was also demonstrated using isocitric acid as an example. Finally, we show that these motifs, together with their visual exhibition, permit better investigating and understanding of protein-ligand recognition process.

  16. Ligand "Brackets" for Ga-Ga Bond.

    PubMed

    Fedushkin, Igor L; Skatova, Alexandra A; Dodonov, Vladimir A; Yang, Xiao-Juan; Chudakova, Valentina A; Piskunov, Alexander V; Demeshko, Serhiy; Baranov, Evgeny V

    2016-09-06

    The reactivity of digallane (dpp-Bian)Ga-Ga(dpp-Bian) (1) (dpp-Bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) toward acenaphthenequinone (AcQ), sulfur dioxide, and azobenzene was investigated. The reaction of 1 with AcQ in 1:1 molar ratio proceeds via two-electron reduction of AcQ to give (dpp-Bian)Ga(μ2-AcQ)Ga(dpp-Bian) (2), in which diolate [AcQ](2-) acts as "bracket" for the Ga-Ga bond. The interaction of 1 with AcQ in 1:2 molar ratio proceeds with an oxidation of the both dpp-Bian ligands as well as of the Ga-Ga bond to give (dpp-Bian)Ga(μ2-AcQ)2Ga(dpp-Bian) (3). At 330 K in toluene complex 2 decomposes to give compounds 3 and 1. The reaction of complex 2 with atmospheric oxygen results in oxidation of a Ga-Ga bond and affords (dpp-Bian)Ga(μ2-AcQ)(μ2-O)Ga(dpp-Bian) (4). The reaction of digallane 1 with SO2 produces, depending on the ratio (1:2 or 1:4), dithionites (dpp-Bian)Ga(μ2-O2S-SO2)Ga(dpp-Bian) (5) and (dpp-Bian)Ga(μ2-O2S-SO2)2Ga(dpp-Bian) (6). In compound 5 the Ga-Ga bond is preserved and supported by dithionite dianionic bracket. In compound 6 the gallium centers are bridged by two dithionite ligands. Both 5 and 6 consist of dpp-Bian radical anionic ligands. Four-electron reduction of azobenzene with 1 mol equiv of digallane 1 leads to complex (dpp-Bian)Ga(μ2-NPh)2Ga(dpp-Bian) (7). Paramagnetic compounds 2-7 were characterized by electron spin resonance spectroscopy, and their molecular structures were established by single-crystal X-ray analysis. Magnetic behavior of compounds 2, 5, and 6 was investigated by superconducting quantum interference device technique in the range of 2-295 K.

  17. [Effect of ligand concentration on the precision of determining the parameters of ligand-receptor interaction by serial dilution methods].

    PubMed

    Bobrovnik, S A

    2004-01-01

    Earlier we suggested the method of serial dilution, which allows one to determine the parameters of ligand-receptor interaction even if the reactants are in a mixture and their concentrations are unknown. The method is especially useful if the liability of studied receptor does not allow its separation from corresponding ligand. The important prerequisite of the method's precision is that the concentration of the ligand should be sufficiently high comparing to the concentration of the receptor. In the present paper it was demonstrated that the method allows one to obtain sufficiently good precision even in the case when the concentration of the ligand is only one tenth of the receptor concentration.

  18. Characterizing mixed phosphonic acid ligand capping on CdSe/ZnS quantum dots using ligand exchange and NMR spectroscopy.

    PubMed

    Davidowski, Stephen K; Lisowski, Carmen E; Yarger, Jeffery L

    2016-03-01

    The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Calculating the mean time to capture for tethered ligands and its effect on the chemical equilibrium of bound ligand pairs.

    PubMed

    Shen, Lu; Decker, Caitlin G; Maynard, Heather D; Levine, Alex J

    2016-09-01

    We present here the calculation of the mean time to capture of a tethered ligand to the receptor. This calculation is then used to determine the shift in the partitioning between (1) free, (2) singly bound, and (3) doubly bound ligands in chemical equilibrium as a function of the length of the tether. These calculations are used in the research article Fibroblast Growth Factor 2 Dimer with Superagonist in vitro Activity Improves Granulation Tissue Formation During Wound Healing (Decker et al., in press [1]) to explain quantitatively how changes in polymeric linker length in the ligand dimers modifies the efficacy of these molecules relative to that of free ligands.

  20. Interaction between alkaline earth cations and oxo ligands: a DFT study of the affinity of Mg2+ for carbonyl ligands.

    PubMed

    Moreira da Costa, Leonardo; Stoyanov, Stanislav R; Walkimar de M Carneiro, José

    2012-09-01

    The affinities of Mg(2+) for various substituted carbonyl ligands were determined at the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) levels of theory. Two sets of carbonyl ligands were studied: monosubstituted [aldehydes R-CHO and RPh-CHO] and homodisubstituted [ketones R(2)C=O and (RPh)(2)C=O], where R = NH(2), OCH(3), OH, CH(3), H, F, Cl, Br, CN, or NO(2)). In the (RPh)(2)CO case, the R group was bonded to the para position of a phenyl ring. The enthalpies of interaction between the ligands and a pentaaquomagnesium(II) complex were calculated to determine the affinity of each ligand for the Mg(2+) cation and to correlate with geometrical and electronic parameters. These parameters exhibited the same trends for all of the ligands studied, showing that the affinity of Mg(2+) for electron-donating ligands is higher than its affinity for electron-withdrawing ligands. In the complexes, electron-donating groups increase both the electrostatic and the covalent components of the Mg-ligand interaction. This behavior correlates with the Mg-O(carbonyl) distance and the ligand electron-donor strength.

  1. Palladium-copper catalyzed synthesis of benzofused heterocycles with two heteroatoms: novel and highly regio- and stereoselective syntheses of (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles and (E)-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzothiazines.

    PubMed

    Kundu, N G; Nandi, B

    2001-06-29

    A highly novel, general, and convenient palladium and copper-catalyzed procedure has been developed for the synthesis of (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 28-40. 3-(2-Aminophenylthio)prop-1-yne 1 reacts with aryl iodides 2-14 under palladium-copper catalysis to yield the disubstituted alkynes 15-27 which after tosylation undergo a novel cyclization with CuI in the presence of triethylamine in THF to (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 28-40 rather than to the expected 3-alkylidene-4-tosyl-3,4-dihydro-2H-1,4-benzothiazines 41. The reaction is highly regio- and stereoselective. The synthesis of 2-(2-arylethyl)-3-tosylbenzothiazolines 42-47, 2-(2-arylvinyl)benzothiazoles 48-54, and a novel 5-substituted uracil derivative 55 of potential biological importance is also being reported. Similarly, the palladium-copper-catalyzed arylation of S-[2-(N-prop-2'-ynyl)aminophenyl]-N,N-dimethylthiocarbamate 58 with aryl iodides yields the disubstituted alkynes 59 which on cyclization with KOH in methanol leads to (E)-2-(2-aryl)methylidene-3,4-dihydro-2H-1,4-benzothiazines 61. The reaction of the diiodo compounds 12-14a, however, with 58 under palladium-copper-catalyzed reactions involves the participation of only one of the iodo groups in the heteroannulation process giving compounds 61i and 61j. These are amenable to further palladium-catalyzed reactions and afford polyunsaturated heteroaromatic compounds 62 and 63.

  2. Early development of sigma-receptor ligands.

    PubMed

    Narayanan, Sanju; Bhat, Rohit; Mesangeau, Christophe; Poupaert, Jacques H; McCurdy, Christopher R

    2011-01-01

    Sigma receptors (σ-1 and σ-2) are non-opioid proteins implicated in the pathophysiology of various neurological disorders and cancer. The σ-1 subtype is a chaperon protein widely distributed in the CNS and peripheral tissues. These receptors are involved in the modulation of K(+)- and Ca(2+)-dependent signaling cascades at the endoplasmic reticulum and modulation of neurotransmitter release. σ-1 receptors are emerging targets for the treatment of neurophychiatric diseases (schizophrenia and depression) and cocaine addiction. σ-2 receptors are lipid raft proteins. They are highly expressed on many tumor cells and hence considered potential targets for anticancer drugs. σ receptors bind to a diverse class of pharmacological compounds like cocaine, methamphetamine, benzomorphans like (±)-pentazocine, (±)-SKF-10,047 and endogenous neurosteroids and sphingolipids. In this review we focus on the early development of σ receptor-specific ligands and radiolabeling agents.

  3. Phosphinothiolates as ligands for polyhydrido copper nanoclusters.

    PubMed

    Huertos, Miguel A; Cano, Israel; Bandeira, Nuno A G; Benet-Buchholz, Jordi; Bo, Carles; van Leeuwen, Piet W N M

    2014-12-01

    The reaction of [CuI(HSC6 H4 PPh2 )]2 with NaBH4 in CH2 Cl2 /EtOH led to air- and moisture-stable copper hydride nanoparticles (CuNPs) containing phosphinothiolates as new ligands, one of which was isolated by crystallization. The X-ray crystal structure of [Cu18 H7 L10 I] (L=(-) S(C6 H4 )PPh2 ) shows unprecedented features in its 28-atom framework (18 Cu and 10 S atoms). Seven hydrogen atoms, in hydride form, are needed for charge balance and were located by density functional theory methods. H2 was released from the copper hydride nanoparticles by thermolysis and visible light irradiation.

  4. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  5. Ligand interactions with galactose oxidase: mechanistic insights.

    PubMed Central

    Whittaker, M M; Whittaker, J W

    1993-01-01

    Interactions between galactose oxidase and small molecules have been explored using a combination of optical absorption, circular dichroism, and electron paramagnetic resonance (EPR) spectroscopies to detect complex formation and characterize the products. Anions bind directly to the cupric center in both active and inactive galactose oxidase, converting to complexes with optical and EPR spectra that are distinctly different from those of the starting aquo enzyme. Azide binding is coupled to stoichiometric proton uptake by the enzyme, reflecting the generation of a strong base (pKa > 9) in the active site anion adduct. At low temperature, the aquo enzyme converts to a form that exhibits the characteristic optical and EPR spectra of an anion complex, apparently reflecting deprotonation of the coordinated water. Anion binding results in a loss of the optical transition arising from coordinated tyrosine, implying displacement of the axial tyrosine ligand on forming the adduct. Nitric oxide binds to galactose oxidase, forming a specific complex exhibiting an unusual EPR spectrum with all g values below 2. The absence of Cu splitting in this spectrum and the observation that the cupric EPR signal from the active site metal ion is not significantly decreased in the complex suggest a nonmetal interaction site for NO in galactose oxidase. These results have been interpreted in terms of a mechanistic scheme where substrate binding displaces a tyrosinate ligand from the active site cupric ion, generating a base that may serve to deprotonate the coordinated hydroxyl group of the substrate, activating it for oxidation. The protein-NO interactions may probe a nonmetal O2 binding site in this enzyme. PMID:8386015

  6. Do organic ligands affect calcite dissolution rates?

    NASA Astrophysics Data System (ADS)

    Oelkers, Eric H.; Golubev, Sergey V.; Pokrovsky, Oleg S.; Bénézeth, Pascale

    2011-04-01

    Steady state Iceland-spar calcite dissolution rates were measured at 25 °C in aqueous solutions containing 0.1 M NaCl and up to 0.05 M dissolved bicarbonate at pH from 7.9 to 9.1 in the presence of 13 distinct dissolved organic ligands in mixed-flow reactors. The organic ligands considered in this study include those most likely to be present in either (1) aquifers at the conditions pertinent to CO 2 sequestration or (2) soil/early diagenetic environments: acetate, phthalate, citrate, EDTA 4-, succinate, D-glucosaminate, L-glutamate, D-gluconate, 2,4-dihydroxybenzoate, 3,4-dihydroxybenzoate, fumarate, malonate, and gallate. Results show that the presence of <0.05 mol/kg of these organic anions changes calcite dissolution rates by less than a factor of 2.5 with the exception of citrate and EDTA 4-. The presence of 0.05 mol/kg citrate and EDTA 4- increases calcite dissolution rates by as much as a factor of 35 and 500, respectively, compared to rates in organic anion-free solutions. Further calcite dissolution experiments were performed in the presence of organic polymers similar to bacterial exudates, cell exopolysaccharides, and analogs of microbial cell envelopes: alginate, lichen extract, humic acid, pectin, and gum xanthan. In no case did the presence of <100 ppm of these organics change calcite dissolution rates by more than a factor of 2.5. Results obtained in this study suggest that the presence of aqueous organic anions negligibly affects calcite forward dissolution rates in most natural environments. Some effect on calcite reactivity may be observed, however, by the presence of organic anions if they change substantially the chemical affinity of the fluid with respect to calcite.

  7. How to Compute Labile Metal-Ligand Equilibria

    ERIC Educational Resources Information Center

    de Levie, Robert

    2007-01-01

    The different methods used for computing labile metal-ligand complexes, which are suitable for an iterative computer solution, are illustrated. The ligand function has allowed students to relegate otherwise tedious iterations to a computer, while retaining complete control over what is calculated.

  8. Improved ligand geometries in crystallographic refinement using AFITT in PHENIX

    PubMed Central

    Janowski, Pawel A.; Moriarty, Nigel W.; Kelley, Brian P.; Case, David A.; York, Darrin M.; Adams, Paul D.; Warren, Gregory L.

    2016-01-01

    Modern crystal structure refinement programs rely on geometry restraints to overcome the challenge of a low data-to-parameter ratio. While the classical Engh and Huber restraints work well for standard amino-acid residues, the chemical complexity of small-molecule ligands presents a particular challenge. Most current approaches either limit ligand restraints to those that can be readily described in the Crystallographic Information File (CIF) format, thus sacrificing chemical flexibility and energetic accuracy, or they employ protocols that substantially lengthen the refinement time, potentially hindering rapid automated refinement workflows. PHENIX–AFITT refinement uses a full molecular-mechanics force field for user-selected small-molecule ligands during refinement, eliminating the potentially difficult problem of finding or generating high-quality geometry restraints. It is fully integrated with a standard refinement protocol and requires practically no additional steps from the user, making it ideal for high-throughput workflows. PHENIX–AFITT refinements also handle multiple ligands in a single model, alternate conformations and covalently bound ligands. Here, the results of combining AFITT and the PHENIX software suite on a data set of 189 protein–ligand PDB structures are presented. Refinements using PHENIX–AFITT significantly reduce ligand conformational energy and lead to improved geometries without detriment to the fit to the experimental data. For the data presented, PHENIX–AFITT refinements result in more chemically accurate models for small-molecule ligands. PMID:27599738

  9. Regulation of ligands for the activating receptor NKG2D

    PubMed Central

    Mistry, Anita R; O'Callaghan, Chris A

    2007-01-01

    The outcome of an encounter between a cytotoxic cell and a potential target cell depends on the balance of signals from inhibitory and activating receptors. Natural Killer group 2D (NKG2D) has recently emerged as a major activating receptor on T lymphocytes and natural killer cells. In both humans and mice, multiple different genes encode ligands for NKG2D, and these ligands are non-classical major histocompatibility complex class I molecules. The NKG2D–ligand interaction triggers an activating signal in the cell expressing NKG2D and this promotes cytotoxic lysis of the cell expressing the ligand. Most normal tissues do not express ligands for NKG2D, but ligand expression has been documented in tumour and virus-infected cells, leading to lysis of these cells. Tight regulation of ligand expression is important. If there is inappropriate expression in normal tissues, this will favour autoimmune processes, whilst failure to up-regulate the ligands in pathological conditions would favour cancer development or dissemination of intracellular infection. PMID:17614877

  10. 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.

  11. Proteome-wide covalent ligand discovery in native biological systems

    PubMed Central

    Backus, Keriann M.; Correia, Bruno E.; Lum, Kenneth M.; Forli, Stefano; Horning, Benjamin D.; González-Páez, Gonzalo E.; Chatterjee, Sandip; Lanning, Bryan R.; Teijaro, John R.; Olson, Arthur J.; Wolan, Dennis W.; Cravatt, Benjamin F.

    2016-01-01

    Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered “undruggable” 1,2. Fragment-based ligand discovery (FBLD) can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries 1,3. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes 4–10, including those that can access regions of proteins that are difficult to access through binding affinity alone 5,10,11. In this manuscript, we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T-cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and −10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems. PMID:27309814

  12. [Peripheral effects of ligands of ORL1 receptors].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L; Lambert, D G

    2003-01-01

    It has been discussed literature data on the role for ORL1 (NOR) receptors in the regulation of function of gastrointestinal, respiratory, cardiovascular, immune, endocrine systems. In addition, it has been discussed a possibility of penetration of blood brain barrier for ORL1 receptor ligands and species dependence of NOR-ligands' effects.

  13. Multifunctional ligand for use as a diagnostic or therapeutic pharmaceutical

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1996-05-14

    A compound and method of making a compound for use as a diagnostic or therapeutic pharmaceutical are revealed. The ligand comprises either a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

  14. Digestive Ripening of Au Nanoparticles Using Multidentate Ligands.

    PubMed

    Sahu, Puspanjali; Shimpi, Jayesh; Lee, Han Ju; Lee, T Randall; Prasad, Bhagavatula L V

    2017-02-16

    The efficiency of multidentate ligands as digestive ripening (DR) agents for the preparation of monodisperse Au nanoparticles (NPs) was investigated. This systematic investigation was performed using ligands possessing one, two, or three thiol moieties as ligands/DR agents. Our results clearly establish that among the different ligands, monodentate ligands and the use of temperature in the range of 60-120 °C offer the best conditions for DR. In addition, when DR was carried out at lower temperatures (e.g., 60 °C), the NP size increased as the number of thiol groups per ligand increased. However, in the case of ligands possessing two and three thiol moieties, when they were heated with polydispersed particles at higher temperatures (120 or 180 °C), the etching process dominated, which affected the quality of the NPs in terms of their monodispersity. We conclude that the temperature-dependent strength of the interaction between the ligand headgroup and the NP surface plays a vital role in controlling the final particle sizes.

  15. Ligand-modified metal clusters for gas separation and purification

    DOEpatents

    Okrut, Alexander; Ouyang, Xiaoying; Runnebaum, Ron; Gates, Bruce C.; Katz, Alexander

    2017-02-21

    Provided is an organic ligand-bound metal surface that selects one gaseous species over another. The species can be closely sized molecular species having less than 1 Angstrom difference in kinetic diameter. In one embodiment, the species comprise carbon monoxide and ethylene. Such organic ligand-bound metal surfaces can be successfully used in gas phase separations or purifications, sensing, and in catalysis.

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

    NASA Astrophysics Data System (ADS)

    Deller, Marc C.; Rupp, Bernhard

    2015-09-01

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

  17. Polymerization catalysts containing electron-withdrawing amide ligands

    DOEpatents

    Watkin, John G.; Click, Damon R.

    2002-01-01

    The present invention describes methods of making a series of amine-containing organic compounds which are used as ligands for group 3-10 and lanthanide metal compounds. The ligands have electron-withdrawing groups bonded to them. The metal compounds, when combined with a cocatalyst, are catalysts for the polymerization of olefins.

  18. An agent based model of integrin clustering: Exploring the role of ligand clustering, integrin homo-oligomerization, integrin-ligand affinity, membrane crowdedness and ligand mobility

    NASA Astrophysics Data System (ADS)

    Jamali, Yousef; Jamali, Tahereh; Mofrad, Mohammad R. K.

    2013-07-01

    Integrins are cell-surface protein heterodimers that coordinate cellular responses to mechanochemical cues from the extracellular matrix (ECM) and stimulate the assembly of small adhesion complexes, which are the initial sites of cell-ECM adhesion. Clustering of integrins is known to mediate signaling through a variety of signal transduction pathways. Yet, the molecular mechanisms of integrin clustering are poorly understood. In this paper, we develop computational models, using agent based modeling (ABM) techniques, to explore two key underlying mechanisms of integrin clustering, namely ligand organization and integrin homo-oligomerization. Our models help to shed light on the potential roles ligand clustering and integrin homo-oligomerization may play in controlling integrin clustering. A potential mechanism for the clustering of integrin is discussed and the effects of other parameters such as integrin-ligand affinity, membrane crowdedness and ligand mobility on integrin clustering are examined.

  19. Enthalpy of ligand substitution in cis organopalladium complexes with monodentate ligands.

    PubMed

    Salas, Gorka; Casares, Juan A; Espinet, Pablo

    2009-10-21

    The enthalpy for the substitution reaction cis-[PdRf(2)(THF)(2)] + 2 L -->cis-[PdRf(2)L(2)] + 2THF (THF = tetrahydrofuran) has been measured in THF by calorimetric methods for Rf = 3,5-dichloro-2,4,6-trifluorophenyl, L = PPh(3), AsPh(3), SbPh(3), PMePh(2), PCyPh(2), PMe(3), AsMePh(2), or L(2) = dppe (1,2-bis(diphenylphosphino)ethane), dppf (1,1'-bis(diphenylphosphino)ferrocene). The values determined show that the substitution enthalpy has a strong dependence on the electronic and steric properties of the ligand. The study of the consecutive substitution reactions cis-[PdRf(2)(THF)(2)] + L -->cis-[PdRf(2)L(THF)] + THF, and cis-[PdRf(2)L(THF)] + L -->cis-[PdRf(2)L(2)] + THF has been carried our for L = PPh(3) and L = PCyPh(2). The first substitution is clearly more favorable for the bulkier leaving ligand, but the second gives practically the same DeltaH value for both cases, indicating that the differences in steric hindrance happen to compensate the electronic differences for both ligands. The X-ray structures of cis-[PdRf(2)(PMePh(2))(2)], cis-[PdRf(2)(dppe)] and cis-[PdRf(2)(dppf)] are reported.

  20. Regulation of ligands for the NKG2D activating receptor

    PubMed Central

    Raulet, David H.; Gasser, Stephan; Gowen, Benjamin G.; Deng, Weiwen; Jung, Heiyoun

    2014-01-01

    NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection. PMID:23298206

  1. Predicting protein-ligand affinity with a random matrix framework.

    PubMed

    Lee, Alpha A; Brenner, Michael P; Colwell, Lucy J

    2016-11-29

    Rapid determination of whether a candidate compound will bind to a particular target receptor remains a stumbling block in drug discovery. We use an approach inspired by random matrix theory to decompose the known ligand set of a target in terms of orthogonal "signals" of salient chemical features, and distinguish these from the much larger set of ligand chemical features that are not relevant for binding to that particular target receptor. After removing the noise caused by finite sampling, we show that the similarity of an unknown ligand to the remaining, cleaned chemical features is a robust predictor of ligand-target affinity, performing as well or better than any algorithm in the published literature. We interpret our algorithm as deriving a model for the binding energy between a target receptor and the set of known ligands, where the underlying binding energy model is related to the classic Ising model in statistical physics.

  2. Exploiting Ultra Tight-Binding Ligands for Separations Technologies

    SciTech Connect

    Busch, Daryle; Givens, Richard S.; Zuo, Xiaobin; Zhang, Chi; Mosha, Donnati; Lee, Jong0Ill; Bushan, K. Mani; Hassan, Mansour M.; Loving, Galen

    2003-09-10

    The classic slowness that has kept the most powerful ligands from being used in separations applications is under attack in two ways: (1) replacing metal ion - ligand equilibration with switch binding and release as the mode of complexation. By exploiting the tight-binding capabilities of cryptands, the capture of selected metal ions isolates them from their environment. These cryptands are constructed with photoactivatable functions that sever the cryptand, releasing encapsulated metal ions. The precursors have been modified to capture the metal ion concomitant with crytate formation. (2) developing a methodology (the soil poultice) so slow that powerful ligands can be used. A solution containing the specially designed ligand is mixed with a solid macroporous imprinted polymer (MIPs) and applied to the contaminated area. The ligand captures the metal ion and the MIPs captures the resulting complex. Current studies focus on combinations of MIPs-complex interactions to optimize strength of binding and selectivity.

  3. Development of chiral sulfoxide ligands for asymmetric catalysis.

    PubMed

    Trost, Barry M; Rao, Meera

    2015-04-20

    Nitrogen-, phosphorus-, and oxygen-based ligands with chiral backbones have been the historic workhorses of asymmetric transition-metal-catalyzed reactions. On the contrary, sulfoxides containing chirality at the sulfur atom have mainly been used as chiral auxiliaries for diastereoselective reactions. Despite several distinct advantages over traditional ligand scaffolds, such as the proximity of the chiral information to the metal center and the ability to switch between S and O coordination, these compounds have only recently emerged as a versatile class of chiral ligands. In this Review, we detail the history of the development of chiral sulfoxide ligands for asymmetric catalysis. We also provide brief descriptions of metal-sulfoxide bonding and strategies for the synthesis of enantiopure sulfoxides. Finally, insights into the future development of this underutilized ligand class are discussed.

  4. Ligand binding was acquired during evolution of nuclear receptors

    PubMed Central

    Escriva, Hector; Safi, Rachid; Hänni, Catherine; Langlois, Marie-Claire; Saumitou-Laprade, Pierre; Stehelin, Dominique; Capron, André; Pierce, Raymond; Laudet, Vincent

    1997-01-01

    The nuclear receptor (NR) superfamily comprises, in addition to ligand-activated transcription factors, members for which no ligand has been identified to date. We demonstrate that orphan receptors are randomly distributed in the evolutionary tree and that there is no relationship between the position of a given liganded receptor in the tree and the chemical nature of its ligand. NRs are specific to metazoans, as revealed by a screen of NR-related sequences in early- and non-metazoan organisms. The analysis of the NR gene duplication pattern during the evolution of metazoans shows that the present NR diversity arose from two waves of gene duplications. Strikingly, our results suggest that the ancestral NR was an orphan receptor that acquired ligand-binding ability during subsequent evolution. PMID:9192646

  5. Non-aqueous chemistry of uranyl complexes with tripodal ligands

    NASA Astrophysics Data System (ADS)

    Burns, Carol J.; Clark, David L.; Duval, Paul B.; Scott, Brian L.

    2000-07-01

    The trans dioxo uranyl(VI) ion (UO22+) is remarkably stable with respect to the U=O bond, which dominates the stereochemistry of its coordination compounds in both aqueous and non-aqueous solutions. The linear O=U=O unit directs all other ligands to coordinate in an equatorial plane perpendicular to the O=U=O axis. In aqueous solution, uranyl coordination chemistry has been developed with a wide array of weak-field ligands that coordinate in the equatorial plane. In contrast, non-aqueous uranyl chemistry incorporating stronger donor ligands at equatorial sites has been less well developed. In this paper, the use of tripodal ligands with strong amide and alkoxide donors is employed, with an aim towards probing the electronic and steric effects of these cis-directing ligands on the structure and bonding of the trans dioxo unit.

  6. CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms.

    PubMed

    Poe, Jonathan C; Fujimoto, Yoko; Hasegawa, Minoru; Haas, Karen M; Miller, Ann S; Sanford, Isaac G; Bock, Cheryl B; Fujimoto, Manabu; Tedder, Thomas F

    2004-10-01

    The interaction of CD22 with alpha2,6-linked sialic acid ligands has been widely proposed to regulate B lymphocyte function and migration. Here, we generated gene-targeted mice that express mutant CD22 molecules that do not interact with these ligands. CD22 ligand binding regulated the expression of cell surface CD22, immunoglobulin M and major histocompatibility complex class II on mature B cells, maintenance of the marginal zone B cell population, optimal B cell antigen receptor-induced proliferation, and B cell turnover rates. However, CD22 negative regulation of calcium mobilization after B cell antigen receptor ligation, CD22 phosphorylation, recruitment of SHP-1 to CD22 and B cell migration did not require CD22 ligand engagement. These observations resolve longstanding questions regarding the physiological importance of CD22 ligand binding in the regulation of B cell function in vivo.

  7. Gas adsorption and gas mixture separations using mixed-ligand MOF material

    DOEpatents

    Hupp, Joseph T.; Mulfort, Karen L.; Snurr, Randall Q.; Bae, Youn-Sang

    2011-01-04

    A method of separating a mixture of carbon dioxiode and hydrocarbon gas using a mixed-ligand, metal-organic framework (MOF) material having metal ions coordinated to carboxylate ligands and pyridyl ligands.

  8. Receptor Specific Ligands for Spect Imaging

    SciTech Connect

    Kung, H. F.

    2003-02-25

    In the past funding period we have concentrated in developing new 99mTc labeled MIBG analogs. Basic chemistry of ligand synthesis, radiochemistry of Re and 99mTc complex formation, separation of stereoisomers and in vitro stability were investigated. We have prepared a number of new MIBG derivatives containing chelating moiety N2S2 and additional groups to increase lipophilicity. Unfortunately none of the new 99mTc labeled MIBG analogs showed promise as an imaging agent for myocardial neuronal function. Radioactive-iodine-labeled meta-iodobenzylguanidine (MIBG) is currently being used as an in vivo imaging agent to evaluate neuroendocrine tumors as well as the myocardial sympathetic nervous system in patients with myocardial infarct and cardiomyopathy. It is generally accepted that MIBG is an analog of norepinephrine and its uptake in the heart corresponds to the distribution of norepinephrine and the density of sympathetic neurons. A series of MIBG derivatives containing suitable chelating functional groups N2S2 for the formation of [Tcv0]+3N2S2 complex was successfully synthesized and the 99mTc-labeled complexes were prepared and tested in rats. One of the compounds, [99mTc]M2, tested showed significant, albeit lower, heart uptakes post iv injection in rats (0.18% dose/organ at 4 hours) as compared to [l25l]MIBG (1.4% dose/organ at 4 hours). The heart uptake of the 99mTc-labeled complex, [99mTc]M2, appears to be specific and can be reduced by coinjection with nonradioactive MIBG or by pretreatment with desipramine. a selective norepinephrine transporter inhibitor. Further evaluation of the in vitro uptake of [99mTc]M2 in cultured neuroblastoma cells displayed consistently lower, but measurable uptake (app. 10% of that for [125l]MlBG). These preliminary results suggested that the mechanisms of heart uptake of [99mTc]M2 may be related to those for [125l]MIBG uptake. To improve the heart uptake of the MIBG derivatives we have developed chemistry related to the

  9. Electronic spectra and photophysics of platinum(II) complexes with alpha-diimine ligands - Solid-state effects. I - Monomers and ligand pi dimers

    NASA Technical Reports Server (NTRS)

    Miskowski, Vincent M.; Houlding, Virginia H.

    1989-01-01

    Two types of emission behavior for Pt(II) complexes containing alpha-diimine ligands have been observed in dilute solution. If the complex also has weak field ligands such as chloride, ligand field (d-d) excited states become the lowest energy excited states. If only strong field ligands are present, a diimine 3(pi-pi/asterisk/) state becomes the lowest. In none of the cases studied did metal-to-ligand charge transfer excited state lie lowest.

  10. Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis.

    PubMed

    Theofilopoulos, Spyridon; Wang, Yuqin; Kitambi, Satish Srinivas; Sacchetti, Paola; Sousa, Kyle M; Bodin, Karl; Kirk, Jayne; Saltó, Carmen; Gustafsson, Magnus; Toledo, Enrique M; Karu, Kersti; Gustafsson, Jan-Åke; Steffensen, Knut R; Ernfors, Patrik; Sjövall, Jan; Griffiths, William J; Arenas, Ernest

    2013-02-01

    Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

  11. Mass spectrometric analysis of protein–ligand interactions

    PubMed Central

    Ishii, Kentaro; Noda, Masanori; Uchiyama, Susumu

    2016-01-01

    The interactions of small molecules with proteins (protein–ligand interactions) mediate various biological phenomena including signal transduction and protein transcription and translation. Synthetic compounds such as drugs can also bind to target proteins, leading to the inhibition of protein–ligand interactions. These interactions typically accompany association–dissociation equilibrium according to the free energy difference between free and bound states; therefore, the quantitative biophysical analysis of the interactions, which uncovers the stoichiometry and dissociation constant, is important for understanding biological reactions as well as for rational drug development. Mass spectrometry (MS) has been used to determine the precise molecular masses of molecules. Recent advancements in MS enable us to determine the molecular masses of protein–ligand complexes without disrupting the non-covalent interactions through the gentle desolvation of the complexes by increasing the vacuum pressure of a chamber in a mass spectrometer. This method is called MS under non-denaturing conditions or native MS and allows the unambiguous determination of protein–ligand interactions. Under a few assumptions, MS has also been applied to determine the dissociation constants for protein–ligand interactions. The structural information of a protein–ligand interaction, such as the location of the interaction and conformational change in a protein, can also be analyzed using hydrogen/deuterium exchange MS. In this paper, we briefly describe the history, principle, and recent applications of MS for the study of protein–ligand interactions. PMID:27924262

  12. BINANA: A Novel Algorithm for Ligand-Binding Characterization

    PubMed Central

    Durrant, Jacob D.; McCammon, J. Andrew

    2011-01-01

    Computational chemists and structural biologists are often interested in characterizing ligand-receptor complexes for hydrogen-bond, hydrophobic, salt-bridge, van der Waals, and other interactions in order to assess ligand binding. When done by hand, this characterization can become tedious, especially when many complexes need be analyzed. In order to facilitate the characterization of ligand binding, we here present a novel Python-implemented computer algorithm called BINANA (BINding ANAlyzer), which is freely available for download at http://www.nbcr.net/binana/. To demonstrate the utility of the new algorithm, we use BINANA to confirm that the number of hydrophobic contacts between a ligand and its protein receptor is positively correlated with ligand potency. Additionally, we show how BINANA can be used to search through a large ligand-receptor database to identify those complexes that are remarkable for selected binding features, and to identify lead candidates from a virtual screen with specific, desirable binding characteristics. We are hopeful that BINANA will be useful to computational chemists and structural biologists who wish to automatically characterize many ligand-receptor complexes for key binding characteristics. PMID:21310640

  13. Novel biosensors for the detection of estrogen receptor ligands.

    PubMed

    De, Siddhartha; Macara, Ian G; Lannigan, Deborah A

    2005-08-01

    There exists a significant need for the detection of novel estrogen receptor (ER) ligands for pharmaceutical uses, especially for treating complications associated with menopause. We have developed fluorescence resonance energy transfer (FRET)-based biosensors that permit the direct in vitro detection of ER ligands. These biosensors contain an ER ligand-binding domain (LBD) flanked by the FRET donor fluorophore, cyan fluorescent protein (CFP), and the acceptor fluorophore, yellow fluorescent protein (YFP). The ER-LBD has been modified so that Ala 430 has been changed to Asp, which increases the magnitude of the FRET signal in response to ligand-binding by more than four-fold compared to the wild-type LBD. The binding of agonists can be distinguished from that of antagonists on the basis of the distinct ligand-induced conformations in the ER-LBD. The approach to binding equilibrium occurs within 30min, and the FRET signal is stable over 24h. The biosensor demonstrates a high signal-to-noise, with a Z' value (a statistical determinant of assay quality) of 0.72. The affinity of the ER for different ligands can be determined using a modified version of the biosensor in which a truncated YFP and an enhanced CFP are used. Thus, we have developed platforms for high-throughput screens for the identification of novel estrogen receptor ligands. Moreover, we have demonstrated that this FRET technology can be applied to other nuclear receptors, such as the androgen receptor.

  14. Structural Analysis of Chemokine Receptor-Ligand Interactions.

    PubMed

    Arimont, Marta; Sun, Shan-Liang; Leurs, Rob; Smit, Martine; de Esch, Iwan J P; de Graaf, Chris

    2017-03-10

    This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure-activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor-ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

  15. NMR-based analysis of protein-ligand interactions.

    PubMed

    Cala, Olivier; Guillière, Florence; Krimm, Isabelle

    2014-02-01

    Physiological processes are mainly controlled by intermolecular recognition mechanisms involving protein-protein and protein-ligand (low molecular weight molecules) interactions. One of the most important tools for probing these interactions is high-field solution nuclear magnetic resonance (NMR) through protein-observed and ligand-observed experiments, where the protein receptor or the organic compounds are selectively detected. NMR binding experiments rely on comparison of NMR parameters of the free and bound states of the molecules. Ligand-observed methods are not limited by the protein molecular size and therefore have great applicability for analysing protein-ligand interactions. The use of these NMR techniques has considerably expanded in recent years, both in chemical biology and in drug discovery. We review here three major ligand-observed NMR methods that depend on the nuclear Overhauser effect-transferred nuclear Overhauser effect spectroscopy, saturation transfer difference spectroscopy and water-ligand interactions observed via gradient spectroscopy experiments-with the aim of reporting recent developments and applications for the characterization of protein-ligand complexes, including affinity measurements and structural determination.

  16. Ethylene glycol modified 2-(2‧-aminophenyl)benzothiazoles at the amino site: the excited-state N-H proton transfer reactions in aqueous solution, micelles and potential application in live-cell imaging

    NASA Astrophysics Data System (ADS)

    Liu, Bo-Qing; Chen, Yi-Ting; Chen, Yu-Wei; Chung, Kun-You; Tsai, Yi-Hsuan; Li, Yi-Jhen; Chao, Chi-Min; Liu, Kuan-Miao; Tseng, Huan-Wei; Chou, Pi-Tai

    2016-03-01

    Triethylene glycol monomethyl ether and poly(ethylene glycol) monomethyl ether modified 2-(2‧-aminophenyl)benzothiazoles, namely ABT-P3EG, ABT-P7EG and ABT-P12EG varied by different chain length of poly(ethylene glycol) at the amino site, were synthesized to probe their photophysical and bio-imaging properties. In polar, aprotic solvents such as CH2Cl2 ultrafast excited-state intramolecular proton transfer (ESIPT) takes place, resulting in a large Stokes shifted tautomer emission in the green-yellow (550 nm) region. In neutral water, ABT-P12EG forms micelles with diameters of 15  ±  3 nm under a critical micelle concentration (CMC) of ~80 μM, in which the tautomer emission is greatly enhanced free from water perturbation. Cytotoxicity experiments showed that all ABT-PnEGs have negligible cytotoxicity against HeLa cells even at doses as high as 1 mM. Live-cell imaging experiments were also performed, the results indicate that all ABT-PnEGs are able to enter HeLa cells. While the two-photon excitation emission of ABT-P3EG in cells cytoplasm shows concentration independence and is dominated by the anion blue fluorescence, ABT-P7EG and ABT-P12EG exhibit prominent green tautomer emission at  >  CMC and in part penetrate to the nuclei, adding an additional advantage for the cell imaging.

  17. ZINC 15 – Ligand Discovery for Everyone

    PubMed Central

    2015-01-01

    Many questions about the biological activity and availability of small molecules remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation, purchasability, target, and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable “drug-like” compounds – effectively all organic molecules that are for sale – a quarter of which are available for immediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites, drugs, natural products, and annotated compounds from the literature. Compounds may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new analysis tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots – all molecules are available in biologically relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org. PMID:26479676

  18. Xylamine, a ligand for the catecholamine transporter

    SciTech Connect

    Waggaman, L.A.

    1985-01-01

    Previous studies have established xylamine (N-2'-chloro-ethyl-N-ethyl-2-methylbenzylamine) irreversibly inhibits neuronal norepinephrine uptake with no concomitant effect on other neurotransmitter systems. Since xylamine is thought to alkylate transport-associated sites in the plasma membrane of noradrenergic neurons, so the loss of endogenous norepinephrine may be a consequence of neuronal membrane damage resulting from the alkylation of membrane components. In these studies, xylamine, under in vitro conditions, irreversibly inhibited both neuronal norepinephrine and dopamine uptake in the rat cortex and striatum, respectively. The efficacy of xylamine as a neuronal dopamine uptake inhibitor appeared to depend on its ability to access dopaminergic neurons during tissue exposure to the drug. In sympathetically innervated peripheral tissues, (/sup 3/H)xylamine was accumulated in noradrenergic neurons in a carrier-dependent manner. Although the data suggested that xylamine was interacting with the norepinephrine uptake carrier, (/sup 3/H)xylamine exposure to isolated synaptic membranes from superior cervical ganglia revealed a large proportion of (/sup 3/H)xylamine binding that was not associated with the noradrenergic transporter. For a closer characterization of xylamine binding in synaptic membranes, brain tissue was chosen as a more practical source of these membranes. While these experiments did not meet with great success, xylamine remains potentially useful as a ligand for identifying the catecholamine transporter, particularly in conjunction with procedures for protein purification and reconstitution.

  19. Cationic aluminum alkyl complexes incorporating aminotroponiminate ligands.

    PubMed

    Korolev, A V; Ihara, E; Guzei, I A; Young, V G; Jordan, R F

    2001-08-29

    The synthesis, structures, and reactivity of cationic aluminum complexes containing the N,N'-diisopropylaminotroponiminate ligand ((i)Pr(2)-ATI(-)) are described. The reaction of ((i)Pr(2)-ATI)AlR(2) (1a-e,g,h; R = H (a), Me (b), Et (c), Pr (d), (i)Bu (e), Cy (g), CH(2)Ph (h)) with [Ph(3)C][B(C(6)F(5))(4)] yields ((i)()Pr(2)-ATI)AlR(+) species whose fate depends on the properties of the R ligand. 1a and 1b react with 0.5 equiv of [Ph(3)C][B(C(6)F(5))(4)] to produce dinuclear monocationic complexes [([(i)Pr(2)-ATI] AlR)(2)(mu-R)][(C(6)F(5))(4)] (2a,b). The cation of 2b contains two ((i)()Pr(2)-ATI)AlMe(+) units linked by an almost linear Al-Me-Al bridge; 2a is presumed to have an analogous structure. 2b does not react further with [Ph(3)C][B(C(6)F(5))(4)]. However, 1a reacts with 1 equiv of [Ph(3)C][B(C(6)F(5))(4)] to afford ((i Pr(2)-ATI)Al(C(6)F(5))(mu-H)(2)B(C(6)F(5))(2) (3) and other products, presumably via C(6)F(5)(-) transfer and ligand redistribution of a [((i)()Pr(2)-ATI)AlH][(C(6)F(5))(4)] intermediate. 1c-e react with 1 equiv of [Ph(3)C][B(C(6)F(5))(4)] to yield stable base-free [((i)Pr(2)-ATI)AlR][B(C(6)F(5))(4)] complexes (4c-e). 4c crystallizes from chlorobenzene as 4c(ClPh).0.5PhCl, which has been characterized by X-ray crystallography. In the solid state the PhCl ligand of 4c(ClPh) is coordinated by a dative PhCl-Al bond and an ATI/Ph pi-stacking interaction. 1g,h react with [Ph(3)C][B(C(6)F(5))(4)] to yield ((i)Pr(2)-ATI)Al(R)(C(6)F(5)) (5g,h) via C(6)F(5)(-) transfer of [((i)Pr(2)-ATI)AlR][(BC(6)F(5))(4)] intermediates. 1c,h react with B(C(6)F(5))(3) to yield ((i)Pr(2)-ATI)Al(R)(C(6)F(5)) (5c,h) via C(6)F(5)(-) transfer of [((i)Pr(2)-ATI)AlR][RB(C(6)F(5))(3)] intermediates. The reaction of 4c-e with MeCN or acetone yields [((i)Pr(2)-ATI)Al(R)(L)][B(C(6)F(5))(4)] adducts (L = MeCN (8c-e), acetone (9c-e)), which undergo associative intermolecular L exchange. 9c-e undergo slow beta-H transfer to afford the dinuclear dicationic alkoxide complex [(((i

  20. Validated ligand mapping of ACE active site

    NASA Astrophysics Data System (ADS)

    Kuster, Daniel J.; Marshall, Garland R.

    2005-08-01

    Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 Å, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

  1. The Death Ligand TRAIL in Diabetic Nephropathy

    PubMed Central

    Lorz, Corina; Benito-Martín, Alberto; Boucherot, Anissa; Ucero, Alvaro C.; Rastaldi, Maria Pia; Henger, Anna; Armelloni, Silvia; Santamaría, Beatriz; Berthier, Celine C.; Kretzler, Matthias; Egido, Jesus; Ortiz, Alberto

    2008-01-01

    Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death–related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-κB, and inhibition of NF-κB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN. PMID:18287563

  2. Charge Optimization Theory for Induced-Fit Ligands

    PubMed Central

    2012-01-01

    The design of ligands with high affinity and specificity remains a fundamental challenge in understanding molecular recognition and developing therapeutic interventions. Charge optimization theory addresses this problem by determining ligand charge distributions that produce the most favorable electrostatic contribution to the binding free energy. The theory has been applied to the design of binding specificity as well. However, the formulations described only treat a rigid ligand—one that does not change conformation upon binding. Here, we extend the theory to treat induced-fit ligands for which the unbound ligand conformation may differ from the bound conformation. We develop a thermodynamic pathway analysis for binding contributions relevant to the theory, and we illustrate application of the theory using HIV-1 protease with our previously designed and validated subnanomolar inhibitor. Direct application of rigid charge optimization approaches to nonrigid cases leads to very favorable intramolecular electrostatic interactions that are physically unreasonable, and analysis shows the ligand charge distribution massively stabilizes the preconformed (bound) conformation over the unbound. After analyzing this case, we provide a treatment for the induced-fit ligand charge optimization problem that produces physically realistic results. The key factor is introducing the constraint that the free energy of the unbound ligand conformation be lower or equal to that of the preconformed ligand structure, which corresponds to the notion that the unbound structure is the ground unbound state. Results not only demonstrate the applicability of this methodology to discovering optimized charge distributions in an induced-fit model, but also provide some insights into the energetic consequences of ligand conformational change on binding. Specifically, the results show that, from an electrostatic perspective, induced-fit binding is not an adaptation designed to enhance binding

  3. Encoding protein-ligand interaction patterns in fingerprints and graphs.

    PubMed

    Desaphy, Jérémy; Raimbaud, Eric; Ducrot, Pierre; Rognan, Didier

    2013-03-25

    We herewith present a novel and universal method to convert protein-ligand coordinates into a simple fingerprint of 210 integers registering the corresponding molecular interaction pattern. Each interaction (hydrophobic, aromatic, hydrogen bond, ionic bond, metal complexation) is detected on the fly and physically described by a pseudoatom centered either on the interacting ligand atom, the interacting protein atom, or the geometric center of both interacting atoms. Counting all possible triplets of interaction pseudoatoms within six distance ranges, and pruning the full integer vector to keep the most frequent triplets enables the definition of a simple (210 integers) and coordinate frame-invariant interaction pattern descriptor (TIFP) that can be applied to compare any pair of protein-ligand complexes. TIFP fingerprints have been calculated for ca. 10,000 druggable protein-ligand complexes therefore enabling a wide comparison of relationships between interaction pattern similarity and ligand or binding site pairwise similarity. We notably show that interaction pattern similarity strongly depends on binding site similarity. In addition to the TIFP fingerprint which registers intermolecular interactions between a ligand and its target protein, we developed two tools (Ishape, Grim) to align protein-ligand complexes from their interaction patterns. Ishape is based on the overlap of interaction pseudoatoms using a smooth Gaussian function, whereas Grim utilizes a standard clique detection algorithm to match interaction pattern graphs. Both tools are complementary and enable protein-ligand complex alignments capitalizing on both global and local pattern similarities. The new fingerprint and companion alignment tools have been successfully used in three scenarios: (i) interaction-biased alignment of protein-ligand complexes, (ii) postprocessing docking poses according to known interaction patterns for a particular target, and (iii) virtual screening for bioisosteric

  4. Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization

    PubMed Central

    Clements, John H.; DeLorbe, John E.; Benfield, Aaron P.; Martin, Stephen F.

    2010-01-01

    Structures of the Grb2 SH2 domain complexed with a series of pseudopeptides containing flexible (benzyl succinate) and constrained (aryl cyclopropanedicarboxylate) replacements of the phosphotyrosine (pY) residue in tripeptides derived from Ac-pYXN-NH2 (where X = V, I, E and Q) were elucidated by X-ray crystallography. Complexes of flexible/constrained pairs having the same pY + 1 amino acid were analyzed in order to ascertain what structural differences might be attributed to constraining the phosphotyrosine replacement. In this context, a given structural dissimilarity between complexes was considered to be significant if it was greater than the corresponding difference in complexes coexisting within the same asymmetric unit. The backbone atoms of the domain generally adopt a similar conformation and orientation relative to the ligands in the complexes of each flexible/constrained pair, although there are some significant differences in the relative orientations of several loop regions, most notably in the BC loop that forms part of the binding pocket for the phosphate group in the tyrosine replacements. These variations are greater in the set of complexes of constrained ligands than in the set of complexes of flexible ligands. The constrained ligands make more direct polar contacts to the domain than their flexible counterparts, whereas the more flexible ligand of each pair makes more single-water-mediated contacts to the domain; there was no correlation between the total number of protein–ligand contacts and whether the phosphotyrosine replacement of the ligand was preorganized. The observed differences in hydrophobic interactions between the complexes of each flexible/constrained ligand pair were generally similar to those observed upon comparing such contacts in coexisting complexes. The average adjusted B factors of the backbone atoms of the domain and loop regions are significantly greater in the complexes of constrained ligands than in the complexes of

  5. Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia.

    PubMed

    Amada, Hideaki; Asanuma, Hajime; Koami, Takeshi; Okada, Atsushi; Endo, Mayumi; Ueda, Yasuji; Naruse, Takumi; Ikeda, Akiko

    2013-01-01

    7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).

  6. Facile dimer synthesis for DNA-binding polyamide ligands.

    PubMed

    Wetzler, Modi; Wemmer, David E

    2010-08-06

    Pyrrole-imidazole polyamide ligands are highly sequence specific synthetic DNA-binding ligands that bind with high affinity. To counter the synthetic difficulties associated with coupling the electron-rich heterocyclic acids to the electron-deficient nucleophilic imidazole amine, a novel approach is described for synthesis of Fmoc-protected dimers for solid-phase peptide synthesis (SPPS). This method produces the dimers in high yields, is broadly applicable to other heterocyclic-containing polyamides, and results in improved ligand yields and synthesis times.

  7. A divergent strategy for attaching polypyridyl ligands to peptides.

    PubMed

    Jabre, Nitinkumar D; Respondek, Tomasz; Ulku, Selma A; Korostelova, Nadiya; Kodanko, Jeremy J

    2010-02-05

    A divergent method for incorporating polypyridyl ligands into peptides is reported. Three N-Fmoc unnatural amino acids (1-3) that contain varying linkers between the alpha-carbon and a 2-(hydroxymethyl)pyridyl group were synthesized in enantioenriched form. These amino acids were used as anchors for incorporating multidentate ligands onto a peptide chain in a site-specific fashion. Multiple peptide-ligand conjugates were synthesized from single precursors by solution- or solid-phase methods. Peptides containing more than one metal-binding unit can be produced by this method.

  8. Plasmon resonance enhanced mechanical detection of ligand binding

    SciTech Connect

    Ariyaratne, Amila; Zocchi, Giovanni

    2015-01-05

    Small molecule binding to the active site of enzymes typically modifies the mechanical stiffness of the enzyme. We exploit this effect, in a setup which combines nano-mechanics and surface plasmon resonance (SPR) enhanced optics, for the label free detection of ligand binding to an enzyme. The large dynamic range of the signal allows to easily obtain binding curves for small ligands, in contrast to traditional SPR methods which rely on small changes in index of refraction. Enzyme mechanics, assessed by nano-rheology, thus emerges as an alternative to electronic and spin resonances, assessed by traditional spectroscopies, for detecting ligand binding.

  9. Ligands targeting the excitatory amino acid transporters (EAATs).

    PubMed

    Dunlop, John; Butera, John A

    2006-01-01

    This review provides an overview of ligands for the excitatory amino acid transporters (EAATs), a family of high-affinity glutamate transporters localized to the plasma membrane of neurons and astroglial cells. Ligand development from the perspective of identifying novel and more selective tools for elucidating transporter subtype function, and the potential of transporter ligands in a therapeutic setting are discussed. Acute pharmacological modulation of EAAT activity in the form of linear and conformationally restricted glutamate and aspartate analogs is presented, in addition to recent strategies aimed more toward modulating transporter expression levels, the latter of particular significance to the development of transporter based therapeutics.

  10. 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

  11. Advances and Challenges in Protein-Ligand Docking

    PubMed Central

    Huang, Sheng-You; Zou, Xiaoqin

    2010-01-01

    Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions—the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion. PMID:21152288

  12. Ligand and Structure-based Methodologies for the Prediction of the Activity of G Protein-Coupled Receptor Ligands

    PubMed Central

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

    2008-01-01

    Summary Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered. PMID:18483766

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

    NASA Astrophysics Data System (ADS)

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

    2009-11-01

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

  14. Role of ligand-dependent GR phosphorylation and half-life in determination of ligand-specific transcriptional activity.

    PubMed

    Avenant, Chanel; Ronacher, Katharina; Stubsrud, Elisabeth; Louw, Ann; Hapgood, Janet P

    2010-10-07

    A central question in glucocorticoid mechanism of action via the glucocorticoid receptor (GR) is what determines ligand-selective transcriptional responses. Using a panel of 12 GR ligands, we show that the extent of GR phosphorylation at S226 and S211, GR half-life and transcriptional response, occur in a ligand-selective manner. While GR phosphorylation at S226 was shown to inhibit maximal transcription efficacy, phosphorylation at S211 is required for maximal transactivation, but not for transrepression efficacy. Both ligand-selective GR phosphorylation and half-life correlated with efficacy for transactivation and transrepression. For both expressed and endogenous GR, in two different cell lines, agonists resulted in the greatest extent of phosphorylation and the greatest extent of GR downregulation, suggesting a link between these functions. However, using phosphorylation-deficient GR mutants we established that phosphorylation of the GR at S226 or S211 does not determine the rank order of ligand-selective GR transactivation. These results are consistent with a model whereby ligand-selective GR phosphorylation and half-life are a consequence of upstream events, such as ligand-specific GR conformations, which are maintained in the phosphorylation mutants.

  15. A Natural Mutation in Helix 5 of the Ligand Binding Domain of Glucocorticoid Receptor Enhances Receptor-Ligand Interaction

    PubMed Central

    Reyer, Henry; Ponsuksili, Siriluck; Kanitz, Ellen; Pöhland, Ralf; Wimmers, Klaus; Murani, Eduard

    2016-01-01

    The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40–50 percent. To unravel the molecular mechanisms behind this gain of function, receptor-ligand interactions were evaluated in silico, in vitro and in vivo. In accordance with previously observed phenotypic effects, the mutant Val610 GR showed significantly increased activation in response to glucocorticoid and non-glucocorticoid steroids, and, as revealed by GR-binding studies in vitro and in pituitary glands, enhanced ligand binding. Concordantly, the protein structure prediction depicted reduced binding distances between the receptor and ligand, and altered interactions in the ligand binding pocket. Consequently, the Ala610Val substitution opens up new structural information for the design of potent GR ligands and to examine effects of the enhanced GR responsiveness to glucocorticoids on the entire organism. PMID:27736993

  16. Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.

    PubMed

    Ericson, Mark D; Lensing, Cody J; Fleming, Katlyn A; Schlasner, Katherine N; Doering, Skye R; Haskell-Luevano, Carrie

    2017-03-29

    The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

  17. Chemistry and pharmacology of GABAB receptor ligands.

    PubMed

    Froestl, Wolfgang

    2010-01-01

    This chapter presents new clinical applications of the prototypic GABA(B) receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol, cocaine, nicotine, morphine, and heroin, a novel baclofen prodrug Arbaclofen placarbil, the GABA(B) receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of gastroesophageal reflux disease, and four positive allosteric modulators of GABA(B) receptors (CGP7930, GS39783, NVP-BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical GABA(B) receptor agonists. All four compounds showed anxiolytic affects. In the presence of positive allosteric modulators the "classical" GABA(B) receptor antagonists CGP35348 and 2-hydroxy-saclofen showed properties of partial GABA(B) receptor agonists. Seven micromolar affinity GABA(B) receptor antagonists, phaclofen; 2-hydroxy-saclofen; CGP's 35348, 36742, 46381, 51176; and SCH50911, are discussed. CGP36742 (SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity GABA(B) receptor antagonists are presented (CGP's 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP's 36742, 51176, 55845, and 56433 showed antidepressant effects. Several compounds are also available as radioligands, such as [(3)H]CGP27492, [(3)H]CGP54626, [(3)H]CGP5699, and [(3)H]CGP62349. Three novel fluorescent and three GABA(B) receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [(125)I]CGP64213 and the photoaffinity ligand [(125)I]CGP71872 allowed the identification of GABA(B1a) and GABA(B1b) receptors in the expression cloning work.

  18. Disulfide Bond Requirements for Active Wnt Ligands*

    PubMed Central

    MacDonald, Bryan T.; Hien, Annie; Zhang, Xinjun; Iranloye, Oladoyin; Virshup, David M.; Waterman, Marian L.; He, Xi

    2014-01-01

    Secreted Wnt lipoproteins are cysteine-rich and lipid-modified morphogens that bind to the Frizzled (FZD) receptor and LDL receptor-related protein 6 (LRP6). Wnt engages FZD through protruding thumb and index finger domains, which are each assembled from paired β strands secured by disulfide bonds and grasp two sides of the FZD ectodomain. The importance of Wnt disulfide bonds has been assumed but uncharacterized. We systematically analyzed cysteines and associated disulfide bonds in the prototypic Wnt3a. Our data show that mutation of any individual cysteine of Wnt3a results in covalent Wnt oligomers through ectopic intermolecular disulfide bond formation and diminishes/abolishes Wnt signaling. Although individual cysteine mutations in the amino part of the saposin-like domain and in the base of the index finger are better tolerated and permit residual Wnt3a secretion/activity, those in the amino terminus, the thumb, and at the tip of the index finger are incompatible with secretion and/or activity. A few select double cysteine mutants based on the disulfide bond pattern restore Wnt secretion/activity. Further, a double cysteine mutation at the index finger tip results in a Wnt3a with normal secretion but minimal FZD binding and dominant negative properties. Our results experimentally validate predictions from the Wnt crystal structure and highlight critical but different roles of the saposin-like and cytokine-like domains, including the thumb and the index finger in Wnt folding/secretion and FZD binding. Finally, we modified existing expression vectors for 19 epitope-tagged human WNT proteins by removal of a tag-supplied ectopic cysteine, thereby generating tagged WNT ligands active in canonical and non-canonical signaling. PMID:24841207

  19. The Foundations of Protein-Ligand Interaction

    NASA Astrophysics Data System (ADS)

    Klebe, Gerhard

    For the specific design of a drug we must first answer the question: How does a drug achieve its activity? An active ingredient must, in order to develop its action, bind to a particular target molecule in the body. Usually this is a protein, but also nucleic acids in the form of RNA and DNA can be target structures for active agents. The most important condition for binding is at first that the active agent exhibits the correct size and shape in order to optimally fit into a cavity exposed to the surface of the protein, the "bindingpocket". It is further necessary for the surface properties of the ligand and protein to be mutually compatible to form specific interactions. In 1894 Emil Fischer compared the exact fit of a substrate for the catalytic centre of an enzyme with the picture of a "lock-and-key". Paul Ehrlich coined in 1913 "Corpora non agunt nisi fixata", literally "bodies do not work when they are not bound". He wanted to imply that active agents that are meant to kill bacteria or parasites must be "fixed" by them, i.e. linked to their structures. Both concepts form the starting point for any rational concept in the development of active pharmaceutical ingredients. In many respects they still apply today. A drug must, after being administered, reach its target and interact with a biological macromolecule. Specific agents have a large affinity and sufficient selectivity to bind to the macromolecule's active site. This is the only way they can develop the desired biological activity without side-effects.

  20. Ligand engineering of lead chalcogenide nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton; Brawand, Nicholas; Galli, Giulia

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

  1. Bivalent Ligands for the Serotonin 5-HT3 Receptor

    PubMed Central

    2011-01-01

    The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function. PMID:24900351

  2. Ligand development in the Ni-catalyzed hydrocyanation of alkenes.

    PubMed

    Bini, Laura; Müller, Christian; Vogt, Dieter

    2010-11-28

    The addition of HCN to alkenes is a very useful reaction for the synthesis of functional organic substrates. Industrially the nickel-catalyzed hydrocyanation has gained considerable importance mainly because of the production of adiponitrile in the DuPont process. In this process the hydrocyanation of butadiene is carried out using aryl phosphite-modified nickel catalyst. Since the performance of organo-transition metal complexes is largely determined by the ligand environment of the metal, fundamental understanding and ligand development is of pivotal importance for any progress. This feature article gives an account of the development and application of different mono- and bidentate phosphorus-based ligands in the Ni-catalyzed hydrocyanation reaction of alkenes. Special attention will be paid to the development of insight and understanding of the ligand structural and electronic properties towards the improvement of the catalyst performance in terms of stability, activity, and selectivity.

  3. 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

  4. "Clickable" affinity ligands for effective separation of glycoproteins.

    PubMed

    Suksrichavalit, Thummaruk; Yoshimatsu, Keiichi; Prachayasittikul, Virapong; Bülow, Leif; Ye, Lei

    2010-06-04

    In this paper, we present a new modular approach to immobilize boronic acid ligands that can offer effective separation of glycoproteins. A new "clickable" boronic acid ligand was synthesized by introducing a terminal acetylene group into commercially available 3-aminophenyl boronic acid. The clickable ligand, 3-(prop-2-ynyloxycarbonylamino)phenylboronic acid (2) could be easily coupled to azide-functionalized hydrophilic Sepharose using Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction under mild condition. Compared to other boronic acid affinity gels, the new affinity gel displayed superior effectiveness in separating model glycoproteins (ovalbumin and RNase B) from closely related bovine serum albumin and RNase A in the presence of crude Escherichia coli proteins. Because of the simplicity of the immobilization through "click chemistry", the new ligand 2 is expected to not only offer improved glycoprotein separation in other formats, but also act as a useful building block to develop new chemical sensors for analysis of other glycan compounds.

  5. Paramagnetic Ligand Tagging To Identify Protein Binding Sites

    PubMed Central

    2015-01-01

    Transient biomolecular interactions are the cornerstones of the cellular machinery. The identification of the binding sites for low affinity molecular encounters is essential for the development of high affinity pharmaceuticals from weakly binding leads but is hindered by the lack of robust methodologies for characterization of weakly binding complexes. We introduce a paramagnetic ligand tagging approach that enables localization of low affinity protein–ligand binding clefts by detection and analysis of intermolecular protein NMR pseudocontact shifts, which are invoked by the covalent attachment of a paramagnetic lanthanoid chelating tag to the ligand of interest. The methodology is corroborated by identification of the low millimolar volatile anesthetic interaction site of the calcium sensor protein calmodulin. It presents an efficient route to binding site localization for low affinity complexes and is applicable to rapid screening of protein–ligand systems with varying binding affinity. PMID:26289584

  6. Unique advantages of organometallic supporting ligands for uranium complexes

    SciTech Connect

    Diaconescu, Paula L.; Garcia, Evan

    2014-05-31

    The objective of our research project was to study the reactivity of uranium complexes supported by ferrocene-based ligands. In addition, this research provides training of graduate students as the next generation of actinide scientists.

  7. Ligand Binding to Macromolecules: Allosteric and Sequential Models of Cooperativity.

    ERIC Educational Resources Information Center

    Hess, V. L.; Szabo, Attila

    1979-01-01

    A simple model is described for the binding of ligands to macromolecules. The model is applied to the cooperative binding by hemoglobin and aspartate transcarbamylase. The sequential and allosteric models of cooperative binding are considered. (BB)

  8. Searching for Practically Useful P-Chirogenic Phosphine Ligands.

    PubMed

    Imamoto, Tsuneo

    2016-12-01

    In this account, the design, synthesis, and application of P-chirogenic phosphine ligands that have been mainly carried out in our laboratory over the last three decades are described. Various enantiopure P-chirogenic phosphine ligands have been efficiently prepared by using phosphine boranes as intermediates. Conformationally rigid and electron-rich P-chirogenic phosphine ligands possessing C2 symmetry as well as a bulky alkyl group and a small group at the phosphorus atoms exhibit excellent enantioselectivities and catalytic efficiency in a variety of transition-metal-catalyzed asymmetric reactions. Enantiopure 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*) is an air-stable crystalline solid that shows superior enantioinduction ability in catalytic asymmetric syntheses. Mechanistic studies of Rh-catalyzed asymmetric hydrogenation using structurally simple P-chirogenic phosphine ligands, such as tBu-BisP*, are briefly described.

  9. CD40 ligand immunotherapy in cancer: an efficient approach.

    PubMed

    Kuwashima, N; Kageyama, S; Eto, Y; Urashima, M

    2001-01-01

    Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system.

  10. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

    PubMed Central

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-01-01

    The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships. PMID:27271616

  11. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands.

    PubMed

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-06-04

    The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO's importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles' membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

  12. Fluorescent and Lanthanide Labeling for Ligand Screens, Assays, and Imaging

    PubMed Central

    Josan, Jatinder S.; De Silva, Channa R.; Yoo, Byunghee; Lynch, Ronald M.; Pagel, Mark D.; Vagner, Josef; Hruby, Victor J.

    2012-01-01

    The use of fluorescent (or luminescent) and metal contrast agents in high-throughput screens, in vitro assays, and molecular imaging procedures has rapidly expanded in recent years. Here we describe the development and utility of high-affinity ligands for cancer theranostics and other in vitro screening studies. In this context, we also illustrate the syntheses and use of heteromultivalent ligands as targeted imaging agents. PMID:21318902

  13. Square planar Cu(I) stabilized by a pyridinediimine ligand.

    PubMed

    Cheung, Pui Man; Berger, Robert F; Zakharov, Lev N; Gilbertson, John D

    2016-03-18

    A set of distorted square planar Cu(I) complexes were synthesized and characterized utilizing the sterically encumbering pyridinediimine ligand, (iPr)PDI (where (iPr)PDI = 2,6-(2,6-(i)Pr2C6H3N=CMe)2C5H3N). The oxidation state of the Cu center(s) were elucidated to be Cu(I) with a neutral PDI ligand system based on structural, spectroscopic, and computational data.

  14. Self-assembled molecular films incorporating a ligand

    DOEpatents

    Bednarski, M.D.; Wilson, T.E.; Mastandra, M.S.

    1996-04-23

    Functionalized monomers are presented which can be used in the fabrication of molecular films for controlling adhesion, detection of receptor-ligand binding and enzymatic reactions; new coatings for lithography; and for semiconductor materials. The monomers are a combination of a ligand, a linker, optionally including a polymerizable group, and a surface attachment group. The processes and an apparatus for making films from these monomers, as well as methods of using the films are also provided. 7 figs.

  15. Drawing Mononuclear Octahedral Coordination Compounds Containing Tridentate Chelating Ligands

    ERIC Educational Resources Information Center

    Mohamadou, Aminou; Ple, Karen; Haudrechy, Arnaud

    2011-01-01

    Complexes with tridentate ligands of the type [M(A-B-C)2], where A [not equal to] B [not equal to] C and with an imposed bonding sequence A-B-C, require special attention to draw all possible stereoisomers. Depending on the nature of the central donor atom B of the tridentate ligand, an easy drawing method is presented that shows seven chiral…

  16. Self-assembled molecular films incorporating a ligand

    DOEpatents

    Bednarski, Mark D.; Wilson, Troy E.; Mastandra, Mark S.

    1996-01-01

    Functionalized monomers are presented which can be used in the fabrication of molecular films for controlling adhesion, detection of receptor-ligand binding and enzymatic reactions; new coatings for lithography; and for semiconductor materials. The monomers are a combination of a ligand, a linker, optionally including a polymerizable group, and a surface attachment group. The processes and an apparatus for making films from these monomers, as well as methods of using the films are also provided.

  17. Reaction chemistry and ligand exchange at cadmium selenide nanocrystal surfaces

    SciTech Connect

    Owen, Jonathan; Park, Jungwon; Trudeau, Paul-Emile; Alivisatos, A. Paul

    2008-12-02

    Chemical modification of nanocrystal surfaces is fundamentally important to their assembly, their implementation in biology and medicine, and greatly impacts their electrical and optical properties. However, it remains a major challenge owing to a lack of analytical tools to directly determine nanoparticle surface structure. Early nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) studies of CdSe nanocrystals prepared in tri-n-octylphosphine oxide (1) and tri-n-octylphosphine (2), suggested these coordinating solvents are datively bound to the particle surface. However, assigning the broad NMR resonances of surface-bound ligands is complicated by significant concentrations of phosphorus-containing impurities in commercial sources of 1, and XPS provides only limited information about the nature of the phosphorus containing molecules in the sample. More recent reports have shown the surface ligands of CdSe nanocrystals prepared in technical grade 1, and in the presence of alkylphosphonic acids, include phosphonic and phosphinic acids. These studies do not, however, distinguish whether these ligands are bound datively, as neutral, L-type ligands, or by X-type interaction of an anionic phosphonate/phosphinate moiety with a surface Cd{sup 2+} ion. Answering this question would help clarify why ligand exchange with such particles does not proceed generally as expected based on a L-type ligand model. By using reagents with reactive silicon-chalcogen and silicon-chlorine bonds to cleave the ligands from the nanocrystal surface, we show that our CdSe and CdSe/ZnS core-shell nanocrystal surfaces are likely terminated by X-type binding of alkylphosphonate ligands to a layer of Cd{sup 2+}/Zn{sup 2+} ions, rather than by dative interactions. Further, we provide spectroscopic evidence that 1 and 2 are not coordinated to our purified nanocrystals.

  18. CD6-ligand interactions: a paradigm for SRCR domain function?

    PubMed

    Aruffo, A; Bowen, M A; Patel, D D; Haynes, B F; Starling, G C; Gebe, J A; Bajorath, J

    1997-10-01

    The scavenger receptor cysteine-rich (SRCR) superfamily, which includes proteins expressed by leukocytes, can be subdivided into groups A and B. Group B contains the lymphocyte cell-surface receptor CD6. This article reviews recent progress in understanding the interaction between CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM). Analysis of the CD6-ALCAM interaction may help to understand how other SRCR domains bind to their ligands.

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

    PubMed Central

    Deller, Marc C.

    2015-01-01

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

  20. Regulation of NKG2D ligand gene expression.

    PubMed

    Eagle, Robert A; Traherne, James A; Ashiru, Omodele; Wills, Mark R; Trowsdale, John

    2006-03-01

    The activating immunoreceptor NKG2D has seven known host ligands encoded by the MHC class I chain-related MIC and ULBP/RAET genes. Why there is such diversity of NKG2D ligands is not known but one hypothesis is that they are differentially expressed in different tissues in response to different stresses. To explore this, we compared expression patterns and promoters of NKG2D ligand genes. ULBP/RAET genes were transcribed independent of each other in a panel of cell lines. ULBP/RAET gene expression was upregulated on infection with human cytomegalovirus; however, a clinical strain, Toledo, induced expression more slowly than did a laboratory strain, AD169. ULBP4/RAET1E was not induced by infection with either strain. To investigate the mechanisms behind the similarities and differences in NKG2D ligand gene expression a comparative sequence analysis of NKG2D ligand gene putative promoter regions was conducted. Sequence alignments demonstrated that there was significant sequence diversity; however, one region of high similarity between most of the genes is evident. This region contains a number of potential transcription factor binding sites, including those involved in shock responses and sites for retinoic acid-induced factors. Promoters of some NKG2D ligand genes are polymorphic and several sequence alterations in these alleles abolished putative transcription factor binding.

  1. Riboswitch structure in the ligand-free state.

    PubMed

    Liberman, Joseph A; Wedekind, Joseph E

    2012-01-01

    Molecular investigations of riboswitches bound to small-molecule effectors have produced a wealth of information on how these molecules achieve high affinity and specificity for a target ligand. X-ray crystal structures have been determined for the ligand-free state for representatives of the preQ₁-I, S-adenosylmethionine I, lysine, and glycine aptamer classes. These structures in conjunction with complimentary techniques, such as in-line probing, NMR spectroscopy, Förster resonance energy transfer, small-angle scattering, and computational simulations, have demonstrated that riboswitches adopt multiple conformations in the absence of ligand. Despite a number of investigations that support ligand-dependent folding, mounting evidence suggests that free-state riboswitches interact with their effectors in the sub-populations of largely prefolded states as embodied by the principle of conformational selection, which has been documented extensively for protein-mediated ligand interactions. Fundamental riboswitch investigations of the bound and free states have advanced our understanding of RNA folding, ligand recognition, and how these factors culminate in communication between an aptamer and its expression platform. An understanding of these topics is essential to comprehend riboswitch gene regulation at the molecular level, which has already provided a basis to understand the mechanism of action of natural antimicrobials.

  2. Orphan receptor ligand discovery by pickpocketing pharmacological neighbors.

    PubMed

    Ngo, Tony; Ilatovskiy, Andrey V; Stewart, Alastair G; Coleman, James L J; McRobb, Fiona M; Riek, R Peter; Graham, Robert M; Abagyan, Ruben; Kufareva, Irina; Smith, Nicola J

    2017-02-01

    Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.

  3. Lyar Is a New Ligand for Retinal Pigment Epithelial Phagocytosis.

    PubMed

    Guo, Feiye; Ding, Ying; Caberoy, Nora B; Alvarado, Gabriela; Liu, Robert; Shen, Chen; Yu, Jisu; Zhou, Yixiong; Salero, Enrique; LeBlanc, Michelle E; Wang, Weiwen; Li, Wei

    2015-10-01

    Phagocytosis is critical to tissue homeostasis, as highlighted by phagocytosis defect of retinal pigment epithelial (RPE) cells with debris accumulation, photoreceptor degeneration and blindness. Phagocytosis ligands are the key to delineating molecular mechanisms and functional roles of phagocytes, but are traditionally identified in individual cases with technical challenges. We recently developed open reading frame phage display (OPD) for phagocytosis-based functional cloning (PFC) to identify unknown ligands. One of the identified ligands was Ly-1 antibody reactive clone (Lyar) with functions poorly defined. Herein, we characterized Lyar as a new ligand to stimulate RPE phagocytosis. In contrast to its reported nucleolar expression, immunohistochemistry showed that Lyar was highly expressed in photoreceptor outer segments (POSs) of the retina. Cytoplasmic Lyar was released from apoptotic cells, and selectively bound to shed POSs and apoptotic cells, but not healthy cells. POS vesicles engulfed through Lyar-dependent pathway were targeted to phagosomes and colocalized with phagosome marker Rab7. These results suggest that Lyar is a genuine RPE phagocytosis ligand, which in turn supports the validity of OPD/PFC as the only available approach for unbiased identification of phagocytosis ligands with broad applicability to various phagocytes.

  4. Cell mechanosensory recognizes ligand compliance at biomaterial interface.

    PubMed

    Cosenza, Chiara; Lettera, Vincenzo; Causa, Filippo; Scognamiglio, Pasqualina Liana; Battista, Edmondo; Netti, Paolo Antonio

    2016-01-01

    Cells activate signalling through ligand-receptor bonds by sensing the mechanical properties of the surrounding extracellular matrix (ECM). Ligands, indeed, have to withstand the pulling force elicited by cell receptors through focal adhesions (FAs). On this basis, we developed functional ligands to be simply adsorbed on surfaces and constituted by a two-domain peptide: one derived from ECM proteins and available to receptors to offer biochemical cues, and another adsorbed on material to withstand the tension upon receptor engagement. Tuneable compliance of the anchoring domain of the peptide ligand was verified by single peptide analysis through molecular dynamics and adsorption measurements. We showed that the highest adsorbed peptides combined with integrin cell-binding motifs allow for the cell recognition and polarization with larger mature FA areas. On the contrary, the lowest adsorbed sequences did not provide mechanical resistance to the integrin pulling action, leading to more rounded cells with smaller FA areas. This evidence demonstrates that cell mechanosensory can discriminate ligands on surfaces and should be considered as a criterion in ligand design for material bioactivation.

  5. Ligand binding analysis and screening by chemical denaturation shift.

    PubMed

    Schön, Arne; Brown, Richard K; Hutchins, Burleigh M; Freire, Ernesto

    2013-12-01

    The identification of small molecule ligands is an important first step in drug development, especially drugs that target proteins with no intrinsic activity. Toward this goal, it is important to have access to technologies that are able to measure binding affinities for a large number of potential ligands in a fast and accurate way. Because ligand binding stabilizes the protein structure in a manner dependent on concentration and binding affinity, the magnitude of the protein stabilization effect elicited by binding can be used to identify and characterize ligands. For example, the shift in protein denaturation temperature (Tm shift) has become a popular approach to identify potential ligands. However, Tm shifts cannot be readily transformed into binding affinities, and the ligand rank order obtained at denaturation temperatures (≥60°C) does not necessarily coincide with the rank order at physiological temperature. An alternative approach is the use of chemical denaturation, which can be implemented at any temperature. Chemical denaturation shifts allow accurate determination of binding affinities with a surprisingly wide dynamic range (high micromolar to sub nanomolar) and in situations where binding changes the cooperativity of the unfolding transition. In this article, we develop the basic analytical equations and provide several experimental examples.

  6. Phage Selection of Chemically Stabilized α-Helical Peptide Ligands.

    PubMed

    Diderich, Philippe; Bertoldo, Davide; Dessen, Pierre; Khan, Maola M; Pizzitola, Irene; Held, Werner; Huelsken, Joerg; Heinis, Christian

    2016-05-20

    Short α-helical peptides stabilized by linkages between constituent amino acids offer an attractive format for ligand development. In recent years, a range of excellent ligands based on stabilized α-helices were generated by rational design using α-helical peptides of natural proteins as templates. Herein, we developed a method to engineer chemically stabilized α-helical ligands in a combinatorial fashion. In brief, peptides containing cysteines in position i and i + 4 are genetically encoded by phage display, the cysteines are modified with chemical bridges to impose α-helical conformations, and binders are isolated by affinity selection. We applied the strategy to affinity mature an α-helical peptide binding β-catenin. We succeeded in developing ligands with Kd's as low as 5.2 nM, having >200-fold improved affinity. The strategy is generally applicable for affinity maturation of any α-helical peptide. Compared to hydrocarbon stapled peptides, the herein evolved thioether-bridged peptide ligands can be synthesized more easily, as no unnatural amino acids are required and the cyclization reaction is more efficient and yields no stereoisomers. A further advantage of the thioether-bridged peptide ligands is that they can be expressed recombinantly as fusion proteins.

  7. Ligand exchange in quaternary alloyed nanocrystals--a spectroscopic study.

    PubMed

    Gabka, Grzegorz; Bujak, Piotr; Giedyk, Kamila; Kotwica, Kamil; Ostrowski, Andrzej; Malinowska, Karolina; Lisowski, Wojciech; Sobczak, Janusz W; Pron, Adam

    2014-11-14

    Exchange of initial, predominantly stearate ligands for pyridine in the first step and butylamine (BA) or 11-mercaptoundecanoic acid (MUA) in the second one was studied for alloyed quaternary Cu-In-Zn-S nanocrystals. The NMR results enabled us to demonstrate, for the first time, direct binding of the pyridine labile ligand to the nanocrystal surface as evidenced by paramagnetic shifts of the three signals attributed to its protons to 7.58, 7.95 and 8.75 ppm. XPS investigations indicated, in turn, a significant change in the composition of the nanocrystal surface upon the exchange of initial ligands for pyridine, which being enriched in indium in the 'as prepared' form became enriched in zinc after pyridine binding. This finding indicated that the first step of ligand exchange had to involve the removal of the surface layer enriched in indium with simultaneous exposure of a new, zinc-enriched layer. In the second ligand exchange step (replacement of pyridine with BA or MUA) the changes in the nanocrystal surface compositions were much less significant. The presence of zinc in the nanocrystal surface layer turned out necessary for effective binding of pyridine as shown by a comparative study of ligand exchange in Cu-In-Zn-S, Ag-In-Zn-S and CuInS2, carried out by complementary XPS and NMR investigations.

  8. Limited proteolysis for assaying ligand binding affinities of nuclear receptors.

    PubMed

    Benkoussa, M; Nominé, B; Mouchon, A; Lefebvre, B; Bernardon, J M; Formstecher, P; Lefebvre, P

    1997-01-01

    The binding of natural or synthetic ligands to nuclear receptors is the triggering event leading to gene transcription activation or repression. Ligand binding to the ligand binding domain of these receptors induces conformational changes that are evidenced by an increased resistance of this domain to proteases. In vitro labeled receptors were incubated with various synthetic or natural agonists or antagonists and submitted to trypsin digestion. Proteolysis products were separated by SDS-PAGE and quantified. The amount of trypsin-resistant fragments was proportional to receptor occupancy by the ligand, and allowed the determination of dissociation constants (kDa). Using the wild-type or mutated human retinoic acid receptor alpha as a model, kDa values determined by classical competition binding assays using tritiated ligands are in agreement with those measured by the proteolytic assay. This method was successfully extended to human retinoic X receptor alpha, glucocorticoid receptor, and progesterone receptor, thus providing a basis for a new, faster assay to determine simultaneously the affinity and conformation of receptors when bound to a given ligand.

  9. Ligand and interfacial dynamics in a homodimeric hemoglobin

    PubMed Central

    Gupta, Prashant Kumar; Meuwly, Markus

    2016-01-01

    The structural dynamics of dimeric hemoglobin (HbI) from Scapharca inaequivalvis in different ligand-binding states is studied from atomistic simulations on the μs time scale. The intermediates are between the fully ligand-bound (R) and ligand-free (T) states. Tertiary structural changes, such as rotation of the side chain of Phe97, breaking of the Lys96–heme salt bridge, and the Fe–Fe separation, are characterized and the water dynamics along the R-T transition is analyzed. All these properties for the intermediates are bracketed by those determined experimentally for the fully ligand-bound and ligand-free proteins, respectively. The dynamics of the two monomers is asymmetric on the 100 ns timescale. Several spontaneous rotations of the Phe97 side chain are observed which suggest a typical time scale of 50–100 ns for this process. Ligand migration pathways include regions between the B/G and C/G helices and, if observed, take place in the 100 ns time scale. PMID:26958581

  10. FXR and its ligands inhibit the function of platelets

    PubMed Central

    Vaiyapuri, Sakthivel; Ali, Marfoua S.; Sasikumar, Parvathy; Sage, Tanya; Flora, Gagan D; Bye, Alex P; Kriek, Neline; Dorchies, Emilie; Molendi-Coste, Olivier; Dombrowicz, David; Staels, Bart; Bishop-Bailey, David

    2016-01-01

    Objective While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease. PMID:27758768

  11. Database of Ligand-Receptor Partners, a DIP subset

    DOE Data Explorer

    Graeber, Thomas G.; Eisenberg, David

    The Database of Ligand-Receptor Partners (DLRP) is a subset of DIP (Database of Interacting Proteins). The DLRP is a database of protein ligand and protein receptor pairs that are known to interact with each other. By interact we mean that the ligand and receptor are members of a ligand-receptor complex and, unless otherwise noted, transduce a signal. In some instances the ligand and/or receptor may form a heterocomplex with other ligands/receptors in order to be functional. We have entered the majority of interactions in DLRP as full DIP entries, with links to references and additional information (see the DIP User's Guide). DLRP is a web supplement for: Thomas G. Graeber and David Eisenberg. Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles. Nature Genetics, 29(3):295-300 (November 2001). [Quoted from the DLRP homepage at http://dip.doe-mbi.ucla.edu/dip/DLRP.cgi] Also available from this page is the DLRP chemokine subset.

  12. Predicting Efficient Antenna Ligands for Tb(III) Emission

    SciTech Connect

    Samuel, Amanda P.S.; Xu, Jide; Raymond, Kenneth

    2008-10-06

    A series of highly luminescent Tb(III) complexes of para-substituted 2-hydroxyisophthalamide ligands (5LI-IAM-X) has been prepared (X = H, CH{sub 3}, (C=O)NHCH{sub 3}, SO{sub 3}{sup -}, NO{sub 2}, OCH{sub 3}, F, Cl, Br) to probe the effect of substituting the isophthalamide ring on ligand and Tb(III) emission in order to establish a method for predicting the effects of chromophore modification on Tb(III) luminescence. The energies of the ligand singlet and triplet excited states are found to increase linearly with the {pi}-withdrawing ability of the substituent. The experimental results are supported by time-dependent density functional theory (TD-DFT) calculations performed on model systems, which predict ligand singlet and triplet energies within {approx}5% of the experimental values. The quantum yield ({Phi}) values of the Tb(III) complex increases with the triplet energy of the ligand, which is in part due to the decreased non-radiative deactivation caused by thermal repopulation of the triplet. Together, the experimental and theoretical results serve as a predictive tool that can be used to guide the synthesis of ligands used to sensitize lanthanide luminescence.

  13. Discovery of GPCR ligands for probing signal transduction pathways

    PubMed Central

    Brogi, Simone; Tafi, Andrea; Désaubry, Laurent; Nebigil, Canan G.

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure–selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity. PMID:25506327

  14. Ligands Slow Down Pure-Dephasing in Semiconductor Quantum Dots.

    PubMed

    Liu, Jin; Kilina, Svetlana V; Tretiak, Sergei; Prezhdo, Oleg V

    2015-09-22

    It is well-known experimentally and theoretically that surface ligands provide additional pathways for energy relaxation in colloidal semiconductor quantum dots (QDs). They increase the rate of inelastic charge-phonon scattering and provide trap sites for the charges. We show that, surprisingly, ligands have the opposite effect on elastic electron-phonon scattering. Our simulations demonstrate that elastic scattering slows down in CdSe QDs passivated with ligands compared to that in bare QDs. As a result, the pure-dephasing time is increased, and the homogeneous luminescence line width is decreased in the presence of ligands. The lifetime of quantum superpositions of single and multiple excitons increases as well, providing favorable conditions for multiple excitons generation (MEG). Ligands reduce the pure-dephasing rates by decreasing phonon-induced fluctuations of the electronic energy levels. Surface atoms are most mobile in QDs, and therefore, they contribute greatly to the electronic energy fluctuations. The mobility is reduced by interaction with ligands. A simple analytical model suggests that the differences between the bare and passivated QDs persist for up to 5 nm diameters. Both low-frequency acoustic and high-frequency optical phonons participate in the dephasing processes in bare QDs, while low-frequency acoustic modes dominate in passivated QDs. The theoretical predictions regarding the pure-dephasing time, luminescence line width, and MEG can be verified experimentally by studying QDs with different surface passivation.

  15. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

    PubMed

    Lipinski, Christopher A

    2016-06-01

    The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier.

  16. 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.

  17. Multipurpose ligand, DAKLI (Dynorphin A-analogue Kappa LIgand), with high affinity and selectivity for dynorphin (. kappa. opioid) binding sites

    SciTech Connect

    Goldstein, A.; Nestor, J.J. Jr.; Naidu, A.; Newman, S.R. )

    1988-10-01

    The authors describe a synthetic ligand, DALKI (Dynorphin A-analogue Kappa LIgand), related to the opioid peptide dynorphin A. A single reactive amino group at the extended carboxyl terminus permits various reporter groups to be attached, such as {sup 125}I-labeled Bolton-Hunter reagent, fluorescein isothiocyanate, or biotin. These derivatives have high affinity and selectivity for the dynorphin ({kappa} opioid) receptor. An incidental finding is that untreated guinea pig brain membranes have saturable avidin binding sites.

  18. electronic Ligand Builder and Optimisation Workbench (eLBOW): A tool for ligand coordinate and restraint generation

    SciTech Connect

    Moriarty, Nigel; Grosse-Kunstleve, Ralf; Adams, Paul

    2009-07-01

    The electronic Ligand Builder and Optimisation Workbench (eLBOW) is a program module of the PHENIX suite of computational crystallographic software. It's designed to be a flexible procedure using simple and fast quantum chemical techniques to provide chemically accurate information for novel and known ligands alike. A variety of input formats and options allow for the attainment of a number of diverse goals including geometry optimisation and generation of restraints.

  19. The biotic ligand model: a historical overview.

    PubMed

    Paquin, Paul R; Gorsuch, Joseph W; Apte, Simon; Batley, Graeme E; Bowles, Karl C; Campbell, Peter G C; Delos, Charles G; Di Toro, Dominic M; Dwyer, Robert L; Galvez, Fernando; Gensemer, Robert W; Goss, Gregory G; Hostrand, Christer; Janssen, Colin R; McGeer, James C; Naddy, Rami B; Playle, Richard C; Santore, Robert C; Schneider, Uwe; Stubblefield, William A; Wood, Chris M; Wu, Kuen Benjamin

    2002-09-01

    During recent years, the biotic ligand model (BLM) has been proposed as a tool to evaluate quantitatively the manner in which water chemistry affects the speciation and biological availability of metals in aquatic systems. This is an important consideration because it is the bioavailability and bioreactivity of metals that control their potential to cause adverse effects. The BLM approach has gained widespread interest amongst the scientific, regulated and regulatory communities because of its potential for use in developing water quality criteria (WQC) and in performing aquatic risk assessments for metals. Specifically, the BLM does this in a way that considers the important influences of site-specific water quality. This journal issue includes papers that describe recent advances with regard to the development of the BLM approach. Here, the current status of the BLM development effort is described in the context of the longer-term history of advances in the understanding of metal interactions in the environment upon which the BLM is based. Early developments in the aquatic chemistry of metals, the physiology of aquatic organisms and aquatic toxicology are reviewed first, and the degree to which each of these disciplines influenced the development of water quality regulations is discussed. The early scientific advances that took place in each of these fields were not well coordinated, making it difficult for regulatory authorities to take full advantage of the potential utility of what had been learned. However, this has now changed, with the BLM serving as a useful interface amongst these scientific disciplines, and within the regulatory arena as well. The more recent events that have led to the present situation are reviewed, and consideration is given to some of the future needs and developments related to the BLM that are envisioned. The research results that are described in the papers found in this journal issue represent a distinct milestone in the ongoing

  20. Quantitative analysis of protein-ligand interactions by NMR.

    PubMed

    Furukawa, Ayako; Konuma, Tsuyoshi; Yanaka, Saeko; Sugase, Kenji

    2016-08-01

    Protein-ligand interactions have been commonly studied through static structures of the protein-ligand complex. Recently, however, there has been increasing interest in investigating the dynamics of protein-ligand interactions both for fundamental understanding of the underlying mechanisms and for drug development. NMR is a versatile and powerful tool, especially because it provides site-specific quantitative information. NMR has widely been used to determine the dissociation constant (KD), in particular, for relatively weak interactions. The simplest NMR method is a chemical-shift titration experiment, in which the chemical-shift changes of a protein in response to ligand titration are measured. There are other quantitative NMR methods, but they mostly apply only to interactions in the fast-exchange regime. These methods derive the dissociation constant from population-averaged NMR quantities of the free and bound states of a protein or ligand. In contrast, the recent advent of new relaxation-based experiments, including R2 relaxation dispersion and ZZ-exchange, has enabled us to obtain kinetic information on protein-ligand interactions in the intermediate- and slow-exchange regimes. Based on R2 dispersion or ZZ-exchange, methods that can determine the association rate, kon, dissociation rate, koff, and KD have been developed. In these approaches, R2 dispersion or ZZ-exchange curves are measured for multiple samples with different protein and/or ligand concentration ratios, and the relaxation data are fitted to theoretical kinetic models. It is critical to choose an appropriate kinetic model, such as the two- or three-state exchange model, to derive the correct kinetic information. The R2 dispersion and ZZ-exchange methods are suitable for the analysis of protein-ligand interactions with a micromolar or sub-micromolar dissociation constant but not for very weak interactions, which are typical in very fast exchange. This contrasts with the NMR methods that are used

  1. Ligand directed self-assembly vs. metal ion coordination algorithm-when does the ligand or the metal take control?

    PubMed

    Shuvaev, Konstantin V; Abedin, Tareque S M; McClary, Corey A; Dawe, Louise N; Collins, Julie L; Thompson, Laurence K

    2009-04-28

    Polyfunctional hydrazone ligands with multidentate terminal donor groups offer metal ions many donor choices, and the coordination outcome depends mainly on the identity of the metal ion. Co(ii) and Ni(ii) prefer to adopt largely undistorted, six-coordinate geometries, while Cu(ii) can easily adapt to a variety of coordination situations (e.g. CN 4-6), and will optimize its coordination number and stereochemistry based on all the available donors. Ni(ii) and Co(ii) form simple [2 x 2] [M(4)-(micro(2)-O)(4)] square grids with such ditopic hydrazone ligands, and ignore other coordination options, while Cu(ii) tries to bind to all the available donors, and forms extended and 2D structures based on linked Cu(ii) triads rather than grids. Ni(ii) is also reluctant to compromise its desire to maximize its crystal field stabilization energy (CFSE) by binding to 'weak' ligands, and with a tetratopic pyrazole bis-hydrazone ligand it ignores the oxygen donors in favour of nitrogen, forming a novel trinuclear, triangular cluster. Also, reaction of a linear Ni(ii)(3) complex of a tetratopic pyridazine bis-hydrazone ligand with NiN(6) coordination spheres with Cu(ii), leads exclusively to a square Cu(12) grid based complex, and complete displacement of nickel. Structural and magnetic properties are highlighted, and metal-ligand interactions are discussed in detail.

  2. Evaluating ligands for use in polymer ligand film (PLF) for plutonium and uranium extraction

    SciTech Connect

    Rim, Jung H.; Peterson, Dominic S.; Armenta, Claudine E.; Gonzales, Edward R.; Ünlü, Kenan

    2015-05-08

    We describe a new analyte extraction technique using Polymer Ligand Film (PLF). PLFs were synthesized to perform direct sorption of analytes onto its surface for direct counting using alpha spectroscopy. The main focus of the new technique is to shorten and simplify the procedure for chemically isolating radionuclides for determination through a radiometric technique. 4'(5')-di-t-butylcyclohexano 18-crown-6 (DtBuCH18C6) and 2-ethylhexylphosphonic acid (HEH[EHP]) were examined for plutonium extraction. Di(2-ethyl hexyl) phosphoric acid (HDEHP) were examined for plutonium and uranium extraction. DtBuCH18C6 and HEH[EHP] were not effective in plutonium extraction. HDEHP PLFs were effective for plutonium but not for uranium.

  3. Evaluating ligands for use in polymer ligand film (PLF) for plutonium and uranium extraction

    DOE PAGES

    Rim, Jung H.; Peterson, Dominic S.; Armenta, Claudine E.; ...

    2015-05-08

    We describe a new analyte extraction technique using Polymer Ligand Film (PLF). PLFs were synthesized to perform direct sorption of analytes onto its surface for direct counting using alpha spectroscopy. The main focus of the new technique is to shorten and simplify the procedure for chemically isolating radionuclides for determination through a radiometric technique. 4'(5')-di-t-butylcyclohexano 18-crown-6 (DtBuCH18C6) and 2-ethylhexylphosphonic acid (HEH[EHP]) were examined for plutonium extraction. Di(2-ethyl hexyl) phosphoric acid (HDEHP) were examined for plutonium and uranium extraction. DtBuCH18C6 and HEH[EHP] were not effective in plutonium extraction. HDEHP PLFs were effective for plutonium but not for uranium.

  4. Triple bioaffinity mass spectrometry concept for thyroid transporter ligands.

    PubMed

    Aqai, Payam; Fryganas, Christos; Mizuguchi, Mineyuki; Haasnoot, Willem; Nielen, Michel W F

    2012-08-07

    For the analysis of thyroid transporter ligands, a triple bioaffinity mass spectrometry (BioMS) concept was developed, with the aim at three different analytical objectives: rapid screening of any ligand, confirmation of known ligands in accordance with legislative requirements, and identification of emerging yet unknown ligands. These three purposes share the same biorecognition element, recombinant thyroid transport protein transthyretin (rTTR), and dedicated modes of liquid chromatography-mass spectrometry (LC-MS). For screening, a rapid and radiolabel-free competitive inhibition MS binding assay was developed with fast ultrahigh performance-liquid chromatography-electrospray ionization-triple-quadrupole-MS (UPLC-QqQ-MS) as the readout system. It uses the nonradioactive stable isotopic thyroid hormone (13)C(6)-L-thyroxine as the label of which the binding to rTTR is inhibited by any ligand such as thyroid drugs and thyroid endocrine disrupting chemicals (EDCs). To this end, rTTR is either used in solution or immobilized on paramagnetic microbeads. The concentration-dependent inhibition of the label by the natural thyroid hormone l-thyroxine (T4), as a model analyte, is demonstrated in water at part-per-trillion and in urine at part-per-billion level. For confirmation of identity of known ligands, rTTR was used for bioaffinity purification for confirmation of naturally present free T4 in urine. As a demonstrator for identification of unknown ligands, the same rTTR was used again but in combination with nano-UPLC-quadrupole time-of-flight-MS (nLC-Q-TOF-MS) and urine samples spiked with the model "unknown" EDCs triclosan and tetrabromobisphenol-A. This study highlights the potential of BioMS using one affinity system, both for rapid screening and for confirmation and identification of known and unknown emerging thyroid EDCs.

  5. Ligand-based virtual screening under partial shape constraints.

    PubMed

    von Behren, Mathias M; Rarey, Matthias

    2017-04-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise ).

  6. Ligand-based virtual screening under partial shape constraints

    NASA Astrophysics Data System (ADS)

    von Behren, Mathias M.; Rarey, Matthias

    2017-03-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

  7. Dimolybdenum cyclopentadienyl complexes with bridging chalcogenophosphinidene ligands.

    PubMed

    Alvarez, Belén; Alvarez, M Angeles; Amor, Inmaculada; García, M Esther; García-Vivó, Daniel; Suárez, Jaime; Ruiz, Miguel A

    2012-07-16

    The reactions of the phosphinidene-bridged complex [Mo(2)Cp(2)(μ-PH)(η(6)-HMes*)(CO)(2)] (1), the arylphosphinidene complexes [Mo(2)Cp(2)(μ-κ(1):κ(1),η(6)-PMes*)(CO)(2)] (2), [Mo(2)Cp(2)(μ-κ(1):κ(1),η(4)-PMes*)(CO)(3)] (3), [Mo(2)Cp(2)(μ-κ(1):κ(1),η(4)-PMes*)(CO)(2)(CN(t)Bu)] (4), and the cyclopentadienylidene-phosphinidene complex [Mo(2)Cp(μ-κ(1):κ(1),η(5)-PC(5)H(4))(η(6)-HMes*)(CO)(2)] (5) toward different sources of chalcogen atoms were investigated (Mes* = 2,4,6-C(6)H(2)(t)Bu(3); Cp = η(5)-C(5)H(5)). The bare elements were appropriate sources in all cases except for oxygen, in which case dimethyldioxirane gave the best results. Complex 1 reacted with the mentioned chalcogen sources at low temperature, to give the corresponding chalcogenophosphinidene derivatives [Mo(2)Cp(2){μ-κ(2)(P,Z):κ(1)(P)-ZPH}(η(6)-HMes*)(CO)(2)] (Z = O, S, Se, Te; P-Se = 2.199(2) Å). The arylphosphinidene complex 2 was the least reactive substrate and gave only chalcogenophosphinidene derivatives [Mo(2)Cp(2)(μ-κ(2)(P,Z):κ(1)(P),η(6)-ZPMes*)(CO)(2)] for Z = O and S (P-O = 1.565(2) Å), along with small amounts of the dithiophosphorane complex [Mo(2)Cp(2)(μ-κ(2)(P,S):κ(1)(S'),η(6)-S(2)PMes*)(CO)(2)], in the reaction with sulfur. The η(4)-complexes 3 and 4 reacted with sulfur and gray selenium to give the corresponding derivatives [Mo(2)Cp(2)(μ-κ(2)(P,Z):κ(1)(P),η(4)-ZPMes*)(CO)(2)L] (L = CO, CN(t)Bu), obtained respectively as syn (Z = Se; P-Se = 2.190(1) Å for L = CO) or a mixture of syn and anti isomers (Z = S; P-S = 2.034(1)-2.043(1) Å), with these diastereoisomers differing in the relative positioning of the chalcogen atom and the terminal ligand at the metallocene fragment, relative to the Mo(2)P plane. The cyclopentadienylidene compound 5 reacted with all chalcogens, and gave with good yields the chalcogenophosphinidene derivatives [Mo(2)Cp(μ-κ(2)(P,Z):κ(1)(P),η(5)-ZPC(5)H(4))(η(6)-HMes*)(CO)(2)] (Z = S, Se, Te), these displaying in solution

  8. Ligand Migration and Binding in Myoglobin Mutant L29W

    NASA Astrophysics Data System (ADS)

    Nienhaus, G. Ulrich; Waschipky, Robert; Nienhaus, Karin; Minkow, Oleksandr; Ostermann, Andreas; Parak, Fritz G.

    2001-09-01

    Myoglobin, a small globular heme protein that binds gaseous ligands such as O2, CO, and NO reversibly at the heme iron, has for many years been a paradigm for studying the effects of structure and dynamics on protein reactions. Time-resolved spectroscopic measurements after photodissociation of the ligand reveal a complex ligand binding reaction with multiple kinetic intermediates, resulting from protein relaxation and movements of the ligand within the protein. To observe structural changes induced by ligand dissociation, we have investigated carbonmonoxy myoglobin (MbCO) mutant L29W using time-resolved infrared spectroscopy in combination with x-ray crystallography. The presence of two distinct infrared stretch bands of the bound CO, AI at 1945 cm-1 and AII at 1955 cm-1, implies that L29W MbCO assumes two different conformations at neutral pH. Low-temperature flash photolysis experiments with monitoring of the absorption changes in the individual CO lines reveal markedly different rebinding properties. While recombination in AII is conceptually simple and well described by a two-state transition involving a distribution of enthalpy barriers, recombination in AI is more complicated: Besides a fast kinetic component, a second, slower kinetic component appears; its population grows with increasing temperature. X-ray crystallography of crystals illuminated below 180 K to photodissociate the CO reveals that the slow component arises from ligands that have migrated from their initial docking site to a remote site within the distal heme pocket. This process occurs in an essentially immobilized, frozen protein. Subsequently, ligands rebind by thermal activation over a barrier that is much higher than the barrier for recombination from the initial docking site. Upon photodissociation above 180 K, ligands escape from the distal pocket, aided by protein fluctuations that transiently open exit channels. The x-ray structure shows a large proportion of ligands in a cavity on

  9. Using chemical shift perturbation to characterise ligand binding.

    PubMed

    Williamson, Mike P

    2013-08-01

    Chemical shift perturbation (CSP, chemical shift mapping or complexation-induced changes in chemical shift, CIS) follows changes in the chemical shifts of a protein when a ligand is added, and uses these to determine the location of the binding site, the affinity of the ligand, and/or possibly the structure of the complex. A key factor in determining the appearance of spectra during a titration is the exchange rate between free and bound, or more specifically the off-rate koff. When koff is greater than the chemical shift difference between free and bound, which typically equates to an affinity Kd weaker than about 3μM, then exchange is fast on the chemical shift timescale. Under these circumstances, the observed shift is the population-weighted average of free and bound, which allows Kd to be determined from measurement of peak positions, provided the measurements are made appropriately. (1)H shifts are influenced to a large extent by through-space interactions, whereas (13)Cα and (13)Cβ shifts are influenced more by through-bond effects. (15)N and (13)C' shifts are influenced both by through-bond and by through-space (hydrogen bonding) interactions. For determining the location of a bound ligand on the basis of shift change, the most appropriate method is therefore usually to measure (15)N HSQC spectra, calculate the geometrical distance moved by the peak, weighting (15)N shifts by a factor of about 0.14 compared to (1)H shifts, and select those residues for which the weighted shift change is larger than the standard deviation of the shift for all residues. Other methods are discussed, in particular the measurement of (13)CH3 signals. Slow to intermediate exchange rates lead to line broadening, and make Kd values very difficult to obtain. There is no good way to distinguish changes in chemical shift due to direct binding of the ligand from changes in chemical shift due to allosteric change. Ligand binding at multiple sites can often be characterised, by

  10. Ligand-Receptor Binding Measured by Laser-Scanning Imaging

    NASA Astrophysics Data System (ADS)

    Zuck, Paul; Lao, Zhege; Skwish, Stephen; Fraser Glickman, J.; Yang, Ke; Burbaum, Jonathan; Inglese, James

    1999-09-01

    This report describes the integration of laser-scanning fluorometric cytometry and nonseparation ligand-binding techniques to provide new assay methods adaptable to miniaturization and high-throughput screening. Receptor-bound, cyanine dye-labeled ligands, [Cy]ligands, were discriminated from those free in solution by measuring the accumulated fluorescence associated with a receptor-containing particle. To illustrate the various binding formats accommodated by this technique, saturation- and competition-binding analyses were performed with [Cy]ligands and their cognate receptors expressed in CHO cells or as fusion proteins coated on polystyrene microspheres. We have successfully applied this technique to the analysis of G protein-coupled receptors, cytokine receptors, and SH2 domains. Multiparameter readouts from ligands labeled separately with Cy5 and Cy5.5 demonstrate the simultaneous analysis of two target receptors in a single well. In addition, laser-scanning cytometry has been used to assay enzymes such as phosphatases and in the development of single-step fluorescent immunoassays.

  11. Thiophene-Core Estrogen Receptor Ligands Having Superagonist Activity

    PubMed Central

    Min, Jian; Wang, Pengcheng; Srinivasan, Sathish; Nwachukwu, Jerome C.; Guo, Pu; Huang, Minjian; Carlson, Kathryn E.; Katzenellenbogen, John A.; Nettles, Kendall W.; Zhou, Hai-Bing

    2013-01-01

    To probe the importance of the heterocyclic core of estrogen receptor (ER) ligands, we prepared a series of thiophene-core ligands by Suzuki cross-coupling of aryl boronic acids with bromo-thiophenes, and we assessed their receptor binding and cell biological activities. The disposition of the phenol substituents on the thiophene core, at alternate or adjacent sites, and the nature of substituents on these phenols all contribute to binding affinity and subtype selectivity. Most of the bis(hydroxyphenyl)-thiophenes were ERβ selective, whereas the tris(hydroxyphenyl)-thiophenes were ERα selective; analogous furan-core compounds generally have lower affinity and less selectivity. Some diarylthiophenes show distinct superagonist activity in reporter gene assays, giving maximal activities 2–3 times that of estradiol, and modeling suggests that these ligands have a different interaction with a hydrogen-bonding residue in helix-11. Ligand-core modification may be a new strategy for developing ER ligands whose selectivity is based on having transcriptional activity greater than that of estradiol. PMID:23586645

  12. Cloud computing for protein-ligand binding site comparison.

    PubMed

    Hung, Che-Lun; Hua, Guan-Jie

    2013-01-01

    The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

  13. Surface Ligand-Mediated Plasmon-Driven Photochemical Reactions.

    PubMed

    Kafle, Bijesh; Poveda, Marisa; Habteyes, Terefe G

    2017-03-02

    Contrary to the general expectation that surface ligands reduce the reactivity of surfaces by blocking the active sites, we present experimental evidence that surface ligands can in fact increase reactivity and induce important reaction pathways in plasmon-driven surface photochemistry. The remarkable effect of surface ligands is demonstrated by comparing the photochemistry of p-aminothiophenol (PATP) on resonant plasmonic gold nanorods (AuNRs) in the presence of citrate, hexadecyltrimethylammonium bromide (CTAB), and no surface ligands under visible light irradiation. The use of AuNRs with citrate and no surface ligand results in the usual azo-coupling reaction. In contrast, CTAB-coated AuNRs oxidize PATP primarily to p-nitrothiophenol (PNTP). Strong correlation has been observed between the N-O and Au-Br vibration band intensities, suggesting that CTAB influences the reaction pathway through the Br(-) counterions that can minimize the electron-hole recombination rate by reacting with the hole and hence increasing the concentration of hot electrons that drive the oxidation reaction.

  14. Ligand specificity and evolution of liver X receptors§

    PubMed Central

    Reschly, Erica J.; Ai, Ni; Welsh, William J.; Ekins, Sean; Hagey, Lee R.; Krasowski, Matthew D.

    2008-01-01

    Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity. PMID:18395439

  15. Structural basis for EGFR ligand sequestration by Argos

    SciTech Connect

    Klein, Daryl E.; Stayrook, Steven E.; Shi, Fumin; Narayan, Kartik; Lemmon, Mark A.

    2008-06-26

    Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR5. Here we describe the 1.6-{angstrom} resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-{beta} family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.

  16. A grand unified model for liganded gold clusters

    NASA Astrophysics Data System (ADS)

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

    2016-12-01

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

  17. Efficient mapping of ligand migration channel networks in dynamic proteins.

    PubMed

    Lin, Tu-Liang; Song, Guang

    2011-08-01

    For many proteins such as myoglobin, the binding site lies in the interior, and there is no obvious route from the exterior to the binding site in the average structure. Although computer simulations for a limited number of proteins have found some transiently open channels, it is not clear if there exist more channels elsewhere or how the channels are regulated. A systematic approach that can map out the whole ligand migration channel network is lacking. Ligand migration in a dynamic protein resembles closely a well-studied problem in robotics, namely, the navigation of a mobile robot in a dynamic environment. In this work, we present a novel robotic motion planning inspired approach that can map the ligand migration channel network in a dynamic protein. The method combines an efficient spatial mapping of protein inner space with a temporal exploration of protein structural heterogeneity, which is represented by a structure ensemble. The spatial mapping of each conformation in the ensemble produces a partial map of protein inner cavities and their inter-connectivity. These maps are then merged to form a super map that contains all the channels that open dynamically. Results on the pathways in myoglobin for gaseous ligands demonstrate the efficiency of our approach in mapping the ligand migration channel networks. The results, obtained in a significantly less amount of time than trajectory-based approaches, are in agreement with previous simulation results. Additionally, the method clearly illustrates how and what conformational changes open or close a channel.

  18. Protein-Ligand Docking Based on Beta-Shape

    NASA Astrophysics Data System (ADS)

    Kim, Chong-Min; Won, Chung-In; Kim, Jae-Kwan; Ryu, Joonghyun; Bhak, Jong; Kim, Deok-Soo

    Protein-ligand docking is to predict the location and orientation of a ligand with respect to a protein within its binding site, and has been known to be essential for the development of new drugs. The protein-ligand docking problem is usually formulated as an energy minimization problem to identify the docked conformation of the ligand. A ligand usually docks around a depressed region, called a pocket, on the surface of a protein. Presented in this paper is a docking method, called BetaDock, based on the newly developed geometric construct called the β-shape and the β-complex. To cope with the computational intractability, the global minimum of the potential energy function is searched using the genetic algorithm. The proposed algorithm first locates initial chromosomes at some locations within the pocket recognized according to the local shape of the β-shape. Then, the algorithm proceeds generations by taking advantage of powerful properties of the β-shape to achieve an extremely fast and good solution. We claim that the proposed method is much faster than other popular docking softwares including AutoDock.

  19. A grand unified model for liganded gold clusters

    PubMed Central

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

    2016-01-01

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

  20. A modified fluorescent intercalator displacement assay for RNA ligand discovery

    PubMed Central

    Asare-Okai, Papa Nii; Chow, Christine S.

    2010-01-01

    Fluorescent intercalator displacement (FID) is a convenient and practical tool for identifying new nucleic-acid-binding ligands. The success of FID is based on the fact that it can be fashioned into a versatile screening assay for assessing the relative binding affinities of compounds to nucleic acids. FID is a tagless approach; the target RNAs and the ligands or small molecules under investigation do not have to be modified in order to be examined. In this study, a modified FID assay for screening RNA-binding ligands was established using 3-methyl-2-((1-(3-(trimethylammonio)propyl)-4-quinolinylidene)methyl)benzothiazolium (TO-PRO) as the fluorescent indicator. Electrospray ionization mass spectrometry (ESI-MS) results provide direct evidence that correlates the reduction in fluorescence intensity observed in the FID assay with displacement of the dye molecule from RNA. The assay was successfully applied to screen a variety of RNA-binding ligands with a set of small hairpin RNAs. Ligands that bind with moderate affinity to the chosen RNA constructs (A-site, TAR, h31, and H69) were identified. PMID:20863807