Binding to the DNA Minor Groove by Heterocyclic Dications: From AT Specific Monomers to GC Recognition with Dimers

PubMed Central

Nanjunda, Rupesh; Wilson, W. David

2012-01-01

Compounds that bind in the DNA minor groove have provided critical information on DNA molecular recognition, they have found extensive uses in biotechnology and they are providing clinically useful drugs against diseases as diverse as cancer and sleeping sickness. This review focuses on the development of clinically useful heterocyclic diamidine minor groove binders. These compounds have shown us that the classical model for minor groove binding in AT DNA sequences must be expanded in several ways: compounds with nonstandard shapes can bind strongly to the groove, water can be directly incorporated into the minor groove complex in an interfacial interaction, and the compounds can form cooperative stacked dimers to recognize GC and mixed AT/GC base pair sequences. PMID:23255206

Dimeric Matrine-Type Alkaloids from the Roots of Sophora flavescens and Their Anti-Hepatitis B Virus Activities.

PubMed

Zhang, Yu-Bo; Zhan, Li-Qin; Li, Guo-Qiang; Wang, Feng; Wang, Ying; Li, Yao-Lan; Ye, Wen-Cai; Wang, Guo-Cai

2016-08-05

Six unusual matrine-type alkaloid dimers, flavesines A-F (1-6, respectively), together with three proposed biosynthetic intermediates (7-9) were isolated from the roots of Sophora flavescens. Compounds 1-5 were the first natural matrine-type alkaloid dimers, and compound 6 represented an unprecedented dimerization pattern constructed by matrine and (-)-cytisine. Their structures were elucidated by NMR, MS, single-crystal X-ray diffraction, and a chemical method. The hypothetical biogenetic pathways of 1-6 were also proposed. Compounds 1-9 exhibited inhibitory activities against hepatitis B virus.

Inhibitory effects of p-cresol and p-hydroxy anisole dimers on expression of the cyclooxygenase-2 gene and lipopolysaccharide-stimulated activation of nuclear factor-κB in RAW264.7 cells.

PubMed

Murakami, Yukio; Kawata, Akifumi; Ito, Shigeru; Katayama, Tadashi; Fujisawa, Seiichiro

2014-01-01

Phenolic compounds, particularly dihydroxybiphenyl-related compounds, possess efficient anti-oxidative and anti-inflammatory activity. We investigated the anti-inflammatory activity of 2,2'-dihydroxy-5,5'-dimethylbiphenol (p-cresol dimer), 2,2'-dihydroxy-5,5'-dimethoxybiphenol (pHA dimer), p-cresol, p-hydroxyanisole (pHA) and 2-t-butyl-4-hydroxyanisole (BHA). The cytotoxicity of the investigated compounds against RAW264.7 cells was determined using a cell counting kit (CCK-8). Their inhibitory effects on cyclooxygenase-2 (Cox2) mRNA expression stimulated by lipopolysaccharide (LPS) were determined using northern blot analysis, and their inhibition of LPS-stimulated nuclear factor-kappa B (Nf-κb) activation was evaluated using enzyme-linked immunosorbent assay-like microwell colorimetric transcription factor activity assay. The molecular orbital energy was calculated on the basis of density function theory BLYP/6-31G*. The cytotoxicity of the compounds declined in the order pHA dimer > p-cresol dimer > BHA > p-cresol > pHA. The inhibitory effect on Cox2 expression and Nf-κb activation was enhanced by p-cresol dimer and pHA dimer, particularly the former, suggesting potent anti-inflammatory activity, whereas p-cresol and pHA showed weak activity, and BHA no activity. Both p-cresol dimer and pHA dimer were highly electronegative, as determined by quantum chemical calculations. Dimerization of p-cresol and pHA enhances their anti-inflammatory activity. p-Cresol dimer and pHA dimer, particularly the former, are potent anti-inflammatory agents. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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

PubMed

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

2017-10-20

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

Quantum chemical determination of young?s modulus of lignin. Calculations on ß-O-4' model compound

Treesearch

Thomas Elder

2007-01-01

The calculation of Young?s modulus of lignin has been examined by subjecting a dimeric model compound to strain, coupled with the determination of energy and stress. The computational results, derived from quantum chemical calculations, are in agreement with available experimental results. Changes in geometry indicate that modifications in dihedral angles occur in...

GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

PubMed

Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

2009-11-01

G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.

Therapeutic Inhibition of Pro-Inflammatory Signaling and Toxicity to Staphylococcal Enterotoxin B by a Synthetic Dimeric BB-Loop Mimetic of MyD88

DTIC Science & Technology

2012-07-27

induce MyD88- mediated signaling [15,16]. Seeking to improve the efficacy of Compound 1 as an inhibitor of MyD88 signaling, we synthesized a dimeric...molecule in which two Compound 1 moieties were covalently linked together, reasoning that the dimeric compound would be a more potent inhibitor of protein...pellets in 50 ml of lysis buffer (Active Motif) in the presence of DTT, protease inhibitors and phosphatase inhibitors and incubated on ice for 30–60

Stabilization of sulfuric acid dimers by ammonia, methylamine, dimethylamine, and trimethylamine

NASA Astrophysics Data System (ADS)

Jen, Coty N.; McMurry, Peter H.; Hanson, David R.

2014-06-01

This study experimentally explores how ammonia (NH3), methylamine (MA), dimethylamine (DMA), and trimethylamine (TMA) affect the chemical formation mechanisms of electrically neutral clusters that contain two sulfuric acid molecules (dimers). Dimers may also contain undetectable compounds, such as water or bases, that evaporate upon ionization and sampling. Measurements were conducted using a glass flow reactor which contained a steady flow of humidified nitrogen with sulfuric acid concentrations of 107 to 109 cm-3. A known molar flow rate of a basic gas was injected into the flow reactor. The University of Minnesota Cluster Chemical Ionization Mass Spectrometer was used to measure the resulting sulfuric acid vapor and cluster concentrations. It was found that, for a given concentration of sulfuric acid vapor, the dimer concentration increases with increasing concentration of the basic gas, eventually reaching a plateau. The base concentrations at which the dimer concentrations saturate suggest NH3 < MA < TMA ≲ DMA in forming stabilized sulfuric acid dimers. Two heuristic models for cluster formation by acid-base reactions are developed to interpret the data. The models provide ranges of evaporation rate constants that are consistent with observations and leads to an analytic expression for nucleation rates that is consistent with atmospheric observations.

A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization

PubMed Central

Kanthala, Shanthi P.; Liu, Yong-Yu; Singh, Sitanshu; Sable, Rushikesh; Pallerla, Sandeep; Jois, Seetharama D.

2017-01-01

Among different types of EGFR dimers, EGFR-HER2 and HER2-HER3 are well known in different types of cancers. Targeting dimerization of EGFR will have a significant impact on cancer therapies. A symmetric peptidomimetic was designed to inhibit the protein-protein interaction of EGFR. The peptidomimetic (Cyclo(1,10)PpR (R) Anapa-FDDF-(R)-Anapa)R, compound 18) was shown to exhibit antiproliferative activity with an IC50 of 194 nM in HER2-expressing breast cancer cell lines and 18 nM in lung cancer cell lines. The peptidomimetic has a Pro-Pro sequence in the structure to stabilize the β-turn and a β-amino acid, amino napthyl propionic acid. To investigate the effect of the chirality of β-amino acid on the structure of the peptide and its antiproliferative activity, diastereoisomers of compound 18 were designed and synthesized. Structure-activity relationships of these compounds indicated that there is a chiral switch at β-amino acid in the designed compound. The peptidomimetic with R configuration at β-amino acid and with a L-Pro-D-Pro sequence was the most active compound (18). Using enzyme complement fragmentation assay and proximity ligation assay, we show that compound 18 inhibits HER2:HER3 and EGFR:HER2 dimerization. Surface plasmon resonance studies suggested that compound 18 binds to the HER2 extracellular domain and in particular to domain IV. The anticancer activity of compound 18 was evaluated using a xenograft model of breast cancer in mice; compound 18 suppressed the tumor growth in mice compared to control. Compound 18 was also shown to have a synergistic effect with erlotinib on EGFR mutated lung cancer cell lines. PMID:29088782

Two new dimeric naphthoquinones with neuraminidase inhibitory activity from Lithospermum erythrorhizon.

PubMed

Yang, Yanqin; Zhao, Dapeng; Yuan, Kailong; Zhou, Guojun; Wang, Yu; Xiao, Yanmeng; Wang, Chenxu; Xu, Jingwei; Yang, Wei

2015-01-01

The crude methanol extract of roots of Lithospermum erythrorhizon was subjected to successive chromatographic fractionation which afforded two new dimeric naphthoquinone derivatives shikometabolin E (2) and shikometabolin F (3) as well as one known compound shikometabolin A (1). The structures of compounds 1-3 were elucidated by using UV, MS, 1D and 2D NMR spectroscopic analysis. The two new dimeric naphthoquinone derivatives showed significant neuraminidase inhibitory activities.

Alkoxyl- and carbon-centered radicals as primary agents for degrading non-phenolic lignin-substructure model compounds.

PubMed

Ohashi, Yasunori; Uno, Yukiko; Amirta, Rudianto; Watanabe, Takahito; Honda, Yoichi; Watanabe, Takashi

2011-04-07

Lignin degradation by white-rot fungi proceeds via free radical reaction catalyzed by oxidative enzymes and metabolites. Basidiomycetes called selective white-rot fungi degrade both phenolic and non-phenolic lignin substructures without penetration of extracellular enzymes into the cell wall. Extracellular lipid peroxidation has been proposed as a possible ligninolytic mechanism, and radical species degrading the recalcitrant non-phenolic lignin substructures have been discussed. Reactions between the non-phenolic lignin model compounds and radicals produced from azo compounds in air have previously been analysed, and peroxyl radical (PR) is postulated to be responsible for lignin degradation (Kapich et al., FEBS Lett., 1999, 461, 115-119). However, because the thermolysis of azo compounds in air generates both a carbon-centred radical (CR) and a peroxyl radical (PR), we re-examined the reactivity of the three radicals alkoxyl radical (AR), CR and PR towards non-phenolic monomeric and dimeric lignin model compounds. The dimeric lignin model compound is degraded by CR produced by reaction of 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), which under N(2) atmosphere cleaves the α-β bond in 1-(4-ethoxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol to yield 4-ethoxy-3-methoxybenzaldehyde. However, it is not degraded by the PR produced by reaction of Ce(4+)/tert-BuOOH. In addition, it is degraded by AR produced by reaction of Ti(3+)/tert-BuOOH. PR and AR are generated in the presence and absence of veratryl alcohol, respectively. Rapid-flow ESR analysis of the radical species demonstrates that AR but not PR reacts with the lignin model compound. Thus, AR and CR are primary agents for the degradation of non-phenolic lignin substructures.

Development of many-body polarizable force fields for Li-battery components: 1. Ether, alkane, and carbonate-based solvents.

PubMed

Borodin, Oleg; Smith, Grant D

2006-03-30

Classical many-body polarizable force fields were developed for n-alkanes, perflouroalkanes, polyethers, ketones, and linear and cyclic carbonates on the basis of quantum chemistry dimer energies of model compounds and empirical thermodynamic liquid-state properties. The dependence of the electron correlation contribution to the dimer binding energy on basis-set size and level of theory was investigated as a function of molecular separation for a number of alkane, ether, and ketone dimers. Molecular dynamics (MD) simulations of the force fields accurately predicted structural, dynamic, and transport properties of liquids and unentangled polymer melts. On average, gas-phase dimer binding energies predicted with the force field were between those from MP2/aug-cc-pvDz and MP2/aug-cc-pvTz quantum chemistry calculations.

Design and synthesis of small molecule agonists of EphA2 receptor.

PubMed

Petty, Aaron; Idippily, Nethrie; Bobba, Viharika; Geldenhuys, Werner J; Zhong, Bo; Su, Bin; Wang, Bingcheng

2018-01-01

Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor. Published by Elsevier Masson SAS.

Novel dimer based descriptors with solvational computation for QSAR study of oxadiazoylbenzoyl-ureas as novel insect-growth regulators.

PubMed

Fan, Feng; Cheng, Jiagao; Li, Zhong; Xu, Xiaoyong; Qian, Xuhong

2010-02-01

Molecular aggregation state of bioactive compounds plays a key role in its bio-interactive procedure. In this article, based on the structure information of dimers, the simplest model of molecular aggregation state, and combined with solvational computation, total four descriptors (DeltaV, MR2, DeltaE(1), and DeltaE(2)) were calculated for QSAR study of a novel insect-growth regulator, N-(5-phenyl-1,3,4-oxadiazol-2-yl)-N'-benzoyl urea. Two QSAR models were constructed with r(2) = 0.671, q(2) = 0.516 and r(2) = 0.816, q(2) = 0.695, respectively. It implicates that the bioactivity may strongly depend on the characters of molecular aggregation state, especially on the dimeric transport ability from oil phase to water phase. Copyright 2009 Wiley Periodicals, Inc.

Ambient observations of dimers from terpene oxidation in the gas phase: Implications for new particle formation and growth: Ambient Observations of Gas-Phase Dimers

DOE PAGES

Mohr, Claudia; Lopez-Hilfiker, Felipe D.; Yli-Juuti, Taina; ...

2017-03-28

Here, we present ambient observations of dimeric monoterpene oxidation products (C 16–20H yO 6–9) in gas and particle phases in the boreal forest in Finland in spring 2013 and 2014, detected with a chemical ionization mass spectrometer with a filter inlet for gases and aerosols employing acetate and iodide as reagent ions. These are among the first online dual-phase observations of such dimers in the atmosphere. Estimated saturation concentrations of 10 -15 to 10 -6 µg m -3 (based on observed thermal desorptions and group-contribution methods) and measured gas-phase concentrations of 10 -3 to 10 -2 µg m -3 (~10more » 6–10 7 molecules cm -3) corroborate a gas-phase formation mechanism. Regular new particle formation (NPF) events allowed insights into the potential role dimers may play for atmospheric NPF and growth. The observationally constrained Model for Acid-Base chemistry in NAnoparticle Growth indicates a contribution of ~5% to early stage particle growth from the ~60 gaseous dimer compounds.« less

Ambient observations of dimers from terpene oxidation in the gas phase: Implications for new particle formation and growth: Ambient Observations of Gas-Phase Dimers

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

Mohr, Claudia; Lopez-Hilfiker, Felipe D.; Yli-Juuti, Taina

Here, we present ambient observations of dimeric monoterpene oxidation products (C 16–20H yO 6–9) in gas and particle phases in the boreal forest in Finland in spring 2013 and 2014, detected with a chemical ionization mass spectrometer with a filter inlet for gases and aerosols employing acetate and iodide as reagent ions. These are among the first online dual-phase observations of such dimers in the atmosphere. Estimated saturation concentrations of 10 -15 to 10 -6 µg m -3 (based on observed thermal desorptions and group-contribution methods) and measured gas-phase concentrations of 10 -3 to 10 -2 µg m -3 (~10more » 6–10 7 molecules cm -3) corroborate a gas-phase formation mechanism. Regular new particle formation (NPF) events allowed insights into the potential role dimers may play for atmospheric NPF and growth. The observationally constrained Model for Acid-Base chemistry in NAnoparticle Growth indicates a contribution of ~5% to early stage particle growth from the ~60 gaseous dimer compounds.« less

Synthesis, kinetic studies and molecular modeling of novel tacrine dimers as cholinesterase inhibitors.

PubMed

de Aquino, Roney Anderson Nascimento; Modolo, Luzia Valentina; Alves, Rosemeire Brondi; de Fátima, Ângelo

2013-12-28

This study presents the synthesis of 15 new tacrine dimers as well as the Ki and IC50 results, studies of the kinetic mechanism, and molecular docking analysis of the dimers in relation to the cholinesterases hAChE, hBChE, EeAChE and eqBChE. In addition to spectroscopic characterization, X-ray structure determination was performed for two of the new compounds. These new dimers were found to be mixed nanomolar inhibitors of the evaluated targets with a broad and significant selectivity profile, and these properties are dependent on both the type of the linker and the volume of the hydroacridine alicyclic ring. The results indicate that the aromatic linkers play a significant role in generating specific interactions with the half-gorge region of the catalytic center. Thus, these types of linkers can positively modulate the electronic properties of the tacrine dimers studied with an improvement of their cholinesterase inhibition activity.

Photodamage of a Mn(III/IV)-oxo mixed-valence compound and photosystem II: evidence that a high-valent manganese species is responsible for UV-induced photodamage of the oxygen-evolving complex in photosystem II.

PubMed

Wei, Zi; Cady, Clyde W; Brudvig, Gary W; Hou, Harvey J M

2011-01-01

The Mn cluster in photosystem II (PS II) is believed to play an important role in the UV photoinhibition of green plants, but the mechanism is still not clear at a molecular level. In this work, the photochemical stability of [Mn(III)(O)(2)Mn(IV)(H(2)O)(2)(Terpy)(2)](NO(3))(3) (Terpy=2,2':6',2''-terpyridine), designated as Mn-oxo mixed-valence dimer, a well characterized functional model of the oxygen-evolving complex in PS II, was examined in aqueous solution by exposing the complex to excess light irradiation at six different wavelengths in the range of 250 to 700 nm. The photodamage of the Mn-oxo mixed-valence dimer was confirmed by the decrease of its oxygen-evolution activity measured in the presence of the chemical oxidant oxone. Ultraviolet light irradiation induced a new absorption peak at around 400-440 nm of the Mn-oxo mixed-valence dimer. Visible light did not have the same effect on the Mn-oxo mixed-valence dimer. We speculate that the spectral change may be caused by conversion of the Mn(III)O(2)Mn(IV) dimer into a new structure--Mn(IV)O(2)Mn(IV). In the processes, the appearance of a 514 nm fluorescence peak was observed in the solution and may be linked to the hydration or protonation of Terpy ligand in the Mn-oxo dimer. In comparing the response of the PS II functional model compound and the PS II complex to excess light radiation, our results support the idea that UV photoinhibition is triggered at the Mn(4)Ca center of the oxygen-evolution complex in PS II by forming a modified structure, possibly a Mn(IV) species, and that the reaction of Mn ions is likely the initial step. Published by Elsevier B.V.

Synthesis of novel ring-contracted artemisinin dimers with potent anticancer activities.

PubMed

Zhang, Ning; Yu, Zhimei; Yang, Xiaohong; Hu, Ping; He, Yun

2018-04-25

Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC 50 value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers.

PubMed

Sum, Tze Han; Sum, Tze Jing; Galloway, Warren R J D; Collins, Súil; Twigg, David G; Hollfelder, Florian; Spring, David R

2016-09-16

Flavonoids are a large family of compounds associated with a broad range of biologically useful properties. In recent years, synthetic compounds that contain two flavonoid units linked together have attracted attention in drug discovery and development projects. Numerous flavonoid dimer systems, incorporating a range of monomers attached via different linkers, have been reported to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to several favourable attributes including proven biological relevance and metabolic stability) and triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this compound type arguably remains underexplored within drug discovery. Herein, we report a modular strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers and also very rare heterotrimers from readily available starting materials. Application of this strategy has enabled step-efficient and systematic access to a library of structurally diverse compounds of this sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid successfully incorporated.

Separation and purification of four phenolic compounds from persimmon by high-speed counter-current chromatography.

PubMed

Peng, Jinming; Li, Kaikai; Zhu, Wei; Deng, Xiangyi; Li, Chunmei

2018-01-01

An efficient method was established by high-speed counter-current chromatography (HSCCC) for preparation of four phenolic compounds from the depolymerization products of persimmon tannin. Using the two solvent systems of n-hexane/ethyl acetate/water (3:17:20, v/v/v) and ethyl acetate/methanol/water (50:1:50, v/v/v), the preparative isolation was successfully performed by a two-step separation. The yields of one run (150mg crude sample) for gallic acid, methyl gallate, and epigallocatechin-3-gallate-(4β→8, 2β→O→7)-epigallocatechin-3-gallate dimer (A-type EGCG dimer) were 4.7, 44.2 and 5.9mg, respectively. In addition, 4.6mg epicatechin-3-gallate-(4β→8, 2β→O→7)-epicatechin-3-gallate dimer (A-type ECG dimer) was obtained by further preparative high-performance liquid chromatography (prep-HPLC). The purities of these compounds were all above 95.0% and their structures were identified by HPLC/ESI-MS. We found that HSCCC had definite advantages for the preparation of dimeric procyanidins compared with previous methods. Furthermore, it was shown that the four phenolic compounds possessed greater antioxidant activities than Trolox. Copyright © 2017. Published by Elsevier B.V.

Surface defect free growth of a spin dimer TlCuCl{sub 3} compound crystals and investigations on its optical and magnetic properties

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

Ryu, Gihun, E-mail: G.Ryu@fkf.mpg.de; Son, Kwanghyo

A defect-free high quality single crystal of spin dimer TlCuCl{sub 3} compound is firstly synthesized at the optimal growth temperature using the vertical Bridgman method. In this study, we clearly found that the cupric chloride is easily decomposed into the Cl{sup −} deficient composition at ≥470 °C. The Cl{sup −}- related gas phase at the high temperature region also always gives rise to a pinhole-like surface defect at the surface of crystal. Therefore, we clearly verified an exotic anisotropic magnetic behavior (anisotropic ratio of M{sub b}/M{sub (201)} at 2 K, 7 T=10) using the defect-free TlCuCl{sub 3} crystals in thismore » three-dimensional spin dimer TlCuCl{sub 3} compound, relatively stronger magnetic ordering in the H//b than that of H//(201) direction at above the transition magnetic field. - Graphical abstract: A single crystal of spin dimer TlCuCl{sub 3} compound with a defect free is successfully synthesized on the basis of TG/DTA result. We newly found that this cupric chloride compound is easily decomposed into the Cl{sup −} deficient composition at ≥470 °C and Cl{sup −} related gas phases also give rise to the defects like a pinhole on the surface of TlCuCl{sub 3} crystal. Using the crystals with a surface defect free, we also clearly verified the crystal structure of spin dimer TlCuCl{sub 3} compound.« less

Modeling the intermolecular interactions: molecular structure of N-3-hydroxyphenyl-4-methoxybenzamide.

PubMed

Karabulut, Sedat; Namli, Hilmi; Kurtaran, Raif; Yildirim, Leyla Tatar; Leszczynski, Jerzy

2014-03-01

The title compound, N-3-hydroxyphenyl-4-methoxybenzamide (3) was prepared by the acylation reaction of 3-aminophenol (1) and 4-metoxybenzoylchloride (2) in THF and characterized by ¹H NMR, ¹³C NMR and elemental analysis. Molecular structure of the crystal was determined by single crystal X-ray diffraction and DFT calculations. 3 crystallizes in monoclinic P2₁/c space group. The influence of intermolecular interactions (dimerization and crystal packing) on molecular geometry has been evaluated by calculations performed for three different models; monomer (3), dimer (4) and dimer with added unit cell contacts (5). Molecular structure of 3, 4 and 5 was optimized by applying B3LYP method with 6-31G+(d,p) basis set in gas phase and compared with X-ray crystallographic data including bond lengths, bond angles and selected dihedral angles. It has been concluded that although the crystal packing and dimerization have a minor effect on bond lengths and angles, however, these interactions are important for the dihedral angles and the rotational conformation of aromatic rings. Copyright © 2013 Elsevier Inc. All rights reserved.

A new hydroxychavicol dimer from the roots of Piper betle.

PubMed

Lin, Chwan-Fwu; Hwang, Tsong-Long; Chien, Chun-Chien; Tu, Huei-Yu; Lay, Horng-Liang

2013-02-26

A new hydroxychavicol dimer, 2-(g'-hydroxychavicol)-hydroxychavicol (1), was isolated from the roots of Piper betle Linn. along with five known compounds, hydroxychavicol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6). The structures of these isolated compounds were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils.

Lignin‐Derived Thioacidolysis Dimers: Reevaluation, New Products, Authentication, and Quantification

PubMed Central

Yue, Fengxia; Regner, Matt; Sun, Runcang

2017-01-01

Abstract Lignin structural studies play an essential role both in understanding the development of plant cell walls and for valorizing lignocellulosics as renewable biomaterials. Dimeric products released by selectively cleaving β–aryl ether linkages between lignin units reflect the distribution of recalcitrant lignin units, but have been neither absolutely defined nor quantitatively determined. Here, 12 guaiacyl‐type thioacidolysis dimers were identified and quantified using newly synthesized standards. One product previously attributed to deriving from β–1‐coupled units was established as resulting from β–5 units, correcting an analytical quandary. Another longstanding dilemma, that no β–β dimers were recognized in thioacidolysis products from gymnosperms, was resolved with the discovery of two such authenticated compounds. Individual GC response factors for each standard compound allowed rigorous quantification of dimeric products released from softwood lignins, affording insight into the various interunit‐linkage distributions in lignins and thereby guiding the valorization of lignocellulosics. PMID:28125766

Antiplasmodial dimeric chalcone derivatives from the roots of Uvaria siamensis.

PubMed

Salae, Abdul-Wahab; Chairerk, Orapan; Sukkoet, Piyanut; Chairat, Therdsak; Prawat, Uma; Tuntiwachwuttikul, Pittaya; Chalermglin, Piya; Ruchirawat, Somsak

2017-03-01

Four dimeric chalcone derivatives, 8″,9″-dihydrowelwitschin H, uvarins A-C, a naphthalene derivative, 2-hydroxy-3-methoxy-6-(4'- hydroxyphenyl)naphthalene, and the known dimeric chalcones, dependensin and welwitschin E, flavonoids, a cyclohexane oxide derivative, an aromatic aldehyde were isolated from the roots of Uvaria siamensis (Annonaceae). The structures of the compounds were elucidated by spectroscopic analysis, as well as by comparison with literature data. The isolated compounds with a sufficient amount for biological assays were evaluated for their antimalarial, antimycobacterial, and cytotoxic activities. The dimeric chalcones 8″,9″-dihydrowelwitschin H, uvarins B and C, dependensin and welwitschin E showed strong antiplasmodial activity with IC 50 values of 3.10, 3.02, 3.09, 4.21 and 3.99 μg/mL, respectively. A possible biosynthesis pathway of the dimeric chalcones is discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Unusual dimeric tetrahydroxanthone derivatives from Aspergillus lentulus and the determination of their axial chiralities

NASA Astrophysics Data System (ADS)

Li, Tian-Xiao; Yang, Ming-Hua; Wang, Ying; Wang, Xiao-Bing; Luo, Jun; Luo, Jian-Guang; Kong, Ling-Yi

2016-12-01

The research on secondary metabolites of Aspergillus lentulus afforded eight unusual heterodimeric tetrahydroxanthone derivatives, lentulins A-H (2-9), along with the known compound neosartorin (1). Compounds 1-6 exhibited potent antimicrobial activities especially against methicillin-resistant Staphylococci. Their absolute configurations, particularly the axial chiralities, were unambiguously demonstrated by a combination of electronic circular dichroism (ECD), Rh2(OCOCF3)4-induced ECD experiments, modified Mosher methods, and chemical conversions. Interestingly, compounds 1-4 were the first samples of atropisomers within the dimeric tetrahydroxanthone class. Further investigation of the relationships between their axial chiralities and ECD Cotton effects led to the proposal of a specific CD Exciton Chirality rule to determine the axial chiralities in dimeric tetrahydroxanthones and their derivatives.

A new dimeric diarylheptanoid from the rhizomes of Alpinia officinarum.

PubMed

Liu, Dan; Qu, Wei; Zhao, Ling; Guan, Fu-Qin; Liang, Jing-Yu

2014-02-01

To study the chemical constituents of the rhizomes of Alpinia officinarum Hance. Compounds were isolated by repeated column chromatography, and their structures were elucidated on the basis of spectral analysis. The cytotoxic activities of these compounds were evaluated with the T98G and B16F10 cell lines by the MTT assay. A dimeric diarylheptanoid, named alpinin B (1), along with three known diarylheptanoids were obtained, and their structures were identified as alpinin B (1), 1, 7-diphenyl-3,5-heptanedione (2), (4E)-1, 7-diphenylhept-4-en-3-one (3) and (4E)-7- (4-hydroxyphenyl)-1-phenylhept-4-en-3-one (4). Compound 1 is a new dimeric diarylheptanoid. The biosynthetic pathway of 1 was speculated to originate from a Michael reaction between compounds 2 and 3. Compound 3 showed cytotoxicity against the human glioblastoma T98G cell line with IC50 of 27 μmol·L(-1). Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Cytotoxic cassaine diterpenoid-diterpenoid amide dimers and diterpenoid amides from the leaves of Erythrophleum fordii.

PubMed

Du, Dan; Qu, Jing; Wang, Jia-Ming; Yu, Shi-Shan; Chen, Xiao-Guang; Xu, Song; Ma, Shuang-Gang; Li, Yong; Ding, Guang-Zhi; Fang, Lei

2010-10-01

Detailed phytochemical investigation from the leaves of Erythrophleum fordii resulted in the isolation of 13 compounds, including three cassaine diterpenoid-diterpenoid amide dimers (1, 3 and 5), and seven cassaine diterpenoid amides (6 and 8-13), together with three previously reported ones, erythrophlesins D (2), C (4) and 3beta-hydroxynorerythrosuamide (7). Compounds 1, 3 and 5 are further additions to the small group of cassaine diterpenoid dimers represented by erythrophlesins A-D. Their structures were determined by analysis of extensive one- and two-dimensional NMR experiments and ESIMS methods. Cytotoxic activities of the isolated compounds were tested against HCT-8, Bel-7402, BGC-823, A549 and A2780 human cancer cell lines in the MTT test. Results showed that compounds 1 and 3-5 exhibited significantly selective cytotoxic activities (IC(50)<10 microM) against these cells, respectively. Copyright © 2010 Elsevier Ltd. All rights reserved.

Stable dimeric magnesium(I) compounds: from chemical landmarks to versatile reagents.

PubMed

Stasch, Andreas; Jones, Cameron

2011-06-07

The chemistry of the s-block metals is dominated by the +1 oxidation state for the Alkali metals (group 1) and the +2 oxidation state for the Alkaline Earth metals (group 2). In recent years, a series of stable dimeric magnesium(I) compounds has been prepared and their chemistry has started to develop. These complexes feature "deformable" Mg-Mg single bonds and are stabilised by sterically demanding and chelating anionic N-ligands that prevent their disproportionation. They have rapidly proven useful in organic and organometallic/inorganic reduction reactions as hydrocarbon soluble, stoichiometric, selective and safe reducing agents. The scope of this perspective focuses on stable molecular compounds of the general type LMgMgL and describes their synthesis, structures, theoretical and spectroscopic studies as well as their further chemistry. Also, comparisons are drawn with related complexes including magnesium(II) hydrides and dimeric zinc(I) compounds.

Dimeric flavonoids from Arrabidaea brachypoda and assessment of their anti-Trypanosoma cruzi activity.

PubMed

da Rocha, Cláudia Quintino; Queiroz, Emerson Ferreira; Meira, Cássio Santana; Moreira, Diogo Rodrigo Magalhães; Soares, Milena Botelho Pereira; Marcourt, Laurence; Vilegas, Wagner; Wolfender, Jean-Luc

2014-06-27

The nonpolar fraction of an aqueous ethanol extract of the roots of Arrabidaea brachypoda, a Brazilian medicinal plant, demonstrated significant in vitro activity against Trypanosoma cruzi, the parasite responsible for Chagas disease. Targeted isolation of the active constituents led to the isolation of three new dimeric flavonoids (1-3), and their structures were elucidated using UV, NMR, and HRMS analysis, as well as by chemical derivatization. The anti-T. cruzi activity and cytotoxicity toward mammalian cells were determined for these substances. Compound 1 exhibited no activity toward T. cruzi, while flavonoids 2 and 3 exhibited selective activity against these trypomastigotes. Compounds 2 and 3 inhibited the parasite invasion process and its intracellular development in host cells with similar potencies to benznidazole. In addition, compound 2 reduced the blood parasitemia of T. cruzi-infected mice. This study has revealed that these two dimeric flavonoids represent potential anti-T. cruzi lead compounds for further drug development.

Antagonizing STAT3 dimerization with a rhodium(III) complex.

PubMed

Ma, Dik-Lung; Liu, Li-Juan; Leung, Ka-Ho; Chen, Yen-Ting; Zhong, Hai-Jing; Chan, Daniel Shiu-Hin; Wang, Hui-Min David; Leung, Chung-Hang

2014-08-25

Kinetically inert metal complexes have arisen as promising alternatives to existing platinum and ruthenium chemotherapeutics. Reported herein, to our knowledge, is the first example of a substitutionally inert, Group 9 organometallic compound as a direct inhibitor of signal transducer and activator of transcription 3 (STAT3) dimerization. From a series of cyclometalated rhodium(III) and iridium(III) complexes, a rhodium(III) complex emerged as a potent inhibitor of STAT3 that targeted the SH2 domain and inhibited STAT3 phosphorylation and dimerization. Significantly, the complex exhibited potent anti-tumor activities in an in vivo mouse xenograft model of melanoma. This study demonstrates that rhodium complexes may be developed as effective STAT3 inhibitors with potent anti-tumor activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Covalent dimers of 1,3-diphenylisobenzofuran for singlet fission: synthesis and electrochemistry.

PubMed

Akdag, Akin; Wahab, Abdul; Beran, Pavel; Rulíšek, Lubomír; Dron, Paul I; Ludvík, Jiří; Michl, Josef

2015-01-02

The synthesis of covalent dimers in which two 1,3-diphenylisobenzofuran units are connected through one phenyl substituent on each is reported. In three of the dimers, the subunits are linked directly, and in three others, they are linked via an alkane chain. A seventh new compound in which two 1,3-diphenylisobenzofuran units share a phenyl substituent is also described. These materials are needed for investigations of the singlet fission process, which promises to increase the efficiency of solar cells. The electrochemical oxidation and reduction of the monomer, two previously known dimers, and the seven new compounds have been examined, and reversible redox potentials have been compared with results obtained from density functional theory. Although the overall agreement is satisfactory, some discrepancies are noted and discussed.

A dimeric ArC2 compound from Peperomia pellucida.

PubMed

Bayma, J D; Arruda, M S; Müller, A H; Arruda, A C; Canto, W C

2000-12-01

Pellucidin A, a novel dimeric ArC2 compound, together with dill-apiol have been isolated from the aerial parts of Peperomia pellucida. The structure of pellucidin A was established by 1D and 2D NMR spectroscopy (1H-1H COSY; 1H-13C COSY; DEPT; NOESY and double irradiation) and other spectroscopic techniques. The biogenesis of pellucidin A is also briefly discussed.

Photochemically Induced Transformations of Transition Complexes.

DTIC Science & Technology

1993-05-17

simple Iron dinuclear species, the DPPM and DPPE phosphine bridged compounds undergo photolysis in CHCI3 to yield products containing formyl substitued...possible reaction pathway for the synthesis of these two monomers as byproducts In the ruthenium phosphine dimer preparation Is suggested. Full structural...DPPM dimer is also described. In contrast to the behavior of the simple iron dinuclear species, the DPPM and DPPE phosphine bridged compounds undergo

Lignin-Derived Thioacidolysis Dimers: Reevaluation, New Products, Authentication, and Quantification

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

Yue, Fengxia; Lu, Fachuang; Regner, Matt

2017-01-26

Lignin structural studies play an essential role both in understanding the development of plant cell walls and for valorizing lignocellulosics as renewable biomaterials. Dimeric products released by selectively cleaving β–aryl ether linkages between lignin units reflect the distribution of recalcitrant lignin units, but have been neither absolutely defined nor quantitatively determined. Here in this work, 12 guaiacyl-type thioacidolysis dimers were identified and quantified using newly synthesized standards. One product previously attributed to deriving from β–1-coupled units was established as resulting from β–5 units, correcting an analytical quandary. Another longstanding dilemma, that no β–β dimers were recognized in thioacidolysis products frommore » gymnosperms, was resolved with the discovery of two such authenticated compounds. Finally, individual GC response factors for each standard compound allowed rigorous quantification of dimeric products released from softwood lignins, affording insight into the various interunit-linkage distributions in lignins and thereby guiding the valorization of lignocellulosics.« less

Lignin-Derived Thioacidolysis Dimers: Reevaluation, New Products, Authentication, and Quantification.

PubMed

Yue, Fengxia; Lu, Fachuang; Regner, Matt; Sun, Runcang; Ralph, John

2017-03-09

Lignin structural studies play an essential role both in understanding the development of plant cell walls and for valorizing lignocellulosics as renewable biomaterials. Dimeric products released by selectively cleaving β-aryl ether linkages between lignin units reflect the distribution of recalcitrant lignin units, but have been neither absolutely defined nor quantitatively determined. Here, 12 guaiacyl-type thioacidolysis dimers were identified and quantified using newly synthesized standards. One product previously attributed to deriving from β-1-coupled units was established as resulting from β-5 units, correcting an analytical quandary. Another longstanding dilemma, that no β-β dimers were recognized in thioacidolysis products from gymnosperms, was resolved with the discovery of two such authenticated compounds. Individual GC response factors for each standard compound allowed rigorous quantification of dimeric products released from softwood lignins, affording insight into the various interunit-linkage distributions in lignins and thereby guiding the valorization of lignocellulosics. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Determination of Abraham model solute descriptors for the monomeric and dimeric forms of trans-cinnamic acid using measured solubilities from the Open Notebook Science Challenge.

PubMed

Bradley, Jean-Claude; Abraham, Michael H; Acree, William E; Lang, Andrew Sid; Beck, Samantha N; Bulger, David A; Clark, Elizabeth A; Condron, Lacey N; Costa, Stephanie T; Curtin, Evan M; Kurtu, Sozit B; Mangir, Mark I; McBride, Matthew J

2015-01-01

Calculating Abraham descriptors from solubility values requires that the solute have the same form when dissolved in all solvents. However, carboxylic acids can form dimers when dissolved in non-polar solvents. For such compounds Abraham descriptors can be calculated for both the monomeric and dimeric forms by treating the polar and non-polar systems separately. We illustrate the method of how this can be done by calculating the Abraham descriptors for both the monomeric and dimeric forms of trans-cinnamic acid, the first time that descriptors for a carboxylic acid dimer have been obtained. Abraham descriptors were calculated for the monomeric form of trans-cinnamic acid using experimental solubility measurements in polar solvents from the Open Notebook Science Challenge together with a number of water-solvent partition coefficients from the literature. Similarly, experimental solubility measurements in non-polar solvents were used to determine Abraham descriptors for the trans-cinnamic acid dimer. Abraham descriptors were calculated for both the monomeric and dimeric forms of trans-cinnamic acid. This allows for the prediction of further solubilities of trans-cinnamic acid in both polar and non-polar solvents with an error of about 0.10 log units. Graphical abstractMolar concentration of trans-cinnamic acid in various polar and non-polar solvents.

Cytotoxic bibenzyl dimers from the stems of Dendrobium fimbriatum Hook.

PubMed

Xu, Feng-Qing; Xu, Fang-Cheng; Hou, Bo; Fan, Wei-Wei; Zi, Cheng-Ting; Li, Yan; Dong, Fa-Wu; Liu, Yu-Qing; Sheng, Jun; Zuo, Zhi-Li; Hu, Jiang-Miao

2014-11-15

The bioassay-guided chemical investigation of the stems of Dendrobium fimbriatum Hook led to the isolation of seven first reported bibenzyl dimers with a linkage of a methylene moiety, fimbriadimerbibenzyls A-G (1-7), together with a new dihydrophenanthrene derivative (S)-2,4,5,9-tetrahydroxy-9,10-dihydrophenanthrene (8) and thirteen known compounds (9-21). The structure of the new compound was established by spectroscopic analysis. Biological evaluation of bibenzyl derivatives against five human cell lines indicated that seven of those compounds exhibited broad-spectrum and cytotoxic activities with IC50 values ranging from 2.2 to 21.2 μM. Those rare bibenzyl dimers exhibited cytotoxic activities in vitro and the cytotoxicity decreased as the number of oxygen-containing groups in the structure decreases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Flavonol dimers from callus cultures of Dysosma versipellis and their in vitro neuraminidase inhibitory activities.

PubMed

Chen, Ridao; Duan, Ruigang; Wei, Yannan; Zou, Jianhua; Li, Junwei; Liu, Xiaoyue; Wang, Haiyan; Guo, Ying; Li, Qiuhong; Dai, Jungui

2015-12-01

A chemical investigation of callus cultures of Dysosma versipellis led to the isolation of five new flavonol dimers, dysoverines A-E (1-5), together with 12 known compounds (6-17). The structures of new compounds were determined by the extensive spectroscopic data analyses. The biosynthetic pathway of the new compounds was proposed to involve O-methylation, prenylation, and Diels-Alder cycloaddition, which successively occurred in cultured plant cells. Compounds 1-17 exhibited in vitro neuraminidase inhibitory activities with the IC50 values of 31.0-93.9μM. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel Isochroman Dimers from Stachybotrys sp. PH30583: Fermentation, Isolation, Structural Elucidation and Biological Activities.

PubMed

Li, Wei; Yang, Ya-Bin; Yang, Xue-Qiong; Xie, Hui-Ding; Shao, Zhi-Hui; Zhou, Hao; Miao, Cui-Ping; Zhao, Li-Xing; Ding, Zhong-Tao

2017-05-01

The rare anishidiol and five new isochromans, including three novel dimers with unprecedented skeletons, were isolated from Stachybotrys sp. PH30583. Their structures were determined by spectral analyses. The bioactivities of these compounds were also investigated. The dimers ( 6 - 10 ) inhibited acetylcholinesterase at 50 µM, but the monomers did not. To investigate the biogenesis of the novel dimers, a time-course investigation of metabolite production was undertaken. Georg Thieme Verlag KG Stuttgart · New York.

Acylphenols and dimeric acylphenols from Myristica maxima Warb.

PubMed

Othman, Muhamad Aqmal; Sivasothy, Yasodha; Looi, Chung Yeng; Ablat, Abdulwali; Mohamad, Jamaludin; Litaudon, Marc; Awang, Khalijah

2016-06-01

Giganteone E (1), a new dimeric acylphenol was isolated as a minor constituent from the bark of Myristica maxima Warb. The structure of 1 was established on the basis of 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Malabaricones A-C (2-4), giganteones A and C (5 and 6), maingayones A and B (7 and 8), maingayic acid B (9) and β-sitosteryl oleate (10) were also characterized in this plant for the first time. Compound 10 was identified for the first time in the Myristicaceae. Compounds 2 and 5 were active against human prostate cancer cell-lines, thus making this the first report on the prostate cancer inhibiting potential of acylphenols and dimeric acylphenols. Compounds 1, 4, 5, 7 and 8 exhibited potent DPPH free radical scavenging activity. This is the first report on their free radical scavenging capacity. Copyright © 2016. Published by Elsevier B.V.

Isolation and purification of two antioxidant isomers of resveratrol dimer from the wine grape by counter-current chromatography.

PubMed

Kong, Qingjun; Ren, Xueyan; Hu, Ruilin; Yin, Xuefeng; Jiang, Guoshan; Pan, Yuanjiang

2016-06-01

Resveratrol dimers belong to a group of compounds called stilbenes, which along with proanthocyanidins, anthocyanins, catechins, and flavonols are natural phenolic compounds found in grapes and red wine. Stilbenes have a variety of structural isomers, all of which exhibit various biological properties. Counter-current chromatography with a two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water (2:5:4:5, v/v/v/v) was applied to isolate and purify stilbene from the stems of wine grape. Two isomers of resveratrol dimers trans-ε-viniferin and trans-δ-viniferin were obtained from the crude sample in a one-step separation, with purities of 93.2 and 97.5%, respectively, as determined by high-performance liquid chromatography. The structures of these two compounds were identified by (1) H and (13) C NMR spectroscopy. In addition, their antioxidant activities were assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The antioxidant activities of trans-δ-viniferin were higher than that of trans-ε-viniferin in this model. This work demonstrated that counter-current chromatography is a powerful and effective method for the isolation and purification of polyphenols from wine grape. Additionally, the DPPH radical assay showed that the isolated component trans-δ-viniferin exhibited stronger antioxidant activities than trans-ε-viniferin and a little bit weaker than vitamin E at the same concentration. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ru(II)-Catalyzed Cross-Coupling of Cyclopropenes with Diazo Compounds: Formation of Olefins from Two Different Carbene Precursors.

PubMed

Wang, Bo; Yi, Heng; Zhang, Hang; Sun, Tong; Zhang, Yan; Wang, Jianbo

2018-01-19

Formal carbene dimerization is a convergent method for the synthesis of alkenes. Herein, we report a Ru(II)-catalyzed carbene dimerization of cyclopropenes and diazo compounds. The yields are up to 97% and the stereoselectivity are up to >20:1. Mechanistically, it has been experimentally demonstrated that the catalyst reacts with cyclopropene first to generate a Ru(II)-carbene species, which is attacked by nucleophilic diazo substrate, followed by dinitrogen extrusion to form the double bond.

Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor.

PubMed

Bongard, Robert D; Lepley, Michael; Thakur, Khushabu; Talipov, Marat R; Nayak, Jaladhi; Lipinski, Rachel A Jones; Bohl, Chris; Sweeney, Noreena; Ramchandran, Ramani; Rathore, Rajendra; Sem, Daniel S

2017-05-31

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC 50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC 50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

Xylopiana A, a Dimeric Guaiane with a Case-Shaped Core from Xylopia vielana: Structural Elucidation and Biomimetic Conversion.

PubMed

Zhang, Ya-Long; Zhou, Xu-Wei; Wang, Xiao-Bing; Wu, Lin; Yang, Ming-Hua; Luo, Jun; Yin, Yong; Luo, Jian-Guang; Kong, Ling-Yi

2017-06-02

Xylopiana A (1), a dimeric guaiane with an unprecedented pentacyclo[5.2.1.0 1,2 .0 4,5' .0 5,4' ]decane-3,2'-dione core, and three biosynthetically related intermediates, compounds 2-4, were isolated from the leaves of Xylopia vielana. Their structures and absolute configurations were determined by a combination of spectroscopic data, X-ray crystallography, electronic circular dichroism calculations, and chemical conversion. The structure of known vielanin A was revised to be compound 3. Compound 4 exerted a 3.7-fold potentiation effect on doxorubicin susceptibility at the tested concentration of 10 μM.

Temperature dependence of the effective interdimer exchange interaction in a weakly coupled antiferromagnetic dimer copper compound

NASA Astrophysics Data System (ADS)

Calvo, Rafael; Santana, Vinicius T.; Nascimento, Otaciro R.

2017-08-01

We report a variation with temperature T of the effective interdimeric interaction Jeff' in the antiferromagnetic (AFM) copper dimeric organic compound Cu2[TzTs] 4 (N -thiazol-2-yl-toluenesulfonamidate CuII). This T dependence was obtained from measurements of the effects in the electron paramagnetic resonance (EPR) spectra of the proposed quantum phase transition associated with the exchange-narrowing processes. Cu2[TzTs] 4 contains exchange-coupled pairs of CuII spins SA and SB (S =1 /2 ), with intradimeric AFM exchange coupling J0=(-115 ±1 ) cm-1 (Hex=-J0SA.SB ). The variation of the EPR linewidth of single crystals with field orientation around a "magic angle" where the transitions intersect and the integrated signal intensity of the so-called U peak of the powder spectrum were measured as a function of T . Modeling these data using arguments of exchange narrowing in the adiabatic regime considering the angular variation of the single-crystal spectra and a geometric description, we find that the effective interdimeric coupling | Jeff'| associated with the exchange frequency ωex is negligible for T ≪| J0/kB| when the units are uncoupled and | Jeff'|=(0.080 ±0.005 ) cm-1 (| Jeff'/J0|=7.0 × 10-4 ) at 298 K. Within this T interval, two ranges of | Jeff'| with linear temperature variation but different slopes, with a kink at ˜80 K, are observed and discussed. This T dependence arises from the growing population of the triplet state, and its relevance to the properties of various arrays of dimeric units is discussed. Our experimental procedures and results are compared with those of previous works in ion radical salts and dimeric metal compounds. The relation between the effective coupling | Jeff'| and the real interdimeric exchange coupling | J'| related to the chemical paths connecting neighbor units is discussed.

Toll-like Receptors as a Target of Food-derived Anti-inflammatory Compounds*

PubMed Central

Shibata, Takahiro; Nakashima, Fumie; Honda, Kazuya; Lu, Yu-Jhang; Kondo, Tatsuhiko; Ushida, Yusuke; Aizawa, Koichi; Suganuma, Hiroyuki; Oe, Sho; Tanaka, Hiroshi; Takahashi, Takashi; Uchida, Koji

2014-01-01

Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co-expressing TLR with the NF-κB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4′-O-β-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds. PMID:25294874

A comprehensive study of the optoelectronic properties of donor-acceptor based derivatives of 1,3,4-oxadiazole

NASA Astrophysics Data System (ADS)

Joshi, Ankita; Ramachandran, C. N.

2017-07-01

A variety of 1,3,4-oxadiazole derivatives based on electron- donor pyrrole and -acceptor nitro groups are modelled. Various isomers of pyrole-oxadiazole-nitro unit and its dimer linked to substituted and unsubstituted phenyl group are studied using the dispersion corrected density functional theoretical method. The electron density distribution in frontier orbitals of the phenyl-spacer compounds bearing amino and phenylamino groups indicates the possibility of intramolecular charge transfer. The isomers of phenyl-spacer compounds absorb in visible region of electromagnetic spectrum. The compounds show high values of light harvesting efficiency, despite the weak anchoring nature of nitro groups.

Lignin dimers: Structures, distribution, and potential geochemical applications

NASA Astrophysics Data System (ADS)

Goñi, Miguel A.; Hedges, John I.

1992-11-01

An extensive suite of thirty lignin-derived phenolic dimers and fourteen additional monomers has been identified among the CuO reaction products of twenty-four different vascular plant tissues. The various lignin dimers are characterized by five different types of linkages between phenolic units, including direct 5,5'-ring-ring bonding, as well as β,1-diketone, α,1-monoketone, α,5-monoketone, and α,2-methyl sidechain-ring couplings. The new lignin-derived monomeric CuO reaction products include vanillyl and syringyl glyoxalic acids and vanillyl phenols with formyl and carboxyl functional groups attached at various ring positions. The distribution of all these novel compounds in twenty-four different vascular plant tissues indicates important differences in the structure and chemical composition of the lignin macromolecule among these sources. The abundances of these compounds in a selected set of sedimentary samples suggest that the lignin dimers and novel lignin monomers can characterize the ultrastructure, sources, and diagenetic state of sedimentary lignin in ways not possible from the routinely utilized lignin monomers alone.

Different β-alanine dimeric forms in trifluoromethanesulfonic acid salts. XRD and vibrational studies.

PubMed

Wołoszyn, Łukasz; Ilczyszyn, Maria M

2018-03-15

Two new crystalline salts: β-alaninium trifluoromethanesulfonate (β-AlaOTf) and bis(β-alanine) trifluoromethanesulfonate (β-2AlaOTf) were obtained. The former one contains diprotonated β-alanine dimer, the latter one monoprotonated β-alanine dimer. Both compounds were studied by single crystal XRD, vibrational (IR and Raman) spectroscopy and calorimetric method. The quantum-mechanical calculations (DFT/B3LYP/6-311++G(2d,2p)) for the diprotonated dimer were carried out. The β-AlaOTf salt crystallizes in the P1¯ space group of triclinic system (Z=2), the β-2AlaOTf in the P2 1 /m space group of monoclinic system (Z=2). The vibrational data for the studied compounds are discussed in relation to their crystal structure, and provide insight into the character of hydrogen bonds and β-alanine protonation. The studied crystals do not exhibit phase transitions in the solid state. Copyright © 2017 Elsevier B.V. All rights reserved.

Proanthocyanidin screening by LC-ESI-MS of Portuguese red wines made with teinturier grapes.

PubMed

Teixeira, Natércia; Azevedo, Joana; Mateus, Nuno; de Freitas, Victor

2016-01-01

Proanthocyanidins (PAs) are one of the most important polyphenolic compounds in wine. Among PAs, prodelphinidin (PD) dimers and trimers have not been widely detected in wines due to the lack of available commercial standards and the difficulty to detect and isolate them from natural sources. LC-ESI-MS (liquid chromatography-electrospray ionization-mass spectrometry) with the right chromatographic conditions has proven to be a powerful tool for PAs detection and identification in complex samples. This technique has been applied to an exhaustive study of PA composition of two Portuguese red wines made with teinturier grapes, especially for the identification of PD dimers and trimers. Tandem mass spectrometry (MS/MS) with ion trap provided additional information about the structures of these compounds through the fragmentation patterns of the pseudomolecular ions. A LC-ESI-MS method was optimized and 41 different compounds were found. Among them are included 8 PD dimers and 13 PD trimers. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pyrolysis reaction networks for lignin model compounds: unraveling thermal deconstruction of β-O-4 and α-O-4 compounds

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

Choi, Yong S.; Singh, Rahul; Zhang, Jing

2016-01-01

Although lignin is one of the main components of biomass, its pyrolysis chemistry is not well understood due to complex heterogeneity. To gain insights into this chemistry, the pyrolysis of seven lignin model compounds (five ..beta..-O-4 and two ..alpha..-O-4 linked molecules) was investigated in a micropyrolyzer connected to GC-MS/FID. According to quantitative product mole balance for the reaction networks, concerted retro-ene fragmentation and homolytic dissociation were strongly suggested as the initial reaction step for ..beta..-O-4 compounds and ..alpha..-O-4 compounds, respectively. The difference in reaction pathway between compounds with different linkages was believed to result from thermodynamics of the radical initiation.more » The rate constants for the different reaction pathways were predicted from ab initio density functional theory calculations and pre-exponential literature values. The computational findings were consistent with the experiment results, further supporting the different pyrolysis mechanisms for the ..beta..-ether linked and ..alpha..-ether linked compounds. A combination of the two pathways from the dimeric model compounds was able to describe qualitatively the pyrolysis of a trimeric lignin model compound containing both ..beta..-O-4 and ..alpha..-O-4 linkages.« less

New salts of amino acids with dimeric cations

NASA Astrophysics Data System (ADS)

Ghazaryan, V. V.; Fleck, M.; Petrosyan, A. M.

2010-10-01

Among salts of amino acids there are compounds with the composition 2A..HX, which consist of dimeric A...A+ cations with short symmetric or asymmetric hydrogen bonds between zwitter-ionic and protonated moieties. These species are materials liable to undergo phase transitions or possess interesting nonlinear optical properties. Here, we report the preparation of 20 new salts with dimeric cations from aqueous solutions, including compounds of glycine, betaine, β- alanine, L-alanine, L-phenylalanine, L-threonine, L-valine, L-leucine and L-proline, with BF4-, ClO4-, Cl-, Br-, HSeO3-, and HC2O4-; as anions. The prepared salts are characterized by IR and Raman spectroscopy. Some of them are grown in form of good quality single crystals, which allowed the determination of their crystal structure.

DFT analysis of the structure and IR spectrum of potassium salt of diphenylsulfophthalide - A model compound for polydiphenylenesulfophthalide salts

NASA Astrophysics Data System (ADS)

Shishlov, N. M.; Akhmetzyanov, Sh S.; Khursan, S. L.

2017-02-01

Experimental IR spectra of crystalline dried and non-dried potassium diphenylsulfophthalide (TAC-K) as a model compound for polymeric salts are presented. DFT analysis (B3LYP/6-311G(d,p)) of the structure and IR spectra of a series of compounds similar in structure to TAC-K as well as their dimers indicates that the sulfonate group environment strongly affects the positions of absorption bands (ABs) of vibrations of Ssbnd O bonds and demonstrates that information on the exact structure of ion clusters is needed for reliable and unambiguous assignment of the ABs in experimental IR spectra of real sulfonate ion containing systems to particular vibrational modes. Various ways of metal ion coordination with sulfonate ion, as well as their reflection in IR spectra of model compounds, are considered and discussed. Using TAC-K as an example, the effect of an intramolecular hydrogen bond on the vibrational modes of sulfonate group and hydroxy group is considered. The effect of ion aggregation on the shape of the IR spectrum of TAC-K is analyzed for an energetically favorable dimer of this salt as an example. Based on a combination of calculated, literature and reference data, a number of ABs in the IR spectra of TAC-K have been tentatively assigned. In particular, the bands in the region of 3230-3180 cm-1 have been assigned to ν(Osbnd H); those at 1240-1160 cm-1, to νas(SO3-); the AB at 1080 cm-1, to νs(SO3-); that at 616 cm-1, to δ(oop)s(SO3-); and that at 570 cm-1, to δ(ip)as(SO3-).

Structure and Energetics of Clusters Relevant to Thorium Tetrachloride Melts

NASA Astrophysics Data System (ADS)

Akdeniz, Z.; Tosi, M. P.

2000-10-01

We study within an ionic model the structure and energetics of neutral and charged molecular clusters which may be relevant to molten ThCl4 and to its liquid mixtures with alkali chlorides, with reference to Raman scattering experiments by Photiadis and Papatheodorou. As stressed by these authors, the most striking facts for ThCl4 in comparison to other tetrachloride compounds (and in particular to ZrCl4) are the appreciable ionic conductivity of the pure melt and the continuous structural changes which occur in the melt mixtures with varying composition. After adjusting our model to data on the isolated ThCl4 tetrahedral molecule, we evaluate (i) the Th2Cl8 dimer and the singly charged species obtained from it by chlorine-ion transfer between two such neutral dimers; (ii) the ThCl6 and ThCl7 clusters both as charged anions and as alkali-compensated species; and (iii) various oligomers carrying positive or negative double charges. Our study shows that the characteristic structural properties of the ThCl4 compound and of the alkali-Th chloride systems are the consequence of the relatively high ionic character of the binding, which is already evident in the isolated ThCl4 monomer.

Dehalogenation of Chlorinated Hydroxybiphenyls by Fungal Laccase

PubMed Central

Schultz, Asgard; Jonas, Ulrike; Hammer, Elke; Schauer, Frieder

2001-01-01

We have investigated the transformation of chlorinated hydroxybiphenyls by laccase produced by Pycnoporus cinnabarinus. The compounds used were transformed to sparingly water-soluble colored precipitates which were identified by gas chromatography-mass spectrometry as oligomerization products of the chlorinated hydroxybiphenyls. During oligomerization of 2-hydroxy-5-chlorobiphenyl and 3-chloro-4-hydroxybiphenyl, dechlorinated C—C-linked dimers were formed, demonstrating the dehalogenation ability of laccase. In addition to these nonhalogenated dimers, both monohalogenated and dihalogenated dimers were identified. PMID:11526052

An ionic force-field study of monomers, dimers and higher polymers in pentafluoride vapors

NASA Astrophysics Data System (ADS)

Çiçek Önem, Z.; Akdeniz, Z.; Tosi, M. P.

2008-08-01

Pentafluoride compounds such as NbF 5 and TaF 5 have been reported in the literature to admit various states of polymerization coexisting with monomers in their vapor phase, in relative concentrations that vary with temperature and pressure. We construct a microscopic interionic force-field model for the molecular monomer of these compounds (including VF 5, SbF 5 and MoF 5 in addition to NbF 5 and TaF 5), the stable form of the monomer being in the shape of a D 3h trigonal bipyramid in all cases. The model emulates chemical bonds by allowing for electrical and short-range overlap polarizabilities of the fluorines, and is used to evaluate the structure and the stability of (MF 5) n molecules with n running from 2 to 6. The dimer is formed by two distorted edge-sharing octahedral, while the trimer and the higher polymers can form rings of distorted corner-sharing octahedra. A chain-like configuration is also found for the trimer of NbF 5, which consists of a seven-fold coordinated Nb bonded to two distorted octahedra via edge sharing. Comparison of calculated vibrational frequencies and bond lengths with experimental data is made whenever possible. We find that there is a small net gain of energy in the formation of a dimer, while otherwise the static energy of the n-mer is very close to that of n separated monomers. High sensitivity of the state of molecular aggregation to the thermodynamic conditions of the vapor is clearly indicated by our calculations.

(M)- and (P)-bicelaphanol A, dimeric trinorditerpenes with promising neuroprotective activity from Celastrus orbiculatus.

PubMed

Wang, Luo-Yi; Wu, Jian; Yang, Zhuo; Wang, Xu-Jie; Fu, Yan; Liu, Shuang-Zhu; Wang, Hong-Min; Zhu, Wei-Liang; Zhang, Hai-Yan; Zhao, Wei-Min

2013-04-26

(M)-Bicelaphanol A (1) and (P)-bicelaphanol A (2), two unprecedented dimeric trinorditerpenes existing as atropisomers, together with their monomer celaphanol A (3), were isolated from the root bark of Celastrus orbiculatus. The structures and absolute configurations of 1 and 2 were determined by spectroscopic and single-crystal X-ray diffraction analyses. Compound 1 exhibited a significant in vitro neuroprotective effect against a hydrogen peroxide-induced cell viability decrease in PC12 cells at 1 μM, while compounds 2 and 3 showed such effects at 10 μM.

Synthesis of monomeric and dimeric steroids containing [1,2,4]triazolo[1,5-a]pyrimidines.

PubMed

Arenas-González, Ailed; Mendez-Delgado, Luis Antonio; Merino-Montiel, Penélope; Padrón, José M; Montiel-Smith, Sara; Vega-Báez, José Luis; Meza-Reyes, Socorro

2016-12-01

The synthesis of several monomeric and dimeric steroidal [1,2,4]triazolo[1,5-a]pyrimidines (TPs) derived from steroids are described. These derivatives were prepared from α,β-unsaturated carbonyl compounds through a Claisen Schmidt condensation and rearrangement of the spiro moiety followed by a cycloaddition with 3-amino-1,2,4-triazole. The antiproliferative activity of compounds 7, 13-15 was tested against human cancer cells; several IG 50 values were below 10μM. Copyright © 2016 Elsevier Inc. All rights reserved.

Two novel dicarboxylic Acid derivatives and a new dimeric hydrolyzable tannin from walnuts.

PubMed

Ito, Hideyuki; Okuda, Takahiro; Fukuda, Toshiyuki; Hatano, Tsutomu; Yoshida, Takashi

2007-02-07

In addition to the 16 previously reported polyphenols including 3 new ellagitannins, 2 novel dicarboxylic acid derivatives, glansreginins A (1) and B (2), and a new dimeric hydrolyzable tannin, glansrin D (3), were isolated, together with 15 known compounds from walnuts, the seeds of Juglans regia. The structures of the new compounds were elucidated on the basis of 1D- and 2D-NMR analyses and chemical data. The antioxidant effect of these isolates was also evaluated by SOD-like and DPPH radical scavenging activities.

A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells

PubMed Central

Peng, Jian-long; Wang, Shi-jie; Geng, Jie-jie; Liu, Ji-de; Feng, Fei; Song, Fei; Li, Ling; Zhu, Ping; Jiang, Jian-li; Chen, Zhi-nan

2016-01-01

CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression. PMID:26882566

A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.

PubMed

Fu, Zhi-guang; Wang, Li; Cui, Hong-yong; Peng, Jian-long; Wang, Shi-jie; Geng, Jie-jie; Liu, Ji-de; Feng, Fei; Song, Fei; Li, Ling; Zhu, Ping; Jiang, Jian-li; Chen, Zhi-nan

2016-02-23

CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.

Synthesis of Artemisinin-Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action.

PubMed

Fröhlich, Tony; Hahn, Friedrich; Belmudes, Lucid; Leidenberger, Maria; Friedrich, Oliver; Kappes, Barbara; Couté, Yohann; Marschall, Manfred; Tsogoeva, Svetlana B

2018-06-07

Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC 50 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC 50 2.4 nm), artesunic acid (EC 50 8.9 nm) and chloroquine (EC 50 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC 50 value of 0.026 μm, representing an even higher activity than the two reference drugs ganciclovir (EC 50 2.60 μm) and artesunic acid (EC 50 5.41 μm). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sulphur shuttling across a chaperone during molybdenum cofactor maturation.

PubMed

Arnoux, Pascal; Ruppelt, Christian; Oudouhou, Flore; Lavergne, Jérôme; Siponen, Marina I; Toci, René; Mendel, Ralf R; Bittner, Florian; Pignol, David; Magalon, Axel; Walburger, Anne

2015-02-04

Formate dehydrogenases (FDHs) are of interest as they are natural catalysts that sequester atmospheric CO2, generating reduced carbon compounds with possible uses as fuel. FDHs activity in Escherichia coli strictly requires the sulphurtransferase EcFdhD, which likely transfers sulphur from IscS to the molybdenum cofactor (Mo-bisPGD) of FDHs. Here we show that EcFdhD binds Mo-bisPGD in vivo and has submicromolar affinity for GDP-used as a surrogate of the molybdenum cofactor's nucleotide moieties. The crystal structure of EcFdhD in complex with GDP shows two symmetrical binding sites located on the same face of the dimer. These binding sites are connected via a tunnel-like cavity to the opposite face of the dimer where two dynamic loops, each harbouring two functionally important cysteine residues, are present. On the basis of structure-guided mutagenesis, we propose a model for the sulphuration mechanism of Mo-bisPGD where the sulphur atom shuttles across the chaperone dimer.

Iterative Mechanism of Macrodiolide Formation in the Anticancer Compound Conglobatin.

PubMed

Zhou, Yongjun; Murphy, Annabel C; Samborskyy, Markiyan; Prediger, Patricia; Dias, Luiz Carlos; Leadlay, Peter F

2015-06-18

Conglobatin is an unusual C2-symmetrical macrodiolide from the bacterium Streptomyces conglobatus with promising antitumor activity. Insights into the genes and enzymes that govern both the assembly-line production of the conglobatin polyketide and its dimerization are essential to allow rational alterations to be made to the conglobatin structure. We have used a rapid, direct in vitro cloning method to obtain the entire cluster on a 41-kbp fragment, encoding a modular polyketide synthase assembly line. The cloned cluster directs conglobatin biosynthesis in a heterologous host strain. Using a model substrate to mimic the conglobatin monomer, we also show that the conglobatin cyclase/thioesterase acts iteratively, ligating two monomers head-to-tail then re-binding the dimer product and cyclizing it. Incubation of two different monomers with the cyclase produces hybrid dimers and trimers, providing the first evidence that conglobatin analogs may in future become accessible through engineering of the polyketide synthase. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sulphur shuttling across a chaperone during molybdenum cofactor maturation

NASA Astrophysics Data System (ADS)

Arnoux, Pascal; Ruppelt, Christian; Oudouhou, Flore; Lavergne, Jérôme; Siponen, Marina I.; Toci, René; Mendel, Ralf R.; Bittner, Florian; Pignol, David; Magalon, Axel; Walburger, Anne

2015-02-01

Formate dehydrogenases (FDHs) are of interest as they are natural catalysts that sequester atmospheric CO2, generating reduced carbon compounds with possible uses as fuel. FDHs activity in Escherichia coli strictly requires the sulphurtransferase EcFdhD, which likely transfers sulphur from IscS to the molybdenum cofactor (Mo-bisPGD) of FDHs. Here we show that EcFdhD binds Mo-bisPGD in vivo and has submicromolar affinity for GDP—used as a surrogate of the molybdenum cofactor’s nucleotide moieties. The crystal structure of EcFdhD in complex with GDP shows two symmetrical binding sites located on the same face of the dimer. These binding sites are connected via a tunnel-like cavity to the opposite face of the dimer where two dynamic loops, each harbouring two functionally important cysteine residues, are present. On the basis of structure-guided mutagenesis, we propose a model for the sulphuration mechanism of Mo-bisPGD where the sulphur atom shuttles across the chaperone dimer.

Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

PubMed Central

Ballet, Steven; Marczak, Ewa D.; Feytens, Debby; Salvadori, Severo; Sasaki, Yusuke; Abell, Andrew D.; Lazarus, Lawrence H.; Balboni, Gianfranco; Tourwé, Dirk

2010-01-01

The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and balanced δ/μ antagonists, as determined by the functional [S35]GTPγS binding assay, the dimerization of potent Aia-based ‘parent’ ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds. PMID:20137938

Spin-Orbit Dimers and Noncollinear Phases in d1 Cubic Double Perovskites

NASA Astrophysics Data System (ADS)

Romhányi, Judit; Balents, Leon; Jackeli, George

2017-05-01

We formulate and study a spin-orbital model for a family of cubic double perovskites with d1 ions occupying a frustrated fcc sublattice. A variational approach and a complementary analytical analysis reveal a rich variety of phases emerging from the interplay of Hund's rule and spin-orbit coupling. The phase digram includes noncollinear ordered states, with or without a net moment, and, remarkably, a large window of a nonmagnetic disordered spin-orbit dimer phase. The present theory uncovers the physical origin of the unusual amorphous valence bond state experimentally suggested for Ba2B Mo O6 (B =Y , Lu) and predicts possible ordered patterns in Ba2B Os O6 (B =Na , Li) compounds.

Berry Phenolic Compounds Increase Expression of Hepatocyte Nuclear Factor-1α (HNF-1α) in Caco-2 and Normal Colon Cells Due to High Affinities with Transcription and Dimerization Domains of HNF-1α

PubMed Central

Real Hernandez, Luis M.; Fan, Junfeng; Johnson, Michelle H.; Gonzalez de Mejia, Elvira

2015-01-01

Hepatocyte nuclear factor-1α (HNF-1α) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1α. By studying the interactions of compounds from berries and citrus fruits have with HNF-1α, pre-transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF-1α were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1α. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1α was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1α expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes. PMID:26413797

Unexpected dimerization of isoprene in a gas chromatography inlet. A study by gas chromatography/mass spectrometry coupling.

PubMed

Estevez, Yannick; Gardrat, Christian; Berthelot, Karine; Grau, Etienne; De Jeso, Bernard; Ouardad, Samira; Peruch, Frédéric

2014-02-28

During analysis of pure isoprene by gas chromatography/mass spectrometry (GC-MS) using a programmed temperature vaporization (PTV) inlet, the presence of several isoprene dimers was detected in the total ion chromatograms (TICs). This study intends to determine the part of the instrument where dimerization occurs and the relative importance of the dimer amounts under different experimental conditions. The reference thermal dimerization of isoprene gives four six-membered cyclic dimers and two eight-membered ones. In all samples containing different amounts of freshly distilled isoprene, only peaks corresponding to the former appeared in TICs. For the same temperature, their amounts increase as the concentration of injected isoprene increases. The main products are diprene (from 80 to 100%) of the total dimers and dipentene (from 1 to 14%). The sum of the two other dimers is never higher than 6%. In conclusion, isomeric dimers are produced through a dimerization in the inlet. No dimerization of isoprene occurs in the mass spectrometer source. Then care is needed when analyzing terpenic compounds in the presence of isoprene by GC-MS because structures, retention times and mass spectra of diprene and dipentene are close. Copyright © 2014 Elsevier B.V. All rights reserved.

The Reach of Linear Protein-DNA Dimerizers

PubMed Central

Stafford, Ryan L.; Dervan, Peter B.

2008-01-01

A protein-DNA dimerizer constructed from a DNA-binding pyrrole-imidazole polyamide and the peptide FYPWMK facilitates binding of the natural transcription factor Exd to an adjacent DNA site. Previous dimerizers have been constructed with the peptide attached to an internal pyrrole monomer in an overall branched oligomer. Linear oligomers constructed by attaching the peptide to the polyamide C-terminus expand the range of protein-DNA dimerization to six additional DNA sites. Replacing the FYPWMK hexapeptide with a WM dipeptide, which was previously functional in branched compounds, does not lead to a functional linear dimerizer. Instead, inserting an additional lysine generates a minimal, linear WMK tripeptide conjugate that maintains the activity of the larger FYPWMK dimerizers in a single DNA-binding site orientation. These studies provide insight into the importance of linker length and composition, binding site spacing and orientation, and the protein-binding domain content that are important for the optimization of protein DNA-dimerizers suitable for biological experiments. PMID:17949089

Inhibition of homophilic dimerization and disruption of cell adhesion by P-cadherin-specific small molecules from SPR-based assays.

PubMed

Senoo, Akinobu; Nagatoishi, Satoru; Moberg, Anna; Babol, Linnea Nygren; Mitani, Tomoya; Tashima, Takumi; Kudo, Shota; Tsumoto, Kouhei

2018-05-09

The inhibitor for the homophilic dimerization of P-cadherin was discovered by SPR-based screening using fragment compounds. Our SPR assays identified a specific P-cadherin binder, which was able to inhibit the cell adhesion of living CHO cells that expressed P-cadherin.

Antifungal dimeric chalcone derivative kamalachalcone E from Mallotus philippinensis.

PubMed

Kulkarni, Roshan R; Tupe, Santosh G; Gample, Suwarna P; Chandgude, Macchindra G; Sarkar, Dhiman; Deshpande, Mukund V; Joshi, Swati P

2014-01-01

From the red coloured extract (Kamala) prepared through acetone extraction of the fresh whole uncrushed fruits of Mallotus philippinensis, one new dimeric chalcone (1) along with three known compounds 1-(5,7-dihydroxy-2,2,6-trimethyl-2H-1-benzopyran-8-yl)-3-phenyl-2-propen-1-one (2), rottlerin (3) and 4'-hydroxyrottlerin (4) were isolated. The structure of compound 1 was elucidated by 1D and 2D NMR analyses that included HSQC, HMBC, COSY and ROESY experiments along with the literature comparison. Compounds 1-4 were evaluated for antifungal activity against different human pathogenic yeasts and filamentous fungi. The antiproliferative activity of the compounds was evaluated against Thp-1 cell lines. Compounds 1 and 2 both exhibited IC50 of 8, 4 and 16 μg/mL against Cryptococcus neoformans PRL518, C. neoformans ATCC32045 and Aspergillus fumigatus, respectively. Compound 4, at 100 μg/mL, showed 54% growth inhibition of Thp-1 cell lines.

New chalcone and dimeric chalcones with 1,4-p-benzoquinone residue from Combretum yunnanense.

PubMed

Wu, Ming-Mei; Wang, Li-Qin; Hua, Yan; Chen, Ye-Gao; Wang, Yuan-Yuan; Li, Xing-Yao; Li, Yan; Li, Ting; Yang, Xun-Yun; Tang, Zheng-Rong

2011-03-01

New chalcone and dimeric chalcones with 1,4- P-benzoquinone residue, combrequinone A (1), combrequinone B (2), and combrequinone C (3), along with three known compounds (4-6), were isolated from the ethanolic extract of the stems and leaves of Combretum yunnanense, and their structures were determined by spectroscopic analysis. Compounds 1-3 were evaluated for in vitro cytotoxicity against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7, and SW480. Compounds 1, 2 and 3 were found to be most potent against HL-60 acute leukemia cells, with IC₅₀ values of 4.63, 4.07, and 1.26 µM, respectively. © Georg Thieme Verlag KG Stuttgart · New York.

Nature and kinetic analysis of carbon-carbon bond fragmentation reactions of cation radicals derived from SET-oxidation of lignin model compounds.

PubMed

Cho, Dae Won; Parthasarathi, Ramakrishnan; Pimentel, Adam S; Maestas, Gabriel D; Park, Hea Jung; Yoon, Ung Chan; Dunaway-Mariano, Debra; Gnanakaran, S; Langan, Paul; Mariano, Patrick S

2010-10-01

Features of the oxidative cleavage reactions of diastereomers of dimeric lignin model compounds, which are models of the major types of structural units found in the lignin backbone, were examined. Cation radicals of these substances were generated by using SET-sensitized photochemical and Ce(IV) and lignin peroxidase promoted oxidative processes, and the nature and kinetics of their C-C bond cleavage reactions were determined. The results show that significant differences exist between the rates of cation radical C1-C2 bond cleavage reactions of 1,2-diaryl-(β-1) and 1-aryl-2-aryloxy-(β-O-4) propan-1,3-diol structural units found in lignins. Specifically, under all conditions C1-C2 bond cleavage reactions of cation radicals of the β-1 models take place more rapidly than those of the β-O-4 counterparts. The results of DFT calculations on cation radicals of the model compounds show that the C1-C2 bond dissociation energies of the β-1 lignin model compounds are significantly lower than those of the β-O-4 models, providing clear evidence for the source of the rate differences.

The two-state dimer receptor model: a general model for receptor dimers.

PubMed

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferrada, Carla; Ferré, Sergi; Fuxe, Kjell; Cortés, Antoni; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2006-06-01

Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces.

PubMed

Xu, Jing; Marsac, Rémi; Costa, Dominique; Cheng, Wei; Wu, Feng; Boily, Jean-François; Hanna, Khalil

2017-08-01

The emergence of antibiotic and anti-inflammatory agents in aquatic and terrestrial systems is becoming a serious threat to human and animal health worldwide. Because pharmaceutical compounds rarely exist individually in nature, interactions between various compounds can have unforeseen effects on their binding to mineral surfaces. This work demonstrates this important possibility for the case of two typical antibiotic and anti-inflammatory agents (nalidixic acid (NA) and niflumic acid (NFA)) bound at goethite (α-FeOOH) used as a model mineral surface. Our multidisciplinary study, which makes use of batch sorption experiments, vibration spectroscopy and periodic density functional theory calculations, reveals enhanced binding of the otherwise weakly bound NFA caused by unforeseen intermolecular interactions with mineral-bound NA. This enhancement is ascribed to the formation of a NFA-NA dimer whose energetically favored formation (-0.5 eV compared to free molecules) is predominantly driven by van der Waals interactions. A parallel set of efforts also showed that no cobinding occurred with sulfamethoxazole (SMX) because of the lack of molecular interactions with coexisting contaminants. As such, this article raises the importance of recognizing drug cobinding, and lack of cobinding, for predicting and developing policies on the fate of complex mixtures of antibiotics and anti-inflammatory agents in nature.

Guaiane dimers from Xylopia vielana.

PubMed

Kamperdick, Christine; Phuong, Nguyen Minh; Adam, Günter; Van Sung, Tran

2003-10-01

From the leaves of Xylopia vielana (Annonaceae) two dimeric guaianes named vielanins D and E were isolated and structurally elucidated by mass and NMR spectroscopy. Vielanin D and E consist of bridged ring systems formally representing the Diels-Alder products from the hypothetical guaiane-type monomers. Due to a hemiketal function at C-8' both compounds occurred as epimeric mixtures.

Di(phenylpropylamino)gossypol: a derivative of the dimeric natural product gossypol

USDA-ARS?s Scientific Manuscript database

Di(phenylpropylamino)gossypol [2,2'-bis(1,6-dihydroxy,-5-isopropyl,-8-methineaminopropylbenzene-3-methyl)-naphthylene-7-one, C48H52N2O6] is formed by reaction of the dimeric natural product gossypol with 3-phenyl-1-propylamine. When crystallized from diethyl ether, the compound has monoclinic (P21/c...

Design of Broad-Spectrum Inhibitors of Influenza A Virus M2 Proton Channels: A Molecular Modeling Approach.

PubMed

Klimochkin, Yuri N; Shiryaev, Vadim A; Petrov, Pavel V; Radchenko, Eugene V; Palyulin, Vladimir A; Zefirov, Nikolay S

2016-01-01

The influenza A virus M2 proton channel plays a critical role in its life cycle. However, known M2 inhibitors have lost their clinical efficacy due to the spread of resistant mutant channels. Thus, the search for broad-spectrum M2 channel inhibitors is of great importance. The goal of the present work was to develop a general approach supporting the design of ligands interacting with multiple labile targets and to propose on its basis the potential broad-spectrum inhibitors of the M2 proton channel. The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. The potential inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics simulation. The binding sites of the M2 proton channel inhibitors were analyzed, a number of potential broad-spectrum inhibitors were identified and the binding modes and probable mechanisms of action of one promising compound were clarified. Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified the binding modes and probable mechanisms of action of one promising compound. The proposed approach is also suitable for the design of ligands interacting with other multiple labile targets.

Unfolding the Quantum Nature of Proton Bound Symmetric Dimers of (MeOH)2H+ and (Me2O)2H+: a Theoretical Study

NASA Astrophysics Data System (ADS)

Tan, Jake Acedera; Kuo, Jer-Lai

2014-06-01

A proton under a tug of war between two competing Lewis bases is a common motif in biological systems and proton transfer processes. Over the past decades, model compounds for such motifs can be prepared by delicate stoichiometric control of salt solutions. Unfortunately, condensed phase studies, which aims to identify the key vibrational signatures are complicated to analyze. As a result, gas-phase studies do provide promising insights on the behavior of the shared proton. This study attempts to understand the quantum nature of the shared proton under theoretical paradigms. Proton bound symmetric dimers of (MeOH)2H+ and (Me2O)2H+ are chosen as the model compounds. The simulation is performed using Density Functional Theory (DFT) at the B3LYP level with 6-311+G(d,p) as the basis set. It was found out that stretching mode of shared proton couples with several other normal modes and its corresponding oscillator strength do distribute to other normal modes. J.R. Roscioli, L.R. McCunn and M.A. Johnson. Science 2007, 316, 249 T.E. DeCoursey. Physiol. Rev., 2003, 83, 475 E.S. Stoyanov. Psys. Chem. Phys., 2000,2,1137

A direct and fast method to monitor lipid oxidation progress in model fatty acid methyl esters by high-performance size-exclusion chromatography.

PubMed

Márquez-Ruiz, G; Holgado, F; García-Martínez, M C; Dobarganes, M C

2007-09-21

A new method based on high-performance size-exclusion chromatography (HPSEC) is proposed to quantitate primary and secondary oxidation compounds in model fatty acid methyl esters (FAMEs). The method consists on simply injecting an aliquot sample in HPSEC, without preliminary isolation procedures neither addition of standard internal. Four groups of compounds can be quantified, namely, unoxidised FAME, oxidised FAME monomers including hydroperoxides, FAME dimers and FAME polymers. Results showed high repeatability and sensitivity, and substantial advantages versus determination of residual substrate by gas-liquid chromatography. Applicability of the method is shown through selected data obtained by numerous oxidation experiments on pure FAME, mainly methyl linoleate, at ambient and moderate temperatures.

Quantum chemical determination of Young's modulus of lignin. Calculations on a beta-O-4' model compound.

PubMed

Elder, Thomas

2007-11-01

The calculation of Young's modulus of lignin has been examined by subjecting a dimeric model compound to strain, coupled with the determination of energy and stress. The computational results, derived from quantum chemical calculations, are in agreement with available experimental results. Changes in geometry indicate that modifications in dihedral angles occur in response to linear strain. At larger levels of strain, bond rupture is evidenced by abrupt changes in energy, structure, and charge. Based on the current calculations, the bond scission may be occurring through a homolytic reaction between aliphatic carbon atoms. These results may have implications in the reactivity of lignin especially when subjected to processing methods that place large mechanical forces on the structure.

Two new cytotoxic stilbenoid dimers isolated from Cajanus cajan.

PubMed

Zhang, Nenling; Shen, Xiangchun; Jiang, Xiaofei; Cai, Jiazhong; Shen, Xiaoling; Hu, Yingjie; Qiu, Samuel X

2018-01-01

Two new stilbenoid dimers, cajanstilbenoids A (1) and B (2), were isolated from the leaves of Cajanus cajan. Planar structures of these compounds were verified by NMR (1D and 2D) and high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Absolute configurations were assigned by comparing experimental and calculated electronic CD values. The cytotoxicity of 1 and 2 against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7), and human lung cancer (A549) cells were evaluated in vitro. Compound 1 showed strong cytotoxicity against all the tested cell lines (IC 50 values: 2.14-2.56 µM), whereas compound 2 showed strong toxicity only against HepG2 (IC 50 value: 5.99 µM) and A549 cells (IC 50 value: 6.18 µM).

Unusual open chain quinolinyl peroxol and its alcohol counterpart obtained through a modified Skraup-Doebner-Von Miller quinoline synthesis: theoretical studies and complete (1) H- and (13) C-NMR assignments.

PubMed

Fotie, Jean; Kemami Wangun, Hilaire V; Dreux, Katelyn; Sommerfeld, Thomas; Pittman, Jacob

2012-01-01

Because of their extreme instability, it is generally difficult to synthesize and fully characterize open chain peroxides, also known as peroxols. In our attempt to investigate the mechanism of the Skraup-Doebner-Von Miller quinoline synthesis, we were able to obtain an unusual open chain peroxy-quinoline, namely, 4-(8-ethoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)butane-1-peroxol (1), and its alcohol counterpart, namely 4-(8-ethoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)butan-1-ol (2) obtained as a side product during the same reaction. Although structurally similar, these two compounds appeared to display some very distinct physical and spectroscopic characteristics. This work reports detailed NMR studies and full (1) H and (13)  C NMR assignments for these two compounds. These assignments are based upon the analysis of the NMR spectra of these compounds including (1) H, (13)  C, COSY, gHSQC and gHMBC. The effect of the peroxide functional group on the chemical shift of neighboring carbons and protons was also investigated by comparing the NMR data of these two compounds. Furthermore, the effects of potential hydrogen bondings in 1, 2, and possible 1-1 dimer, 2-2 dimer and in prototypical model systems, as well as the stability of these compounds, were investigated computationally. The computed dissociation energies and NMR data support the interpretation of the experimental data. Copyright © 2012 John Wiley & Sons, Ltd.

Rhenium(I) tricarbonyl compounds of bioactive thiosemicarbazones: Synthesis, characterization and activity against Trypanosoma cruzi.

PubMed

Rodríguez Arce, Esteban; Machado, Ignacio; Rodríguez, Belén; Lapier, Michel; Zúñiga, María Carolina; Maya, Juan Diego; Olea Azar, Claudio; Otero, Lucía; Gambino, Dinorah

2017-05-01

American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[Re I (CO) 3 Br(HL)] where HL=5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state. The in vitro evaluation of the compounds on T. cruzi trypomastigotes (Dm28c strain) showed that the Re(I) compounds are 8 to 15 times more active than the reference drug Nifurtimox and show a 4 to 17 fold increase in activity in respect to the free (HL) ligands. Obtained compounds also show good selectivity indexes (IC 50 endothelial cells Ea.hy926 /IC 50 T. cruzi (Dm28c tripomastigotes) ). 1 H NMR and MS studies, performed with time, showed that the fac-[Re(CO) 3 Br(HL)] species convert into the dimers [Re 2 (CO) 6 (L) 2 ] in solution. Crystal structure of [Re I 2 (CO) 6 (L2) 2 ], the product of complexes' dimerization, was solved. Related to the mechanism of action, the studied compounds do not generate radical oxygen species in the parasite (as 5-nitrofuryl derived thiosemicarbazones do) probably due to the unfavorable nitro reduction potential of the generated dimeric species. On the contrary, the compounds produce a decrease of the oxygen consumption rate of the parasites, maybe inhibiting their mitochondrial respiration. Copyright © 2017 Elsevier Inc. All rights reserved.

Selective Oxidation of Lignin Model Compounds.

PubMed

Gao, Ruili; Li, Yanding; Kim, Hoon; Mobley, Justin K; Ralph, John

2018-05-02

Lignin, the planet's most abundant renewable source of aromatic compounds, is difficult to degrade efficiently to welldefined aromatics. We developed a microwave-assisted catalytic Swern oxidation system using an easily prepared catalyst, MoO 2 Cl 2 (DMSO) 2 , and DMSO as the solvent and oxidant. It demonstrated high efficiency in transforming lignin model compounds containing the units and functional groups found in native lignins. The aromatic ring substituents strongly influenced the selectivity of β-ether phenolic dimer cleavage to generate sinapaldehyde and coniferaldehyde, monomers not usually produced by oxidative methods. Time-course studies on two key intermediates provided insight into the reaction pathway. Owing to the broad scope of this oxidation system and the insight gleaned with regard to its mechanism, this strategy could be adapted and applied in a general sense to the production of useful aromatic chemicals from phenolics and lignin. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of thermal sterilization on ferulic, coumaric and cinnamic acids: dimerization and antioxidant activity.

PubMed

Arrieta-Baez, Daniel; Dorantes-Álvarez, Lidia; Martinez-Torres, Rocio; Zepeda-Vallejo, Gerardo; Jaramillo-Flores, Maria Eugenia; Ortiz-Moreno, Alicia; Aparicio-Ozores, Gerardo

2012-10-01

Some phenolic compounds, such as ferulic acid and p-coumaric acid, exist in the form of free acids, in fruits, rice, corn and other grains. Thermal treatment (121 °C at 15-17 psi) for different times on ferulic, p-coumaric and cinnamic acids as well as equimolar mixtures of these acids was investigated. Ferulic and p-coumaric acids underwent decarboxylation, yielding dimeric products formed through their corresponding radical intermediates, while cinnamic acid was recovered unreacted. High-performance liquid chromatography analysis showed no cross-dimerization when equimolar mixtures of pairs of hydroxycinnamic acids were treated under the same conditions. Dimers were characterized as (E)-4',4″-(but-1-ene-1,3-diyl)bis(2'-methoxyphenol)) (dimer of 4-vinylguaiacol) and (E)-4,4'-(but-1-ene-1,3-diyl)diphenol) (dimer of 4-vinylphenol) by nuclear magnetic resonance and mass spectrometry. Sterilization by thermal processing produced dimers of ferulic and coumaric acid. The antioxidant activity of these dimers was greater than that of the respective hydroxycinnamic acids. These results may be relevant for fruits and grains that contain hydroxycinnamic acids and undergo sterilization processes such as canning. Copyright © 2012 Society of Chemical Industry.

Guaiane dimers from Xylopia vielana.

PubMed

Kamperdick, C; Phuong, N M; Van Sung, T; Adam, G

2001-02-01

From the leaves of Xylopia vielana (Annonaceae) the three dimeric guaianes vielanin A-C were isolated and structurally elucidated by mass and NMR spectroscopy as 1-3. The structure of 1 contains a bridged ring system formed probably via a Diels-Alder reaction of two different guaiane monomers. Compounds 2 and 3 represent symmetric cyclobutanes formally generated from two equal guaiane moieties by [2 + 2] cycloaddition.

Bisquaternary dimers of strychnine and brucine. A new class of potent enhancers of antagonist binding to muscarinic M2 receptors.

PubMed

Zlotos, D P; Buller, S; Holzgrabe, U; Mohr, K

2003-06-12

Bisquaternary dimers of strychnine and brucine were synthesized and their allosteric effect on muscarinic acetylcholine M(2) receptors was examined. The compounds retarded the dissociation of the antagonist [(3)H]N-methylscopolamine ([(3)H]NMS) from porcine cardiac cholinoceptors. This action indicated ternary complex formation. All compounds exhibited higher affinity to the allosteric site of [(3)H]NMS-occupied M(2) receptors than the monomeric strychnine and brucine, while the positive cooperativity with NMS was fully maintained. SAR studies revealed the unchanged strychnine ring as an important structural feature for high allosteric potency.

Asymmetric Quintuplet Condensation in the Frustrated S=1 Spin Dimer Compound Ba3Mn2O8

NASA Astrophysics Data System (ADS)

Samulon, E. C.; Kohama, Y.; McDonald, R. D.; Shapiro, M. C.; Al-Hassanieh, K. A.; Batista, C. D.; Jaime, M.; Fisher, I. R.

2009-07-01

Ba3Mn2O8 is a spin-dimer compound based on pairs of S=1, 3d2, Mn5+ ions arranged on a triangular lattice. Antiferromagnetic intradimer exchange leads to a singlet ground state in zero field, with excited triplet and quintuplet states at higher energy. High field thermodynamic measurements are used to establish the phase diagram, revealing a substantial asymmetry of the quintuplet condensate. This striking effect, all but absent for the triplet condensate, is due to a fundamental asymmetry in quantum fluctuations of the paramagnetic phases near the various critical fields.

A kinetico-mechanistic study on the C-H bond activation of primary benzylamines; cooperative and solid-state cyclopalladation on dimeric complexes.

PubMed

Font, Helena; Font-Bardia, Mercè; Gómez, Kerman; González, Gabriel; Granell, Jaume; Macho, Israel; Martínez, Manuel

2014-09-28

The cyclometallation reactions of dinuclear μ-acetato complexes of the type [Pd(AcO)(μ-AcO)L]2 (L = 4-RC6H4CH2NH2, R = H, Cl, F, CF3), a process found to occur readily even in the solid state, have been studied from a kinetico-mechanistic perspective. Data indicate that the dinuclear acetato bridged derivatives are excellent starting materials to activate carbon-hydrogen bonds in a facile way. In all cases the established concerted ambiphilic proton abstraction by a coordinated acetato ligand has been proved. The metallation has also been found to occur in a cooperative manner, with the metallation of the first palladium unit of the dimeric complex being rate determining; no intermediate mono-metallated compounds are observed in any of the processes. The kinetically favoured bis-cyclopalladated compound obtained after complete C-H bond activation does not correspond to the final isolated XRD-characterized complexes. This species, bearing the classical open-book dimeric form, has a much more complex structure than the final isolated compound, with different types of acetato ligands.

Characterization of the polymerization of furfuryl alcohol during roasting of coffee.

PubMed

Swasti, Yuliana Reni; Murkovic, Michael

2012-09-01

The polymerization of furfuryl alcohol contributes to the formation of the brown colour in heated foods, in addition to the Maillard and caramelization reactions. During the heating of food, furfuryl alcohol is formed via the degradation of quinic acid or 1,2-enediols. Furfuryl alcohol is a mutagenic compound. In acidic conditions it is able to polymerize and form aliphatic polymers that show a brown colour. Herein we show that furfuryl alcohol polymerizes in a model system by incubating it in 1 M HCl at room temperature. Some of the reaction products are dimers, trimers, tetramers, and pentamers with methylene linkages. The degree of polymerization and the amount of those furfuryl alcohol oligomers increased with increasing reaction time. The results of this model system were used to characterize the polymerization of furfuryl alcohol which is produced during roasting of coffee. The coffee was roasted at 210 °C for 2, 3, 4, 5, and 6 min with a home coffee roaster. Furfuryl alcohol and its dimer were found in roasted coffee after 2 and 3 min of roasting respectively, reaching a maximum amount after 4 min. Perhaps due to further reactions, the dimeric furfuryl alcohol concentration starts to decrease after 4 min. We propose that the polymers of furfuryl alcohol contribute to the brown colour of roasted foods.

Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non-enzymatic Biosynthesis.

PubMed

Fu, Peng; Legako, Aaron; La, Scott; MacMillan, John B

2016-03-01

Dibohemamines A-C (5-7), three new dimeric bohemamine analogues dimerized through a methylene group, were isolated from a marine-derived Streptomyces spinoverrucosus. The structures determined by spectroscopic analysis were confirmed through the semi-synthetic derivatization of monomeric bohemamines and formaldehyde. These reactions, which could occur under mild conditions, together with the detection of formaldehyde in the culture, revealed that this dimerization is a non-enzymatic process. In addition to the unique dimerization of the dibohemamines, dibohemamines B and C were found to have nm cytotoxicity against the non-small cell-lung cancer cell line A549. In view of the potent cytotoxicity of compounds 6 and 7, a small library of bohemamine analogues was generated for biological evaluation by utilizing a series of aryl and alkyl aldehydes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Efficient photosensitized splitting of the thymine dimer/oxetane unit on its modifying beta-cyclodextrin by a binding electron donor.

PubMed

Tang, Wen-Jian; Song, Qin-Hua; Wang, Hong-Bo; Yu, Jing-Yu; Guo, Qing-Xiang

2006-07-07

Two modified beta-cyclodextrins (beta-CDs) with a thymine dimer and a thymine oxetane adduct respectively, TD-CD and Ox-CD, have been prepared, and utilized to bind an electron-rich chromophore, indole or N,N-dimethylaniline (DMA), to form a supramolecular complex. We have examined the photosensitized splitting of the dimer/oxetane unit in TD-CD/Ox-CD by indole or DMA via an electron-transfer pathway, and observed high splitting efficiencies of the dimer/oxetane unit. On the basis of measurements of fluorescence spectra and splitting quantum yields, it is suggested that the splitting reaction occurs in a supramolecular complex by an inclusion interaction between the modified beta-CDs and DMA or indole. The back electron transfer, which leads low splitting efficiencies for the covalently-linked chromophore-dimer/oxetane compounds, is suppressed in the non-covalently-bound complex, and the mechanism has been discussed.

Molecular modeling reveals binding interface of γ-tubulin with GCP4 and interactions with noscapinoids.

PubMed

Suri, Charu; Joshi, Harish C; Naik, Pradeep Kumar

2015-05-01

The initiation of microtubule assembly within cells is guided by a cone shaped multi-protein complex, γ-tubulin ring complex (γTuRC) containing γ-tubulin and atleast five other γ-tubulin-complex proteins (GCPs), i.e., GCP2, GCP3, GCP4, GCP5, and GCP6. The rim of γTuRC is a ring of γ-tubulin molecules that interacts, via one of its longitudinal interfaces, with GCP2, GCP3, or GCP4 and, via other interface, with α/β-tubulin dimers recruited for the microtubule lattice formation. These interactions however, are not well understood in the absence of crystal structure of functional reconstitution of γTuRC subunits. In this study, we elucidate the atomic interactions between γ-tubulin and GCP4 through computational techniques. We simulated two complexes of γ-tubulin-GCP4 complex (we called dimer1 and dimer2) for 25 ns to obtain a stable complex and calculated the ensemble average of binding free energies of -158.82 and -170.19 kcal/mol for dimer1 and -79.53 and -101.50 kcal/mol for dimer2 using MM-PBSA and MM-GBSA methods, respectively. These highly favourable binding free energy values points to very robust interactions between GCP4 and γ-tubulin. From the results of the free-energy decomposition and the computational alanine scanning calculation, we identified the amino acids crucial for the interaction of γ-tubulin with GCP4, called hotspots. Furthermore, in the endeavour to identify chemical leads that might interact at the interface of γ-tubulin-GCP4 complex; we found a class of compounds based on the plant alkaloid, noscapine that binds with high affinity in a cavity close to γ-tubulin-GCP4 interface compared with previously reported compounds. All noscapinoids displayed stable interaction throughout the simulation, however, most robust interaction was observed for bromo-noscapine followed by noscapine and amino-noscapine. This offers a novel chemical scaffold for γ-tubulin binding drugs near γ-tubulin-GCP4 interface. © 2015 Wiley Periodicals, Inc.

Industrial Organic Electrosynthesis.

ERIC Educational Resources Information Center

Wagenknecht, John H.

1983-01-01

Four examples of industrial electrochemical synthesis of organic compounds are described. These include acrylonitrile dimerization, tetramethyl lead, electrochemical fluorination, and production of diacetone-2-keto-L-gulonic acid. Additional examples are also cited, including the production of several compounds by the BASF company of Germany. (JN)

The impact of solvent relative permittivity on the dimerisation of organic molecules well below their solubility limits: examples from brewed coffee and beyond.

PubMed

Bradley, Ellen S; Hendon, Christopher H

2017-03-22

The formation of aqueous intermolecular dimers is governed by both the nature and strength of the intermolecular interactions and the entropy of dissolution. The former interaction energies are determined by the polarity of the solvent and the functionality of the solute. Using quantum chemical methods, we probe the energetics of dimer formation of representative compounds found in coffee well below their solubility limits. We find that with the exclusion of entropy, the dimer formation is thermodynamically unfavorable with negligible dependence on the dielectric medium.

Advanced Model Compounds for Understanding Acid-Catalyzed Lignin Depolymerization: Identification of Renewable Aromatics and a Lignin-Derived Solvent.

PubMed

Lahive, Ciaran W; Deuss, Peter J; Lancefield, Christopher S; Sun, Zhuohua; Cordes, David B; Young, Claire M; Tran, Fanny; Slawin, Alexandra M Z; de Vries, Johannes G; Kamer, Paul C J; Westwood, Nicholas J; Barta, Katalin

2016-07-20

The development of fundamentally new approaches for lignin depolymerization is challenged by the complexity of this aromatic biopolymer. While overly simplified model compounds often lack relevance to the chemistry of lignin, the direct use of lignin streams poses significant analytical challenges to methodology development. Ideally, new methods should be tested on model compounds that are complex enough to mirror the structural diversity in lignin but still of sufficiently low molecular weight to enable facile analysis. In this contribution, we present a new class of advanced (β-O-4)-(β-5) dilinkage models that are highly realistic representations of a lignin fragment. Together with selected β-O-4, β-5, and β-β structures, these compounds provide a detailed understanding of the reactivity of various types of lignin linkages in acid catalysis in conjunction with stabilization of reactive intermediates using ethylene glycol. The use of these new models has allowed for identification of novel reaction pathways and intermediates and led to the characterization of new dimeric products in subsequent lignin depolymerization studies. The excellent correlation between model and lignin experiments highlights the relevance of this new class of model compounds for broader use in catalysis studies. Only by understanding the reactivity of the linkages in lignin at this level of detail can fully optimized lignin depolymerization strategies be developed.

Hydrogen bonding: part 78. Ab initio molecular orbital study of intra- and intermolecular hydrogen bonding in choline and betaine and their compounds with HF and H 2O

NASA Astrophysics Data System (ADS)

Harmon, K. M.; Avci, G. F.; Madeira, S. L.; Mounts, P. A.; Thiel, A. C.

2001-10-01

We previously prepared several compounds of the zwitterions [(CH3)3NCH2CH2O]0 (deprotonated choline, herein named cholaine) and [(CH3)3NCH2CO2]0 (betaine) and proposed structures based on infrared spectroscopy. We now examine these compounds with use of ab initio molecular orbital methods to further elucidate possible structure. These calculations demonstrate that: (1) cholaine and betaine both have internal CHO hydrogen bonds, and these are retained in some form in all other compounds. (2) Cholaine hydrate and hydrofluoride and betaine hydrofluoride monomers have covalent three-center hydrogen bonds between H2O or HF and negative zwitterion oxygen, and additional CHX hydrogen bonds to H2O oxygen or HF fluorine. (3) Cholaine monohydrate and cholaine hydrofluoride monohydrate form dimers of Ci symmetry which contain planar C2h (H2O·O)2 and (HOH·F)2 clusters. (4) Cholaine hydrofluoride forms head-to-tail dimers bound by intermolecular CHX hydrogen bonds; this arrangement could lead to extended linear structures in the solid state. (5) Betaine hydrofluoride, in contrast, forms a tightly bound discrete dimeric unit in which two molecules join in a head-to-head manner held together by five intermolecular hydrogen bonds and by the mutual proximities of negative fluorides to positive nitrogens.

Excited-State Deactivation of Branched Phthalocyanine Compounds.

PubMed

Zhu, Huaning; Li, Yang; Chen, Jun; Zhou, Meng; Niu, Yingli; Zhang, Xinxing; Guo, Qianjin; Wang, Shuangqing; Yang, Guoqiang; Xia, Andong

2015-12-21

The excited-state relaxation dynamics and chromophore interactions in two phthalocyanine compounds (bis- and trisphthalocyanines) are studied by using steady-state and femtosecond transient absorption spectral measurements, where the excited-state energy-transfer mechanism is explored. By exciting phthalocyanine compounds to their second electronically excited states and probing the subsequent relaxation dynamics, a multitude of deactivation pathways are identified. The transient absorption spectra show the relaxation pathway from the exciton state to excimer state and then back to the ground state in bisphthalocyanine (bis-Pc). In trisphthalocyanine (tris-Pc), the monomeric and dimeric subunits are excited and the excitation energy transfers from the monomeric vibrationally hot S1 state to the exciton state of a pre-associated dimer, with subsequent relaxation to the ground state through the excimer state. The theoretical calculations and steady-state spectra also show a face-to-face conformation in bis-Pc, whereas in tris-Pc, two of the three phthalocyanine branches form a pre-associated face-to-face dimeric conformation with the third one acting as a monomeric unit; this is consistent with the results of the transient absorption experiments from the perspective of molecular structure. The detailed structure-property relationships in phthalocyanine compounds is useful for exploring the function of molecular aggregates in energy migration of natural photosynthesis systems. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Verbalactone, a new macrocyclic dimer lactone from the roots of Verbascum undulatum with antibacterial activity.

PubMed

Magiatis, P; Spanakis, D; Mitaku, S; Tsitsa, E; Mentis, A; Harvala, C

2001-08-01

A novel macrocyclic dimer lactone, named verbalactone, was isolated from the roots of Verbascum undulatum and exhibited interesting antibacterial activity. It is the first time that 1,7-dioxacyclododecane is reported as the ring system of a natural product. The structure and the absolute stereochemistry of the new compound were determined by spectral methods and chemical correlation.

Modelling the contribution of biogenic volatile organic compounds to new particle formation in the Jülich plant atmosphere chamber

NASA Astrophysics Data System (ADS)

Roldin, P.; Liao, L.; Mogensen, D.; Dal Maso, M.; Rusanen, A.; Kerminen, V.-M.; Mentel, T. F.; Wildt, J.; Kleist, E.; Kiendler-Scharr, A.; Tillmann, R.; Ehn, M.; Kulmala, M.; Boy, M.

2015-09-01

We used the Aerosol Dynamics gas- and particle-phase chemistry model for laboratory CHAMber studies (ADCHAM) to simulate the contribution of BVOC plant emissions to the observed new particle formation during photooxidation experiments performed in the Jülich Plant-Atmosphere Chamber and to evaluate how well smog chamber experiments can mimic the atmospheric conditions during new particle formation events. ADCHAM couples the detailed gas-phase chemistry from Master Chemical Mechanism with a novel aerosol dynamics and particle phase chemistry module. Our model simulations reveal that the observed particle growth may have either been controlled by the formation rate of semi- and low-volatility organic compounds in the gas phase or by acid catalysed heterogeneous reactions between semi-volatility organic compounds in the particle surface layer (e.g. peroxyhemiacetal dimer formation). The contribution of extremely low-volatility organic gas-phase compounds to the particle formation and growth was suppressed because of their rapid and irreversible wall losses, which decreased their contribution to the nano-CN formation and growth compared to the atmospheric situation. The best agreement between the modelled and measured total particle number concentration (R2 > 0.95) was achieved if the nano-CN was formed by kinetic nucleation involving both sulphuric acid and organic compounds formed from OH oxidation of BVOCs.

Heat capacity of the site-diluted spin dimer system Ba₃(Mn 1-xV x)₂O₈

DOE PAGES

Samulon, E. C.; Shapiro, M. C.; Fisher, I. R.

2011-08-05

Heat-capacity and susceptibility measurements have been performed on the diluted spin dimer compound Ba₃(Mn 1-xV x)₂O₈. The parent compound Ba₃Mn₂O₈ is a spin dimer system based on pairs of antiferromagnetically coupled S=1, 3d² Mn⁵⁺ ions such that the zero-field ground state is a product of singlets. Substitution of nonmagnetic S=0, 3d⁰ V⁵⁺ ions leads to an interacting network of unpaired Mn moments, the low-temperature properties of which are explored in the limit of small concentrations 0≤x≤0.05. The zero-field heat capacity of this diluted system reveals a progressive removal of magnetic entropy over an extended range of temperatures, with no evidencemore » for a phase transition. The concentration dependence does not conform to expectations for a spin-glass state. Rather, the data suggest a low-temperature random singlet phase, reflecting the hierarchy of exchange energies found in this system.« less

Hydrolyzable tannins of tamaricaceous plants. V. Structures of monomeric-trimeric tannins and cytotoxicity of macrocyclic-type tannins isolated from Tamarix nilotica (1).

PubMed

Orabi, Mohamed A A; Taniguchi, Shoko; Sakagami, Hiroshi; Yoshimura, Morio; Yoshida, Takashi; Hatano, Tsutomu

2013-05-24

Three new ellagitannin monomers, nilotinins M5-M7 (1-3), a dimer, nilotinin D10 (4), and a trimer, nilotinin T1 (5), together with three known dimers, hirtellin D (7) and tamarixinins B (8) and C (9), and a trimer, hirtellin T2 (6), were isolated from Tamarix nilotica dried leaves. The structures of the tannins were elucidated by intensive spectroscopic methods and chemical conversions into known tannins. The new trimer (5) is a unique macrocyclic type whose monomeric units are linked together by an isodehydrodigalloyl and two dehydrodigalloyl moieties. Additionally, dimeric and trimeric macrocyclic-type tannins isolated from T. nilotica in this study were assessed for possible cytotoxic activity against four human tumor cell lines. Tumor-selective cytotoxicities of the tested compounds were higher than those of synthetic and natural potent cytotoxic compounds, including polyphenols, and comparable with those of 5-fluorouracil and melphalan.

PSD-95 uncoupling from NMDA receptors by Tat- N-dimer ameliorates neuronal depolarization in cortical spreading depression.

PubMed

Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders; Strømgaard, Kristian; Lauritzen, Martin

2017-05-01

Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat- N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat- N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat- N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO 2 ) responses were preserved. During cortical spreading depression, the Tat- N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO 2 . We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarization wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

Elucidation of the active conformation of vancomycin dimers with antibacterial activity against vancomycin-resistant bacteria.

PubMed

Nakamura, Jun; Yamashiro, Hidenori; Hayashi, Sayaka; Yamamoto, Mami; Miura, Kenji; Xu, Shu; Doi, Takayuki; Maki, Hideki; Yoshida, Osamu; Arimoto, Hirokazu

2012-10-01

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dimers of coumarin-1,2,3-triazole hybrids bearing alkyl spacer: Design, microwave-assisted synthesis, molecular docking and evaluation as antimycobacterial and antimicrobial agents

NASA Astrophysics Data System (ADS)

Ashok, Dongamanti; Gundu, Srinivas; Aamate, Vikas Kumar; Devulapally, Mohan Gandhi; Bathini, Raju; Manga, Vijjulatha

2018-04-01

The present study demonstrated the synthesis of new series of coumarin-1,2,3-triazole hybrids under microwave irradiation method. Several dimers of coumarin based 1,2,3-triazole derivatives were synthesized and their antimycobacterial and antimicrobial activities were investigated. The antimycobacterial activity screening results revealed that compounds 6i and 6j were the most active against Mycobacterium tuberculosis H37Rv strain. The active compounds were further evaluated for cytotoxicity with HEK cell lines and exhibited less % of inhibition. The same synthetic hybrids were evaluated for their antimicrobial activity against various bacterial strains and fungal strains and compounds 6e, 6h, 6i and 6j were found to be the most promising antimicrobial potent molecules. Furthermore, the active compounds against Mycobacterium tuberculosis were evaluated for their molecular docking studies against pantothenate synthetase (PS) enzyme of MTB and the docking results are in well agreement with the antitubercular evaluation results.

Reactivity of pi-complexes of Ti, V, and Nb towards dithioacetic acid: Synthesis and structure of novel metal sulfur-containing complexes

NASA Technical Reports Server (NTRS)

Duraj, Stan A.; Andras, Maria T.; Hepp, Aloysius F.

1990-01-01

In order to use sulfur-containing resources economically and with minimal environmental damage, it is important to understand the desulfurization processes. Hydrodesulfurization, for example, is carried out on the surface of a heterogeneous metal sulfide catalyst. Studies of simple, soluble inorganic systems provide information regarding the structure and reactivity of sulfur-containing compounds with metal complexes. Further, consistent with recent trends in materials chemistry, many model compounds warrant further study as catalyst precursors. The reactivity of low-valent organometallic sandwich pi-complexes toward dithiocarboxylic acids is described. For example, treatment of bisbenzene vanadium with CH3CSSH affords a divanadium tetrakis(dithioacetate) complex. The crystallographically determined V-V bond distance, 2.800(2), is nearly the same as the V-V bond distance in a V(mu-nu squared-S2)2V' unit in the mineral patonite (VS4)n. The stability of the V2S4 core in the dimer is demonstrated by evidence of V2S4(+) in the mass spectrum (70 eV, solid probe) of the vanadium dimer. Several other systems relevant to HDS catalysis are also discussed.

Controllable synthesis, crystal structure and magnetic properties of Monomer-Dimer Cocrystallized MnIII Salen-type composite material

NASA Astrophysics Data System (ADS)

Wu, Qiong; Wu, Wei; Wu, Yongmei; Li, Weili; Qiao, Yongfeng; Wang, Ying; Wang, Baoling

2018-04-01

By the reaction of manganese-Schiff-base complexes with penta-anionic Anderson heteropolyanion, a new supramolecular architecture [Mn2(Salen)2(H2O)2][Mn(Salen)(H2O)2]2Na[IMo6O24]·8H2O (1) (salen = N,N‧-ethylene-bis (salicylideneiminate) has been isolated. Compound 1 was characterized by the single-crystal X-ray diffraction, elemental, IR and thermal gravimetric analyses. Structural analysis reveals that the unit cell simultaneously contains MnIII-Salen dimer and monomer cation fragments, for which the Anderson-type polyanions serve as counter anions. In the packing arrangement, all the MnIII dimers are well separated by polyoxometalate units and form tertiary structure together with MnIII monomers. Interestingly, different from the previous work, in the exact same reaction conditions, we are able to template MnIII-Salen complexes into different configurations by varying the charge state of polyanions. Besides, the magnetic properties of 1 were also examined by using both dc and ac magnetic field of the superconducting quantum interference devices. Most importantly, our fitting of the experimental data to a Heisenberg-type spin model shows that there exists a ferromagnetic exchange interaction ∼5 K between the spins (S = 2) on MnIII in the dimer, while antiferromagnetic ones exist among monomers and dimer (∼2 K). This meta-magnetic state could induce a slight spin frustration at low temperature, which would in turn affect the magnetic behavior. In addition, our ac field measurement of the susceptibilities suggests a typical signature for a single-molecule magnet.

Fibrosterol sulfates from the Philippine sponge Lissodendoryx (Acanthodoryx) fibrosa: sterol dimers that inhibit PKCzeta.

PubMed

Whitson, Emily L; Bugni, Tim S; Chockalingam, Priya S; Concepcion, Gisela P; Feng, Xidong; Jin, Guixian; Harper, Mary Kay; Mangalindan, Gina C; McDonald, Leonard A; Ireland, Chris M

2009-08-21

Three new sulfated sterol dimers, fibrosterol sulfates A-C (1-3), have been isolated from the sponge Lissodendoryx (Acanthodoryx) fibrosa, collected in the Philippines. The structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1 and 2 inhibited PKCzeta with IC(50) values of 16.4 and 5.6 microM, respectively.

Model-based Analysis of HER Activation in Cells Co-Expressing EGFR, HER2 and HER3.

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

Shankaran, Harish; Zhang, Yi; Tan, Yunbing

2013-08-22

The HER/ErbB family of receptor tyrosine kinases drive critical responses in normal physiology and cancer, and the expression levels of the various HER receptors are critical determinants of clinical outcomes. HER activation is driven by the formation of various dimer complexes between members of this receptor family. The HER dimer types can have differential effects on downstream signaling and phenotypic outcomes. We constructed an integrated mathematical model of HER activation and trafficking to quantitatively link receptor expression levels to dimerization and activation. We parameterized the model with a comprehensive set of HER phosphorylation and abundance data collected in a panelmore » of human mammary epithelial cells expressing varying levels of EGFR, HER2 and HER3. Although parameter estimation yielded multiple solutions, predictions for dimer phosphorylation were in agreement with each other. We validated the model using experiments where pertuzumab was used to block HER2 dimerization. We used the model to predict HER dimerization and activation patterns in a panel of epithelial cells lines with known HER expression levels. Simulations over the range of expression levels seen in various cell lines indicate that: i) EGFR phosphorylation is driven by HER1/1 and HER1/2 dimers, and not HER1/3 dimers, ii) HER1/2 and HER2/3 dimers both contribute significantly to HER2 activation with the EGFR expression level determining the relative importance of these species, and iii) the HER2/3 dimer is largely responsible for HER3 activation. The model can be used to predict phosphorylated dimer levels for any given HER expression profile. This information in turn can be used to quantify the potencies of the various HER dimers, and can potentially inform personalized therapeutic approaches.« less

Vibrational analysis of carbonyl modes in different stages of light-induced cyclopyrimidine dimer repair reactions

NASA Astrophysics Data System (ADS)

Schmitz, Matthias; Tavan, Paul; Nonella, Marco

2001-11-01

The formation of cyclopyrimidine dimers is a DNA defect, which is repaired by the enzyme DNA photolyase in a light-induced reaction. Radical anions of the dimers have been suggested to occur as short-lived intermediates during repair. For their identification time-resolved Fourier-transform infrared (FTIR) spectroscopy will be a method of choice. To support and guide such spectroscopic studies we have calculated the vibrational spectra of various pyrimidine compounds using density functional methods. Our results suggest that the carbonyl vibrations of these molecules can serve as marker modes to identify and distinguish intermediates of the repair reaction.

Kosterlitz-Thouless transitions and phase diagrams of the interacting monomer-dimer model on a checkerboard lattice

NASA Astrophysics Data System (ADS)

Li, Sazi; Li, Wei; Chen, Ziyu

2014-11-01

Using the tensor network approach, we investigate the monomer-dimer models on a checkerboard lattice, in which there are interactions (with strength v ) between the parallel dimers on half of the plaquettes. For the fully packed interacting dimer model, we observe a Kosterlitz-Thouless (KT) transition between the low-temperature symmetry breaking and the high-temperature critical phases; for the doped monomer-dimer case with finite chemical potential μ , we also find an order-disorder phase transition which is of second order instead. We use the boundary matrix product state approach to detect the KT and second-order phase transitions and obtain the phase diagrams v -T and μ -T . Moreover, for the noninteracting monomer-dimer model (setting μ =ν =0 ), we get an extraordinarily accurate determination of the free energy per site (negative of the monomer-dimer constant h2) as f =-0.662 798 972 833 746 with the dimer density n =0.638 123 109 228 547 , both of 15 correct digits.

Constituents of Clerodendrum bungei.

PubMed

Yang, Hui; Hou, Ai-Jun; Mei, Shuang-Xi; Sun, Han-Dong; Che, Chun-Tao

2002-09-01

Two new compounds, 5-O-ethylcleroindicin D (1) and bungein A (2), together with 12 known compounds (3-14), were isolated from the aerial parts of the medicinal plant Clerodendrum bungei. The structures of 1 and 2 were elucidated as a perhydrobenzofuran derivative and a peroxide dimer by spectral and chemical evidence. Compounds 3-14 have been obtained from this species for the first time.

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

PubMed Central

Bassanini, Ivan; Hult, Karl

2015-01-01

Summary Dicarboxylic acids and their derivatives (esters and anhydrides) have been used as acylating agents in lipase-catalyzed reactions in organic solvents. The synthetic outcomes have been dimeric or hybrid derivatives of bioactive natural compounds as well as functionalized polyesters. PMID:26664578

Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

PubMed

Olivares, Christopher I; Sierra-Alvarez, Reyes; Abrell, Leif; Chorover, Jon; Simonich, Michael; Tanguay, Robert L; Field, Jim A

2016-11-01

2,4-Dinitroanisole (DNAN) is an emerging insensitive munitions compound that readily undergoes anaerobic nitro-group reduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN), followed by formation of unique azo dimers. Currently there is little knowledge on the ecotoxicity of DNAN (bio)transformation products. In the present study, mortality, development, and behavioral effects of DNAN (bio)transformation products were assessed using zebrafish (Danio rerio) embryos. The authors tested individual products, MENA and DAAN, as well as dimer and trimer surrogates. As pure compounds, 3-nitro-4-methoxyaniline and 2,2'-dimethoxy-4,4'-azodianiline caused statistically significant effects, with lowest-observable-adverse effect levels (LOAEL) at 6.4 μM on 1 or 2 developmental endpoints, respectively. The latter had 6 additional statistically significant developmental endpoints with LOAELs of 64 μM. Based on light-to-dark swimming behavioral tests, DAAN (640 μM) caused reduction in swimming, suggestive of neurotoxicity. No statistically significant mortality occurred (≤64 μM) for any of the individual compounds. However, metabolite mixtures formed during different stages of MENA (bio)transformation in soil were characterized using high-resolution mass spectrometry in parallel with zebrafish embryo toxicity assays, which demonstrated statistically significant mortality during the onset of azo-dimer formation. Overall the results indicate that several DNAN (bio)transformation products cause different types of toxicity to zebrafish embryos. Environ Toxicol Chem 2016;35:2774-2781. © 2016 SETAC. © 2016 SETAC.

Solitary waves in dimer binary collision model

NASA Astrophysics Data System (ADS)

Ahsan, Zaid; Jayaprakash, K. R.

2017-01-01

Solitary wave propagation in nonlinear diatomic (dimer) chains is a very interesting topic of research in the study of nonlinear lattices. Such waves were recently found to be supported by the essentially nonlinear granular lattice and Toda lattice. An interesting aspect of this discovery is attributed to the realization of a spectrum of the mass ratio (the only system parameter governing the dynamics) that supports the propagation of such waves corresponding to the considered interaction potential. The objective of this exposition is to explore solitary wave propagation in the dimer binary collision (BC) model. Interestingly, the dimer BC model supports solitary wave propagation at a discrete spectrum of mass ratios similar to those observed in granular and Toda dimers. Further, we report a qualitative and one-to-one correspondence between the spectrum of the mass ratio corresponding to the dimer BC model and those corresponding to granular and Toda dimer chains.

Synthesis, pharmacological activities and molecular docking studies of pyrazolyltriazoles as anti-bacterial and anti-inflammatory agents.

PubMed

Dayakar, Cherupally; Kumar, Buddana Sudheer; Sneha, Galande; Sagarika, Gudem; Meghana, Koneru; Ramakrishna, Sistla; Prakasham, Reddy Shetty; China Raju, Bhimapaka

2017-10-15

A series of novel pyrazolyl alcohols (5a-h), pyrazolyl azides (6a-h), and pyrazolyltriazoles (8a-h, 10a-p and 12a-l) were prepared and evaluated for their bioactivity (anti-bacterial and anti-inflammatory) profile. The compound 5c displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81µg/mL). In vitro anti-inflammatory activity data denoted that compound 8b is effective among the tested compounds against IL-6 (IC 50 6.23μM). Docking analysis of compounds 5f, 8a-b, 8e-f and 8h displayed high binding energies for the compounds 8a-b and 8h towards TNF-α dimer (2AZ5 protein) and IL-6 (1ALU protein). In vivo anti-inflammatory activity of compounds 8b and 8h with respect to LPS induced mice model indicated that compound 8h showed significant reduction in TNF-α. Copyright © 2017 Elsevier Ltd. All rights reserved.

Photochemical Dimerization of Dibenzylideneacetone: A Convenient Exercise in [2+2] Cycloaddition Using Chemical Ionization Mass Spectrometry

ERIC Educational Resources Information Center

Rao, G. Nageswara; Janardhana, Chelli; Ramanathan, V.; Rajesh, T.; Kumar, P. Harish

2006-01-01

Chemical reactions induced by light have been utilized for synthesizing highly strained, thermodynamically unstable compounds, which are inaccessible through non-photochemical methods. Photochemical cycloaddition reactions, especially those leading to the formation of four-membered rings, constitute a convenient route to compounds that are…

The complex of hypericin with β-lactoglobulin has antimicrobial activity with potential applications in dairy industry.

PubMed

Rodríguez-Amigo, Beatriz; Delcanale, Pietro; Rotger, Gabriel; Juárez-Jiménez, Jordi; Abbruzzetti, Stefania; Summer, Andrea; Agut, Montserrat; Luque, F Javier; Nonell, Santi; Viappiani, Cristiano

2015-01-01

Using a combination of molecular modeling and spectroscopic experiments, the naturally occurring, pharmacologically active hypericin compound is shown to form a stable complex with the dimeric form of β-lactoglobulin (β-LG). Binding is predicted to occur at the narrowest cleft found at the interface between monomers in the dimeric β-LG. The complex is able to preserve the fluorescence and singlet oxygen photosensitizing properties of the dye. The equilibrium constant for hypericin binding has been determined as Ka=1.40±0.07µM(-1), equivalent to a dissociation constant, Kd=0.71±0.03µM. The complex is active against Staphylococcus aureus bacteria. Overall, the results are encouraging for pursuing the potential application of the complex between hypericin and β-LG as a nanodevice with bactericidal properties for disinfection. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

N-Benzyl­pyridin-2-amine

PubMed Central

Wang, Jun; Dai, Chuntao; Nie, Jianhua

2010-01-01

In the crystal of the title compound, C12H12N2, inter­molecular N—H⋯N hydrogen bonds form rings of graph-set motif R 2 2(8) and C—H⋯π inter­actions further consolidate the dimers. Neighbouring dimers are further connected into a three-dimensional network by C—H⋯π inter­actions. The benzyl and pyridyl rings form a dihedral angle of 67.2 (1)° PMID:21589385

Tamoxifen metabolism in rat liver microsomes: identification of a dimeric metabolite derived from free radical intermediates by liquid chromatography/mass spectrometry.

PubMed

Jones, R M; Yuan, Z X; Lim, C K

1999-01-01

Tamoxifen has been shown to be a potent liver carcinogen in rats, and generates covalent DNA adducts. On-line high performance liquid chromatography/electrospray ionisation mass spectrometry (HPLC/ESI-MS) has been used to further study the metabolites of tamoxifen formed by rat liver microsomes in the presence of NADPH with a view to identifying potential reactive metabolites which may be responsible for the formation of DNA adducts, and liver carcinogenesis. A metabolite has been detected with a protonated molecule at m/z 773. The mass of this compound is consistent with a dimer of hydroxylated tamoxifen (m/z 388). Analysis of 4-hydroxytamoxifen incubated with a rat liver microsomal preparation showed the formation of a similar metabolite with an apparent MH+ ion at m/z 773, believed to be a dimer of 4-hydroxytamoxifen formed by a free radical reaction. The retention time for this metabolite from 4-hydroxytamoxifen is identical to that of the tamoxifen metabolite, suggesting that these two compounds are the same. The levels of the dimer were higher when 4-hydroxytamoxifen was used as substrate and, in addition, two isomers were detected. It is proposed that tamoxifen was first converted to arene oxides which react with DNA or to 4-hydroxytamoxifen, either directly or via 3,4-epoxytamoxifen, which then undergoes activation via a free radical reaction to give reactive intermediates which can then react with DNA and protein, or with themselves, to give the dimers (m/z 773).

Quantitative analysis of phenolic compounds in Chinese hawthorn (Crataegus spp.) fruits by high performance liquid chromatography-electrospray ionisation mass spectrometry.

PubMed

Liu, Pengzhan; Kallio, Heikki; Lü, Deguo; Zhou, Chuansheng; Yang, Baoru

2011-08-01

Eleven major phenolic compounds (hyperoside, isoquercitrin, chlorogenic acid, ideain, epicatechin, two procyanidin (PA) dimers, three PA trimers and a PA dimer-hexoside) were quantified in the fruits of 22 cultivars/origins of three species of the Chinese hawthorn (Crataegus spp.) by HPLC-ESI-MS-SIR. Hyperoside (0.1-0.8mg/g dry mass [DM]), isoquercitrin (0.1-0.3mg/g DM), chlorogenic acid (0.2-1.6mg/g DM), epicatechin (0.9-11.7mg/g DM), PA B2 (0.7-12.4mg/g DM), PA dimer II (0.1-1.5mg/g DM), PA trimer I (0.1-2.7mg/g DM), PA trimer II (0.7-6.9mg/g DM), PA trimer III (0.01-1.2mg/g DM) and a PA dimer-hexoside (trace-1.1mg/g DM) were detected in all the samples. Ideain (0.0-0.7mg/g DM) was found in all the samples except Crataegus scabrifolia. Significant correlations between the contents of individual PA aglycons were observed (r>0.9, P<0.01). A strong correlation between flavonols was also shown (r=0.71, P<0.01). Fruits of Crataegus pinnatifida var. major had higher contents of PAs but lower contents of flavonols compared with Crataegus brettschneideri. The fruits of C. scabrifolia contained the highest level of PA dimer-hexoside, which was present in trace amounts in the fruits of C. pinnatifida. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dimer-based model for heptaspanning membrane receptors.

PubMed

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferré, Sergi; Fuxe, Kjell; Cortés, Antonio; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2005-07-01

The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our two-state-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.

Crystal structure and chemical bonding in the mixed anion compound BaSF.

PubMed

Driss, D; Cadars, S; Deniard, P; Mevellec, J-Y; Corraze, B; Janod, E; Cario, L

2017-11-28

BaSF was synthesised by a solid state reaction at high temperature and its crystal structure was determined thanks to X-ray diffraction on a single crystal. This transparent yellow fluorochalcogenide has an intergrowth structure built from the stacking of fluorite type layers and sulfur layers. In BaSF sulfur atoms form dimers with interatomic distances as short as 2.1074(10) Å. DFT calculations confirm that this compound is a band insulator with the Fermi level lying in between the antibonding π* and σ* molecular orbitals of the sulfur dimers. Reflectance measurements show that the optical band gap of BaSF is about 2.7 eV in good agreement with the value found from DFT calculations.

Two structurally distinct chalcone dimers from Helichrysum zivojinii and their activities in cancer cell lines.

PubMed

Aljančić, Ivana S; Vučković, Ivan; Jadranin, Milka; Pešić, Milica; Dorđević, Iris; Podolski-Renić, Ana; Stojković, Sonja; Menković, Nebojša; Vajs, Vlatka E; Milosavljević, Slobodan M

2014-02-01

Dimers tomoroside A (1) and tomoroside B (2) of the co-occuring known chalcone monomer (3), along with the seven known flavonoid glucosides (4-10), were isolated from the aerial parts of Helichrysum zivojinii Černjavski & Soška. The structures of the isolated compounds were elucidated by spectroscopic techniques. Compound 1 inhibited topo IIα and hif-1α expression and stimulated doxorubicin anticancer effect, while 2 increased the expression of hif-1α, probably acting as antioxidant and redox status modulator. Notably, 2 synergized with Tipifarnib showing potential to improve the action of this new chemotherapeutic involved in the modulation of mitogene activated protein (MAP) kinase signaling pathway. Copyright © 2013 Elsevier Ltd. All rights reserved.

Self-Assembled Pyridine-Dipyrrolate Cages.

PubMed

Zhang, Huacheng; Lee, Juhoon; Lammer, Aaron D; Chi, Xiaodong; Brewster, James T; Lynch, Vincent M; Li, Hao; Zhang, Zhan; Sessler, Jonathan L

2016-04-06

An inherently nonlinear pyridine dipyrrolate ligand, namely 2,6-bis(3,4-diethyl-5-carboxy-1H-pyrrol-2yl)pyridine (compound 1), is able to distinguish between different zinc(II) cation sources, namely Zn(acac)2 and Zn(OAc)2, respectively. This differentiation is manifest both in terms of the observed fluorescent behavior in mixed organic media and the reaction chemistry. Treatment of 1 with Zn(acac)2 gives rise to a cage dimer, cage-1, wherein two molecules of compound 1 act as double bridging units to connect two individual cage subunits. As inferred from X-ray crystallographic studies, this cage system consists of discrete zinc dimers with hydroxide bridges that, with the assistance of bound DMF solvent molecules, serve to fix the geometry and orientation of the pyridine dipyrrolate building blocks. When a different zinc source, Zn(OAc)2, is used to carry out an ostensibly similar complexation reaction with compound 1, an acetate-bridged 1D abacus-like cage polymer is obtained as inferred from X-ray diffraction analysis. This extended solid state structure, cage-2, contains individual zinc dimer cage submits and appears stabilized by solvent molecules (DMF) and the counteranion (acetate). Rod-like assemblies are also observed by DLS and SEM. This construct, in contrast to cage-1, proved fluorescent in mixed organic media. The structure of the ligand itself (i.e., in the absence of Zn(II)) was confirmed by X-ray crystallographic analysis and was found to assemble into a supramolecular polymer. Conversion to a dimer form was seen upon the addition of TBAOAc. On the basis of the metric parameters, the structures seen in the solid state are stabilized via hydrogen bonding interactions involving solvent molecules.

Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium Stiboglucanate Resistance in Leishmania▿

PubMed Central

Wong, Iris L. K.; Chan, Kin-Fai; Burkett, Brendan A.; Zhao, Yunzhe; Chai, Yi; Sun, Hongzhe; Chan, Tak Hang; Chow, Larry M. C.

2007-01-01

Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ∼3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1−/−, LeMDR1+/+, and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania. PMID:17194831

Development of an HTS-Compatible Assay for Discovery of Melanoma-Related Microphthalmia Transcription Factor Disruptors Using AlphaScreen Technology.

PubMed

Wang, Jing; Fang, Pengfei; Chase, Peter; Tshori, Sagi; Razin, Ehud; Spicer, Timothy P; Scampavia, Louis; Hodder, Peter; Guo, Min

2017-01-01

Microphthalmia transcription factor (MITF) is a master transcription factor expressed in melanocytes, essential for melanocyte survival, differentiation, and pigment formation, and is a key oncogenic factor in melanoma initiation, migration, and treatment resistance. Although identified as an important therapeutic target for melanoma, clinical inhibitors directly targeting the MITF protein are not available. Based on the functional state of MITF, we have designed an MITF dimerization-based AlphaScreen (MIDAS) assay that sensitively and specifically mirrors the dimerization of MITF in vitro. This assay is further exploited for identification of the MITF dimer disruptor for high-throughput screening. A pilot screen against a library of 1280 pharmacologically active compounds indicates that the MIDAS assay performance exhibits exceptional results with a Z' factor of 0.81 and a signal-to-background (S/B) ratio of 3.92 while identifying initial hit compounds that yield an ability to disrupt MITF-DNA interaction. The results presented demonstrate that the MIDAS assay is ready to screen large chemical libraries in order to discover novel modulators of MITF for potential melanoma treatment.

Tanshinones and diethyl blechnics with anti-inflammatory and anti-cancer activities from Salvia miltiorrhiza Bunge (Danshen)

NASA Astrophysics Data System (ADS)

Gao, Hongwei; Sun, Wen; Zhao, Jianping; Wu, Xiaxia; Lu, Jin-Jian; Chen, Xiuping; Xu, Qiong-Ming; Khan, Ikhlas A.; Yang, Shilin

2016-09-01

Four novel compounds (1-4) as well as fourteen reported compounds (5-18) were isolated and purified from Salvia miltiorrhiza Bunge (Danshen). The structures of novel compounds were determined by 1D and 2D NMR, HRESIMS data, etc. The anti-inflammatory properties of all the compounds on RAW264.7 macrophages and their cytotoxicity on H1299 and Bel-7402 cell lines coupled with a structure-activity relationship (SAR) were investigated. Compound 4 demonstrated the best anti-inflammatory activity and was chosen for further research. Compound 4 greatly suppressed secretion of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) in the RAW264.7 macrophages stimulated by LPS. Additionally, the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was decreased and the nuclear translocation of NF-κB was attenuated after treatment with compound 4 in vitro. Compound 4 was able to dramatically inhibit LPS-induced activation of JNK1/2 and ERK1/2 and remarkably disrupted the TLR4 dimerization in LPS-induced RAW264.7 macrophages. Thus, the new compound 4 suppressed LPS-induced inflammation partially is due to the blocking TLR4 dimerization. In addition, the anti-cancer activity investigation indicated that most of isolated compounds exhibited cytotoxicity and the SAR analysis showed that the intact D ring was indispensable and unsaturated D ring played vital role.

Statistical transmutation in doped quantum dimer models.

PubMed

Lamas, C A; Ralko, A; Cabra, D C; Poilblanc, D; Pujol, P

2012-07-06

We prove a "statistical transmutation" symmetry of doped quantum dimer models on the square, triangular, and kagome lattices: the energy spectrum is invariant under a simultaneous change of statistics (i.e., bosonic into fermionic or vice versa) of the holes and of the signs of all the dimer resonance loops. This exact transformation enables us to define the duality equivalence between doped quantum dimer Hamiltonians and provides the analytic framework to analyze dynamical statistical transmutations. We investigate numerically the doping of the triangular quantum dimer model with special focus on the topological Z(2) dimer liquid. Doping leads to four (instead of two for the square lattice) inequivalent families of Hamiltonians. Competition between phase separation, superfluidity, supersolidity, and fermionic phases is investigated in the four families.

Phase transitions in nanocomposites of hydrogen-bonded dimeric liquid crystals with mesogenic and non-mesogenic components

NASA Astrophysics Data System (ADS)

Katranchev, Boyko; Petrov, Minko

2016-02-01

Microtextural polarization, phase transitions, and electro-optical effects are studied in a series of nanocomposites, grown by mixing alkyloxybenzoic acids (nOBAs), displaying hydrogen-bonded dimeric liquid crystal (LC) state, with non-mesogens (single-walled carbon nanotubes (SWCNTs), perfluorooctanoic acid) or mesogens (bent-core LC compound D14F3). Each of the studied nanocomposites, in which the nOBA serves as a matrix, forms complexes with bent-shaped dimeric, caused by the interaction between the dopant structural units and the dimer rings. This feature, coordinated with the surface anchoring, bulk and electrical effects, leads to drastic reduction of the LC system symmetry. As a result, transitions from achiral (characteristic for the pristine nOBA) to chiral states (including ferroelectric smectic C with C2 symmetry and ferroelectric smectic CG with the lowest C1 triclinic one) take place. The functionalization of the SWCNTs causes drastic increase of the ferroelectricity.

Rational Organization of Lanthanide-Based SMM Dimers into Three-Dimensional Networks.

PubMed

Yi, Xiaohui; Calvez, Guillaume; Daiguebonne, Carole; Guillou, Olivier; Bernot, Kevin

2015-06-01

Optimization of the reaction of [Ln(hfac)3]·2H2O and pyridine-N-oxide (PyNO), which is known to afford double-bridged dimers, leads to triple-bridged dimers of formula [(Ln(hfac)3)2(PyNO)3] (Ln = Gd (1), Dy (2)) from which the Dy derivative (2) behaves as a single-molecule magnet (SMM). The pseudo threefold axis symmetry of this zero-dimensional building block makes possible its extension into a tridimensional network. By changing PyNO for 4,4'-bipyridine N,N'-dioxide (4,4'BipyNO) a tridimensional compound of formula {[Ln(hfac)3]2(4,4'BipyNO)2]} (Ln = Eu (3), Gd (4), and Dy (5)) is then rationally obtained. This covalent three-dimensional (3D) network has a remarkably high cell volume (V = 24 419 A(3)) and is an arrangement of interpenetrated 3D subnetworks whose triple-bridged dimers still behave as SMMs.

Electronic structure and acid-base properties of Kojic acid and its dimers. A DFT and quantum topology study

NASA Astrophysics Data System (ADS)

Aziz, Saadullah G.; Alyoubi, Abdulrahman O.; Elroby, Shaaban A.; Hilal, Rifaat H.

2017-10-01

Kojic acid is a polyfunctional heterocyclic compound, with several important reaction centres; it has a wide range of applications in the cosmetic, medicine, food, agriculture and chemical industries. The present study aims at better insight into its electronic structure and bonding characteristics. Thus, density functional theory at the M06-2x /6-311++G** level of theory is used to investigate its ground state electronic and acid-base properties. Protonation and deprotonation enthalpies are computed and analysed. The ability of Kojic acid to form both water complexes and dimers is explored. Several different complexes and dimer structures were examined. Natural bond order and quantum topology features of the charge density were analysed. The origin of the stability of the studied complexes and dimer structures can be traced to hydrogen bonding, π-conjugative and non-covalent dispersive interactions.

Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities.

PubMed

Reiter, Christoph; Fröhlich, Tony; Gruber, Lisa; Hutterer, Corina; Marschall, Manfred; Voigtländer, Cornelia; Friedrich, Oliver; Kappes, Barbara; Efferth, Thomas; Tsogoeva, Svetlana B

2015-09-01

New pharmaceutically active compounds can be obtained by modification of existing drugs to access more effective agents in the wake of drug resistance amongst others. To achieve this goal the concept of hybridization was established during the last decade. We employed this concept by coupling two artemisinin-derived precursors to obtain dimers or trimers with increased in vitro activity against Plasmodiumfalciparum 3D7 strain, leukemia cells (CCRF-CEM and multidrug-resistant subline CEM/ADR5000) and human cytomegalovirus (HCMV). Dimer 4 (IC50 of 2.6 nM) possess superior antimalarial activity compared with its parent compound artesunic acid(3) (IC50 of 9.0 nM). Dimer5 and trimers6 and 7 display superior potency against both leukemia cell lines (IC50 up to 0.002 μM for CCRF-CEM and IC50 up to 0.20 μM for CEM/ADR5000) and are even more active than clinically used doxorubicin (IC50 1.61 μM for CEM/ADR5000). With respect to anti-HCMV activity, trimer6 is the most efficient hybrid (IC50 0.04 μM) outperforming ganciclovir (IC50 2.6 μM), dihydroartemisinin(IC50 >10 μM) and artesunic acid (IC50 3.8 μM). Copyright © 2015 Elsevier Ltd. All rights reserved.

THE SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME 4-HYDROXYCOUMARIN DERIVATIVES

PubMed Central

Završnik, Davorka; Muratović, Samija; Špirtović, Selma; Softić, Dženita; Medić-Šarić, Marica

2008-01-01

Due to exceptional reactivity of 4-hydroxycoumarin, the synthesis of new coumarin derivatives of dimer and tetramer type has been carried out. The synthesis was carried out from 4-hydroxycoumarin and various aromatic aldehydes. In this way, compounds of the dimer 3,3’-(benzilidene)bis (4-hydroxycoumarin) type, as well as of the tetramer 3,3,’3’,’3’’’-(1,4-dim- ethylenphenyl)tetra (4-hydroxycoumarin) type were prepared. The newly synthesized derivatives contain different functional groups, and as such they could exhibit microbiological activity. Therefore, we tested the microbiological activity of these derivatives on various species of bacteria and fungi. The tested compounds have shown different activity in terms of growth inhibition of microorganisms. Newly synthesized derivatives exhibit antibacterial activities, manifested as growth inhibition on Grampositive bacteria types (Bacillus, Staphylococcus), while the activity against Candida was much weaker. The same compound did not show any antimicrobial activity against two Gram-negative bacteria types (Escherichia coli, Pseudomonas aeruginosa). The compound 1 showed the best microbiological activity. The obtained results confirmed its good antibacterial and antimycotic activities against different microorganisms. PMID:18816263

Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation.

PubMed

Fulton, Melody D; Hanold, Laura E; Ruan, Zheng; Patel, Sneha; Beedle, Aaron M; Kannan, Natarajan; Kennedy, Eileen J

2018-03-15

Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide "stapling" to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cyclobutane pyrimidine dimers are photosensitised by carprofen plus UVA in human HaCaT cells.

PubMed

Robinson, K S; Traynor, N J; Moseley, H; Ferguson, J; Woods, J A

2010-06-01

Every year in the UK about 75,000 cases of non-melanoma skin cancer (NMSC) are registered, and about 9500 people are diagnosed with cutaneous melanoma (CM). The main risk factor for these cancers is exposure to sunlight. The effects of light on skin are wavelength dependent, with wavelengths in the UVB waveband (280-315 nm) being the most carcinogenic. UVB is directly absorbed by DNA, producing dimeric pyrimidine photoproducts including cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimodone photoproducts (6-4PP). However UVA (315-400 nm) can also produce CPD, induce skin tumours in mice, and has been shown to be mutagenic in cell culture. Although the precise role of UVA in human skin cancer remains to be elucidated, it comprises the major portion of solar UV radiation, transmits through window glass and can be delivered in high doses from tanning lamps. Non-steroidal anti-inflammatory drugs (NSAIDs), in particular the 2-aryl propionic acid derivatives, are a well-documented group of photosensitising chemicals producing clinical phototoxic and photoallergic reactions. We have used carprofen, a model compound from this group to see if it could amplify the effects of UVA and contribute to the formation of CPD by UVA. Preliminary work has shown that carprofen combined with low doses of UVA (lambda(max): 365 nm; 5 J/cm(2)) can produce both strand breaks (SB) and CPD in human skin or blood cells. CPD were detected indirectly by both an immunofluorescence method and as T4 endonuclease V sensitive sites in the comet assay. These findings show that compounds other than fluoroquinolones and psoralen derivatives may contribute to CPD formation in skin cells in combination with UVA. Copyright 2010 Elsevier Ltd. All rights reserved.

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication.

PubMed

Thenin-Houssier, Suzie; de Vera, Ian Mitchelle S; Pedro-Rosa, Laura; Brady, Angela; Richard, Audrey; Konnick, Briana; Opp, Silvana; Buffone, Cindy; Fuhrmann, Jakob; Kota, Smitha; Billack, Blase; Pietka-Ottlik, Magdalena; Tellinghuisen, Timothy; Choe, Hyeryun; Spicer, Timothy; Scampavia, Louis; Diaz-Griffero, Felipe; Kojetin, Douglas J; Valente, Susana T

2016-04-01

The human immunodeficiency virus type 1 (HIV-1) capsid plays crucial roles in HIV-1 replication and thus represents an excellent drug target. We developed a high-throughput screening method based on a time-resolved fluorescence resonance energy transfer (HTS-TR-FRET) assay, using the C-terminal domain (CTD) of HIV-1 capsid to identify inhibitors of capsid dimerization. This assay was used to screen a library of pharmacologically active compounds, composed of 1,280in vivo-active drugs, and identified ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], an organoselenium compound, as an inhibitor of HIV-1 capsid CTD dimerization. Nuclear magnetic resonance (NMR) spectroscopic analysis confirmed the direct interaction of ebselen with the HIV-1 capsid CTD and dimer dissociation when ebselen is in 2-fold molar excess. Electrospray ionization mass spectrometry revealed that ebselen covalently binds the HIV-1 capsid CTD, likely via a selenylsulfide linkage with Cys198 and Cys218. This compound presents anti-HIV activity in single and multiple rounds of infection in permissive cell lines as well as in primary peripheral blood mononuclear cells. Ebselen inhibits early viral postentry events of the HIV-1 life cycle by impairing the incoming capsid uncoating process. This compound also blocks infection of other retroviruses, such as Moloney murine leukemia virus and simian immunodeficiency virus, but displays no inhibitory activity against hepatitis C and influenza viruses. This study reports the use of TR-FRET screening to successfully identify a novel capsid inhibitor, ebselen, validating HIV-1 capsid as a promising target for drug development. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Lignin peroxidase-catalyzed oxidation of nonphenolic trimeric lignin model compounds: fragmentation reactions in the intermediate radical cations.

PubMed

Baciocchi, Enrico; Fabbri, Claudia; Lanzalunga, Osvaldo

2003-11-14

The H(2)O(2)-promoted oxidations of the two nonphenolic beta-O-aryl lignin model trimers 1 and 2, catalyzed by lignin peroxidase (LiP) at pH = 3.5, have been studied. The results have been compared with those obtained in the oxidation of 1 and 2 with the genuine one-electron oxidant potassium 12-tungstocobalt(III)ate. These models present a different substitution pattern of the three aromatic rings, and by one-electron oxidation, they form radical cations with the positive charge, which is localized in the dialkoxylated ring as also evidenced by a pulse radiolysis study. Both the oxidations with the enzymatic and with the chemical systems lead to the formation of products deriving from the cleavage of C-C and C-H bonds in a beta position with respect to the radical cation with the charge residing in the dialkoxylated ring (3,4-dimethoxybenzaldehyde (5) and a trimeric ketone 6 in the oxidation of 1 and a dimeric aldehyde 8 and a trimeric ketone 9 in the oxidation of 2). These products are accompanied by a dimeric aldehyde 7 in the oxidation of 1 and 4-methoxybenzaldehyde (10) in the oxidation of 2. The unexpected formation of these two products has been explained by suggesting that 1.+ and 2.+ can also undergo an intramolecular electron transfer leading to the radical cations 1a.+ and 2a.+ with the charge residing in a monoalkoxylated ring. The fast cleavage of a C-C bond beta to this ring, leading to 7 from 1.+ and to 10 from 2.+, is the driving force of the endoergonic electron transfer. A kinetic steady-state investigation of the LiP-catalyzed oxidation of the trimer 2, the dimeric model 1-(3,4-dimethoxyphenyl)-2-phenoxy-1-ethanol (4), and 3,4-dimethoxybenzyl alcohol (3) has indicated that the turnover number (k(cat)) and the affinity for the enzyme decrease significantly by increasing the size of the model compound. In contrast, the three substrates exhibited a very similar reactivity toward a chemical oxidant [Co(III)W]. This suggests a size-dependent interaction of the enzyme with the substrate which may influence the efficiency of the electron transfer.

Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photodimers

PubMed Central

McCracken, Stephen T.; Kaiser, Marcel; Boshoff, Helena I.; Boyd, Peter D. W.; Copp, Brent R.

2012-01-01

Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards. infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesised. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and T. cruzi. Of the styryl-pyranones, natural product 3 and non-natural styrene and naphthalene substituted examples 13, 18, 21, 22 and 23 exhibited antimalarial activity (IC50 < 10 μM) with selectivity indices (SI) > 10. Δ7 Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC50s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers 31 and 33 were identified as being moderately active towards P. falciparum (IC50 1.5 and 1.7 μM) with good selectivity (SI ∼ 80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC50 4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis. PMID:22285027

Charge disproportionation in tetragonal La2MoO5, a small band gap semiconductor influenced by direct Mo-Mo bonding.

PubMed

Colabello, Diane M; Camino, Fernando E; Huq, Ashfia; Hybertsen, Mark; Khalifah, Peter G

2015-01-28

The structure of the novel compound La2MoO5 has been solved from powder X-ray and neutron diffraction data and belongs to the tetragonal space group P4/m (no. 83) with a = 12.6847(3) Å and c = 6.0568(2) Å and with Z = 8. It consists of equal proportions of bioctahedral (Mo2O10) and square prismatic (Mo2O8) dimers, both of which contain direct Mo-Mo bonds and are arranged in 1D chains. The Mo-Mo bond length in the Mo2O10 dimers is 2.684(8) Å, while there are two types of Mo2O8 dimers with Mo-Mo bonds lengths of 2.22(2) and 2.28(2) Å. Although the average Mo oxidation state in La2MoO5 is 4+, the very different Mo-Mo distances reflect the fact that the Mo2O10 dimers contain only Mo(5+) (d(1)), while the prismatic Mo2O8 dimers only contain Mo(3+) (d(3)), a result directly confirmed by density function theory calculations. This is due to the complete disproportionation of Mo(4+), a phenomenon which has not previously been observed in solid-state compounds. La2MoO5 is diamagnetic, behavior which is not expected for a nonmetallic transition-metal oxide whose cation sites have an odd number of d-electrons. The resistivity displays the Arrhenius-type activated behavior expected for a semiconductor with a band gap of 0.5 eV, exhibiting an unusually small transport gap relative to other diamagnetic oxides. Diffuse reflectance studies indicate that La2MoO5 is a rare example of a stable oxide semiconductor with strong infrared absorbance. It is shown that the d-orbital splitting associated with the Mo2O8 and Mo2O10 dimeric units can be rationalized using simple molecular orbital bonding concepts.

Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State.

PubMed

Kalra, Arjun; Tishmack, Patrick; Lubach, Joseph W; Munson, Eric J; Taylor, Lynne S; Byrn, Stephen R; Li, Tonglei

2017-06-05

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid-pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid-acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid-pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid-pyridine chains. Conversely, for the compounds that form acid-acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization.

Development and validation of a high-content bimolecular fluorescence complementation assay for small-molecule inhibitors of HIV-1 Nef dimerization.

PubMed

Poe, Jerrod A; Vollmer, Laura; Vogt, Andreas; Smithgall, Thomas E

2014-04-01

Nef is a human immunodeficiency virus 1 (HIV-1) accessory factor essential for viral pathogenesis and AIDS progression. Many Nef functions require dimerization, and small molecules that block Nef dimerization may represent antiretroviral drug leads. Here we describe a cell-based assay for Nef dimerization inhibitors based on bimolecular fluorescence complementation (BiFC). Nef was fused to nonfluorescent, complementary fragments of yellow fluorescent protein (YFP) and coexpressed in the same cell population. Dimerization of Nef resulted in juxtaposition of the YFP fragments and reconstitution of the fluorophore. For automation, the Nef-YFP fusion proteins plus a monomeric red fluorescent protein (mRFP) reporter were expressed from a single vector, separated by picornavirus "2A" linker peptides to permit equivalent translation of all three proteins. Validation studies revealed a critical role for gating on the mRFP-positive subpopulation of transfected cells, as well as use of the mRFP signal to normalize the Nef-BiFC signal. Nef-BiFC/mRFP ratios resulting from cells expressing wild-type versus dimerization-defective Nef were very clearly separated, with Z factors consistently in the 0.6 to 0.7 range. A fully automated pilot screen of the National Cancer Institute Diversity Set III identified several hit compounds that reproducibly blocked Nef dimerization in the low micromolar range. This BiFC-based assay has the potential to identify cell-active small molecules that directly interfere with Nef dimerization and function.

Development and Validation of a High-Content Bimolecular Fluorescence Complementation Assay for Small Molecule Inhibitors of HIV-1 Nef Dimerization

PubMed Central

Poe, Jerrod A.; Vollmer, Laura; Vogt, Andreas; Smithgall, Thomas E.

2014-01-01

Nef is an HIV-1 accessory factor essential for viral pathogenesis and AIDS progression. Many Nef functions require dimerization, and small molecules that block Nef dimerization may represent antiretroviral drug leads. Here we describe a cell-based assay for Nef dimerization inhibitors based on bimolecular fluorescence complementation (BiFC). Nef was fused to non-fluorescent, complementary fragments of YFP and co-expressed in the same cell population. Dimerization of Nef resulted in juxtaposition of the YFP fragments and reconstitution of the fluorophore. For automation, the Nef-YFP fusion proteins plus an mRFP reporter were expressed from a single vector, separated by picornavirus ‘2A’ linker peptides to permit equivalent translation of all three proteins. Validation studies revealed a critical role for gating on the mRFP-positive subpopulation of transfected cells, as well as use of the mRFP signal to normalize the Nef-BiFC signal. Nef-BiFC/mRFP ratios resulting from cells expressing wild-type vs. dimerization-defective Nef were very clearly separated, with Z-factors consistently in the 0.6–0.7 range. A fully automated pilot screen of the NIH Diversity Set III identified several hit compounds that reproducibly blocked Nef dimerization in the low micromolar range. This BiFC-based assay has the potential to identify cell-active small molecules that directly interfere with Nef dimerization and function. PMID:24282155

Vibrational spectra of Mg2KH(XO4)2·15H2O (X = P, As) containing dimer units [H(XO4)2

NASA Astrophysics Data System (ADS)

Stefov, V.; Koleva, V.; Najdoski, M.; Abdija, Z.; Cahil, A.; Šoptrajanov, B.

2017-08-01

Infrared and Raman spectra of Mg2KH(PO4)2·15H2O and Mg2KH(AsO4)2·15H2O and a series of their partially deuterated analogues were recorded and analyzed. Compounds of the type Mg2KH(XO4)2·15H2O (X = P, As) are little-known and a rare case of phosphate and arsenate salts containing dimer units [H(XO4)2] in the crystal structure. The analysis of their IR spectra (recorded at room and liquid nitrogen temperature) and Raman spectra showed that the spectral characteristics of the XO4 groups connected in a dimer through a proton are not consistent with the presence of X-O-H covalent linkage and C1 crystallographic symmetry of the XO4 groups. The observation of a singlet Raman band for the ν1(XO4) mode as well as the absence of substantial splitting of the ν3(XO4) modes and IR activation of the ν1(XO4) mode suggest that the dimer units [H(XO4)2] are most probably symmetric rather than non-symmetric ones. It was found that, in the vibrational spectra of Mg2KH(AsO4)2·15H2O, both ν1(AsО4) and ν3(AsО4) modes have practically the same wavenumber around 830 cm- 1. It was also established that the ν4(PО4) modes in the deuterated hydrogendiphosphate compound are strongly coupled, most probably with HDO and/or D2O librations. As a whole, the spectral picture of Mg2KH(XO4)2·15H2O (X = P, As) very much resembles that observed for the struvite type compounds with the formula KMgXO4·6H2O (X = P, As) which do not contain X-OH groups. This means that vibrations of the dimers [H(XO4)2] play a relatively small part in the general spectral appearance.

Vibrational spectra of Mg2KH(XO4)2·15H2O (X=P, As) containing dimer units [H(XO4)2].

PubMed

Stefov, V; Koleva, V; Najdoski, M; Abdija, Z; Cahil, A; Šoptrajanov, B

2017-08-05

Infrared and Raman spectra of Mg 2 KH(PO 4 ) 2 ·15H 2 O and Mg 2 KH(AsO 4 ) 2 ·15H 2 O and a series of their partially deuterated analogues were recorded and analyzed. Compounds of the type Mg 2 KH(XO 4 ) 2 ·15H 2 O (X=P, As) are little-known and a rare case of phosphate and arsenate salts containing dimer units [H(XO 4 ) 2 ] in the crystal structure. The analysis of their IR spectra (recorded at room and liquid nitrogen temperature) and Raman spectra showed that the spectral characteristics of the XO 4 groups connected in a dimer through a proton are not consistent with the presence of X-O-H covalent linkage and C 1 crystallographic symmetry of the XO 4 groups. The observation of a singlet Raman band for the ν 1 (XO 4 ) mode as well as the absence of substantial splitting of the ν 3 (XO 4 ) modes and IR activation of the ν 1 (XO 4 ) mode suggest that the dimer units [H(XO 4 ) 2 ] are most probably symmetric rather than non-symmetric ones. It was found that, in the vibrational spectra of Mg 2 KH(AsO 4 ) 2 ·15H 2 O, both ν 1 (AsО 4 ) and ν 3 (AsО 4 ) modes have practically the same wavenumber around 830cm -1 . It was also established that the ν 4 (PО 4 ) modes in the deuterated hydrogendiphosphate compound are strongly coupled, most probably with HDO and/or D 2 O librations. As a whole, the spectral picture of Mg 2 KH(XO 4 ) 2 ·15H 2 O (X=P, As) very much resembles that observed for the struvite type compounds with the formula KMgXO 4 ·6H 2 O (X=P, As) which do not contain X-OH groups. This means that vibrations of the dimers [H(XO 4 ) 2 ] play a relatively small part in the general spectral appearance. Copyright © 2017 Elsevier B.V. All rights reserved.

2-[2-(3-Chloro­phen­yl)hydrazinyl­idene]-1,3-diphenyl­propane-1,3-dione

PubMed Central

Bustos, Carlos; Alvarez-Thon, Luis; Cárcamo, Juan-Guillermo; Ibañez, Andrés; Sánchez, Christian

2011-01-01

The mol­ecular structure of the title compound, C21H15ClN2O2, features one strong intra­molecular N—H⋯O resonance-assisted hydrogen bond (RAHB). In the crystal, mol­ecules form inversion-related dimers via pairs of weak inter­molecular N—H⋯O contacts. These dimers are further stabilized via three weak C—H⋯O contacts, developing the three-dimensional structure. PMID:21754825

[Cochinchinenin--a new chalcone dimer from the Chinese dragon blood].

PubMed

Zhou, Z H; Wang, J L; Yang, C R

2001-03-01

To study the active constituents of Dracaena cochinchinensis (Lour.) S.C. Chen. in the commercial dragon blood. Various column chromatographies with Sephadex L-20 gel, MCI gel and silica gel were employed for the isolation and purification. The structures of compounds were elucidated by spectral analysis. Nine chalcones were isolated from the commercial dragon's blood which was made of D. cochinchinensis (Lour.) S.C. Chen.. By means of spectral data, they were identified as 1-[5-(2,4,4'-trihydroxydihydrochalconyl)]-1- (p-hydroxyphenyl)-3-(2-methoxy-4-hydroxy-phenyl)-propane (1), 2'-methoxysocotrin-5'-ol (2), socotrin-4'-ol (3), 2-methoxy-4, 4'-dihydroxydihydrochalcone (4), 2, 4, 4'-trihydroxy-dihydrochalcone (5), 2, 4, 4'-trihydroxy-6-methoxydihydrochalcone (6), 2', 4', 4-trihydroxychalcone (7), 2-methoxy-4, 4'-dihydroxychalcone (8) and 2'-methoxy-4', 4-dihydroxychalcone (9). Compound 1 is a new chalcone dimer and named as cochinchinenin. Compounds 2-9 were isolated from D. cochinchinensis (Lour.) S.C. Chen. for the first time.

Monomeric and dimeric hydrolysable tannins of Tamarix nilotica.

PubMed

Orabi, Mohamed A A; Taniguchi, Shoko; Hatano, Tsutomu

2009-07-01

An ellagitannin monomer, nilotinin M1 (1), and three dimers, nilotinins D1 (2), D2 (3), and D3 (4), were isolated from leaves of Tamarix nilotica (Ehrenb.) Bunge. Structures were elucidated based on analysis of spectroscopic data and chemical correlations with known compounds. In addition, six known tannins, hirtellin A (5) (dimer), remurin A (6), remurin B (7), 1,3-di-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl-beta-D-glucose (8), gemin D (9), and hippomanin A (10) (monomers), were isolated for the first time from this plant species. The reported (13)C NMR assignments of the dehydrodigalloyl moiety and glucose cores of 5 are revised, and the (13)C NMR spectroscopic data for 6 and 7 are also reported for the first time.

Tests of Si(111)-7 × 7 structural models by comparison with transmission electron diffraction patterns

NASA Astrophysics Data System (ADS)

McRae, E. G.; Petroff, P. M.

1984-11-01

Several structural models of the Si(111)-7 × 7 surface are tested by comparing calculated and observed transmission electron diffraction (TED) patterns. The models comprise "adatom" models where the unit mesh contains 12 adatoms or atom clusters in a locally (2 × 2) arrangement, and "triangle-dimer" models where the unit mesh contains 9 dimers or pairs of dimers bordering a triangular subunit of the unit mesh. The distribution of diffraction intensity among fractional-order spots is calculated kinematically and compared with TED patterns observed by Petroff and Wilson and others. No agreement is found for adatom models. Good but not perfect agreement is found for one triangle-dimer model.

Binding Energies of Proton-Bound Dimers of Imidazole and n-Acetylalanine Methyl Ester Obtained by Blackbody Infrared Radiative Dissociation

PubMed Central

Jockusch, Rebecca A.; Williams*, Evan R.

2005-01-01

The dissociation kinetics of protonated n-acetyl-L-alanine methyl ester dimer (AcAlaMEd), imidazole dimer, and their cross dimer were measured using blackbody infrared radiative dissociation (BIRD). Master equation modeling of these data was used to extract threshold dissociation energies (Eo) for the dimers. Values of 1.18 ± 0.06, 1.11 ± 0.04, and 1.12 ± 0.08 eV were obtained for AcAlaMEd, imidazole dimer, and the cross dimer, respectively. Assuming that the reverse activation barrier for dissociation of the ion–molecule complex is negligible, the value of Eo can be compared to the dissociation enthalpy (ΔHd°) from HPMS data. The Eo values obtained for the imidazole dimer and the cross dimer are in agreement with HPMS values; the value for AcAlaMEd is somewhat lower. Radiative rate constants used in the master equation modeling were determined using transition dipole moments calculated at the semiempirical (AM1) level for all dimers and compared to ab initio (RHF/3-21G*) calculations where possible. To reproduce the experimentally measured dissociation rates using master equation modeling, it was necessary to multiply semiempirical transition dipole moments by a factor between 2 and 3. Values for transition dipole moments from the ab initio calculations could be used for two of the dimers but appear to be too low for AcAlaMEd. These results demonstrate that BIRD, in combination with master equation modeling, can be used to determine threshold dissociation energies for intermediate size ions that are in neither the truncated Boltzmann nor the rapid energy exchange limit. PMID:16604163

Studies on the Effect of Sub-zero Temperatures on the Formation of Extremely Low Volatility Dimer Esters in Secondary Organic Aerosol from Alpha-Pinene

NASA Astrophysics Data System (ADS)

Kristensen, Kasper; Normann Jensen, Louise; Bilde, Merete

2016-04-01

The oxidation of volatile organic compounds (VOC) is considered a major source of secondary organic aerosols (SOA) in the atmosphere. Recently, extremely low volatility organic compounds, or ELVOC, formed from the oxidation of VOCs have been shown to play a crucial role in new particle formation (Ehn et al., 2014). In addition, higher molecular weight dimer esters originating from the oxidation of the biogenic VOC alpha-pinene have been observed in both laboratory-generated and ambient SOA (Kristensen et al., 2013). The low volatility of the dimer esters along with an observed rapid formation makes these high molecular weight compounds likely candidates involved in new particle formation from the oxidation of alpha-pinene. Furthermore, laboratory experiments show that the dimer esters only form in the presence of ozone, thus may be used as tracers for the ozone-initiated oxidation of alpha-pinene, and are therefore indicative of enhanced anthropogenic activities. In this work, we present the results of a series of oxidation experiments performed in the newly constructed cold-room smog chamber at Aarhus University. This unique and state-of-the-art Teflon chamber allows for atmospheric simulations of the oxidation VOCs and subsequent SOA formation at temperatures down to -16 °C. In this study, ozonolysis and photochemical oxidations of alpha-pinene are performed at temperatures ranging from +20 to -16 °C. Chemical characterization of the formed SOA is performed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The results show significant differences in the chemical composition related to the experiment temperature. In particularly, the concentration of the high molecular weight dimer esters showed to be highly affected by temperature. Interestingly, preliminary results show higher formation of dimer esters related to increased SOA formation rate, thus indicating that these particle-phase ELVOCs may be linked with new particle formation. Ehn, M., Thornton, J. A., Kleist, E., Sipila, M., Junninen, H., Pullinen, I., Springer, M., Rubach, F., Tillmann, R., Lee, B., Lopez-Hilfiker, F., Andres, S., Acir, I. H., Rissanen, M., Jokinen, T., Schobesberger, S., Kangasluoma, J., Kontkanen, J., Nieminen, T., Kurten, T., Nielsen, L. B., Jorgensen, S., Kjaergaard, H. G., Canagaratna, M., Dal Maso, M., Berndt, T., Petaja, T., Wahner, A., Kerminen, V. M., Kulmala, M., Worsnop, D. R., Wildt, J., and Mentel, T. F.: A large source of low-volatility secondary organic aerosol, Nature, 506, 476-+, 10.1038/nature13032, 2014. Kristensen, K., Enggrob, K. L., King, S. M., Worton, D. R., Platt, S. M., Mortensen, R., Rosenoern, T., Surratt, J. D., Bilde, M., Goldstein, A. H., and Glasius, M.: Formation and occurrence of dimer esters of pinene oxidation products in atmospheric aerosols, Atmospheric Chemistry and Physics, 13, 3763-3776, 2013.

L-Cysteine halogenides: A new family of salts with an L-cysteine⋯L-cysteinium dimeric cation

NASA Astrophysics Data System (ADS)

Ghazaryan, V. V.; Minkov, V. S.; Boldyreva, E. V.; Petrosyan, A. M.

2016-10-01

Two L-cysteinium-halogenides with (L-cysteine···L-cysteinium) dimeric cations have been obtained, (L-Cys⋯L-Cys+)·Cl-, and (L-Cys⋯L-Cys+)·Br-. Both salts crystallize in monoclinic space group P21. Although these salts have the same dimeric cations and isotypical halogen anions, crystal packing is different. The main difference between the two salts rests in the conformation of (L-Cys⋯L-Cys+) dimeric cation, which also differs from that of the dimeric cation in the previously reported compound L-Cys+(L-Cys⋯L-Cys+)·F-·(F-⋯HF). The dimeric cation is formed by a very short O-H⋯O hydrogen bond with d(O···O) of 2.449(2) Å and 2.435(11) Å in the chloride and bromide, respectively. In addition to crystal structure analysis, Infrared and Raman spectra have been registered and discussed with a particular focus on intermolecular interactions. The L-Cys+·Br-·H2O salt with a simple L-cysteinium cation was also obtained and the crystal structure solved. It resembles its chloride analogue, L-Cys+·Cl-·H2O.

Mechanism of Inducible Nitric-oxide Synthase Dimerization Inhibition by Novel Pyrimidine Imidazoles*

PubMed Central

Nagpal, Latika; Haque, Mohammad M.; Saha, Amit; Mukherjee, Nirmalya; Ghosh, Arnab; Ranu, Brindaban C.; Stuehr, Dennis J.; Panda, Koustubh

2013-01-01

Overproduction of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) has been etiologically linked to several inflammatory, immunological, and neurodegenerative diseases. As dimerization of NOS is required for its activity, several dimerization inhibitors, including pyrimidine imidazoles, are being evaluated for therapeutic inhibition of iNOS. However, the precise mechanism of their action is still unclear. Here, we examined the mechanism of iNOS inhibition by a pyrimidine imidazole core compound and its derivative (PID), having low cellular toxicity and high affinity for iNOS, using rapid stopped-flow kinetic, gel filtration, and spectrophotometric analysis. PID bound to iNOS heme to generate an irreversible PID-iNOS monomer complex that could not be converted to active dimers by tetrahydrobiopterin (H4B) and l-arginine (Arg). We utilized the iNOS oxygenase domain (iNOSoxy) and two monomeric mutants whose dimerization could be induced (K82AiNOSoxy) or not induced (D92AiNOSoxy) with H4B to elucidate the kinetics of PID binding to the iNOS monomer and dimer. We observed that the apparent PID affinity for the monomer was 11 times higher than the dimer. PID binding rate was also sensitive to H4B and Arg site occupancy. PID could also interact with nascent iNOS monomers in iNOS-synthesizing RAW cells, to prevent their post-translational dimerization, and it also caused irreversible monomerization of active iNOS dimers thereby accomplishing complete physiological inhibition of iNOS. Thus, our study establishes PID as a versatile iNOS inhibitor and therefore a potential in vivo tool for examining the causal role of iNOS in diseases associated with its overexpression as well as therapeutic control of such diseases. PMID:23696643

Stabilization of higher-valent states of iron porphyrin by hydroxide and methoxide ligands: electrochemical generation of iron(IV)-oxo porphyrins.

PubMed Central

Lee, W A; Calderwood, T S; Bruice, T C

1985-01-01

An electrochemical study of hydroxide- and methoxide-ligated iron(III) tetraphenylporphyrins possessing ortho-phenyl substituents that block mu-oxo dimer formation has been carried out. Ligation by these strongly basic oxyanions promotes the formation of iron(IV)-oxo porphyrins upon one-electron oxidation. Further one-electron oxidation of the latter provides the iron(IV)-oxo porphyrin pi-cation radical. These results are discussed in terms of chemical model studies and the enzymatic intermediate compounds I and II of the peroxidases. PMID:3859865

Exact Solution of a Two-Species Quantum Dimer Model for Pseudogap Metals

NASA Astrophysics Data System (ADS)

Feldmeier, Johannes; Huber, Sebastian; Punk, Matthias

2018-05-01

We present an exact ground state solution of a quantum dimer model introduced by Punk, Allais, and Sachdev [Quantum dimer model for the pseudogap metal, Proc. Natl. Acad. Sci. U.S.A. 112, 9552 (2015)., 10.1073/pnas.1512206112], which features ordinary bosonic spin-singlet dimers as well as fermionic dimers that can be viewed as bound states of spinons and holons in a hole-doped resonating valence bond liquid. Interestingly, this model captures several essential properties of the metallic pseudogap phase in high-Tc cuprate superconductors. We identify a line in parameter space where the exact ground state wave functions can be constructed at an arbitrary density of fermionic dimers. At this exactly solvable line the ground state has a huge degeneracy, which can be interpreted as a flat band of fermionic excitations. Perturbing around the exactly solvable line, this degeneracy is lifted and the ground state is a fractionalized Fermi liquid with a small pocket Fermi surface in the low doping limit.

Dynamics and kinetics of reversible homo-molecular dimerization of polycyclic aromatic hydrocarbons

NASA Astrophysics Data System (ADS)

Mao, Qian; Ren, Yihua; Luo, K. H.; van Duin, Adri C. T.

2017-12-01

Physical dimerization of polycyclic aromatic hydrocarbons (PAHs) has been investigated via molecular dynamics (MD) simulation with the ReaxFF reactive force field that is developed to bridge the gap between the quantum mechanism and classical MD. Dynamics and kinetics of homo-molecular PAH collision under different temperatures, impact parameters, and orientations are studied at an atomic level, which is of great value to understand and model the PAH dimerization. In the collision process, the enhancement factors of homo-molecular dimerizations are quantified and found to be larger at lower temperatures or with smaller PAH instead of size independent. Within the capture radius, the lifetime of the formed PAH dimer decreases as the impact parameter increases. Temperature and PAH characteristic dependent forward and reverse rate constants of homo-molecular PAH dimerization are derived from MD simulations, on the basis of which a reversible model is developed. This model can predict the tendency of PAH dimerization as validated by pyrene dimerization experiments [H. Sabbah et al., J. Phys. Chem. Lett. 1(19), 2962 (2010)]. Results from this study indicate that the physical dimerization cannot be an important source under the typical flame temperatures and PAH concentrations, which implies a more significant role played by the chemical route.

Quantum dimer model for the pseudogap metal

PubMed Central

Punk, Matthias; Allais, Andrea; Sachdev, Subir

2015-01-01

We propose a quantum dimer model for the metallic state of the hole-doped cuprates at low hole density, p. The Hilbert space is spanned by spinless, neutral, bosonic dimers and spin S=1/2, charge +e fermionic dimers. The model realizes a “fractionalized Fermi liquid” with no symmetry breaking and small hole pocket Fermi surfaces enclosing a total area determined by p. Exact diagonalization, on lattices of sizes up to 8×8, shows anisotropic quasiparticle residue around the pocket Fermi surfaces. We discuss the relationship to experiments. PMID:26195771

Heteroaryldihydropyrimidine (HAP) and Sulfamoylbenzamide (SBA) Inhibit Hepatitis B Virus Replication by Different Molecular Mechanisms

PubMed Central

Zhou, Zheng; Hu, Taishan; Zhou, Xue; Wildum, Steffen; Garcia-Alcalde, Fernando; Xu, Zhiheng; Wu, Daitze; Mao, Yi; Tian, Xiaojun; Zhou, Yuan; Shen, Fang; Zhang, Zhisen; Tang, Guozhi; Najera, Isabel; Yang, Guang; Shen, Hong C.; Young, John A. T.; Qin, Ning

2017-01-01

Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) are promising non-nucleos(t)ide HBV replication inhibitors. HAPs are known to promote core protein mis-assembly, but the molecular mechanism of abnormal assembly is still elusive. Likewise, the assembly status of core protein induced by SBA remains unknown. Here we show that SBA, unlike HAP, does not promote core protein mis-assembly. Interestingly, two reference compounds HAP_R01 and SBA_R01 bind to the same pocket at the dimer-dimer interface in the crystal structures of core protein Y132A hexamer. The striking difference lies in a unique hydrophobic subpocket that is occupied by the thiazole group of HAP_R01, but is unperturbed by SBA_R01. Photoaffinity labeling confirms the HAP_R01 binding pose at the dimer-dimer interface on capsid and suggests a new mechanism of HAP-induced mis-assembly. Based on the common features in crystal structures we predict that T33 mutations generate similar susceptibility changes to both compounds. In contrast, mutations at positions in close contact with HAP-specific groups (P25A, P25S, or V124F) only reduce susceptibility to HAP_R01, but not to SBA_R01. Thus, HAP and SBA are likely to have distinctive resistance profiles. Notably, P25S and V124F substitutions exist in low-abundance quasispecies in treatment-naïve patients, suggesting potential clinical relevance. PMID:28205569

Exciton Correlations in Intramolecular Singlet Fission

DOE PAGES

Sanders, Samuel N.; Kumarasamy, Elango; Pun, Andrew B.; ...

2016-05-16

We have synthesized a series of asymmetric pentacene-tetracene heterodimers with a variable-length conjugated bridge that undergo fast and efficient intramolecular singlet fission (iSF). These compounds have distinct singlet and triplet energies, which allow us to study the spatial dynamics of excitons during the iSF process, including the significant role of exciton correlations in promoting triplet pair generation and recombination. We demonstrate that the primary photoexcitations in conjugated dimers are delocalized singlets that enable fast and efficient iSF. However, in these asymmetric dimers, the singlet becomes more localized on the lower energy unit as the length of the bridge is increased,more » slowing down iSF relative to analogous symmetric dimers. We resolve the recombination kinetics of the inequivalent triplets produced via iSF, and find that they primarily decay via concerted processes. By identifying different decay channels, including delayed fluorescence via triplet-triplet annihilation, we can separate transient species corresponding to both correlated triplet pairs and uncorrelated triplets. Recombination of the triplet pair proceeds rapidly despite our experimental and theoretical demonstration that individual triplets are highly localized and unable to be transported across the conjugated linker. In this class of compounds, the rate of formation and yield of uncorrelated triplets increases with bridge length. Overall, these constrained, asymmetric systems provide a unique platform to isolate and study transient species essential for singlet fission, which are otherwise difficult to observe in symmetric dimers or condensed phases.« less

Ligand-bridged dinuclear cyclometalated Ir(III) complexes: from metallamacrocycles to discrete dimers.

PubMed

Chandrasekhar, Vadapalli; Hajra, Tanima; Bera, Jitendra K; Rahaman, S M Wahidur; Satumtira, Nisa; Elbjeirami, Oussama; Omary, Mohammad A

2012-02-06

Metallamacrocycles 1, 2, and 3 of the general formula [{Ir(ppy)(2)}(2)(μ-BL)(2)](OTf)(2) (ppyH = 2-phenyl pyridine; BL = 1,2-bis(4-pyridyl)ethane (bpa) (1), 1,3-bis(4-pyridyl)propane (bpp) (2), and trans-1,2-bis(4-pyridyl)ethylene (bpe) (3)) have been synthesized by the reaction of [{(ppy)(2)Ir}(2)(μ-Cl)(2)], first with AgOTf to effect dechlorination and later with various bridging ligands. Open-frame dimers [{Ir(ppy)(2)}(2)(μ-BL)](OTf)(2) were obtained in a similar manner by utilizing N,N'-bis(2-pyridyl)methylene-hydrazine (abp) and N,N'-(bis(2-pyridyl)formylidene)ethane-1,2-diamine (bpfd) (for compounds 4 and 5, respectively) as bridging ligands. Molecular structures of 1, 3, 4, and 5 were established by X-ray crystallography. Cyclic voltammetry experiments reveal weakly interacting "Ir(ppy)(2)" units bridged by ethylene-linked bpe ligand in 3; on the contrary the metal centers are electronically isolated in 1 and 2 where the bridging ligands are based on ethane and propane linkers. The dimer 4 exhibits two accessible reversible reduction couples separated by 570 mV indicating the stability of the one-electron reduced species located on the diimine-based bridge abp. The "Ir(ppy)(2)" units in compound 5 are noninteracting as the electronic conduit is truncated by the ethane spacer in the bpfd bridge. The dinuclear compounds 1-5 show ligand centered (LC) transitions involving ppy ligands and mixed metal to ligand/ligand to ligand charge transfer (MLCT/LLCT) transitions involving both the cyclometalating ppy and bridging ligands (BL) in the UV-vis spectra. For the conjugated bridge bpe in compound 3 and abp in compound 4, the lowest-energy charge-transfer absorptions are red-shifted with enhanced intensity. In accordance with their similar electronic structures, compounds 1 and 2 exhibit identical emissions. The presence of vibronic structures in these compounds indicates a predominantly (3)LC excited states. On the contrary, broad and unstructured phosphorescence bands in compounds 3-5 strongly suggest emissive states of mixed (3)MLCT/(3)LLCT character. Density functional theory (DFT) calculations have been carried out to gain insight on the frontier orbitals, and to rationalize the electrochemical and photophysical properties of the compounds based on their electronic structures.

A rare positively charged nicotinic acid di­sulfide: 2,2′-di­thio­dinicotinic acid hydro­chloride monohydrate

PubMed Central

McGuire, Chad M.; Albrecht-Schmitt, Thomas E.

2018-01-01

The title compound {systematic name: 3-carb­oxy-2-[2-(3-carb­oxy­pyridin-2-yl)disulfan-1-yl)]pyridin-1-ium chloride monohydrate}, C12H9N2O4S2 +·Cl−·H2O, crystallizes in the triclinic space group P . A pair of 2-mercaptonicotinic acid moieties is connected by a 2,2′-di­sulfide bond with a dihedral angle of 78.79 (3)°. One of the N atom is protonated, as are both carboxyl­ate groups, resulting in an overall +1 charge on the dimer. The structure comprises a zigzagging layer of the dimerized di­thio­dinicotinic acid rings, with charge-balancing chloride ions and water mol­ecules between the layers. Hydrogen bonding between the chloride and water sites with the dimer appears to hold the structure together. Nearest neighbor nicotinic acid rings are offset when viewed down the a axis, suggesting no added stability from ring stacking. The asymmetric unit corresponds to the empirical formula of the compound, and it packs with two formula units per unit cell.

Arylglycerol-γ-Formyl Ester as an Aromatic Ring Cleavage Product of Nonphenolic β-O-4 Lignin Substructure Model Compounds Degraded by Coriolus versicolor†

PubMed Central

Kawai, Shingo; Umezawa, Toshiaki; Higuchi, Takayoshi

1985-01-01

4-Ethoxy-3-methoxyphenylglycerol-γ-formyl ester (compound IV) was identified as a degradation product of both 4-ethoxy-3-methoxyphenylglycerol-β-syringaldehyde ether (compound I) and 4-ethoxy-3-methoxyphenylglycerol-β-2,6-dimethoxyphenyl ether (compound II) by a ligninolytic culture of Coriolus versicolor. An isotopic experiment with a 13C-labeled compound (compound II′) indicated that the formyl group of compound IV was derived from the β-phenoxyl group of β-O-4 dimer as an aromatic ring cleavage fragment. However, compound IV was not formed from 4-ethoxy-3-methoxyphenylglycerol-β-guaiacyl ether (compound III). γ-Formyl arylglycerol (compound IV) could be a precursor of 4-ethoxy-3-methoxyphenylglycerol (compound VI), because 3-(4-ethoxy-3-methoxyphenyl)-1-formyloxy propane (compound VII) was cleaved to give 3-(4-ethoxy-3-methoxyphenyl)-1-propanol (compound VIII) by C. versicolor. 4-Ethoxy-3-methoxyphenylglycerol-β,γ-cyclic carbonate (compound V), previously found as a degradation product of compound III by Phanerochaete chrysosporium (T. Umezawa, and T. Higuchi, FEBS Lett., 25:123-126, 1985), was also identified from the cultures with compound I, II, and III and degraded to give the arylglycerol (compound VI). An isotopic experiment with 13C-labeled compounds II′ and III′ indicated that the carbonate carbon of compound V was derived from the β-phenoxyl groups of β-O-4 substructure. PMID:16346950

Coumarins with α-glucosidase and α-amylase inhibitory activities from the flower of Edgeworthia gardneri.

PubMed

Zhao, Deng-Gao; Zhou, Ai-Yu; Du, Zhiyun; Zhang, Yu; Zhang, Kun; Ma, Yan-Yan

2015-12-01

The flower of Edgeworthia gardneri is consumed in beverages in Tibet and has potential health benefits for diabetes. As a part of our continuous studies on dietary supplements for diabetes, two monomers, five dimers and one trimer of coumarins were isolated from the flowers of E. gardneri. One dimer was a new compound (1) and its structure was determined by spectroscopic methods, including multiple NMR techniques and mass spectrometry. The inhibitory activities of all coumarins against α-amylase and α-glucosidase were evaluated. Compound 4 displayed potent inhibitory effect on both α-amylase and α-glucosidase, with an IC50 of 90 and 86μg/mL, respectively. The IC50 of compound 3 against α-glucosidase was 18.7μg/mL, and its inhibition mode was noncompetitive. Based on the fluorescence analysis, the binding constant and the number of binding sites of compound 3 were calculated as 2.05×10(5) and 1.24, respectively. Furthermore, the interaction between compound 3 and α-glucosidase was a spontaneous process that was driven mainly by hydrophobic force. This study could facilitate the utilization of E gardneri as functional food ingredient. Copyright © 2015 Elsevier B.V. All rights reserved.

Structure of Thermobifida fusca DyP-type peroxidase and activity towards Kraft lignin and lignin model compounds.

PubMed

Rahmanpour, Rahman; Rea, Dean; Jamshidi, Shirin; Fülöp, Vilmos; Bugg, Timothy D H

2016-03-15

A Dyp-type peroxidase enzyme from thermophilic cellulose degrader Thermobifida fusca (TfuDyP) was investigated for catalytic ability towards lignin oxidation. TfuDyP was characterised kinetically against a range of phenolic substrates, and a compound I reaction intermediate was observed via pre-steady state kinetic analysis at λmax 404 nm. TfuDyP showed reactivity towards Kraft lignin, and was found to oxidise a β-aryl ether lignin model compound, forming an oxidised dimer. A crystal structure of TfuDyP was determined, to 1.8 Å resolution, which was found to contain a diatomic oxygen ligand bound to the heme centre, positioned close to active site residues Asp-203 and Arg-315. The structure contains two channels providing access to the heme cofactor for organic substrates and hydrogen peroxide. Site-directed mutant D203A showed no activity towards phenolic substrates, but reduced activity towards ABTS, while mutant R315Q showed no activity towards phenolic substrates, nor ABTS. Copyright © 2016 Elsevier Inc. All rights reserved.

Natural Occurrence of Aldol Condensation Products in Valencia Orange Oil.

PubMed

Abreu, Ingo; Da Costa, Neil C; van Es, Alfred; Kim, Jung-A; Parasar, Uma; Poulsen, Mauricio L

2017-12-01

Cold pressed orange oils contain predominantly d-limonene (approximately 95%) and various other lower concentration monoterpenes, sesquiterpenes, sinensals plus 3 key aliphatic aldehydes: hexanal, octanal. and decanal. The aldol self-condensation products or "dimers" for each aldehyde have been postulated as being present at low concentrations in the oil. However, to date only the hexanal dimer has been previously reported. In this paper, cold pressed Valencia orange oil was fractionally distilled/folded and analyzed by GC and high resolution GC-MS to detect these compounds on 2 different capillary column phases. Subsequently the hexanal, octanal, and decanal self-aldol condensation products, 2-butyl-2-octenal, 2-hexyl-2-decenal, and 2-octyl-2-dodecenal, respectively, were detected in the folded oil. These predominantly trans configuration isomeric compounds were synthesized, to confirm them as being present in nature and evaluated organoleptically by a panel of evaluators. To further confirm the mechanism of their formation, the enriched oil was made into a simple beverage to show the effect on the formation of these aldol compounds under acidic conditions. Finally aliphatic aldehydes from hexanal to undecanal were reacted together in various combinatorial pairs to give an additional 33 self and mixed aldol condensation products, some of which were also detected in the folded oil. This paper discloses the structural elucidation and synthesis of 8 novel aldol condensation products found at trace concentrations in citrus and leading to a further 31 mass spectrally determined aldol products. Sensory evaluations and application of some of these components were demonstrated in a model citrus beverage. © 2017 Institute of Food Technologists®.

Chemical profiling of guarana seeds (Paullinia cupana) from different geographical origins using UPLC-QTOF-MS combined with chemometrics.

PubMed

da Silva, Givaldo Souza; Canuto, Kirley Marques; Ribeiro, Paulo Riceli Vasconcelos; de Brito, Edy Sousa; Nascimento, Madson Moreira; Zocolo, Guilherme Julião; Coutinho, Janclei Pereira; de Jesus, Raildo Mota

2017-12-01

Paullinia cupana, commonly known as guarana, is an Amazonian fruit whose seeds are used to produce the powdered guarana, which is rich in caffeine and consumed for its stimulating activity. The metabolic profile of guarana from the two largest producing regions was investigated using UPLC-MS combined with multivariate statistical analysis. The principal component analysis (PCA) showed significant differences between samples produced in the states of Bahia and Amazonas. The metabolites responsible for the differentiation were identified by orthogonal partial least squares discriminant analysis (OPLS-DA). Fourteen phenolic compounds were characterized in guarana powder samples, and catechin, epicatechin, B-type procyanidin dimer, A-type procyanidin trimer and A-type procyanidin dimer were the main compounds responsible for the geographical variation of the samples. Copyright © 2017. Published by Elsevier Ltd.

A novel dimeric flavonol glycoside from Cynanchum acutum subsp. sibiricum.

PubMed

Yuan, Si-Wen; Dai, Wei; Pan, Xin-Hui; Lu, Yan; Chen, Dao-Feng; Wang, Qi

2018-06-11

A novel dimeric flavonol glycoside, Cynanflavoside A (1), together with six analogues, kaempferol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (2), quercetin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (3), kaempferol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside (4), quercetin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside (5), kaempferol-3-O-β-D-glucopyranosyl-7-O-α-L-rhamnopyranoside (6), and quercetin-3-O-galactoside (7) were isolated from the n-butyl alcohol extract of Cynanchum acutum subsp. sibiricum. Their structures were determined spectroscopically and compared with previously reported spectral data. All compounds were evaluated for their anti-complementary activity in vitro, and only compound 5 exhibited anti-complement effects with CH 50 value of 0.33 mM.

Antichlamydial Dimeric Indole Derivatives from Marine Actinomycete Rubrobacter radiotolerans.

PubMed

Li, Jian Lin; Chen, Dandan; Huang, Lei; Ni, Min; Zhao, Yu; Fan, Huizhou; Bao, Xiaofeng

2017-06-01

Chlamydiae are widely distributed pathogens of human populations, which can lead to serious reproductive and other health problems. In our search for novel antichlamydial metabolites from marine derived-microorganisms, one new ( 1 ) and two known ( 2, 3 ) dimeric indole derivatives were isolated from the sponge-derived actinomycete Rubrobacter radiotolerans . The chemical structures of these metabolites were elucidated by NMR spectroscopic data as well as CD calculations. All three metabolites suppressed chlamydial growth in a concentration-dependent manner. Among them, compound 1 exhibited the most effective antichlamydial activity with IC 50 values of 46.6 ~ 96.4 µM in the production of infectious progeny. Compounds appeared to target the mid-stage of the chlamydial developmental cycle by interfering with reticular body replication, but not directly inactivating the infectious elementary body. Georg Thieme Verlag KG Stuttgart · New York.

Diels-Alderase-free, bis-pericyclic, [4+2] dimerization in the biosynthesis of (±)-paracaseolide A

NASA Astrophysics Data System (ADS)

Wang, Tao; Hoye, Thomas R.

2015-08-01

The natural product paracaseolide A is a tetracyclic dilactone containing six adjacent stereocentres. Its skeleton occupies a unique structural space among the >200,000 characterized secondary metabolites. Six different research groups have reported a chemical synthesis of this compound, five of which used a thermal, net Diels-Alder [4+2] cycloaddition and dehydration at 110 °C to access the target by dimerization of a simple butenolide precursor. Here, we report that this dimerization proceeds under much milder conditions and with a different stereochemical outcome than previously recognized. This can be rationalized by invoking a bis-pericyclic transition state. Furthermore, we find that spontaneous epimerization, necessary to correct the configuration at one key stereocentre, is viable and that natural paracaseolide A is racemic. Together, these facts point to the absence of enzymatic catalysis (that is, Diels-Alderase activity) in the cycloaddition and strongly suggest that a non-enzyme-mediated dimerization is the actual event by which paracaseolide A is produced in nature.

Crystal structure of benzyl (E)-2-(3,4-di-meth-oxy-benzyl-idene)hydrazine-1-carbodi-thio-ate.

PubMed

Tan, Yew-Fung; Break, Mohammed Khaled Bin; Tahir, M Ibrahim M; Khoo, Teng-Jin

2015-02-01

The title compound, C17H18N2O2S2, synthesized via a condensation reaction between S-benzyl di-thio-carbazate and 3,4-di-meth-oxy-benzaldehyde, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an L-shape but differ in the orientation of the benzyl ring with respect to the 3,4-di-meth-oxy-benzyl-idine ring, this dihedral angle is 65.59 (8)° in mol-ecule A and 73.10 (8)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H⋯O hydrogen bonds, giving inversion dimers of dimers. These units are linked by C-H⋯π inter-actions, forming ribbons propagating in the [100] direction.

Is the Chemical Strategy for Imbuing "Polyene" Character in Diketopyrrolopyrrole-Based Chromophores Sufficient for Singlet Fission?

PubMed

Mukhopadhyay, Tushita; Musser, Andrew J; Puttaraju, Boregowda; Dhar, Joydeep; Friend, Richard H; Patil, Satish

2017-03-02

In this work, we have rationally designed and synthesized a novel thiophene-diketopyrrolopyrrole (TDPP)-vinyl-based dimer. We have investigated the optical and electronic properties and have probed the photophysical dynamics using transient absorption to investigate the possibility of singlet exciton fission. These revealed extremely rapid decay to the ground state (<50 ps), which we confirm is due to intramolecular excitonic processes rather than large-scale conformational change enabled by the vinyl linker. In all cases, the main excited state appears to be "dark", suggesting rapid internal conversion into a dark 2A g -type singlet state. We found no evidence of triplet formation in TDPP-V-TDPP under direct photoexcitation. This may be a consequence of significant singlet stabilization in the dimer, bringing it below the energy needed to form two triplets. Our studies on this model compound set valuable lessons for design of novel triplet-forming materials and highlight the need for more broadly applicable design principles.

Anti-hepatitis B virus activities and absolute configurations of sesquiterpenoid glycosides from Phyllanthus emblica.

PubMed

Lv, Jun-Jiang; Wang, Ya-Feng; Zhang, Jing-Min; Yu, Shan; Wang, Dong; Zhu, Hong-Tao; Cheng, Rong-Rong; Yang, Chong-Ren; Xu, Min; Zhang, Ying-Jun

2014-11-21

During the process exploring anti-viral compounds from Phyllanthus species, eight new highly oxygenated bisabolane sesquiterpenoid glycoside phyllaemblicins G1–G8 (1–8) were isolated from Phyllanthus emblica, along with three known compounds, phyllaemblicin F (9), phyllaemblic acid (10) and glochicoccin D (11). Phyllaemblicin G2 (2), bearing a tricyclo [3.1.1.1] oxygen bridge ring system, is an unusual sesquiterpenoid glycoside, while phyllaemblicins G6–G8 (6–8) are dimeric sesquiterpenoid glycosides with two norbisabolane units connecting through a disaccharide. All the structures were elucidated by the extensive analysis of HRMS and NMR data. The relative configuration of phyllaemblicin G2 was constructed based on heteronuclear coupling constants measurement, and the absolute configurations for all new compounds were established by calculated electronic circular dichroism (ECD) using time dependent density functional theory. The sesquiterpenoid glycoside dimers 6–9 displayed potential anti-hepatitis B virus (HBV) activities, especially for the new compound 6 with IC50 of 8.53 ± 0.97 and 5.68 ± 1.75 μM towards the HBV surface antigen (HBsAg) and HBV excreted antigen (HBeAg) secretion, respectively.

Economic evaluation of different screening alternatives for patients with clinically suspected acute deep vein thrombosis.

PubMed

Bogavac-Stanojević, Natasa; Dopsaj, Violeta; Jelić-Ivanović, Zorana; Lakić, Dragana; Vasić, Dragan; Petrova, Guenka

2013-01-01

We examined the cost-effectiveness of the three different D-dimer measurements in the screening of DVT in models with and without calculation of pre-test probability (PTP) score. Moreover, we calculated the minimal cost in DVT detection. In the group of 192 patients with clinically suspected acute DVT, we examined the three different D-dimer measurements (Innovance D-dimer, Hemosil D-dimer HS and Vidas D-dimer Exclusion II) in combination with and without PTP assessment. The diagnostic alternative employing Vidas D-dimer Exclusion II assay without and with PTP calculation gave lower incremental cost-effectiveness ratio (ICER) than the alternative employing Hemosil D-dimer HS assay (0.187 Euros vs. 0.998 Euros per one additional DVT positive patient selected for CUS in model without PTP assessment and 0.450 vs. 0.753 Euros per one DVT positive patient selected for CUS in model with PTP assessment). According to sensitivity analysis, the Hemosil D-dimer HS assay was the most cost effective alternative when one patient was admitted to the vascular ambulance per day. Vidas D-dimer Exclusion II assay was the most cost effective alternative when more than one patient were admitted to the vascular ambulance per day. Cost minimisation analysis indicated that selection of patients according to PTP score followed by D-dimer analysis decreases the cost of DVT diagnosis. ICER analysis enables laboratories to choose optimal laboratory tests according to number of patients admitted to laboratory. Results support the feasibility of using PTP scoring and D-dimer measurement before CUS examination in DVT screening.

cis elements and trans-acting factors involved in dimer formation of murine leukemia virus RNA.

PubMed

Prats, A C; Roy, C; Wang, P A; Erard, M; Housset, V; Gabus, C; Paoletti, C; Darlix, J L

1990-02-01

The genetic material of all retroviruses examined so far consists of two identical RNA molecules joined at their 5' ends by the dimer linkage structure (DLS). Since the precise location of the DLS as well as the mechanism and role(s) of RNA dimerization remain unclear, we analyzed the dimerization process of Moloney murine leukemia virus (MoMuLV) genomic RNA. For this purpose we derived an in vitro model for RNA dimerization. By using this model, murine leukemia virus RNA was shown to form dimeric molecules. Deletion mutagenesis in the 620-nucleotide leader of MoMuLV RNA showed that the dimer promoting sequences are located within the encapsidation element Psi between positions 215 and 420. Furthermore, hybridization assays in which DNA oligomers were used to probe monomer and dimer forms of MoMuLV RNA indicated that the DLS probably maps between positions 280 and 330 from the RNA 5' end. Also, retroviral nucleocapsid protein was shown to catalyze dimerization of MoMuLV RNA and to be tightly bound to genomic dimer RNA in virions. These results suggest that MoMuLV RNA dimerization and encapsidation are probably controlled by the same cis element, Psi, and trans-acting factor, nucleocapsid protein, and thus might be linked during virion formation.

cis elements and trans-acting factors involved in dimer formation of murine leukemia virus RNA.

PubMed Central

Prats, A C; Roy, C; Wang, P A; Erard, M; Housset, V; Gabus, C; Paoletti, C; Darlix, J L

1990-01-01

The genetic material of all retroviruses examined so far consists of two identical RNA molecules joined at their 5' ends by the dimer linkage structure (DLS). Since the precise location of the DLS as well as the mechanism and role(s) of RNA dimerization remain unclear, we analyzed the dimerization process of Moloney murine leukemia virus (MoMuLV) genomic RNA. For this purpose we derived an in vitro model for RNA dimerization. By using this model, murine leukemia virus RNA was shown to form dimeric molecules. Deletion mutagenesis in the 620-nucleotide leader of MoMuLV RNA showed that the dimer promoting sequences are located within the encapsidation element Psi between positions 215 and 420. Furthermore, hybridization assays in which DNA oligomers were used to probe monomer and dimer forms of MoMuLV RNA indicated that the DLS probably maps between positions 280 and 330 from the RNA 5' end. Also, retroviral nucleocapsid protein was shown to catalyze dimerization of MoMuLV RNA and to be tightly bound to genomic dimer RNA in virions. These results suggest that MoMuLV RNA dimerization and encapsidation are probably controlled by the same cis element, Psi, and trans-acting factor, nucleocapsid protein, and thus might be linked during virion formation. Images PMID:2153242

Dipole Approximation to Predict the Resonances of Dimers Composed of Dielectric Resonators for Directional Emission: Dielectric Dimers Dipole Approximation

DOE PAGES

Campione, Salvatore; Warne, Larry K.; Basilio, Lorena I.

2017-09-29

In this paper we develop a fully-retarded, dipole approximation model to estimate the effective polarizabilities of a dimer made of dielectric resonators. They are computed from the polarizabilities of the two resonators composing the dimer. We analyze the situation of full-cubes as well as split-cubes, which have been shown to exhibit overlapping electric and magnetic resonances. We compare the effective dimer polarizabilities to ones retrieved via full-wave simulations as well as ones computed via a quasi-static, dipole approximation. We observe good agreement between the fully-retarded solution and the full-wave results, whereas the quasi-static approximation is less accurate for the problemmore » at hand. The developed model can be used to predict the electric and magnetic resonances of a dimer under parallel or orthogonal (to the dimer axis) excitation. This is particularly helpful when interested in locating frequencies at which the dimer will emit directional radiation.« less

Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-nitrosated human serum albumin dimer.

PubMed

Kinoshita, Ryo; Ishima, Yu; Chuang, Victor T G; Nakamura, Hideaki; Fang, Jun; Watanabe, Hiroshi; Shimizu, Taro; Okuhira, Keiichiro; Ishida, Tatsuhiro; Maeda, Hiroshi; Otagiri, Masaki; Maruyama, Toru

2017-09-01

In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane ® ). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Kuz'mina, L. G., E-mail: kuzmina@igic.ras.ru; Sitin, A. G.; Gulakova, E. N.

The crystal and molecular structures of five styrylheterocycles of the quinoline series are studied. All molecules are planar. The double bond in the ethylene fragment is essentially localized. In the molecule of 2-(4-methylstyryl)quinoline, the ethylene fragment is disordered by the bicycle-pedal pattern. In four of the five compounds, the crystal packings do not contain stacking dimers prearranged for the [2+2] photocycloaddition (PCA) reaction. In the crystal of 2-(3-nitrostyryl)quinoline, pairs of crystallographically independent molecules form stacking dimers. In a dimer, the ethylene fragments have a twist orientation, which is incompatible with the PCA reaction. An attempt to initiate a temperature-dependent processmore » of bicyclepedal isomerization in the crystal and, as a consequence, the PCA reaction by means of simultaneous irradiation and heating of a single crystal is unsuccessful.« less

Effects of Glycine, Water, Ammonia, and Ammonium Bicarbonate on the Oligomerization of Methionine

NASA Astrophysics Data System (ADS)

Huang, Rui; Furukawa, Yoshihiro; Otake, Tsubasa; Kakegawa, Takeshi

2017-06-01

The abiotic oligomerization of amino acids may have created primordial, protein-like biological catalysts on the early Earth. Previous studies have proposed and evaluated the potential of diagenesis for the amino acid oligomerization, simulating the formation of peptides that include glycine, alanine, and valine, separately. However, whether such conditions can promote the formation of peptides composed of multiple amino acids remains unclear. Furthermore, the chemistry of pore water in sediments should affect the oligomerization and degradation of amino acids and oligomers, but these effects have not been studied extensively. In this study, we investigated the effects of water, ammonia, ammonium bicarbonate, pH, and glycine on the oligomerization and degradation of methionine under high pressure (150 MPa) and high temperature conditions (175 °C) for 96 h. Methionine is more difficult to oligomerize than glycine and methionine dimer was formed in the incubation of dry powder of methionine. Methionine oligomers as long as trimers, as well as methionylglycine and glycylmethionine, were formed under every condition with these additional compounds. Among the compounds tested, the oligomerization reaction rate was accelerated by the presence of water and by an increase in pH. Ammonia also increased the oligomerization rate but consumed methionine by side reactions and resulted in the rapid degradation of methionine and its peptides. Similarly, glycine accelerated the oligomerization rate of methionine and the degradation of methionine, producing water, ammonia, and bicarbonate through its decomposition. With Gly, heterogeneous dimers (methionylglycine and glycylmethionine) were formed in greater amounts than with other additional compounds although smaller amount of these heterogeneous dimers were formed with other additional compounds. These results suggest that accelerated reaction rates induced by water and co-existing reactive compounds promote the oligomerization of less reactive amino acids during diagenesis and enhance the formation of peptides composed of multiple amino acids.

Sigma- versus Pi-Dimerization Modes of Triangulene.

PubMed

Mou, Zhongyu; Kertesz, Miklos

2018-04-20

We show that the diradicaloid triangulene, a graphene nano-flake molecule, can aggregate in a variety of dimerization modes. We found by density functional theory modeling a number of triangulene dimers including six doubly bonded σ-dimers in addition to the previously reported six pancake bonded π-dimer isomers. The σ-dimers display a wide range of stabilities: the interaction energy of the most stable σ-dimer is -25.17 kcal mol -1 . Besides the doubly bonded σ-dimers with closed shell ground states, we also found an open-shell singly σ-bonded diradicaloid dimer. We found an interesting isomerization route between a doubly bonded σ-dimer, a singly bonded σ-dimer with a low-lying triplet state and two π-bonded dimers with low-lying quintet states. Derivatives of triangulene, trioxo-triangulenes (TOTs) have been previously characterized experimentally. Here, we show the reasons why so far only the π-dimer but not the σ-dimer was experimentally observed for all TOTs. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intermetallic compounds of the heaviest elements and their homologs: the electronic structure and bonding of MM', where M=Ge, Sn, Pb, and element 114, and M'=Ni, Pd, Pt, Cu, Ag, Au, Sn, Pb, and element 114.

PubMed

Pershina, V; Anton, J; Fricke, B

2007-10-07

Fully relativistic (four-component) density-functional theory calculations were performed for intermetallic dimers MM', where M=Ge, Sn, Pb, and element 114, and MM'=group 10 elements (Ni, Pd, and Pt) and group 11 elements (Cu, Ag, and Au). PbM and 114M, where M are group 14 elements, were also considered. The results have shown that trends in spectroscopic properties-atomization energies D(e), vibrational frequencies omega(e), and bond lengths R(e), as a function of MM', are similar for compounds of Ge, Sn, Pb, and element 114, except for D(e) of PbNi and 114Ni. They were shown to be determined by trends in the energies and space distribution of the valence ns(MM')atomic orbitals (AOs). According to the results, element 114 should form the weakest bonding with Ni and Ag, while the strongest with Pt due to the largest involvement of the 5d(Pt) AOs. In turn, trends in the spectroscopic properties of MM' as a function of M were shown to be determined by the behavior of the np(1/2)(M) AOs. Overall, D(e) of the element 114 dimers are about 1 eV smaller and R(e) are about 0.2 a.u. larger than those of the corresponding Pb compounds. Such a decrease in bonding of the element 114 dimers is caused by the large SO splitting of the 7p orbitals and a decreasing contribution of the relativistically stabilized 7p(1/2)(114) AO. On the basis of the calculated D(e) for the dimers, adsorption enthalpies of element 114 on the corresponding metal surfaces were estimated: They were shown to be about 100-150 kJ/mol smaller than those of Pb.

Tuning Singlet Fission in π-Bridge-π Chromophores

DOE PAGES

Kumarasamy, Elango; Sanders, Samuel N.; Tayebjee, Murad J. Y.; ...

2017-08-11

For this study, we have designed a series of pentacene dimers separated by homoconjugated or nonconjugated bridges that exhibit fast and efficient intramolecular singlet exciton fission (iSF). These materials are distinctive among reported iSF compounds because they exist in the unexplored regime of close spatial proximity but weak electronic coupling between the singlet exciton and triplet pair states. Using transient absorption spectroscopy to investigate photophysics in these molecules, we find that homoconjugated dimers display desirable excited-state dynamics, with significantly reduced recombination rates as compared to conjugated dimers with similar singlet fission rates. In addition, unlike conjugated dimers, the time constantsmore » for singlet fission are relatively insensitive to the interplanar angle between chromophores, since rotation about σ bonds negligibly affects the orbital overlap within the π-bonding network. In the nonconjugated dimer, where the iSF occurs with a time constant >10 ns, comparable to the fluorescence lifetime, we used electron spin resonance spectroscopy to unequivocally establish the formation of triplet–triplet multiexcitons and uncoupled triplet excitons through singlet fission. Together, these studies enable us to articulate the role of the conjugation motif in iSF.« less

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

PubMed Central

Roy, Sujayita; He, Ran; Kapoor, Arun; Forman, Michael; Mazzone, Jennifer R.; Posner, Gary H.

2015-01-01

Artemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G0/G1 stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G1 with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G1 arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G1/S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition. PMID:25870074

One-dimensional Kondo lattice model at quarter filling

NASA Astrophysics Data System (ADS)

Xavier, J. C.; Miranda, E.

2008-10-01

We revisit the problem of the quarter-filled one-dimensional Kondo lattice model, for which the existence of a dimerized phase and a nonzero charge gap had been reported by Xavier [Phys. Rev. Lett. 90, 247204 (2003)]. Recently, some objections were raised claiming that the system is neither dimerized nor has a charge gap. In the interest of clarifying this important issue, we show that these objections are based on results obtained under conditions in which the dimer order is artificially suppressed. We use the incontrovertible dimerized phase of the Majumdar-Ghosh point of the J1-J2 Heisenberg model as a paradigm with which to illustrate this artificial suppression. Finally, by means of extremely accurate density-matrix renormalization-group calculations, we show that the charge gap is indeed nonzero in the dimerized phase.

Far-UV-induced dimeric photoproducts in short oligonucleotides: sequence effects.

PubMed

Douki, T; Zalizniak, T; Cadet, J

1997-08-01

Cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone adducts represent the two major classes of far-UV-induced DNA photoproducts. Because of the lack of appropriate detection methods for each individual photoproduct, little is known about the effect of the sequence on their formation. In the present work, the photoproduct distribution obtained upon exposure of a series of dinucleoside monophosphates to 254 nm light was determined. In the latter model compounds, the presence of a cytosine, located at either the 5'- or the 3'-side of a thymine moiety, led to the preferential formation of (6-4) adducts, whereas the cis-syn cyclobutane dimer was the main thymine-thymine photoproduct. In contrast, the yield of dimeric photoproducts, and particularly of (6-4) photoadducts, was very low upon irradiation of the cytosine-cytosine dinucleoside monophosphate. However, substitution of cytosine by uracil led to an increase in the yield of (6-4) photoproduct. It was also shown that the presence of a phosphate group at the 5'- end of a thymine-thymine dinucleoside monophosphate does not modify the photoproduct distribution. As an extension of the studies on dinucleoside monophosphates, the trinucleotide TpdCpT was used as a more relevant DNA model. The yields of formation of the thymine-cytosine and cytosine-thymine (6-4) photoproducts were in a 5:1 ratio, very close to the value obtained upon photolysis of the related dinucleoside monophosphates. The characterization of the two TpdCpT (6-4) adducts was based on 1H NMR, UV and mass spectroscopy analyses. Additional evidence for the structures was inferred from the analysis of the enzymatic digestion products of the (6-4) adducts of TpdCpT with phosphodiesterases. The latter enzymes were shown to induce the quantitative release of the photoproduct as a modified dinucleoside monophosphate in a highly sequence-specific manner.

Integrability and conformal data of the dimer model

NASA Astrophysics Data System (ADS)

Morin-Duchesne, Alexi; Rasmussen, Jørgen; Ruelle, Philippe

2016-04-01

The central charge of the dimer model on the square lattice is still being debated in the literature. In this paper, we provide evidence supporting the consistency of a c=-2 description. Using Lieb’s transfer matrix and its description in terms of the Temperley-Lieb algebra {{TL}}n at β =0, we provide a new solution of the dimer model in terms of the model of critical dense polymers on a tilted lattice and offer an understanding of the lattice integrability of the dimer model. The dimer transfer matrix is analyzed in the scaling limit, and the result for {L}0-\\frac{c}{24} is expressed in terms of fermions. Higher Virasoro modes are likewise constructed as limits of elements of {{TL}}n and are found to yield a c=-2 realization of the Virasoro algebra, familiar from fermionic bc ghost systems. In this realization, the dimer Fock spaces are shown to decompose, as Virasoro modules, into direct sums of Feigin-Fuchs modules, themselves exhibiting reducible yet indecomposable structures. In the scaling limit, the eigenvalues of the lattice integrals of motion are found to agree exactly with those of the c=-2 conformal integrals of motion. Consistent with the expression for {L}0-\\frac{c}{24} obtained from the transfer matrix, we also construct higher Virasoro modes with c = 1 and find that the dimer Fock space is completely reducible under their action. However, the transfer matrix is found not to be a generating function for the c = 1 integrals of motion. Although this indicates that Lieb’s transfer matrix description is incompatible with the c = 1 interpretation, it does not rule out the existence of an alternative, c = 1 compatible, transfer matrix description of the dimer model.

Charge Disproportionation in Tetragonal La 2MoO 5 , a Small Band Gap Semiconductor Influenced by Direct Mo–Mo Bonding

DOE PAGES

Colabello, Diane M.; Camino, Fernando E.; Huq, Ashfia; ...

2014-12-31

The structure of the novel compound La 2MoO 5 has been solved from powder X-ray and neutron diffraction data and belongs to the tetragonal space group P4/m (no. 83) with a = 12.6847(3) Å and c = 6.0568(2) Å and with Z = 8. It consists of equal proportions of bioctahedral (Mo 2O 10) and square prismatic (Mo 2O 8) dimers, both of which contain direct Mo-Mo bonds and are arranged in 1D chains. The Mo-Mo bond length in the Mo 2O 10dimers is 2.684(8) Å, while there are two types of Mo 2O 8 dimers with Mo-Mo bonds lengthsmore » of 2.22(2) and 2.28(2) Å. Although the average Mo oxidation state in La 2MoO 5 is 4+, the very different Mo-Mo distances reflect the fact that the Mo 2O 10 dimers contain only Mo5+ (d(1)), while the prismatic Mo2O8 dimers only contain Mo 3+ (d 3), a result directly confirmed by density function theory calculations. This is due to the complete disproportionation of Mo 4+, a phenomenon which has not previously been observed in solid-state compounds. La 2MoO 5 is diamagnetic, behavior which is not expected for a nonmetallic transition-metal oxide whose cation sites have an odd number of d-electrons. The resistivity displays the Arrhenius-type activated behavior expected for a semiconductor with a band gap of 0.5 eV, exhibiting an unusually small transport gap relative to other diamagnetic oxides. Diffuse reflectance studies indicate that La 2MoO 5 is a rare example of a stable oxide semiconductor with strong infrared absorbance. Lastly, we show that the d-orbital splitting associated with the Mo 2O 8 and Mo 2O 10 dimeric units can be rationalized using simple molecular orbital bonding concepts.« less

Dimeric Fe (II, III) complex of quinoneoxime as functional model of PAP enzyme: Mössbauer, magneto-structural and DNA cleavage studies

NASA Astrophysics Data System (ADS)

Salunke-Gawali, Sunita; Ahmed, Khursheed; Varret, François; Linares, Jorge; Zaware, Santosh; Date, Sadgopal; Rane, Sandhya

2008-07-01

Purple acid phosphatase, ( PAP), is known to contain dinuclear Fe2 + 2, + 3 site with characteristic Fe + 3 ← Tyr ligand to metal charge transfer in coordination. Phthiocoloxime (3-methyl-2-hydroxy-1,4-naphthoquinone-1-oxime) ligand L, mimics (His/Tyr) ligation with controlled and unique charge transfers resulting in valence tautomeric coordination with mixed valent diiron site in model compound Fe-1: [μ-OH-Fe2 + 2, + 3 ( o-NQCH3ox) ( o-NSQCH3ox)2 (CAT) H2O]. Fe-2: [Fe + 3( o-NQCH3ox) ( p-NQCH3ox)2]2 a molecularly associated dimer of phthiocoloxime synthesized for comparison of charge transfer. 57Fe Mössbauer studies was used to quantitize unusual valences due to ligand in dimeric Fe-1 and Fe-2 complexes which are supported by EPR and SQUID studies. 57Fe Mössbauer spectra for Fe-1 at 300 K indicates the presence of two quadrupole split asymmetric doublets due to the differences in local coordination geometries of [Fe + 3]A and [Fe + 2]B sites. The hyperfine interaction parameters are δ A = 0.152, (Δ E Q)A = 0.598 mm/s with overlapping doublet at δ B = 0.410 and (Δ E Q)B = 0.468 mm/s. Due to molecular association tendency of ligand, dimer Fe-2 possesses 100% Fe + 3(h.s.) hexacoordinated configuration with isomer shift δ = 0.408 mm/s. Slightly distorted octahedral symmetry created by NQCH3ox ligand surrounding Fe + 3(h.s.) state generates small field gradient indicated by quadrupole split Δ E Q = 0.213 mm/s. Decrease of isomer shifts together with variation of quadrupole splits with temperature in Fe-1 dimer compared to Fe-2 is result of charge transfers in [Fe2 + 2, + 3 SQ] complexes. EPR spectrum of Fe-1 shows two strong signals at g 1 = 4.17 and g 2 = 2.01 indicative of S = 3/2 spin state with an intermediate spin of Fe + 3(h.s.) configuration. SQUID data of χ _m^{corr} .T were best fitted by using HDVV spin pair model S = 2, 3/2 resulting in antiferromagnetic exchange ( J = -13.5 cm - 1 with an agreement factor of R = 1.89 × 10 - 5). The lower J value of antiferromagnetic exchange leads to Fe+3μ-(OH) Fe + 2 bridging in Fe-1 dimer instead of μ-oxo bridge. The intermolecular association through H-bonds may lead to weakly coupled antiferromagnetic interaction between two Fe-2 molecules having Fe + 3(h.s.) centers. Using S = 5/2, 5/2 spin pair model we obtained best-fitted parameters such as J = -12.4 cm - 1, g = 2.3 with R = 3.58 × 10 - 5. Synthetic strategy results in non-equivalent iron sites in Fe-1 dimer analogues to PAP enzyme hence its reconstitution results in pUC-19 DNA cleavage activity, as physiological functionality of APase. It is compared with nuclease activity of Fe-2 RAPase.

First-principles prediction of the effects of temperature and solvent selection on the dimerization of benzoic acid.

PubMed

Pham, Hieu H; Taylor, Christopher D; Henson, Neil J

2013-01-24

We introduce a procedure of quantum chemical calculations (B3P86/6-31G**) to study carboxylic acid dimerization and its correlation with temperature and properties of the solvent. Benzoic acid is chosen as a model system for studying dimerization via hydrogen bonding. Organic solvents are simulated using the self-consistent reaction field (SCRF) method with the polarized continuum model (PCM). The cyclic dimer is the most stable structure both in gas phase and solution. Dimer mono- and dihydrates could be found in the gas phase if acid molecules are in contact with water vapor. However, the formation of these hydrated conformers is very limited and cyclic dimer is the principal conformer to coexist with monomer acid in solution. Solvation of the cyclic dimer is more favorable compared to other complexes, partially due to the diminishing of hydrogen bonding capability and annihilation of dipole moments. Solvents have a strong effect on inducing dimer dissociation and this dependence is more pronounced at low dielectric constants. By accounting for selected terms in the total free energy of solvation, the solvation entropy could be incorporated to predict the dimer behavior at elevated temperatures. The temperature dependence of benzoic acid dimerization obtained by this technique is in good agreement with available experimental measurements, in which a tendency of dimer to dissociate is observed with increased temperatures. In addition, dimer breakup is more sensitive to temperature in low dielectric environments rather than in solvents with a higher dielectric constant.

A short autocomplementary sequence plays an essential role in avian sarcoma-leukosis virus RNA dimerization.

PubMed

Fossé, P; Motté, N; Roumier, A; Gabus, C; Muriaux, D; Darlix, J L; Paoletti, J

1996-12-24

Retroviral genomes consist of two identical RNA molecules joined noncovalently near their 5'-ends. Recently, two models have been proposed for RNA dimer formation on the basis of results obtained in vitro with human immunodeficiency virus type 1 RNA and Moloney murine leukemia virus RNA. It was first proposed that viral RNA dimerizes by forming an interstrand quadruple helix with purine tetrads. The second model postulates that RNA dimerization is initiated by a loop-loop interaction between the two RNA molecules. In order to better characterize the dimerization process of retroviral genomic RNA, we analyzed the in vitro dimerization of avian sarcoma-leukosis virus (ASLV) RNA using different transcripts. We determined the requirements for heterodimer formation, the thermal dissociation of RNA dimers, and the influence of antisense DNA oligonucleotides on dimer formation. Our results strongly suggest that purine tetrads are not involved in dimer formation. Data show that an autocomplementary sequence located upstream from the splice donor site and within a major packaging signal plays a crucial role in ASLV RNA dimer formation in vitro. This sequence is able to form a stem-loop structure, and phylogenetic analysis reveals that it is conserved in 28 different avian sarcoma and leukosis viruses. These results suggest that dimerization of ASLV RNA is initiated by a loop-loop interaction between two RNA molecules and provide an additional argument for the ubiquity of the dimerization process via loop-loop interaction.

Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

PubMed Central

Szelag, Malgorzata; Czerwoniec, Anna; Wesoly, Joanna; Bluyssen, Hans A. R.

2015-01-01

Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. PMID:25710482

Flavan hetero-dimers in the Cymbopogon citratus infusion tannin fraction and their contribution to the antioxidant activity.

PubMed

Costa, Gustavo; González-Manzano, Susana; González-Paramás, Ana; Figueiredo, Isabel Vitória; Santos-Buelga, Celestino; Batista, Maria Teresa

2015-03-01

Cymbopogon citratus (lemongrass) leaf infusion, a commonly used ingredient in Asian, African and Latin American cuisines, is also used in traditional medicine for the treatment of several pathological conditions; however, little is known about their bioactive compounds. Recent studies revealed the crucial role of the phenolic compounds namely flavonoids and tannins on the infusion bioactivity. Flavonoids have already been characterized; however the tannin fraction of lemongrass infusion is still uncharted. The aim of the present work is to characterize this fraction, and to evaluate its contribution to the antioxidant potential of this plant. Chemical characterization was achieved by HPLC-DAD-ESI/tandem MS and the antioxidant activity was evaluated using DPPH, ABTS and FRAP assays. Hetero-dimeric flavan structures have been described for the first time in lemongrass consisting of apigeniflavan or luteoliflavan units linked to a flavanone, either naringenin or eriodictyol, which may occur as aglycone or glycosylated forms. The antioxidant capacity of the fraction containing these compounds was significantly higher than the infusion, indicating its potential as a source of natural antioxidants.

Hydrogen Dimers in Giant-planet Infrared Spectra

NASA Astrophysics Data System (ADS)

Fletcher, Leigh N.; Gustafsson, Magnus; Orton, Glenn S.

2018-03-01

Despite being one of the weakest dimers in nature, low-spectral-resolution Voyager/IRIS observations revealed the presence of (H2)2 dimers on Jupiter and Saturn in the 1980s. However, the collision-induced H2–H2 opacity databases widely used in planetary science have thus far only included free-to-free transitions and have neglected the contributions of dimers. Dimer spectra have both fine-scale structure near the S(0) and S(1) quadrupole lines (354 and 587 cm‑1, respectively), and broad continuum absorption contributions up to ±50 cm‑1 from the line centers. We develop a new ab initio model for the free-to-bound, bound-to-free, and bound-to-bound transitions of the hydrogen dimer for a range of temperatures (40–400 K) and para-hydrogen fractions (0.25–1.0). The model is validated against low-temperature laboratory experiments, and used to simulate the spectra of the giant planets. The new collision-induced opacity database permits high-resolution (0.5–1.0 cm‑1) spectral modeling of dimer spectra near S(0) and S(1) in both Cassini Composite Infrared Spectrometer observations of Jupiter and Saturn, and in Spitzer Infrared Spectrometer (IRS) observations of Uranus and Neptune for the first time. Furthermore, the model reproduces the dimer signatures observed in Voyager/IRIS data near S(0) on Jupiter and Saturn, and generally lowers the amount of para-H2 (and the extent of disequilibrium) required to reproduce IRIS observations.

The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex.

PubMed

Alumasa, John N; Gorka, Alexander P; Casabianca, Leah B; Comstock, Erica; de Dios, Angel C; Roepe, Paul D

2011-03-01

Quinoline antimalarial drugs bind both monomeric and dimeric forms of free heme, with distinct preferences depending on the chemical environment. Under biological conditions, chloroquine (CQ) appears to prefer to bind to μ-oxo dimeric heme, while quinine (QN) preferentially binds monomer. To further explore this important distinction, we study three newly synthesized and several commercially available QN analogues lacking various functional groups. We find that removal of the QN hydroxyl lowers heme affinity, hemozoin (Hz) inhibition efficiency, and antiplasmodial activity. Elimination of the rigid quinuclidyl ring has similar effects, but elimination of either the vinyl or methoxy group does not. Replacing the quinuclidyl N with a less rigid tertiary aliphatic N only partially restores activity. To further study these trends, we probe drug-heme interactions via NMR studies with both Fe and Zn protoporphyrin IX (FPIX, ZnPIX) for QN, dehydroxyQN (DHQN), dequinuclidylQN (DQQN), and deamino-dequinuclidylQN (DADQQN). Magnetic susceptibility measurements in the presence of FPIX demonstrate that these compounds differentially perturb FPIX monomer-dimer equilibrium. We also isolate the QN-FPIX complex formed under mild aqueous conditions and analyze it by mass spectrometry, as well as fluorescence, vibrational, and solid-state NMR spectroscopies. The data elucidate key features of QN pharmacology and allow us to propose a refined model for the preferred binding of QN to monomeric FPIX under biologically relevant conditions. With this model in hand, we also propose how QN, CQ, and amodiaquine (AQ) differ in their ability to inhibit Hz formation. Copyright © 2010 Elsevier Inc. All rights reserved.

A study of the dimer formation of Rous sarcoma virus RNA and of its effect on viral protein synthesis in vitro.

PubMed

Bieth, E; Gabus, C; Darlix, J L

1990-01-11

The genetic material of all retroviruses examined so far is an RNA dimer where two identical RNA subunits are joined at their 5' ends by a structure named dimer linkage structure (DLS). Since the precise location and structure of the DLS as well as the mechanism and role(s) of RNA dimerization remain unclear, we analysed the dimerization process of Rous sarcoma virus (RSV) RNA. For this purpose we set up an in vitro model for RSV RNA dimerization. Using this model RSV RNA was shown to form dimeric molecules and this dimerization process was greatly activated by nucleocapsid protein (NCp12) of RSV. Furthermore, RSV RNA dimerization was performed in the presence of complementary 5'32P-DNA oligomers in order to probe the monomer and dimer forms of RSV RNA. Data indicated that the DLS of RSV RNA probably maps between positions 544-564 from the 5' end. In an attempt to define sequences needed for the dimerization of RSV RNA, deletion mutageneses were generated in the 5' 600 nt. The results showed that the dimer promoting sequences probably are located within positions 208-270 and 400-600 from the 5' end and hence possibly encompassing the cis-acting elements needed for the specific encapsidation of RSV genomic RNA. Also it is reported that synthesis of the polyprotein precursor Pr76gag is inhibited upon dimerization of RSV RNA. These results suggest that dimerization and encapsidation of genome length RSV RNA might be linked in the course of virion formation since they appear to be under the control of the same cis elements, E and DLS, and the trans-acting factor nucleocapsid protein NCp12.

A study of the dimer formation of Rous sarcoma virus RNA and of its effect on viral protein synthesis in vitro.

PubMed Central

Bieth, E; Gabus, C; Darlix, J L

1990-01-01

The genetic material of all retroviruses examined so far is an RNA dimer where two identical RNA subunits are joined at their 5' ends by a structure named dimer linkage structure (DLS). Since the precise location and structure of the DLS as well as the mechanism and role(s) of RNA dimerization remain unclear, we analysed the dimerization process of Rous sarcoma virus (RSV) RNA. For this purpose we set up an in vitro model for RSV RNA dimerization. Using this model RSV RNA was shown to form dimeric molecules and this dimerization process was greatly activated by nucleocapsid protein (NCp12) of RSV. Furthermore, RSV RNA dimerization was performed in the presence of complementary 5'32P-DNA oligomers in order to probe the monomer and dimer forms of RSV RNA. Data indicated that the DLS of RSV RNA probably maps between positions 544-564 from the 5' end. In an attempt to define sequences needed for the dimerization of RSV RNA, deletion mutageneses were generated in the 5' 600 nt. The results showed that the dimer promoting sequences probably are located within positions 208-270 and 400-600 from the 5' end and hence possibly encompassing the cis-acting elements needed for the specific encapsidation of RSV genomic RNA. Also it is reported that synthesis of the polyprotein precursor Pr76gag is inhibited upon dimerization of RSV RNA. These results suggest that dimerization and encapsidation of genome length RSV RNA might be linked in the course of virion formation since they appear to be under the control of the same cis elements, E and DLS, and the trans-acting factor nucleocapsid protein NCp12. Images PMID:2155394

Asymmetric Oxidation of o-Alkylphenols with Chiral 2-(o-Iodoxyphenyl)-Oxazolines

PubMed Central

Boppisetti, Jagadish K.; Birman, Vladimir B.

2009-01-01

A new class of chiral iodine (V) derivatives has been prepared. These compounds have been found to transform ortho-alkylphenols into ortho-quinol Diels-Alder dimers with significant levels of asymmetric induction. PMID:19231848

Anti-Cancer Activity of Resveratrol and Derivatives Produced by Grapevine Cell Suspensions in a 14 L Stirred Bioreactor.

PubMed

Nivelle, Laetitia; Hubert, Jane; Courot, Eric; Jeandet, Philippe; Aziz, Aziz; Nuzillard, Jean-Marc; Renault, Jean-Hugues; Clément, Christophe; Martiny, Laurent; Delmas, Dominique; Tarpin, Michel

2017-03-16

In the present study, resveratrol and various oligomeric derivatives were obtained from a 14 L bioreactor culture of elicited grapevine cell suspensions (Vitis labrusca L.). The crude ethyl acetate stilbene extract obtained from the culture medium was fractionated by centrifugal partition chromatography (CPC) using a gradient elution method and the major stilbenes contained in the fractions were subsequently identified by using a 13 C-NMR-based dereplication procedure and further 2D NMR analyses including HSQC, HMBC, and COSY. Beside δ-viniferin (2), leachianol F (4) and G (4'), four stilbenes (resveratrol (1), ε-viniferin (5), pallidol (3) and a newly characterized dimer (6)) were recovered as pure compounds in sufficient amounts to allow assessment of their biological activity on the cell growth of three different cell lines, including two human skin malignant melanoma cancer cell lines (HT-144 and SKMEL-28) and a healthy human dermal fibroblast HDF line. Among the dimers obtained in this study, the newly characterized resveratrol dimer (6) has never been described in nature and its biological potential was evaluated here for the first time. ε-viniferin as well as dimer (6) showed IC 50 values on the three tested cell lines lower than the ones exerted by resveratrol and pallidol. However, activities of the first two compounds were significantly decreased in the presence of fetal bovine serum although that of resveratrol and pallidol was not. The differential tumor activity exerted by resveratrol on healthy and cancer lines was also discussed.

Two Populations Mean-Field Monomer-Dimer Model

NASA Astrophysics Data System (ADS)

Alberici, Diego; Mingione, Emanuele

2018-04-01

A two populations mean-field monomer-dimer model including both hard-core and attractive interactions between dimers is considered. The pressure density in the thermodynamic limit is proved to satisfy a variational principle. A detailed analysis is made in the limit of one population is much smaller than the other and a ferromagnetic mean-field phase transition is found.

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

Ryan, T.R.

The cyclo-addition of two Mo/sub 2/Cl/sub 4/(P(C/sub 6/H/sub 5/)/sub 3/)/sub 2/(CH/sub 3/OH)/sub 2/ molecules has produced a new type of tetrameric molybdenum cluster, Mo/sub 4/Cl/sub 8/L/sub 4/. Structural characterization of this dimer revealed weak molybdenum-methanol bonding which was consistent with the observed reactivity of the compound. New synthetic methods were devised for the preparation of Mo/sub 4/X/sub 8/L/sub 4/ clusters where X = Cl, Br, I, and L = PR/sub 3/, PO/sub 3/, RCN, CH/sub 3/OH. A scheme for the metal-metal bonding in these clusters was presented which was in agreement with the known structural features of Mo/sub 4/Cl/sub 8/(PR/submore » 3/)/sub 4/, R = C/sub 2/H/sub 5/, n-C/sub 4/H/sub 9/. The preparation of the analogous W/sub 4/Cl/sub 8/(PR/sub 3/)/sub 4/ cluster from WCl/sub 4/ was accomplished by application of techniques used in the molybdenum syntheses. The single crystal x-ray structure revealed slight differences from the molybdenum analog which were rationalized in terms of the known behavior in dimeric tungsten and molybdenum species. The attempted preparation of a tetrameric tungsten cluster from W/sub 2/(mhp)/sub 4/ was unsuccessful (mhp = anion of 2-methyl-6-hydroxypyridine). Instead, the new tungsten dimer, W/sub 2/Cl/sub 2/(mhp)/sub 3/, was isolated which possessed a metal-metal bond order of 3.5. The x-ray crystal structure of the dimer revealed that the chlorine atoms was situated cis, one bound to each tungsten. Cyclic voltammetry showed that the compound could be reversibly reduced, presumably to a W/sub 2//sup 4 +/ dimer containing a quadruple metal-metal bond.« less

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

Ryan, T.R.

The cyclo-addition of two Mo/sub 2/Cl/sub 4/(P(C/sub 6/H/sub 5/)/sub 3/)/sub 2/(CH/sub 3/OH)/sub 2/ molecules has produced a new type of tetrameric molybdenum cluster, Mo/sub 4/Cl/sub 8/L/sub 4/. Structural characterization of this dimer revealed weak molybdenum-methanol bonding which was consistent with the observed reactivity of the compound. New synthetic methods were devised for the preparation of Mo/sub 4/X/sub 8/L/sub 4/ clusters where X = Cl, Br, I and L = PR/sub 3/, Po/sub 3/, RCN, CH/sub 3/OH. A scheme for the metal-metal bonding in these clusters was presented which was in agreement with the known structural features of Mo/sub 4/Cl/sub 8/(PR/submore » 3/)/sub 4/, R = C/sub 2/H/sub 5/, n-C/sub 4/H/sub 9/. The preparation of the analogous W/sub 4/Cl/sub 8/(PR/sub 3/)/sub 4/ cluster from WCl/sub 4/ was accomplished by application of techniques used in the molybdenum syntheses. The single crystal x-ray structure revealed slight differences from the molybdenum analog which were rationalized in terms of the known behavior in dimeric tungsten and molybdenum species. The attempted preparation of a tetrameric tungsten cluster from W/sub 2/(mhp)/sub 4/ was unsuccessful (mhp = anion of 2-methyl-6-hydroxypyridine). Instead, the new tungsten dimer, W/sub 2/Cl/sub 2/(mhp)/sub 3/, was isolated which possessed a metal-metal bond order of 3.5. The x-ray crystal structure of the dimer revealed that the chlorine atoms were situated cis, one bound to each tungsten. Cyclic voltammetry showed that the compound could be reversibly reduced, presumably to a W/sub 2//sup 4 +/ dimer containing a quadruple metal-metal bond.« less

Fano-like resonance in symmetry-broken gold nanotube dimer.

PubMed

Wu, DaJian; Jiang, ShuMin; Cheng, Ying; Liu, XiaoJun

2012-11-19

The influences of the symmetry-breaking on the plasmon resonance couplings in the isolated gold nanotube and the gold nanotube dimer have been investigated by means of the finite element method. It is found that the core offset of gold nanotubes leads to the red-shifts of the low energy modes and the enhanced near-field on the thin shell side of the symmetry-broken gold nanotube (SBGNT). In the weak coupling model of the SBGNT dimer, the interference of the bonding octupole mode of the dimer with the dipole modes causes a strong Fano-like resonance in scattering spectrum. The Fano dip shows a red-shift and becomes deep with the increase of the offset-value. In the strong coupling model of the SBGNT dimer, the coupling between two SBGNTs induces giant electric field enhancement at the gap of the dimer, which is much larger than that in the symmetry gold nanotube dimer. The SBGNT with larger offset-value exhibits stronger near-field at the "hot spot".

High Molecular Weight Dimer Esters in α-Pinene Secondary Organic Aerosol

NASA Astrophysics Data System (ADS)

Kristensen, Kasper; Cui, Tianqu; Zhang, Haofei; Gold, Avram; Glasius, Marianne; Surratt, Jason D.

2014-05-01

Monoterpenes, such as α-pinene, constitute an important group of biogenic volatile organic compounds (BVOC). Once emitted into the atmosphere α-pinene is removed by oxidization by the hydroxyl radical (OH), reactions with ozone (O3), and with nitrate radicals (NO3) resulting in the formation of first-generation oxidation products, such as semi-volatile carboxylic acids. In addition, higher molecular weight dimer esters originating from the oxidation of α-pinene have been observed in both laboratory-generated and ambient secondary organic aerosols (SOA). While recent studies suggest that the dimers are formed through esterification between carboxylic acids in the particle phase, the formation mechanism of the dimer esters is still ambiguous. In this work, we present the results of a series of smog chamber experiments to assess the formation of dimer esters formed from the oxidation of α-pinene. Experiments were conducted in the University of North Carolina (UNC) dual outdoor smog chamber facility to investigate the effect of oxidant species (OH versus O3), relative humidity (RH), and seed aerosol acidity in order to obtain a better understanding of the conditions leading to the formation of the dimer esters and how these parameters may affect the formation and chemical composition of SOA. The chemical composition of α-pinene SOA was investigated by ultra-performance liquid chromatography/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry (UPLC/ESI-HR-Q-TOFMS), and a total of eight carboxylic acids and four dimer esters were identified, constituting between 8 and 12 % of the total α-pinene SOA mass.

Synthesis and structural characterization of oaklin-catechins.

PubMed

Sousa, André; Fernandes, Ana; Mateus, Nuno; De Freitas, Victor

2012-02-15

Condensation reactions of procyanidin dimer B4 with two representative oak wood cinnamic aldehydes (coniferaldehyde and sinapaldehyde) were conducted in winelike model solutions. Coniferaldehyde led to the formation of guaiacylcatechin-pyrylium-catechin (GCP-catechin, 737 m/z), whereas sinapaldehyde led to the formation of syringylcatechin-pyrylium-catechin (SCP-catechin, 767 m/z). The former was also structurally characterized by 1D and 2D NMR, allowing an elucidation of the formation mechanism of these oaklin-catechin adducts and demonstrating the importance of procyanidins in the formation of colored compounds through the reaction with cinnamic aldehydes extracted from oaks during storage.

Substituent effects on photosensitized splitting of thymine cyclobutane dimer by an attached indole.

PubMed

Tang, Wenjian; Zhou, Hongmei; Wang, Jing; Pan, Chunxiao; Shi, Jingbo; Song, Qinhua

2012-12-21

In chromophore-containing cyclobutane pyrimidine dimer (CPD) model systems, solvent effects on the splitting efficiency may depend on the length of the linker, the molecular conformation, and the oxidation potential of the donor. To further explore the relationship between chromophore structure and splitting efficiency, we prepared a series of substituted indole-T< >T model compounds 2 a-2 g and measured their splitting quantum yields in various solvents. Two reverse solvent effects were observed: an increase in splitting efficiency in solvents of lower polarity for models 2 a-2 d with an electron-donating group (EDG), and vice versa for models 2 e-2 g with an electron-withdrawing group (EWG). According to the Hammett equation, the negative value of the slope of the Hammett plot indicates that the indole moiety during the T< >T-splitting reaction loses negative charge, and the larger negative value implies that the repair reaction is more sensitive to substituent effects in low-polarity solvents. The EDGs of the models 2 a-2 d can delocalize the charge-separated state, and low-polarity solvents make it more stable, which leads to higher splitting efficiency in low-polarity solvents. Conversely, the EWGs of models 2 e-2 g favor destabilization of the charge-separated state, and high-polarity solvents decrease the destabilization and hence lead to more efficient splitting in high-polarity solvents. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Picosecond spectroscopic study of chlorophyll-based models for the primary photochemistry of photosynthesis. [Dimers and trimers of chlorophyllide derivatives

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

Bucks, R.R.; Netzel, T.L.; Fujita, I.

1982-05-27

A series of covalently linked dimers and trimers of chlorophyllide derivatives was investigated by time-resolved absorption and fluorescence spectroscopy (3 to 10/sup 4/ ps). For these compounds, the free energy difference between the singlet excited state of the electron donor and the anticipated cation-anion photoproduct (..delta..G/sub ET/) is estimated to range from +200 to -400 MeV. For the dimers studied, the singlet-excited-state lifetimes range from 1 to 7 ns and depend inversely on the solvent's static dielectric constant. Since no decrease in lifetime or fluorescence quantum yield was found as ..delta..G/sub ET/ became more negative, this effect is unlikely tomore » be due to slow electron transfer. It may be a result of fluctuating intramolecular association of the nonpolar macrocycles in solvents with a high dielectric constant. We also studied two trimers, each having the same chlorophyllide a dimer as the electron donor, but with pyropheophorbide a or pheophorbide a as the electron acceptor (the latter is 90 MeV easier to reduce than the former). For the trimer with pheophorbide a as the acceptor, there is evidence for a new path of radiationless decay which may involve an electron-transfer product. However, the rate of formation of this product is slow (less than or equal to 10/sup 10/ s/sup -1/), and its yield is low (less than or equal to 50%). Taken together, these results suggest that chlorophyll-based, donor-acceptor pairs connected by flexible chains longer than five atoms are not likely to duplicate the highly efficient excited-singlet-state electron-transfer reactions characteristic of the primary photochemistry of photosynthetic organisms.« less

Dynamic and magneto-optic properties of bent-core liquid crystals

NASA Astrophysics Data System (ADS)

Salili, Seyyed Muhammad

In this work, we describe dynamic behavior of free-standing bent-core liquid crystal filaments under dilative and axial compressive stresses in the B7 phase. We found that such filaments demonstrate very complex structures depending on the filament's temperature relative to the isotropic phase, initial filament thickness, and velocity at which the filament is pulled or compressed. We also present our experimental methods, results and analysis of the rupture and recoil properties of several bent-core liquid crystal filaments, anticipating that they may serve as a model system for complex biological fibers. After that, we systematically describe rheological measurements for dimeric liquid crystal compounds. We studied the shear-induced alignment properties, measured the viscoelastic properties as a function of temperature, shear rate, stress and frequency, and compared the results with the rheological properties of conventional chiral nematic and smectic phases. Then we present results of chiral nematic liquid crystals composed of flexible dimer molecules subject to large DC magnetic fields between 0 and 31T. We observe that these fields lead to selective reflection of light depending on temperature and magnetic field. The band of reflected wavelengths can be tuned from ultraviolet to beyond the IR-C band. A similar effect induced by electric fields has been presented previously, and was explained by a field-induced oblique-heliconical director deformation in accordance with early theoretical predictions. Finally, we report an unprecedented magnetic field-induced shifts of the isotropic-nematic phase transition temperature observed in liquid crystal dimers where two rigid linear mesogens are linked by flexible chains of either even- or odd-numbered hydrocarbon groups. This effect is explained in terms of quenching of the thermal fluctuations and decrease of the average bend angle of molecules in the odd-numbered dimers.

Plaquette order in a dimerized frustrated spin ladder

NASA Astrophysics Data System (ADS)

Shlagman, Ofer; Shimshoni, Efrat

2014-11-01

We study the effect of dimerization (due to, e.g., spin-Peierls instability) on the phase diagram of a frustrated antiferromagnetic spin-1/2 ladder, with weak transverse and diagonal rung coupling. Our analysis focuses on a one-dimensional version of the model (i.e., a single two-leg ladder) where we consider two forms of dimerization on the legs: columnar dimers (CDs) and staggered dimers (SDs). We examine in particular the regime of parameters (corresponding to an intermediate X X Z anisotropy) in which the leg dimerization and the rung coupling terms are equally relevant. In both the CD and SD cases, we find that the effective field theory describing the system is a self-dual sine-Gordon model, which favors ordering and the opening of a gap to excitations. The order parameter, which reflects the interplay between the leg and rung dimerization interactions, represents a crystal of 4-spin plaquettes on which longitudinal and transverse dimers are in a coherent superposition. Depending on the leg dimerization mode, these plaquettes are closed or open, however both types spontaneously break reflection symmetry across the ladder. The closed plaquettes are stable, while the open plaquette order is relatively fragile and the corresponding gap may be tuned to zero under extreme conditions. We further find that a first-order transition occurs from the plaquette order to a valence bond crystal (VBC) of dimers on the legs. This suggests that in a higher-dimensional version of this system, this variety of distinct VBC states with comparable energies leads to the formation of domains. Effectively one-dimensional gapless spinon modes on domain boundaries may account for the experimental observation of spin-liquid behavior in a physical realization of the model.

ZnCl 2 induced catalytic conversion of softwood lignin to aromatics and hydrocarbons

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

Wang, Hongliang; Zhang, Libing; Deng, Tiansheng

2016-01-01

Selective cleavage of C-O-C bonds in lignin without disrupting C-C linkages can result in releasing aromatic monomers and dimers that can be subsequently converted into chemicals and fuels. Results showed that both biomass-derived lignin and lignin model compounds were depolymerized in a highly concentrated ZnCl2 solution. Zn2+ ions in highly concentrated ZnCl2 solutions appeared to selectively coordinate with C-O-C bonds to cause key linkages of lignin much easier to cleave. In 63 wt.% ZnCl2 solution at 200 °C for 6 h, nearly half of the softwood technical lignin was converted to liquid products, of which the majority was alkylphenols. Resultsmore » indicated that most β-O-4 and Cmethyl-OAr bonds of model compounds were cleaved undersame conditions, providing a foundation towards understanding lignin depolymerization in a concentrated ZnCl2 solution. The phenolic products were further converted into cyclic hydrocarbons via hydrodeoxygenation and coupling reactions by co-catalyst Ru/C.« less

Anti-cooperative supramolecular polymerization: a new K2-K model applied to the self-assembly of perylene bisimide dye proceeding via well-defined hydrogen-bonded dimers.

PubMed

Gershberg, Jana; Fennel, Franziska; Rehm, Thomas H; Lochbrunner, Stefan; Würthner, Frank

2016-03-01

A perylene bisimide dye bearing amide functionalities at the imide positions derived from amino acid l-alanine and a dialkoxy-substituted benzyl amine self-assembles into tightly bound dimers by π-π-stacking and hydrogen bonding in chloroform. In less polar or unpolar solvents like toluene and methylcyclohexane, and in their mixtures, these dimers further self-assemble into extended oligomeric aggregates in an anti-cooperative process in which even numbered aggregates are highly favoured. The stepwise transition from dimers into oligomers can not be properly described by conventional K 2 - K model, and thus a new K 2 - K aggregation model has been developed, which interpretes the present anti-cooperative supramolecular polymerization more appropriately. The newly developed K 2 - K model will be useful to describe self-assembly processes of a plethora of other π-conjugated molecules that are characterized by a favored dimer species.

Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation

PubMed Central

Corrada, Dario; Soshilov, Anatoly A.; Denison, Michael S.

2016-01-01

The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the functional activity of the AhR. PMID:27295348

Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation.

PubMed

Corrada, Dario; Soshilov, Anatoly A; Denison, Michael S; Bonati, Laura

2016-06-01

The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the functional activity of the AhR.

Characterization of Terpenoids from the Root of Ceriops tagal with Antifouling Activity

PubMed Central

Chen, Jun-De; Yi, Rui-Zao; Lin, Yi-Ming; Feng, Dan-Qing; Zhou, Hai-Chao; Wang, Zhan-Chang

2011-01-01

One new dimeric diterpenoid, 8(14)-enyl-pimar-2′(3′)-en-4′(18′)-en-15′(16′)-endolabr- 16,15,2′,3′-oxoan-16-one (1) and five known terpenoids: Tagalsin C (2), Tagalsin I (3), lup-20(29)-ene-3β,28-diol (4), 3-oxolup-20(29)-en-28-oic acid (5) and 28-hydroxylup- 20(29)-en-3-one (6) were isolated from the roots of the mangrove plant Ceriops tagal. Their structures and relative stereochemistry were elucidated by means of extensive NMR, IR and MS analysis. The antifouling activity against larval settlement of the barnacle Balanus albicostatus were evaluated using capsaicin as a positive control. All these terpenoids exhibited antifouling activity against cyprid larvae of the barnacle without significant toxicity. The structure-activity relationship results demonstrated that the order of antifouling activity was diterpenoid (Compound 2) > triterpenoid (Compounds 4, 5 and 6) > dimeric diterpenoid (Compounds 1 and 3). The functional groups on the C-28 position of lupane triterpenoid significantly affect the antifouling activity. The diterpenoid dimmer with two identical diterpenoid subunits might display more potent antifouling activity than one with two different diterpenoid subunits. The stability test showed that Compounds 2, 4, 5 and 6 remained stable over 2-month exposure under filtered seawater. PMID:22072902

Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer's disease.

PubMed

Eslami, Mahboobeh; Hashemianzadeh, Seyed Majid; Bagherzadeh, Kowsar; Seyed Sajadi, Seyed Abolfazl

2016-01-01

The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short-term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine, and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase and butylcholinesterase) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analog of B7T, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations have been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have raised the potency of the analog in comparison with the parent compound to design more potent multi target ligands to heal Alzheimer's disease.

Molecular-level understanding of ground- and excited-state O-H...O hydrogen bonding involving the tyrosine side chain: a combined high-resolution laser spectroscopy and quantum chemistry study.

PubMed

Biswal, Himansu S; Bhattacharyya, Surjendu; Wategaonkar, Sanjay

2013-12-16

The present study combines both laser spectroscopy and ab initio calculations to investigate the intermolecular OH⋅⋅⋅O hydrogen bonding of complexes of the tyrosine side chain model chromophore compounds phenol (PH) and para-cresol (pCR) with H2 O, MeOH, PH and pCR in the ground (S0 ) state as well as in the electronic excited (S1 ) state. All the experimental and computational findings suggest that the H-bond strength increases in the S1 state and irrespective of the hydrogen bond acceptor used, the dispersion energy contribution to the total interaction energy is about 10-15 % higher in the S1 state compared to that in the S0 state. The alkyl-substituted (methyl; +I effect) H-bond acceptor forms a significantly stronger H bond both in the S0 and the S1 state compared to H2 O, whereas the aryl-substituted (phenyl; -R effect) H-bond donor shows a minute change in energy compared to H2 O. The theoretical study emphasizes the significant role of the dispersive interactions in the case of the pCR and PH dimers, in particular the CH⋅⋅⋅O and the CH⋅⋅⋅π interactions between the donor and acceptor subunits in controlling the structure and the energetics of the aromatic dimers. The aromatic dimers do not follow the acid-base formalism, which states that the stronger the base, the more red-shifted is the XH stretching frequency, and consequently the stronger is the H-bond strength. This is due to the significant contribution of the dispersion interaction to the total binding energy of these compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diethyl [(4-bromo­phen­yl)(5-chloro-2-hydroxy­anilino)meth­yl]phospho­nate

PubMed Central

Babu, V. H. H. Surendra; Krishnaiah, M.; Prasad, G. Syam; C. Suresh Reddy; Kant, Rajni

2009-01-01

In the title compound, C17H20BrClNO4P, inter­molecular C—H⋯O and N—H⋯O hydrogen bonds form centrosymmetric R 2 2(10) dimers linked through O—H⋯O inter­molecular hydrogen bonds, which form centrosymmetric R 2 2(16) dimers. All these hydrogen bonds form chains along [010]. In addition, the crystal structure is stabilized by weak C—H⋯Br hydrogen bonds. The very weak intramolecular N—H⋯O interaction forms a five-membered ring. PMID:21578446

A New Iridoid Dimer and Other Constituents from the Traditional Kurdish Plant Pterocephalus nestorianus Nábělek.

PubMed

Abdullah, Fuad O; Hussain, Faiq H S; Clericuzio, Marco; Porta, Alessio; Vidari, Giovanni

2017-03-01

Accompanied by other rare compounds, a new iridoid dimer, named kurdnestorianoside (1), showing an unprecedented secologanol configuration, has been isolated for the first time from the Kurdish medicinal plant Pterocephalus nestorianus, which is used in Kurdistan for treating oral diseases and inflammation. The structure of 1 was established from 1D- and 2D-NMR spectroscopic data. Kaempferol 3-O-[3,6-di-O-(E)-p-coumaroyl]-β-d-glucopyranoside (7) showed a remarkable antiproliferative activity against several human tumor cell lines. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

PubMed

Chicha, Hakima; Rakib, El Mostapha; Gamouh, Ahmed; Saadi, Mohamed; El Ammari, Lahcen

2014-09-01

In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 Å) and the benzene ring is 89.05 (7)°. The meth-oxy C atom deviates from its attached ring by 0.196 (3) Å. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R 2 (2)(8) loops. The dimers are connected into [010] chains by C-H⋯O inter-actions.

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.

PubMed

Gunasekera, Sarath P; Li, Yang; Ratnayake, Ranjala; Luo, Danmeng; Lo, Jeannette; Reibenspies, Joseph H; Xu, Zhengshuang; Clare-Salzler, Michael J; Ye, Tao; Paul, Valerie J; Luesch, Hendrik

2016-06-06

A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X-ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A-D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth-Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and β-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DFT approach to (benzylthio)acetic acid: Conformational search, molecular (monomer and dimer) structure, vibrational spectroscopy and some electronic properties

NASA Astrophysics Data System (ADS)

Sienkiewicz-Gromiuk, Justyna

2018-01-01

The DFT studies were carried out with the B3LYP method utilizing the 6-31G and 6-311++G(d,p) basis sets depending on whether the aim of calculations was to gain the geometry at equilibrium, or to calculate the optimized molecular structure of (benzylthio)acetic acid (Hbta) in the forms of monomer and dimer. The minimum conformational energy search was followed by the potential energy surface (PES) scan of all rotary bonds existing in the acid molecule. The optimized geometrical monomeric and dimeric structures of the title compound were compared with the experimental structural data in the solid state. The detailed vibrational interpretation of experimental infrared and Raman bands was performed on the basis of theoretically simulated ESFF-scaled wavenumbers calculated for the monomer and dimer structures of Hbta. The electronic characteristics of Hbta is also presented in terms of Mulliken atomic charges, frontier molecular orbitals and global reactivity descriptors. Additionally, the MEP and ESP surfaces were computed to predict coordination sites for potential metal complex formation.

Crystal structure of 3-(2,5-di-meth-oxy-phen-yl)propionic acid.

PubMed

Bugenhagen, Bernhard; Al Jasem, Yosef; AlAzani, Mariam; Thiemann, Thies

2015-05-01

In the crystal of the title compound, C11H14O4, the aromatic ring is almost coplanar with the 2-position meth-oxy group with which it subtends a dihedral of 0.54 (2)°, while the 5-position meth-oxy group makes a corresponding dihedral angle of just 5.30 (2)°. The angle between the mean planes of the aromatic ring and the propionic acid group is 78.56 (2)°. The fully extended propionic side chain is in a trans configuration with a C-C-C-C torsion angle of -172.25 (7)°. In the crystal, hydrogen bonding is limited to dimer formation via R 2 (2)(8) rings. The hydrogen-bonded dimers are stacked along the b axis. The average planes of the two benzene rings in a dimer are parallel to each other, but at an offset of 4.31 (2) Å. Within neighbouring dimers along the [101] direction, the average mol-ecular benzene planes are almost perpendicular to each other, with a dihedral angle of 85.33 (2)°.

Fragment-based protein-protein interaction antagonists of a viral dimeric protease

PubMed Central

Gable, Jonathan E.; Lee, Gregory M.; Acker, Timothy M.; Hulce, Kaitlin R.; Gonzalez, Eric R.; Schweigler, Patrick; Melkko, Samu; Farady, Christopher J.; Craik, Charles S.

2016-01-01

Fragment-based drug discovery has shown promise as an approach for challenging targets such as protein-protein interfaces. We developed and applied an activity-based fragment screen against dimeric Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) using an optimized fluorogenic substrate. Dose response determination was performed as a confirmation screen and NMR spectroscopy was used to map fragment inhibitor binding to KSHV Pr. Kinetic assays demonstrated that several initial hits also inhibit human cytomegalovirus protease (HCMV Pr). Binding of these hits to HCMV Pr was also confirmed via NMR spectroscopy. Despite the use of a target-agnostic fragment library, more than 80% of confirmed hits disrupted dimerization and bound to a previously reported pocket at the dimer interface of KSHV Pr, not to the active site. One class of fragments, an aminothiazole scaffold, was further explored using commercially available analogs. These compounds demonstrated greater than 100-fold improvement of inhibition. This study illustrates the power of fragment-based screening for these challenging enzymatic targets and provides an example of the potential druggability of pockets at protein-protein interfaces. PMID:26822284

Dimerization Products of Chloroprene are Background Contaminants Emitted from ALTEF (Polyvinylidene Difluoride) Gas Sampling Bags.

PubMed

Kwak, Jae; Fan, Maomian; Martin, Jennifer A; Ott, Darrin K; Grigsby, Claude C

2017-01-01

Gas sampling bags have been used for collecting air samples. Tedlar bags are most commonly used, but bleed background chemicals such as N,N-dimethylacetamide and phenol. It is often necessary to remove the contaminant by flushing the bags with pure nitrogen or air. In this study, we identified four chloroprene dimerization products as background contaminants emitted from ALTEF bags that are made of a proprietary polyvinylidene difluoride (PVDF). No monomer chloroprene was detected in the bags analyzed. All of the dimers gradually increased once bags were filled with nitrogen due to diffusion from the bag surface. Flushing the bags with nitrogen reduced their concentrations, but was not effective for removing the contaminants. When the bags that had been flushed with nitrogen 5 times were left for 24 h, they increased again, indicating that the dimers were constantly emitted from the ALTEF bag surface. To our knowledge, these compounds have never been demonstrated in ALTEF or other PVDF bags. Our finding indicates that ALTEF might be incorporated with Neoprene (chloroprene-based polymer) during its manufacturing process.

Self-homodimerization of an actinoporin by disulfide bridging reveals implications for their structure and pore formation.

PubMed

Valle, Aisel; Pérez-Socas, Luis Benito; Canet, Liem; Hervis, Yadira de la Patria; de Armas-Guitart, German; Martins-de-Sa, Diogo; Lima, Jônatas Cunha Barbosa; Souza, Adolfo Carlos Barros; Barbosa, João Alexandre Ribeiro Gonçalves; de Freitas, Sonia Maria; Pazos, Isabel Fabiola

2018-04-26

The Trp111 to Cys mutant of sticholysin I, an actinoporin from Stichodactyla helianthus sea anemone, forms a homodimer via a disulfide bridge. The purified dimer is 193 times less hemolytic than the monomer. Ultracentrifugation, dynamic light scattering and size-exclusion chromatography demonstrate that monomers and dimers are the only independent oligomeric states encountered. Indeed, circular dichroism and fluorescence spectroscopies showed that Trp/Tyr residues participate in homodimerization and that the dimer is less thermostable than the monomer. A homodimer three-dimensional model was constructed and indicates that Trp147/Tyr137 are at the homodimer interface. Spectroscopy results validated the 3D-model and assigned 85° to the disulfide bridge dihedral angle responsible for dimerization. The homodimer model suggests that alterations in the membrane/carbohydrate-binding sites in one of the monomers, as result of dimerization, could explain the decrease in the homodimer ability to form pores.

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

Campione, Salvatore; Warne, Larry K.; Basilio, Lorena I.

In this paper we develop a fully-retarded, dipole approximation model to estimate the effective polarizabilities of a dimer made of dielectric resonators. They are computed from the polarizabilities of the two resonators composing the dimer. We analyze the situation of full-cubes as well as split-cubes, which have been shown to exhibit overlapping electric and magnetic resonances. We compare the effective dimer polarizabilities to ones retrieved via full-wave simulations as well as ones computed via a quasi-static, dipole approximation. We observe good agreement between the fully-retarded solution and the full-wave results, whereas the quasi-static approximation is less accurate for the problemmore » at hand. The developed model can be used to predict the electric and magnetic resonances of a dimer under parallel or orthogonal (to the dimer axis) excitation. This is particularly helpful when interested in locating frequencies at which the dimer will emit directional radiation.« less

The dimerization domain in DapE enzymes is required for catalysis.

PubMed

Nocek, Boguslaw; Starus, Anna; Makowska-Grzyska, Magdalena; Gutierrez, Blanca; Sanchez, Stephen; Jedrzejczak, Robert; Mack, Jamey C; Olsen, Kenneth W; Joachimiak, Andrzej; Holz, Richard C

2014-01-01

The emergence of antibiotic-resistant bacterial strains underscores the importance of identifying new drug targets and developing new antimicrobial compounds. Lysine and meso-diaminopimelic acid are essential for protein production and bacterial peptidoglycan cell wall remodeling and are synthesized in bacteria by enzymes encoded within dap operon. Therefore dap enzymes may serve as excellent targets for developing a new class of antimicrobial agents. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) converts N-succinyl-L,L-diaminopimelic acid to L,L-diaminopimelic acid and succinate. The enzyme is composed of catalytic and dimerization domains, and belongs to the M20 peptidase family. To understand the specific role of each domain of the enzyme we engineered dimerization domain deletion mutants of DapEs from Haemophilus influenzae and Vibrio cholerae, and characterized these proteins structurally and biochemically. No activity was observed for all deletion mutants. Structural comparisons of wild-type, inactive monomeric DapE enzymes with other M20 peptidases suggest that the dimerization domain is essential for DapE enzymatic activity. Structural analysis and molecular dynamics simulations indicate that removal of the dimerization domain increased the flexibility of a conserved active site loop that may provide critical interactions with the substrate.

Epigenetics and Breast Cancers

PubMed Central

Vo, An T.; Millis, Richard M.

2012-01-01

Several of the active compounds in foods, poisons, drugs, and industrial chemicals may, by epigenetic mechanisms, increase or decrease the risk of breast cancers. Enzymes that are involved in DNA methylation and histone modifications have been shown to be altered in several types of breast and other cancers resulting in abnormal patterns of methylation and/or acetylation. Hypermethylation at the CpG islands found in estrogen response element (ERE) promoters occurs in conjunction with ligand-bonded alpha subunit estrogen receptor (Erα) dimers wherein the ligand ERα dimer complex acts as a transcription factor and binds to the ERE promoter. Ligands could be 17-β-estradiol (E2), phytoestrogens, heterocyclic amines, and many other identified food additives and heavy metals. The dimer recruits DNA methyltransferases which catalyze the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to 5′-cytosine on CpG islands. Other enzymes are recruited to the region by ligand-ERα dimers which activate DNA demethylases to act simultaneously to increase gene expression of protooncogenes and growth-promoting genes. Ligand-ERα dimers also recruit histone acetyltransferase to the ERE promoter region. Histone demethylases such as JMJD2B and histone methyltransferases are enzymes which demethylate lysine residues on histones H3 and/or H4. This makes the chromatin accessible for transcription factors and enzymes. PMID:22567014

Characterization of procyanidin B2 oxidation products in an apple juice model solution and confirmation of their presence in apple juice by high-performance liquid chromatography coupled to electrospray ion trap mass spectrometry.

PubMed

Poupard, Pascal; Sanoner, Philippe; Baron, Alain; Renard, Catherine M G C; Guyot, Sylvain

2011-11-01

Procyanidins (i.e. condensed tannins) are polyphenols commonly found in fruits. During juice and cider making, apple polyphenol oxidase catalyzes the oxidation of caffeoylquinic acid (CQA) into its corresponding o-quinone which further reacts with procyanidins and other polyphenols, leading to the formation of numerous oxidation products. However, the structure and the reaction pathways of these neoformed phenolic compounds are still largely unknown. Experiments were carried out on a model system to gain insights into the chemical processes occurring during the initial steps of fruit processing. Procyanidin B2 was oxidized by caffeoylquinic acid o-quinone (CQAoq) in an apple juice model solution. The reaction products were monitored using high performance liquid chromatography (HPLC) coupled to ultraviolet (UV)-visible and electrospray tandem mass spectrometry (ESI-MS/MS) in the negative mode. Oxidative conversion of procyanidin B2 ([M-H](-) at m/z 577) into procyanidin A2 at m/z 575 was unambiguously confirmed. In addition, several classes of products were characterized by their deprotonated molecules ([M-H](-)) and their MS/MS fragmentation patterns: hetero-dimers (m/z 929) and homo-dimers (m/z 1153 and 705) resulting from dimerization involving procyanidin and CQA molecules; intramolecular addition products at m/z 575, 573, 927, 1151 and 703. Interestingly, no extensive polymerization was observed. Analysis of a cider apple juice enabled comparison with the results obtained on a biosynthetic model solution. However, procyanidin A2 did not accumulate but seemed to be an intermediate in the formation of an end-product at m/z 573 for which two structural hypotheses are given. These structural modifications of native polyphenols as a consequence of oxidation probably have an impact on the organoleptic and nutritional properties of apple juices and other apple-derived foods. Copyright © 2011 John Wiley & Sons, Ltd.

Rapid dimerization of quercetin through an oxidative mechanism in the presence of serum albumin decreases its ability to induce cytotoxicity in MDA-MB-231 cells

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

Pham, Anh; Bortolazzo, Anthony; White, J. Brandon, E-mail: Brandon.White@sjsu.edu

Highlights: Black-Right-Pointing-Pointer Quercetin cannot be detected intracellularly despite killing MDA-MB-231 cells. Black-Right-Pointing-Pointer Quercetin forms a heterodimer through oxidation in media with serum. Black-Right-Pointing-Pointer The quercetin heterodimer does not kill MDA-MB-231 cells. Black-Right-Pointing-Pointer Ascorbic acid stabilizes quercetin increasing cell death in quercetin treated cells. Black-Right-Pointing-Pointer Quercetin, and not a modified form, is responsible for apoptosis and cell death. -- Abstract: Quercetin is a member of the flavonoid family and has been previously shown to have a variety of anti-cancer activities. We and others have reported anti-proliferation, cell cycle arrest, and induction of apoptosis of cancer cells after treatment with quercetin. Quercetinmore » has also been shown to undergo oxidation. However, it is unclear if quercetin or one of its oxidized forms is responsible for cell death. Here we report that quercetin rapidly oxidized in cell culture media to form a dimer. The quercetin dimer is identical to a dimer that is naturally produced by onions. The quercetin dimer and quercetin-3-O-glucopyranoside are unable to cross the cell membrane and do not kill MDA-MB-231 cells. Finally, supplementing the media with ascorbic acid increases quercetin's ability to induce cell death probably by reduction oxidative dimerization. Our results suggest that an unmodified quercetin is the compound that elicits cell death.« less

Quantitative Experimental Determination of Primer-Dimer Formation Risk by Free-Solution Conjugate Electrophoresis

PubMed Central

Desmarais, Samantha M.; Leitner, Thomas; Barron, Annelise E.

2012-01-01

DNA barcodes are short, unique ssDNA primers that “mark” individual biomolecules. To gain better understanding of biophysical parameters constraining primer-dimer formation between primers that incorporate barcode sequences, we have developed a capillary electrophoresis method that utilizes drag-tag-DNA conjugates to quantify dimerization risk between primer-barcode pairs. Results obtained with this unique free-solution conjugate electrophoresis (FSCE) approach are useful as quantitatively precise input data to parameterize computation models of dimerization risk. A set of fluorescently labeled, model primer-barcode conjugates were designed with complementary regions of differing lengths to quantify heterodimerization as a function of temperature. Primer-dimer cases comprised two 30-mer primers, one of which was covalently conjugated to a lab-made, chemically synthesized poly-N-methoxyethylglycine drag-tag, which reduced electrophoretic mobility of ssDNA to distinguish it from ds primer-dimers. The drag-tags also provided a shift in mobility for the dsDNA species, which allowed us to quantitate primer-dimer formation. In the experimental studies, pairs of oligonucleotide primer-barcodes with fully or partially complementary sequences were annealed, and then separated by free-solution conjugate CE at different temperatures, to assess effects on primer-dimer formation. When less than 30 out of 30 basepairs were bonded, dimerization was inversely correlated to temperature. Dimerization occurred when more than 15 consecutive basepairs formed, yet non-consecutive basepairs did not create stable dimers even when 20 out of 30 possible basepairs bonded. The use of free-solution electrophoresis in combination with a peptoid drag-tag and different fluorophores enabled precise separation of short DNA fragments to establish a new mobility shift assay for detection of primer-dimer formation. PMID:22331820

Shape-Persistent, Sterically Crowded Star Mesogens: From Exceptional Columnar Dimer Stacks to Supermesogens.

PubMed

Lehmann, Matthias; Maier, Philipp

2015-08-10

Hexasubstituted C3 -symmetric benzenes with three oligophenylenevinylene (OPV) arms and three pyridyl or phenyl substituents are shape-persistent star mesogens that are sterically crowded in the center. Such molecular structures possess large void spaces between their arms, which have to be filled in condensed phases. For the neat materials, this is accomplished by an exceptional formation of dimers and short-range helical packing in columnar mesophases. The mesophase is thermodynamically stable for the pyridyl compound. Only this derivative forms filled star-shaped supermesogens in the presence of various carboxylic acids. The latter do not arrange as dimers, but as monomers along the columnar stacks. In this liquid crystal (LC) phase, the guests are completely enclosed by the hosts. Therefore, the host can be regarded as a new LC endoreceptor, which allows the design of columnar functional structures in the future. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A tocotrienol series with an oxidative terminal prenyl unit from Garcinia amplexicaulis.

PubMed

Lavaud, Alexis; Richomme, Pascal; Gatto, Julia; Aumond, Marie-Christine; Poullain, Cyril; Litaudon, Marc; Andriantsitohaina, Ramaroson; Guilet, David

2015-01-01

Ten tocotrienol derivatives, i.e., amplexichromanols (1-10), were isolated from stem bark of Garcinia amplexicaulis Vieill. ex Pierre collected in Caledonia. The structures of the compounds 1-5 were determined to be chromanol derivatives substituted by a polyprenyl chain oxidized in terminal position. The remaining compounds 6-10 are the corresponding dimeric derivatives. Eleven known compounds, including xanthones, tocotrienol derivatives, triterpenes and phenolic compounds, were also isolated. Their structures were mainly determined using one and two-dimensional NMR and mass spectroscopy analysis. The compounds and some amplexichromanol molecules formerly isolated from G. amplexicaulis exhibited significant antioxidant activity against lipid peroxidation and in the ORAC assay. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

Herman, Michael F.; Currier, Robert P.; Peery, Travis B.

Intermolecular coupling of dipole moments is studied for a model system consisting of two diatomic molecules (AB monomers) arranged co-linearly and which can form non-covalently bound dimers. The dipolar coupling is a function of the bond length in each molecule as well as of the distance between the centers-of-mass of the two molecules. The calculations show that intermolecular coupling of the vibrations results in an isotope-dependent modification of the AB-AB intermolecular potential. This in turn alters the energies of the low-lying bound states of the dimers, producing isotope-dependent changes in the AB-AB dimer partition function. Explicit inclusion of intermolecular vibrationalmore » coupling then changes the predicted gas-dimer isotopic fractionation. In addition, a mass dependence in the intermolecular potential can also result in changes in the number of bound dimer states in an equilibrium mixture. This in turn leads to a significant dimer population shift in the model monomer-dimer equilibrium system considered here. Finally, the results suggest that intermolecular coupling terms should be considered when probing the origins of isotopic fractionation.« less

A test of the significance of intermolecular vibrational coupling in isotopic fractionation

DOE PAGES

Herman, Michael F.; Currier, Robert P.; Peery, Travis B.; ...

2017-07-15

Intermolecular coupling of dipole moments is studied for a model system consisting of two diatomic molecules (AB monomers) arranged co-linearly and which can form non-covalently bound dimers. The dipolar coupling is a function of the bond length in each molecule as well as of the distance between the centers-of-mass of the two molecules. The calculations show that intermolecular coupling of the vibrations results in an isotope-dependent modification of the AB-AB intermolecular potential. This in turn alters the energies of the low-lying bound states of the dimers, producing isotope-dependent changes in the AB-AB dimer partition function. Explicit inclusion of intermolecular vibrationalmore » coupling then changes the predicted gas-dimer isotopic fractionation. In addition, a mass dependence in the intermolecular potential can also result in changes in the number of bound dimer states in an equilibrium mixture. This in turn leads to a significant dimer population shift in the model monomer-dimer equilibrium system considered here. Finally, the results suggest that intermolecular coupling terms should be considered when probing the origins of isotopic fractionation.« less

Active and regulatory sites of cytosolic 5'-nucleotidase.

PubMed

Pesi, Rossana; Allegrini, Simone; Careddu, Maria Giovanna; Filoni, Daniela Nicole; Camici, Marcella; Tozzi, Maria Grazia

2010-12-01

Cytosolic 5'-nucleotidase (cN-II), which acts preferentially on 6-hydroxypurine nucleotides, is essential for the survival of several cell types. cN-II catalyses both the hydrolysis of nucleotides and transfer of their phosphate moiety to a nucleoside acceptor through formation of a covalent phospho-intermediate. Both activities are regulated by a number of phosphorylated compounds, such as diadenosine tetraphosphate (Ap₄A), ADP, ATP, 2,3-bisphosphoglycerate (BPG) and phosphate. On the basis of a partial crystal structure of cN-II, we mutated two residues located in the active site, Y55 and T56. We ascertained that the ability to catalyse the transfer of phosphate depends on the presence of a bulky residue in the active site very close to the aspartate residue that forms the covalent phospho-intermediate. The molecular model indicates two possible sites at which adenylic compounds may interact. We mutated three residues that mediate interaction in the first activation site (R144, N154, I152) and three in the second (F127, M436 and H428), and found that Ap₄A and ADP interact with the same site, but the sites for ATP and BPG remain uncertain. The structural model indicates that cN-II is a homotetrameric protein that results from interaction through a specific interface B of two identical dimers that have arisen from interaction of two identical subunits through interface A. Point mutations in the two interfaces and gel-filtration experiments indicated that the dimer is the smallest active oligomerization state. Finally, gel-filtration and light-scattering experiments demonstrated that the native enzyme exists as a tetramer, and no further oligomerization is required for enzyme activation. © 2010 The Authors Journal compilation © 2010 FEBS.

Role of the ancillary ligand N,N-dimethylaminoethanol in the sensitization of Eu(III) and Tb(III) luminescence in dimeric beta-diketonates.

PubMed

Eliseeva, Svetlana V; Kotova, Oxana V; Gumy, Frédéric; Semenov, Sergey N; Kessler, Vadim G; Lepnev, Leonid S; Bünzli, Jean-Claude G; Kuzmina, Natalia P

2008-04-24

Two types of dimeric complexes [Ln2(hfa)6(mu2-O(CH2)2NHMe2)2] and [Ln(thd)2(mu2,eta2-O(CH2)2NMe2)]2 (Ln = YIII, EuIII, GdIII, TbIII, TmIII, LuIII; hfa- = hexafluoroacetylacetonato, thd- = dipivaloylmethanato) are obtained by reacting [Ln(hfa)3(H2O)2] and [Ln(thd)3], respectively, with N,N-dimethylaminoethanol in toluene and are fully characterized. X-ray single crystal analysis performed for the TbIII compounds confirms their dimeric structure. The coordination mode of N,N-dimethylaminoethanol depends on the nature of the beta-diketonate. In [Tb2(hfa)6(mu2-O(CH2)2NHMe2)2], eight-coordinate TbIII ions adopt distorted square antiprismatic coordination environments and are O-bridged by two zwitterionic N,N-dimethylaminoethanol ligands with a Tb1...Tb2 separation of 3.684(1) A. In [Tb(thd)2(mu2,eta2-O(CH2)2NMe2)]2, the N,N-dimethylaminoethanol acts as chelating-bridging O,N-donor anion and the TbIII ions are seven-coordinate; the Tb1...Tb1A separation amounts to 3.735(2) A within centrosymmetric dimers. The dimeric complexes are thermally stable up to 180 degrees C, as shown by thermogravimetric analysis, and their volatility is sufficient for quantitative sublimation under reduced pressure. The EuIII and TbIII dimers display metal-centered luminescence, particularly [Eu2(hfa)6(O(CH2)2NHMe2)2] (quantum yield Q(L)Ln = 58%) and [Tb(thd)2(O(CH2)2NMe2)]2 (32%). Consideration of energy migration paths within the dimers, based on the study of both pure and EuIII- or TbIII-doped (0.01-0.1 mol %) LuIII analogues, leads to the conclusion that both the beta-diketone and N,N-dimethylaminoethanol ligands contribute significantly to the sensitization process of the EuIII luminescence. The ancillary ligand increases considerably the luminescence of [Eu2(hfa)6(O(CH2)2NHMe2)2], compared to [Ln(hfa)3(H2O)2], through the formation of intra-ligand states while it is detrimental to TbIII luminescence in both beta-diketonates. Thin films of the most luminescent compound [Eu2(hfa)6(O(CH2)2NHMe2)2] obtained by vacuum sublimation display photophysical properties analogous to those of the solid-state sample, thus opening perspectives for applications in electroluminescent devices.

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

PubMed Central

Streicher, Wolfgang; Luedeke, Manuel; Azoitei, Anca; Zengerling, Friedemann; Herweg, Alexander; Genze, Felicitas; Schrader, Mark G.; Schrader, Andres J.; Cronauer, Marcus V.

2014-01-01

Background Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. Methodology In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. Results The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. Conclusion RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors. PMID:24887556

Microtubules as mechanical force sensors.

PubMed

Karafyllidis, Ioannis G; Lagoudas, Dimitris C

2007-03-01

Microtubules are polymers of tubulin subunits (dimers) arranged on a hexagonal lattice. Each tubulin dimer comprises two monomers, the alpha-tubulin and beta-tubulin, and can be found in two states. In the first state a mobile negative charge is located into the alpha-tubulin monomer and in the second into the beta-tubulin monomer. Each tubulin dimer is modeled as an electrical dipole coupled to its neighbors by electrostatic forces. The location of the mobile charge in each dimer depends on the location of the charges in the dimer's neighborhood. Mechanical forces that act on the microtubule affect the distances between the dimers and alter the electrostatic potential. Changes in this potential affect the mobile negative charge location in each dimer and the charge distribution in the microtubule. The net effect is that mechanical forces affect the charge distribution in microtubules. We propose to exploit this effect and use microtubules as mechanical force sensors. We model each dimer as a two-state quantum system and, following the quantum computation paradigm, we use discrete quantum random walk on the hexagonal microtubule lattice to determine the charge distribution. Different forces applied on the microtubule are modeled as different coin biases leading to different probability distributions of the quantum walker location, which are directly connected to different charge distributions. Simulation results show that there is a strong indication that microtubules can be used as mechanical force sensors and that they can also detect the force directions and magnitudes.

Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter.

PubMed

Steiger, Scott A; Li, Chun; Backos, Donald S; Reigan, Philip; Natale, N R

2017-06-15

A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n=2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Probing the Allosteric Modulator Binding Site of GluR2 with Thiazide Derivatives

PubMed Central

Ptak, Christopher P.; Ahmed, Ahmed H.; Oswald, Robert E.

2009-01-01

Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission and are therapeutic targets for cognitive enhancement and treatment of schizophrenia. The binding domains of these tetrameric receptors consist of two dimers, and the dissociation of the dimer interface of the ligand-binding domain leads to desensitization in the continued presence of agonist. Positive allosteric modulators act by strengthening the dimer interface and reducing desensitization, thereby increasing steady-state activation. Removing the desensitized state for simplified analysis of receptor activation is commonly achieved using cyclothiazide (CTZ), the most potent modulator of the benzothiadiazide class, with the flip form of the AMPA receptor subtype. IDRA-21, the first benzothiadiazide to have an effect in behavioral tests, is an important lead compound in clinical trials for cognitive enhancement as it can cross the blood-brain barrier. Intermediate structures between CTZ and IDRA-21 show reduced potency suggesting that these two compounds have different contact points associated with binding. To understand how benzothiadiazides bind to the pocket bridging the dimer interface, we generated a series of crystal structures of the GluR2 ligand-binding domain complexed with benzothiadiazide derivatives (IDRA-21, hydroflumethiazide, hydrochlorothiazide, chlorothiazide, trichlormethiazide, and althiazide) for comparison with an existing structure for cyclothiazide. The structures detail how changes in the substituents in the 3- and 7-positions of the hydrobenzothiadiazide ring shift the orientation of the drug in the binding site and, in some cases, change the stoichiometry of binding. All derivatives maintain a hydrogen bond with the Ser754 hydroxyl, affirming the partial selectivity of the benzothiadiazides for the flip form of AMPA receptors. PMID:19673491

Antimicrobial activity, structural evaluation and vibrational (FT-IR and FT-Raman) study of pyrrole containing vinyl derivatives

NASA Astrophysics Data System (ADS)

Singh, R. N.; Rawat, Poonam; Sahu, Sangeeta; Kumar, Yashvinder

2016-02-01

In this paper we present structural and vibrational study of three vinylpyrrole derivatives: 2-Cyano-3-(1H-pyrrol-2-yl)-acrylamide (CPA), 1-(1H-Pyrrol-2-yl)-Pent-1-en-3-one (PP) and 1-(1H-Pyrrol-2-yl)-but-1-en-3-one (PB), using ab initio, DFT and experimental approaches. The quantum chemical calculation have been performed on B3LYP method and 6-311 + G(d,p) basis set. The experimental FT-IR and Raman wavenumbers were compared with the respective theoretical values obtained from DFT calculations and found to agree well. The experimental FT-IR and Raman study clearly indicate that the compound exist as dimer in solid state. The binding energies of (CPA), (PP) and (PB) dimers are found to be 20.95, 18.75 and 19.18 kcal/mol, respectively. The vibrational analysis shows red shifts in vN-H and vCdbnd O stretching as result of dimer formation. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using NBO analysis. Topological and energetic parameters reveal the nature of interactions in dimer. The local electronic descriptors analyses were used to predict the reactive sites in the molecule. Calculated first static hyperpolarizability of CPA, PP and PB is found to be 10.41 × 10- 30, 18.93 × 10- 30, 18.29 × 10- 30 esu, respectively, shows that investigated molecules will have non-linear optical response and might be used as non-linear optical (NLO) material. These vinylpyrrole compounds (CPA), (PP) and (PB) showed antifungal and antibacterial activity against Aspergillus niger and gram-positive bacteria Bacillus subtili.

Structural modeling of the AhR:ARNT complex in the bHLH-PASA-PASB region elucidates the key determinants of dimerization.

PubMed

Corrada, Dario; Denison, Michael S; Bonati, Laura

2017-05-02

Elucidation of the dimerization process of the aryl hydrocarbon receptor (AhR) with the AhR nuclear translocator (ARNT) is crucial for understanding the mechanisms underlying the functional activity of AhR, including mediation of the toxicity of environmental contaminants. In this work, for the first time a structural model of the AhR:ARNT dimer encompassing the entire bHLH-PASA-PASB domain region is proposed. It is developed by using a template-based modeling approach, relying on the recently available crystallographic structures of two dimers of homologous systems in the bHLH-PAS family of proteins: the CLOCK:BMAL1 and the HIF2α:ARNT heterodimers. The structural and energetic characteristics of the modeled AhR:ARNT protein-protein interface are determined by evaluating the variations in solvent accessible surface area, the total binding free energy and the per-residue free energy contributions obtained by the MM-GBSA method and the Energy Decomposition Analysis. The analyses of the intricate network of inter-domain interactions at the dimerization interfaces provide insights into the key determinants of dimerization. These are confirmed by comparison of the computational findings with the available experimental mutagenesis and functional analysis data. The results presented here on the AhR:ARNT dimer structure and interactions provide a framework to start analyzing the mechanism of AhR transformation into its functional DNA binding form.

Jozilebomines A and B, Naphthylisoquinoline Dimers from the Congolese Liana Ancistrocladus ileboensis, with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.

PubMed

Li, Jun; Seupel, Raina; Bruhn, Torsten; Feineis, Doris; Kaiser, Marcel; Brun, Reto; Mudogo, Virima; Awale, Suresh; Bringmann, Gerhard

2017-10-27

Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A 2 (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C 2 -symmetric jozimine A 2 (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A 2 (2) represent novel potential candidates for future drug development against pancreatic cancer.

The human dopamine transporter forms a tetramer in the plasma membrane: cross-linking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs.

PubMed

Hastrup, Hanne; Sen, Namita; Javitch, Jonathan A

2003-11-14

Using cysteine cross-linking, we demonstrated previously that the dopamine transporter (DAT) is at least a homodimer, with the extracellular end of transmembrane segment (TM) 6 at a symmetrical dimer interface. We have now explored the possibility that DAT exists as a higher order oligomer in the plasma membrane. Cysteine cross-linking of wild type DAT resulted in bands on SDS-PAGE consistent with dimer, trimer, and tetramer, suggesting that DAT forms a tetramer in the plasma membrane. A cysteine-depleted DAT (CD-DAT) into which only Cys243 or Cys306 was reintroduced was cross-linked to dimer, suggesting that these endogenous cysteines in TM4 and TM6, respectively, were cross-linked at a symmetrical dimer interface. Reintroduction of both Cys243 and Cys306 into CD-DAT led to a pattern of cross-linking indistinguishable from that of wild type, with dimer, trimer, and tetramer bands. This indicated that the TM4 interface and the TM6 interface are distinct and further suggested that DAT may exist in the plasma membrane as a dimer of dimers, with two symmetrical homodimer interfaces. The cocaine analog MFZ 2-12 and other DAT inhibitors, including benztropine and mazindol, protected Cys243 against cross-linking. In contrast, two substrates of DAT, dopamine and tyramine, did not significantly impact cross-linking. We propose that the impairment of cross-linking produced by the inhibitors results from a conformational change at the TM4 interface, further demonstrating that these compounds are not neutral blockers but by themselves have effects on the structure of the transporter.

Reaction of Diazo Compounds with Difluorocarbene: An Efficient Approach towards 1,1-Difluoroolefins.

PubMed

Zhang, Zhikun; Yu, Weizhi; Wu, Chenggui; Wang, Chengpeng; Zhang, Yan; Wang, Jianbo

2016-01-04

A transition-metal-free difluoromethylenation of diazo compounds that proceeds under mild conditions has been developed and is based on the use of TMSCF2 Br as the difluoromethylene source and tetrabutylammonium bromide (TBAB) as the promoter. The chemoselective formal carbene dimerization reaction is achieved owing to the electronic properties and the relative stability of the difluorocarbene intermediate. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

From Cycle Rooted Spanning Forests to the Critical Ising Model: an Explicit Construction

NASA Astrophysics Data System (ADS)

de Tilière, Béatrice

2013-04-01

Fisher established an explicit correspondence between the 2-dimensional Ising model defined on a graph G and the dimer model defined on a decorated version {{G}} of this graph (Fisher in J Math Phys 7:1776-1781, 1966). In this paper we explicitly relate the dimer model associated to the critical Ising model and critical cycle rooted spanning forests (CRSFs). This relation is established through characteristic polynomials, whose definition only depends on the respective fundamental domains, and which encode the combinatorics of the model. We first show a matrix-tree type theorem establishing that the dimer characteristic polynomial counts CRSFs of the decorated fundamental domain {{G}_1}. Our main result consists in explicitly constructing CRSFs of {{G}_1} counted by the dimer characteristic polynomial, from CRSFs of G 1, where edges are assigned Kenyon's critical weight function (Kenyon in Invent Math 150(2):409-439, 2002); thus proving a relation on the level of configurations between two well known 2-dimensional critical models.

Dynamics and mechanism of UV-damaged DNA repair in indole-thymine dimer adduct: molecular origin of low repair quantum efficiency.

PubMed

Guo, Xunmin; Liu, Zheyun; Song, Qinhua; Wang, Lijuan; Zhong, Dongping

2015-02-26

Many biomimetic chemical systems for repair of UV-damaged DNA showed very low repair efficiency, and the molecular origin is still unknown. Here, we report our systematic characterization of the repair dynamics of a model compound of indole-thymine dimer adduct in three solvents with different polarity. By resolving all elementary steps including three electron-transfer processes and two bond-breaking and bond-formation dynamics with femtosecond resolution, we observed the slow electron injection in 580 ps in water, 4 ns in acetonitrile, and 1.38 ns in dioxane, the fast back electron transfer without repair in 120, 150, and 180 ps, and the slow bond splitting in 550 ps, 1.9 ns, and 4.5 ns, respectively. The dimer bond cleavage is clearly accelerated by the solvent polarity. By comparing with the biological repair machine photolyase with a slow back electron transfer (2.4 ns) and a fast bond cleavage (90 ps), the low repair efficiency in the biomimetic system is mainly determined by the fast back electron transfer and slow bond breakage. We also found that the model system exists in a dynamic heterogeneous C-clamped conformation, leading to a stretched dynamic behavior. In water, we even identified another stacked form with ultrafast cyclic electron transfer, significantly reducing the repair efficiency. Thus, the comparison of the repair efficiency in different solvents is complicated and should be cautious, and only the dynamics by resolving all elementary steps can finally determine the total repair efficiency. Finally, we use the Marcus electron-transfer theory to analyze all electron-transfer reactions and rationalize all observed electron-transfer dynamics.

In vitro resolution of the dimer bridge of the minute virus of mice (MVM) genome supports the modified rolling hairpin model for MVM replication.

PubMed

Liu, Q; Yong, C B; Astell, C R

1994-06-01

Previous characterization of the terminal sequences of the minute virus of mice (MVM) genome demonstrated that the right hand palindrome contains two sequences, each the inverted complement of the other. However, the left hand palindrome was shown to exist as a unique sequence [Astell et al., J. Virol. 54: 179-185 (1985)]. The modified rolling hairpin (MRH) model for MVM replication provided an explanation of how the right hand palindrome could undergo hairpin transfer to generate two sequences, while the left end palindrome within the dimer bridge could undergo asymmetric resolution and retain the unique left end sequence. This report describes in vitro resolution of the wild-type dimer bridge sequence of MVM using recombinant (baculovirus) expressed NS-1 and a replication extract from LA9 cells. The resolution products are consistent with those predicted by the MRH model, providing support for this replication mechanism. In addition, mutant dimer bridge clones were constructed and used in the resolution assay. The mutant structures included removal of the asymmetry in the hairpin stem, inversion of the sequence at the initiating nick site, and a 2-bp deletion within one stem of the dimer bridge. In all cases, the mutant dimer bridge structures are resolved; however, the resolution pattern observed with the mutant dimer bridge compared with the wild-type dimer bridge is shifted toward symmetrical resolution. These results suggest that sequences within the left hand hairpin (and hence dimer bridge sequence) are responsible for asymmetric resolution and conservation of the unique sequence within the left hand palindrome of the MVM genome.

Dynamics and asymmetry in the dimer of the norovirus major capsid protein.

PubMed

Tubiana, Thibault; Boulard, Yves; Bressanelli, Stéphane

2017-01-01

Noroviruses are the major cause of non-bacterial acute gastroenteritis in humans and livestock worldwide, despite being physically among the simplest animal viruses. The icosahedral capsid encasing the norovirus RNA genome is made of 90 dimers of a single ca 60-kDa polypeptide chain, VP1, arranged with T = 3 icosahedral symmetry. Here we study the conformational dynamics of this main building block of the norovirus capsid. We use molecular modeling and all-atom molecular dynamics simulations of the VP1 dimer for two genogroups with 50% sequence identity. We focus on the two points of flexibility in VP1 known from the crystal structure of the genogroup I (GI, human) capsid and from subsequent cryo-electron microscopy work on the GII capsid (also human). First, with a homology model of the GIII (bovine) VP1 dimer subjected to simulated annealing then classical molecular dynamics simulations, we show that the N-terminal arm conformation seen in the GI crystal structure is also favored in GIII VP1 but depends on the protonation state of critical residues. Second, simulations of the GI dimer show that the VP1 spike domain will not keep the position found in the GII electron microscopy work. Our main finding is a consistent propensity of the VP1 dimer to assume prominently asymmetric conformations. In order to probe this result, we obtain new SAXS data on GI VP1 dimers. These data are not interpretable as a population of symmetric dimers, but readily modeled by a highly asymmetric dimer. We go on to discuss possible implications of spontaneously asymmetric conformations in the successive steps of norovirus capsid assembly. Our work brings new lights on the surprising conformational range encoded in the norovirus major capsid protein.

Polyphenol Compound as a Transcription Factor Inhibitor.

PubMed

Park, Seyeon

2015-10-30

A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.

PubMed

Alam, Shahabuddin; Javor, Sacha; Degardin, Melissa; Ajami, Dariush; Rebek, Mitra; Kissner, Teri L; Waag, David M; Rebek, Julius; Saikh, Kamal U

2015-08-01

Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non-polar cyclohexane linker which strongly inhibited the production of pro-inflammatory cytokines in human primary cells to SEB (IC50 1-50 μm) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10-200 μm). Consistent with cytokine inhibition, in a ligand-induced cell-based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS-induced MyD88-mediated NF-kB-dependent expression of reporter activity (IC50 10-30 μm). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro-inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin-induced inflated pro-inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic. © 2014 John Wiley & Sons A/S.

A comparative experimental and quantum chemical study on monomeric and dimeric structures of 3,5-dibromoanthranilic acid.

PubMed

Karabacak, Mehmet; Cinar, Mehmet

2012-10-01

This study presents the structural and spectroscopic characterization of 3,5-dibromoanthranilic acid with help of experimental techniques (FT-IR, FT-Raman, UV, NMR) and quantum chemical calculations. The vibrational spectra of title compound were recorded in solid state with FT-IR and FT-Raman in the range of 4000-400 and 4000-50 cm(-1), respectively. The vibrational frequencies were also computed using B3LYP method of DFT with 6-311++G(d,p) basis set. The fundamental assignments were done on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanical (SQM) method. The (1)H, (13)C and DEPT NMR spectra were recorded in DMSO solution and calculated by gauge-invariant atomic orbitals (GIAO) method. The UV absorption spectra of the compound were recorded in the range of 200-400 nm in ethanol, water and DMSO solutions. Solvent effects were calculated using time-dependent density functional theory and CIS method. The ground state geometrical structure of compound was predicted by B3LYP method and compared with the crystallographic structure of similar compounds. All calculations were made for monomeric and dimeric structure of compound. Moreover, molecular electrostatic potential (MEP) and thermodynamic properties were performed. Mulliken atomic charges of neutral and anionic form of the molecule were computed and compared with anthranilic acid. Copyright © 2012 Elsevier B.V. All rights reserved.

Dimer model for Tau proteins bound in microtubule bundles

NASA Astrophysics Data System (ADS)

Hall, Natalie; Kluber, Alexander; Hayre, N. Robert; Singh, Rajiv; Cox, Daniel

2013-03-01

The microtubule associated protein tau is important in nucleating and maintaining microtubule spacing and structure in neuronal axons. Modification of tau is implicated as a later stage process in Alzheimer's disease, but little is known about the structure of tau in microtubule bundles. We present preliminary work on a proposed model for tau dimers in microtubule bundles (dimers are the minimal units since there is one microtubule binding domain per tau). First, a model of tau monomer was created and its characteristics explored using implicit solvent molecular dynamics simulation. Multiple simulations yield a partially collapsed form with separate positively/negatively charged clumps, but which are a factor of two smaller than required by observed microtubule spacing. We argue that this will elongate in dimer form to lower electrostatic energy at a cost of entropic ``spring'' energy. We will present preliminary results on steered molecular dynamics runs on tau dimers to estimate the actual force constant. Supported by US NSF Grant DMR 1207624.

Optoelectronic properties and structural effects of the incremental addition of pyridyl moieties on a rhodium dimer.

PubMed

Chartrand, Daniel; Hanan, Garry S

2014-11-13

The synthesis and characterization of five C-C coupling products obtained from the reaction of a paddlewheel tetrakis 4-bromo-N,N'-diphenylbenzamidinate dirhodium dimer with 4-pyridineboronic acid pinacol ester are reported. The coupling reactions occur on one to four amidinate ligands, leading to rhodium dimers containing [tetrakis, tris, cis-bis, trans-bis, or mono]-N,N'-diphenyl-4-(pyridin-4-yl)benzamidinate ligands, effectively creating new binding sites on the metal complexes. The new compounds were isolated by column chromatography, and the exact conformations were verified by X-ray crystallography. Redox processes showed only a small variation within the coupling products and included two oxidations (1.30 ± 0.02 V, 0.27 ± 0.01 V vs SCE) and one reduction (-1.55 ± 0.02 V vs SCE), all centered on the Rh-Rh core. Time-dependent density functional theory (TD-DFT) was used to analyze this series with four other fully characterized N,N'-diphenyl-aryl-amidinate rhodium dimers that were found in the literature. The two main absorption bands of these nine rhodium dimers were compared to TD-DFT calculations, both giving excellent correlation. The first, a metal-to-metal (MM) transition around 11800 cm(-1) (845 nm) was blue-shifted in the calculation, with an average difference of 1378 cm(-1) but had only a 15 cm(-1) standard deviation, showing a strong correlation despite the energy difference. The second, a metal-to-ligand charge transfer (MLCT) transition around 18900 cm(-1) (530 nm) was a near perfect match with only a 64 cm(-1) average difference and a 35 cm(-1) standard deviation. The electronic transition, redox potentials, and HOMO and LUMO energies of all dimers were plotted versus the Hammett parameter (σ) of the aryl group and Taft's model with 2 components: field effects (σF) and resonance (σR). The properties involving only the Rh-Rh core (MM band, all oxidation potentials, HOMO and LUMO) were fit with a single set of σF and σR contributions (73% and 27%), with a goodness-of-fit (R(2)) value ranging from 90% to 99.7%. The metal-dimer to ligand charge-transfer band, involving the amidinate ligand, displayed different values of contribution with 45% and 55% for the σF and σR, respectively, with a fit of 94.8%. The accuracy of these fits enables the designed modification of amidinate-based dirhodium complexes to achieve desirable redox and spectroscopic properties.

Polymorphism and mesomorphism of oligomeric surfactants: effect of the degree of oligomerization.

PubMed

Jurašin, D; Pustak, A; Habuš, I; Šmit, I; Filipović-Vinceković, N

2011-12-06

A series of cationic oligomeric surfactants (quaternary dodecyldimethylammonium ions with two, three, or four chains connected by an ethylene spacer at the headgroup level, abbreviated as dimer, trimer, and tetramer) were synthesized and characterized. The influence of the degree of oligomerization on their polymorphic and mesomorphic properties was investigated by means of X-ray diffraction, polarizing optical microscopy, thermogravimetry, and differential scanning calorimetry. All compounds display layered arrangements with interdigitated dodecyl chains. The increase in the degree of oligomerization increases the interlayer distance and decreases the ordering in the solid phase; whereas the dimer sample is fully crystalline with well-developed 3D ordering and the trimer and tetramer crystallize as highly ordered crystal smectic phases. The number of thermal phase transitions and sequence of phases are markedly affected by the number of dodecyl chains. Anhydrous samples exhibit polymorphism and thermotropic mesomorphism of the smectic type, with the exception of the tetramer that displays only transitions at higher temperature associated with decomposition and melting. All hydrated compounds form lyotropic mesophases showing reversible phase transitions upon heating and cooling. The sequence of liquid-crystalline phases for the dimer, typical of concentrated ionic surfactant systems, comprises a hexagonal phase at lower temperatures and a smectic phase at higher temperatures. In contrast, the trimer and tetramer reveal textures of the hexagonal phase. © 2011 American Chemical Society

A designed point mutant in Fis1 disrupts dimerization and mitochondrial fission

PubMed Central

Lees, Jonathan P. B.; Manlandro, Cara Marie; Picton, Lora K.; Ebie Tan, Alexandra Z.; Casares, Salvador; Flanagan, John M.; Fleming, Karen G.; Hill, R. Blake

2012-01-01

Mitochondrial and peroxisomal fission are essential processes with defects resulting in cardiomyopathy and neonatal lethality. Central to organelle fission is Fis1, a monomeric tetratricopeptide-like repeat (TPR) protein whose role in assembly of the fission machinery remains obscure. Two non-functional, Saccharomyces cerevisiae Fis1 mutants (L80P or E78D/I85T/Y88H) were previously identified in genetic screens. Here, we find that these two variants in the cytosolic domain of Fis1 (Fis1ΔTM) are unexpectedly dimeric. A truncation variant of Fis1ΔTM that lacks an N-terminal regulatory domain is also found to be dimeric. The ability to dimerize is a property innate to the native Fis1ΔTM amino acid sequence as we find this domain is dimeric after transient exposure to elevated temperature or chemical denaturants and is kinetically trapped at room temperature. This is the first demonstration of a specific self-association in solution for the Fis1 cytoplasmic domain. We propose a three-dimensional domain-swapped model for dimerization that is validated by a designed mutation, A72P, which potently disrupts dimerization of wild type Fis1. A72P also disrupts dimerization of non-functional variants indicating a common structural basis for dimerization. The obligate monomer variant A72P, like the dimer-promoting variants, is non-functional in fission consistent with a model in which Fis1 activity depends on its ability to interconvert between monomer and dimer species. These studies suggest a new functionally important manner in which TPR containing proteins may reversibly self-associate. PMID:22789569

Hydroacylation of 2-vinyl benzaldehyde systems: an efficient method for the synthesis of chiral 3-substituted indanones.

PubMed

Kundu, Kousik; McCullagh, James V; Morehead, Andrew T

2005-11-23

Asymmetric rhodium-catalyzed hydroacylation has been utilized in the synthesis of 3-substituted indanones with high conversions and enantioselectivity. The hydroacylation reaction of 2-vinyl benzaldehyde had been previously reported to give a low yield of indanone and an unidentified product. We have identified this compound as a dimer of the starting material. Substitution at the alpha-position of the 2-vinyl benzaldehyde substrates blocks the competitive dimerization reaction and allows the reaction to proceed with yields generally greater than 90%. Utilization of BINAP as a chiral ligand results in good chemical yields and enantioselectivity greater than 95% in most cases.

Two new phthalide dimers from the rhizomes of Ligusticum chuanxiong.

PubMed

Wei, Wei; Xu, Wei; Yang, Xiu-Wei

2017-07-01

Two pairs of diastereoisomers, namely (3'Z)-(3S,8S,3a'S,6'R)-4,5-dehydro-3.3a',8.6'-diligustilide (1) and (3'Z)-(3S,8R,3a'S,6'R)-4,5-dehydro-3.3a',8.6'-diligustilide (3), chuanxiongdiolide R3 (2), and chuanxiongdiolide R1 (4), were isolated from the 95% ethanolic aqueous extract of the rhizomes of Ligusticum chuanxiong. Among these Phthalide dimers, compounds 1 and 2 were new ones. The structures of the new isolates were elucidated based on spectroscopic data analyses, and their absolute configurations were determined by comparison of experimental and calculated electronic circular dichroism spectra.

Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth­oxy­benzene­sulfonamide

PubMed Central

Chicha, Hakima; Rakib, El Mostapha; Gamouh, Ahmed; Saadi, Mohamed; El Ammari, Lahcen

2014-01-01

In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 Å) and the benzene ring is 89.05 (7)°. The meth­oxy C atom deviates from its attached ring by 0.196 (3) Å. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds generate R 2 2(8) loops. The dimers are connected into [010] chains by C—H⋯O inter­actions. PMID:25309293

Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation

NASA Astrophysics Data System (ADS)

Liao, Chenyi; Zhang, Zhi; Kale, Justin; Andrews, David W.; Lin, Jialing; Li, Jianing

2016-07-01

Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.

Structural insights into the intertwined dimer of fyn SH2.

PubMed

Huculeci, Radu; Garcia-Pino, Abel; Buts, Lieven; Lenaerts, Tom; van Nuland, Nico

2015-12-01

Src homology 2 domains are interaction modules dedicated to the recognition of phosphotyrosine sites incorporated in numerous proteins found in intracellular signaling pathways. Here we provide for the first time structural insight into the dimerization of Fyn SH2 both in solution and in crystalline conditions, providing novel crystal structures of both the dimer and peptide-bound structures of Fyn SH2. Using nuclear magnetic resonance chemical shift analysis, we show how the peptide is able to eradicate the dimerization, leading to monomeric SH2 in its bound state. Furthermore, we show that Fyn SH2's dimer form differs from other SH2 dimers reported earlier. Interestingly, the Fyn dimer can be used to construct a completed dimer model of Fyn without any steric clashes. Together these results extend our understanding of SH2 dimerization, giving structural details, on one hand, and suggesting a possible physiological relevance of such behavior, on the other hand. © 2015 The Protein Society.

Heptacopper(II) and dicopper(II)-adenine complexes: synthesis, structural characterization, and magnetic properties

DOE PAGES

Leite Ferreira, B. J. M.; Brandão, Paula; Dos Santos, A. M.; ...

2015-07-13

The syntheses, crystal structures, and magnetic properties of two new copper(II) complexes with molecular formulas [Cu 7(μ 2-OH 2) 6(μ 3-O) 6(adenine) 6(NO 3) 26H 2O (1) and [Cu 2(μ 2-H 2O) 2(adenine) 2(H 2O) 4](NO 3) 42H 2O (2) are reported. We composed the heptanuclear compound of a central octahedral CuO 6 core sharing edges with six adjacent copper octahedra. In 2, the copper octahedra shares one equatorial edge. In both compounds, these basic copper cluster units are further linked by water bridges and bridging adenine ligands through N3 and N9 donors. All copper(II) centers exhibit Jahn-Teller distorted octahedralmore » coordination characteristic of a d 9 center. Our study of the magnetic properties of the heptacopper complex revealed a dominant ferromagnetic intra-cluster interaction, while the dicopper complex exhibits antiferromagnetic intra-dimer interactions with weakly ferromagnetic inter-dimer interaction.« less

α-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies

PubMed Central

Shityakov, Sergey; Broscheit, Jens; Förster, Carola

2012-01-01

This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl-imidazopyridine moiety with the α-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is used to determine the energetic profiles, hydrogen bond formation, and hydrophobic effect of 14 host–guest complexes. The results show that the “chemical branching” represented by additional ethyl-acetate residue is energetically unfavorable and promotes a conformational shift due to the high root mean square deviation levels. This phenomenon is characterized by a low number of H-bonds and a significant decrease of the host–guest hydrophobic potential surface. Finally, the overall docking procedure presents a powerful rationale for screening and analyzing various sets of promising drug-like chemical compounds in the fields of supramolecular chemistry, molecular sensing, synthetic receptors, and nanobiotechnology. PMID:22811606

Anti-inflammatory Hydrolyzable Tannins from Myricaria bracteata.

PubMed

Liu, Jia-Bao; Ding, Ya-Si; Zhang, Ying; Chen, Jia-Bao; Cui, Bao-Song; Bai, Jin-Ye; Lin, Ming-Bao; Hou, Qi; Zhang, Pei-Cheng; Li, Shuai

2015-05-22

Twelve hydrolyzable tannins were obtained from the twigs of Myricaria bracteata, including two new hellinoyl-type dimers, bracteatinins D1 (1) and D2 (2); a new hellinoyl-type trimer, bracteatinin T1 (3); two known monomers, nilotinin M4 (4) and 1,3-di-O-galloyl-4,6-O-(aS)-hexahydroxydiphenoyl-β-d-glucose (5); six known dimers, tamarixinin A (6), nilotinin D8 (7), hirtellins A (10), B (9), and E (8), and isohirtellin C (11); and a known trimer, hirtellin T3 (12). The structures of the tannins were elucidated by spectroscopic data analysis and comparisons to known tannins. All compounds were evaluated as free radical scavengers using 1,1-diphenyl-2-picrylhydrazyl and hydroxy radicals and compared to the activity of BHT and Trolox. Compound 6 showed a significant anti-inflammatory effect on croton oil-induced ear edema in mice (200 mg/kg, inhibition rate 69.8%) and on collagen-induced arthritis in DBA/1 mice (20 mg/kg, inhibition rate 46.0% at day 57).

Syntheses of mono- and dinuclear diiodoboryl complexes of platinum.

PubMed

Braunschweig, Holger; Radacki, Krzysztof; Uttinger, Katharina

2007-10-15

Treatment of [Pt(PCy(3))(2)] (Cy = cyclohexyl) with BI(3) afforded trans-[(Cy(3)P)(2)Pt(I)(BI(2))] by the oxidative addition of a B-I bond. The title compound represents the first diiodoboryl complex and was fully characterized by NMR spectroscopy and X-ray diffraction analysis. The latter revealed a very short Pt-B distance, thus indicating a pronounced pi contribution to this bond. By the addition of another 1 equiv of BI(3) to trans-[(Cy(3)P)(2)Pt(I)(BI(2))], a new Pt species [(Cy(3)P)(I(2)B)Pt(mu-I)](2) was formed with concomitant buildup of the phosphine borane adduct [Cy(3)P-BI(3)]. The former is obviously obtained by abstraction of PCy(3) from trans-[(Cy(3)P)(2)Pt(I)(BI(2))] and the subsequent dimerization of two remaining fragments. Interestingly, the dimerization is reversible, and the dinuclear compound can be converted to trans-[(Cy(3)P)(2)Pt(I)(BI(2))] upon the addition of PCy(3).

Experimental Study of Mechanistic Acid Deconstruction of Lignin

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

Sturgeon, M.; Kim, S.; Chmely, S. C.

2012-01-01

Lignin is a major component of biomass, which remains highly underutilized in selective biomass conversion strategies to renewable fuels and chemicals. Here we are interested in studying the mechanisms related to the acid deconstruction of lignin with a combined theoretical and experimental approach. Quantum mechanical calculations were employed to elucidate possible deconstruction mechanisms with transition state theory. Model dimers, imitating H, S, and G lignins, were synthesized with the most abundant {beta} - O - 4 linkage in lignin. These compounds were then depolymerized using various acids and at different operating conditions. The deconstruction products were analyzed to complement themore » QM studies and investigate proposed mechanisms.« less

Ultrafast photodimerization dynamics in α-cyano-4-hydroxycinnamic and sinapinic acid crystals

NASA Astrophysics Data System (ADS)

Hoyer, Theo; Tuszynski, Wilfried; Lienau, Christoph

2007-07-01

We report a sub-picosecond time-resolved fluorescence spectroscopic study of different cinnamic acid crystals, model systems for solid-state photodimerization reactions. For α-cyano-4-hydroxycinnamic acid (α-CHC), we identify the emission spectra of both monomers and dimers, allowing us to directly probe the photoinduced dynamics of both species. The dimerization occurs on a timescale of 10 ps and results in a long-lived dimer product, stable for hours. For sinapinic acid, we find an extremely fast, sub-picosecond dimerization reaction and a short-lived dimer. This first sub-picosecond time-resolved dimerization study in cinnamic acid crystals provides a new basis for relating their structural properties and microscopic reaction dynamics.

Study of vibrational spectra and hydrogen bonding network in dimeric and tetrameric model of ampicillin using DFT and AIM approach

NASA Astrophysics Data System (ADS)

Shukla, Anuradha; Khan, Eram; Tandon, Poonam; Sinha, Kirti

2017-03-01

Ampicillin is a β-lactam antibiotic that is active against both gram-positive and gram-negative bacteria and is widely used for the treatment of infections. In this work, molecular properties of ampicillin are calculated on the basis of calculations on its dimeric and tetrameric models using DFT/B3LYP/6-311G(d,p). HOMO-LUMO energy gap shows that chemical reactivity of tetrameric model of ampicillin is higher than the dimeric and monomeric model of ampicillin. To get a better understanding of intra and intermolecular bonding and interactions among bonds, NBO analysis is carried out with tetrameric model of ampicillin, and is further finalized with an 'quantum theory of atoms-in-molecules' (QTAIM) analysis. The binding energy of dimeric model of ampicillin is calculated as -26.84 kcal/mol and -29.34 kcal/mol using AIM and DFT calculations respectively. The global electrophilicity index (ω = 2.8118 eV) of tetrameric model of ampicillin shows that this behaves as a strong electrophile in comparison to dimeric and monomeric model of ampicillin. The FT-Raman and FT-IR spectra were recorded in the solid phase, and interpreted in terms of potential energy distribution analysis. A collective theoretical and experimental vibrational analysis approves the presence of hydrogen bonds in the ampicillin molecule.

Fragment-Based Protein-Protein Interaction Antagonists of a Viral Dimeric Protease.

PubMed

Gable, Jonathan E; Lee, Gregory M; Acker, Timothy M; Hulce, Kaitlin R; Gonzalez, Eric R; Schweigler, Patrick; Melkko, Samu; Farady, Christopher J; Craik, Charles S

2016-04-19

Fragment-based drug discovery has shown promise as an approach for challenging targets such as protein-protein interfaces. We developed and applied an activity-based fragment screen against dimeric Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) using an optimized fluorogenic substrate. Dose-response determination was performed as a confirmation screen, and NMR spectroscopy was used to map fragment inhibitor binding to KSHV Pr. Kinetic assays demonstrated that several initial hits also inhibit human cytomegalovirus protease (HCMV Pr). Binding of these hits to HCMV Pr was also confirmed by NMR spectroscopy. Despite the use of a target-agnostic fragment library, more than 80 % of confirmed hits disrupted dimerization and bound to a previously reported pocket at the dimer interface of KSHV Pr, not to the active site. One class of fragments, an aminothiazole scaffold, was further explored using commercially available analogues. These compounds demonstrated greater than 100-fold improvement of inhibition. This study illustrates the power of fragment-based screening for these challenging enzymatic targets and provides an example of the potential druggability of pockets at protein-protein interfaces. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of dimeric analogs of adenophostin A that potently evoke Ca2+ release through IP3 receptors† †Electronic supplementary information (ESI) available: NMR spectral data for all the new compounds. See DOI: 10.1039/c6ra19413c Click here for additional data file.

PubMed Central

Vibhute, Amol M.; Pushpanandan, Poornenth; Varghese, Maria; Koniecnzy, Vera; Taylor, Colin W.

2016-01-01

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca2+ signals that regulate diverse cellular responses. There is considerable interest in developing novel ligands of IP3R. Adenophostin A (AdA) is a potent agonist of IP3R and since some dimeric analogs of IP3R ligands are more potent than the corresponding monomer; we considered whether dimeric AdA analogs might provide agonists with increased potency. We previously synthesized traizolophostin, in which a simple triazole replaced the adenine of AdA, and showed it to be equipotent to AdA. Here, we used click chemistry to synthesize four homodimeric analogs of triazolophostin, connected by oligoethylene glycol chains of different lengths. We evaluated the potency of these analogs to release Ca2+ through type 1 IP3R and established that the newly synthesized dimers are equipotent to AdA and triazolophostin. PMID:28066549

Development of a bioluminescence resonance energy transfer (BRET) for monitoring estrogen receptor alpha activation

NASA Astrophysics Data System (ADS)

Michelini, Elisa; Mirasoli, Mara; Karp, Matti; Virta, Marko; Roda, Aldo

2004-06-01

Estrogen receptor (ER) is a ligand-activated transcriptional factor, able to dimerize after activation and to bind specific DNA sequences (estrogen response elements), thus activating gene target transcription. Since ER homo- and hetero-dimerization (giving a-a and a-b isoforms) is a fundamental step for receptor activation, we developed an assay for detecting compounds that induce human ERa homo-dimerization based on bioluminescence resonance energy transfer (BRET). BRET is a non-radiative energy transfer, occurring between a luminescent donor and a fluorescent acceptor, that strictly depends on the closeness between the two proteins and can therefore be used for studying protein-protein interactions. We cloned ERa coding sequence in frame with either a variant of the green fluorescent protein (enhanced yellow fluorescent protein, EYFP) or Renilla luciferase (RLuc). Upon ERa homo-dimerization, BRET process takes place in the presence of the RLuc substrate coelenterazine resulting in EYFP emission at its characteristic wavelength. The ER alpha-Rluc and ER alpha-EYFP fusion proteins were cloned, then the occurrence of BRET in the presence of ER alpha activators was assayed both in vivo, within cells, and in vitro, with purified fusion proteins.

Structural and functional characterisation of multi-copper oxidase CueO from lignin-degrading bacterium Ochrobactrum sp. reveal its activity towards lignin model compounds and lignosulfonate.

PubMed

Granja-Travez, Rommel Santiago; Wilkinson, Rachael C; Persinoti, Gabriela Felix; Squina, Fabio M; Fülöp, Vilmos; Bugg, Timothy D H

2018-05-01

The identification of enzymes responsible for oxidation of lignin in lignin-degrading bacteria is of interest for biotechnological valorization of lignin to renewable chemical products. The genome sequences of two lignin-degrading bacteria, Ochrobactrum sp., and Paenibacillus sp., contain no B-type DyP peroxidases implicated in lignin degradation in other bacteria, but contain putative multicopper oxidase genes. Multi-copper oxidase CueO from Ochrobactrum sp. was expressed and reconstituted as a recombinant laccase-like enzyme, and kinetically characterized. Ochrobactrum CueO shows activity for oxidation of β-aryl ether and biphenyl lignin dimer model compounds, generating oxidized dimeric products, and shows activity for oxidation of Ca-lignosulfonate, generating vanillic acid as a low molecular weight product. The crystal structure of Ochrobactrum CueO (OcCueO) has been determined at 1.1 Å resolution (PDB: 6EVG), showing a four-coordinate mononuclear type I copper center with ligands His495, His434 and Cys490 with Met500 as an axial ligand, similar to that of Escherichia coli CueO and bacterial azurin proteins, whereas fungal laccase enzymes contain a three-coordinate type I copper metal center. A trinuclear type 2/3 copper cluster was modeled into the active site, showing similar structure to E. coli CueO and fungal laccases, and three solvent channels leading to the active site. Site-directed mutagenesis was carried out on amino acid residues found in the solvent channels, indicating the importance for residues Asp102, Gly103, Arg221, Arg223, and Asp462 for catalytic activity. The work identifies a new bacterial multicopper enzyme with activity for lignin oxidation, and implicates a role for bacterial laccase-like multicopper oxidases in some lignin-degrading bacteria. Structural data are available in the PDB under the accession number 6EVG. © 2018 Federation of European Biochemical Societies.

Multidrug-Resistant Enterococcal Infections: New Compounds, Novel Antimicrobial Therapies?

PubMed

van Harten, Roel M; Willems, Rob J L; Martin, Nathaniel I; Hendrickx, Antoni P A

2017-06-01

Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structure and catalytic activation of the TRIM23 RING E3 ubiquitin ligase: DAWIDZIAK et al.

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

Dawidziak, Daria M.; Sanchez, Jacint G.; Wagner, Jonathan M.

Tripartite motif (TRIM) proteins comprise a large family of RING-type ubiquitin E3 ligases that regulate important biological processes. An emerging general model is that TRIMs form elongated antiparallel coiled-coil dimers that prevent interaction of the two attendant RING domains. The RING domains themselves bind E2 conjugating enzymes as dimers, implying that an active TRIM ligase requires higher-order oligomerization of the basal coiled-coil dimers. Here, we report crystal structures of the TRIM23 RING domain in isolation and in complex with an E2–ubiquitin conjugate. Our results indicate that TRIM23 enzymatic activity requires RING dimerization, consistent with the general model of TRIM activation.

Excited and ionic states of dimeric chlorophyll derivatives. Biomimetic modelling of the primary events of photosynthesis

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

Wasielewski, M. R.

1978-01-01

The following topics are discussed: preparation of covalently bound dimeric species of chlorophyll; molecular structure of bis(bacteriochlorophyllide a) ethylene glycol diester; /sup 1/H spectra of BChl, a covalent dimer, dissolved in various solvents; chemical shift changes in proton resonances; C/sub 2/ symmetric folded configuration of covalently linked BChl; electronic transition spectrum of Chl a covalent dimer in dry CCl/sub 4/ and in water-saturated CCl/sub 4/; special pair models of bis(chlorophyll) cyclophanes; synthetic pathway for preparation of bis(chlorophyll) cyclophane 8; proton magnetic resonance data; redox potentials of chlorophyll; and optical and EPR properties of special pairs. (HLW)

Atomic model for the dimeric FO region of mitochondrial ATP synthase.

PubMed

Guo, Hui; Bueler, Stephanie A; Rubinstein, John L

2017-11-17

Mitochondrial adenosine triphosphate (ATP) synthase produces the majority of ATP in eukaryotic cells, and its dimerization is necessary to create the inner membrane folds, or cristae, characteristic of mitochondria. Proton translocation through the membrane-embedded F O region turns the rotor that drives ATP synthesis in the soluble F 1 region. Although crystal structures of the F 1 region have illustrated how this rotation leads to ATP synthesis, understanding how proton translocation produces the rotation has been impeded by the lack of an experimental atomic model for the F O region. Using cryo-electron microscopy, we determined the structure of the dimeric F O complex from Saccharomyces cerevisiae at a resolution of 3.6 angstroms. The structure clarifies how the protons travel through the complex, how the complex dimerizes, and how the dimers bend the membrane to produce cristae. Copyright © 2017, American Association for the Advancement of Science.

Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.

PubMed

Robbiano, Angela; Frecer, Vladimir; Miertus, Jan; Zadro, Cristina; Ulivi, Sheila; Bevilacqua, Elena; Mandrile, Giorgia; De Marchi, Mario; Miertus, Stanislav; Amoroso, Antonio

2010-01-01

Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria. Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins. Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding. This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.

Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target

PubMed Central

Chen, Mo; Peters, Alec; Huang, Tao; Nan, Xiaolin

2016-01-01

The K-, N-, and HRas small GTPases are key regulators of cell physiology and are frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive Ras based on known mechanisms of Ras signaling have been met with little success. Several studies have provided compelling evidence for the existence and biological relevance of Ras dimers, establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane. We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this model in both basic and translational Ras biology. PMID:26423697

Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging

PubMed Central

2012-01-01

Background Gastrin-releasing peptide receptors [GRPR] are highly over-expressed in multiple cancers and have been studied as a diagnostic target. Multimeric gastrin-releasing peptides are expected to have enhanced tumor uptake and affinity for GRPR. In this study, a 64Cu-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-monomer and two NOTA-dimers of [D-Tyr6,βAla11, Thi13, Nle14]bombesin(6-14) ] [BBN(6-14)] were compared. Methods Monomeric and dimeric peptides were synthesized on solid phase support and radiolabeled with 64Cu. NOTA-dimer 1 consists of asymmetrically linked BBN(6-14), while NOTA-dimer 2 has similar spacer between the two BBN(6-14) ligands and the chelator. In vitro GRPR-binding affinities were determined with competitive binding assays on PC3 human prostate cancer cells. In vivo stability and biodistribution of radiolabeled compounds were assessed in Balb/c mice. Cellular uptake and efflux were measured with radiolabeled NOTA-monomer and NOTA-dimer 2 on PC3 cells for up to 4 h. In vivo biodistribution kinetics were measured in PC3 tumor-bearing Balb/c nude mice by μ-positron emission tomography [μPET] imaging and confirmed by dissection and counting. Results NOTA-monomer, NOTA-dimers 1 and 2 were prepared with purity of 99%. The inhibition constants of the three BBN peptides were comparable and in the low nanomolar range. All 64Cu-labeled peptides were stable up to 24 h in mouse plasma and 1 h in vivo. 64Cu/NOTA-dimer 2 featuring a longer spacer between the two BBN(6-14) ligands is a more potent GRPR-targeting probe than 64Cu/NOTA-dimer 1. PC3 tumor uptake profiles are slightly different for 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2; the monomeric BBN-peptide tracer exhibited higher tumor uptake during the first 0.5 h and a fast renal clearance resulting in higher tumor-to-muscle ratio when compared to 64Cu/NOTA-dimer 2. The latter exhibited higher tumor-to-blood ratio and was retained longer at the tumor site when compared to 64Cu/NOTA-monomer. Lower ratios of tumor-to-blood and tumor-to-muscle in blocking experiments showed GRPR-dependant tumor uptake for both tracers. Conclusion Both 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2 are suitable for detecting GRPR-positive prostate cancer in vivo by PET. Tumor retention was improved in vivo with 64Cu/NOTA-dimer 2 by applying polyvalency effect and/or statistical rebinding. PMID:22333272

Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging.

PubMed

Fournier, Patrick; Dumulon-Perreault, Véronique; Ait-Mohand, Samia; Langlois, Réjean; Bénard, François; Lecomte, Roger; Guérin, Brigitte

2012-02-14

Gastrin-releasing peptide receptors [GRPR] are highly over-expressed in multiple cancers and have been studied as a diagnostic target. Multimeric gastrin-releasing peptides are expected to have enhanced tumor uptake and affinity for GRPR. In this study, a 64Cu-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-monomer and two NOTA-dimers of [D-Tyr6,βAla11, Thi13, Nle14]bombesin(6-14) ] [BBN(6-14)] were compared. Monomeric and dimeric peptides were synthesized on solid phase support and radiolabeled with 64Cu. NOTA-dimer 1 consists of asymmetrically linked BBN(6-14), while NOTA-dimer 2 has similar spacer between the two BBN(6-14) ligands and the chelator. In vitro GRPR-binding affinities were determined with competitive binding assays on PC3 human prostate cancer cells. In vivo stability and biodistribution of radiolabeled compounds were assessed in Balb/c mice. Cellular uptake and efflux were measured with radiolabeled NOTA-monomer and NOTA-dimer 2 on PC3 cells for up to 4 h. In vivo biodistribution kinetics were measured in PC3 tumor-bearing Balb/c nude mice by μ-positron emission tomography [μPET] imaging and confirmed by dissection and counting. NOTA-monomer, NOTA-dimers 1 and 2 were prepared with purity of 99%. The inhibition constants of the three BBN peptides were comparable and in the low nanomolar range. All 64Cu-labeled peptides were stable up to 24 h in mouse plasma and 1 h in vivo. 64Cu/NOTA-dimer 2 featuring a longer spacer between the two BBN(6-14) ligands is a more potent GRPR-targeting probe than 64Cu/NOTA-dimer 1. PC3 tumor uptake profiles are slightly different for 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2; the monomeric BBN-peptide tracer exhibited higher tumor uptake during the first 0.5 h and a fast renal clearance resulting in higher tumor-to-muscle ratio when compared to 64Cu/NOTA-dimer 2. The latter exhibited higher tumor-to-blood ratio and was retained longer at the tumor site when compared to 64Cu/NOTA-monomer. Lower ratios of tumor-to-blood and tumor-to-muscle in blocking experiments showed GRPR-dependant tumor uptake for both tracers. Both 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2 are suitable for detecting GRPR-positive prostate cancer in vivo by PET. Tumor retention was improved in vivo with 64Cu/NOTA-dimer 2 by applying polyvalency effect and/or statistical rebinding.

Defect propagation in one-, two-, and three-dimensional compounds doped by magnetic atoms

DOE PAGES

Furrer, A.; Podlesnyak, A.; Krämer, K. W.; ...

2014-10-29

Inelastic neutron scattering experiments were performed to study manganese(II) dimer excitations in the diluted one-, two-, and three-dimensional compounds CsMn xMg 1-xBr 3, K 2Mn xZn 1-xF 4, and KMn xZn 1-xF 3 (x≤0.10), respectively. The transitions from the ground-state singlet to the excited triplet, split into a doublet and a singlet due to the single-ion anisotropy, exhibit remarkable fine structures. These unusual features are attributed to local structural inhomogeneities induced by the dopant Mn atoms which act like lattice defects. Statistical models support the theoretically predicted decay of atomic displacements according to 1/r 2, 1/r, and constant (for three-,more » two-, and one-dimensional compounds, respectively) where r denotes the distance of the displaced atoms from the defect. In conclusion, the observed fine structures allow a direct determination of the local exchange interactions J, and the local intradimer distances R can be derived through the linear law dJ/dR.« less

Alpha-V Integrin Targeted PET Imagining of Breast Cancer Angiogenesis and Lose-Dose Metronomic Anti-Angiogenic Chemotherapy Efficacy

DTIC Science & Technology

2005-08-01

Chen X, Plasencia C, Hou Y, Neamati N. Synthesis and Biological Evaluation of Dimeric RGD Peptide-Paclitaxel Conjugate as Model for Integrin Targeted...Plasencia C, Hou Y, Neamati N. Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug...Targeted Imaging of Lung Cancer. Neoplasia 2005;7:271-279. 6. Chen X, Plasencia C, Hou Y, Neamati N. Synthesis and Biological Evaluation of Dimeric RGD

Influence of biphenyl spacer appended to the flexible phosphonate arms in modulating the dimensionality of the coordination polymers: Synthesis, structural chemistry and magnetic properties

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

Tripuramallu, Bharat Kumar; Das, Samar K., E-mail: skdsc@uohyd.ernet.in

2013-01-15

Two new compounds [Co (2,2 Prime -bipy) (H{sub 2}dbp)]{sub n} (1) and [Ni (2,2 Prime -bipy){sub 2}(H{sub 2}dbp)(H{sub 2}O)]{center_dot}H{sub 2}O (2) based on the flexible ligand 4,4 Prime -dimethylenebiphenyldiphosphonic acid (H{sub 4}dbp) with 2,2 Prime -bipyridine as secondary ligand have been synthesized under hydrothermal conditions. Both the compounds are well characterized by routine elemental analysis, IR, electronic spectroscopies, thermogravimetric analysis and finally by single crystal X-ray diffraction analysis. Compound 1 is a 1D extended coordination polymer and 2 is a discrete molecular compound. A comparative study between the geometries of H{sub 4}dbp ligand (in compounds 1 and 2, present study)more » and p-xylylenediphosphonic acid (H{sub 4}pxp) ligand (in previously reported compounds [Cu(2,2 Prime -bipy)(H{sub 2}pxp)]{center_dot}nH{sub 2}O (1A) and Ni(2,2 Prime -bipy){sub 2}H{sub 4}pxp]{sub n}[H{sub 2}pxp]{sub n} (2A), see text) demonstrate the effect of the twisting in the benzene rings in changing higher dimensional H{sub x}pxp (x refers to number of protonated hydroxyl groups) compounds to lower dimensional H{sub x}dbp compounds. The eight membered Co-dimer rings formed in compound 1 represents the simple and isolated Co-dimer, exhibiting weak antiferromagnetic exchange between metal centers through OPO bridges. - Graphical abstract: Two new compounds based on the dimethylenebiphenyldiphosphonic acid have been synthesized. The effect of twisting of benzene rings in the biphenyl spacer containing multidentate ligands alters dimensionality of final compounds. Highlights: Black-Right-Pointing-Pointer Cobalt containing coordination polymer and a nickel discrete compound have been synthesized. Black-Right-Pointing-Pointer Flexible ligand 4,4'-dimethylenebiphenyldiphosphonic acid has been employed. Black-Right-Pointing-Pointer Co(II) and Ni(II) ions are square pyramidal and octahedral respectively. Black-Right-Pointing-Pointer The effect of the twisting in the benzene rings in the associated ligand has been demonstrated.« less

Asymptotics of the monomer-dimer model on two-dimensional semi-infinite lattices

NASA Astrophysics Data System (ADS)

Kong, Yong

2007-05-01

By using the asymptotic theory of Pemantle and Wilson [R. Pemantle and M. C. Wilson, J. Comb. Theory, Ser. AJCBTA70097-316510.1006/jcta.2001.3201 97, 129 (2002)], asymptotic expansions of the free energy of the monomer-dimer model on two-dimensional semi-infinite ∞×n lattices in terms of dimer density are obtained for small values of n , at both high- and low-dimer-density limits. In the high-dimer-density limit, the theoretical results confirm the dependence of the free energy on the parity of n , a result obtained previously by computational methods by Y. Kong [Y. Kong, Phys. Rev. EPLEEE81063-651X10.1103/PhysRevE.74.061102 74, 061102 (2006); Phys. Rev. EPLEEE81063-651X10.1103/PhysRevE.73.016106 73, 016106 (2006);Phys. Rev. EPLEEE81063-651X10.1103/PhysRevE.74.011102 74, 011102 (2006)]. In the low-dimer-density limit, the free energy on a cylinder ∞×n lattice strip has exactly the same first n terms in the series expansion as that of an infinite ∞×∞ lattice.

Enhancement of electron correlation due to the molecular dimerization in organic superconductors β -(BDA-TTP )2X (X =I3, SbF6)

NASA Astrophysics Data System (ADS)

Aizawa, Hirohito; Kuroki, Kazuhiko; Yamada, Jun-ichi

2015-10-01

We perform a first-principles band calculation for quasi-two-dimensional organic superconductors β -(BDA -TTP) 2I3 and β -(BDA -TTP) 2SbF6. The first-principles band structures between the I3 and SbF6 salts are apparently different. We construct a tight-binding model for each material which accurately reproduces the first-principles band structure. The obtained transfer energies give the differences as follows: (i) larger dimerization in the I3 salt than the SbF6 salt, and (ii) different signs and directions of the interstacking transfer energies. To decompose the origin of the difference into the dimerization and the interstacking transfer energies, we adopt a simplified model by eliminating the dimerization effect and focus only on the difference caused by the interstacking transfer energies. From the analysis using the simplified model, we find that the difference of the band structure comes mainly from the strength of the dimerization. To compare the strength of the electron correlation having roots in the band structure, we calculate the physical properties originating from the effect of the electron correlation such as the spin susceptibility applying the two-particle self-consistent method. We find that the maximum value of the spin susceptibility for the I3 salt is larger than that of the SbF6 salt. Hypothetically decreasing the dimerization within the model of the I3 salt, the spin susceptibility takes almost the same value as that of the SbF6 salt for the same magnitude of the dimerization. We expect that the different ground state between the I3 and SbF6 salt mainly comes from the strength of the dimerization which is apparently masked in the band calculation along a particular k path.

Theory of the β-Type Organic Superconductivity under Uniaxial Compression

NASA Astrophysics Data System (ADS)

Suzuki, Takeo; Onari, Seiichiro; Ito, Hiroshi; Tanaka, Yukio

2011-09-01

We study theoretically the shift of the superconducting transition temperature (Tc) under uniaxial compression in β-type organic superconductors, β-(BEDT-TTF)2I3 and β-(BDA-TTP)2X (X=SbF6, AsF6), in order to clarify the electron correlation, the spin frustration, and the effect of dimerization. The transfer integrals are calculated by the extended Hückel method assuming the uniaxial strain, and the superconducting state mediated by the spin fluctuation is solved using Eliashberg's equation with the fluctuation--exchange approximation. The calculation is carried out on both the dimerized (one-band) and nondimerized (two-band) Hubbard models. We have found that (i) the behavior of Tc in β-(BEDT-TTF)2I3 with a stronger dimerization is well reproduced by the dimer model, while that in weakly dimerized β-BDA-TTP salts is rather well reproduced by the two-band model, and (ii) the competition between the spin frustration and the effect induced by the fluctuation is important in these materials, which causes the nonmonotonic shift of Tc against uniaxial compression.

Identification of novel modulators for ionotropic glutamate receptor, iGluA2 by in-silico screening

PubMed Central

2013-01-01

Background Ionotropic glutamate receptors (iGluAs, IUPHAR nomenclature) are the major excitatory amino acid neurotransmitter receptors in the mammalian central nervous system (CNS). iGluAs are potential therapeutic drug targets for various neurological disorders including ischemia, epilepsy, Parkinson’s and Alzheimer’s diseases. The known iGluA modulators, cyclothiazide (CTZ), IDRA-21, and other benzothiadiazide derivatives (ALTZ, HCTZ, and CLTZ) bind to the ligand-binding domain of flip-form of iGluA2 at the dimer interface, thereby increasing steady-state activation by reducing desensitization. Methods To discover new modulator compounds, we performed virtual screening for the ligand binding domain (LBD) of iGluA2 against NCI Diversity Set III library containing 1597 compounds, and subsequently performed binding-energy analysis for selected compounds. The crystal structure of rat iGluA2 S1S2J (PDB ID: 3IJO) was used for docking studies. Results and conclusion From this study, we obtained four compounds: (1) 10-2(methoxyethyl)-3-phenylbenzo[g]pteridine-2,4-dione, (2) 2-benzo[e]benzotriazol-2-yl-aniline, (3) 9-nitro-6H-indolo-(2,3,-b)quinoxaline, and (4) 1-hydroxy-n-(3-nitrophenyl)-2-napthamide. The binding mode of these four compounds is very similar to that of abovementioned established modulators: two molecules of each compound independently bind to the protein symmetrically at the dimer interface; occupy the subsites B, C, B’ and C’; potentially interact with Ser518 and Ser775. Binding energy analysis shows that all the four hits are comparable to the drug molecule, CTZ, and hence, we propose that the discovered hits may be potential molecules to develop new chemical libraries for modulating the flip form of iGluA2 function. PMID:23855825

Bio-guided isolation of antioxidant compounds from Chrysophyllum perpulchrum, a plant used in the Ivory Coast pharmacopeia.

PubMed

Philippe, Bidie Alain; Karine, Ndjoko; Barthélemy, Attioua Koffi; Noél, Zirihi Guédé; David, N'guessan Jean; Joseph, Djaman Allico; Hosttetmann, Kurt

2010-09-13

Chrysophyllum perpulchrum (Sapotaceae) is used in the traditional Ivory Coast pharmacopeia to cure fevers. The extract of C. perpulchrum used for this study was the powdered form obtained from the maceration of the dried plant bark in 96% methanol, followed by evaporation to dryness. In the present study, the antioxidative and radical-scavenging activities of the methanolic extract were studied with three standard biological tests: DPPH reduction, ferric thiocyanate (FTC) lipidic peroxidation inhibition and thiobarbituric acid reacting substances (TBARS). Gallic acid and quercetin were used as references. The total amount of phenolic compounds in the extract was determined by ultraviolet (UV) spectrometry and calculated as gallic acid equivalents. Catechin and two dimeric procyanidins were found to be the compounds responsible for the activities. They were chemically dereplicated in the extract by LC-MS. For quantitation purposes, they were isolated by successive chromatographic methods and characterized by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectrometry. The quantities of these compounds in C. perpulchrum were 5.4% for catechin (P1), and 5.6 and 9.2% for dimers (compounds 2 (P2) and 3 (P3)), respectively. They displayed antioxidant activity with IC(50) values of 2.50 ± 0.15 µg/mL (P1), 2.10 ± 0.2 µg/mL (P2) and 2.10 ± 0.1 µg/mL (P3). The total extract, the active fractions and the pure compounds inhibited the lipid peroxidation by the FTC method and the TBARS method in the range of 60%. These values were comparable to those seen for quercetin.

Identification of novel modulators for ionotropic glutamate receptor, iGluA2 by in-silico screening.

PubMed

Padmanabhan, Balasundaram

2013-07-15

Ionotropic glutamate receptors (iGluAs, IUPHAR nomenclature) are the major excitatory amino acid neurotransmitter receptors in the mammalian central nervous system (CNS). iGluAs are potential therapeutic drug targets for various neurological disorders including ischemia, epilepsy, Parkinson's and Alzheimer's diseases. The known iGluA modulators, cyclothiazide (CTZ), IDRA-21, and other benzothiadiazide derivatives (ALTZ, HCTZ, and CLTZ) bind to the ligand-binding domain of flip-form of iGluA2 at the dimer interface, thereby increasing steady-state activation by reducing desensitization. To discover new modulator compounds, we performed virtual screening for the ligand binding domain (LBD) of iGluA2 against NCI Diversity Set III library containing 1597 compounds, and subsequently performed binding-energy analysis for selected compounds. The crystal structure of rat iGluA2 S1S2J (PDB ID: 3IJO) was used for docking studies. From this study, we obtained four compounds: (1) 10-2(methoxyethyl)-3-phenylbenzo[g]pteridine-2,4-dione, (2) 2-benzo[e]benzotriazol-2-yl-aniline, (3) 9-nitro-6H-indolo-(2,3,-b)quinoxaline, and (4) 1-hydroxy-n-(3-nitrophenyl)-2-napthamide. The binding mode of these four compounds is very similar to that of abovementioned established modulators: two molecules of each compound independently bind to the protein symmetrically at the dimer interface; occupy the subsites B, C, B' and C'; potentially interact with Ser518 and Ser775. Binding energy analysis shows that all the four hits are comparable to the drug molecule, CTZ, and hence, we propose that the discovered hits may be potential molecules to develop new chemical libraries for modulating the flip form of iGluA2 function.

Ligand-induced type II interleukin-4 receptor dimers are sustained by rapid re-association within plasma membrane microcompartments

NASA Astrophysics Data System (ADS)

Richter, David; Moraga, Ignacio; Winkelmann, Hauke; Birkholz, Oliver; Wilmes, Stephan; Schulte, Markos; Kraich, Michael; Kenneweg, Hella; Beutel, Oliver; Selenschik, Philipp; Paterok, Dirk; Gavutis, Martynas; Schmidt, Thomas; Garcia, K. Christopher; Müller, Thomas D.; Piehler, Jacob

2017-07-01

The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.

Structure and dynamics of human vimentin intermediate filament dimer and tetramer in explicit and implicit solvent models.

PubMed

Qin, Zhao; Buehler, Markus J

2011-01-01

Intermediate filaments, in addition to microtubules and microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells, and play an important role in mechanotransduction as well as in providing mechanical stability to cells at large stretch. The molecular structures, mechanical and dynamical properties of the intermediate filament basic building blocks, the dimer and the tetramer, however, have remained elusive due to persistent experimental challenges owing to the large size and fibrillar geometry of this protein. We have recently reported an atomistic-level model of the human vimentin dimer and tetramer, obtained through a bottom-up approach based on structural optimization via molecular simulation based on an implicit solvent model (Qin et al. in PLoS ONE 2009 4(10):e7294, 9). Here we present extensive simulations and structural analyses of the model based on ultra large-scale atomistic-level simulations in an explicit solvent model, with system sizes exceeding 500,000 atoms and simulations carried out at 20 ns time-scales. We report a detailed comparison of the structural and dynamical behavior of this large biomolecular model with implicit and explicit solvent models. Our simulations confirm the stability of the molecular model and provide insight into the dynamical properties of the dimer and tetramer. Specifically, our simulations reveal a heterogeneous distribution of the bending stiffness along the molecular axis with the formation of rather soft and highly flexible hinge-like regions defined by non-alpha-helical linker domains. We report a comparison of Ramachandran maps and the solvent accessible surface area between implicit and explicit solvent models, and compute the persistence length of the dimer and tetramer structure of vimentin intermediate filaments for various subdomains of the protein. Our simulations provide detailed insight into the dynamical properties of the vimentin dimer and tetramer intermediate filament building blocks, which may guide the development of novel coarse-grained models of intermediate filaments, and could also help in understanding assembly mechanisms.

Mapping energetics of atom probe evaporation events through first principles calculations.

PubMed

Peralta, Joaquín; Broderick, Scott R; Rajan, Krishna

2013-09-01

The purpose of this work is to use atomistic modeling to determine accurate inputs into the atom probe tomography (APT) reconstruction process. One of these inputs is evaporation field; however, a challenge occurs because single ions and dimers have different evaporation fields. We have calculated the evaporation field of Al and Sc ions and Al-Al and Al-Sc dimers from an L1₂-Al₃Sc surface using ab initio calculations and with a high electric field applied to the surface. The evaporation field is defined as the electric field at which the energy barrier size is calculated as zero, corresponding to the minimum field that atoms from the surface can break their bonds and evaporate from the surface. The evaporation field of the surface atoms are ranked from least to greatest as: Al-Al dimer, Al ion, Sc ion, and Al-Sc dimer. The first principles results were compared with experimental data in the form of an ion evaporation map, which maps multi-ion evaporations. From the ion evaporation map of L1₂-Al₃Sc, we extract relative evaporation fields and identify that an Al-Al dimer has a lower evaporation field than an Al-Sc dimer. Additionally, comparatively an Al-Al surface dimer is more likely to evaporate as a dimer, while an Al-Sc surface dimer is more likely to evaporate as single ions. These conclusions from the experiment agree with the ab initio calculations, validating the use of this approach for modeling APT energetics. Copyright © 2013 Elsevier B.V. All rights reserved.

On discrete field theory properties of the dimer and Ising models and their conformal field theory limits

NASA Astrophysics Data System (ADS)

Kriz, Igor; Loebl, Martin; Somberg, Petr

2013-05-01

We study various mathematical aspects of discrete models on graphs, specifically the Dimer and the Ising models. We focus on proving gluing formulas for individual summands of the partition function. We also obtain partial results regarding conjectured limits realized by fermions in rational conformal field theories.

Structure of Ristocetin A in Complex with a Bacterial Cell-wall Mimetic

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

Nahoum, V.; Spector, S; Loll, P

2009-01-01

Antimicrobial drug resistance is a serious public health problem and the development of new antibiotics has become an important priority. Ristocetin A is a class III glycopeptide antibiotic that is used in the diagnosis of von Willebrand disease and which has served as a lead compound for the development of new antimicrobial therapeutics. The 1.0 A resolution crystal structure of the complex between ristocetin A and a bacterial cell-wall peptide has been determined. As is observed for most other glycopeptide antibiotics, it is shown that ristocetin A forms a back-to-back dimer containing concave binding pockets that recognize the cell-wall peptide.more » A comparison of the structure of ristocetin A with those of class I glycopeptide antibiotics such as vancomycin and balhimycin identifies differences in the details of dimerization and ligand binding. The structure of the ligand-binding site reveals a likely explanation for ristocetin A's unique anticooperativity between dimerization and ligand binding.« less

From small sweeteners to sweet proteins: anatomy of the binding sites of the human T1R2_T1R3 receptor.

PubMed

Morini, Gabriella; Bassoli, Angela; Temussi, Piero A

2005-08-25

The sweet taste receptor, a heterodimeric G protein coupled receptor (GPCR) protein, formed by the T1R2 and T1R3 subunits, recognizes several sweet compounds including carbohydrates, amino acids, peptides, proteins, and synthetic sweeteners. Its similarity with the metabotropic glutamate mGluR1 receptor allowed us to build homology models. All possible dimers formed by combinations of the human T1R2 and T1R3 subunits, modeled on the A (closed) or B (open) chains of the extracellular ligand binding domain of the mGluR1 template, yield four ligand binding sites for low-molecular-weight sweeteners. These sites were probed by docking a set of molecules representative of all classes of sweet compounds and calculating the free energy of ligand binding. These sites are not easily accessible to sweet proteins, but docking experiments in silico showed that sweet proteins can bind to a secondary site without entering the deep cleft. Our models account for many experimental observations on the tastes of sweeteners, including sweetness synergy, and can help to design new sweeteners.

Electron Donor-Acceptor Nature of the Ethanol-CO2 Dimer

NASA Astrophysics Data System (ADS)

McGuire, Brett A.; Martin-Drumel, Marie-Aline; McCarthy, Michael A.

2017-08-01

Supercritical CO2 is an appealing nontoxic, environmentally friendly solvent for the industrial extraction of many classes of compounds, from caffeine to natural product drug precursors to petrochemical impurities. Apolar in isolation, the ability of supercritical CO2 to dissolve polar species has been empirically shown to be greatly enhanced by the addition of a small molar percentage of a polar cosolvent, often ethanol. Computational work predicts that the isolated ethanol-CO2 complex can exist either in an electron-donor configuration or through a hydrogen-bonding one; yet, neither has been previously experimentally observed. Here, we demonstrate by rotational spectroscopy that the isolated, gas-phase ethanol-CO2 dimer is an electron donor-acceptor complex.

14-Eth­oxy-4,6-dimethyl-9-phenyl-8,12-dioxa-4,6-diaza­tetra­cyclo­[8.8.0.02,7.013,18]octa­deca-2(7),13,15,17-tetra­ene-3,5,11-trione

PubMed Central

Jagadeesan, G.; Kannan, D.; Bakthadoss, M.; Aravindhan, S.

2013-01-01

In the title compound, C23H20N2O6, the fused pyrone and pyran rings each adopt a sofa conformation. The dihedral angle between the mean planes of the pyran and phenyl rings is 61.9 (1)°. In the crystal, mol­ecules are linked by two pairs of C—H⋯O hydrogen bonds, forming dimers. These dimers are linked via a third C—H⋯O hydrogen bond, forming a two-dimensional network parallel to (10-2). PMID:23476462

Crystal structure of 3-amino-1-(4-meth-oxy-phen-yl)-1H-benzo[f]chromene-2-carbo-nitrile.

PubMed

Mohamed, Shaaban K; Horton, Peter N; Akkurt, Mehmet; Younes, Sabry H H; Albayati, Mustafa R

2015-07-01

In the title compound, C21H16N2O2, the meth-oxy-benzene ring is almost perpendicular to the mean plane of the naphthalene ring system, making a dihedral angle of 83.62 (5)°. The 4H-pyran ring fused with the naphthalene ring system is almost planar [maximum deviation = 0.033 (1) Å]. In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H⋯N hydrogen bonds. N-H⋯O hydrogen bonds connect the dimers, forming a helical supra-molecular chain along the a-axis direction. The crystal packing also features C-H⋯π inter-actions.

Ethyl 4-(4-hydroxy­phen­yl)-6-methyl-2-oxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate monohydrate

PubMed Central

Das, Ushati; Chheda, Shardul B.; Pednekar, Suhas R.; Karambelkar, Narendra P; Guru Row, T. N.

2008-01-01

There are three formula units in the asymmetric unit of the title compound, C14H16N2O4·H2O. Mol­ecules are linked by N—H⋯O hydrogen bonds into dimers with the common R 2 2(8) graph-set motif. Between dimers, single N—H⋯O hydrogen bonds are formed between the other N—H group of each pyrimidine ring and the hydroxyl groups. The water mol­ecules accept O—H⋯O hydrogen bonds from the hydroxyl groups and donate hydrogen bonds to the ester groups. PMID:21581452

5-Nitro-N 4,N 6-diphenyl­pyrimidine-4,6-diamine: polarized mol­ecules linked into π-stacked chains via three-centre C—H⋯(O)2 hydrogen bonds

PubMed Central

Rodríguez, Ricaurte; Nogueras, Manuel; Cobo, Justo; Glidewell, Christopher

2009-01-01

Mol­ecules of the title compound, C16H13N5O2, have no inter­nal symmetry despite the symmetric pattern of substitution in the pyrimidine ring. The intra­molecular distances indicate polarization of the electronic structure. There are two intra­molecular N—H⋯O hydrogen bonds and mol­ecules are linked into centrosymmetric dimers by pairs of three-centre C—H⋯(O)2 hydrogen bonds. These dimers are linked into chains by means of a π–π stacking inter­action. PMID:19726856

Computational study of Zn-doped quantum spin chains and ladders

NASA Astrophysics Data System (ADS)

Laukamp, Markus

In this dissertation, the powerful Density Matrix Renormalization Group method is applied to examine the properties of spin models. The method allows to determine accurately the properties of low lying states of finite systems of large sizes. The results gained with this technique are compared to results generated with exact diagonalization and Monte Carlo techniques. Spin models have been proposed to describe dimerized chains, ladders, two dimensional antiferromagnets, and other compounds. Here the focus is on the case where some spins are replaced by spinless vacancies. This happens e.g. upon Zn doping, when Cusp{2+} atoms are replaced by Znsp{2+}. A small percentage of vacancies rapidly destroys the spin gap, and their presence induces enhanced antiferromagnetic correlations near those vacancies. Since the phenomenon of enhanced antiferromagnetism is found to occur in several models and cluster geometries, a common simple explanation for its presence may exist. In this thesis it is argued that the resonating-valence-bond character of the spin correlations at short distances of a large variety of models is responsible for the presence of robust staggered spin correlations near vacancies and lattice edges. The phenomenon takes place regardless of the long distance properties of the ground state, and it is caused by a "pruning" of the available spin singlets in the vicinity of the vacancies. The effect produces a broadening of the low temperature NMR signal for the compounds analyzed here. This broadening should be experimentally observable in the structurally dimerized chain systems Cu(NOsb3)sb{*}2.5Hsb2O,\\ CuWOsb4,\\ (VO)sb2Psb2Osb7, and Srsb{14}Cusb{24}Osb{41}, in ladder materials such as SrCusb2Osb3, in the spin-Peierls systems CuGeOsb3 and NaVsb2Osb5, and in several others since it is a universal effect common to a wide variety of models and compounds. In addition, it is argued that the Neel order observed in SrCusb2Osb3 upon Zn doping is induced by the local antiferromagnetic order discussed in this paper, enhanced by a favorable ratio between the actual Heisenberg couplings along chains and rungs, as reported in recent experimental literature. Based on this reasoning it is here predicted that other ladder materials such as Zn-doped Cusb2(Csb5Hsb{12}Nsb2)sb2Clsb4 will not present Neel order at small Zn concentrations.

Modeling interactions between a β-O-4 type lignin model compound and 1-allyl-3-methylimidazolium chloride ionic liquid.

PubMed

Zhu, Youtao; Yan, Jing; Liu, Chengbu; Zhang, Dongju

2017-08-01

Aiming at understanding the molecular mechanism of the lignin dissolution in imidazolium-based ionic liquids (ILs), this work presents a combined quantum chemistry (QC) calculation and molecular dynamics (MD) simulation study on the interaction of the lignin model compound, veratrylglycerol-β-guaiacyl ether (VG) with 1-allyl-3-methylimidazolium chloride ([Amim]Cl). The monomer of VG is shown to feature a strong intramolecular hydrogen bond, and its dimer is indicated to present important π-π stacking and intermolecular hydrogen bonding interactions. The interactions of both the cation and anion of [Amim]Cl with VG are shown to be stronger than that between the two monomers, indicating that [Amim]Cl is capable of dissolving lignin. While Cl - anion forms a hydrogen-bonded complex with VG, the imidazolium cation interacts with VG via both the π-π stacking and intermolecular hydrogen bonding. The calculated interaction energies between VG and the IL or its components (the cation, anion, and ion pair) indicate the anion plays a more important role than the cation for the dissolution of lignin in the IL. Theoretical results provide help for understanding the molecular mechanism of lignin dissolution in imidazolium-based IL. The theoretical calculations on the interaction between the lignin model compound and [Amim]Cl ionic liquid indicate that the anion of [Amim]Cl plays a more important role for lignin dissolution although the cation also makes a substantial contribution. © 2017 Wiley Periodicals, Inc.

A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects

PubMed Central

Rauf, Abdur; Uddin, Ghias; Siddiqui, Bina S.; Molnár, Joseph; Csonka, Ákos; Ahmad, Bashir; Szabó, Diana; Farooq, Umar; Khan, Ajmal

2015-01-01

Three new dimeric naphthoquinones, 5,4′-dihydroxy-1′-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,5′,8′-tetraone (1), 5′,8′-dihydroxy-5-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (2) and 8,5′,8′-trihydroxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1–3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1–3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism. PMID:26732580

Rational design of small-molecule stabilizers of spermine synthase dimer by virtual screening and free energy-based approach.

PubMed

Zhang, Zhe; Martiny, Virginie; Lagorce, David; Ikeguchi, Yoshihiko; Alexov, Emil; Miteva, Maria A

2014-01-01

Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now.

The use of molecular dynamics simulations to evaluate the DNA sequence-selectivity of G-A cross-linking PBD-duocarmycin dimers.

PubMed

Jackson, Paul J M; Rahman, Khondaker M; Thurston, David E

2017-01-01

The pyrrolobenzodiazepine (PBD) and duocarmycin families are DNA-interactive agents that covalently bond to guanine (G) and adenine (A) bases, respectively, and that have been joined together to create synthetic dimers capable of cross-linking G-G, A-A, and G-A bases. Three G-A alkylating dimers have been reported in publications to date, with defined DNA-binding sites proposed for two of them. In this study we have used molecular dynamics simulations to elucidate preferred DNA-binding sites for the three published molecular types. For the PBD-CPI dimer UTA-6026 (1), our simulations correctly predicted its favoured binding site (i.e., 5'-C(G)AATTA-3') as identified by DNA cleavage studies. However, for the PBD-CI molecule ('Compound 11', 3), we were unable to reconcile the results of our simulations with the reported preferred cross-linking sequence (5'-ATTTTCC(G)-3'). We found that the molecule is too short to span the five base pairs between the A and G bases as claimed, but should target instead a sequence such as 5'-ATTTC(G)-3' with two less base pairs between the reacting G and A residues. Our simulation results for this hybrid dimer are also in accord with the very low interstrand cross-linking and in vitro cytotoxicity activities reported for it. Although a preferred cross-linking sequence was not reported for the third hybrid dimer ('27eS', 2), our simulations predict that it should span two base pairs between covalently reacting G and A bases (e.g., 5'-GTAT(A)-3'). Copyright © 2016. Published by Elsevier Ltd.

Polyphenolic Composition and Antioxidant Activity of Aqueous and Ethanolic Extracts from Uncaria tomentosa Bark and Leaves.

PubMed

Navarro-Hoyos, Mirtha; Alvarado-Corella, Diego; Moreira-Gonzalez, Ileana; Arnaez-Serrano, Elizabeth; Monagas-Juan, Maria

2018-05-11

Uncaria tomentosa constitutes an important source of secondary metabolites with diverse biological activities mainly attributed until recently to alkaloids and triterpenes. We have previously reported for the first-time the polyphenolic profile of extracts from U. tomentosa , using a multi-step process involving organic solvents, as well as their antioxidant capacity, antimicrobial activity on aerial bacteria, and cytotoxicity on cancer cell lines. These promising results prompted the present study using food grade solvents suitable for the elaboration of commercial extracts. We report a detailed study on the polyphenolic composition of aqueous and ethanolic extracts of U. tomentosa bark and leaves ( n = 16), using High Performance Liquid Chromatography coupled with Mass Spectrometry (HPLC-DAD/TQ-ESI-MS). A total of 32 compounds were identified, including hydroxybenzoic and hydroxycinnamic acids, flavan-3-ols monomers, procyanidin dimers and trimers, flavalignans⁻cinchonains and propelargonidin dimers. Our findings showed that the leaves were the richest source of total phenolics and proanthocyanidins, in particular propelargonidin dimers. Two-way Analysis of Variance (ANOVA) indicated that the contents of procyanidin and propelargonidin dimers were significantly different ( p < 0.05) in function of the plant part, and leaves extracts showed higher contents. Oxygen Radical Absorbance Capacity (ORAC) and 2,2-diphenyl-1-picrylhidrazyl (DPPH) values indicated higher antioxidant capacity for the leaves ( p < 0.05). Further, correlation between both methods and procyanidin dimers was found, particularly between ORAC and propelargonidin dimers. Finally, Principal Component Analysis (PCA) analysis results clearly indicated that the leaves are the richest plant part in proanthocyanidins and a very homogenous material, regardless of their origin. Therefore, our findings revealed that both ethanol and water extraction processes are adequate for the elaboration of potential commercial extracts from U. tomentosa leaves rich in proanthocyanidins and exhibiting high antioxidant activity.

Polyphenolic Composition and Antioxidant Activity of Aqueous and Ethanolic Extracts from Uncaria tomentosa Bark and Leaves

PubMed Central

Alvarado-Corella, Diego; Moreira-Gonzalez, Ileana; Arnaez-Serrano, Elizabeth; Monagas-Juan, Maria

2018-01-01

Uncaria tomentosa constitutes an important source of secondary metabolites with diverse biological activities mainly attributed until recently to alkaloids and triterpenes. We have previously reported for the first-time the polyphenolic profile of extracts from U. tomentosa, using a multi-step process involving organic solvents, as well as their antioxidant capacity, antimicrobial activity on aerial bacteria, and cytotoxicity on cancer cell lines. These promising results prompted the present study using food grade solvents suitable for the elaboration of commercial extracts. We report a detailed study on the polyphenolic composition of aqueous and ethanolic extracts of U. tomentosa bark and leaves (n = 16), using High Performance Liquid Chromatography coupled with Mass Spectrometry (HPLC-DAD/TQ-ESI-MS). A total of 32 compounds were identified, including hydroxybenzoic and hydroxycinnamic acids, flavan-3-ols monomers, procyanidin dimers and trimers, flavalignans–cinchonains and propelargonidin dimers. Our findings showed that the leaves were the richest source of total phenolics and proanthocyanidins, in particular propelargonidin dimers. Two-way Analysis of Variance (ANOVA) indicated that the contents of procyanidin and propelargonidin dimers were significantly different (p < 0.05) in function of the plant part, and leaves extracts showed higher contents. Oxygen Radical Absorbance Capacity (ORAC) and 2,2-diphenyl-1-picrylhidrazyl (DPPH) values indicated higher antioxidant capacity for the leaves (p < 0.05). Further, correlation between both methods and procyanidin dimers was found, particularly between ORAC and propelargonidin dimers. Finally, Principal Component Analysis (PCA) analysis results clearly indicated that the leaves are the richest plant part in proanthocyanidins and a very homogenous material, regardless of their origin. Therefore, our findings revealed that both ethanol and water extraction processes are adequate for the elaboration of potential commercial extracts from U. tomentosa leaves rich in proanthocyanidins and exhibiting high antioxidant activity. PMID:29751684

A quantitative systems pharmacology model of blood coagulation network describes in vivo biomarker changes in non-bleeding subjects.

PubMed

Lee, D; Nayak, S; Martin, S W; Heatherington, A C; Vicini, P; Hua, F

2016-12-01

Essentials Baseline coagulation activity can be detected in non-bleeding state by in vivo biomarker levels. A detailed mathematical model of coagulation was developed to describe the non-bleeding state. Optimized model described in vivo biomarkers with recombinant activated factor VII treatment. Sensitivity analysis predicted prothrombin fragment 1 + 2 and D-dimer are regulated differently. Background Prothrombin fragment 1 + 2 (F 1 + 2 ), thrombin-antithrombin III complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatically normal subjects or hemophilic patients. They are often used as safety or pharmacodynamic biomarkers for hemostatis-modulating therapies in the clinic, and provide insights into in vivo coagulation activity. Objectives To develop a quantitative systems pharmacology (QSP) model of the blood coagulation network to describe in vivo biomarkers, including F 1 + 2 , TAT, and D-dimer, under non-bleeding conditions. Methods The QSP model included intrinsic and extrinsic coagulation pathways, platelet activation state-dependent kinetics, and a two-compartment pharmacokinetics model for recombinant activated factor VII (rFVIIa). Literature data on F 1 + 2 and D-dimer at baseline and changes with rFVIIa treatment were used for parameter optimization. Multiparametric sensitivity analysis (MPSA) was used to understand key proteins that regulate F 1 + 2 , TAT and D-dimer levels. Results The model was able to describe tissue factor (TF)-dependent baseline levels of F 1 + 2 , TAT and D-dimer in a non-bleeding state, and their increases in hemostatically normal subjects and hemophilic patients treated with different doses of rFVIIa. The amount of TF required is predicted to be very low in a non-bleeding state. The model also predicts that these biomarker levels will be similar in hemostatically normal subjects and hemophilic patients. MPSA revealed that F 1 + 2 and TAT levels are highly correlated, and that D-dimer is more sensitive to the perturbation of coagulation protein concentrations. Conclusions A QSP model for non-bleeding baseline coagulation activity was established with data from clinically relevant in vivo biomarkers at baseline and changes in response to rFVIIa treatment. This model will provide future mechanistic insights into this system. © 2016 International Society on Thrombosis and Haemostasis.

Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease.

PubMed

Jung, Jun-Sub; Yan, Ji-Jing; Li, Hong-Mei; Sultan, Md Tipu; Yu, Jaehoon; Lee, Hee-Sul; Shin, Kye-Jung; Song, Dong-Keun

2016-07-05

Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Aß1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Aß1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Aβ1-40 and Aβ1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Aβ decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD. Copyright © 2016 Elsevier B.V. All rights reserved.

A Link between Dimerization and Autophosphorylation of the Response Regulator PhoB*

PubMed Central

Creager-Allen, Rachel L.; Silversmith, Ruth E.; Bourret, Robert B.

2013-01-01

Response regulator proteins within two-component signal transduction systems are activated by phosphorylation and can catalyze their own covalent phosphorylation using small molecule phosphodonors. To date, comprehensive kinetic characterization of response regulator autophosphorylation is limited to CheY, which follows a simple model of phosphodonor binding followed by phosphorylation. We characterized autophosphorylation of the response regulator PhoB, known to dimerize upon phosphorylation. In contrast to CheY, PhoB time traces exhibited an initial lag phase and gave apparent pseudo-first order rate constants that increased with protein concentration. Furthermore, plots of the apparent autophosphorylation rate constant versus phosphodonor concentration were sigmoidal, as were PhoB binding isotherms for the phosphoryl group analog BeF3−. Successful mathematical modeling of the kinetic data necessitated inclusion of the formation of a PhoB heterodimer (one phosphorylated and one unphosphorylated monomer) with an enhanced rate of phosphorylation. Specifically, dimerization constants for the PhoB heterodimer and homodimer (two phosphorylated monomers) were similar, but the rate constant for heterodimer phosphorylation was ∼10-fold higher than for the monomer. In a test of the model, disruption of the known PhoBN dimerization interface by mutation led to markedly slower and noncooperative autophosphorylation kinetics. Furthermore, phosphotransfer from the sensor kinase PhoR was enhanced by dimer formation. Phosphorylation-mediated dimerization allows many response regulators to bind to tandem DNA-binding sites and regulate transcription. Our data challenge the notion that response regulator dimers primarily form between two phosphorylated monomers and raise the possibility that response regulator heterodimers containing one phosphoryl group may participate in gene regulation. PMID:23760278

Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid.

PubMed

Kalra, Arjun; Lubach, Joseph W; Munson, Eric J; Li, Tonglei

2018-02-07

Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular -COOH∙∙∙pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state. Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated. The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates - either as hydrogen-bonded neutral molecules or as zwitterions - as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed. The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.

Alkali metal complexes of sterically demanding amino-functionalized secondary phosphanide ligands.

PubMed

Izod, Keith; Stewart, John C; Clegg, William; Harrington, Ross W

2007-01-14

The reaction between {(Me(3)Si)(2)CH}PCl(2) (4) and one equivalent of either [C(6)H(4)-2-NMe(2)]Li or [2-C(5)H(4)N]ZnCl, followed by in situ reduction with LiAlH(4) gives the secondary phosphanes {(Me(3)Si)(2)CH}(C(6)H(4)-2-NMe(2))PH (5) and {(Me(3)Si)(2)CH}(2-C(5)H(4)N)PH (6) in good yields as colourless oils. Metalation of 5 with Bu(n)Li in THF gives the lithium phosphanide [[{(Me(3)Si)(2)CH}(C(6)H(4)-2-NMe(2))P]Li(THF)(2)] (7), which undergoes metathesis with either NaOBu(t) or KOBu(t) to give the heavier alkali metal derivatives [[{(Me(3)Si)(2)CH}(C(6)H(4)-2-NMe(2))P]Na(tmeda)] (8) and [[{(Me(3)Si)(2)CH}(C(6)H(4)-2-NMe(2))P]K(pmdeta)] (9) after recrystallization in the presence of the corresponding amine co-ligand [tmeda = N,N,N',N'-tetramethylethylenediamine, pmdeta = N,N,N',N'',N''-pentamethyldiethylenetriamine]. The pyridyl-functionalized phosphane 6 undergoes deprotonation on treatment with Bu(n)Li to give a red oil corresponding to the lithium compound [{(Me(3)Si)(2)CH}(2-C(5)H(4)N)P]Li (10) which could not be crystallized. Treatment of this oil with NaOBu(t) gives the sodium derivative [{[{(Me(3)Si)(2)CH}(2-C(5)H(4)N)P]Na}(2) x (Et(2)O)](2) (11), whilst treatment of with KOBu(t), followed by recrystallization in the presence of pmdeta gives the complex [[{(Me(3)Si)(2)CH}(2-C(5)H(4)N)P]K(pmdeta)](2) (12). Compounds 5-12 have been characterised by (1)H, (13)C{(1)H} and (31)P{(1)H} NMR spectroscopy and elemental analyses; compounds 7-9, and 12 have additionally been characterised by X-ray crystallography. Compounds 7-9 crystallize as discrete monomers, whereas 11 crystallizes as an unusual dimer of dimers and 12 crystallizes as a dimer with bridging pyridyl-phosphanide ligands.

Substituent Effects in the Benzene Dimer are Due to Direct Interactions of the Substituents with the Unsubstituted Benzene

PubMed Central

Wheeler, Steven E.; Houk, K. N.

2009-01-01

The prevailing views of substituent effects in the sandwich configuration of the benzene dimer are flawed. For example, in the polar/π model of Cozzi and co-workers (J. Am. Chem. Soc. 1992, 114, 5729), electron-withdrawing substituents enhance binding in the benzene dimer by withdrawing electron density from the π-cloud of the substituted ring, reducing the repulsive electrostatic interaction with the non-substituted benzene. Conversely, electron-donating substituents donate excess electrons into the π-system and diminish the π-stacking interaction. We present computed interaction energies for the sandwich configuration of the benzene dimer and 24 substituted dimers, as well as sandwich complexes of substituted benzenes with perfluorobenzene. While the computed interaction energies correlate well with σm values for the substituents, interaction energies for related model systems demonstrate that this trend is independent of the substituted ring. Instead, the observed trends are consistent with direct electrostatic and dispersive interactions of the substituents with the unsubstituted ring. PMID:18652453

Overcoming HSP27-mediated resistance by altered dimerization of HSP27 using small molecules.

PubMed

Kim, Jee Hye; Jung, Ye Jin; Choi, Byeol; Lee, Na Lim; Lee, Hae Jun; Kwak, Soo Yeon; Kwon, Youngjoo; Na, Younghwa; Lee, Yun-Sil

2016-08-16

Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27. However, unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, we found that a small molecule, zerumbone (ZER), induced altered dimerization of HSP27 by cross linking the cysteine residues required to build a large oligomer, led to sensitization in combination with radiation. In this study, we identified another small molecule, a xanthone compound, more capable of altering dimeric HSP27 than ZER and yielding sensitization in human lung cancer cells when combined with HSP90 inhibitors or standard anticancer modalities such as irradiation and cytotoxic anticancer drugs. Therefore, altered dimerization of HSP27 represents a good strategy for anticancer therapy in HSP27-overexpressing cancer cells.

Overcoming HSP27-mediated resistance by altered dimerization of HSP27 using small molecules

PubMed Central

Choi, Byeol; Lee, Na Lim; Lee, Hae Jun; Kwak, Soo Yeon; Kwon, Youngjoo; Na, Younghwa; Lee, Yun-Sil

2016-01-01

Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27. However, unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, we found that a small molecule, zerumbone (ZER), induced altered dimerization of HSP27 by cross linking the cysteine residues required to build a large oligomer, led to sensitization in combination with radiation. In this study, we identified another small molecule, a xanthone compound, more capable of altering dimeric HSP27 than ZER and yielding sensitization in human lung cancer cells when combined with HSP90 inhibitors or standard anticancer modalities such as irradiation and cytotoxic anticancer drugs. Therefore, altered dimerization of HSP27 represents a good strategy for anticancer therapy in HSP27-overexpressing cancer cells. PMID:27449291

Dimerization of a flocculent protein from Moringa oleifera: experimental evidence and in silico interpretation.

PubMed

Pavankumar, Asalapuram R; Kayathri, Rajarathinam; Murugan, Natarajan A; Zhang, Qiong; Srivastava, Vaibhav; Okoli, Chuka; Bulone, Vincent; Rajarao, Gunaratna K; Ågren, Hans

2014-01-01

Many proteins exist in dimeric and other oligomeric forms to gain stability and functional advantages. In this study, the dimerization property of a coagulant protein (MO2.1) from Moringa oleifera seeds was addressed through laboratory experiments, protein-protein docking studies and binding free energy calculations. The structure of MO2.1 was predicted by homology modelling, while binding free energy and residues-distance profile analyses provided insight into the energetics and structural factors for dimer formation. Since the coagulation activities of the monomeric and dimeric forms of MO2.1 were comparable, it was concluded that oligomerization does not affect the biological activity of the protein.

Procyanidin content of grape seed and pomace, and total anthocyanin content of grape pomace as affected by extrusion processing.

PubMed

Khanal, R C; Howard, L R; Prior, R L

2009-08-01

Grape juice processing by-products, grape seed and pomace are a rich source of procyanidins, compounds that may afford protection against chronic disease. This study was undertaken to identify optimal extrusion conditions to enhance the contents of monomers and dimers at the expense of large molecular weight procyanidin oligomers and polymers in grape seed and pomace. Extrusion variables, temperature (160, 170, and 180 degrees C in grape seed, and 160, 170, 180, and 190 degrees C in pomace) and screw speed (100, 150, and 200 rpm in both) were tested using mixtures of grape seed as well as pomace with decorticated white sorghum flour at a ratio of 30 : 70 and moisture content of 45%. Samples of grape seed and pomace were analyzed for procyanidin composition before and after extrusion, and total anthocyanins were determined in pomace. Additionally, chromatograms from diol and normal phase high-performance liquid chromatography were compared for the separation of procyanidins. Extrusion of both grape by-products increased the biologically important monomer and dimers considerably across all temperature and screw speeds. Highest monomer content resulted when extruded at a temperature of 170 degrees C and screw speed of 200 rpm, which were 120% and 80% higher than the unextruded grape seed and pomace, respectively. Increases in monomer and dimer contents were apparently the result of reduced polymer contents, which declined by 27% to 54%, or enhanced extraction facilitated by disruption of the food matrix during extrusion. Extrusion processing reduced total anthocyanins in pomace by 18% to 53%. Extrusion processing can be used to increase procyanidin monomer and dimer contents in grape seed and pomace. Procyanidins in grape by-products have many health benefits, but most are present as large molecular weight compounds, which are poorly absorbed. Extrusion processing appears to be a promising technology to increase levels of the bioactive low molecular weight procyanidins.

Architecture and Assembly of HIV Integrase Multimers in the Absence of DNA Substrates*

PubMed Central

Bojja, Ravi Shankar; Andrake, Mark D.; Merkel, George; Weigand, Steven; Dunbrack, Roland L.; Skalka, Anna Marie

2013-01-01

We have applied small angle x-ray scattering and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution. By blocking interactions that stabilize either a core-core domain interface or N-terminal domain intermolecular contacts, we show that full-length HIV IN can form two dimer types. One is an expected dimer, characterized by interactions between two catalytic core domains. The other dimer is stabilized by interactions of the N-terminal domain of one monomer with the C-terminal domain and catalytic core domain of the second monomer as well as direct interactions between the two C-terminal domains. This organization is similar to the “reaching dimer” previously described for wild type ASV apoIN and resembles the inner, substrate binding dimer in the crystal structure of the PFV intasome. Results from our small angle x-ray scattering and modeling studies indicate that in the absence of its DNA substrate, the HIV IN tetramer assembles as two stacked reaching dimers that are stabilized by core-core interactions. These models of full-length HIV IN provide new insight into multimer assembly and suggest additional approaches for enzyme inhibition. PMID:23322775

Vibrationally induced flip motion of a hydroxyl dimer on Cu(110)

NASA Astrophysics Data System (ADS)

Ootsuka, Yasuhiro; Frederiksen, Thomas; Ueba, Hiromu; Paulsson, Magnus

2011-11-01

Recent low-temperature scanning-tunneling microscopy experiments [T. Kumagai , Phys. Rev. BPLRBAQ0556-280510.1103/PhysRevB.79.035423 79, 035423 (2009)] observed the vibrationally induced flip motion of a hydroxyl dimer (OD)2 on Cu(110). We propose a model to describe two-level fluctuations and current-voltage characteristics of nanoscale systems that undergo vibrationally induced switching. The parameters of the model are based on comprehensive density functional calculations of the system’s vibrational properties. For the dimer (OD)2, the calculated population of the high- and low-conductance states, the I-V, dI/dV, and d2I/dV2 curves are in good agreement with the experimental results and underline the different roles played by the free and shared OD stretch modes of the dimer.

In Vitro Enzymatic Depolymerization of Lignin with Release of Syringyl, Guaiacyl, and Tricin Units

PubMed Central

Gall, Daniel L.; Kontur, Wayne S.; Lan, Wu; Kim, Hoon; Li, Yanding; Ralph, John

2017-01-01

ABSTRACT New environmentally sound technologies are needed to derive valuable compounds from renewable resources. Lignin, an abundant polymer in terrestrial plants comprised predominantly of guaiacyl and syringyl monoaromatic phenylpropanoid units, is a potential natural source of aromatic compounds. In addition, the plant secondary metabolite tricin is a recently discovered and moderately abundant flavonoid in grasses. The most prevalent interunit linkage between guaiacyl, syringyl, and tricin units is the β-ether linkage. Previous studies have shown that bacterial β-etherase pathway enzymes catalyze glutathione-dependent cleavage of β-ether bonds in dimeric β-ether lignin model compounds. To date, however, it remains unclear whether the known β-etherase enzymes are active on lignin polymers. Here we report on enzymes that catalyze β-ether cleavage from bona fide lignin, under conditions that recycle the cosubstrates NAD+ and glutathione. Guaiacyl, syringyl, and tricin derivatives were identified as reaction products when different model compounds or lignin fractions were used as substrates. These results demonstrate an in vitro enzymatic system that can recycle cosubstrates while releasing aromatic monomers from model compounds as well as natural and engineered lignin oligomers. These findings can improve the ability to produce valuable aromatic compounds from a renewable resource like lignin. IMPORTANCE Many bacteria are predicted to contain enzymes that could convert renewable carbon sources into substitutes for compounds that are derived from petroleum. The β-etherase pathway present in sphingomonad bacteria could cleave the abundant β–O–4-aryl ether bonds in plant lignin, releasing a biobased source of aromatic compounds for the chemical industry. However, the activity of these enzymes on the complex aromatic oligomers found in plant lignin is unknown. Here we demonstrate biodegradation of lignin polymers using a minimal set of β-etherase pathway enzymes, the ability to recycle needed cofactors (glutathione and NAD+) in vitro, and the release of guaiacyl, syringyl, and tricin as depolymerized products from lignin. These observations provide critical evidence for the use and future optimization of these bacterial β-etherase pathway enzymes for industrial-level biotechnological applications designed to derive high-value monomeric aromatic compounds from lignin. PMID:29180366

STIM1 dimers undergo unimolecular coupling to activate Orai1 channels

NASA Astrophysics Data System (ADS)

Zhou, Yandong; Wang, Xizhuo; Wang, Xianming; Loktionova, Natalia A.; Cai, Xiangyu; Nwokonko, Robert M.; Vrana, Erin; Wang, Youjun; Rothberg, Brad S.; Gill, Donald L.

2015-09-01

The endoplasmic reticulum (ER) Ca2+ sensor, STIM1, becomes activated when ER-stored Ca2+ is depleted and translocates into ER-plasma membrane junctions where it tethers and activates Orai1 Ca2+ entry channels. The dimeric STIM1 protein contains a small STIM-Orai-activating region (SOAR)--the minimal sequence sufficient to activate Orai1 channels. Since SOAR itself is a dimer, we constructed SOAR concatemer-dimers and introduced mutations at F394, which is critical for Orai1 coupling and activation. The F394H mutation in both SOAR monomers completely blocks dimer function, but F394H introduced in only one of the dimeric SOAR monomers has no effect on Orai1 binding or activation. This reveals an unexpected unimolecular coupling between STIM1 and Orai1 and argues against recent evidence suggesting dimeric interaction between STIM1 and two adjacent Orai1 channel subunits. The model predicts that STIM1 dimers may be involved in crosslinking between Orai1 channels with implications for the kinetics and localization of Orai1 channel opening.

Reduced dimer production in solar-simulator-pumped continuous wave iodine lasers based on model simulations and scaling and pumping studies

NASA Technical Reports Server (NTRS)

Costen, Robert C.; Heinbockel, John H.; Miner, Gilda A.; Meador, Willard E., Jr.; Tabibi, Bagher M.; Lee, Ja H.; Williams, Michael D.

1995-01-01

A numerical rate equation model for a continuous wave iodine laser with longitudinally flowing gaseous lasant is validated by approximating two experiments that compare the perfluoroalkyl iodine lasants n-C3F7I and t-C4F9I. The salient feature of the simulations is that the production rate of the dimer (C4F9)2 is reduced by one order of magnitude relative to the dimer (C3F7)2. The model is then used to investigate the kinetic effects of this reduced dimer production, especially how it improves output power. Related parametric and scaling studies are also presented. When dimer production is reduced, more monomer radicals (t-C4F9) are available to combine with iodine ions, thus enhancing depletion of the laser lower level and reducing buildup of the principal quencher, molecular iodine. Fewer iodine molecules result in fewer downward transitions from quenching and more transitions from stimulated emission of lasing photons. Enhanced depletion of the lower level reduces the absorption of lasing photons. The combined result is more lasing photons and proportionally increased output power.

N-(1,3-Thia­zol-2-yl)benzamide

PubMed Central

Zonouzi, Afsaneh; Mirzazadeh, Roghieh; Rahmani, Hossein; Ng, Seik Weng

2009-01-01

The title compound, C10H8N2OS, features a nonplanar mol­ecule [dihedral angle between the two aromatic rings = 43.6 (1)°]. Two mol­ecules are linked by N—H⋯N hydrogen bonds about a centre of inversion, giving rise to a hydrogen-bonded dimer. PMID:21582538

The Application of Magnesium(I) Compounds to Energy Storage Materials - Phase 2

DTIC Science & Technology

2013-06-24

currently exploring the use of 10 as a catalyst for a number of other processes, e.g. the selective hydroboration of ketone , aldehydes and nitriles...hydroboration of ketones ; (vi) a variety of related results, including the preparation of an iron(I) dimer with the shortest Fe-Fe multiple bond

Light-triggered self-assembly of triarylamine-based nanospheres

NASA Astrophysics Data System (ADS)

Moulin, Emilie; Niess, Frédéric; Fuks, Gad; Jouault, Nicolas; Buhler, Eric; Giuseppone, Nicolas

2012-10-01

Tailored triarylamine units modified with terpyridine ligands were coordinated to Zn2+ ions and characterized as discrete dimeric entities. Interestingly, when these complexes were subsequently irradiated with simple visible light in chloroform, they readily self-assembled into monodisperse spheres with a mean diameter of 160 nm.Tailored triarylamine units modified with terpyridine ligands were coordinated to Zn2+ ions and characterized as discrete dimeric entities. Interestingly, when these complexes were subsequently irradiated with simple visible light in chloroform, they readily self-assembled into monodisperse spheres with a mean diameter of 160 nm. Electronic supplementary information (ESI) available: Synthetic procedures and products' characterization (2-4 and 6-9). 1H NMR titration of compound 6 by Zn(OTf)2 to form complex 7. Kinetic measurements by UV-Vis-NIR spectroscopy. Transmission electron microscopy imaging for complexes 8 and 9. UV-Vis-NIR for an Fe2+ analogue of complex 7. Dynamic light scattering and time autocorrelation function for self-assembly of complexes 7-9. Copies of 1H and 13C NMR spectra for compounds 2-4 and 6. See DOI: 10.1039/c2nr32168h

New quaternary ammonium camphor derivatives and their antiviral activity, genotoxic effects and cytotoxicity.

PubMed

Sokolova, Anastasiya S; Yarovaya, Capital O Cyrilliclga I; Shernyukov, Capital A Cyrillicndrey V; Pokrovsky, Capital Em Cyrillicichail A; Pokrovsky, Capital A Cyrillicndrey G; Lavrinenko, Valentina A; Zarubaev, Vladimir V; Tretiak, Tatiana S; Anfimov, Pavel M; Kiselev, Oleg I; Beklemishev, Anatoly B; Salakhutdinov, Nariman F

2013-11-01

The synthesis and biological evaluation of a novel series of dimeric camphor derivatives are described. The resulting compounds were studied for their antiviral activity, cyto- and genotoxicity. Compounds 3a and 3d in which the quaternary nitrogen atoms are separated by the C5H10 and С9H18 aliphatic chain, exhibited the highest efficiency as an agent inhibiting the reproduction of the influenza virus A(H1N1)pdm09. The cytotoxicity data of compounds 3 and 4 revealed their moderate activity against malignant cell lines; compound 3f had the highest activity for the CEM-13 cells. These results show close agreement with the data of independent studies on toxicity of these compounds, in particular that the toxicity of compounds strongly depends on spacer length. Copyright © 2013 Elsevier Ltd. All rights reserved.

New chalcanonol glycoside from the seeds of saw palmetto: antiproliferative and antioxidant effects.

PubMed

Abdel Bar, Fatma M

2015-01-01

A new chalcanonol glycoside dimer, bis-O-[(I-4') → (II-6')]-α-hydroxyphloretin-2'-O-β-glucoside (1), in addition to six known compounds, namely (-)-epicatechin (2) and (-)-epiafzelechin (3), 4-hydroxybenzoic acid (4), protocatechuic acid (5), methylgallate (6), β-sitosterol (7) and β-sitosterol-3-O-glucoside (8), was isolated from the seeds of saw palmetto. The structures of the isolated compounds were established from the analysis of their MS and 1D and 2D NMR spectroscopic data. The antiproliferative activities of the isolated compounds towards PC3, the human prostate cancer cells were investigated. Amongst the isolated compounds, the new compound and the sterolic derivatives showed antiproliferative effects. Screening of the antioxidant effects of the isolated compounds by 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid radical assay revealed that the isolated phenolics were active free radical scavengers.

Screening for lead compounds and herbal extracts with potential anti-influenza viral activity.

PubMed

Klaywong, Konrapob; Khutrakul, Gachagorn; Choowongkomon, Kiattawee; Lekcharoensuk, Chalermpol; Petcharat, Nantawan; Leckcharoensuk, Porntippa; Ramasoota, Pongrama

2014-01-01

Nonstructural protein 1 (NS1) of the highly pathogenic avian influenza virus (H5N1) contains a conserved RNA binding domain (RBD) that inhibits antiviral functions of host-innate immune response. Dimerization of NS1 forms a central groove and binds to double stranded (ds) RNA. This region might serve as a potential drug target. In this study, three dimensional structure model of NS1 RBD protein was constructed and virtual screening was performed to identify lead compounds that bound within and around the central groove. The virtual screening showed that 5 compounds bound within the central groove with binding energy ranging between -16.05 and -17.36 Kcal/mol. Two commercially available compounds, estradiol and veratridine, were selected for using in an in vitro screening assay. The results showed that neither of the compounds could inhibit the association between dsRNA and NS1 RBD protein. In addition, 34 herbal extracts were examined for their inhibitory effects. Five of them were able to inhibit association between NS1 RBD and dsRNA in electrophoresis mobility shift assay. Four herbs, Terminalia belirica, Salacia chinensis, Zingiber montanum and Peltophorum pterocarpum, could reduce > 50% of infectivity of H5N1 in a cell-based assay, and it is worth further studying their potential use as source of antiviral drugs.

Plasma D-dimer Can Effectively Predict the Prospective Occurrence of Ascites in Advanced Schistosomiasis Japonica Patients.

PubMed

Wu, Xiaoying; Ren, Jianwei; Gao, Zulu; Xu, Yun; Xie, Huiqun; Li, Tingfang; Cheng, Yanhua; Hu, Fei; Liu, Hongyun; Gong, Zhihong; Liang, Jinyi; Shen, Jia; Liu, Zhen; Wu, Feng; Sun, Xi; Niu, Zhongzheng; Ning, An

2017-04-01

China still has more than 30,000 patients of advanced schistosomiasis while new cases being reported consistently. D-dimer is a fibrin degradation product. As ascites being the dominating symptom in advanced schistosomiasis, the present study aimed to explore a prediction model of ascites with D-dimer and other clinical easy-achievable indicators. A case-control study nested in a prospective cohort was conducted in schistosomiasis-endemic area of southern China. A total of 291 patients of advanced schistosomiasis were first investigated in 2013 and further followed in 2014. Information on clinical history, physical examination, and abdominal ultrasonography, including the symptom of ascites was repeatedly collected. Result showed 44 patients having ascites. Most of the patients' ascites were confined in the kidney area with median area of 20 mm 2 . The level of plasma D-dimer and pertinent liver function indicators were measured at the initial investigation in 2013. Compared with those without ascites, cases with ascites had significantly higher levels of D-dimer (0.71±2.44 μg/L vs 0.48±2.12 μg/L, P =0.005), as well ALB (44.5 vs 46.2, g/L) and Type IV collagen (50.04 vs 44.50 μg/L). Receiver operating characteristic curve analyses indicated a moderate predictive value of D-dimer by its own area under curve (AUC) of 0.64 (95% CI: 0.54-0.73) and the cutoff value as 0.81 μg/L. Dichotomized by the cutoff level, D-dimer along with other categorical variables generated a prediction model with AUC of 0.76 (95% CI: 0.68-0.89). Risks of patients with specific characteristics in the prediction model were summarized. Our study suggests that the plasma D-dimer level is a reliable predictor for incident ascites in advanced schistosomiasis japonica patients.

Plasma D-dimer Can Effectively Predict the Prospective Occurrence of Ascites in Advanced Schistosomiasis Japonica Patients

PubMed Central

Wu, Xiaoying; Ren, Jianwei; Gao, Zulu; Xu, Yun; Xie, Huiqun; Li, Tingfang; Cheng, Yanhua; Hu, Fei; Liu, Hongyun; Gong, Zhihong; Liang, Jinyi; Shen, Jia; Liu, Zhen; Wu, Feng; Sun, Xi; Niu, Zhongzheng; Ning, An

2017-01-01

China still has more than 30,000 patients of advanced schistosomiasis while new cases being reported consistently. D-dimer is a fibrin degradation product. As ascites being the dominating symptom in advanced schistosomiasis, the present study aimed to explore a prediction model of ascites with D-dimer and other clinical easy-achievable indicators. A case-control study nested in a prospective cohort was conducted in schistosomiasis-endemic area of southern China. A total of 291 patients of advanced schistosomiasis were first investigated in 2013 and further followed in 2014. Information on clinical history, physical examination, and abdominal ultrasonography, including the symptom of ascites was repeatedly collected. Result showed 44 patients having ascites. Most of the patients’ ascites were confined in the kidney area with median area of 20 mm2. The level of plasma D-dimer and pertinent liver function indicators were measured at the initial investigation in 2013. Compared with those without ascites, cases with ascites had significantly higher levels of D-dimer (0.71±2.44 μg/L vs 0.48±2.12 μg/L, P=0.005), as well ALB (44.5 vs 46.2, g/L) and Type IV collagen (50.04 vs 44.50 μg/L). Receiver operating characteristic curve analyses indicated a moderate predictive value of D-dimer by its own area under curve (AUC) of 0.64 (95% CI: 0.54–0.73) and the cutoff value as 0.81 μg/L. Dichotomized by the cutoff level, D-dimer along with other categorical variables generated a prediction model with AUC of 0.76 (95% CI: 0.68–0.89). Risks of patients with specific characteristics in the prediction model were summarized. Our study suggests that the plasma D-dimer level is a reliable predictor for incident ascites in advanced schistosomiasis japonica patients. PMID:28506039

N-tert-Butyl-N'-(5,7-dimethyl-1,8-naphthyridin-2-yl)urea.

PubMed

Lüning, U; Kühl, C; Bolte, M

2001-08-01

The title compound, C(15)H(20)N(4)O, has been synthesized as an AADD recognition unit for quadruple hydrogen bonds. All non-H atoms of the molecule apart from two methyl groups of the tert-butyl group lie in a common plane. An intramolecular hydrogen bond is formed connecting two N atoms. In the solid state, the title compound crystallizes as a centrosymmetric dimer connected by N-H...O=C interactions with an N...O distance of 2.824 (2) A.

Push-pull quinoidal porphyrins.

PubMed

Smith, Martin J; Blake, Iain M; Clegg, William; Anderson, Harry L

2018-05-01

A family of push-pull quinoidal porphyrin monomers has been prepared from a meso-formyl porphyrin by bromination, thioacetal formation, palladium-catalyzed coupling with malononitrile and oxidation with DDQ. Attempts at extending this synthesis to a push-pull quinoidal/cumulenic porphyrin dimer were not successful. The crystal structures of the quinoidal porphyrins indicate that there is no significant contribution from singlet biradical or zwitterionic resonance forms. The crystal structure of an ethyne-linked porphyrin dimer shows that the torsion angle between the porphyrin units is only about 3°, in keeping with crystallographic results on related compounds, but contrasting with the torsion angle of about 35° predicted by computational studies. The free-base quinoidal porphyrin monomers form tightly π-stacked layer structures, despite their curved geometries and bulky aryl substituents.

Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

PubMed

Tang, Lisha; Zhu, Hengrui; Yang, Xianmei; Xie, Fang; Peng, Jingtao; Jiang, Deke; Xie, Jun; Qi, Meiyan; Yu, Long

2016-01-01

Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

Mineral catalysis of a potentially prebiotic aldol condensation

NASA Technical Reports Server (NTRS)

De Graaf, R. M.; Visscher, J.; Xu, Y.; Arrhenius, G.; Schwartz, A. W.

1998-01-01

Minerals may have played a significant role in chemical evolution. In the course of investigating the chemistry of phosphonoacetaldehyde (PAL), an analogue of glycolaldehyde phosphate, we have observed a striking case of catalysis by the layered hydroxide mineral hydrotalcite ([Mg2Al(OH)6][Cl.nH2O]). In neutral or moderately basic aqueous solutions, PAL is unreactive even at a concentration of 0.1 M. In the presence of a large excess of NaOH (2 M), the compound undergoes aldol condensation to produce a dimer containing a C3-C4 double-bond. In dilute neutral solutions and in the presence of the mineral, however, condensation takes place rapidly, to produce a dimer which is almost exclusively the C2-C3 unsaturated product.

A highly directional fourfold hydrogen-bonding motif for supramolecular structures through self-assembly of fullerodendrimers.

PubMed

Hahn, Uwe; González, Juan J; Huerta, Elisa; Segura, Margarita; Eckert, Jean-François; Cardinali, François; de Mendoza, Javier; Nierengarten, Jean-François

2005-11-04

Supramolecular dendrimers resulting from the dimerization of fullerene-functionalized dendrons through a quadruple hydrogen-bonding motif were prepared. The synthetic strategy is based on the esterification of a tert-butoxycarbonyl (Boc)-protected 2-ureido-4-[1H]pyrimidinone precursor possessing an alcohol function with fullerodendrons bearing a carboxylic acid unit at the focal point. Subsequent acidic treatment to cleave the protecting group and reaction of the resulting amine with octylisocyanate affords the targeted compounds. As demonstrated by the results of MALDI-TOF mass spectrometry and 1H NMR spectroscopy, both of the 2-ureido-4-[1H]pyrimidinone derivatives form self-assembled dimers spontaneously through hydrogen-bonding interactions, thus leading to supramolecular structures containing two or ten fullerene moieties.

Antitumor activity of four macrocyclic ellagitannins from Cuphea hyssopifolia.

PubMed

Wang, C C; Chen, L G; Yang, L L

1999-06-01

We evaluated the antitumor activities of four macrocyclic hydrolyzable tannin dimers, cuphiin D1, cuphiin D2, oenothein B and woodfordin C isolated from Cuphea hyssopifolia (Lythraceae). All significantly inhibited the growth of the human carcinoma cell lines KB, HeLa, DU-145, Hep 3B, and the leukemia cell line HL-60, and showed less cytotoxicity than adriamycin against a normal cell line (WISH). All four compounds inhibited the viability of S-180 tumor cells in an in vitro assay and an in vivo S-180 tumor-bearing ICR mice model. Oenothein B demonstrated the greatest cytotoxicity (IC50 = 11.4 microg/ml) against S-180 tumor cells in culture, while cuphiin D1 resulted in the greatest increase in survival on S-180 tumor-bearing mice (%ILS = 84.1%). Our findings suggest that the antitumor effects of these compounds are not only related to their cytotoxicity on carcinoma cell lines, but also depended on a host-mediated mechanism; they may therefore have potential for antitumor applications.

Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma

PubMed Central

Chao, Ying; Babic, Ivan; Nurmemmedov, Elmar; Pastorino, Sandra; Jiang, Pengfei; Calligaris, David; Agar, Nathalie; Scadeng, Miriam; Pingle, Sandeep C.; Wrasidlo, Wolfgang; Makale, Milan T.; Kesari, Santosh

2017-01-01

Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer—glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics. PMID:26517684

Purification and characterization of a novel lignin peroxidase from white-rot fungus Phanerochaete sordida YK-624.

PubMed

Sugiura, Mutsumi; Hirai, Hirofumi; Nishida, Tomoaki

2003-07-29

We characterized kinetics and substrate oxidation of a novel lignin peroxidase (YK-LiP) isolated from white-rot fungus Phanerochaete sordida YK-624. YK-LiP enzyme was identified and purified to homogeneity by anion-exchange chromatography and gel permeation chromatography. The molecular mass of YK-LiP was approximately 50 kDa, and the absorption spectrum of YK-LiP was almost the same as that of the LiP (Pc-LiP) from Phanerochaete chrysosporium. Steady-state kinetics of veratryl alcohol oxidation by YK-LiP (unlike that by Pc-LiP) revealed a bi-reactant sequential mechanism, although reactivity of YK-LiP to various monomeric substituted aromatic compounds was similar to that of Pc-LiP. Degradation of dimeric lignin model compounds was more effective by YK-LiP than by Pc-LiP, and the oxidation rate of sinapyl alcohol oligomer by YK-LiP was much faster than that by Pc-LiP.

DFT Insights into the Competitive Adsorption of Sulfur- and Nitrogen-Containing Compounds and Hydrocarbons on Co-Promoted Molybdenum Sulfide Catalysts

DOE PAGES

Rangarajan, Srinivas; Mavrikakis, Manos

2016-04-07

The adsorption of 20 nitrogen-/sulfur-containing and hydrocarbon compounds on the sulfur edge of cobalt-promoted molybdenum sulfide (CoMoS) catalyst was studied using density functional theory, accounting for van der Waals interactions, to elicit comparative structure–property trends across different classes of molecules relevant to hydrotreating. Unhindered organosulfur compounds preferentially adsorb on a “CUS-like” site formed by the dimerization of two neighboring sulfur atoms on the edge to create a vacancy. Nitrogen-containing compounds and 4,6-dimethyldibenzothiophene, however, prefer the brim sites. Binding energy trends indicate that nitrogen-containing compounds will inhibit hydrodesulfurization on the brim sites and, relatively weakly, on the CUS-like sites. Edge vacanciesmore » are,thus, likely to be essential for hydrodesulfurization of unhindered organosulfur compounds. Furthermore, van der Waals forces contribute significantly to the binding energy of compounds (up to 1.0 eV for large compounds such as alkyl-substituted acridines) on CoMoS.« less

Dimer geometry, amoebae and a vortex dimer model

NASA Astrophysics Data System (ADS)

Nash, Charles; O'Connor, Denjoe

2017-09-01

We present a geometrical approach and introduce a connection for dimer problems on bipartite and non-bipartite graphs. In the bipartite case the connection is flat but has non-trivial {Z}2 holonomy round certain curves. This holonomy has the universality property that it does not change as the number of vertices in the fundamental domain of the graph is increased. It is argued that the K-theory of the torus, with or without punctures, is the appropriate underlying invariant. In the non-bipartite case the connection has non-zero curvature as well as non-zero Chern number. The curvature does not require the introduction of a magnetic field. The phase diagram of these models is captured by what is known as an amoeba. We introduce a dimer model with negative edge weights which correspond to vortices. The amoebae for various models are studied with particular emphasis on the case of negative edge weights. Vortices give rise to new kinds of amoebae with certain singular structures which we investigate. On the amoeba of the vortex full hexagonal lattice we find the partition function corresponds to that of a massless Dirac doublet.

EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

PubMed Central

Needham, Sarah R.; Roberts, Selene K.; Arkhipov, Anton; Mysore, Venkatesh P.; Tynan, Christopher J.; Zanetti-Domingues, Laura C.; Kim, Eric T.; Losasso, Valeria; Korovesis, Dimitrios; Hirsch, Michael; Rolfe, Daniel J.; Clarke, David T.; Winn, Martyn D.; Lajevardipour, Alireza; Clayton, Andrew H. A.; Pike, Linda J.; Perani, Michela; Parker, Peter J.; Shan, Yibing; Shaw, David E.; Martin-Fernandez, Marisa L.

2016-01-01

Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling. PMID:27796308

1-[(Anthracen-9-yl)carbon­yl]-2,7-di­meth­oxy­naphthalene: a chain-like structure composed of face-to-face type dimeric mol­ecular aggregates

PubMed Central

Siqingaowa; Tsumuki, Takehiro; Ogata, Kazuki; Yonezawa, Noriyuki; Okamoto, Akiko

2016-01-01

The asymmetric unit of the title compound, C27H20O3, contains two independent mol­ecules (A and B). The anthracene ring system is connected to the 2,7-di­meth­oxy­naphthalene core in a twisted manner, with dihedral angles of 86.38 (5) and 79.36 (8)°, respectively, for conformers A and B. In the crystal, face-to-face type dimeric mol­ecular aggregates of each conformer are observed. The dimer of conformer A is formed by two pairs of C—H⋯π inter­actions, and that of conformer B by a pair of (sp 2)C—H⋯O hydrogen bonds. The dimers of conformer A are linked to each other via a π–π stacking inter­action between the anthracene rings to form a chain along the b axis and the chains are aligned along the c axis, forming a sheet structure. The dimers of conformer B are connected to each other via a couple of C—H⋯π inter­actions to form a chain along the b axis. The chains are aligned along the c axis through (sp 2)C—H⋯O=C hydrogen bonds, forming a sheet parallel to the bc plane. The sheets of conformers A and B are alternately stacked along the a axis via two kinds of inter­molecular (sp 2)C—H⋯O=C hydrogen bonds. PMID:27980839

Density functional Gaussian-type-orbital approach to theoretical study of nitric oxide dimers

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

Jursic, B.S.; Zdravkovski, Z.

Structure and total energies of the cis NO dimer, the trans NO dimer, and the NO monomer were calculated by ab initio methods (UHF, UMP2, and MP3) and density functional theory methods (LSDA and BLYP) with different basis sets [from 3-21G* to 6-311++(3df,3pd)]. The system is especially hard to model because two NO molecules are weakly associated in a dimer that has very long N-N bond. The results obtained by different methods are compared and the necessity of correlational methods for studying these systems is discussed.

Single-molecule photobleaching reveals increased MET receptor dimerization upon ligand binding in intact cells

PubMed Central

2013-01-01

Background The human receptor tyrosine kinase MET and its ligand hepatocyte growth factor/scatter factor are essential during embryonic development and play an important role during cancer metastasis and tissue regeneration. In addition, it was found that MET is also relevant for infectious diseases and is the target of different bacteria, amongst them Listeria monocytogenes that induces bacterial uptake through the surface protein internalin B. Binding of ligand to the MET receptor is proposed to lead to receptor dimerization. However, it is also discussed whether preformed MET dimers exist on the cell membrane. Results To address these issues we used single-molecule fluorescence microscopy techniques. Our photobleaching experiments show that MET exists in dimers on the membrane of cells in the absence of ligand and that the proportion of MET dimers increases significantly upon ligand binding. Conclusions Our results indicate that partially preformed MET dimers may play a role in ligand binding or MET signaling. The addition of the bacterial ligand internalin B leads to an increase of MET dimers which is in agreement with the model of ligand-induced dimerization of receptor tyrosine kinases. PMID:23731667

The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics.

PubMed

Kaczor, Agnieszka A; Jörg, Manuela; Capuano, Ben

2016-09-01

In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalent antagonists. Our approach was based on protein-protein docking, applying the Rosetta software to obtain populations of dimers as present in membranes with all the main possible interfaces. Consensus scoring based on the values and frequencies of best interfaces regarding four scoring parameters, Rosetta interface score, interface area, free energy of binding and energy of hydrogen bond interactions indicated that the best scored dimer model possesses a TM4-TM5-TM7-TM1 interface, which is in agreement with experimental data. This model was used to study interactions of the previously published dopamine D2 receptor homobivalent antagonists based on clozapine,1,4-disubstituted aromatic piperidines/piperazines and arylamidoalkyl substituted phenylpiperazine pharmacophores. It was found that the homobivalent antagonists stabilize the receptor-inactive conformation by maintaining the ionic lock interaction, and change the dimer interface by disrupting a set of hydrogen bonds and maintaining water- and ligand-mediated hydrogen bonds in the extracellular and intracellular part of the interface. Graphical Abstract Structure of the final model of the dopamine D2 receptor homodimer, indicating the distancebetween Tyr37 and Tyr 5.42 in the apo form (left) and in the complex with the ligand (right).

The Preparation and Structural Characterization of Three Structural Types of Gallium Compounds Derived from Gallium (II) Chloride

NASA Technical Reports Server (NTRS)

Gordon, Edward M.; Hepp, Aloysius F.; Duraj. Stan A.; Habash, Tuhfeh S.; Fanwick, Phillip E.; Schupp, John D.; Eckles, William E.; Long, Shawn

1997-01-01

The three compounds Ga2Cl4(4-mepy)2 (1),[GaCl2(4-mepy)4]GaCl4x1/2(4-mepy); (2) and GaCl2(4-mepy)2(S2CNEt2); (3) (4-mepy= 4-methylpyridine) have been prepared from reactions of gallium (II) chloride in 4-methylpyridine and characterized by single-crystal X-ray analysis. Small variations in the reaction conditions for gallium(II) chloride can produce crystals with substantially different structural properties. The three compounds described here encompass a neutral gallium(II) dimer in which each gallium is four-coordinate, an ionic compound containing both anionic and cationic gallium complex ions with different coordination numbers and a neutral six-coordinate heteroleptic

Synthesis and biological evaluation of 6-carboxy-3,4-methanoprolines, new rigid glutamate analogs.

PubMed

Marinozzi, M; Natalini, B; Ni, M H; Costantino, G; Pellicciari, R; Thomsen, C

1995-05-01

6-Carboxy-3,4-methanoprolines were prepared by reacting ethyl diazoacetate with the suitable 3,4-didehydroproline derivative in the presence of rhodium(II)acetate dimer as catalyst. The affinities of the title compounds for displacement of receptor binding to ionotropic and metabotropic (mGluR1 alpha) glutamate receptors were also determined.

Multiscale modeling of a conditionally disordered pH-sensing chaperone.

PubMed

Ahlstrom, Logan S; Law, Sean M; Dickson, Alex; Brooks, Charles L

2015-04-24

The pH-sensing chaperone HdeA promotes the survival of enteropathogenic bacteria during transit through the harshly acidic environment of the mammalian stomach. At low pH, HdeA transitions from an inactive, folded, dimer to chaperone-active, disordered, monomers to protect against the acid-induced aggregation of periplasmic proteins. Toward achieving a detailed mechanistic understanding of the pH response of HdeA, we develop a multiscale modeling approach to capture its pH-dependent thermodynamics. Our approach combines pK(a) (logarithmic acid dissociation constant) calculations from all-atom constant pH molecular dynamics simulations with coarse-grained modeling and yields new, atomic-level, insights into HdeA chaperone function that can be directly tested by experiment. "pH triggers" that significantly destabilize the dimer are each located near the N-terminus of a helix, suggesting that their neutralization at low pH destabilizes the helix macrodipole as a mechanism of monomer disordering. Moreover, we observe a non-monotonic change in the pH-dependent stability of HdeA, with maximal stability of the dimer near pH5. This affect is attributed to the protonation Glu37, which exhibits an anomalously high pK(a) value and is located within the hydrophobic dimer interface. Finally, the pH-dependent binding pathway of HdeA comprises a partially unfolded, dimeric intermediate that becomes increasingly stable relative to the native dimer at lower pH values and displays key structural features for chaperone-substrate interaction. We anticipate that the insights from our model will help inform ongoing NMR and biochemical investigations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dynamics of the Glycophorin A Dimer in Membranes of Native-Like Composition Uncovered by Coarse-Grained Molecular Dynamics Simulations.

PubMed

Flinner, Nadine; Schleiff, Enrico

2015-01-01

Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution.

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair

PubMed Central

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M.; Friedhoff, Peter; Plotz, Guido

2010-01-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome which predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased co-expression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations. PMID:20533529

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

PubMed

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M; Friedhoff, Peter; Plotz, Guido

2010-08-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome that predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased coexpression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations.

Annealing to sequences within the primer binding site loop promotes an HIV-1 RNA conformation favoring RNA dimerization and packaging

PubMed Central

Seif, Elias; Niu, Meijuan; Kleiman, Lawrence

2013-01-01

The 5′ untranslated region (5′ UTR) of HIV-1 genomic RNA (gRNA) includes structural elements that regulate reverse transcription, transcription, translation, tRNALys3 annealing to the gRNA, and gRNA dimerization and packaging into viruses. It has been reported that gRNA dimerization and packaging are regulated by changes in the conformation of the 5′-UTR RNA. In this study, we show that annealing of tRNALys3 or a DNA oligomer complementary to sequences within the primer binding site (PBS) loop of the 5′ UTR enhances its dimerization in vitro. Structural analysis of the 5′-UTR RNA using selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) shows that the annealing promotes a conformational change of the 5′ UTR that has been previously reported to favor gRNA dimerization and packaging into virus. The model predicted by SHAPE analysis is supported by antisense experiments designed to test which annealed sequences will promote or inhibit gRNA dimerization. Based on reports showing that the gRNA dimerization favors its incorporation into viruses, we tested the ability of a mutant gRNA unable to anneal to tRNALys3 to be incorporated into virions. We found a ∼60% decrease in mutant gRNA packaging compared with wild-type gRNA. Together, these data further support a model for viral assembly in which the initial annealing of tRNALys3 to gRNA is cytoplasmic, which in turn aids in the promotion of gRNA dimerization and its incorporation into virions. PMID:23960173

Slow aging in Secondary Organic Aerosol observed by Liquid Chromatography coupled with High-Resolution Mass Spectrometry

NASA Astrophysics Data System (ADS)

Bones, D. L.; Bateman, A. P.; Nguyen, T. B.; Laskin, J.; Laskin, A.; Nizkorodov, S.

2009-12-01

This study investigated long term changes in the chemical composition of model biogenic secondary organic aerosol (SOA) prepared via ozonolysis of the terpene limonene. This SOA has been observed to turn brown when exposed to NH4+. Our hypothesis is that the chromophoric compounds responsible for this color change are suspected to be imidazole-like or pyridinium-like compounds. These compounds are only present in small relative amounts, hence standard mass spectrometry is insufficient to unambiguously detect these compounds. However, a combination of HPLC and high resolution electrospray ionization mass spectrometry allows assignments of chemical formulae to individual peaks. These and other experiments confirm the presence of N-containing compounds in treated SOA. We are in the process of determining the exact identity of these species by MS/MS methods. LC-MS can also provide information about the polarity of the compounds in SOA. Most compounds in limonene-O3 SOA are polar and are detected at short retention times; peaks suggesting trimeric species appear at longer retention times in the case of fresh SOA, but at shorter times with the bulk of the components for aged SOA. Limonene SOA has been shown to be composed of monomers, dimers, trimers and larger oligomers. The appearance of trimers in specific regions of the chromatogram suggests these species are genuine SOA components and not an artifact of electrospray ionization. Changes in biogenic SOA over time are important because of the propensity of SOA to affect direct and indirect radiative forcing.

Phenoxo bridged dinuclear Zn(II) Schiff base complex as new precursor for preparation zinc oxide nanoparticles: Synthesis, characterization, crystal structures and photoluminescence studies

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

Saeednia, S., E-mail: sami_saeednia@yahoo.com; Iranmanesh, P.; Ardakani, M. Hatefi

Highlights: • A novel nano-scale Zn(II) complex was synthesized by solvothermal method. • Chemical structure of the nanostructures was characterized as well as bulk complex. • The photoluminescence property of the complex was investigated at room temperature. • The thermogravimetry and differential thermal analysis were carried out. • Thermal decomposition of the nanostructures was prepared zinc oxide nanoparticles. - Abstract: Nanoparticles of a novel Zn(II) Schiff base complex, [Zn(HL)NO{sub 3}]{sub 2} (1), (H{sub 2}L = 2-[(2-hydroxy-propylimino) methyl] phenol), was synthesized by using solvothermal method. Shape, morphology and chemical structure of the synthesized nanoparticles were characterized by scanning electron microscopy (SEM),more » X-ray powder diffraction (XRD), Fourier Transform Infrared Spectoscopy (FT-IR) and UV–vis spectroscopy. Structural determination of compound 1 was determined by single-crystal X-ray diffraction. The results were revealed that the zinc complex is a centrosymmetric dimer in which deprotonated phenolates bridge the two five-coordinate metal atoms and link the two halves of the dimer. The thermal stability of compound 1 was analyzed by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). The effect of the initial substrates concentration and reaction time on size and morphology of compound 1 nanostructure was investigated as well. Furthermore, the luminescent properties of the complex 1 were examined. ZnO nanoparticles with diameter between 15 and 20 nm were simply synthesized by solid-state transformation of compound 1 at 700 °C.« less

Synthetic iron complexes as models for natural iron-humic compounds: Synthesis, characterization and algal growth experiments.

PubMed

Orlowska, Ewelina; Roller, Alexander; Pignitter, Marc; Jirsa, Franz; Krachler, Regina; Kandioller, Wolfgang; Keppler, Bernhard K

2017-01-15

A series of monomeric and dimeric Fe III complexes with O,O-; O,N-; O,S-coordination motifs has been prepared and characterized by standard analytical methods in order to elucidate their potential to act as model compounds for aquatic humic acids. Due to the postulated reduction of iron in humic acids and following uptake by microorganisms, the redox behavior of the models was investigated with cyclic voltammetry. Most of the investigated compounds showed iron reduction potentials accessible to biological reducing agents. Additionally, observed reduction processes were predominantly irreversible, suggesting that subsequent reactions can take place after reduction of the iron center. Also the stability of the synthesized complexes in pure water and artificial seawater was monitored from 24h up to 21days by means of UV-Vis spectrometry. Several complexes remained stable even after 21days, showing only partially precipitation but some of them showed changes in UV-Vis spectra already after 24h which were connected to protonation/deprotonation processes as well as redox processes and degradation of the complexes. The ability to act as an iron source for primary producers was tested in algal growth experiments with two marine algae species Chlorella salina and Prymnesium parvum. Some of the compounds showed effects on the algal cultures, which are comparable with natural humic acids and better as for the samples kept under ideal conditions. Those findings help to understand which functional groups of humic acids could be responsible for the reversible iron binding and transport in aquatic humic substances. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The dimerization equilibrium of a ClC Cl−/H+ antiporter in lipid bilayers

PubMed Central

Chadda, Rahul; Krishnamani, Venkatramanan; Mersch, Kacey; Wong, Jason; Brimberry, Marley; Chadda, Ankita; Kolmakova-Partensky, Ludmila; Friedman, Larry J; Gelles, Jeff; Robertson, Janice L

2016-01-01

Interactions between membrane protein interfaces in lipid bilayers play an important role in membrane protein folding but quantification of the strength of these interactions has been challenging. Studying dimerization of ClC-type transporters offers a new approach to the problem, as individual subunits adopt a stable and functionally verifiable fold that constrains the system to two states – monomer or dimer. Here, we use single-molecule photobleaching analysis to measure the probability of ClC-ec1 subunit capture into liposomes during extrusion of large, multilamellar membranes. The capture statistics describe a monomer to dimer transition that is dependent on the subunit/lipid mole fraction density and follows an equilibrium dimerization isotherm. This allows for the measurement of the free energy of ClC-ec1 dimerization in lipid bilayers, revealing that it is one of the strongest membrane protein complexes measured so far, and introduces it as new type of dimerization model to investigate the physical forces that drive membrane protein association in membranes. DOI: http://dx.doi.org/10.7554/eLife.17438.001 PMID:27484630

Improvement of catalytic performance of lignin peroxidase for the enhanced degradation of lignocellulose biomass based on the imbedded electron-relay in long-range electron transfer route.

PubMed

Pham, Le Thanh Mai; Kim, Su Jin; Kim, Yong Hwan

2016-01-01

Although lignin peroxidase is claimed as a key enzyme in enzyme-catalyzed lignin degradation, in vitro enzymatic degradation of lignin was not easily observed in lab-scale experiments. It implies that other factors may hinder the enzymatic degradation of lignin. Irreversible interaction between phenolic compound and lignin peroxidase was hypothesized when active enzyme could not be recovered after the reaction with degradation product (guaiacol) of lignin phenolic dimer. In the study of lignin peroxidase isozyme H8 from white-rot fungi Phanerochaete chrysosporium (LiPH8), W251 site was revealed to make the covalent coupling with one moiety of monolignolic radical (guaiacol radical) by LC-MS/MS analysis. Hypothetical electron-relay containing W251 residue was newly suggested based on the observation of repressed radical coupling and remarkably lower electron transfer rate for W215A mutant. Furthermore, the retardation of the suicidal radical coupling between the W251 residue and the monolignolic radical was attempted by supplementing the acidic microenvironment around the W251 residue to engineer radical-robust LiPH8. Among many mutants, mutant A242D showed exceptional catalytic performances by yielding 21.1- and 4.9-fold higher increases of k cat and k cat /K M values, respectively, in the oxidation of non-phenolic model lignin dimer. A mechanism-based suicide inhibition of LiPH8 by phenolic compounds was firstly revealed and investigated in this work. Radical-robust LiPH8 was also successfully engineered by manipulating the transient radical state of radical-susceptible electron-relay. Radical-robust LiPH8 will play an essential role in degradation of lignin, which will be consequently linked with improved production of sugars from lignocellulose biomass.

SL1 revisited: functional analysis of the structure and conformation of HIV-1 genome RNA.

PubMed

Sakuragi, Sayuri; Yokoyama, Masaru; Shioda, Tatsuo; Sato, Hironori; Sakuragi, Jun-Ichi

2016-11-11

The dimer initiation site/dimer linkage sequence (DIS/DLS) region of HIV is located on the 5' end of the viral genome and suggested to form complex secondary/tertiary structures. Within this structure, stem-loop 1 (SL1) is believed to be most important and an essential key to dimerization, since the sequence and predicted secondary structure of SL1 are highly stable and conserved among various virus subtypes. In particular, a six-base palindromic sequence is always present at the hairpin loop of SL1 and the formation of kissing-loop structure at this position between the two strands of genomic RNA is suggested to trigger dimerization. Although the higher-order structure model of SL1 is well accepted and perhaps even undoubted lately, there could be stillroom for consideration to depict the functional SL1 structure while in vivo (in virion or cell). In this study, we performed several analyses to identify the nucleotides and/or basepairing within SL1 which are necessary for HIV-1 genome dimerization, encapsidation, recombination and infectivity. We unexpectedly found that some nucleotides that are believed to contribute the formation of the stem do not impact dimerization or infectivity. On the other hand, we found that one G-C basepair involved in stem formation may serve as an alternative dimer interactive site. We also report on our further investigation of the roles of the palindromic sequences on viral replication. Collectively, we aim to assemble a more-comprehensive functional map of SL1 on the HIV-1 viral life cycle. We discovered several possibilities for a novel structure of SL1 in HIV-1 DLS. The newly proposed structure model suggested that the hairpin loop of SL1 appeared larger, and genome dimerization process might consist of more complicated mechanism than previously understood. Further investigations would be still required to fully understand the genome packaging and dimerization of HIV.

A multimode vibronic treatment of absorption, resonance Raman, and hyper-Rayleigh scattering of excitonically coupled molecular dimers

NASA Astrophysics Data System (ADS)

Myers Kelley, Anne

2003-08-01

The linear absorption spectra, resonance Raman excitation profiles and depolarization dispersion curves, and hyper-Rayleigh scattering profiles are calculated for excitonically coupled homodimers of a model electron donor-acceptor "push-pull" conjugated chromophore as a function of dimer geometry. The vibronic eigenstates of the dimer are calculated by diagonalizing the matrix of transition dipole couplings among the vibronic transitions of the constituent monomers. The absorption spectra show the usual red- or blueshifted transitions for J-type or H-type dimers, respectively. When the electronic coupling is large compared with the vibronic width of the monomer spectrum, the dimer absorption spectra exhibit simple Franck-Condon progressions having reduced vibronic intensities compared with the monomer, and the resonance Raman excitation profiles are shifted but otherwise only weakly perturbed. When the coupling is comparable to the vibronic width, the H-dimer absorption spectra exhibit irregular vibronic frequency spacings and intensity patterns and the effects on the Raman excitation profiles are larger. There is strong dispersion in the Raman depolarization ratios for dimer geometries in which both transitions carry oscillator strength. The first hyperpolarizabilities are somewhat enhanced in J-dimers and considerably reduced in H-dimers. These effects on the molecular β will amplify the effects of dimerization on the ground-state dipole moment in electro-optic materials formed from chromophore-doped polymers that must be electric field poled to obtain the net alignment needed for a macroscopic χ(2).

Selective ligand activity at Nur/retinoid X receptor complexes revealed by dimer-specific bioluminescence resonance energy transfer-based sensors

PubMed Central

Giner, Xavier C; Cotnoir-White, David; Mader, Sylvie; Lévesque, Daniel

2017-01-01

Retinoid X receptors (RXR) play a role as master regulators due to their capacity to form heterodimers with other nuclear receptors. Accordingly, retinoid signaling is involved in multiple biological processes, including development, cell differentiation, metabolism and cell death. However, the role and functions of RXR in different heterodimer complexes remain unsolved, mainly because most RXR drugs (called rexinoids) are not selective to specific heterodimer complexes. This also strongly limits the use of rexinoids for specific therapeutic approaches. In order to better characterize rexinoids at specific nuclear receptor complexes, we have developed and optimized luciferase protein complementation-based Bioluminescence Resonance Energy Transfer (BRET) assays, which can directly measure recruitment of a co-activator motif fused to yellow fluorescent protein (YFP) by specific nuclear receptor dimers. To validate the assays, we compared rexinoid modulation of co-activator recruitment by RXR homodimer, and heterodimers Nur77/RXR and Nurr1/RXR. Results reveal that some rexinoids display selective co-activator recruitment activities with homo- or hetero-dimer complexes. In particular, SR11237 (BMS649) has increased potency for recruitment of co-activator motif and transcriptional activity with the Nur77/RXR heterodimer compared to other complexes. This technology should prove useful to identify new compounds with specificity for individual dimeric species formed by nuclear receptors. PMID:26148973

Induction of G2/M arrest and apoptosis through mitochondria pathway by a dimer sesquiterpene lactone from Smallanthus sonchifolius in HeLa cells.

PubMed

Kitai, Yurika; Zhang, Xia; Hayashida, Yushi; Kakehi, Yoshiyuki; Tamura, Hirotoshi

2017-07-01

Dimer sesquiterpene lactones (SLs), uvedafolin and enhydrofolin, against four monomer SLs isolated from yacon, Smallanthus sonchifolius, leaf were the most cytotoxic substances on HeLa cells (IC 50 values 2.96-3.17 μM at 24 hours). However, the cytotoxic mechanism of dimer SL has not been elucidated yet. Therefore, in this study, we clarified the in vitro cytotoxic mechanism of uvedafolin on the HeLa cells, and evaluated the cytotoxicity against NIH/3T3 cells which were used as normal cells. In consequence, the dimer SLs had low toxicity for the NIH/3T3 cells (IC 50 4.81-4.98 μM at 24 hours) and then the uvedafolin mediated cell cycle arrest at the G 2 /M phase and induced apoptosis on the HeLa cells evidenced by appearance of a subG1 peak. Uvedafolin induced apoptosis was attributed to caspase-9 and caspase-3/7 activities. An effectively induced apoptosis pathway was demonstrated from mitochondria membrane potential change and cytochrome c release to cytosol. These results reveal that uvedafolin induced apoptosis via the mitochondria pathway. The present results indicate the potential of uvedafolin as a leading compound of new anticancer agents. Copyright © 2016. Published by Elsevier B.V.

Crystal structure of ethyl (E)-2-cyano-3-(thio-phen-2-yl)acrylate: two conformers forming a discrete disorder.

PubMed

Castro Agudelo, Brian; Cárdenas, Juan C; Macías, Mario A; Ochoa-Puentes, Cristian; Sierra, Cesar A

2017-09-01

In the title compound, C 10 H 9 NO 2 S, all the non-H atoms, except for the ethyl fragment, lie nearly in the same plane. Despite the mol-ecular planarity, the ethyl fragment presents more than one conformation, giving rise to a discrete disorder, which was modelled with two different crystallographic sites for the eth-oxy O and eth-oxy α-C atoms, with occupancy values of 0.5. In the crystal, the three-dimensional array is mainly directed by C-H⋯(O,N) inter-actions, giving rise to inversion dimers with R 2 2 (10) and R 2 2 (14) motifs and infinite chains running along the [100] direction.

Synthesis, crystal structure determination and antiproliferative activity of novel 2-amino-4-aryl-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazoles

NASA Astrophysics Data System (ADS)

Hranjec, Marijana; Pavlović, Gordana; Karminski-Zamola, Grace

2012-01-01

This manuscript describes the synthesis of novel 2-amino-4-aryl-4,10-dihydro-[1,3,5]triazino[1,2- a]benzimidazoles as hydrochloride salts 4a-n and 5b which were prepared in the reaction of cyclocondensation between 2-guanidinobenzimidazole and versatile heteroaromatic aldehydes. Structures of all prepared compounds have been studied by using 1H and 13C NMR, IR and UV/Vis spectroscopy. The crystal and molecular structure of 4f was determined by X-ray diffraction on single crystals. The molecule of 2-amino-4-(4'-methylphenyl)-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole hydrochloride 4f (C 16H 16N 5+·Cl -) exists in the solid state in one of the possible tautomeric forms, being protonated at the one of the nitrogen atoms of the 1,4-dihydrotriazine ring. The molecule is highly delocalized within the 4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole moiety with the highest deviation from the plane for the methine carbon atom and the protonated nitrogen atom of the 1,4-dihydrotriazine ring. The cations are joined via N-H⋯N hydrogen bonds into R22(8) centrosymmetric dimers. Cation dimers are further connected with Cl - ions via N-H⋯Cl and C-H⋯Cl hydrogen bonds into 2D chains spreading along the b axis. The obtained single-crystal X-ray structure determination unequivocally confirms tautomeric form of the compound present in the solid-state and can represent tantative pattern for other prepared compounds. All prepared compounds were tested on their antiproliferative activity in vitro on several human cancer cell lines. Compound 4m was the most active one (IC 50 ≈ 20 μM), while compounds 4d, 4f, 4k, 4l4m showed moderate, but non-selective, antiproliferative activity with IC 50 25-60 μM.

Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization

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

Kim, Sun Young; Song, Kyung-A; Samsung Biomedical Research Institute

Highlights: Black-Right-Pointing-Pointer Evidence that targeting EBNA1 dimer, an EBV onco-antigen, can be achievable. Black-Right-Pointing-Pointer A small molecule and a peptide as EBNA1 dimerization inhibitors identified. Black-Right-Pointing-Pointer Both inhibitors associated with EBNA1 and blocked EBNA1 DNA binding activity. Black-Right-Pointing-Pointer Also, prevented its dimerization, and repressed viral gene transcription. -- Abstract: Latent Epstein-Barr virus (EBV) infection is associated with human B cell lymphomas and certain carcinomas. EBV episome persistence, replication, and gene expression are dependent on EBV-encoded nuclear antigen 1 (EBNA1)'s DNA binding domain (DBD)/dimerization domain (DD)-mediated sequence-specific DNA binding activity. Homodimerization of EBNA1 is essential for EBNA1 DNA binding and transactivation.more » In this study, we characterized a novel small molecule EBNA1 inhibitor EiK1, screened from the previous high throughput screening (HTS). The EiK1 compound specifically inhibited the EBNA1-dependent, OriP-enhanced transcription, but not EBNA1-independent transcription. A Surface Plasmon Resonance Biacore assay revealed that EiK1 associates with EBNA1 amino acid 459-607 DBD/DD. Consistent with the SPR data, in vitro gel shift assays showed that EiK1 suppressed the activity of EBNA1 binding to the cognate familial repeats (FR) sequence, but not control RBP-J{kappa} binding to the J{kappa} site. Subsequently, a cross-linker-mediated in vitro multimerization assay and EBNA1 homodimerization-dependent yeast two-hybrid assay showed that EiK1 significantly inhibited EBNA1 dimerization. In an attempt to identify more highly specific peptide inhibitors, small peptides encompassing the EBNA1 DBD/DD were screened for inhibition of EBNA1 DBD-mediated DNA binding function. The small peptide P85, covering EBNA1 a.a. 560-574, significantly blocked EBNA1 DNA binding activity in vitro, prevented dimerization in vitro and in vivo, associated with EBNA1 in vitro, and repressed EBNA1-dependent transcription in vivo. Collectively, this study describes two novel inhibitors of EBNA1 dimerization. This study demonstrates that EBNA1 homodimerization can be effectively targeted by a small molecule or peptide.« less

The Far Infrared Vibration-Rotation Spectrum of the Ammonia Dimer.

NASA Astrophysics Data System (ADS)

Loeser, Jennifer Gertrud

1995-11-01

The ammonia dimer has been shown to exhibit unusual weak bonding properties relative to those of the other prototypical second row systems, the hydrogen fluoride dimer and the water dimer. The ultimate goal of the work initiated in this dissertation is to determine a complete intermolecular potential energy surface for the ammonia dimer. It is first necessary to observe its far infrared vibration-rotation-tunneling (VRT) spectrum and to develop a group theoretical model that explains this spectrum in terms of the internal dynamics of the ammonia dimer. These first steps are the subject of this dissertation. First, the current understanding of the ammonia dimer system is reviewed. Group theoretical descriptions of the nature of the ammonia dimer VRT states are explained in detail. An overview of the experimental and theoretical studies of the ammonia dimer made during the last decade is presented. Second, progress on the analysis of the microwave and far infrared spectrum of (ND_3)_2 below 13 cm^{-1} is reported. These spectra directly measure the 'donor -acceptor' interchange splittings in (ND_3) _2, and determine some of the monomer umbrella inversion tunneling splittings. Third, new 80-90 cm^{-1} far infrared spectra of (NH_3)_2 are presented and a preliminary analysis is proposed. Most of the new excited VRT states have been assigned as tunneling sublevels of an out-of-plane intermolecular vibration.

Microwave Spectrum of the Isopropanol-Water Dimer

NASA Astrophysics Data System (ADS)

Mead, Griffin; Finneran, Ian A.; Carroll, Brandon; Blake, Geoffrey

2016-06-01

Microwave spectroscopy provides a unique opportunity to study model non-covalent interactions. Of particular interest is the hydrogen bonding of water, whose various molecular properties are influenced by both strong and weak intermolecular forces. More specifically, measuring the hydrogen bonded structures of water-alcohol dimers investigates both strong (OH ··· OH) and weak (CH ··· OH) hydrogen bond interactions. Recently, we have measured the pure rotational spectrum of the isopropanol-water dimer using chirped-pulse Fourier transform microwave spectroscopy (CP-FTMW) between 8-18 GHz. Here, we present the spectrum of this dimer and elaborate on the structure's strong and weak hydrogen bonding.

Resolution of concerted versus sequential mechanisms in photo-induced double-proton transfer reaction in 7-azaindole H-bonded dimer

PubMed Central

Catalán, Javier; del Valle, Juan Carlos; Kasha, Michael

1999-01-01

The experimental and theoretical bases for a synchronous or concerted double-proton transfer in centro-symmetric H-bonded electronically excited molecular dimers are presented. The prototype model is the 7-azaindole dimer. New research offers confirmation of a concerted mechanism for excited-state biprotonic transfer. Recent femtosecond photoionization and coulombic explosion techniques have given rise to time-of-flight MS observations suggesting sequential two-step biprotonic transfer for the same dimer. We interpret the overall species observed in the time-of-flight experiments as explicable without conflict with the concerted mechanism of proton transfer. PMID:10411876

Ligand-induced perturbation of the HIF-2α:ARNT dimer dynamics

PubMed Central

Motta, Stefano

2018-01-01

Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix−loop−helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy. Following the discovery of a druggable cavity within the PAS-B domain of HIF-2α, research efforts have been directed to identify artificial ligands that can impair heterodimerization. Although the crystallographic structures of the HIF-2α:ARNT complex have elucidated the dimer architecture and the 0X3-inhibitor placement within the HIF-2α PAS-B, unveiling the inhibition mechanism requires investigation of how ligand-induced perturbations could dynamically propagate through the structure and affect dimerization. To this end, we compared evolutionary features, intrinsic dynamics and energetic properties of the dimerization interfaces of HIF-2α:ARNT in both the apo and holo forms. Residue conservation analysis highlighted inter-domain connecting elements that have a role in dimerization. Analysis of domain contributions to the dimerization energy demonstrated the importance of bHLH and PAS-A of both partners and of HIF-2α PAS-B domain in dimer stabilization. Among quaternary structure oscillations revealed by Molecular Dynamics simulations, the hinge-bending motion of the ARNT PAS-B domain around the flexible PAS-A/PAS-B linker supports a general model for ARNT dimerization in different heterodimers. Comparison of the HIF-2α:ARNT dynamics in the apo and 0X3-bound forms indicated a model of inhibition where the HIF-2α-PAS-B interfaces are destabilised as a result of water-bridged ligand-protein interactions and these local effects allosterically propagate to perturb the correlated motions of the domains and inter-domain communication. These findings will guide the design of improved inhibitors to contrast cell survival in tumor masses. PMID:29489822

Lattice model simulation of interchain protein interactions and the folding dynamics and dimerization of the GCN4 Leucine zipper

NASA Astrophysics Data System (ADS)

Liu, Yanxin; Chapagain, Prem P.; Parra, Jose L.; Gerstman, Bernard S.

2008-01-01

The highest level in the hierarchy of protein structure and folding is the formation of protein complexes through protein-protein interactions. We have made modifications to a well established computer lattice model to expand its applicability to two-protein dimerization and aggregation. Based on Brownian dynamics, we implement translation and rotation moves of two peptide chains relative to each other, in addition to the intrachain motions already present in the model. We use this two-chain model to study the folding dynamics of the yeast transcription factor GCN4 leucine zipper. The calculated heat capacity curves agree well with experimental measurements. Free energy landscapes and median first passage times for the folding process are calculated and elucidate experimentally measured characteristics such as the multistate nature of the dimerization process.

Cooperative behavior of molecular motions giving rise to two glass transitions in the same supercooled mesophase of a smectogenic liquid crystal dimer

NASA Astrophysics Data System (ADS)

López, David O.; Salud, Josep; de la Fuente, María Rosario; Sebastián, Nerea; Diez-Berart, Sergio

2018-01-01

In the present work, a detailed analysis of the glassy behavior and the relaxation dynamics of the liquid crystal dimer α-(4-cyanobiphenyl-4'-yloxy)-ω-(1-pyrenimine-benzylidene-4'-oxy) heptane (CBO7O.Py) throughout both nematic and smectic-A mesophases by means of broadband dielectric spectroscopy has been performed. CBO7O.Py shows three different dielectric relaxation modes and two glass transition (Tg) temperatures: The higher Tg is due to the freezing of the molecular motions responsible for the relaxation mode with the lowest frequency (μ1 L); the lower Tg is due to the motions responsible for the two relaxation modes with highest frequencies (μ1 H and μ2), which converge just at their corresponding Tg. It is shown how the three modes follow a critical-like description via the dynamic scaling model. The two modes with lowest frequencies (μ1 L and μ1 H) are cooperative in the whole range of the mesophases, whereas the highest frequency mode (μ2) is cooperative just below some crossover temperature. In terms of fragility, at the glass transition, the ensemble (μ1 H+μ2 ) presents a value of the steepness index and μ1 L a different one, meaning that fragility is a property intrinsic to the molecular motion itself. Finally, the steepness index seems to have a universal behavior with temperature for the dielectric relaxation modes of liquid crystal dimers, being almost constant at high temperatures and increasing drastically when cooling the compound down to the glass transition from a temperature about 3/4 TN I .

Molecular structures of the inclusion complexes beta-cyclodextrin-1,2-bis(4-aminophenyl)ethane and beta-cyclodextrin-4,4'-diaminobiphenyl; packing of dimeric beta-cyclodextrin inclusion complexes.

PubMed

Giastas, Petros; Yannakopoulou, Konstantina; Mavridis, Irene M

2003-04-01

The present investigation is part of an ongoing study on the influence of the long end-functonalized guest molecules DBA and BNZ in the crystal packing of beta-cyclodextrin (betaCD) dimeric complexes. The title compounds are 2:2 host:guest complexes showing limited host-guest hydrogen bonding at the primary faces of the betaCD dimers. Within the betaCD cavity the guests exhibit mutual pi...pi interactions and between betaCD dimers perpendicular NH...pi interactions. The DBA guest molecule exhibits one extended and two bent conformations in the complex. The BNZ guest molecule is not planar inside betaCD, in contrast to the structure of BNZ itself, which indicates that the cavity isolates the molecules and forbids the pi...pi stacking of the aromatic rings. NMR spectroscopy studies show that in aqueous solution both DBA and BNZ form strong complexes that have 1:1 stoichiometry and structures similar to the solid state ones. The relative packing of the dimers is the same in both complexes. The axes of two adjacent dimers form an angle close to 20 degrees and have a lateral displacement approximately 2.45 A, both of which characterize the screw-channel mode of packing. Although the betaCD/BNZ complex indeed crystallizes in a space group characterizing the latter mode, the betaCD/DBA complex crystallizes in a space group with novel dimensions not resembling any of the packing modes reported so far. The new lattice is attributed to the three conformations exhibited by the guest in the crystals. However, this lattice can be transformed into another, which is isostructural to that of the betaCD/BNZ inclusion complex, if the conformation of the guest is not taken into account.

Honokiol Dimers and Magnolol Derivatives with New Carbon Skeletons from the Roots of Magnolia officinalis and Their Inhibitory Effects on Superoxide Anion Generation and Elastase Release

PubMed Central

Chen, Hung-Chung; Kuo, Ping-Chung; Lee, E-Jian; Lee, Kuo-Hsiung; Wu, Tian-Shung

2013-01-01

Two honokiol dimers, houpulins A and B (1 and 2), and two magnolol derivatives, houpulins C and D (3 and 4), were isolated and characterized from an ethanol extract obtained from the roots of Magnolia officinalis. The chemical structures were determined based on spectroscopic and physicochemical analyses, which included 1D and 2D NMR, as well as mass spectrometry data. These four oligomers possess new carbon skeletons postulated to be biosynthesized from the coupling of three or four C6-C3 subunits. In addition, the new oligomers were evaluated for inhibition of superoxide anion generation and elastase release, and houpulin B (2) was identified as a new anti-inflammatory lead compound. PMID:23667420

Crystal structure of diethyl 2-amino-6-[(thio­phen-3-yl)ethyn­yl]azulene-1,3-di­carboxyl­ate

PubMed Central

Förster, Sebastian; Seichter, Wilhelm; Weber, Edwin

2015-01-01

The title compound, C22H19NO4S, has an almost planar geometry supported by intra­molecular N—H⋯O and C—H⋯O hydrogen bonds. The thio­phene ring is inclined to the azulene ring by 4.85 (16)°, while the eth­oxy­carbonyl groups are inclined to the azulene ring by 7.0 (2) and 5.7 (2)°. In the crystal, mol­ecules are linked by pairs of N—H⋯O hydrogen bonds, forming inversion dimers with an R 2 2(12) ring motif. The dimers are linked via C—H⋯π inter­actions, forming sheets parallel to (10-1). PMID:25844254

Base-stabilized silaimine and its donor-free dimer derived from the reaction of NHC-supported silylene with SiCl4.

PubMed

Cui, Haiyan; Cui, Chunming

2015-12-21

Reaction of the N-heterocyclic carbene (NHC)-stabilized silylene ArN(SiMe3)Si(IiPr)Cl (1, Ar = 2,6-iPr2C6H3, IiPr = 1,3-diisopropyl-4,5-dimethyl-imidazol-2-ylidene) with SiCl4 resulted in the formation of three different products NHC-stabilized dichlorosilaimine ArN=Si(IiPr)Cl2 (2), aminotrichlorosilane ArN(SiMe3)SiCl3 (3) and a silaimine dimer (ArNSiCl2)2 (4) under different conditions. The products can be controlled by reaction conditions. Compound 2 is the first example of a less bulky NHC-supported silaimine via the reaction of a silylene with SiCl4.

5-Methylpyrazine-2-carboxamide

DOE PAGES

Rillema, D. Paul; Senaratne, Nilmini K.; Moore, Curtis; ...

2017-07-28

The title compound, C 6H 7N 3O, is nearly planar, with a dihedral angle of 2.14 (11)° between the pyrazine ring and the mean plane of the carboxamide group [C—C(=O)—N]. In the crystal, molecules are linked via pairs of N—H...O hydrogen bonds forming inversion dimers with an R 2 2 (8) ring motif. These dimers are further linked by a pair of N—H...N hydrogen bonds, enclosing an R 2 2 (10) ring motif, and C—H...O hydrogen bonds, forming ribbons lying parallel to the ab plane. The ribbons are linked by offset π–π interactions [intercentroid distance = 3.759(1)Å], forming two setsmore » of mutually perpendicular slabs parallel to planes (110) and (1-10).« less

High-Order Coupled Cluster Method (CCM) Calculations for Quantum Magnets with Valence-Bond Ground States

NASA Astrophysics Data System (ADS)

Farnell, D. J. J.; Richter, J.; Zinke, R.; Bishop, R. F.

2009-04-01

In this article, we prove that exact representations of dimer and plaquette valence-bond ket ground states for quantum Heisenberg antiferromagnets may be formed via the usual coupled cluster method (CCM) from independent-spin product (e.g. Néel) model states. We show that we are able to provide good results for both the ground-state energy and the sublattice magnetization for dimer and plaquette valence-bond phases within the CCM. As a first example, we investigate the spin-half J 1- J 2 model for the linear chain, and we show that we are able to reproduce exactly the dimerized ground (ket) state at J 2/ J 1=0.5. The dimerized phase is stable over a range of values for J 2/ J 1 around 0.5, and results for the ground-state energies are in good agreement with the results of exact diagonalizations of finite-length chains in this regime. We present evidence of symmetry breaking by considering the ket- and bra-state correlation coefficients as a function of J 2/ J 1. A radical change is also observed in the behavior of the CCM sublattice magnetization as we enter the dimerized phase. We then consider the Shastry-Sutherland model and demonstrate that the CCM can span the correct ground states in both the Néel and the dimerized phases. Once again, very good results for the ground-state energies are obtained. We find CCM critical points of the bra-state equations that are in agreement with the known phase transition point for this model. The results for the sublattice magnetization remain near to the "true" value of zero over much of the dimerized regime, although they diverge exactly at the critical point. Finally, we consider a spin-half system with nearest-neighbor bonds for an underlying lattice corresponding to the magnetic material CaV4O9 (CAVO). We show that we are able to provide excellent results for the ground-state energy in each of the plaquette-ordered, Néel-ordered, and dimerized regimes of this model. The exact plaquette and dimer ground states are reproduced by the CCM ket state in their relevant limits. Furthermore, we estimate the range over which the Néel order is stable, and we find the CCM result is in reasonable agreement with the results obtained by other methods. Our new approach has the dual advantages that it is simple to implement and that existing CCM codes for independent-spin product model states may be used from the outset. Furthermore, it also greatly extends the range of applicability to which the CCM may be applied. We believe that the CCM now provides an excellent choice of method for the study of systems with valence-bond quantum ground states.

Low-Resolution Structure of the Full-Length Barley (Hordeum vulgare) SGT1 Protein in Solution, Obtained Using Small-Angle X-Ray Scattering

PubMed Central

Taube, Michał; Pieńkowska, Joanna R.; Jarmołowski, Artur; Kozak, Maciej

2014-01-01

SGT1 is an evolutionarily conserved eukaryotic protein involved in many important cellular processes. In plants, SGT1 is involved in resistance to disease. In a low ionic strength environment, the SGT1 protein tends to form dimers. The protein consists of three structurally independent domains (the tetratricopeptide repeats domain (TPR), the CHORD- and SGT1-containing domain (CS), and the SGT1-specific domain (SGS)), and two less conserved variable regions (VR1 and VR2). In the present study, we provide the low-resolution structure of the barley (Hordeum vulgare) SGT1 protein in solution and its dimer/monomer equilibrium using small-angle scattering of synchrotron radiation, ab-initio modeling and circular dichroism spectroscopy. The multivariate curve resolution least-square method (MCR-ALS) was applied to separate the scattering data of the monomeric and dimeric species from a complex mixture. The models of the barley SGT1 dimer and monomer were formulated using rigid body modeling with ab-initio structure prediction. Both oligomeric forms of barley SGT1 have elongated shapes with unfolded inter-domain regions. Circular dichroism spectroscopy confirmed that the barley SGT1 protein had a modular architecture, with an α-helical TPR domain, a β-sheet sandwich CS domain, and a disordered SGS domain separated by VR1 and VR2 regions. Using molecular docking and ab-initio protein structure prediction, a model of dimerization of the TPR domains was proposed. PMID:24714665

Potential of mean force analysis of the self-association of leucine-rich transmembrane α-helices: difference between atomistic and coarse-grained simulations.

PubMed

Nishizawa, Manami; Nishizawa, Kazuhisa

2014-08-21

Interaction of transmembrane (TM) proteins is important in many biological processes. Large-scale computational studies using coarse-grained (CG) simulations are becoming popular. However, most CG model parameters have not fully been calibrated with respect to lateral interactions of TM peptide segments. Here, we compare the potential of mean forces (PMFs) of dimerization of TM helices obtained using a MARTINI CG model and an atomistic (AT) Berger lipids-OPLS/AA model (AT(OPLS)). For helical, tryptophan-flanked, leucine-rich peptides (WL15 and WALP15) embedded in a parallel configuration in an octane slab, the AT(OPLS) PMF profiles showed a shallow minimum (with a depth of approximately 3 kJ/mol; i.e., a weak tendency to dimerize). A similar analysis using the CHARMM36 all-atom model (AT(CHARMM)) showed comparable results. In contrast, the CG analysis generally showed steep PMF curves with depths of approximately 16-22 kJ/mol, suggesting a stronger tendency to dimerize compared to the AT model. This CG > AT discrepancy in the propensity for dimerization was also seen for dilauroylphosphatidylcholine (DLPC)-embedded peptides. For a WL15 (and WALP15)/DLPC bilayer system, AT(OPLS) PMF showed a repulsive mean force for a wide range of interhelical distances, in contrast to the attractive forces observed in the octane system. The change from the octane slab to the DLPC bilayer also mitigated the dimerization propensity in the CG system. The dimerization energies of CG (AALALAA)3 peptides in DLPC and dioleoylphosphatidylcholine bilayers were in good agreement with previous experimental data. The lipid headgroup, but not the length of the lipid tails, was a key causative factor contributing to the differences between octane and DLPC. Furthermore, the CG model, but not the AT model, showed high sensitivity to changes in amino acid residues located near the lipid-water interface and hydrophobic mismatch between the peptides and membrane. These findings may help interpret CG and AT simulation results on membrane proteins.

Experimental study of transport of a dimer on a vertically oscillating plate

PubMed Central

Wang, Jiao; Liu, Caishan; Ma, Daolin

2014-01-01

It has recently been shown that a dimer, composed of two identical spheres rigidly connected by a rod, under harmonic vertical vibration can exhibit a self-ordered transport behaviour. In this case, the mass centre of the dimer will perform a circular orbit in the horizontal plane, or a straight line if confined between parallel walls. In order to validate the numerical discoveries, we experimentally investigate the temporal evolution of the dimer's motion in both two- and three-dimensional situations. A stereoscopic vision method with a pair of high-speed cameras is adopted to perform omnidirectional measurements. All the cases studied in our experiments are also simulated using an existing numerical model. The combined investigations detail the dimer's dynamics and clearly show that its transport behaviours originate from a series of combinations of different contact states. This series is critical to our understanding of the transport properties in the dimer's motion and related self-ordered phenomena in granular systems. PMID:25383029

Naproxen Interferes with the Assembly of Aβ Oligomers Implicated in Alzheimer's Disease

PubMed Central

Kim, Seongwon; Chang, Wenling E.; Kumar, Rashmi; Klimov, Dmitri K.

2011-01-01

Experimental and epidemiological studies have shown that the nonsteroidal antiinflammatory drug naproxen may be useful in the treatment of Alzheimer's disease. To investigate the interactions of naproxen with Aβ dimers, which are the smallest cytotoxic aggregated Aβ peptide species, we use united atom implicit solvent model and exhaustive replica exchange molecular dynamics. We show that naproxen ligands bind to Aβ dimer and penetrate its volume interfering with the interpeptide interactions. As a result naproxen induces a destabilizing effect on Aβ dimer. By comparing the free-energy landscapes of naproxen interactions with Aβ dimers and fibrils, we conclude that this ligand has stronger antiaggregation potential against Aβ fibrils rather than against dimers. The analysis of naproxen binding energetics shows that the location of ligand binding sites in Aβ dimer is dictated by the Aβ amino acid sequence. Comparison of the in silico findings with experimental observations reveals potential limitations of naproxen as an effective therapeutic agent in the treatment of Alzheimer's disease. PMID:21504739

Chloroperoxidase-catalyzed oxidation of 4,6-dimethyldibenzothiophene as dimer complexes: evidence for kinetic cooperativity.

PubMed

Torres, Eduardo; Aburto, Jorge

2005-05-15

A sigmoidal kinetic behavior of chloroperoxidase for the oxidation of 4,6-dimethyldibenzothiophene (4,6-DMDBT) in water-miscible organic solvent is for the first time reported. Kinetics of 4,6-DMDBT oxidation showed a cooperative profile probably due to the capacity of chloroperoxidase to recognize a substrate dimer (pi-pi dimer) in its active site. Experimental evidence is given for dimer formation and its presence in the active site of chloroperoxidase. The kinetic data were adjusted for a binding site able to interact with either monomer or dimer substrates, producing a cooperative model describing a one-site binding of two related species. Determination of kinetics constants by iterative calculations of possible oxidation paths of 4,6-DMDBT suggests that kinetics oxidation of dimer substrate is preferred when compared to monomer oxidation. Steady-state fluorometry of substrate in the absence and presence of chloroperoxidase, described by the spectral center of mass, supports this last conclusion.

Specific adhesion model for bonding hot-melt polyamides to vinyl

Treesearch

Charles R. Frihart

2004-01-01

Hot-melt polyamides are an important market for the dimer acid made from the tall oil fatty acids liberated during the Kraft pulping process. These polyamides bond well to many substrates, but not to polyvinyl chloride (PVC), commonly called vinyl. Dimer-based polyamides made from secondary amines such as piperazine bond well to vinyl. No model for this unique adhesion...

Laccase-Catalyzed Synthesis of Low-Molecular-Weight Lignin-Like Oligomers and their Application as UV-Blocking Materials.

PubMed

Lim, Jieyan; Sana, Barindra; Krishnan, Ranganathan; Seayad, Jayasree; Ghadessy, Farid J; Jana, Satyasankar; Ramalingam, Balamurugan

2018-02-02

The laccase-catalyzed oxidative polymerization of monomeric and dimeric lignin model compounds was carried out with oxygen as the oxidant in aqueous medium. The oligomers were characterized by using gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS) analysis. Oxidative polymerization led to the formation of oligomeric species with a number-average molecular weight (M n ) that ranged from 700 to 2300 Da with a low polydispersity index. Spectroscopic analysis provided insight into the possible modes of linkages present in the oligomers, and the oligomerization is likely to proceed through the formation of C-C linkages between phenolic aromatic rings. The oligomers were found to show good UV light absorption characteristics with high molar extinction coefficient (5000-38 000 m -1  cm -1 ) in the UV spectral region. The oligomers were blended independently with polyvinyl chloride (PVC) by using solution blending to evaluate the compatibility and UV protection ability of the oligomers. The UV/Vis transmittance spectra of the oligomer-embedded PVC films indicated that these lignin-like oligomers possessed a notable ability to block UV light. In particular, oligomers obtained from vanillyl alcohol and the dimeric lignin model were found to show good photostability in accelerated UV weathering experiments. The UV-blocking characteristics and photostability were finally compared with the commercial low-molecular-weight UV stabilizer 2,4-dihydroxybenzophenone. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Archean geochemistry of formaldehyde and cyanide and the oligomerization of cyanohydrin

NASA Technical Reports Server (NTRS)

Arrhenius, T.; Arrhenius, G.; Paplawsky, W.

1994-01-01

The sources and speciation of reduced carbon and nitrogen inferred for the early Archean are reviewed in terms of current observations and models, and known chemical reactions. Within this framework hydrogen cyanide and cyanide ion in significant concentration would have been eliminated by reaction with excess formaldehyde to form cyanohydrin (glycolonitrile), and with ferrous ion to formferrocyanide. Natural reactions of these molecules would under such conditions deserve special consideration in modeling of primordial organochemical processes. As a step in this direction, transformation reactions have been investigated involving glycolonitrile in the presence of water. We find that glycolonitrile, formed from formaldehyde and hydrogen cyanide or cyanide ion, spontaneously cyclodimerizes to 4-amino-2-hydroxymethyloxazole. The crystalline dimer is the major product at low temperatue (approximately 0 C); the yield diminishes with increasing temperature at the expense of polymerization and hydrolysis products. Hydrolysis of glycolamide and of oxazole yields a number of simpler organic molecules, including ammonia and glycolamide. The spontaneous polymerization of glycolonitrile and its dimer gives rise to soluble, cationic oligomers of as yet unknown structure, and, unless arrested, to a viscous liquid, insoluble in water. A loss of cyanide by reaction with formaldehyde, inferred for the early terrestrial hydrosphere and cryosphere would present a dilemma for hypotheses invoking cyanide and related compounds as concentrated reactants capable of forming biomolecular precursor species. Attempts to escape from its horns may take advantage of the efficient concentration and separation of cyanide as solid ferriferrocyanide, and most directly of reactions of glycolonitrile and its derivatives.

Chloroplast Preproteins Bind to the Dimer Interface of the Toc159 Receptor during Import1[OPEN

PubMed Central

Chen, Lih-Jen; Yeh, Yi-Hung; Hsiao, Chwan-Deng

2017-01-01

Most chloroplast proteins are synthesized in the cytosol as higher molecular weight preproteins and imported via the translocons in the outer (TOC) and inner (TIC) envelope membranes of chloroplasts. Toc159 functions as a primary receptor and directly binds preproteins through its dimeric GTPase domain. As a first step toward a molecular understanding of how Toc159 mediates preprotein import, we mapped the preprotein-binding regions on the Toc159 GTPase domain (Toc159G) of pea (Pisum sativum) using cleavage by bound preproteins conjugated with the artificial protease FeBABE and cysteine-cysteine cross-linking. Our results show that residues at the dimer interface and the switch II region of Toc159G are in close proximity to preproteins. The mature portion of preproteins was observed preferentially at the dimer interface, whereas the transit peptide was found at both regions equally. Chloroplasts from transgenic plants expressing engineered Toc159 with a cysteine placed at the dimer interface showed increased cross-linking to bound preproteins. Our data suggest that, during preprotein import, the Toc159G dimer disengages and the dimer interface contacts translocating preproteins, which is consistent with a model in which conformational changes induced by dimer-monomer conversion in Toc159 play a direct role in facilitating preprotein import. PMID:28250068

Magnetic Properties of Porous Metal-Organic Frameworks: Ni2(BODC)2(TED) and Ni2(BDC)2(TED)

NASA Astrophysics Data System (ADS)

Hamida, Youcef; Danilovic, Dusan; Lin, Chyan; Yuen, Tan; Li, Kunhao; Padmanabhan, Moothetty; Li, Jing

2010-03-01

Results of χ(T), M(H), and heat capacity C(T) measurements on two Ni dimer based porous materials Ni2(BODC)2(TED) and Ni2(BDC)2(TED) are reported. These materials form a tetragonal crystal structure of space group P4/ncc with a=b = 14.9 å and c = 19.4 å and Ni-Ni separation of 2.61å within the dimer. Magnetic data of Ni2(BODC)2(TED) revealed a ferromagnetic-like transition at about 17 K with θ = 8 K, and a coercivity field of 1700 G was observed in the hysteresis curve. Though isostructural to Ni2(BODC)2(TED), χ(T) and M(H) results of Ni2(BDC)2(TED) showed an antiferromagnetic transition at 10 K with θ = - 132 K, and no hysteresis was observed. Although specific heat data C(T) showed no clear transition in both compounds, nonlinear behavior is clearly seen in C/T vs. T plots, and a fit to the electron and phonon contributions to C(T) gives a large heavy-fermion-like γ in both cases. A model for the magnetic interactions is proposed and a comparison to the Cu and Co analogues is also made.

Coordination-Driven Dimerization of Zinc Chlorophyll Derivatives Possessing a Dialkylamino Group.

PubMed

Watanabe, Hiroaki; Kamatani, Yusuke; Tamiaki, Hitoshi

2017-04-04

Zinc chlorophyll derivatives Zn-1-3 possessing a tertiary amino group at the C3 1 position have been synthesized through reductive amination of methyl pyropheophorbide-d obtained from naturally occurring chlorophyll-a. In a dilute CH 2 Cl 2 solution as well as in a dilute 10 %(v/v) CH 2 Cl 2 /hexane solution, Zn-1 possessing a dimethylamino group at the C3 1 position showed red-shifted UV/Vis absorption and intensified exciton-coupling circular dichroism (CD) spectra at room temperature owing to its dimer formation via coordination to the central zinc by the 3 1 -N atom of the dimethylamino group. However, Zn-2/3 bearing 3 1 -ethylmethylamino/diethylamino groups did not. The difference was dependent on the steric factor of the substituents in the tertiary amino group, where an increase of the carbon numbers on the N atom reduced the intermolecular N⋅⋅⋅Zn coordination. UV/Vis, CD, and 1 H NMR spectroscopic analyses including DOSY measurements revealed that Zn-1 formed closed-type dimers via an opened dimer by single-to-double axial coordination with an increase in concentration and a temperature decrease in CH 2 Cl 2 , while Zn-2/3 gave open and flexible dimers in a concentrated CH 2 Cl 2 solution at low temperature. The supramolecular closed dimer structures of Zn-1 were estimated by molecular modelling calculations, which showed these structures were promising models for the chlorophyll dimer in a photosynthetic reaction center. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neurodevelopmental Expression Profile of Dimeric and Monomeric Group 1 mGluRs: Relevance to Schizophrenia Pathogenesis and Treatment.

PubMed

Lum, Jeremy S; Fernandez, Francesca; Matosin, Natalie; Andrews, Jessica L; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A

2016-10-10

Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippocampus throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia. Under control conditions, mGluR1α dimer expression increased between juvenile and adolescence (209-328%), while monomeric levels remained consistent. Dimeric mGluR5 was steadily expressed across all time points; monomeric mGluR5 was present in juveniles, dramatically declining at adolescence and adulthood (-97-99%). The mGluR regulators, Homer 1b/c and Norbin, significantly increased with age in the PFC and hippocampus. Perinatal PCP treatment significantly increased juvenile dimeric mGluR5 levels in the PFC and hippocampus (37-50%) but decreased hippocampal mGluR1α (-50-56%). Perinatal PCP treatment also reduced mGluR1α dimer levels in the PFC at adulthood (-31%). These results suggest that Group 1 mGluRs have distinct dimeric and monomeric neurodevelopmental patterns, which may impact their pharmacological profiles at specific ages. Perinatal PCP treatment disrupted the early expression of Group 1 mGluRs which may underlie neurodevelopmental alterations observed in this model.

Serendipitous preparation of fac-(aceto-nitrile-κN)tri-chlorido-[(1,2,5,6-η)-cyclo-octa-1,5-diene]iridium(III).

PubMed

Morris, David M; Merola, Joseph S

2015-04-01

A reaction between [(COD)IrCl]2 (COD is cyclo-octa-1,5-diene), HCl and indene failed to provide the hoped for chlorido-indenyliridium dimer, but instead produced the title compound, [IrCl3(CH3CN)(C8H12)], which is an octa-hedral complex of iridium(III) with a chelating cyclo-octa-1,5-diene ligand, three chloride ligands in a fac arrangement, and one aceto-nitrile ligand. Attempts to devise a rational synthesis for the title compound were unsuccessful.

Electron transfer beyond the static picture: A TDDFT/TD-ZINDO study of a pentacene dimer

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

Reslan, Randa; Lopata, Kenneth A.; Arntsen, Christopher D.

2012-12-14

We use time-dependent density functional theory and time-dependent ZINDO (a semi-empirical method) to study transfer of an extra electron between a pair of pentacene dimers. A measure of the electronic transfer integral is computed in a dynamic picture via the vertical excitation energy from a delocalized anionic ground state. With increasing dimer separation, this dynamical measurement of charge transfer is shown to be significantly larger than the commonly used static approximation (i.e., LUMO+1 - LUMO of the neutral dimer, or HOMO - LUMO of the charged dimer), up to an order of magnitude higher at 6 Å. These results offermore » a word of caution for calculations involving large separations, as in organic photovoltaics, where care must be taken when using a static picture to model charge transfer.« less

Functional Validation of Heteromeric Kainate Receptor Models.

PubMed

Paramo, Teresa; Brown, Patricia M G E; Musgaard, Maria; Bowie, Derek; Biggin, Philip C

2017-11-21

Kainate receptors require the presence of external ions for gating. Most work thus far has been performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers. Agonists bind to the ligand-binding domain (LBD) which is arranged as a dimer of dimers as exemplified in homomeric structures, but no high-resolution structure currently exists of heteromeric kainate receptors. In a full-length heterotetramer, the LBDs could potentially be arranged either as a GluK2 homomer alongside a GluK5 homomer or as two GluK2/K5 heterodimers. We have constructed models of the LBD dimers based on the GluK2 LBD crystal structures and investigated their stability with molecular dynamics simulations. We have then used the models to make predictions about the functional behavior of the full-length GluK2/K5 receptor, which we confirmed via electrophysiological recordings. A key prediction and observation is that lithium ions bind to the dimer interface of GluK2/K5 heteromers and slow their desensitization. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Rough energy landscapes in protein folding: dimeric E. coli Trp repressor folds through three parallel channels.

PubMed

Gloss, L M; Simler, B R; Matthews, C R

2001-10-05

The folding mechanism of the dimeric Escherichia coli Trp repressor (TR) is a kinetically complex process that involves three distinguishable stages of development. Following the formation of a partially folded, monomeric ensemble of species, within 5 ms, folding to the native dimer is controlled by three kinetic phases. The rate-limiting step in each phase is either a non-proline isomerization reaction or a dimerization reaction, depending on the final denaturant concentration. Two approaches have been employed to test the previously proposed folding mechanism of TR through three parallel channels: (1) unfolding double-jump experiments demonstrate that all three folding channels lead directly to native dimer; and (2) the differential stabilization of the transition state for the final step in folding and the native dimer, by the addition of salt, shows that all three channels involve isomerization of a dimeric species. A refined model for the folding of Trp repressor is presented, in which all three channels involve a rapid dimerization reaction between partially folded monomers followed by the isomerization of the dimeric intermediates to yield native dimer. The ensemble of partially folded monomers can be captured at equilibrium by low pH; one-dimensional proton NMR spectra at pH 2.5 demonstrate that monomers exist in two distinct, slowly interconverting conformations. These data provide a potential structural explanation for the three-channel folding mechanism of TR: random association of two different monomeric forms, which are distinguished by alternative packing modes of the core dimerization domain and the DNA-binding, helix-turn-helix, domain. One, perhaps both, of these packing modes contains non-native contacts. Copyright 2001 Academic Press.

5-Bromo-2-methyl­pyridine N-oxide

PubMed Central

Liu, Bo-Nian; Tang, Shi-Gui; Li, Hao-Yuan; Xu, Ye-Ming; Guo, Cheng

2008-01-01

In the mol­ecule of the title compound, C6H6BrNO, the methyl C and oxide O atoms lie in the pyridine ring plane, while the Br atom is displaced by 0.103 (3) Å. In the crystal structure, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into centrosymmetric dimers. PMID:21202579

(E)-N'-[1-(Thio-phen-2-yl)ethyl-idene]isonicotinohydrazide.

PubMed

Dileep, C S; Abdoh, M M M; Chakravarthy, M P; Mohana, K N; Sridhar, M A

2012-10-01

In the title compound, C(12)H(11)N(3)OS, the dihedral angle between the pyridine and thio-phene rings is 46.70 (9)° and the C-N-N-C torsion angle is 178.61 (15)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops.

Kinetics of acid-catalyzed cleavage of procyanindins

Treesearch

Richard W. Hemingway; Gerald W. McGraw

1983-01-01

Comparison of the rates of cleavage of isomeric procyanidin dimers in the presence of excess phenylmethane thiol and acetic acid showed that compounds with a C(4)-C(8) interflavanoid bond were cleaved more rapidly than their C(4)-C(6) linked isomers, that 2,3-cis isomers with an axial flavan substituent were cleaved more-rapidly than a 2,3-...

rac-4-(2-Meth-oxy-phen-yl)-2,6-dimethyl-cyclo-hex-3-ene-carb-oxy-lic acid.

PubMed

Xie, Songwen; Fowler, Brian P; Deyo, Sara M; Pink, Maren

2010-05-29

The title compound, C(16)H(20)O(3), was synthesized to study the hydrogen-bonding inter-actions of the two enanti-omers in the solid state. Inter-molecular O-H⋯O hydrogen bonds produce centrosymmetric R(2) (2)(8) rings which dimerize the two chiral enanti-omers together through their carboxyl groups.

Crystal structure of tri­hydrogen bis­{[1,1,1-tris­(2-oxido­ethyl­amino­meth­yl)ethane]­cobalt(III)} trinitrate

PubMed Central

Sethi, Waqas; Johannesen, Heini V.; Morsing, Thorbjørn J.; Piligkos, Stergios; Weihe, Høgni

2015-01-01

The title compound, [Co2(L)2]3+·3NO3 − [where L = CH3C(CH2NHCH2CH2OH1/2)3], has been synthesized from the ligand 1,1,1-tris­(2-hy­droxy­ethyl­amino­meth­yl)ethane. The cobalt(III) dimer has an inter­esting and uncommon O—H⋯O hydrogen-bonding motif with the three bridging hy­droxy H atoms each being equally disordered over two positions. In the dimeric trication, the octa­hedrally coordinated CoIII atoms and the capping C atoms lie on a threefold rotation axis. The N atoms of two crystallographically independent nitrate anions also lie on threefold rotation axes. N—H⋯O hydrogen bonding between the complex cations and nitrate anions leads to the formation of a three-dimensional network structure. The compound is a racemic conglomerate of crystals containing either d or l mol­ecules. The crystal used for this study is a d crystal. PMID:26870462

New flavan-3-ol dimer from green tea produced from Camellia taliensis in the Ai-Lao mountains of Southwest China.

PubMed

Zhu, Li-Fang; Xu, Min; Zhu, Hong-Tao; Wang, Dong; Yang, Shi-Xiong; Yang, Chong-Ren; Zhang, Ying-Jun

2012-12-12

Camellia taliensis (W. W. Smith) Melchior, belonging to the genus Camellia sect. Thea (Theaceae), is an endemic species distributed from the west and southwest of Yunnan province, China, to the north of Myanmar. Known as a wild tea tree, its leaves have been used commonly for producing tea beverages by the local people of its growing area. One new flavan-3-ol dimer, talienbisflavan A (1), was isolated from green tea prepared from the leaves of C. taliensis collected from the east side of the Ai-Lao mountains, Yuanjiang county of Yunnan province, China. In addition, five hydrolyzable tannins (2-6), five flavonols and flavonol glycosides (9-13), three flavan-3-ols (14-16), nine simple phenolic compounds and glycosides (7, 8, and 17-23), and caffeine (24) were identified. Their structures were determined by detailed spectroscopic analysis. All of the isolated phenolic compounds were tested for their antioxidant activities by DPPH and ABTS(+) radical scavenging assays. The contents of its main chemical compositions were also compared with those collected from the Lincang area of Yunnan province by high-performance liquid chromatography analysis.

Two New Stilbenoids from the Aerial Parts of Arundina graminifolia (Orchidaceae).

PubMed

Auberon, Florence; Olatunji, Opeyemi Joshua; Krisa, Stéphanie; Antheaume, Cyril; Herbette, Gaëtan; Bonté, Frédéric; Mérillon, Jean-Michel; Lobstein, Annelise

2016-10-27

Two new phenanthrene derivatives, a phenanthrenequinone named arundiquinone ( 1 ) and a 9,10-dihydrophenanthrene named arundigramin ( 2 ) together with a known lignin dimer ( 3 ) and seven known stilbenoids ( 4 - 10 ) were isolated from the aerial parts of the Asian orchid Arundina graminifolia . The structures of the isolated compounds were elucidated by spectroscopic methods, including extensive 1D, 2D NMR (heteronuclear single quantum coherence (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC), and HR-ESI-MS techniques, as well as comparison with respective literature reports. The cytoprotective activity of the isolated compounds were evaluated for their ability to reduce beta amyloid induced toxicity on undifferentiated PC12 cells. Compound 8 showed moderate cytoprotective activity at 0.5 µmol/L (71% of cell viability) while the other compounds showed no significant activity at the highest concentration tested.

Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity

PubMed Central

Fodor, James; Riley, Blake; Godlewska, Marlena; Góra, Monika; Czarnocka, Barbara; Banga, J Paul; Hoke, David E.; Kass, Itamar; Buckle, Ashley M.

2015-01-01

Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto’s disease—the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The “trans” model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the “cis” model favours it slightly over the “trans” model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data. PMID:26623656

Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity.

PubMed

Le, Sarah N; Porebski, Benjamin T; McCoey, Julia; Fodor, James; Riley, Blake; Godlewska, Marlena; Góra, Monika; Czarnocka, Barbara; Banga, J Paul; Hoke, David E; Kass, Itamar; Buckle, Ashley M

2015-01-01

Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.

Chemical constituents of the leaf of Alpinia mutica Roxb.

PubMed

Sirat, Hasnah Mohd; Jani, Nor Akmalazura

2013-01-01

Hydrodistillation of the fresh leaves of Alpinia mutica afforded 0.005% colourless essential oil. GC and GC-MS analysis revealed the presence of 33 components accounting for 92.9% of the total oil, dominated by 20 sesquiterpenes (76.7%) and 10 monoterpenes (8.3%). The major constituent was found to be β-sesquiphellandrene which was 29.2% of the total oil. Soxhlet extraction, followed by repeated column chromatography of the dried leaves yielded two phenolic compounds, identified as 5,6-dehydrokawain and aniba dimer A, together with one amide assigned as auranamide. The structures of these compounds were determined by using spectroscopic analysis. Antibacterial screening of the essential oil, the crude and isolated compounds showed weak to moderate inhibitory activity.

Dimers in Piecewise Temperleyan Domains

NASA Astrophysics Data System (ADS)

Russkikh, Marianna

2018-03-01

We study the large-scale behavior of the height function in the dimer model on the square lattice. Richard Kenyon has shown that the fluctuations of the height function on Temperleyan discretizations of a planar domain converge in the scaling limit (as the mesh size tends to zero) to the Gaussian Free Field with Dirichlet boundary conditions. We extend Kenyon's result to a more general class of discretizations. Moreover, we introduce a new factorization of the coupling function of the double-dimer model into two discrete holomorphic functions, which are similar to discrete fermions defined in Smirnov (Proceedings of the international congress of mathematicians (ICM), Madrid, Spain, 2006; Ann Math (2) 172:1435-1467, 2010). For Temperleyan discretizations with appropriate boundary modifications, the results of Kenyon imply that the expectation of the double-dimer height function converges to a harmonic function in the scaling limit. We use the above factorization to extend this result to the class of all polygonal discretizations, that are not necessarily Temperleyan. Furthermore, we show that, quite surprisingly, the expectation of the double-dimer height function in the Temperleyan case is exactly discrete harmonic (for an appropriate choice of Laplacian) even before taking the scaling limit.

Hydrodynamic Torques and Rotations of Superparamagnetic Bead Dimers

NASA Astrophysics Data System (ADS)

Pease, Christopher; Etheridge, J.; Wijesinghe, H. S.; Pierce, C. J.; Prikockis, M. V.; Sooryakumar, R.

Chains of micro-magnetic particles are often rotated with external magnetic fields for many lab-on-a-chip technologies such as transporting beads or mixing fluids. These applications benefit from faster responses of the actuated particles. In a rotating magnetic field, the magnetization of superparamagnetic beads, created from embedded magnetic nano-particles within a polymer matrix, is largely characterized by induced dipoles mip along the direction of the field. In addition there is often a weak dipole mop that orients out-of-phase with the external rotating field. On a two-bead dimer, the simplest chain of beads, mop contributes a torque Γm in addition to the torque from mip. For dimers with beads unbound to each other, mop rotates individual beads which generate an additional hydrodynamic torque on the dimer. Whereas, mop directly torques bound dimers. Our results show that Γm significantly alters the average frequency-dependent dimer rotation rate for both bound and unbound monomers and, when mop exceeds a critical value, increases the maximum dimer rotation frequency. Models that include magnetic and hydrodynamics torques provide good agreement with the experimental findings over a range of field frequencies.

Lifetime of Feshbach dimers in a Fermi-Fermi mixture of 6Li and 40K

NASA Astrophysics Data System (ADS)

Jag, M.; Cetina, M.; Lous, R. S.; Grimm, R.; Levinsen, J.; Petrov, D. S.

2016-12-01

We present a joint experimental and theoretical investigation of the lifetime of weakly bound dimers formed near narrow interspecies Feshbach resonances in mass-imbalanced Fermi-Fermi systems, considering the specific example of a mixture of 6Li and 40K atoms. Our work addresses the central question of the increase in the stability of the dimers resulting from Pauli suppression of collisional losses, which is a well-known effect in mass-balanced fermionic systems near broad resonances. We present measurements of the spontaneous dissociation of dimers in dilute samples, and of the collisional losses in dense samples arising from both dimer-dimer processes and from atom-dimer processes. We find that all loss processes are suppressed close to the Feshbach resonance. Our general theoretical approach for fermionic mixtures near narrow Feshbach resonances provides predictions for the suppression of collisional decay as a function of the detuning from resonance, and we find excellent agreement with the experimental benchmarks provided by our 40K-6Li system. We finally present model calculations for other Feshbach-resonant Fermi-Fermi systems, which are of interest for experiments in the near future.

Magnetic and superconducting competition within the Hubbard dimer. Exact solution

NASA Astrophysics Data System (ADS)

Matlak, M.; Somska, T.; Grabiec, B.

2005-02-01

We express the Hubbard dimer Hamiltonian in the second quantization with theuse of the Hubbard and spin operators. We consider the case of positive and negative U. We decompose the resulting Hamiltonian into several parts collecting all the terms belonging to the same energy level. Such a decomposition visualizes explicitely all intrinsic interactions competing together and deeply hidden in the original form of the dimer Hamiltonian. Among them are competitive ferromagnetic and antiferromagnetic interactions. There are also hopping terms present which describe Cooper pairs hopping between sites 1 and 2 with positive and negative coupling constants (similar as in Kulik-Pedan, Penson-Kolb models). We show that the competition between intrinsic interactions strongly depends on the model parametrs and the averaged occupation number of electrons n [0, 4] resulting in different regimes of the model (as e.g. t-J model regime, etc.).

A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation.

PubMed

Voziyan, Paul A; Metz, Thomas O; Baynes, John W; Hudson, Billy G

2002-02-01

Reactive carbonyl compounds are formed during autoxidation of carbohydrates and peroxidation of lipids. These compounds are intermediates in the formation of advanced glycation end products (AGE) and advanced lipoxidation end products (ALE) in tissue proteins during aging and in chronic disease. We studied the reaction of carbonyl compounds glyoxal (GO) and glycolaldehyde (GLA) with pyridoxamine (PM), a potent post-Amadori inhibitor of AGE formation in vitro and of development of renal and retinal pathology in diabetic animals. PM reacted rapidly with GO and GLA in neutral, aqueous buffer, forming a Schiff base intermediate that cyclized to a hemiaminal adduct by intramolecular reaction with the phenolic hydroxyl group of PM. This bicyclic intermediate dimerized to form a five-ring compound with a central piperazine ring, which was characterized by electrospray ionization-liquid chromatography/mass spectrometry, NMR, and x-ray crystallography. PM also inhibited the modification of lysine residues and loss of enzymatic activity of RNase in the presence of GO and GLA and inhibited formation of the AGE/ALE N(epsilon)-(carboxymethyl)lysine during reaction of GO and GLA with bovine serum albumin. Our data suggest that the AGE/ALE inhibitory activity and the therapeutic effects of PM observed in diabetic animal models depend, at least in part, on its ability to trap reactive carbonyl intermediates in AGE/ALE formation, thereby inhibiting the chemical modification of tissue proteins.

Production of Entanglement Entropy by Decoherence

NASA Astrophysics Data System (ADS)

Merkli, M.; Berman, G. P.; Sayre, R. T.; Wang, X.; Nesterov, A. I.

We examine the dynamics of entanglement entropy of all parts in an open system consisting of a two-level dimer interacting with an environment of oscillators. The dimer-environment interaction is almost energy conserving. We find the precise link between decoherence and production of entanglement entropy. We show that not all environment oscillators carry significant entanglement entropy and we identify the oscillator frequency regions which contribute to the production of entanglement entropy. For energy conserving dimer-environment interactions the models are explicitly solvable and our results hold for all dimer-environment coupling strengths. We carry out a mathematically rigorous perturbation theory around the energy conserving situation in the presence of small non-energy conserving interactions.

Magnetic susceptibility of alkali-tetracyanoquinodimethane salts and extended Hubbard models with bond order and charge density wave phases

NASA Astrophysics Data System (ADS)

Kumar, Manoranjan; Topham, Benjamin J.; Yu, RuiHui; Ha, Quoc Binh Dang; Soos, Zoltán G.

2011-06-01

The molar spin susceptibilities χ(T) of Na-tetracyanoquinodimethane (TCNQ), K-TCNQ, and Rb-TCNQ(II) are fit quantitatively to 450 K in terms of half-filled bands of three one-dimensional Hubbard models with extended interactions using exact results for finite systems. All three models have bond order wave (BOW) and charge density wave (CDW) phases with boundary V = Vc(U) for nearest-neighbor interaction V and on-site repulsion U. At high T, all three salts have regular stacks of TCNQ^- anion radicals. The χ(T) fits place Na and K in the CDW phase and Rb(II) in the BOW phase with V ≈ Vc. The Na and K salts have dimerized stacks at T < Td while Rb(II) has regular stacks at 100 K. The χ(T) analysis extends to dimerized stacks and to dimerization fluctuations in Rb(II). The three models yield consistent values of U, V, and transfer integrals t for closely related TCNQ^- stacks. Model parameters based on χ(T) are smaller than those from optical data that in turn are considerably reduced by electronic polarization from quantum chemical calculation of U, V, and t of adjacent TCNQ^- ions. The χ(T) analysis shows that fully relaxed states have reduced model parameters compared to optical or vibration spectra of dimerized or regular TCNQ^- stacks.

Model calculations of the interaction of two parallel antiaromatic 4n π-electron systems

PubMed Central

Böhm, Michael C.; Bickert, Peter; Hafner, Klaus; Boekelheide, V.

1984-01-01

The nature of the interaction between decks of a pentalene dimer and an s-indacene dimer has been studied by semi-empirical MNDO/1 and MINDO/3 calculations for distances between decks of from 5 Å to 2 Å. In contradiction to qualitative predictions from a frontier orbital analysis, it is found that the 4n-4n π-electron interaction between decks for such dimers is destabilizing for distances exceeding about 2.5 Å. PMID:16593458

A Monte Carlo simulation study of associated liquid crystals

NASA Astrophysics Data System (ADS)

Berardi, R.; Fehervari, M.; Zannoni, C.

We have performed a Monte Carlo simulation study of a system of ellipsoidal particles with donor-acceptor sites modelling complementary hydrogen-bonding groups in real molecules. We have considered elongated Gay-Berne particles with terminal interaction sites allowing particles to associate and form dimers. The changes in the phase transitions and in the molecular organization and the interplay between orientational ordering and dimer formation are discussed. Particle flip and dimer moves have been used to increase the convergency rate of the Monte Carlo (MC) Markov chain.

Effects of the dimeric PSD-95 inhibitor UCCB01-144 in mouse models of pain, cognition and motor function.

PubMed

Andreasen, Jesper T; Nasser, Arafat; Caballero-Puntiverio, Maitane; Sahlholt, Maj; Bach, Anders; Gynther, Mikko; Strømgaard, Kristian; Pickering, Darryl S

2016-06-05

NMDAR antagonism shows analgesic action in humans and animal pain models, but disrupts cognitive and motor functions. NMDAR-dependent NO production requires tethering of the NMDAR to neuronal NO synthase (nNOS) by the postsynaptic density protein-95 (PSD-95). Perturbing the NMDAR/PSD-95/nNOS interaction has therefore been proposed as an alternative analgesic mechanism. We recently reported that UCCB01-125, a dimeric PSD-95 inhibitor with limited blood-brain-barrier permeability, reduced mechanical hypersensitivity in the complete Freund's adjuvant (CFA) inflammatory pain model, without disrupting cognitive or motor functions. Here, we investigated the analgesic efficacy in the CFA model of UCCB01-144, a PSD-95 inhibitor with improved blood-brain-barrier permeability. To extend the comparison of UCCB01-125 and UCCB01-144, we also tested both compounds in the spared nerve injury (SNI) model of neuropathic pain. Potential cognitive effects of UCCB01-144 were examined using the social transmission of food preference (STFP) test and the V-maze test, and motor coordination was assessed with the rotarod test. UCCB01-144 (10mg/kg) reversed CFA-induced mechanical hypersensitivity after 1h, and completely normalised sensitivity after 24h. In the SNI model, UCCB01-144 (30mg/kg) partially reversed hypersensitivity after 1h, but no effect was observed after 24h. UCCB01-125 did not affect SNI-induced hypersensitivity. Rotarod performance was unaffected by UCCB01-144, but 30mg/kg UCCB01-144 impaired performance in the STFP test. Collectively, UCCB01-144 reversed both CFA and SNI-induced hypersensitivity, but the efficacy in the SNI model was only transient. This suggests that enhanced BBB permeability of PSD-95 inhibitors improves the analgesic action in neuropathic pain states. Copyright © 2016 Elsevier B.V. All rights reserved.

Van der Waals potential and vibrational energy levels of the ground state radon dimer

NASA Astrophysics Data System (ADS)

Sheng, Xiaowei; Qian, Shifeng; Hu, Fengfei

2017-08-01

In the present paper, the ground state van der Waals potential of the Radon dimer is described by the Tang-Toennies potential model, which requires five essential parameters. Among them, the two dispersion coefficients C6 and C8 are estimated from the well determined dispersion coefficients C6 and C8 of Xe2. C10 is estimated by using the approximation equation that C6C10/C82 has an average value of 1.221 for all the rare gas dimers. With these estimated dispersion coefficients and the well determined well depth De and Re the Born-Mayer parameters A and b are derived. Then the vibrational energy levels of the ground state radon dimer are calculated. 40 vibrational energy levels are observed in the ground state of Rn2 dimer. The last vibrational energy level is bound by only 0.0012 cm-1.

Theoretical Study of Indium Compounds of Interest for Organometallic Chemical Vapor Deposition

NASA Technical Reports Server (NTRS)

Cardelino, B. H.; Moore, C. E.; Cardelino, C. A.; Frazier, D. O.; Backmann, K. J.

2000-01-01

The structural. electronic and therinochemical properties of indium compounds which are of interest in halide transport and organometallic chemical vapor deposition processes have been studied by ab initio and statistical mechanics methods. The compounds reported include: indium halides and hydrides (InF, InCl, InCl3, InH, InH2, InH3); indium clusters (In2, In3); methylindium, dimethylindium, and their hydrogen derivatives [In(CH3), In(CH3)H, In(CH3)H2, In(CH3)2, In(CH3)2H]; dimethyl-indium dimer [In2(CH3)4], trimethyl-indium [In(CH3)3]; dehydrogenated methyl, dimethyl and trimethylindium [In(CH3)2CH2, In(CH3)CH2, In(CH2)], trimethylindium adducts with ammonia, trimethylamine and hydrazine [(CH3)3In:NH3, (CH3)3In:N(CH3)3, (CH3)3In:N(H2)N(H2)]; dimethylamino-indium and methylimino-indium [In(CH3)2(NH2), In(CH3)(NH)]; indium nitride and indium nitride dimer (InN, In2N2), indium phosphide, arsenide and antimonide ([InP, InAs, InSb). The predicted electronic properties are based on density functional theory calculations; the calculated thermodynamic properties are reported following the format of the JANAF (Joint Army, Navy, NASA, Air Force) Tables. Equilibrium compositions at two temperatures (298 and 1000 K) have been analyzed for groups of competing simultaneous reactions.

Magnetic properties of a metal-organic porous network [Ni2(BODC)2(TED)

NASA Astrophysics Data System (ADS)

Yuen, Tan; Danilovic, D.; Li, Kunhao; Li, Jing

2008-04-01

A new material [Ni2(BODC)2(TED)], (BODC =4,4'-bicyclo[2.2.2]octane dicarboxylate and TED =triethylene-4,4'-diamine), which is a guest-free, porous metal-organic coordination network, has been successfully synthesized. The crystal structure of this compound is tetragonal with the space group P4/mmm. It is a three-dimensional network that can be deconstructed into rectangular gridlike layers along ab planes. These planes are formed by BODC and Zn2O4 paddle-wheel-like clusters, and the TED ligands from the axial directions of the paddle-wheels connect the layers into a three-dimesional structure. There are no guest molecules found in the pores. The shortest Ni-Ni distance within the paddle wheel is found to be 2.613Å. Magnetic susceptibility χ(T )=M(T)/H and isothermal magnetization M(H ) measurements have been measured on powder samples of this compound. The results of χ(T ) show that there is a rapid increase in the susceptibility below 20K due to a spontaneous ordering of the Ni2+ moments. The effective moment μeff of Ni2+ is about 2.20μB at room temperature. The M(H ) result at 1.8K shows a clear hysteresis with a coercivity of Hcoe≈1700G. The behavior of this compound is discussed in terms of Ni-Ni coupling within the Ni dimers and dimer chains.

Dynamics of the Glycophorin A Dimer in Membranes of Native-Like Composition Uncovered by Coarse-Grained Molecular Dynamics Simulations

PubMed Central

Flinner, Nadine; Schleiff, Enrico

2015-01-01

Membranes are central for cells as borders to the environment or intracellular organelle definition. They are composed of and harbor different molecules like various lipid species and sterols, and they are generally crowded with proteins. The membrane system is very dynamic and components show lateral, rotational and translational diffusion. The consequence of the latter is that phase separation can occur in membranes in vivo and in vitro. It was documented that molecular dynamics simulations of an idealized plasma membrane model result in formation of membrane areas where either saturated lipids and cholesterol (liquid-ordered character, Lo) or unsaturated lipids (liquid-disordered character, Ld) were enriched. Furthermore, current discussions favor the idea that proteins are sorted into the liquid-disordered phase of model membranes, but experimental support for the behavior of isolated proteins in native membranes is sparse. To gain insight into the protein behavior we built a model of the red blood cell membrane with integrated glycophorin A dimer. The sorting and the dynamics of the dimer were subsequently explored by coarse-grained molecular dynamics simulations. In addition, we inspected the impact of lipid head groups and the presence of cholesterol within the membrane on the dynamics of the dimer within the membrane. We observed that cholesterol is important for the formation of membrane areas with Lo and Ld character. Moreover, it is an important factor for the reproduction of the dynamic behavior of the protein found in its native environment. The protein dimer was exclusively sorted into the domain of Ld character in the model red blood cell plasma membrane. Therefore, we present structural information on the glycophorin A dimer distribution in the plasma membrane in the absence of other factors like e.g. lipid anchors in a coarse grain resolution. PMID:26222139

Self-assembly Controls Self-cleavage of HHR from ASBVd (-): a Combined SANS and Modeling Study

NASA Astrophysics Data System (ADS)

Leclerc, Fabrice; Zaccai, Giuseppe; Vergne, Jacques; Řìhovà, Martina; Martel, Anne; Maurel, Marie-Christine

2016-07-01

In the Avocado Sunblotch Viroid (ASBVd: 249-nt) from the Avsunviroidae family, a symmetric rolling-circle replication operates through an autocatalytic mechanism mediated by hammerhead ribozymes (HHR) embedded in both polarity strands. The concatenated multimeric ASBVd (+) and ASBVd (-) RNAs thus generated are processed by cleavage to unit-length where ASBVd (-) self-cleaves with more efficiency. Absolute scale small angle neutron scattering (SANS) revealed a temperature-dependent dimer association in both ASBVd (-) and its derived 79-nt HHR (-). A joint thermodynamic analysis of SANS and catalytic data indicates the rate-determining step corresponds to the dimer/monomer transition. 2D and 3D models of monomeric and dimeric HHR (-) suggest that the inter-molecular contacts stabilizing the dimer (between HI and HII domains) compete with the intra-molecular ones stabilizing the active conformation of the full-length HHR required for an efficient self-cleavage. Similar competing intra- and inter-molecular contacts are proposed in ASBVd (-) though with a remoter region from an extension of the HI domain.

Influence of the C-terminus of the glycophorin A transmembrane fragment on the dimerization process.

PubMed Central

Orzáez, M.; Pérez-Payá, E.; Mingarro, I.

2000-01-01

The monomer-dimer equilibrium of the glycophorin A (GpA) transmembrane (TM) fragment has been used as a model system to investigate the amino acid sequence requirements that permit an appropriate helix-helix packing in a membrane-mimetic environment. In particular, we have focused on a region of the helix where no crucial residues for packing have been yet reported. Various deletion and replacement mutants in the C-terminal region of the TM fragment showed that the distance between the dimerization motif and the flanking charged residues from the cytoplasmic side of the protein is important for helix packing. Furthermore, selected GpA mutants have been used to illustrate the rearrangement of TM fragments that takes place when leucine repeats are introduced in such protein segments. We also show that secondary structure of GpA derivatives was independent from dimerization, in agreement with the two-stage model for membrane protein folding and oligomerization. PMID:10892817

Classical dimer model with anisotropic interactions on the square lattice

NASA Astrophysics Data System (ADS)

Otsuka, Hiromi

2009-07-01

We discuss phase transitions and the phase diagram of a classical dimer model with anisotropic interactions defined on a square lattice. For the attractive region, the perturbation of the orientational order parameter introduced by the anisotropy causes the Berezinskii-Kosterlitz-Thouless transitions from a dimer-liquid to columnar phases. According to the discussion by Nomura and Okamoto for a quantum-spin chain system [J. Phys. A 27, 5773 (1994)], we proffer criteria to determine transition points and also universal level-splitting conditions. Subsequently, we perform numerical diagonalization calculations of the nonsymmetric real transfer matrices up to linear dimension specified by L=20 and determine the global phase diagram. For the repulsive region, we find the boundary between the dimer-liquid and the strong repulsion phases. Based on the dispersion relation of the one-string motion, which exhibits a twofold “zero-energy flat band” in the strong repulsion limit, we give an intuitive account for the property of the strong repulsion phase.

Crystal structure and function of an unusual dimeric Hsp20.1 provide insight into the thermal protection mechanism of small heat shock proteins.

PubMed

Liu, Liang; Chen, Jiyun; Yang, Bo; Wang, Yonghua

2015-03-06

Small heat shock proteins (sHSPs) are ubiquitous chaperones that play a vital role in protein homeostasis. sHSPs are characterized by oligomeric architectures and dynamic exchange of subunits. The flexible oligomeric assembling associating with function remains poorly understood. Based on the structural data, it is certainly agreed that two dimerization models depend on the presence or absence of a β6 strand to differentiate nonmetazoan sHSPs from metazoan sHSPs. Here, we report the Sulfolobus solfataricus Hsp20.1 ACD dimer structure, which shows a distinct dimeric interface. We observed that, in the absence of β6, Hsp20.1 dimer does not depend on β7 strand for forming dimer interface as metazoan sHSPs, nor dissociates to monomers. This is in contrast to other published sHSPs. Our structure reveals a variable, highly polar dimer interface that has advantages for rapid subunits exchange and substrate binding. Remarkably, we find that the C-terminal truncation variant has chaperone activity comparable to that of wild-type despite lack of the oligomer structure. Our further study indicates that the N-terminal region is essential for the oligomer and dimer binding to the target protein. Together, the structure and function of Hsp20.1 give more insight into the thermal protection mechanism of sHSPs. Copyright © 2015 Elsevier Inc. All rights reserved.

Dimerization of the EphA1 Receptor Tyrosine Kinase Transmembrane Domain: Insights into the Mechanism of Receptor Activation

PubMed Central

2014-01-01

EphA1 is a receptor tyrosine kinase (RTK) that plays a key role in developmental processes, including guidance of the migration of axons and cells in the nervous system. EphA1, in common with other RTKs, contains an N-terminal extracellular domain, a single transmembrane (TM) α-helix, and a C-terminal intracellular kinase domain. The TM helix forms a dimer, as seen in recent NMR studies. We have modeled the EphA1 TM dimer using a multiscale approach combining coarse-grain (CG) and atomistic molecular dynamics (MD) simulations. The one-dimensional potential of mean force (PMF) for this system, based on interhelix separation, has been calculated using CG MD simulations. This provides a view of the free energy landscape for helix–helix interactions of the TM dimer in a lipid bilayer. The resulting PMF profiles suggest two states, consistent with a rotation-coupled activation mechanism. The more stable state corresponds to a right-handed helix dimer interacting via an N-terminal glycine zipper motif, consistent with a recent NMR structure (2K1K). A second metastable state corresponds to a structure in which the glycine zipper motif is not involved. Analysis of unrestrained CG MD simulations based on representative models from the PMF calculations or on the NMR structure reveals possible pathways of interconversion between these two states, involving helix rotations about their long axes. This suggests that the interaction of TM helices in EphA1 dimers may be intrinsically dynamic. This provides a potential mechanism for signaling whereby extracellular events drive a shift in the repopulation of the underlying TM helix dimer energy landscape. PMID:25286141

Investigation of the electronic ground states for a reduced pyridine(diimine) uranium series: evidence for a ligand tetraanion stabilized by a uranium dimer.

PubMed

Anderson, Nickolas H; Odoh, Samuel O; Williams, Ursula J; Lewis, Andrew J; Wagner, Gregory L; Lezama Pacheco, Juan; Kozimor, Stosh A; Gagliardi, Laura; Schelter, Eric J; Bart, Suzanne C

2015-04-15

The electronic structures of a series of highly reduced uranium complexes bearing the redox-active pyridine(diimine) ligand, (Mes)PDI(Me) ((Mes)PDI(Me) = 2,6-(2,4,6-Me3-C6H2-N═CMe)2C5H3N) have been investigated. The complexes, ((Mes)PDI(Me))UI3(THF) (1), ((Mes)PDI(Me))UI2(THF)2 (2), [((Mes)PDI(Me))UI]2 (3), and [((Mes)PDI(Me))U(THF)]2 (4), were examined using electronic and X-ray absorption spectroscopies, magnetometry, and computational analyses. Taken together, these studies suggest that all members of the series contain uranium(IV) centers with 5f (2) configurations and reduced ligand frameworks, specifically [(Mes)PDI(Me)](•/-), [(Mes)PDI(Me)](2-), [(Mes)PDI(Me)](3-) and [(Mes)PDI(Me)](4-), respectively. In the cases of 2, 3, and 4 no unpaired spin density was found on the ligands, indicating a singlet diradical ligand in monomeric 2 and ligand electron spin-pairing through dimerization in 3 and 4. Interaction energies, representing enthalpies of dimerization, of -116.0 and -144.4 kcal mol(-1) were calculated using DFT for the monomers of 3 and 4, respectively, showing there is a large stabilization gained by dimerization through uranium-arene bonds. Highlighted in these studies is compound 4, bearing a previously unobserved pyridine(diimine) tetraanion, that was uniquely stabilized by backbonding between uranium cations and the η(5)-pyridyl ring.

Self-association properties of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl] methylimidazole-5-carboxylic acid monohydrate (CS-088), an antiglaucoma ophthalmic agent.

PubMed

Kikuchi, Takayuki; Ito, Nobuya; Suzuki, Masahiko; Kusai, Akira; Iseki, Ken; Sasaki, Hitoshi

2005-08-11

Self-association properties of CS-088, an antiglaucoma ophthalmic agent, were investigated. Various analytical methods, such as surface tension measurement, demonstrated that CS-088 is a self-associating compound with critical micellar concentration (CMC) of approximately 10 mg/mL. Light scattering analysis revealed that the micellar molecular weight (MMW) of CS-088 aggregates well above the CMC was approximately 2260, corresponding to a pentamer. In addition, the MMW corresponding to a dimer was detected by NMR spectroscopy, indicating that self-association of monomers to pentamers is via the formation of dimers. According to the Stokes-Einstein equation, hydrodynamic radii of the dimer and pentamer were calculated to be 0.87 and 1.16 nm, respectively. The concentration-dependent change in the NMR chemical shift indicated that hydrophobic interaction between biphenyl groups is an important factor in the self-association of CS-088 molecules. Furthermore, measurement of particle size distribution using a Nicomp Submicron Particle-Sizer revealed that the addition of either n-propanol or urea to CS-088 solution led to monomerization of the dimers and pentamers, suggesting that not only hydrophobic interaction but also hydrogen bonding is involved in stabilizing CS-088 aggregates. No bigger aggregate than a pentamer was formed in the absence of NaCl, whereas further aggregation was observed with increasing concentrations of NaCl.

Deprotonated Dicarboxylic Acid Homodimers: Hydrogen Bonds and Atmospheric Implications

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

Hou, Gao-Lei; Valiev, Marat; Wang, Xue-Bin

Dicarboxylic acids represent an important class of water-soluble organic compounds found in the atmosphere. In this work we are studying properties of dicarboxylic acid homodimer complexes (HO 2(CH 2) nCO 2 -[HO 2(CH 2) nCO 2H], n = 0-12), as potentially important intermediates in aerosol formation processes. Our approach is based on experimental data from negative ion photoelectron spectra of the dimer complexes combined with updated measurements of the corresponding monomer species. These results are analyzed with quantum-mechanical calculations, which provide further information about equilibrium structures, thermochemical parameters associated with the complex formation, and evaporation rates. We find that uponmore » formation of the dimer complexes the electron binding energies increase by 1.3–1.7 eV (30.0–39.2 kcal/mol), indicating increased stability of the dimerized complexes. Calculations indicate that these dimer complexes are characterized by the presence of strong intermolecular hydrogen bonds with high binding energies and are thermodynamically favorable to form with low evaporation rates. Comparison with previously studied HSO 4 -[HO 2(CH 2) 2CO 2H] complex (J. Phys. Chem. Lett. 2013, 4, 779-785) shows that HO 2(CH 2) 2CO 2 -[HO 2(CH 2) 2CO 2H] has very similar thermochemical properties. These results imply that dicarboxylic acids not only can contribute to the heterogeneous complexes formation involving sulfuric acid and dicarboxylic acids, but also can promote the formation of homogenous complexes by involving dicarboxylic acids themselves.« less

Mechanism for the Inhibition of the Carboxyl-transferase

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

L Yu; Y Kim; L Tong

Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and have been targeted for drug development against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of this enzyme is the site of action for three different classes of herbicides, as represented by haloxyfop, tepraloxydim, and pinoxaden. Our earlier studies have demonstrated that haloxyfop and tepraloxydim bind in the CT active site at the interface of its dimer. However, the two compounds probe distinct regions of the dimer interface, sharing primarily only two common anchoring points of interaction with the enzyme. We report here the crystal structure of the CT domain ofmore » yeast ACC in complex with pinoxaden at 2.8-{angstrom} resolution. Despite their chemical diversity, pinoxaden has a similar binding mode as tepraloxydim and requires a small conformational change in the dimer interface for binding. Crystal structures of the CT domain in complex with all three classes of herbicides confirm the importance of the two anchoring points for herbicide binding. The structures also provide a foundation for understanding the molecular basis of the herbicide resistance mutations and cross resistance among the herbicides, as well as for the design and development of new inhibitors against plant and human ACCs.« less

Diphenylphenoxy-Thiophene-PDI Dimers as Acceptors for OPV Applications with Open Circuit Voltage Approaching 1 Volt.

PubMed

Stenta, Caterina; Molina, Desiré; Viterisi, Aurélien; Montero-Rama, María Pilar; Pla, Sara; Cambarau, Werther; Fernández-Lázaro, Fernando; Palomares, Emilio; Marsal, Lluis F; Sastre-Santos, Ángela

2018-03-30

Two new perylenediimides (PDIs) have been developed for use as electron acceptors in solution-processed bulk heterojunction solar cells. The compounds were designed to exhibit maximal solubility in organic solvents, and reduced aggregation in the solid state. In order to achieve this, diphenylphenoxy groups were used to functionalize a monomeric PDI core, and two PDI dimers were bridged with either one or two thiophene units. In photovoltaic devices prepared using PDI dimers and a monomer in conjunction with PTB7, it was found that the formation of crystalline domains in either the acceptor or donor was completely suppressed. Atomic force microscopy, X-ray diffraction, charge carrier mobility measurements and recombination kinetics studies all suggest that the lack of crystallinity in the active layer induces a significant drop in electron mobility. Significant surface recombination losses associated with a lack of segregation in the material were also identified as a significant loss mechanism. Finally, the monomeric PDI was found to have sub-optimum LUMO energy matching the cathode contact, thus limiting charge carrier extraction. Despite these setbacks, all PDIs produced high open circuit voltages, reaching almost 1 V in one particular case.

High-temperature magnetostructural transition in van der Waals-layered α - MoCl 3

DOE PAGES

McGuire, Michael A.; Yan, Jiaqiang; Lampen-Kelley, Paula; ...

2017-11-07

Here, the crystallographic and magnetic properties of the cleavable 4d 3 transition metal compound α–MoCl 3 are reported, with a focus on the behavior above room temperature. Crystals were grown by chemical vapor transport and characterized using temperature dependent x-ray diffraction, Raman spectroscopy, and magnetization measurements. A structural phase transition occurs near 585 K, at which the Mo-Mo dimers present at room temperature are broken. A nearly regular honeycomb net of Mo is observed above the transition, and an optical phonon associated with the dimerization instability is identified in the Raman data and in first-principles calculations. The crystals are diamagneticmore » at room temperature in the dimerized state, and the magnetic susceptibility increases sharply at the structural transition. Moderately strong paramagnetism in the high-temperature structure indicates the presence of local moments on Mo. This is consistent with results of spin-polarized density functional theory calculations using the low- and high-temperature structures. Above the magnetostructural phase transition the magnetic susceptibility continues to increase gradually up to the maximum measurement temperature of 780 K, with a temperature dependence that suggests two-dimensional antiferromagnetic correlations.« less

Heavier Group 13 Metal(I) Heterocycles Stabilized by Sterically Demanding Diiminophosphinates: A Structurally Characterized Monomer-Dimer Pair For Gallium.

PubMed

Hawley, Andrew L; Ohlin, C André; Fohlmeister, Lea; Stasch, Andreas

2017-01-05

We have synthesized and characterized the monomeric diiminophosphinate-stabilized Group 13 metal(I) complexes [ Dip LE:], Dip L=Ph 2 P(NDip) 2 , Dip=2,6-iPr 2 C 6 H 3 ; E=Ga (1), In (2) and Tl (3). In addition, we structurally characterized the dimeric complex [( Dip LGa) 2 ], 1 2 . Similar synthetic attempts using Mes L=Ph 2 P(NMes) 2 , Mes=2,4,6-Me 3 C 6 H 2 afforded product mixtures from which the mixed oxidation state species [( Mes L) 3 Ga 4 I 3 ] 4 was isolated. [ Dip LGa:] 1 is converted with dry air to the gallium(III) oxide species [( Dip LGaO) 2 ] 5. Density Functional Theory studies on [ Dip LE:] and [( Dip LE) 2 ], E=Al-Tl, shed light on the bonding in these compounds and show that the newly formed E-E bonding interactions can be described as weak single σ-bond with no significant π-bonding contribution for E=Al, Ga. A large contribution to the dimer binding enthalpies results from London dispersion forces. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

High-temperature magnetostructural transition in van der Waals-layered α -MoCl3

NASA Astrophysics Data System (ADS)

McGuire, Michael A.; Yan, Jiaqiang; Lampen-Kelley, Paula; May, Andrew F.; Cooper, Valentino R.; Lindsay, Lucas; Puretzky, Alexander; Liang, Liangbo; KC, Santosh; Cakmak, Ercan; Calder, Stuart; Sales, Brian C.

2017-11-01

The crystallographic and magnetic properties of the cleavable 4 d3 transition metal compound α -MoCl3 are reported, with a focus on the behavior above room temperature. Crystals were grown by chemical vapor transport and characterized using temperature dependent x-ray diffraction, Raman spectroscopy, and magnetization measurements. A structural phase transition occurs near 585 K, at which the Mo-Mo dimers present at room temperature are broken. A nearly regular honeycomb net of Mo is observed above the transition, and an optical phonon associated with the dimerization instability is identified in the Raman data and in first-principles calculations. The crystals are diamagnetic at room temperature in the dimerized state, and the magnetic susceptibility increases sharply at the structural transition. Moderately strong paramagnetism in the high-temperature structure indicates the presence of local moments on Mo. This is consistent with results of spin-polarized density functional theory calculations using the low- and high-temperature structures. Above the magnetostructural phase transition the magnetic susceptibility continues to increase gradually up to the maximum measurement temperature of 780 K, with a temperature dependence that suggests two-dimensional antiferromagnetic correlations.

Crystal structures of 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(naphthalen-1-yl)acetamide and 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]-N-(4-fluoro-phen-yl)acetamide.

PubMed

Subasri, S; Kumar, Timiri Ajay; Sinha, Barij Nayan; Jayaprakash, Venkatesan; Viswanathan, Vijayan; Velmurugan, Devadasan

2017-02-01

The title compounds, C 16 H 15 N 5 OS, (I), and C 12 H 12 FN 5 OS, (II), are [(di-amino-pyrimidine)-sulfan-yl]acetamide derivatives. In (I), the pyrimidine ring is inclined to the naphthalene ring system by 55.5 (1)°, while in (II), the pyrimidine ring is inclined to the benzene ring by 58.93 (8)°. In (II), there is an intra-molecular N-H⋯N hydrogen bond and a short C-H⋯O contact. In the crystals of (I) and (II), mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with R 2 2 (8) ring motifs. In the crystal of (I), the dimers are linked by bifurcated N-H⋯(O,O) and C-H⋯O hydrogen bonds, forming layers parallel to (100). In the crystal of (II), the dimers are linked by N-H⋯O hydrogen bonds, also forming layers parallel to (100). The layers are linked by C-H⋯F hydrogen bonds, forming a three-dimensional architecture.

Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease

PubMed Central

Wang, Hao; Barreyro, Laura; Provasi, Davide; Djemil, Imane; Torres-Arancivia, Celia; Filizola, Marta; Ubarretxena-Belandia, Iban

2011-01-01

The deposition of toxic amyloid-β peptide (Aβ) aggregates in the brain is a hallmark of Alzheimer's disease. The intramembrane proteolysis by γ-secretase of the amyloid precursor protein carboxy-terminal fragment (APP-βCTF) constitutes the final step in the production of Aβs. Mounting evidence suggests that APP-βCTF is a transmembrane domain (TMD) dimer, and that dimerization might modulate the production of Aβ species that are prone to aggregation, and therefore most toxic. We combined experimental and computational approaches to study the molecular determinants and thermodynamics of APP-βCTF dimerization, and produced a unifying structural model that reconciles much of the published data. Using a cell assay, which exploits a dimerization-dependent activator of transcription, we identified specific dimerization-disrupting mutations located mostly at the N-terminus of the TMD of APP-βCTF. The ability of selected mutants to disrupt the dimerization of full length APP-βCTF was confirmed by fluorescence resonance energy transfer experiments. Free-energy estimates of wild-type (WT) and mutants of the TMD of APP-βCTF derived from enhanced molecular dynamics simulations showed that the dimeric state is comprised of different arrangements, in which either 709GXXXA713 or 700GXXXG704GXXXG708 interaction motifs can engage in symmetric or asymmetric associations. Mutations along the TMD of APP-βCTF were found to modulate the relative free energy of the dimeric configurations, and to differently affect the distribution of interfaces within the dimeric state. This observation might have important biological implications, since dimers with a different arrangement of the transmembrane helices are likely to be recognized differently by γ-secretase and lead to a variation of Aβ levels. PMID:21440556

Interaction investigations of HipA binding to HipB dimer and HipB dimer + DNA complex: a molecular dynamics simulation study.

PubMed

Li, Chaoqun; Wang, Yaru; Wang, Yan; Chen, Guangju

2013-11-01

We carried out molecular dynamics simulations and free energy calculations for a series of ternary and diplex models for the HipA protein, HipB dimer, and DNA molecule to address the mechanism of HipA sequestration and the binding order of events from apo HipB/HipA to 2HipA + HipB dimer + DNA complex. The results revealed that the combination of DNA with the HipB dimer is energetically favorable for the combination of HipB dimer with HipA protein. The binding of DNA to HipB dimer induces a long-range allosteric communication from the HipB2 -DNA interface to the HipA-HipB2 interface, which involves the closeness of α1 helices of HipB dimer to HipA protein and formations of extra hydrogen bonds in the HipA-HipB2 interface through the extension of α2/3 helices in the HipB dimer. These simulated results suggested that the DNA molecule, as a regulative media, modulates the HipB dimer conformation, consequently increasing the interactions of HipB dimer with the HipA proteins, which explains the mechanism of HipA sequestration reported by the previous experiment. Simultaneously, these simulations also explored that the thermodynamic binding order in a simulated physiological environment, that is, the HipB dimer first bind to DNA to form HipB dimer + DNA complex, then capturing strongly the HipA proteins to form a ternary complex, 2HipA + HipB dimer + DNA, for sequestrating HipA in the nucleoid. Copyright © 2013 John Wiley & Sons, Ltd.

Genetic Manipulation of the COP9 Signalosome Subunit PfCsnE Leads to the Discovery of Pestaloficins in Pestalotiopsis fici.

PubMed

Zheng, Yanjing; Ma, Ke; Lyu, Haining; Huang, Ying; Liu, Hongwei; Liu, Ling; Che, Yongsheng; Liu, Xingzhong; Zou, Huixi; Yin, Wen-Bing

2017-09-01

By deleting the COP9 signalosome subunit PfcsnE from Pestalotiopsis fici, seven compounds that were newly produced by the mutant could be characterized, including five new structures, pestaloficins A-E (1 and 3-6). Pestaloficin A (1) represents a new type of dimeric cyclohexanone derivative linked through an unprecedented pentacyclic spiral ring.

Synthesis of novel heterocycles through reaction of indolin-2-one derivatives with active methylene and amino reagents.

PubMed

Abdel-Latif, F F; Ahmed, E K; Mekheimer, R; Mashaly, M M

1997-10-01

Several new spiro compounds were synthesized via one-pot ternary condensation of isatin, malononitrile and each of thiobarbituric acid, barbituric acid, 3-methyl-pyrazolin-5-one, 1-phenyl-3-methyl-pyrazolin-5-one, acetylacetone, benzoylacetone, ethyl acetoacetate, phenacyl cyanide or ethyl-cyanoacetate dimer. Structures and reaction mechanism were reported and supported via a second synthetic route.

Photoelectron spectra and biological activity of cinnamic acid derivatives revisited

NASA Astrophysics Data System (ADS)

Novak, Igor; Klasinc, Leo; McGlynn, Sean P.

2018-01-01

The electronic structures of several derivatives of cinnamic acid have been studied by UV photoelectron spectroscopy (UPS) and Green's function quantum chemical calculations. The spectra reveal the presence of dimers in the gas phase for p-coumaric and ferulic acids. The electronic structure analysis has been related to the biological properties of these compounds through the analysis of some structure-activity relationships (SAR).

1-(4-Chloro-2-fluoro-phen-yl)-4-difluoro-methyl-3-methyl-1H-1,2,4-triazol-5(4H)-one.

PubMed

Ren, Dong-Mei; Wang, Yong-Yi

2012-04-01

In the crystal structure of the title compound, C(10)H(7)ClF(3)N(3)O, pairs of mol-ecules are connected into dimers via pairs of C-H⋯O hydrogen bonds. The dihedral angle between the benzene ring and attached triazolone ring is 53.2 (1)°.

3-(4-Methoxy­phen­yl)pent-2-ene-1,5-dioic acid

PubMed Central

Das, Ushati; Chheda, Shardul B.; Pednekar, Suhas R.; Karambelkar, Narendra P; Guru Row, T. N.

2008-01-01

In the title compound, C12H12O5, mol­ecules are linked into anti­parallel hydrogen-bonded sheets through inversion dimers generated via two O—H⋯O hydrogen bonds. Using the R 2 2(8) motif as a building block, hydrogen-bonded chains of a C 2 2(8) superstructure are then generated. PMID:21581357

Poison ivy/oak dermatitis. Use of polyamine salts of a linoleic acid dimer for topical prophylaxis.

PubMed

Orchard, S; Fellman, J H; Storrs, F J

1986-07-01

Closed patch tests were used to evaluate the ability of 156 different preparations (based on 22 different chemicals) to prevent poison ivy dermatitis. Several polyamine salts of a linoleic acid dimer were identified that were totally able to prevent the usual dermatitis in approximately 70% of subjects. The effectiveness of the preparations improved when the antigen and the protectant were washed off within eight to 12 hours, instead of remaining on the skin for 48 hours. When washed off, and depending on the protectant, concentration, and vehicle used, several of the preparations were totally able to prevent a dermatitis in a range of 56% to 100% of subjects tested. Further work with these compounds may greatly benefit the many people currently plagued by their allergy to poison ivy and poison oak.

Venlafaxine besylate monohydrate

PubMed Central

Corvalan, Carolina H.; Vega, Daniel R.

2013-01-01

The title compound {systematic name: [2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl]dimethylazanium benzene­sulfonate monohydrate}, C17H28NO2 +·C6H5O3S−·H2O, is a besylate salt hydrate of the anti­depressant drug venlafaxine. In the crystal, besylate anions and water mol­ecules self-assemble, forming hydrogen-bonded dimers linked around inversion centers, with graph set R 4 4(6). The crystal packing features a chain of alternate dimers and venlafaxine cations in the b-axis direction with the components linked by O—H⋯O hydrogen bonds and C—H⋯O and C—H⋯π inter­actions. This is the first example of a venlafaxine cation with a closed conformation, as it features an intra­molecular N—H⋯O inter­action involving the protonated N atom. PMID:24454196

Evidence for dimer formation by an amphiphilic heptapeptide that mediates chloride and carboxyfluorescein release from liposomes

PubMed Central

Pajewski, Robert; Ferdani, Riccardo; Pajewska, Jolanta; Djedovič, Natasha; Schlesinger, Paul H.; Gokel, George W.

2008-01-01

Heptapeptides having dioctadecyl, N-terminal hydrocarbon chains insert in phospholipid bilayer membranes and form pores through which at least chloride ions pass. Although amphiphilic, these compounds do not typically form vesicles themselves. They insert in the bilayers of phospholipid vesicles and mediate the release of carboxyfluorescein. Hill analysis indicates that at least two molecules of the amphiphile are involved in pore formation. In CD2Cl2, dimer formation is detected by NMR chemical shift changes. The anion release activity of individual anion transporters is increased by linking them covalently at the C-terminus or, even more, by linking them at the N-terminus. Evidence is presented that either linked molecule releases chloride from liposomes more effectively and rapidly than the individual transporter molecule at a comparable concentration. PMID:15703797

2-(4-Meth-oxy-phen-yl)-1-pentyl-4,5-di-phenyl-1H-imidazole.

PubMed

Simpson, Jim; Mohamed, Shaaban K; Marzouk, Adel A; Talybov, Avtandil H; Abdelhamid, Antar A

2013-01-01

The title compound, C27H28N2O, is a lophine (2,4,5-triphenyl-1H-imidazole) derivative with an n-pentyl chain on the amine N atom and a 4-meth-oxy substituent on the benzene ring. The two phenyl and meth-oxy-benzene rings are inclined to the imidazole ring at angles of 25.32 (7), 76.79 (5) and 35.42 (7)°, respectively, while the meth-oxy substituent lies close to the plane of its benzene ring, with a maximum deviation of 0.126 (3) Å for the meth-oxy C atom. In the crystal, inversion dimers linked by pairs of C-H⋯O hydrogen bonds generate R2(2)(22) loops. These dimers are stacked along the a-axis direction.

Molecular simulation studies on chemical reactivity of methylcyclopentadiene.

PubMed

Wang, Qingsheng; Zhang, Yingchun; Rogers, William J; Mannan, M Sam

2009-06-15

Molecular simulations are important to predict thermodynamic values for reactive chemicals especially when sufficient experimental data are not available. Methylcyclopentadiene (MCP) is an example of a highly reactive and hazardous compound in the chemical process industry. In this work, chemical reactivity of 2-methylcyclopentadiene, including isomerization, dimerization, and oxidation reactions, is investigated in detail by theoretical computational chemistry methods and empirical thermodynamic-energy correlation. On the basis of molecular simulations, an average value of -15.2 kcal/mol for overall heat of dimerization and -45.6 kcal/mol for overall heat of oxidation were obtained in gaseous phase at 298 K and 1 atm. These molecular simulation studies can provide guidance for the design of safer chemical processes, safer handling of MCP, and also provide useful information for an investigation of the T2 Laboratories explosion on December 19, 2007, in Florida.

N-H.N hydrogen bonding in 4,6-diphenyl-2-pyrimidinylamine isolated from the plant Justicia secunda (Acanthaceae).

PubMed

Gallagher, John F; Goswami, Shyamaprosad; Chatterjee, Baidyanath; Jana, Subrata; Dutta, Kalyani

2004-04-01

The title compound, C(16)H(13)N(3), isolated from Justicia secunda (Acanthaceae), comprises two molecules (which differ slightly in conformation) in the asymmetric unit of space group P-1. Intermolecular N(amino)-H.N(pyrm) interactions (N(pyrm) is a pyrimidine ring N atom) involve only one of the two donor amino H atoms and pyrimidine N atoms per molecule, forming dimeric units via R(2)(2)(8) rings, with N.N distances of 3.058 (2) and 3.106 (3) A, and N-H.N angles of 172.7 (18) and 175.8 (17) degrees. The dimers are linked by C-H.pi(arene) contacts, with an H.centroid distance of 2.77 A and a C-H.centroid angle of 141 degrees.

Methyl 6-eth-oxy-3-phenyl-3a,4-dihydro-3H-chromeno[4,3-c]isoxazole-3a-car-boxylate.

PubMed

Suresh, G; Srinivasan, J; Bakthadoss, M; Aravindhan, S

2013-02-01

In the title compound, C(20)H(19)NO(5), the dihedral angle between the mean plane of the pyran ring (which has a half-chair conformation) and the benzene ring of the chromeno ring system is 7.21 (7)°. The dihedral angle between the mean plane of the chromeno ring system and the isoxazole ring is 21.78 (6)°, while the isoxazole ring forms a dihedral angle of 72.60 (8)° with the attached phenyl ring. In the crystal, mol-ecules are linked via pairs of C-H⋯O hydrogen bonds, forming inversion dimers with an R(2) (2)(10) ring motif. These dimers are linked via C-H⋯N hydrogen bonds, forming chains along [001].

Optochemical Control of Protein Localization and Activity within Cell-like Compartments.

PubMed

Caldwell, Reese M; Bermudez, Jessica G; Thai, David; Aonbangkhen, Chanat; Schuster, Benjamin S; Courtney, Taylor; Deiters, Alexander; Hammer, Daniel A; Chenoweth, David M; Good, Matthew C

2018-05-08

We report inducible dimerization strategies for controlling protein positioning, enzymatic activity, and organelle assembly inside synthetic cell-like compartments upon photostimulation. Using a photocaged TMP-Haloligand compound, we demonstrate small molecule and light-induced dimerization of DHFR and Haloenzyme to localize proteins to a compartment boundary and reconstitute tripartite sfGFP assembly. Using photocaged rapamycin and fragments of split TEV protease fused to FRB and FKBP, we establish optical triggering of protease activity inside cell-size compartments. We apply light-inducible protease activation to initiate assembly of membraneless organelles, demonstrating the applicability of these tools for characterizing cell biological processes in vitro. This modular toolkit, which affords spatial and temporal control of protein function in a minimal cell-like system, represents a critical step toward the reconstitution of a tunable synthetic cell, built from the bottom up.

Identification of proanthocyanidin dimers and trimers, flavone C-Glycosides, and antioxidants in Ficus deltoidea , a malaysian herbal tea.

PubMed

Omar, Maizatul Hasyima; Mullen, William; Crozier, Alan

2011-02-23

Phenolic compounds in an aqueous infusion of leaves of Ficus deltoidea (Moraceae), a well-known herbal tea in Malaysia, were analyzed by HPLC coupled to photodiode array and fluorescence detectors and an electrospray ionization tandem mass spectrometer. Following chromatography of extracts on a reversed phase C(12) column, 25 flavonoids were characterized and/or tentatively identified with the main constituents being flavan-3-ol monomers, proanthocyanidins, and C-linked flavone glycosides. The proanthocyanidins were dimers and trimers comprising (epi)catechin and (epi)afzelechin units. No higher molecular weight proanthocyanidin polymers were detected. The antioxidant activity of F. deltoidea extract was analyzed using HPLC with online antioxidant detection. This revealed that 85% of the total antioxidant activity of the aqueous F. deltoidea infusion was attributable to the flavan-3-ol monomers and the proanthocyanidins.

4-Mercaptophenylboronic acid: conformation, FT-IR, Raman, OH stretching and theoretical studies.

PubMed

Parlak, Cemal; Ramasami, Ponnadurai; Tursun, Mahir; Rhyman, Lydia; Kaya, Mehmet Fatih; Atar, Necip; Alver, Özgür; Şenyel, Mustafa

2015-06-05

4-Mercaptophenylboronic acid (4-mpba, C6H7BO2S) was investigated experimentally by vibrational spectroscopy. The molecular structure and spectroscopic parameters were studied by computational methods. The molecular dimer was investigated for intermolecular hydrogen bonding. Potential energy distribution analysis of normal modes was performed to identify characteristic frequencies. The present work provides a simple physical picture of the OH stretch vibrational spectra of 4-mpba and analogues of the compound studied. When the different computational methods are compared, there is a strong evidence of the better performance of the BLYP functional than the popular B3LYP functional to describe hydrogen bonding in the dimer. The findings of this research work should be useful to experimentalists in their quests for functionalised 4-mpba derivatives. Copyright © 2015 Elsevier B.V. All rights reserved.

A cadinene biopolymer in fossil and extant dammar resins as a source for cadinanes and bicadinanes in crude oils from South East Asia

NASA Astrophysics Data System (ADS)

Van Aarssen, B. G. K.; Cox, H. C.; Hoogendoorn, P.; De Leeuw, J. W.

1990-11-01

The chemical composition of a fossil resin from a Miocene outcrop in Brunei, South East Asia, is compared with its extant counterpart dammar, obtained from trees of the family Dipterocarpaceae, to establish the nature of the precursor of bicadinanes. The alcohol soluble fractions of the resins consist of functionalised triterpenoids and a small amount of sesquiterpenoids. None of the compounds present in this fraction bears any structural relation to bicadinanes. The alcohol insoluble fractions of the resins consist of a polymer based on cadinene. A structure for this polymer is proposed. Heating the polymer in dammar resin resulted in the formation of monomeric, dimeric, and trimeric cadinenes. It is thought that the naturally occurring bicadinanes result from dimeric cadinenes upon cyclisation.

High pretreatment plasma D-dimer predicts poor survival of colorectal cancer: insight from a meta-analysis of observational studies

PubMed Central

Lu, Shao-Long; Ye, Zhi-Hua; Ling, Tong; Liang, Si-Yuan; Li, Hui; Tang, Xiao-Zhun; Xu, Yan-Song; Tang, Wei-Zhong

2017-01-01

D-dimer, one of the canonical markers of hypercoagulability, was reported to be a potential prognostic marker of colorectal cancer. However, an inconsistent conclusion existed in several published studies. Thus, we performed this meta-analysis to provide a comprehensive insight into the prognostic role for pretreatment D-dimer in colorectal cancer. Six databases (English: Pubmed, Embase and Web of Science; Chinese: CNKI, Wangfang and VIP) were utilized for the literature retrieval. Hazard ratio (HR) was pooled by Stata 12.0. A total of fifteen studies (2283 cases) corresponded to this meta-analysis and provided available data to evaluate the prognostic role of D-dimer for colorectal cancer. The pooled HR reached 2.167 (95%. CI (confidence interval): 1.672–2.809, P < 0.001) utilizing random effect model due to obvious heterogeneity among the included studies (I2: 73.3%; P < 0.001). To explore the heterogeneity among the studies, we conducted a sensitivity analysis and found a heterogeneous study. After removing it, the heterogeneity reduced substantially (I2: 0%; P = 0.549) and we obtained a more convincing result by fixed effect model (HR = 2.143, 95% CI = 1.922–2.390, P < 0.001, 14 studies with 2179 cases). In summary, high pretreatment plasma D-dimer predicts poor survival of colorectal cancer based on the current evidence. Further prospective researches are necessary to confirm the role of D-dimer in colorectal cancer. PMID:29113378

Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

PubMed Central

2011-01-01

Background Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics. PMID:21418624

Spin excitations used to probe the nature of exchange coupling in the magnetically ordered ground state of Pr 0.5 Ca 0.5 MnO 3

DOE PAGES

Ewings, R. A.; Perring, T. G.; Sikora, O.; ...

2016-07-06

We have used time-of-flight inelastic neutron scattering to measure the spin wave spectrum of the canonical half-doped manganite Pr 0.5Ca 0.5MnO 3 in its magnetic and orbitally ordered phase. Comparison of the data, which cover multiple Brillouin zones and the entire energy range of the excitations, with several different models shows that only the CE-type ordered state provides an adequate description of the magnetic ground state, provided interactions beyond nearest neighbor are included. We are able to rule out a ground state in which there exist pairs of dimerized spins which interact only with their nearest neighbors. The Zener polaronmore » ground state, which comprises strongly bound magnetic dimers, can be ruled out on the basis of gross features of the observed spin wave spectrum. A model with weaker dimerization reproduces the observed dispersion but can be ruled out on the basis of subtle discrepancies between the calculated and observed structure factors at certain positions in reciprocal space. Adding further neighbor interactions results in almost no dimerization, i.e. interpolating back to the CE model. These results are consistent with theoretical analysis of the degenerate double exchange model for half-doping.« less

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms.

PubMed

Bonati, Laura; Corrada, Dario; Tagliabue, Sara Giani; Motta, Stefano

2017-02-01

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.

PubMed

Yu, Wenying; Xiao, Hui; Lin, Jiayuh; Li, Chenglong

2013-06-13

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

Real-space mapping of the strongly coupled plasmons of nanoparticle dimers.

PubMed

Kim, Deok-Soo; Heo, Jinhwa; Ahn, Sung-Hyun; Han, Sang Woo; Yun, Wan Soo; Kim, Zee Hwan

2009-10-01

We carried out the near-field optical imaging of isolated and dimerized gold nanocubes to directly investigate the strong coupling between two adjacent nanoparticles. The high-resolution (approximately 10 nm) local field maps (intensities and phases) of self-assembled nanocube dimers reveal antisymmetric plasmon modes that are starkly different from a simple superposition of two monomeric dipole plasmons, which is fully reproduced by the electrodynamics simulations. The result decisively proves that, for the closely spaced pair of nanoparticles (interparticle distance/particle size approximately 0.04), the strong Coulombic attraction between the charges at the interparticle gap dominates over the intraparticle charge oscillations, resulting in a hybridized dimer plasmon mode that is qualitatively different from those expected from a simple dipole-dipole coupling model.

Polarization to the field enhancement by a gold dimer

NASA Astrophysics Data System (ADS)

Hong, Xin; Jin, Zheng

2016-11-01

Due to the effect of plasmonic coupling, gold nanoparticle dimers have been paid more attentions in bio-imaging. The coupling effect existing at the gap between a closely linked particle pair can make the local field strongly enhanced and in which the angle between the excitation polarization and the dimer axis plays a dominant role. We calculated the amplitude distribution under a highly focused illumination objective. The simulation results show that for such a model, 45 degrees between the excitation polarization and the dimer axis can produce an optimum signal. The enhancement thus obtained is 10.78 fold while the variation between peak-peak can reach 6.59 fold compared to a single plasmoic particle during the rotation of the polarization.

Dynamics of a Chlorophyll Dimer in Collective and Local Thermal Environments

DOE PAGES

Merkli, M.; Berman, Gennady Petrovich; Sayre, Richard Thomas; ...

2016-01-30

Here we present a theoretical analysis of exciton transfer and decoherence effects in a photosynthetic dimer interacting with collective (correlated) and local (uncorrelated) protein-solvent environments. Our approach is based on the framework of the spin-boson model. We derive explicitly the thermal relaxation and decoherence rates of the exciton transfer process, valid for arbitrary temperatures and for arbitrary (in particular, large) interaction constants between the dimer and the environments. We establish a generalization of the Marcus formula, giving reaction rates for dimer levels possibly individually and asymmetrically coupled to environments. We identify rigorously parameter regimes for the validity of the generalizedmore » Marcus formula. The existence of long living quantum coherences at ambient temperatures emerges naturally from our approach.« less

Determination of the absolute configurations of synthetic daunorubicin analogues using vibrational circular dichroism spectroscopy and density functional theory.

PubMed

Yang, Guochun; Tran, Ha; Fan, Eric; Shi, Wei; Lowary, Todd L; Xu, Yunjie

2010-08-01

The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl(3) solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6-311G** and 6-311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified. Copyright 2010 Wiley-Liss, Inc.

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

NASA Astrophysics Data System (ADS)

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

2011-03-01

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

Overall conformation of covalently stabilized domain-swapped dimer of human cystatin C in solution

NASA Astrophysics Data System (ADS)

Murawska, Magdalena; Szymańska, Aneta; Grubb, Anders; Kozak, Maciej

2017-11-01

Human cystatin C (HCC), a small protein, plays a crucial role in inhibition of cysteine proteases. The most common structural form of human cystatin C in crystals is a dimer, which has been evidenced both for the native protein and its mutants. In these structures, HCC dimers were formed through the mechanism of domain swapping. The structure of the monomeric form of human cystatin C was determined for V57N mutant and the mutant with the engineered disulfide bond (L47C)-(G69C) (known as stab1-HCC). On the basis of stab1-HCC, a number of covalently stabilized oligomers, including also dimers have been obtained. The aim of this study was to analyze the structure of the covalently stabilized dimer HCC in solution by the small angle X-ray scattering (SAXS) technique and synchrotron radiation. Experimental data confirmed that in solution this protein forms a dimer, which is characterized by the radius of gyration RG = 3.1 nm and maximum intramolecular distance Dmax = 10.3 nm. Using the ab initio method and program DAMMIN, we propose a low resolution structure of stabilized covalently cystatin C in solution. Stab-HCC dimer adopts in solution an elongated conformation, which is well reconstructed by the ab initio model.

Hepatitis B Virus Core Protein Dephosphorylation Occurs during Pregenomic RNA Encapsidation.

PubMed

Zhao, Qiong; Hu, Zhanying; Cheng, Junjun; Wu, Shuo; Luo, Yue; Chang, Jinhong; Hu, Jianming; Guo, Ju-Tao

2018-07-01

Hepatitis B virus (HBV) core protein consists of an N-terminal assembly domain and a C-terminal domain (CTD) with seven conserved serines or threonines that are dynamically phosphorylated/dephosphorylated during the viral replication cycle. Sulfamoylbenzamide derivatives are small molecular core protein allosteric modulators (CpAMs) that bind to the heteroaryldihydropyrimidine (HAP) pocket between the core protein dimer-dimer interfaces. CpAM binding alters the kinetics and pathway of capsid assembly and can result in the formation of morphologically "normal" capsids devoid of viral pregenomic RNA (pgRNA) and DNA polymerase. In order to investigate the mechanism underlying CpAM inhibition of pgRNA encapsidation, we developed an immunoblotting assay that can resolve core protein based on its phosphorylation status and demonstrated, for the first time, that core protein is hyperphosphorylated in free dimers and empty capsids from both mock-treated and CpAM-treated cells but is hypophosphorylated in pgRNA- and DNA-containing nucleocapsids. Interestingly, inhibition of pgRNA encapsidation by a heat shock protein 90 (HSP90) inhibitor prevented core protein dephosphorylation. Moreover, core proteins with point mutations at the wall of the HAP pocket, V124A and V124W, assembled empty capsids and nucleocapsids with altered phosphorylation status. The results thus suggest that core protein dephosphorylation occurs in the assembly of pgRNA and that interference with the interaction between core protein subunits at dimer-dimer interfaces during nucleocapsid assembly alters not only capsid structure, but also core protein dephosphorylation. Hence, inhibition of pgRNA encapsidation by CpAMs might be due to disruption of core protein dephosphorylation during nucleocapsid assembly. IMPORTANCE Dynamic phosphorylation of HBV core protein regulates multiple steps of viral replication. However, the regulatory function was mainly investigated by phosphomimetic mutagenesis, which disrupts the natural dynamics of core protein phosphorylation/dephosphorylation. Development of an immunoblotting assay capable of resolving hyper- and hypophosphorylated core proteins allowed us to track the phosphorylation status of core proteins existing as free dimers and the variety of intracellular capsids and to investigate the role of core protein phosphorylation/dephosphorylation in viral replication. Here, we found that disruption of core protein interaction at dimer-dimer interfaces during nucleocapsid assembly (by CpAMs or mutagenesis) inhibited core protein dephosphorylation and pgRNA packaging. Our work has thus revealed a novel function of core protein dephosphorylation in HBV replication and the mechanism by which CpAMs, a class of compounds that are currently in clinical trials for treatment of chronic hepatitis B, induce the assembly of empty capsids. Copyright © 2018 American Society for Microbiology.

Temperature-dependent conformations of exciton-coupled Cy3 dimers in double-stranded DNA

NASA Astrophysics Data System (ADS)

Kringle, Loni; Sawaya, Nicolas P. D.; Widom, Julia; Adams, Carson; Raymer, Michael G.; Aspuru-Guzik, Alán; Marcus, Andrew H.

2018-02-01

Understanding the properties of electronically interacting molecular chromophores, which involve internally coupled electronic-vibrational motions, is important to the spectroscopy of many biologically relevant systems. Here we apply linear absorption, circular dichroism, and two-dimensional fluorescence spectroscopy to study the polarized collective excitations of excitonically coupled cyanine dimers (Cy3)2 that are rigidly positioned within the opposing sugar-phosphate backbones of the double-stranded region of a double-stranded (ds)-single-stranded (ss) DNA fork construct. We show that the exciton-coupling strength of the (Cy3)2-DNA construct can be systematically varied with temperature below the ds-ss DNA denaturation transition. We interpret spectroscopic measurements in terms of the Holstein vibronic dimer model, from which we obtain information about the local conformation of the (Cy3)2 dimer, as well as the degree of static disorder experienced by the Cy3 monomer and the (Cy3)2 dimer probe locally within their respective DNA duplex environments. The properties of the (Cy3)2-DNA construct we determine suggest that it may be employed as a useful model system to test fundamental concepts of protein-DNA interactions and the role of electronic-vibrational coherence in electronic energy migration within exciton-coupled bio-molecular arrays.

Structure of the dimeric RC–LH1–PufX complex from Rhodobaca bogoriensis investigated by electron microscopy

PubMed Central

Semchonok, Dmitry A.; Chauvin, Jean-Paul; Frese, Raoul N.; Jungas, Colette; Boekema, Egbert J.

2012-01-01

Electron microscopy and single-particle averaging were performed on isolated reaction centre (RC)—antenna complexes (RC–LH1–PufX complexes) of Rhodobaca bogoriensis strain LBB1, with the aim of establishing the LH1 antenna conformation, and, in particular, the structural role of the PufX protein. Projection maps of dimeric complexes were obtained at 13 Å resolution and show the positions of the 2 × 14 LH1 α- and β-subunits. This new dimeric complex displays two open, C-shaped LH1 aggregates of 13 αβ polypeptides partially surrounding the RCs plus two LH1 units forming the dimer interface in the centre. Between the interface and the two half rings are two openings on each side. Next to the openings, there are four additional densities present per dimer, considered to be occupied by four copies of PufX. The position of the RC in our model was verified by comparison with RC–LH1–PufX complexes in membranes. Our model differs from previously proposed configurations for Rhodobacter species in which the LH1 ribbon is continuous in the shape of an S, and the stoichiometry is of one PufX per RC. PMID:23148268

New cytotoxic diarylheptanoids from the rhizomes of Alpinia officinarum Hance.

PubMed

Liu, Dan; Liu, Yan-Wen; Guan, Fu-Qin; Liang, Jing-Yu

2014-07-01

Two new dimeric diarylheptanoids, named Alpinin C (1) and D (2), a new natural product of diarylheptanoid (3) along with three known diarylheptanoids (4-6) were isolated from the rhizomes of Alpinia officinarum Hance. Their structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR, HRTOFMS, IR). The isolated compounds were evaluated for their cytotoxicity against human tumor cell lines HepG2, MCF-7, T98G and B16-F10. Compound 1 showed selective cytotoxicity against cell lines of MCF-7 and T98G, while compound 6 showed significant cytotoxicity to the all tested tumor cell lines with IC50 in the range from 8.46 to 22.68 μmol/L. Copyright © 2014 Elsevier B.V. All rights reserved.

Improved photosensitizers for photodynamic therapy

NASA Astrophysics Data System (ADS)

Pandey, Ravindra K.; Shiau, Fuu-Yau; Meunier, Isabelle; Ramaprasad, Subbaraya; Sumlin, Adam B.; Dougherty, Thomas J.; Smith, Kevin M.

1992-06-01

In order to evaluate the effect of substituents in photosensitizing activity, a series of long wavelength absorbing photosensitizers related to pyropheophorbides, bacteriopheophorbides, and benzoporphyrin derivatives were synthesized. Pheophorbide dimers, covalently joining two molecules of pyropheophorbide-a and bacteriopheophorbide-a with lysine as a cross-link were also prepared. The syntheses and spectroscopic properties of these compounds are discussed. Some of these compounds were tested for in vivo photosensitizing activity vis-a-vis Photofrin IITM, using the standard screening system of DBA/2 mice bearing transplanted SMT/F tumors. The preliminary in vivo results suggest that replacement of substituents at peripheral positions of the macrocycles causes a significant difference in photosensitizing efficacy.

Investigating electron spin resonance spectroscopy of a spin-½ compound in a home-built spectrometer

NASA Astrophysics Data System (ADS)

Sarkar, Jit; Roy, Subhadip; Singh, Jitendra Kumar; Singh, Sourabh; Chakraborty, Tanmoy; Mitra, Chiranjib

2018-05-01

In this work we report electron spin resonance (ESR) measurements performed on NH4CuPO4.H2O, a Heisenberg spin ½ dimer compound. We carried out the experiments both at room temperature and at 78 K, which are well above the antiferromagnetic ordering temperature of the system where the paramagnetic spins have a dominant role in determining its magnetic behavior. We performed the measurements in a home built custom designed continuous wave electron spin resonance (CW-ESR) spectrometer. By analyzing the experimental data, we were able to quantify the Landé g-factor and the ESR line-width of the sample.

Is time to search the Wells Score 4.0?

PubMed

Rosa-Jiménez, F; Rosa-Jiménez, A; Lozano-Rodríguez, A; Martín-Moreno, P; Hinojosa-Martínez, M D; Montijano-Cabrera, Á M

2015-01-01

Wells score for deep vein thrombosis presents problems for implementation in the hospital emergencies, mainly due to the complexity of its enforcement. To assess whether the inclusion of D-dimer as a predictor might lead to a simplification of this clinical decision rule. A database of deep vein thrombosis patients was studied by logistic regression model in which the 10 predictors in the Wells score and the dimer D were included. The diagnosis was made with compression ultrasonography with Doppler signal. D-dimer was determined by a quantitative method of latex, a technique immunofiltration or a turbidimetric technique. 577 patients (54.1% women) were studied, with a mean age of 66.7 (14.2) years. 25.1% were diagnosed with deep vein thrombosis. Only four variables were independent, building a weighted model with greater predictive ability (area under the curve) than the original model (0.844 vs. 0.751, p<0.001). Both models showed an acceptable safety, with a similar rate of failure (0.8% vs. 1%). The simplified model allowed to select a higher percentage of patients who could have benefited from the non performance of the imaging test (20.6% vs. 15.8%, p=0.039). The introduction of D-dimer in a regression model simplifies the Wells score and maintain the same efficacy and safety, which could improve its implementation in the hospital emergencies. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Phenolic Compounds of Pomegranate Byproducts (Outer Skin, Mesocarp, Divider Membrane) and Their Antioxidant Activities.

PubMed

Ambigaipalan, Priyatharini; de Camargo, Adriano Costa; Shahidi, Fereidoon

2016-08-31

Pomegranate peel was separated into outer leathery skin (PS), mesocarp (PM), and divider membrane (PD), and its phenolic compounds were extracted as free (F), esterified (E), and insoluble-bound (B) forms for the first time. The total phenolic content followed the order PD > PM > PS. ABTS(•+), DPPH, and hydroxyl radical scavenging activities and metal chelation were evaluated. In addition, pomegranate peel extracts showed inhibitory effects against α-glucosidase activity, lipase activity, and cupric ion-induced LDL-cholesterol oxidation as well as peroxyl and hydroxyl radical-induced DNA scission. Seventy-nine phenolic compounds were identified using HPLC-DAD-ESI-MS(n) mainly in the form of insoluble-bound. Thirty compounds were identified for the first time. Gallic acid was the major phenolic compound in pomegranate peel, whereas kaempferol 3-O-glucoside was the major flavonoid. Moreover, ellagic acid and monogalloyl-hexoside were the major hydrolyzable tannins, whereas the dominant proanthocyanidin was procyanidin dimers. Proanthocyanidins were detected for the first time.

Enantioselective syntheses of lignin models: an efficient synthesis of B-O-4 dimers and trimers by using the Evans chiral auxiliary

Treesearch

Costyl N. Njiojob; Joseph J. Bozell; Brian K. Long; Thomas Elder; Rebecca E. Key; William T. Hartwig

2016-01-01

We describe an efficient five-step, enantioselective synthesis of (R,R)- and (S,S)-lignin dimer models possessing a B-O-4 linkage, by using the Evans chiral aldol reaction as a key step. Mitsunobu inversion of the (R,R)- or (S,S)-isomers generates the corresponding (R,S)- and (S,R)-diastereomers. We further extend this approach to the...

Topology-driven phase transitions in the classical monomer-dimer-loop model.

PubMed

Li, Sazi; Li, Wei; Chen, Ziyu

2015-06-01

In this work, we investigate the classical loop models doped with monomers and dimers on a square lattice, whose partition function can be expressed as a tensor network (TN). In the thermodynamic limit, we use the boundary matrix product state technique to contract the partition function TN, and determine the thermodynamic properties with high accuracy. In this monomer-dimer-loop model, we find a second-order phase transition between a trivial monomer-condensation and a loop-condensation (LC) phase, which cannot be distinguished by any local order parameter, while nevertheless the two phases have distinct topological properties. In the LC phase, we find two degenerate dominating eigenvalues in the transfer-matrix spectrum, as well as a nonvanishing (nonlocal) string order parameter, both of which identify the topological ergodicity breaking in the LC phase and can serve as the order parameter for detecting the phase transitions.

Mechanisms of carbon dimer formation in colliding laser-produced carbon plasmas

NASA Astrophysics Data System (ADS)

Sizyuk, Tatyana; Oliver, John; Diwakar, Prasoon K.

2017-07-01

It has been demonstrated that the hot stagnation region formed during the collision of laser-produced carbon plasmas is rich with carbon dimers which have been shown to be synthesized into large carbon macromolecules such as carbon fullerene onions and nanotubes. In this study, we developed and integrated experimental and multidimensional modeling techniques to access the temporal and spatial resolution of colliding plasma characteristics that elucidated the mechanism for early carbon dimer formation. Plume evolution imaging, monochromatic imaging, and optical emission spectroscopy of graphite-produced, carbon plasmas were performed. Experimental results were compared with the results of the 3D comprehensive modeling using our HEIGHTS simulation package. The results are explained based on a fundamental analysis of plasma evolution, colliding layer formation, stagnation, and expansion. The precise mechanisms of the plasma collision, plume propagation, and particle formation are discussed based on the experimental and modeling results.

Ab initio correlated calculations of rare-gas dimer quadrupoles

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

Donchev, Alexander G.

2007-10-15

This paper reports ab initio calculations of rare gas (RG=Kr, Ar, Ne, and He) dimer quadrupoles at the second order of Moeller-Plesset perturbation theory (MP2). The study reveals the crucial role of the dispersion contribution to the RG{sub 2} quadrupole in the neighborhood of the equilibrium dimer separation. The magnitude of the dispersion quadrupole is found to be much larger than that predicted by the approximate model of Hunt. As a result, the total MP2 quadrupole moment is significantly smaller than was assumed in virtually all previous related studies. An analytical model for the distance dependence of the RG{sub 2}more » quadrupole is proposed. The model is based on the effective-electron approach of Jansen, but replaces the original Gaussian approximation to the electron density in an RG atom by an exponential one. The role of the nonadditive contribution in RG{sub 3} quadrupoles is discussed.« less

The Reaction of Criegee Intermediate CH 2OO with Water Dimer: Primary Products and Atmospheric Impact

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

Sheps, Leonid; Rotavera, Brandon; Eskola, Arkke J.

The rapid reaction of the smallest Criegee intermediate, CH 2OO, with water dimers is the dominant removal mechanism for CH 2OO in the Earth's atmosphere, but its products are not well understood. This reaction was recently suggested as a significant source of the most abundant tropospheric organic acid, formic acid (HCOOH), which is consistently underpredicted by atmospheric models. Furthermore, using time-resolved measurements of reaction kinetics by UV absorption and product analysis by photoionization mass spectrometry, we show that the primary products of this reaction are formaldehyde and hydroxymethyl hydroperoxide (HMHP), with direct HCOOH yields of less than 10%. Incorporating ourmore » results into a global chemistry-transport model further reduces HCOOH levels by 10–90%, relative to previous modeling assumptions, which indicates that the reaction CH 2OO + water dimer by itself cannot resolve the discrepancy between the measured and predicted HCOOH levels.« less

The Reaction of Criegee Intermediate CH 2OO with Water Dimer: Primary Products and Atmospheric Impact

DOE PAGES

Sheps, Leonid; Rotavera, Brandon; Eskola, Arkke J.; ...

2017-08-04

The rapid reaction of the smallest Criegee intermediate, CH 2OO, with water dimers is the dominant removal mechanism for CH 2OO in the Earth's atmosphere, but its products are not well understood. This reaction was recently suggested as a significant source of the most abundant tropospheric organic acid, formic acid (HCOOH), which is consistently underpredicted by atmospheric models. Furthermore, using time-resolved measurements of reaction kinetics by UV absorption and product analysis by photoionization mass spectrometry, we show that the primary products of this reaction are formaldehyde and hydroxymethyl hydroperoxide (HMHP), with direct HCOOH yields of less than 10%. Incorporating ourmore » results into a global chemistry-transport model further reduces HCOOH levels by 10–90%, relative to previous modeling assumptions, which indicates that the reaction CH 2OO + water dimer by itself cannot resolve the discrepancy between the measured and predicted HCOOH levels.« less

Immunolocalization of 8-5' and 8-8' linked structures of lignin in cell walls of Chamaecyparis obtusa using monoclonal antibodies.

PubMed

Kiyoto, Shingo; Yoshinaga, Arata; Tanaka, Naoyuki; Wada, Munehisa; Kamitakahara, Hiroshi; Takabe, Keiji

2013-03-01

Mouse monoclonal antibodies were generated against dehydrodiconiferyl alcohol- or pinoresinol-p-aminohippuric acid (pAHA)-bovine serum albumin (BSA) conjugate as probes that specifically react with 8-5' or 8-8' linked structure of lignin in plant cell walls. Hybridoma clones were selected that produced antibodies that positively reacted with dehydrodiconiferyl alcohol- or pinoresinol-pAHA-BSA and negatively reacted with pAHA-BSA and guaiacylglycerol-beta-guaiacyl ether-pAHA-BSA conjugates containing 8-O-4' linkage. Eight clones were established for each antigen and one of each clone that positively reacted with wood sections was selected. The specificity of these antibodies was examined by competitive ELISA tests using various lignin dimers with different linkages. The anti-dehydrodiconiferyl alcohol antibody reacted specifically with dehydrodiconiferyl alcohol and did not react with other model compounds containing 8-O-4', 8-8', or 5-5' linkages. The anti-pinoresinol antibody reacted specifically with pinoresinol and syringaresinol and did not react with the other model compounds containing 8-O-4', 8-5', or 5-5' linkages. The antibodies also did not react with dehydrodiconiferyl alcohol acetate or pinoresinol acetate, indicating that the presence of free phenolic or aliphatic hydroxyl group was an important factor in their reactivity. In sections of Japanese cypress (Chamaecyparis obtusa), labeling by the anti-dehydrodiconiferyl alcohol antibody was found in the secondary walls of phloem fibers and in the compound middle lamellae, and secondary walls of tracheids. Weak labeling by the anti-pinoresinol antibody was found in secondary walls of phloem fibers and secondary walls and compound middle lamellae of developed tracheids. These labelings show the localization of 8-5' and 8-8' linked structure of lignin in the cell walls.

Combination of six enzymes of a marine Novosphingobium converts the stereoisomers of β-O-4 lignin model dimers into the respective monomers

PubMed Central

Ohta, Yukari; Nishi, Shinro; Hasegawa, Ryoichi; Hatada, Yuji

2015-01-01

Lignin, an aromatic polymer of phenylpropane units joined predominantly by β-O-4 linkages, is the second most abundant biomass component on Earth. Despite the continuous discharge of terrestrially produced lignin into marine environments, few studies have examined lignin degradation by marine microorganisms. Here, we screened marine isolates for β-O-4 cleavage activity and determined the genes responsible for this enzymatic activity in one positive isolate. Novosphingobium sp. strain MBES04 converted all four stereoisomers of guaiacylglycerol-β-guaiacyl ether (GGGE), a structural mimic of lignin, to guaiacylhydroxypropanone as an end metabolite in three steps involving six enzymes, including a newly identified Nu-class glutathione-S-transferase (GST). In silico searches of the strain MBES04 genome revealed that four GGGE-metabolizing GST genes were arranged in a cluster. Transcriptome analysis demonstrated that the lignin model compounds GGGE and (2-methoxyphenoxy)hydroxypropiovanillone (MPHPV) enhanced the expression of genes in involved in energy metabolism, including aromatic-monomer assimilation, and evoked defense responses typically expressed upon exposure to toxic compounds. The findings from this study provide insight into previously unidentified bacterial enzymatic systems and the physiological acclimation of microbes associated with the biological transformation of lignin-containing materials in marine environments. PMID:26477321

Unconventional antiferromagnetic correlations of the doped Haldane gapsystem Y 2 BaNi 1 - x Zn x O 5

NASA Astrophysics Data System (ADS)

Villar, V.; Mélin, R.; Paulsen, C.; Souletie, J.; Janod, E.; Payen, C.

2002-01-01

We make a new proposal to describe the very low temperature susceptibility of the doped Haldane gap compound Y2BaNi1-xZnxO5. We propose a new mean field model relevant for this compound. The ground state of this mean field model is unconventional because antiferromagnetism coexists with random dimers. We present new susceptibility experiments at very low temperature. We obtain a Curie-Weiss susceptibility χ(T) C/(Θ + T) as expected for antiferromagnetic correlations but we do not obtain a direct signature of antiferromagnetic long range order. We explain how to obtain the ``impurity'' susceptibility (T) by subtracting the Haldane gap contribution to the total susceptibility. In the temperature range [1 K, 300 K] the experimental data are well fitted by T (T) = Cimp 1 + Timp/T . In the temperature range [100 mK, 1 K] the experimental data are well fitted by T (T) = A ln(T/Tc), where Tc increases with x. This fit suggests the existence of a finite Néel temperature which is however too small to be probed directly in our experiments. We also obtain a maximum in the temperature dependence of the ac-susceptibility (T) which suggests the existence of antiferromagnetic correlations at very low temperature.