Sample records for cyclization reversible base-mediated
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Zhang, Wen-Zhen; Xia, Tian; Yang, Xu-Tong; Lu, Xiao-Bing
2015-04-11
The oxazolidine-2,4-dione motif is found frequently in biologically important compounds. A tandem phosphorus-mediated carboxylative condensation of primary amines and α-ketoesters/base-catalyzed cyclization reaction have been developed. These processes provide a novel and convenient access to various oxazolidine-2,4-diones in a one-pot fashion using atmospheric carbon dioxide and readily available substrates under very mild and transition-metal-free conditions.
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Li, Bai-Jian; Zhong, Hua; Yu, Hai-Tao
2016-12-22
In this study, we employed the density functional method to simulate AIBN/HSnBu 3 -mediated radical cyclizations with different axially chiral conformers of N-(2-iodo-4,6-dimethylphenyl)-N,2-dimethyl-(2E)-butenamide as substrates. We constructed a reaction potential energy profile using the Gibbs free energies of the located stationary points. The thermodynamic and kinetic data of the profile were further used to evaluate the regioselectivity, stereoselectivity, and product distribution of the cyclizations. Additionally, we compared the present HSnBu 3 -mediated radical cyclization with the experimentally available Heck reaction and found that such a radical cyclization can convert (M,Z) and (P,Z) o-iodoanilide substrates to centrally chiral products with high chirality transfer. The goal of this study was to estimate the practicality of theoretically predicting the memory of chirality in such radical cyclizations. The present results can provide a strategy from a theoretical viewpoint for experimentally synthesizing highly stereoselective carbocyclic and heterocyclic compounds using radical cyclization methods.
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Gold-catalyzed and N-iodosuccinimide-mediated cyclization of gamma-substituted allenamides.
Hyland, Christopher J T; Hegedus, Louis S
2006-10-27
Chiral gamma-substituted allenamides have been shown to undergo efficient gold-catalyzed and N-iodosuccinimide-mediated cyclization to highly functionalized dihydrofurans. These reactions proceed rapidly and without loss of stereochemistry.
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Nandi, Ganesh Chandra; Singh, Maya Shankar
2016-07-15
Metal-free, p-toluenesulfonic acid (p-TSA)-mediated, straightforward propargylation of β-ketothioamides with aryl propargyl alcohol has been achieved at room temperature. In addition, the reaction also provided thiazole rings as byproducts. Furthermore, the propargylated thioamides undergo intramolecular 1,5-cyclization to afford fully substituted (hydro)thiophenes in the presence of base. Notably, the approach is pot, atom, and step economical (PASE).
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Locked and proteolysis-based transcription activator-like effector (TALE) regulation.
Lonzarić, Jan; Lebar, Tina; Majerle, Andreja; Manček-Keber, Mateja; Jerala, Roman
2016-02-18
Development of orthogonal, designable and adjustable transcriptional regulators is an important goal of synthetic biology. Their activity has been typically modulated through stimulus-induced oligomerization or interaction between the DNA-binding and activation/repression domain. We exploited a feature of the designable Transcription activator-like effector (TALE) DNA-binding domain that it winds around the DNA which allows to topologically prevent it from binding by intramolecular cyclization. This new approach was investigated through noncovalent ligand-induced cyclization or through a covalent split intein cyclization strategy, where the topological inhibition of DNA binding by cyclization and its restoration by a proteolytic release of the topologic constraint was expected. We show that locked TALEs indeed have diminished DNA binding and regain full transcriptional activity by stimulation with the rapamycin ligand or site-specific proteolysis of the peptide linker, with much higher level of activation than rapamycin-induced heterodimerization. Additionally, we demonstrated reversibility, activation of genomic targets and implemented logic gates based on combinations of protein cyclization, proteolytic cleavage and ligand-induced dimerization, where the strongest fold induction was achieved by the proteolytic cleavage of a repression domain from a linear TALE. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Zhang, Jian; Lv, Yanlin; Zhang, Wei; Ding, Hui; Liu, Rongji; Zhao, Yongsheng; Zhang, Guangjin; Tian, Zhiyuan
2016-01-01
A new type of flavone-based fluorescent probe (DMAF) capable of cysteine (Cys)/homocysteine (Hcy) sensing with high selectivity over other amino acids was developed. Such type of probe undergoes Cys/Hcy-mediated cyclization reaction with the involvement of its aldehyde group, which suppresses of the photoinduced electron transfer (PET) process of the probe molecule and consequently leads to the enhancement of fluorescence emission upon excitation using visible light. The formation of product of the Cys/Hcy-mediated cyclization reaction was confirmed and the preliminary fluorescence imaging experiments revealed the biocompatibility of the as-prepared probe and validated its practicability for intracellular Cys/Hcy sensing. Copyright © 2015 Elsevier B.V. All rights reserved.
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Domínguez, Laura; van Nhien, Albert Nguyen; Tomassi, Cyrille; Len, Christophe; Postel, Denis; Marco-Contelles, José
2004-02-06
The carbanion-mediated sulfonate intramolecular cyclizations (CSIC protocols) of glyco-alpha-sulfonamidonitriles derived from readily available monosaccharides have been extensively investigated using potassium carbonate, cesium carbonate, n-BuLi, and LDA as bases. As a result, a series of enantiomerically pure spiro(4-amino-5-H-2,3-dihydroisothiazole-1,1-dioxide) derivatives have been prepared efficiently and isolated in good yield. The synthesis of these new bicyclic systems is key to accessing a novel range of aza analogues of TSAO nucleosides (ATSAOs).
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Sunsdahl, Bryce; Mickelsen, Ky; Zabawa, Sean; Anderson, Bryon K; Livinghouse, Tom
2016-11-04
Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as reaction participants in metalloamination/cyclization-allylation cascades.
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Schoene, C; Bennett, S P; Howarth, M
2016-01-01
Enzymes often have marginal stability, with unfolding typically leading to irreversible denaturation. This sensitivity is a major barrier, both for de novo enzyme development and for expanding enzyme impact beyond the laboratory. Seeking an approach to enhance resilience to denaturation that could be applied to a range of different enzymes, we developed SpyRing cyclization. SpyRings contain genetically encoded SpyTag (13 amino acids) on the N-terminus and SpyCatcher (12kDa) on the C-terminus of the enzyme, so that the Spy partners spontaneously react together through an irreversible isopeptide bond. SpyRing cyclization gave major increases in thermal resilience, including on a model for enzyme evolution, β-lactamase, and an industrially important enzyme in agriculture and nutrition, phytase. We outline the SpyRing rationale, including comparison of SpyRing cyclization to other cyclization strategies. The cloning strategy is presented for the simple insertion of enzyme genes for recombinant expression. We discuss structure-based approaches to select suitable enzyme cyclization targets. Approaches to evaluate the cyclization reaction and its effect on enzyme resilience are described. We also highlight the use of differential scanning calorimetry to understand how SpyRing cyclization promotes enzyme refolding. Efficiently searching sequence space will continue to be important for enzyme improvement, but the SpyRing platform may be a valuable rational adjunct for conferring resilience. © 2016 Elsevier Inc. All rights reserved.
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Selenium-mediated synthesis of biaryls through rearrangement.
Shahzad, Sohail A; Vivant, Clotilde; Wirth, Thomas
2010-03-19
A new cyclization of beta-keto ester substituted stilbene derivatives using selenium electrophiles in the presence of Lewis acids is described. Substituted naphthols are obtained through cyclization and subsequent 1,2-rearrangement of aryl groups under very mild reaction conditions.
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Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J.
2013-01-01
A study of the reactivity and diastereoselectivity of the Lewis acid-promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone, followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic ynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID:23724905
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Read, Matthew Lovell; Gundersen, Lise-Lotte
2013-02-01
A novel and efficient synthesis of phenanthridines and aza analogues is reported. The key step is a microwave-mediated intramolecular Diels-Alder cyclization of o-furyl(allylamino)arenes. In the presence of a catalytic amount of acid, the DA-adduct reacts further to give the dihydrophenanthridines, which easily can be oxidized to fully aromatic compounds by air in the presence of UV light or by DDQ.
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Mechanistic Study of Nickel-Catalyzed Ynal Reductive Cyclizations Through Kinetic Analysis
Baxter, Ryan D.; Montgomery, John
2011-01-01
The mechanism of nickel-catalyzed, silane-mediated reductive cyclization of ynals has been evaluated. The cyclizations are first-order in [Ni] and [ynal] and zeroth-order in [silane]. These results, in combination with the lack of rapid silane consumption upon reaction initiation are inconsistent with mechanisms involving reaction initiation by oxidative addition of Ni(0) to the silane. Silane consumption occurs only when both the alkyne and aldehyde and are present. Mechanisms involving rate-determining oxidative cyclization to a metallacycle followed by rapid reaction with the silane are consistent with the data obtained. PMID:21438642
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Krenske, Elizabeth H; Davison, Edwin C; Forbes, Ian T; Warner, Jacqueline A; Smith, Adrian L; Holmes, Andrew B; Houk, K N
2012-02-01
Quantum mechanical calculations have been used to study the intramolecular additions of hydroxylamines to alkenes and alkynes ("reverse Cope eliminations"). In intermolecular reverse Cope eliminations, alkynes are more reactive than alkenes. However, competition experiments have shown that tethering the hydroxylamine to the alkene or alkyne can reverse the reactivity order from that normally observed. The exact outcome depends on the length of the tether. In agreement with experiment, a range of density functional theory methods and CBS-QB3 calculations predict that the activation energies for intramolecular reverse Cope eliminations follow the order 6-exo-dig < 5-exo-trig < 5-exo-dig ≈ 7-exo-dig. The order of the barriers for the 5-, 6-, and 7-exo-dig reactions of alkynes arises mainly from differences in tether strain in the transition states (TSs), but is also influenced by the TS interaction between the hydroxylamine and alkyne. Cyclization onto an alkene in the 5-exo-trig fashion incurs slightly less tether strain than a 6-exo-dig alkyne cyclization, but its activation energy is higher because the hydroxylamine fragment must distort more before the TS is reached. If the alkene terminus is substituted with two methyl groups, the barrier becomes so much higher that it is also disfavored compared to the 5- and 7-exo-dig cyclizations. © 2012 American Chemical Society
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Krenske, Elizabeth H.; Davison, Edwin C.; Forbes, Ian T.; Warner, Jacqueline A.; Smith, Adrian L.; Holmes, Andrew B.; Houk, K. N.
2012-01-01
Quantum mechanical calculations have been used to study the intramolecular additions of hydroxylamines to alkenes and alkynes (“reverse Cope eliminations”). In intermolecular reverse Cope eliminations, alkynes are more reactive than alkenes. However, competition experiments have shown that tethering the hydroxylamine to the alkene or alkyne can reverse the reactivity order from that normally observed. The exact outcome depends on the length of the tether. In agreement with experiment, a range of density functional theory methods and CBS-QB3 calculations predict that the activation energies for intramolecular reverse Cope eliminations follow the order 6-exo-dig < 5-exo-trig < 5-exo-dig ≈ 7-exo-dig. The order of the barriers for the 5-, 6-, and 7-exo-dig reactions of alkynes arises mainly from differences in tether strain in the transition states, but is also influenced by the transition-state interaction between the hydroxylamine and alkyne. Cyclization onto an alkene in the 5-exo-trig fashion incurs slightly less tether strain than a 6-exo-dig alkyne cyclization, but its activation energy is higher because the hydroxylamine fragment must distort more before the TS is reached. If the alkene terminus is substituted with two methyl groups, the barrier becomes so much higher that it is also disfavored compared to the 5- and 7-exo-dig cyclizations. PMID:22280245
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Chen, Haorong; Weng, Te-Wei; Riccitelli, Molly M; Cui, Yi; Irudayaraj, Joseph; Choi, Jong Hyun
2014-05-14
DNA origami represents a class of highly programmable macromolecules that can go through conformational changes in response to external signals. Here we show that a two-dimensional origami rectangle can be effectively folded into a short, cylindrical tube by connecting the two opposite edges through the hybridization of linker strands and that this process can be efficiently reversed via toehold-mediated strand displacement. The reconfiguration kinetics was experimentally studied as a function of incubation temperature, initial origami concentration, missing staples, and origami geometry. A kinetic model was developed by introducing the j factor to describe the reaction rates in the cyclization process. We found that the cyclization efficiency (j factor) increases sharply with temperature and depends strongly on the structural flexibility and geometry. A simple mechanical model was used to correlate the observed cyclization efficiency with origami structure details. The mechanical analysis suggests two sources of the energy barrier for DNA origami folding: overcoming global twisting and bending the structure into a circular conformation. It also provides the first semiquantitative estimation of the rigidity of DNA interhelix crossovers, an essential element in structural DNA nanotechnology. This work demonstrates efficient DNA origami reconfiguration, advances our understanding of the dynamics and mechanical properties of self-assembled DNA structures, and should be valuable to the field of DNA nanotechnology.
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Armaly, Ahlam M; Bar, Sukanta; Schindler, Corinna S
2017-08-04
The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on 13 C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides.
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Oxidative Folding and N-terminal Cyclization of Onconase+
Welker, Ervin; Hathaway, Laura; Xu, Guoqiang; Narayan, Mahesh; Pradeep, Lovy; Shin, Hang-Cheol; Scheraga, Harold A.
2008-01-01
Cyclization of the N-terminal glutamine residue to pyroglutamic acid in onconase, an anti-cancer chemotherapeutic agent, increases the activity and stability of the protein. Here, we examine the correlated effects of the folding/unfolding process and the formation of this N-terminal pyroglutamic acid. The results in this study indicate that cyclization of the N-terminal glutamine has no significant effect on the rate of either reductive unfolding or oxidative folding of the protein. Both the cyclized and uncyclized proteins seem to follow the same oxidative folding pathways; however, cyclization altered the relative flux of the protein in these two pathways by increasing the rate of formation of a kinetically trapped intermediate. Glutaminyl cyclase (QC) catalyzed the cyclization of the unfolded, reduced protein, but had no effect on the disulfide-intact, uncyclized, folded protein. The structured intermediates of uncyclized onconase were also resistant to QC-catalysis, consistent with their having a native-like fold. These observations suggest that, in vivo, cyclization takes place during the initial stages of oxidative folding, specifically, before the formation of structured intermediates. The competition between oxidative folding and QC-mediated cyclization suggests that QC-catalyzed cyclization of the N-terminal glutamine in onconase occurs in the endoplasmic reticulum, probably co-translationally. PMID:17439243
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Shibahara, Fumitoshi; Kitagawa, Asumi; Yamaguchi, Eiji; Murai, Toshiaki
2006-11-23
Iodine-mediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides serves as an efficient and versatile method for the preparation of 2-azaindolizines (imidazo[1,5-a]pyridines) and rare 2-azaindolizine sulfur-bridged dimers. The 2-azaindolizines prepared in this manner are readily converted to a variety of fluorescent compounds by using transition-metal-catalyzed cross-coupling reactions. [reaction: see text].
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Butelase-mediated cyclization and ligation of peptides and proteins.
Nguyen, Giang K T; Qiu, Yibo; Cao, Yuan; Hemu, Xinya; Liu, Chuan-Fa; Tam, James P
2016-10-01
Enzymes that catalyze efficient macrocyclization or site-specific ligation of peptides and proteins can enable tools for drug design and protein engineering. Here we describe a protocol to use butelase 1, a recently discovered peptide ligase, for high-efficiency cyclization and ligation of peptides and proteins ranging in size from 10 to >200 residues. Butelase 1 is the fastest known ligase and is found in pods of the common medicinal plant Clitoria ternatea (also known as butterfly pea). It has a very simple C-terminal-specific recognition motif that requires Asn/Asp (Asx) at the P1 position and a dipeptide His-Val at the P1' and P2' positions. Substrates for butelase-mediated ligation can be prepared by standard Fmoc (9-fluorenylmethyloxycarbonyl) chemistry or recombinant expression with the minimal addition of this tripeptide Asn-His-Val motif at the C terminus. Butelase 1 achieves cyclizations that are 20,000 times faster than those of sortase A, a commonly used enzyme for backbone cyclization. Unlike sortase A, butelase is traceless, and it can be used for the total synthesis of naturally occurring peptides and proteins. Furthermore, butelase 1 is also useful for intermolecular ligations and synthesis of peptide or protein thioesters, which are versatile activated intermediates necessary for and compatible with many chemical ligation methods. The protocol describes steps for isolation and purification of butelase 1 from plant extract using a four-step chromatography procedure, which takes ∼3 d. We then describe steps for intramolecular cyclization, intermolecular ligation and butelase-mediated synthesis of protein thioesters. Butelase reactions are generally completed within minutes and often achieve excellent yields.
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Catalytic Enantioselective Cyclization and C3-Fluorination of Polyenes
Cochrane, Nikki A.; Nguyen, Ha; Gagne, Michel R.
2013-01-01
(xylyl-phanephos)Pt2+ in combination with XeF2 mediates the consecutive diastereoselective cation-olefin cyclization/fluorination of polyene substrates. Isolated yields were typically in the 60s while enantioselectivies reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P2Pt-alkyl cation intermediate. PMID:23282101
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Shimamura, Hiroyuki; Breazzano, Steven P; Garfunkle, Joie; Kimball, F Scott; Trzupek, John D; Boger, Dale L
2010-06-09
Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration. In this instance, the complexity of the substrate and the reverse macrocyclization order did not diminish the atropodiastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with the analogous substrate used to provide the isolated DEF ring system in our first-generation approach. Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling.
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Miranda, James A; Wade, Carolyn J; Little, R Daniel
2005-09-30
[Chemical reaction: See text] We describe efforts to achieve the electroreductive cyclization (ERC) and the electrohydrocyclization (EHC) reactions using catalytic nickel(II) salen as a mediator. While nickel(II) salen proved effective, the analogous cobalt complex as well as nickel(II) cyclam were not. The transformations were achieved in yields ranging from 60 to 94% using either a mercury pool or an environmentally preferable reticulated vitreous carbon (RVC) cathode. These examples represent the first instances wherein a nickel salen complex has been used in this manner. Clear differences between the voltammetric behavior of the ERC and EHC substrates were observed. The bisenoate 14, for example, displays a substantially larger catalytic current. When the structurally modified mediator 31 was used, the electron-transfer pathway shuts down. Instead, the reduced form of 31 behaves as an electrogenerated base, leading to the formation of the intramolecular Michael adduct 23. Presumably, the methyl groups of the modified ligand diminish the ability of the reduced form of the complex to serve as a nucleophile but not as a base. Aldehyde 23 was also characterized as a side product of the nickel(II) salen mediated electroreductive cyclization of 11. Given that it is absent from nonmediated processes, its formation is linked to the presence of the mediator. To account for the results, we favor the existence of a mechanistic continuum involving an equilibrium between nickel(II) salen (15) and two reduced forms, one being the metal-centered species 16, the other being a ligand-centered species 17. We postulate that one form may be more prominently involved with the chemistry than another, depending upon the electronic properties/requirements of the substrate, and suggest that the equilibrium will shift to accommodate the need. Thus, for a hard electrophile like an alkyl halide, the properties of 16 ought to dominate, whereas 17 ought to predominate as the reactive species accounting for the chemistry described herein since it properly matches a soft ligand-centered nucleophile with a soft electron deficient alkene.
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Wang, Rui-Xiang; Yuan, Si-Tian; Liu, Jin-Biao; Wu, Jie; Qiu, Guanyinsheng
2018-06-06
A TBAB-mediated brominative 5-exo-dig oxy-cyclization of 2-alkynylbenzamide is described here for the synthesis of isobenzofuran-1-imines and isobenzofuran derivatives at room temperature with a high efficiency and a broad reaction scope. The resulting isobenzofuran derivatives are also applied for synthesising various substituted isobenzofuran derivatives.
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Karad, Somnath Narayan; Panchal, Heena; Clarke, Christopher; Lewis, William; Lam, Hon Wai
2018-05-16
The enantioselective synthesis of highly functionalized chiral cyclopent-2-enones by the reaction of alkynyl malonate esters with arylboronic acids is described. These desymmetrizing arylative cyclizations are catalyzed by a chiral phosphinooxazoline-nickel complex, and cyclization is enabled by the reversible E/Z isomerization of alkenylnickel species. The general methodology is also applicable to the synthesis of 1,6-dihydropyridin-3(2H)-ones. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Li, De-Yao; Wei, Yin; Shi, Min
2013-11-11
Diynes containing a cyclopropane group smoothly undergo a novel intramolecular and stereoselective cascade addition/cyclization reaction to produce the corresponding 1-methyleneindene derivatives in moderate to good yields. This interesting transformation is mediated by Grignard reagent/CuI with LiCl as an additive under mild conditions. The obtained product can easily be further functionalized through cyclopropyl ring opening. A plausible reaction mechanism has also been presented on the basis of deuterium labeling and control experiments. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Preparation of dibenzo[e,g]isoindol-1-ones via Scholl-type oxidative cyclization reactions.
van Loon, Amy A; Holton, Maeve K; Downey, Catherine R; White, Taryn M; Rolph, Carly E; Bruening, Stephen R; Li, Guanqun; Delaney, Katherine M; Pelkey, Sarah J; Pelkey, Erin T
2014-09-05
A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki-Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.
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Preparation of Dibenzo[e,g]isoindol-1-ones via Scholl-Type Oxidative Cyclization Reactions
2015-01-01
A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki–Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization. PMID:25138638
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Al Hazmi, Ali M; Sheikh, Nadeem S; Bataille, Carole J R; Al-Hadedi, Azzam A M; Watkin, Sam V; Luker, Tim J; Camp, Nicholas P; Brown, Richard C D
2014-10-03
The permanganate-mediated oxidative cyclization of a series of 2-methylenehept-5-eneoates bearing different chiral auxiliaries was investigated, leading to the discovery of trans-2-tritylcyclohexanol (TTC) as a highly effective chiral controller for the formation of the 2,5-substituted THF diol product with high diastereoselectivity (dr ∼97:3). Chiral resolution of (±)-TTC, prepared in one step from cyclohexene oxide, afforded (-)-(1S,2R)-TTC (er >99:1), which was applied to the synthesis of (+)-trans-(2S,5S)-linalool oxide.
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Álvarez-Calero, José María; Ruiz, Enrique; López-Pérez, José Luis; Jaraíz, Martín; Rubio, José E; Jorge, Zacarías D; Suárez, Margarita; Massanet, Guillermo M
2018-05-18
A study on the electrophile-induced rearrangement of two 15-hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15-diol acetonide being the main product obtained. The δ-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken.
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Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals
NASA Astrophysics Data System (ADS)
Kern, Nicolas; Plesniak, Mateusz P.; McDouall, Joseph J. W.; Procter, David J.
2017-12-01
The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.
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Luo, Dan; Callari, Roberta; Hamberger, Britta; ...
2016-08-09
The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon–carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved inmore » the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids.« less
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Soriano, Elena; Marco-Contelles, José
2009-06-05
The mechanisms for the formation of conformationally constrained epibatidine analogues by intramolecular free radical processes have been computationally addressed by means of DFT methods. The mechanism and the critical effect of the 7-nitrogen protecting group on the outcome of these radical-mediated cyclizations are discussed. Theoretical findings account for unexpected experimental results and can assist in the selection of proper precursors for a successful cyclization.
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Liang, Zhongwei; Xu, Song; Tian, Wenyan; Zhang, Ronghua
2015-01-01
A novel and simple strategy for the efficient synthesis of the corresponding tetrahydroquinolines from N,N-dimethylanilines and maleimides using visible light in an air atmosphere in the presence of Eosin Y as a photocatalyst has been developed. The metal-free protocol involves aerobic oxidative cyclization via sp(3) C-H bond functionalization process to afford good yields in a one-pot procedure under mild conditions.
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One-Pot Synthesis of Cyclopropane-Fused Cyclic Amidines: An Oxidative Carbanion Cyclization.
Veeranna, Kirana Devarahosahalli; Das, Kanak Kanti; Baskaran, Sundarababu
2017-12-18
A novel and efficient one-pot method has been developed for the synthesis of cyclopropane-fused bicyclic amidines on the basis of a CuBr 2 -mediated oxidative cyclization of carbanions. The usefulness of this unique multicomponent strategy has been demonstrated by the use of a wide variety of substrates to furnish novel cyclopropane-containing amidines with a quaternary center in very good yields. This ketenimine-based approach provides straightforward access to biologically active and pharmaceutically important 3-azabicyclo[n.1.0]alkane frameworks under mild conditions. The synthetic power of this methodology is exemplified in the concise synthesis of the pharmaceutically important antidepressant drug candidate GSK1360707 and key intermediates for the synthesis of amitifadine, bicifadine, and narlaprevir. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Satou, Ryutaro; Miyanaga, Akimasa; Ozawa, Hiroki; Funa, Nobutaka; Katsuyama, Yohei; Miyazono, Ken-ichi; Tanokura, Masaru; Ohnishi, Yasuo; Horinouchi, Sueharu
2013-11-22
Type III polyketide synthases (PKSs) show diverse cyclization specificity. We previously characterized two Azotobacter type III PKSs (ArsB and ArsC) with different cyclization specificity. ArsB and ArsC, which share a high sequence identity (71%), produce alkylresorcinols and alkylpyrones through aldol condensation and lactonization of the same polyketomethylene intermediate, respectively. Here we identified a key amino acid residue for the cyclization specificity of each enzyme by site-directed mutagenesis. Trp-281 of ArsB corresponded to Gly-284 of ArsC in the amino acid sequence alignment. The ArsB W281G mutant synthesized alkylpyrone but not alkylresorcinol. In contrast, the ArsC G284W mutant synthesized alkylresorcinol with a small amount of alkylpyrone. These results indicate that this amino acid residue (Trp-281 of ArsB or Gly-284 of ArsC) should occupy a critical position for the cyclization specificity of each enzyme. We then determined crystal structures of the wild-type and G284W ArsC proteins at resolutions of 1.76 and 1.99 Å, respectively. Comparison of these two ArsC structures indicates that the G284W substitution brings a steric wall to the active site cavity, resulting in a significant reduction of the cavity volume. We postulate that the polyketomethylene intermediate can be folded to a suitable form for aldol condensation only in such a relatively narrow cavity of ArsC G284W (and presumably ArsB). This is the first report on the alteration of cyclization specificity from lactonization to aldol condensation for a type III PKS. The ArsC G284W structure is significant as it is the first reported structure of a microbial resorcinol synthase.
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On-Surface Pseudo-High-Dilution Synthesis of Macrocycles: Principle and Mechanism.
Fan, Qitang; Wang, Tao; Dai, Jingya; Kuttner, Julian; Hilt, Gerhard; Gottfried, J Michael; Zhu, Junfa
2017-05-23
Macrocycles have attracted much attention due to their specific "endless" topology, which results in extraordinary properties compared to related linear (open-chain) molecules. However, challenges still remain in their controlled synthesis with well-defined constitution and geometry. Here, we report the successful application of the (pseudo-)high-dilution method to the conditions of on-surface synthesis in ultrahigh vacuum. This approach leads to high yields (up to 84%) of cyclic hyperbenzene ([18]-honeycombene) via an Ullmann-type reaction from 4,4″-dibromo-meta-terphenyl (DMTP) as precursor on a Ag(111) surface. The mechanism of macrocycle formation was explored in detail using scanning tunneling microscopy and X-ray photoemission spectroscopy. We propose that the dominant pathway for hyperbenzene (MTP) 6 formation is the stepwise desilverization of an organometallic (MTP-Ag) 6 macrocycle, which forms via cyclization of (MTP-Ag) 6 chains under pseudo-high-dilution conditions. The high probability of cyclization on the stage of the organometallic phase results from the reversibility of the C-Ag bond. The case is different from that in solution, in which cyclization typically occurs on the stage of a covalently bonded open-chain precursor. This difference in the cyclization mechanism on a surface compared to that in solution stems mainly from the 2D confinement exerted by the surface template, which hinders the flipping of chain segments necessary for cyclization.
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Eichberg, M J; Dorta, R L; Grotjahn, D B; Lamottke, K; Schmidt, M; Vollhardt, K P
2001-09-26
Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2] cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.
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Genome Cyclization as Strategy for Flavivirus RNA Replication
Villordo, Sergio M.; Gamarnik, Andrea V.
2017-01-01
Long-range and local RNA-RNA contacts in viral RNA genomes result in tertiary structures that modulate the function of enhancers, promoters, and silencers during translation, RNA replication, and encapsidation. In the case of flaviviruses, the presence of inverted complementary sequences at the 5′ and 3′ ends of the genome mediate long-range RNA interactions and RNA cyclization. The circular conformation of flavivirus genomes was demonstrated to be essential for RNA amplification. New ideas about the mechanisms by which circular genomes participate in flavivirus replication have emerged in the last few years. Here, we will describe the latest information about cis-acting elements involved in flavivirus genome cyclization, RNA promoter elements required for viral polymerase recognition, and how these elements together coordinate viral RNA synthesis. PMID:18703097
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Iridium-mediated isomerization-cyclization of bicyclic Pauson-Khand derived allylic alcohols.
Kavanagh, Yvonne; Chaney, Cíara M; Muldoon, Jimmy; Evans, Paul
2008-11-07
Treatment of 2-(toluene-4-sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-[2]pyrindin-6-ol 10, accessed from the diastereoselective Luche reduction of a Pauson-Khand derived bicylic cyclopentenone, with a catalytic amount of (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate 1 (Crabtree's catalyst) under a hydrogen atmosphere resulted in the formation of 4-(toluene-4-sulfonyl)-2-oxa-4-azatricyclo[5.2.1.0(3,8)]decane 12 as a single diastereoisomer. This process is likely to proceed via an initial Ir(I)-mediated isomerization of the alkene to form an N-sulfonyl enamine 11, followed by cyclization. Evidence to support this came when, after short reaction periods, 11 was isolated, characterized spectroscopically, and on resubmission to the reaction conditions formed 12.
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Wang, Shanshan; Dong, Cheng; Yu, Lian; Guo, Cheng; Jiang, Kezhi
2016-01-15
In the tandem mass spectrometry of protonated N-(3-phenyl-2H-chromen-2-ylidene)benzenesulfonamides, the precursor ions have been observed to undergo gas-phase dissociation via two competing channels: (a) the predominant channel involves migration of the sulfonyl cation to the phenyl C atom and the subsequent loss of benzenesulfinic acid along with cyclization reaction, and (b) the minor one involves dissociation of the precursor ion to give an ion/neutral complex of [sulfonyl cation/imine], followed by decomposition to afford sulfonyl cation or the INC-mediated electron transfer to give an imine radical cation. The proposed reaction channels have been supported by theoretical calculations and D-labeling experiments. The gas-phase cyclization reaction originating from the N- to C-sulfonyl cation transfer has been first reported to the best of our knowledge. For the substituted sulfonamides, the presence of electron-donating groups (R(2) -) at the C-ring effectively facilitates the reaction channel of cyclization reaction, whereas that of electron-withdrawing groups inhibits this pathway. Copyright © 2015 John Wiley & Sons, Ltd.
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Kurouchi, Hiroaki; Sugimoto, Hiromichi; Otani, Yuko; Ohwada, Tomohiko
2010-01-20
The chemical features, such as substrate stability, product distribution, and substrate generality, and the reaction mechanism of Brønsted superacid-catalyzed cyclization reactions of aromatic ring-containing acetoacetates (beta-ketoesters) were examined in detail. While two types of carbonyl cyclization are possible, i.e., keto cyclization and ester cyclization, the former was found to take place exclusively. The reaction constitutes an efficient method to synthesize indene and 3,4-dihydronapthalene derivatives. Acid-base titration monitored with (13)C NMR spectroscopy showed that the acetoacetates are fully O(1),O(3)-diprotonated at H(0) = -11. While the five-membered ring cyclization of the arylacetoacetates proceeded slowly at H(0) = -11, a linear increase in the rate of the cyclization was found with increasing acidity in the high acidity region of H(0) = -11.8 to -13.3. Therefore, the O(1),O(3)-diprotonated acetoacetates exhibited some cyclizing reactivity, but they are not the reactive intermediates responsible for the acceleration of the cyclization in the high acidity region. The reactive cationic species might be formed by further protonation (or protosolvation) of the O(1),O(3)-diprotonated acetoacetates; i.e., they may be tricationic species. Thermochemical data on the acid-catalyzed cyclization of the arylacetoacetates showed that the activation energy is decreased significantly as compared with that of the related acid-catalyzed cyclization reaction of a compound bearing a single functional group, such as a ketone. These findings indicate that intervention of the trication contributes to the activation of the cyclization of arylacetoacetates in strong acid, and the electron-withdrawing nature of the O-protonated ester functionality significantly increases the electrophilicity of the ketone moiety.
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Synthesis, characterization and intramolecular cyclisation study of three new liquid crystals
NASA Astrophysics Data System (ADS)
Saïdat, B.; Guermouche, M. H.; Bayle, J.-P.
2004-12-01
Internal cyclization of three new phenyldiazene liquid crystals (R is an alkyl substituent with 4, 6 or 8 carbons) with activated methylene group in the ortho position to the diazo linkage was studied . The initial liquid crystals was synthesised and characterized by ^1H NMR, electrospray mass spectrometry and differential scanning calorimetry. The final compound was characterized by ^1H NMR and differential scanning calorimetry. The kinetic of cyclization was studied at different temperatures and followed by reversed phase HPLC and a UV detection. For all the temperatures used, it appeared that the cyclisation was a first order reaction for the three compounds. The Arrhenius plot (ln reaction constant k against 1000/T) gave the mean activation energy of the cyclisation.
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Synthesis of the BCDE molecular fragment of azadiradione mediated by titanocene(III).
Fernández-Mateos, A; Madrazo, S Encinas; Teijón, P Herrero; Clemente, R Rabanedo; González, R Rubio; González, F Sanz
2013-10-04
A practical, short, and diastereoselective synthesis of the azadiradione BCDE fragment from a readily available starting material is described. The key step was the titanocene(III)-promoted tandem cyclization of unsaturated epoxy nitrile.
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García Santos, William H; Puerto Galvis, Carlos E; Kouznetsov, Vladimir V
2015-02-07
A selective and mild method for the esterification of a variety of carboxylic acids with geraniol is developed. We demonstrated that the use of triphenylphosphine, I2, 2-methylimidazole or imidazole and a catalytic amount of Gd(OTf)3 resulted to be more active than the previous protocols, providing a 16-membered library of geranyl esters in higher yields and in shorter reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with geraniol, as a raw material for the synthesis of the target compounds complemented and proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation of the obtained geranyl esters led us to study their regio-controlled radical cyclization mediated by titanocene(III) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities.
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Takahashi, Ohgi; Kirikoshi, Ryota; Manabe, Noriyoshi
2015-01-01
Succinimide formation from aspartic acid (Asp) residues is a concern in the formulation of protein drugs. Based on density functional theory calculations using Ace-Asp-Nme (Ace = acetyl, Nme = NHMe) as a model compound, we propose the possibility that acetic acid (AA), which is often used in protein drug formulation for mildly acidic buffer solutions, catalyzes the succinimide formation from Asp residues by acting as a proton-transfer mediator. The proposed mechanism comprises two steps: cyclization (intramolecular addition) to form a gem-diol tetrahedral intermediate and dehydration of the intermediate. Both steps are catalyzed by an AA molecule, and the first step was predicted to be rate-determining. The cyclization results from a bond formation between the amide nitrogen on the C-terminal side and the side-chain carboxyl carbon, which is part of an extensive bond reorganization (formation and breaking of single bonds and the interchange of single and double bonds) occurring concertedly in a cyclic structure formed by the amide NH bond, the AA molecule and the side-chain C=O group and involving a double proton transfer. The second step also involves an AA-mediated bond reorganization. Carboxylic acids other than AA are also expected to catalyze the succinimide formation by a similar mechanism. PMID:25588215
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Takahashi, Ohgi; Kirikoshi, Ryota; Manabe, Noriyoshi
2015-01-12
Succinimide formation from aspartic acid (Asp) residues is a concern in the formulation of protein drugs. Based on density functional theory calculations using Ace-Asp-Nme (Ace = acetyl, Nme = NHMe) as a model compound, we propose the possibility that acetic acid (AA), which is often used in protein drug formulation for mildly acidic buffer solutions, catalyzes the succinimide formation from Asp residues by acting as a proton-transfer mediator. The proposed mechanism comprises two steps: cyclization (intramolecular addition) to form a gem-diol tetrahedral intermediate and dehydration of the intermediate. Both steps are catalyzed by an AA molecule, and the first step was predicted to be rate-determining. The cyclization results from a bond formation between the amide nitrogen on the C-terminal side and the side-chain carboxyl carbon, which is part of an extensive bond reorganization (formation and breaking of single bonds and the interchange of single and double bonds) occurring concertedly in a cyclic structure formed by the amide NH bond, the AA molecule and the side-chain C=O group and involving a double proton transfer. The second step also involves an AA-mediated bond reorganization. Carboxylic acids other than AA are also expected to catalyze the succinimide formation by a similar mechanism.
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Total Synthesis of (±)–Rocaglamide via Oxidation-Initiated Nazarov Cyclization
Malona, John A.; Cariou, Kevin; Spencer, William T.
2012-01-01
This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)–rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide. PMID:22283818
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Liu, Xingyan; Li, Gaocan; Song, Feijie; You, Jingsong
2014-09-25
Rhodium-catalyzed carbon-hydrogen bond activation has attracted great interest in the construction of carbon-carbon and carbon-heteroatom bonds. In recent years, transition metal-mediated oxygen transposition through a 'dehydration-rehydration' process has been considered as a promising strategy towards oxygen-functionalized compounds. Here we describe an unexpected rhodium-catalyzed regioselective carbon-hydrogen bond activation/cyclization of easily available indolyl aldehydes or ketones with alkynes to afford benzo-fused oxindoles, involving the sequential carbonyl-assisted carbon-hydrogen activation of the indole ring at the 4-position, [4+2] cyclization, aromatization via dehydration, nucleophilic addition of water to iminium and oxidation. Isotopic labelling experiments disclose the occurrence of apparent oxygen transposition via dehydration-rehydration from the indolyl-3-carbonyl group to the 2-position of pyrrole to forge a new carbonyl bond. The tandem reaction has been used as the key step for the concise synthesis of priolines, a type of alkaloid isolated from the roots of Salvia prionitis.
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Mild and efficient molybdenum-mediated Pauson-Khand-type reaction.
Adrio, Javier; Rivero, Marta Rodríguez; Carretero, Juan Carlos
2005-02-03
[reaction: see text] The molybdenum-mediated Pauson-Khand reaction promoted by Mo(CO)3(DMF)3 takes place under very mild conditions in the absence of any promoter. High yields in Pauson-Khand adducts are obtained in the cyclization of a wide variety of functionalized 1,6- and 1,7-enynes. Enynes bearing electron withdrawing groups at the alkene terminus are particularly good substrates.
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Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization.
Feng, Ruozhu; Smith, Jake A; Moeller, Kevin D
2017-09-19
Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to overoxidation. Solutions to this problem require an approach that either slows down elimination side reactions or changes the reaction conditions so that the cation can be quickly trapped in an irreversible fashion. Again, this Account highlights these strategies along with the specific experimental protocols utilized.
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Prebiotic synthesis and reactions of nucleosides and nucleotides
NASA Astrophysics Data System (ADS)
Ferris, J. P.; Yanagawa, H.; Hagan, W. J.
Diiminosuccinonitrile (DISN) has been investigated as a potential prebiotic phosphorylating agent. It is formed readily by the oxidation of diaminomaleonitrile (DAMN), a tetramer of HCN, DISN effects the cyclization of 3'-adenosine monophosphate to adenosine 2',3'-cyclic phosphate in up to 40% yield. The DISN-mediated phosphorylation of uridine to uridine monophosphate does not proceed efficiently in aqueous solution. The reaction of DISN and BrCN with uridine-5'-phosphate and uridine results in the formation of 2,2'-anhydronucleotides and 2,2'-anhydronucleosides respectively, and other reaction products resulting from an initial reaction at the 2'- and 3'-hydroxyl groups. The clay mineral catalysis of the cyclization of adenosine-3'-phosphate was investigated using homoionic montmorillonites.
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The prebiotic chemistry of nucleotides
NASA Technical Reports Server (NTRS)
Ferris, J. P.; Yanagawa, H.; Hagan, W. J., Jr.
1984-01-01
Diminosuccinonitrile (DISN), formed by the oxidation of diaminomaleonitrile, has been investigated as a potential prebiotic phosphorylating agent. DISN affects the cyclization of 3'-adenosine monophosphate to adenosine 2',3'-cyclic phosphate in up to 39 percent yield. The mechanism of this reaction was investigated. The DISN-mediated phosphorylation of uridine to uridine monophosphate does not proceed efficiencly in aqueous solution. The reaction of DISN with uridine-5'-phosphate and uridine results in the formation of 2,2'-anhydronucleotides and 2,2'-anhydronucleosides respectively, and other reaction products resulting from an initial reaction at the 2'- and 3'-hydroxyl groups. The clay mineral catalysis of the cyclization of adenosine-3'-phosphate was investigated using homoionic montmorillonites.
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The Prebiotic Chemistry of Nucleotides
NASA Astrophysics Data System (ADS)
Ferris, J. P.; Yanagawa, H.; Hagan, W. J., Jr.
1984-12-01
Diiminosuccinonitrile (DISN), formed by the oxidation of diaminomaleonitrile (DAMN), has been investigated as a potential prebiotic phosphorylating agent. DISN effects the cyclization of 3'-adenosine monophosphate to adenosine 2', 3'-cyclic phosphate in up to 39% yield. The mechanism of this reaction was investigated. The DISN-mediated phosphorylation of uridine to uridine monophosphate does not proceed efficiently in aqueous solution. The reaction of DISN with uridine-5'-phosphate and uridine results in the formation of 2,2'-anhydronucleotides and 2,2'-anhydronucleosides respectively, and other reaction products resulting from an initial reaction at the 2'- and 3'-hydroxyl groups. The clay mineral catalysis of the cyclization of adenosine-3'-phosphate was investigated using homoionic montmorillonites.
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Titanium(IV) isopropoxide mediated synthesis of pyrimidin-4-ones.
Ramanjulu, Joshi M; Demartino, Michael P; Lan, Yunfeng; Marquis, Robert
2010-05-21
A novel, one-step method for the synthesis of tri- and tetrasubstituted pyrimidin-4-ones is reported. This method involves a titanium(IV)-mediated cyclization involving two sequential condensations of primary and beta-ketoamides. The reaction is operationally facile, readily scalable, and offers rapid entry into differentially substituted pyrimidin-4-one scaffolds. The high functional group compatibility allows for substantial diversification in the products generated from this transformation.
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NASA Astrophysics Data System (ADS)
Adams, Kirsty; Ball, Anthony K.; Birkett, James; Brown, Lee; Chappell, Ben; Gill, Duncan M.; Lo, P. K. Tony; Patmore, Nathan J.; Rice, Craig. R.; Ryan, James; Raubo, Piotr; Sweeney, Joseph B.
2017-04-01
Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.
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Amine-selective bioconjugation using arene diazonium salts.
Diethelm, Stefan; Schafroth, Michael A; Carreira, Erick M
2014-08-01
A novel bioconjugation strategy is presented that relies on the coupling of diazonium terephthalates with amines in proteins. The diazonium captures the amine while the vicinal ester locks it through cyclization, ensuring no reversibility. The reaction is highly efficient and proceeds under mild conditions and short reaction times. Densely functionalized, complex natural products were directly coupled to proteins using low concentrations of coupling partners.
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Synthesis of two potent glucocorticoid receptor agonists labeled with carbon-14 and stable isotopes.
Latli, Bachir; Reeves, Jonathan T; Tan, Zhulin; Hrapchak, Matt; Song, Jinhua J; Busacca, Carl B; Senanayake, Chris H
2015-01-01
Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-(14)C]pyrimidine [(14)C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [(14)C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [(14)C]-carbon dioxide. A chiral auxiliary (S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [(14)C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [(14)C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [(14)C]-(18) and finally removal of the chiral auxiliary gave [(14)C]-(2) in 7% overall yield. For stable isotope syntheses, [(13)C6]-(1) was obtained in three steps using [(13)C4]-(6) and trimethylsilylacetylene-[(13)C2] in 26% yield, while [(2)H5]-(2) was obtained by first preparing the iodopyridine [(2)H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [(2)H5]-(2) in 42% overall yield. Copyright © 2015 John Wiley & Sons, Ltd.
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SYNTHESIS OF ALLENE ARYL DELTA-LACTONES VIA INDIUM-MEDIATED [4+2] CYCLIZATION IN WATER. (R822668)
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...
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Terminal structures of West Nile virus genomic RNA and their interactions with viral NS5 protein
DOE Office of Scientific and Technical Information (OSTI.GOV)
Dong Hongping; Zhang Bo; Shi Peiyong
2008-11-10
Genome cyclization is essential for flavivirus replication. We used RNases to probe the structures formed by the 5'-terminal 190 nucleotides and the 3'-terminal 111 nucleotides of the West Nile virus (WNV) genomic RNA. When analyzed individually, the two RNAs adopt stem-loop structures as predicted by the thermodynamic-folding program. However, when mixed together, the two RNAs form a duplex that is mediated through base-pairings of two sets of RNA elements (5'CS/3'CSI and 5'UAR/3'UAR). Formation of the RNA duplex facilitates a conformational change that leaves the 3'-terminal nucleotides of the genome (position - 8 to - 16) to be single-stranded. Viral NS5more » binds specifically to the 5'-terminal stem-loop (SL1) of the genomic RNA. The 5'SL1 RNA structure is essential for WNV replication. The study has provided further evidence to suggest that flavivirus genome cyclization and NS5/5'SL1 RNA interaction facilitate NS5 binding to the 3' end of the genome for the initiation of viral minus-strand RNA synthesis.« less
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NASA Astrophysics Data System (ADS)
Sarma, Bani Kanta
2013-09-01
The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its sulfenic acid (PTP1B-SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule chemical models. These studies suggest that the sulfenic acids derived from the H2O2-mediated reactions o-amido thiophenols do not efficiently cyclize to sulfenyl amides and the sulfenic acids produced in situ can be trapped by using methyl iodide. Theoretical calculations suggest that the most stable conformer of such sulfenic acids are stabilized by nO → σ*S-OH orbital interactions, which force the -OH group to adopt a position trans to the S⋯O interaction, leading to an almost linear arrangement of the O⋯S-O moiety and this may be the reason for the slow cyclization of such sulfenic acids to their corresponding sulfenyl amides. On the other hand, additional substituents at the 6-position of o-amido phenylsulfenic acids that can induce steric environment and alter the electronic properties around the sulfenic acid moiety by S⋯N or S⋯O nonbonded interactions destabilize the sulfenic acids by inducing strain in the molecule. This may lead to efficient the cyclization of such sulfenic acids. This model study suggests that the amino acid residues in the close proximity of the sulfenic acid moiety in PTP1B may play an important role in the cyclization of PTP1B-SOH to produce the corresponding sulfenyl amide.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sawano, Takahiro; Thacker, Nathan C.; Lin, Zekai
2016-05-06
We report here the design of BINAP-based metal–organic frameworks and their postsynthetic metalation with Rh complexes to afford highly active and enantioselective single-site solid catalysts for the asymmetric cyclization reactions of 1,6-enynes. Robust, chiral, and porous Zr-MOFs of UiO topology, BINAP-MOF (I) or BINAP-dMOF (II), were prepared using purely BINAP-derived dicarboxylate linkers or by mixing BINAP-derived linkers with unfunctionalized dicarboxylate linkers, respectively. Upon metalation with Rh(nbd)2BF4 and [Rh(nbd)Cl]2/AgSbF6, the MOF precatalysts I·Rh(BF4) and I·Rh(SbF6) efficiently catalyzed highly enantioselective (up to 99% ee) reductive cyclization and Alder-ene cycloisomerization of 1,6-enynes, respectively. I·Rh catalysts afforded cyclization products at comparable enantiomeric excesses (ee’s)more » and 4–7 times higher catalytic activity than the homogeneous controls, likely a result of catalytic site isolation in the MOF which prevents bimolecular catalyst deactivation pathways. However, I·Rh is inactive in the more sterically encumbered Pauson–Khand reactions between 1,6-enynes and carbon monoxide. In contrast, with a more open structure, Rh-functionalized BINAP-dMOF, II·Rh, effectively catalyzed Pauson–Khand cyclization reactions between 1,6-enynes and carbon monoxide at 10 times higher activity than the homogeneous control. II·Rh was readily recovered and used three times in Pauson–Khand cyclization reactions without deterioration of yields or ee’s. Our work has expanded the scope of MOF-catalyzed asymmetric reactions and showed that the mixed linker strategy can effectively enlarge the open space around the catalytic active site to accommodate highly sterically demanding polycyclic metallocycle transition states/intermediates in asymmetric intramolecular cyclization reactions.« less
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Easy access to a cyclic key intermediate for the synthesis of trisporic acids and related compounds.
González-Delgado, José A; Escobar, Gustavo; Arteaga, Jesús F; Barrero, Alejandro F
2014-02-03
The synthesis of a cyclohexane skeleton possessing different oxygenated functional groups at C-3, C-8 and C-9, and a D1,6-double bond has been accomplished in 10 steps with an overall 17% yield. This compound is a key intermediate for access to a wide range of compounds of the bioactive trisporoid family. The synthetic sequence consists of the preparation of a properly functionalized epoxygeraniol derivative, and its subsequent stereoselective cyclization mediated by Ti(III). This last step implies a domino process that starts with a homolytic epoxide opening followed by a radical cyclization and regioselective elimination. This concerted process gives access to the cyclohexane moiety with stereochemical control of five of its six carbon atoms.
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Synthesis of (±)-Tetrapetalone A-Me Aglycon**
Carlsen, Peter N.; Mann, Tyler J.; Hoveyda, Amir H.
2014-01-01
The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis (RCM) promoted with complete diastereoselectivity by a chiral Mo-based complex, tandem conjugate reduction-intramolecular aldol cyclization, and oxidative dearomatization. PMID:25045072
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The t-Butylsulfinamide Lynchpin in Transition Metal-Mediated Multiscaffold Library Synthesis
Bauer, Renato A.; DiBlasi, Christine M.; Tan, Derek S.
2010-01-01
A unified synthetic approach to diverse polycyclic scaffolds has been developed using transition metal-mediated cycloaddition and cyclization reactions of enynes and diynes. The t-butylsulfinamide group has been identified as a particularly versatile lynchpin in these reactions, with a reactivity profile uniquely suited for efficient, stereoselective substrate synthesis and downstream transformations. This approach provides ten distinct, functionalized scaffold classes related to common core structures in alkaloid and terpenoid natural products. PMID:20356070
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Eisch, J.J.; Dluzniewski, T.
1989-03-17
The hydrochlorides of cinnamaldehyde anils of the type ArCH=CHCH=NAr{prime}, where Ar and Ar{prime} are phenyl or p-tolyl groups, have been shown to react between 25{degree}C and 100{degree}C, in a toluene suspension or in a solution of DMSO or acetonitrile, to yield 2-substituted quinolines and N-cinnamylanilines ArCH=CHCH{sub 2}NHAr{prime}. The reaction proceeds under anhydrous conditions by cyclization of the anil hydrochlorides themselves to produce ultimately 2-substituted quinolines. The kinetics of the reaction follow a first-order dependence on the anil hydrochloride. Rapid exchange occurring between dissimilar anil hydrochlorides suggests that such anil metatheses take place by way of 1,3-diazetidinium ion intermediates, which previousmore » studies have shown would possess the requisite metastability. The foregoing experimental observations are reconciled in terms of a novel mechanism for the formation of quinolines directly from anils under acidic conditions, namely, the reversible formation of diazetidinium ions and their irreversible cyclization to quinolines. It is proposed that this pathway is the operative mechanism in the classic Skraup and Doehner-von Miller quinoline syntheses. 28 refs., 2 tabs.« less
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Divac, Vera M; Puchta, Ralph; Bugarčić, Zorica M
2012-08-02
The mechanism of phenylselenoetherification of (Z)- and (E)-hex-4-en-1-ols using some bases (triethylamine, pyridine, quinoline, 2,2'-bipyridine) as catalysts and some solvents [tetrahydrofuran (THF) and CCl4] as reaction media was examined through studies of kinetics of the cyclization by UV-vis spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of bases as a result of the hydrogen bond between the base and the alkenol's OH group. The rate constants in the base-catalyzed reactions are remarkably influenced by the bulkiness and basicity of the base used and the nature of the considered nitrogen donors. The obtained values for rate constants show that the reaction with triethylamine is the fastest one. THF with higher polarity and higher basic character is better as a solvent than CCl4. Quantum-chemical calculations [MP2(fc)/6-311+G**//B3LYP/6-311+G** + ZPE(B3LYP/6-311+G**] show that the cyclization of (Z)-hex-4-en-1-ol to a tetrahydrofuranoid five-membered ring is kinetically controlled, while the cyclization of (E)-hex-4-en-1-ol to the tetrahydropyranoid six-membered ring is thermodynamically controlled. This is in accordance with previous experimental findings.
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Abstract
The reaction of aldehyde with homoallyl alcohols mediated by indium trichloride generated 4-chlorotetrahydropyrans in high yields and with high stereoselectivity. The same type of compounds can be generated through a single step, multi-component coupling be...
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Prebiotic synthesis and reactions of nucleosides and nucleotides
NASA Technical Reports Server (NTRS)
Ferris, J. P.; Yanagawa, H.; Hagan, W. J., Jr.
1983-01-01
The potential of diiminosuccinonitrile (DISN) as a prebiotic phosphorylating agent is studied. This compound is formed readily by the oxidation of diaminomaleonitrile, a tetramer of HCN. DISN is shown to produce the cyclization of 3'-adenosine monophosphate to adenosine 2',3'-cyclic phosphate in up to 40 percent yield. The DISN-mediated phosphorylation of uridine to uridine monophosphate is determined not to proceed efficiently in aqueous solution. The reaction of DISN and BrCN with uridine-5'-phosphate and uridine is found to result in the formation of 2,2'-anhydronucleotides and 2,2'-anhydronucleosides, respectively, and other reaction products resulting from an initial reaction at the 2' and 3'-hydroxyl groups. Homoionic montmorillonites were employed to study the clay mineral catalysis of the cyclization of adenosine-3'-phosphate.
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NASA Astrophysics Data System (ADS)
Sydor, Paulina K.; Barry, Sarah M.; Odulate, Olanipekun M.; Barona-Gomez, Francisco; Haynes, Stuart W.; Corre, Christophe; Song, Lijiang; Challis, Gregory L.
2011-05-01
Oxidative cyclizations, exemplified by the biosynthetic assembly of the penicillin nucleus from a tripeptide precursor, are arguably the most synthetically powerful implementation of C-H activation reactions in nature. Here, we show that Rieske oxygenase-like enzymes mediate regio- and stereodivergent oxidative cyclizations to form 10- and 12-membered carbocyclic rings in the key steps of the biosynthesis of the antibiotics streptorubin B and metacycloprodigiosin, respectively. These reactions represent the first examples of oxidative carbocyclizations catalysed by non-haem iron-dependent oxidases and define a novel type of catalytic activity for Rieske enzymes. A better understanding of how these enzymes achieve such remarkable regio- and stereocontrol in the functionalization of unactivated hydrocarbon chains will greatly facilitate the development of selective man-made C-H activation catalysts.
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Chen, Ji-Peng; He, Wei; Yang, Zhen-Yu; Yao, Zhu-Jun
2015-07-17
An efficient synthesis of the tricyclo[4,3,1,0(1, 5)]decane core (B/C/D rings) of plumisclerin A, a unique cytotoxic marine diterpenoid, is described. A Pauson-Khand reaction and a SmI2-mediated radical 1,4-conjugate addition successfully served as key reactions for construction of the fully functionalized 5,6-fused rings and the highly strained cyclobutanol moiety with correct relative stereochemistries, respectively.
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A discrete scattering series representation for lattice embedded models of chain cyclization
NASA Astrophysics Data System (ADS)
Fraser, Simon J.; Winnik, Mitchell A.
1980-01-01
In this paper we develop a lattice based model of chain cyclization in the presence of a set of occupied sites V in the lattice. We show that within the approximation of a Markovian chain propagator the effect of V on the partition function for the system can be written as a time-ordered exponential series in which V behaves like a scattering potential and chainlength is the timelike parameter. The discrete and finite nature of this model allows us to obtain rigorous upper and lower bounds to the series limit. We adapt these formulas to calculation of the partition functions and cyclization probabilities of terminally and globally cyclizing chains. Two classes of cyclization are considered: in the first model the target set H may be visited repeatedly (the Markovian model); in the second case vertices in H may be visited at most once(the non-Markovian or taboo model). This formulation depends on two fundamental combinatorial structures, namely the inclusion-exclusion principle and the set of subsets of a set. We have tried to interpret these abstract structures with physical analogies throughout the paper.
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Mukherjee, Arindam; Dhar, Shanta; Nethaji, Munirathinam; Chakravarty, Akhil R
2005-01-21
The ternary iron(II) complex [Fe(L')(L")](PF6)3(1) as a synthetic model for the bleomycins, where L' and L" are formed from metal-mediated cyclizations of N,N'-(2-hydroxypropane-1,3-diyl)bis(pyridine-2-aldimine)(L), is synthesized and structurally characterized by X-ray crystallography. In the six-coordinate iron(ii) complex, ligands L' and L" show tetradentate and bidentate chelating modes of bonding. Ligand L' is formed from an intramolecular attack of the alcoholic OH group of L to one imine moiety leading to the formation of a stereochemically constrained five-membered ring. Ligand L" which is formed from an intermolecular reaction involving one imine moiety of L and pyridine-2-carbaldehyde has an emissive cationic imidazopyridine pendant arm. The complex binds to double-stranded DNA in the minor groove giving a Kapp value of 4.1 x 10(5) M(-1) and displays oxidative cleavage of supercoiled DNA in the presence of H2O2 following a hydroxyl radical pathway. The complex also shows photo-induced DNA cleavage activity on UV light exposure involving formation of singlet oxygen as the reactive species.
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Total Synthesis of Jiadifenolide**
Paterson, Ian; Xuan, Mengyang; Dalby, Stephen M
2014-01-01
As a potent neurotrophic agent, the sesquiterpenoid jiadifenolide represents a valuable small-molecule lead for the potential therapeutic treatment of neurodegenerative diseases. A stereocontrolled total synthesis of this densely functionalized natural product is reported, central to which is an adventurous samarium-mediated cyclization reaction to establish the tricyclic core and the adjacent C5 and C6 quaternary stereocenters. PMID:24861364
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Cyclization Reactions through DDQ-Mediated Vinyl Oxazolidinone Oxidation
Liu, Lei; Floreancig, Paul E.
2009-01-01
Vinyl oxazolidinones react with DDQ to form α,β-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon–hydrogen bond functionalization to increase molecular complexity. PMID:19552390
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Xiang, Shi-Kai; Tan, Wen; Zhang, Dong-Xue; Tian, Xian-Li; Feng, Chun; Wang, Bi-Qin; Zhao, Ke-Qing; Hu, Ping; Yang, Hua
2013-11-14
The synthesis of benzimidazoles by intermolecular cyclization reaction of 2-iodoanilines with nitriles has been developed. These reactions proceeded without the aid of any transition metals or ligands and just using KOBu(t) as the base. A variety of substituted benzimidazole derivatives can be synthesized by the approach.
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Controlled Acceleration and Inhibition of Bergman Cyclization by Metal Chlorides
NASA Astrophysics Data System (ADS)
Warner, Benjamin P.; Millar, Susan P.; Broene, Richard D.; Buchwald, Stephen L.
1995-08-01
The Bergman cyclization has been the subject of renewed interest with the discovery of naturally occurring enediyne-based antitumor agents that cleave DNA by means of an aromatic diradical. These natural substrates have a means to trigger this cycloaromatization process. Control of this reaction by substrate modification would allow aromatic diradicals to be generated selectively. In the studies presented here it is disclosed that the Bergman cyclization of 1,2-bis(diphenyl phosphinoethynyl)benzene was accelerated by a factor of >30,000 by the addition of palladium(II) chloride or platinum(II) chloride and was inhibited by the addition of mercury(II) chloride.
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Borkin, Dmitry; Morzhina, Elena; Datta, Silpi; Rudnitskaya, Aleksandra; Sood, Abha; Török, Marianna; Török, Béla
2011-03-07
A highly diastereoselective microwave-assisted three component synthesis of azabicyclo[2.2.2]octan-5-ones by a silicotungstic acid-catalyzed aza-Diels-Alder cyclization is described. The one-pot process involves the formation of the in situ generated Schiff base and its immediate cyclization with cyclohex-2-enone. The short reaction times, good yields and excellent diastereoselectivity make this annulation a practical and environmentally attractive method for the synthesis of the target compounds. Preliminary assays were carried out to determine the activity of the products in AChE as well as in amyloid β fibrillogenesis inhibition.
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Synthesis of cyclic, multivalent Arg-Gly-Asp using sequential thiol-ene/thiol-yne photoreactions
Aimetti, Alex A.; Feaver, Kristen R.
2014-01-01
A unique method has been developed for the formation of multivalent cyclic peptides. This procedure exploits on-resin peptide cyclization using a photoinitiated thiol-ene click reaction and subsequent clustering using thiol-yne photochemistry. Both reactions utilize the sulfhydryl group on natural cysteine amino acids to participate in the thiol-mediated reactions. PMID:20552127
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Engineering an Affinity-Enhanced Peptide through Optimization of Cyclization Chemistry.
Ngambenjawong, Chayanon; Pineda, Julio Marco B; Pun, Suzie H
2016-12-21
Peptide cyclization is a strategy used to improve stability and activity of peptides. The most commonly used cyclization method is disulfide bridge formation of cysteine-containing peptides, as is typically found in nature. Over the years, an increasing number of alternative chemistries for peptide cyclization with improved efficiency, kinetics, orthogonality, and stability have been reported. However, there has been less appreciation for the opportunity to fine-tune peptide activity via the diverse chemical entities introduced at the site of linkage by different cyclization strategies. Here, we demonstrate how cyclization optimization of an M2 "anti-inflammatory" macrophage-binding peptide (M2pep) resulted in a significant increase in binding affinity of the optimized analog to M2 macrophages while maintaining binding selectivity compared to M1 "pro-inflammatory" macrophages. In this study, we report synthesis and evaluation of four cyclic M2pep(RY) analogs with diverse cyclization strategies: (1) Asp-[amide]-Lys, (2) azido-Lys-[triazole(copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC))]-propargyl-Gly, (3) Cys-[decafluorobiphenyl (DFBP)]-Cys, and (4) Cys-[decafluorobiphenyl sulfone (DFS)]-Cys, whereby the chemical entity or linker at the linkage site is shown in the square bracket and is between the residues involved in cyclization. These peptides are compared to a disulfide-cyclized M2pep(RY) that we previously reported as a serum-stable, affinity-enhanced analog to the original linear M2pep. DFBP-cyclized M2pep(RY) exhibits the highest binding activity to M2 macrophages with apparent dissociation constant (K D ) about 2.03 μM compared to 36.3 μM for the original disulfide-cyclized M2pep(RY) and 220 μM for the original linear peptide. DFS-cyclized M2pep(RY) also binds more strongly than the original cyclized analog, whereas amide- and triazole-cyclized M2pep(RY) analogs bind less strongly. We verified that DFBP alone has negligible binding to M2 macrophages and the incorporation of diphenylalanine to the original sequence improves binding activity at the expense of solubility and increased toxicity. In conclusion, we report development of cyclic M2pep(RY) analogs with diverse cyclization strategies leading to the discovery of DFBP-cyclized M2pep(RY) with enhanced M2 macrophage-binding activity.
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Biogenetically inspired synthesis and skeletal diversification of indole alkaloids.
Mizoguchi, Haruki; Oikawa, Hideaki; Oguri, Hiroki
2014-01-01
To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.
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The photocatalyzed Meerwein arylation: classic reaction of aryl diazonium salts in a new light.
Hari, Durga Prasad; König, Burkhard
2013-04-26
The use of diazonium salts for aryl radical generation and C-H arylation processes has been known since 1896 when Pschorr first used the reaction for intramolecular cyclizations. Meerwein developed it further in the early 1900s into a general arylation method. However, this reaction could not compete with the transition-metal-mediated formation of C(sp(2))-C(sp(2)) bonds. The replacement of the copper catalyst with iron and titanium compounds improved the situation, but the use of photocatalysis to induce the one-electron reduction and activation of the diazonium salts is even more advantageous. The first photocatalyzed Pschorr cyclization was published in 1984, and just last year a series of papers described applications of photocatalytic Meerwein arylations leading to aryl-alkene coupling products. In this Minireview we summarize the origins of this reaction and its scope and applications. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Titanium(IV)-Catalyzed Stereoselective Synthesis of Spirooxindole-1-pyrrolines
2015-01-01
A stereoselective cyclization between alkylidene oxindoles and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (as low as 5 mol %) to afford spiro[3,3′-oxindole-1-pyrrolines] in excellent yield (up to 99%) and diastereoselectivity (up to 99:1). Using a chiral scandium(III)–indapybox/BArF complex affords enantioenriched spirooxindole-1-pyrrolines where a ligand-induced reversal of diastereoselectivity is observed. This methodology is further demonstrated for the synthesis of pyrrolines from malonate alkylidene and coumarin derivatives. PMID:25474118
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Schoene, Christopher; Bennett, S. Paul; Howarth, Mark
2016-01-01
Enzymes catalyze reactions with exceptional selectivity and rate acceleration but are often limited by instability. Towards a generic route to thermo-resilience, we established the SpyRing approach, cyclizing enzymes by sandwiching between SpyTag and SpyCatcher (peptide and protein partners which lock together via a spontaneous isopeptide bond). Here we first investigated the basis for this resilience, comparing alternative reactive peptide/protein pairs we engineered from Gram-positive bacteria. Both SnoopRing and PilinRing cyclization gave dramatic enzyme resilience, but SpyRing cyclization was the best. Differential scanning calorimetry for each ring showed that cyclization did not inhibit unfolding of the inserted β-lactamase. Cyclization conferred resilience even at 100 °C, where the cyclizing domains themselves were unfolded. Phytases hydrolyze phytic acid and improve dietary absorption of phosphate and essential metal ions, important for agriculture and with potential against human malnutrition. SpyRing phytase (PhyC) resisted aggregation and retained catalytic activity even following heating at 100 °C. In addition, SpyRing cyclization made it possible to purify phytase simply by heating the cell lysate, to drive aggregation of non-cyclized proteins. Cyclization via domains forming spontaneous isopeptide bonds is a general strategy to generate resilient enzymes and may extend the range of conditions for isolation and application of enzymes. PMID:26861173
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[Synthesis of Circular DNA Templates with T4 RNA Ligase for Rolling Circle Amplification].
Sakhabutdinova, A R; Maksimova, M A; Garafutdinov, R R
2017-01-01
Currently, isothermal methods of nucleic acid amplification have been well established; in particular, rolling circle amplification is of great interest. In this approach, circular ssDNA molecules have been used as a target that can be obtained by the intramolecular template-dependent ligation of an oligonucleotide C-probe. Here, a new method of synthesizing small circular DNA molecules via the cyclization of ssDNA based on T4 RNA ligase has been proposed. Circular ssDNA is further used as the template for the rolling circle amplification. The maximum yield of the cyclization products was observed in the presence of 5-10% polyethylene glycol 4000, and the optimum DNA length for the cyclization constituted 50 nucleotides. This highly sensitive method was shown to detect less than 10^(2) circular DNA molecules. The method reliability was proved based on artificially destroyed dsDNA, which suggests its implementation for analyzing any significantly fragmented dsDNA.
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Santana, Andrés G; Paz, Nieves R; Francisco, Cosme G; Suárez, Ernesto; González, Concepción C
2013-08-02
The synthesis of a novel type of branched iminosugars is described. This synthetic strategy is based on two key reactions: first, an aldol reaction with formaldehyde in order to introduce selectively the hydroxymethyl branch, and second, a tandem β-fragmentation-intramolecular cyclization reaction. The combination of both reactions afforded a battery of compounds exhibiting a great structural complexity, with the concomitant formation of a quaternary center, starting from readily available aldoses. With this approach we have demonstrated the usefulness of the fragmentation of anomeric alkoxyl radicals (ARF) promoted by the PhIO/I2 system for the preparation of new compounds with potential interest for both medicinal and synthetic chemists.
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Liu, Hao; Yu, Jing; Li, Xinyu; Yan, Rui; Xiao, Ji-Chang; Hong, Ran
2015-09-18
A stereoselective N-iminium ion cyclization with allylsilane to construct vicinal quaternary-tertiary carbon centers was developed for the concise synthesis of (±)-cephalotaxine. The current strategy features a TiCl4-promoted cyclization and ring-closure metathesis to furnish the spiro-ring system. The stereochemical outcome in the N-acyliminium ion cyclization was rationalized by the stereoelectronic effect of the Z- or E-allylsilane. Two diastereomers arising from the cyclization were merged into the formal synthesis of (±)-cephalotaxine.
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Polarizing the Nazarov cyclization: efficient catalysis under mild conditions.
He, Wei; Sun, Xiufeng; Frontier, Alison J
2003-11-26
Substituted divinyl ketones were studied in the Nazarov cyclization. alpha-Carbomethoxy divinyl ketones underwent efficient Nazarov cyclization with catalytic copper triflate (2 mol %) to give a single cyclopentenone regio- and stereoisomer. The efficiency of the cyclizations correlated with the ability of the substituents to favorably polarize the pi-system of the cationic intermediate.
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Isostrychnine synthesis mediated by hypervalent iodine reagent.
Jacquemot, Guillaume; Maertens, Gaëtan; Canesi, Sylvain
2015-05-18
Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with an oxidative dearomatizing process mediated by hypervalent iodine as the key step. The new syntheses of isostrychnine and strychnine have been achieved from an readily available phenol in nine and ten steps. In addition to the key step, these syntheses involve an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Code of Federal Regulations, 2010 CFR
2010-07-01
... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting under...
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Code of Federal Regulations, 2011 CFR
2011-07-01
... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting under...
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Code of Federal Regulations, 2012 CFR
2012-07-01
... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting under...
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Code of Federal Regulations, 2014 CFR
2014-07-01
... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting under...
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Code of Federal Regulations, 2013 CFR
2013-07-01
... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting under...
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Oxidative Carbocation Formation in Macrocycles: Synthesis of the Neopeltolide Macrocycle**
Tu, Wangyang
2009-01-01
Processes for the functionalization of carbon–hydrogen bonds are the focus of significant attention in organic synthesis[1] in response to the need to streamline molecular assembly. As a continuation of our efforts to generate carbocations through single-electron oxidation reactions,[2] we recently reported[3] DDQ-mediated cyclization reactions of benzylic and allylic ethers (Scheme 1; DDQ =2,3-dichloro-4,5-dicyanoquinone). PMID:19455526
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SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme.
Schoene, Christopher; Fierer, Jacob O; Bennett, S Paul; Howarth, Mark
2014-06-10
SpyTag is a peptide that spontaneously forms an amide bond with its protein partner SpyCatcher. SpyTag was fused at the N terminus of β-lactamase and SpyCatcher at the C terminus so that the partners could react to lock together the termini of the enzyme. The wild-type enzyme aggregates above 37 °C, with irreversible loss of activity. Cyclized β-lactamase was soluble even after heating at 100 °C; after cooling, the catalytic activity was restored. SpyTag/SpyCatcher cyclization led to a much larger increase in stability than that achieved through point mutation or alternative approaches to cyclization. Cyclized dihydrofolate reductase was similarly resilient. Analyzing unfolding through calorimetry indicated that cyclization did not increase the unfolding temperature but rather facilitated refolding after thermal stress. SpyTag/SpyCatcher sandwiching represents a simple and efficient route to enzyme cyclization, with potential to greatly enhance the robustness of biocatalysts. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Serum Stabilities of Short Tryptophan- and Arginine-Rich Antimicrobial Peptide Analogs
Nguyen, Leonard T.; Chau, Johnny K.; Perry, Nicole A.; de Boer, Leonie; Zaat, Sebastian A. J.; Vogel, Hans J.
2010-01-01
Background Several short antimicrobial peptides that are rich in tryptophan and arginine residues were designed with a series of simple modifications such as end capping and cyclization. The two sets of hexapeptides are based on the Trp- and Arg-rich primary sequences from the “antimicrobial centre” of bovine lactoferricin as well as an antimicrobial sequence obtained through the screening of a hexapeptide combinatorial library. Methodology/Principal Findings HPLC, mass spectrometry and antimicrobial assays were carried out to explore the consequences of the modifications on the serum stability and microbicidal activity of the peptides. The results show that C-terminal amidation increases the antimicrobial activity but that it makes little difference to its proteolytic degradation in human serum. On the other hand, N-terminal acetylation decreases the peptide activities but significantly increases their protease resistance. Peptide cyclization of the hexameric peptides was found to be highly effective for both serum stability and antimicrobial activity. However the two cyclization strategies employed have different effects, with disulfide cyclization resulting in more active peptides while backbone cyclization results in more proteolytically stable peptides. However, the benefit of backbone cyclization did not extend to longer 11-mer peptides derived from the same region of lactoferricin. Mass spectrometry data support the serum stability assay results and allowed us to determine preferred proteolysis sites in the peptides. Furthermore, isothermal titration calorimetry experiments showed that the peptides all had weak interactions with albumin, the most abundant protein in human serum. Conclusions/Significance Taken together, the results provide insight into the behavior of the peptides in human serum and will therefore aid in advancing antimicrobial peptide design towards systemic applications. PMID:20844765
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General base-general acid catalysis by terpenoid cyclases.
Pemberton, Travis A; Christianson, David W
2016-07-01
Terpenoid cyclases catalyze the most complex reactions in biology, in that more than half of the substrate carbon atoms often undergo changes in bonding during the course of a multistep cyclization cascade that proceeds through multiple carbocation intermediates. Many cyclization mechanisms require stereospecific deprotonation and reprotonation steps, and most cyclization cascades are terminated by deprotonation to yield an olefin product. The first bacterial terpenoid cyclase to yield a crystal structure was pentalenene synthase from Streptomyces exfoliatus UC5319. This cyclase generates the hydrocarbon precursor of the pentalenolactone family of antibiotics. The structures of pentalenene synthase and other terpenoid cyclases reveal predominantly nonpolar active sites typically lacking amino acid side chains capable of serving general base-general acid functions. What chemical species, then, enables the Brønsted acid-base chemistry required in the catalytic mechanisms of these enzymes? The most likely candidate for such general base-general acid chemistry is the co-product inorganic pyrophosphate. Here, we briefly review biological and nonbiological systems in which phosphate and its derivatives serve general base and general acid functions in catalysis. These examples highlight the fact that the Brønsted acid-base activities of phosphate derivatives are comparable to the Brønsted acid-base activities of amino acid side chains.
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General Base-General Acid Catalysis by Terpenoid Cyclases§
Pemberton, Travis A.; Christianson, David W.
2016-01-01
Terpenoid cyclases catalyze the most complex reactions in biology, in that more than half of the substrate carbon atoms often undergo changes in bonding during the course of a multistep cyclization cascade that proceeds through multiple carbocation intermediates. Many cyclization mechanisms require stereospecific deprotonation and reprotonation steps, and most cyclization cascades are terminated by deprotonation to yield an olefin product. The first bacterial terpenoid cyclase to yield a crystal structure was pentalenene synthase from Streptomyces exfoliatus UC5319. This cyclase generates the hydrocarbon precursor of the pentalenolactone family of antibiotics. The structures of pentalenene synthase and other terpenoid cyclases reveal predominantly nonpolar active sites typically lacking amino acid side chains capable of serving general base-general acid functions. What chemical species, then, enables the Brønsted acid-base chemistry required in the catalytic mechanisms of these enzymes? The most likely candidate for such general base-general acid chemistry is the co-product inorganic pyrophosphate. Here, we briefly review biological and nonbiological systems in which phosphate and its derivatives serve general base and general acid functions in catalysis. These examples highlight the fact that the Brønsted acid-base activities of phosphate derivatives are comparable to the Brønsted acid-base activities of amino acid side chains. PMID:27072285
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Photochemical and thermal bergman cyclization of a pyrimidine enediynol and enediynone.
Choy, N; Blanco, B; Wen, J; Krishan, A; Russell, K C
2000-11-30
[reaction: see text] Novel 10-membered pyrimidine enediynes (3 and 4) were synthesized in seven and eight steps, respectively. These compounds were compared for their abilities to undergo Bergman cyclization both thermally and photochemically. Alcohol 3 readily cyclized both thermally and photochemically in (i)PrOH, while ketone 4 only showed efficient thermal cyclization. Both compounds were also shown to cleave dsDNA under the appropriate conditions.
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Harris, Golda G.; Lombardi, Patrick M.; Pemberton, Travis A.; Matsui, Tsutomu; Weiss, Thomas M.; Cole, Kathryn E.; Köksal, Mustafa; Murphy, Frank V.; Vedula, L. Sangeetha; Chou, Wayne K.W.; Cane, David E.; Christianson, David W.
2015-01-01
Geosmin synthase from Streptomyces coelicolor (ScGS) catalyzes an unusual, metal-dependent terpenoid cyclization and fragmentation reaction sequence. Two distinct active sites are required for catalysis: the N-terminal domain catalyzes the ionization and cyclization of farnesyl diphosphate to form germacradienol and inorganic pyrophosphate (PPi), and the C-terminal domain catalyzes the protonation, cyclization, and fragmentation of germacradienol to form geosmin and acetone through a retro-Prins reaction. A unique αα domain architecture is predicted for ScGS based on amino acid sequence: each domain contains the metal-binding motifs typical of a class I terpenoid cyclase, and each domain requires Mg2+ for catalysis. Here, we report the X-ray crystal structure of the unliganded N-terminal domain of ScGS and the structure of its complex with 3 Mg2+ ions and alendronate. These structures highlight conformational changes required for active site closure and catalysis. Although neither full-length ScGS nor constructs of the C-terminal domain could be crystallized, homology models of the C-terminal domain were constructed based on ~36% sequence identity with the N-terminal domain. Small-angle X-ray scattering experiments yield low resolution molecular envelopes into which the N-terminal domain crystal structure and the C-terminal domain homology model were fit, suggesting possible αα domain architectures as frameworks for bifunctional catalysis. PMID:26598179
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NASA Astrophysics Data System (ADS)
Ye, Deju; Shuhendler, Adam J.; Cui, Lina; Tong, Ling; Tee, Sui Seng; Tikhomirov, Grigory; Felsher, Dean W.; Rao, Jianghong
2014-06-01
Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo.
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Janka, Mesfin; He, Wei; Frontier, Alison J; Eisenberg, Richard
2004-06-09
The dicationic Ir(III) complex [IrMe(CO)(dppe)(DIB)](BARF)2 having adjacent labile sites has been found to be a very effective catalyst for promoting the Nazarov cyclization of aryl vinyl and divinyl ketones. Spectroscopic evidence for a substate-catalyst complex before cyclization is presented. The efficiency of the cyclization is attributed to the electrophilicity of the Ir(III) complex and substrate activation via chelation.
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A general method for the catalytic nazarov cyclization of heteroaromatic compounds.
Malona, John A; Colbourne, Jessica M; Frontier, Alison J
2006-11-23
A general, catalytic method for efficient Nazarov cyclization of systems containing heteroaromatic components has been developed. Scandium triflate was identified as the most reactive promoter, and it was found that addition of lithium perchlorate was necessary for synthetically useful catalytic cyclizations. The method was used to synthesize a range of cyclopentanone-fused heteroaromatic systems in 36-97% yield, and the reactivity trends observed demonstrate the impact of polarization on cyclization efficiency. [reaction: see text].
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Fukazawa, Aiko; Ichihashi, Yasunori; Kosaka, Youhei; Yamaguchi, Shigehiro
2009-11-02
The intramolecular trans-halophosphanylation of 2-(aminophosphanyl)phenylacetylenes mediated by PBr3 followed by the oxidation with H2O2, produces 3-bromobenzo[b]phosphole oxide derivatives. This cyclization is also used for the synthesis of a 3-iodo derivative by conducting the reaction in the presence of LiI. Based on this synthetic method, various benzophosphole-containing pi-conjugated compounds, including a phosphoryl and methylene-bridged stilbene 10, 2,3,6,7-tetraphenylbenzo[1,2-b:4,5-b']diphosphole-P,P'-dioxides 11, and their phosphine sulfide derivatives 12, are synthesized. The study of the structure-property relationships in a series of the bridged stilbenes, including a bis(methylene)-bridged stilbene 10, and a bis(phosphoryl)-bridged stilbene, reveals that as the contribution of the phosphoryl groups increased, the absorption and emission maxima substantially shift to longer wavelengths. The intrinsic substituent effects of the phosphoryl group in this skeleton are to decrease the oscillator strength of the electronic transition and thus decrease the radiative decay rate constants from the singlet excited state. Nevertheless, these compounds maintain high fluorescence quantum yields (Phi(F)>0.8) owing to the significantly retarded nonradiative decay process. In the study of the benzodiphosphole derivatives 11 and 12, their cyclic voltammetry revealed that both of the phosphoryl and phosphine sulfide derivatives have low reduction potentials (-1.7 to -1.8 V vs ferrocene/ferrocenium couple) with the high reversibility of the redox waves. These compounds also showed high thermal stabilities with the high glass transition temperatures of 147-159 degrees C, indicative of their potential utilities as amorphous materials.
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Blandl, Tamas; Cochran, Andrea G; Skelton, Nicholas J
2003-02-01
The turn-forming ability of a series of three-residue sequences was investigated by substituting them into a well-characterized beta-hairpin peptide. The starting scaffold, bhpW, is a disulfide-cyclized 10-residue peptide that folds into a stable beta-hairpin with two antiparallel strands connected by a two-residue reverse turn. Substitution of the central two residues with the three-residue test sequences leads to less stable hairpins, as judged by thiol-disulfide equilibrium measurements. However, analysis of NMR parameters indicated that each molecule retains a significant folded population, and that the type of turn adopted by the three-residue sequence is the same in all cases. The solution structure of a selected peptide with a PDG turn contained an antiparallel beta-hairpin with a 3:5 type I + G1 bulge turn. Analysis of the energetic contributions of individual turn residues in the series of peptides indicates that substitution effects have significant context dependence, limiting the predictive power of individual amino acid propensities for turn formation. The most stable and least stable sequences were also substituted into a more stable disulfide-cyclized scaffold and a linear beta-hairpin scaffold. The relative stabilities remained the same, suggesting that experimental measurements in the bhpW context are a useful way to evaluate turn stability for use in protein design projects. Moreover, these scaffolds are capable of displaying a diverse set of turns, which can be exploited for the mimicry of protein loops or for generating libraries of reverse turns.
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USDA-ARS?s Scientific Manuscript database
A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the detection of Apple chlorotic leaf spot virus (ACLSV) was developed. In this method, a set of four primers was designed based on the conserved regions in the coat protein gene of ACLSV, and was synthesized for the ...
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A kinetic study of xanthohumol cyclization to isoxanthohumol - A role of water
NASA Astrophysics Data System (ADS)
Kamiński, Daniel M.; Gawęda, Karolina; Arczewska, Marta; Senczyna, Bogusław; Gagoś, Mariusz
2017-07-01
Xanthohumol, a major prenylated chalcone found in hop resin, has recently attracted scientific interest due to its health-promoting properties. In the present work, we investigated the mechanism of xanthohumol cyclization to isoxanthohumol in an aqueous solution with a high pH by means of UV-Vis spectroscopy and liquid chromatography. The results were modeled by DFT methods with the SMD solvation model. The results of theoretical calculations were consistent with experimental data. The proposed mechanism comprises two stages, where the first step involves cyclization of xanthohumol ions and the second step involves the addition of H+ ion from a water molecule to an isoxanthohumol ion. The second step is responsible for the stabilization of isoxanthohumol. Based on these results some practical information can be drawn, which may be important from the point of view of the problem xanthohumol stability in commercial dietary supplements.
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Li, Yawen; Ma, Lixin; Gaddam, Vikram; Gallazzi, Fabio; Hennkens, Heather M; Harmata, Michael; Lewis, Michael R; Deakyne, Carol A; Jurisson, Silvia S
2016-02-01
Radiolabeled proteolytic degradation-resistant somatostatin analogues have been of long-standing interest as cancer imaging and radiotherapy agents for targeting somatostatin receptor-positive tumors. Our interest in developing (186)Re- and (188)Re-based therapeutic radiopharmaceuticals led to investigation of a new Re(V)-cyclized octreotide analogue, Re(V)-cyclized, thiolated-DPhe(1)-Cys(2)-Tyr(3)-DTrp(4)-Lys(5)-Thr(6)-Cys(7)-Thr(OH)(8) (Re-SDPhe-TATE) using both experimental and quantum chemical methods. The metal is directly coordinated to SDPhe-TATE through cyclization of the peptide around the [ReO](3+) core. Upon complexation, four isomers were observed; the isolated/semi-isolated isomers exhibited different somatostatin receptor (sstr) binding affinities, 0.13 to 1.5 μM, in rat pancreatic tumor cells. Two-dimensional NMR experiments and electronic structure calculations were employed to elucidate the structural differences among the different isomers. According to NMR studies, the metal is coordinated to three thiolates and the backbone amide of Cys(2) in isomers 1 and 4, whereas the metal is coordinated to three thiolates and the backbone amide of Tyr(3) in isomer 2. Quantum chemical methods clarified the stereochemistry of Re-SDPhe-TATE and the possible peptide arrangements around the [ReO](3+) core. The re-cyclization reaction was translated to the (99m)Tc radiotracer level with four isomers observed on complexation with comparable HPLC retention times as the Re-SDPhe-TATE isomers. About 85% total (99m)Tc labeling yield was achieved by ligand exchange from (99m)Tc-glucoheptonate at 60 °C for an hour. About 100% and 51% of (99m)Tc(V)-cyclized SDPhe-TATE remained intact in phosphate buffered saline and 1 mM cysteine solution under physiological conditions at 6 h, respectively.
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Brzezinska, Jolanta; Witkowska, Agnieszka; Kaczyński, Tomasz P; Krygier, Dominika; Ratajczak, Tomasz; Chmielewski, Marcin K
2017-03-02
Application of 2-pyridinyl thermolabile protecting groups (2-PyTPGs) for protection of hydroxyl, phosphate, and carboxyl functions is presented in this unit. Their characteristic feature is a unique removal process following the intramolecular cyclization mechanism and induced only by temperature rise. Deprotection rate of 2-PyTPGs is dependent on certain parameters, such as solvent (aqueous or non-aqueous medium), pH values, and electron distribution in a pyridine ring. The presented approach pertains not only to protecting groups but also to an advanced system of controlling certain properties of 2-pyridinyl derivatives. We improved the "chemical switch" method, allowing us to regulate the protecting group stability by inversing the electron distribution in 2-PyTPG. Together with pH values manipulation, this allows us to regulate the protecting group stability. Moreover, phosphite cyclization to oxazaphospholidine provides a very stable but easily reversible tool for phosphate protection/modifications. For all TPGs we confirmed their utility in a system of protecting groups. This concept can contribute to designing the general protecting group that could be useful in bioorganic chemistry. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.
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Takikawa, Hiroshi; Suzuki, Keisuke
2007-07-05
Asymmetric synthesis of (+)-sappanone B (1), a natural product with a 3-hydroxy chromanone structure, was achieved via enantioselective benzoin cyclization by using a modified Rovis catalyst and triethylamine. This catalyst enabled the successful benzoin cyclization of readily enolizable keto-aldehydes.
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Cyclization Cascades Initiated by 1,6-Conjugate Addition
Brooks, Joshua L.; Frontier, Alison J.
2012-01-01
Dienyl diketones containing tethered acetates selectively undergo two different 1,6-conjugate addition-initiated cyclization cascades. One is a 1,6-conjugate addition/cyclization sequence with incorporation of the nucleophile, and the other is catalyzed by DABCO and is thought to proceed via a cyclic acetoxonium intermediate. The reaction behavior of substrates lacking the tethered acetate was also studied. The scope of both types of cyclization cascades, the role of the amine additive, and the factors controlling reactivity and selectivity in the two different reaction pathways is discussed. PMID:23004564
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Fast Fmoc synthesis of hAmylin1-37 with pseudoproline assisted on-resin disulfide formation.
Page, Karen; Hood, Christina A; Patel, Hirendra; Fuentes, German; Menakuru, Mahendra; Park, Jae H
2007-12-01
Human amylin (1-37) and the (1-13) fragment were synthesized with and without pseudoproline dipeptides. Thallium (III) trifluoroacetate, a mild oxidant, was used to cyclize the peptides by forming a disulfide bridge from C(2) to C(7). On the basis of our model studies, incorporation of a pseudoproline dipeptide decreases the amount of time necessary for the crude linear amylin (1-13) to cyclize on the resin. Without pseudoproline dipeptides, the 1-37 crude linear amylin was not pure enough to undergo the cyclization reaction. Following the cyclization studies, the synthesis time of the linear human amylin (1-37) was systematically reduced from 58 h to 8.5 h by shortening the reaction times. Cyclization and cleavage times were also reduced to 1.5 h.
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Carbon Dioxide-Mediated C(sp3)-H Arylation of Amine Substrates.
Kapoor, Mohit; Liu, Daniel; Young, Michael C
2018-05-25
Elaborating amines via C-H functionalization has been an important area of research over the past decade but has generally relied on an added directing group or sterically hindered amine approach. Since free-amine-directed C(sp 3 )-H activation is still primarily limited to cyclization reactions and to improve the sustainability and reaction scope of amine-based C-H activation, we present a strategy using CO 2 in the form of dry ice that facilitates intermolecular C-H arylation. This methodology has been used to enable an operationally simple procedure whereby 1° and 2° aliphatic amines can be arylated selectively at their γ-C-H positions. In addition to potentially serving as a directing group, CO 2 has also been demonstrated to curtail the oxidation of sensitive amine substrates.
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Cholera toxin activation of adenylate cyclase in cancer cell membrane fragments.
Bitensky, M W; Wheeler, M A; Mehta, H; Miki, N
1975-01-01
Activation of adenylate [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by cholera toxin (84,000 daltons, 5.5 S) is demonstrated in plasma membrane fragments of mouse ascites cancer cells. The activation of adenylate cyclase is mediated by a macromolecular cyclase activating factor (MCAF), which has a sedimentation constant of 2.7 S and a molecular weight of about 26,000. MCAF is derived from, and may be identical to the "A fragment" of cholera toxin. Generation of MCAF depends on prior interaction of cholera toxin with either dithiothreitol, NADH, NAD, or a low-molecular-weight component (less than 700 daltons) present in cytoplasm. Subsequent exposure of this pretreated cholera toxin to cell membranes from a variety of mouse ascites cancer cells is followed rapidly by the appearance of MCAF, which no longer requires dithiothreitol, NADH, or NAD for the activation of adenylate cyclase. Activation of adenylate cyclase by MCAF in ascites cancer cell membrane fragments is not reversed by repeated washing of these membrane fragments. Adenylate cyclase in normal cell membrane fragments fails to respond either to cholera toxin or MCAF in the presence of dithiothreitol. In striking contrast, the adenylate cyclase in membrane fragments from five ascites cancer cells responds to either MCAF or native cholera toxin preincubated with dithiothreitol, NADH, or NAD. PMID:1058474
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Weltrowska, Grazyna; Nguyen, Thi M.-D.; Chung, Nga N.; Wood, JodiAnne; Ma, Xiaoyu; Guo, Jason; Wilkes, Brian C.; Ge, Yang; Laferrière, André; Coderre, Terence J.; Schiller, Peter W.
2016-01-01
Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt1]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2 (9; Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c[-d-Arg-Phe-Lys-Dmt-] (1) (“cyclodal”), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp127 and Glu229 receptor residues. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c[-Arg-d-Phe-d-Lys-d-Dmt-] (2), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c[-d-Arg-Phe-LysΨ[CH2NH]Dmt-] (8), with MOR agonist activity. PMID:27676089
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Rawat, Varun; Kumar, B Senthil; Sudalai, Arumugam
2013-06-14
A new sequential organocatalytic method for the synthesis of chiral 3-substituted (X = OH, NH2) tetrahydroquinoline derivatives (THQs) [ee up to 99%, yield up to 87%] based on α-aminooxylation or -amination followed by reductive cyclization of o-nitrohydrocinnamaldehydes has been described. This methodology has been efficiently demonstrated in the synthesis of two important bioactive molecules namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone (92% ee).
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SpyTag/SpyCatcher Cyclization Enhances the Thermostability of Firefly Luciferase
Si, Meng; Xu, Qing
2016-01-01
SpyTag can spontaneously form a covalent isopeptide bond with its protein partner SpyCatcher. Firefly luciferase from Photinus pyralis was cyclized in vivo by fusing SpyCatcher at the N terminus and SpyTag at the C terminus. Circular LUC was more thermostable and alkali-tolerant than the wild type, without compromising the specific activity. Structural analysis indicated that the cyclized LUC increased the thermodynamic stability of the structure and remained more properly folded at high temperatures when compared with the wild type. We also prepared an N-terminally and C-terminally shortened form of the SpyCatcher protein and cyclization using this truncated form led to even more thermostability than the original form. Our findings suggest that cyclization with SpyTag and SpyCatcher is a promising and effective strategy to enhance thermostability of enzymes. PMID:27658030
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Zhang, Zhen; Li, Cheng; Wang, Shao-Hua; Zhang, Fu-Min; Han, Xue; Tu, Yong-Qiang; Zhang, Xiao-Ming
2017-04-11
A novel and efficient tandem S N 2' nucleophilic substitution/oxidative radical cyclization reaction of aryl substituted allylic alcohols with 1,3-dicarbonyl compounds has been developed by using Mn(OAc) 3 as an oxidant, which enables the expeditious synthesis of polysubstituted dihydrofuran (DHF) derivatives in moderate to high yields. The use of weakly acidic hexafluoroisopropanol (HFIP) as the solvent rather than AcOH has successfully improved the yields and expanded the substrate scope of this type of radical cyclization reactions. Mechanistic studies confirmed the cascade reaction process involving a final radical cyclization.
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Fichna, Jakub; Perlikowska, Renata; Wyrębska, Anna; Gach, Katarzyna; Piekielna, Justyna; do-Rego, Jean Claude; Toth, Geza; Kluczyk, Alicja; Janecki, Tomasz; Janecka, Anna
2011-12-01
This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa)NH(2) or Tyr-c(Xaa-Phe-D-Pro-Yaa)NH(2), respectively, where Xaa and Yaa were L/D Asp or L/D Lys. Further modification of these analogs was achieved by introduction of 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt(1)-substituted analogs displayed high affinity at the μ-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting μ-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood-brain barrier permeability. Copyright © 2011. Published by Elsevier Ltd.
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Nazarov cyclization initiated by peracid oxidation: the total synthesis of (+/-)-rocaglamide.
Malona, John A; Cariou, Kevin; Frontier, Alison J
2009-06-10
The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.
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A theoretical study of the cyclization processes of energized CCCSi and CCCP.
Maclean, Micheal J; Eichinger, Peter C H; Wang, Tianfang; Fitzgerald, Mark; Bowie, John H
2008-12-11
Calculations at the CCSD(T)/aug-cc-pVDZ//B3LYP/6-31+G(d) level of theory have shown that cyclization of both the ground state triplet and the corresponding singlet state of CCCSi may rearrange to give cyclic isomers which upon ring opening may reform linear C(3)Si isomers in which the carbon atoms are scrambled. The cyclization processes are energetically favorable with barriers to the transition states from 13 to 16 kcal mol(-1). This should be contrasted with the analogous process of triplet CCCC to triplet rhombic C(4), which requires an excess energy of 25.8 kcal mol(-1). A similar cyclization of doublet CCCP requires 50.4 kcal mol(-1) of excess energy; this should be contrasted with the same process for CCCN, which requires 54.7 kcal mol(-1) to effect cyclization.
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Marco-Contelles, J; Pozuelo, C; de Opazo, E
2001-06-15
We report the synthesis, free-radical cyclization of precursors 1,2,7-trideoxy-7-iodo-3,4:5,6-di-O-isopropylidene-D-gluco-hept-1-enitol (1), methyl 7-O-acetyl-6-O-benzyl-8-bromo-2,3,8-trideoxy-4,5-O-isopropylidene-D-gluco-oct-2-enonate (2) and 5-O-acetyl-4-O-benzyl-6-bromo-6-deoxy-2,3-O-isopropylidene-D-glucose-O-benzyloxime (3), readily prepared from D-glucose, and some selected transformations of the carbocycles obtained from these intermediates. In compound 1 we have installed a terminal double bond and an iodide as radical acceptor and leaving group, respectively. Compounds 2 and 3 are epsilon-bromo aldehydes substituted with alpha,beta-unsaturated ester and oxime ether functions as radical traps, respectively. The tributyltin hydride mediated ring closure of these radical precursors have afforded a series of interesting, diverse and highly functionalized carbocycles which can be considered useful building blocks for the synthesis of branched-chain cyclitols, aminocyclitols and aminoconduritols. In these processes, a good chemical yield and high stereoselectivity has been found in the newly formed stereocenters. Particularly interesting has been the finding that the stereochemical outcome of the free-radical cyclization is independent of the ratio of isomers (E or Z) in oxime ether 3. These results show the power and the state of art of this strategy for the stereocontrolled synthesis of enantiomerically pure inositols from carbohydrates.
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Clive, Derrick L J; Fletcher, Stephen P; Liu, Dazhan
2004-05-14
An indirect method is described for effecting radical cyclization onto a benzene ring. Cross-conjugated dienones 6, which are readily prepared from phenols, undergo radical cyclization (6 --> 7 --> 8), and the products (8) are easily aromatized. The method has been applied to the synthesis of ent-nocardione A (21).
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Spencer, William T.; Vaidya, Tulaza; Frontier, Alison J.
2013-01-01
The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in the study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediate central to the cyclization. Methods reviewed include carbon-heteroatom ionization, functionalization of a double bond, nucleophilic addition, or electrocyclic ring opening. Additional variations employ unconventional substrates to produce novel pentacycles, such as the iso- and imino-Nazarov. Herein, we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization. PMID:24348092
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Li, Xiang; Qin, Aiwen; Zhao, Xinzhen; Liu, Dapeng; Wang, Haiye; He, Chunju
2015-09-14
Drawing to change the structural properties and cyclization behaviors of the polyacrylonitrile (PAN) chains in crystalline and amorphous regions is carried out on PAN and PAN/carbon nanotube (CNT) composite fibers. Various characterization methods including Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and thermal gravimetric analysis are used to monitor the structural evolution and cyclization behaviors of the fibers. With an increase of the draw ratio during the plasticized spinning process, the structural parameters of the fibers, i.e. crystallinity and planar zigzag conformation, are decreased at first, and then increased, which are associated with the heat exchange rate and the oriented-crystallization rate. A possible mechanism for plasticized spinning is proposed to explain the changing trends of crystallinity and planar zigzag conformation. PAN and PAN/CNT fibers exhibit various cyclization behaviors induced by drawing, e.g., the initiation temperature for the cyclization (Ti) of PAN fibers is increased with increasing draw ratio, while Ti of PAN/CNT fibers is decreased. Drawing also facilitates cyclization and lowers the percentage of β-amino nitrile for PAN/CNT fibers during the stabilization.
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Cyclization strategies of meditopes: affinity and diffraction studies of meditope–Fab complexes
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bzymek, Krzysztof P.; Ma, Yuelong; Avery, Kendra A.
An overview of cyclization strategies of a Fab-binding peptide to maximize affinity. Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented.more » The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic ‘pocket’ and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope–Fab complex.« less
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Davis, Owen A; Croft, Rosemary A; Bull, James A
2016-11-18
1,4-Dioxenes present interesting potential as synthetic intermediates and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with β-halohydrins followed by treatment with base results in cyclization with excellent selectivity, through O-alkylation of the keto-enolate. A variety of halohydrins and anion-stabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes. Enantioenriched β-bromohydrins provide enantioenriched 1,4-dioxenes.
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Miao, Yubin; Gallazzi, Fabio; Guo, Haixun; Quinn, Thomas P
2008-02-01
The purpose of this study was to examine the influence of the lactam bridge cyclization on melanoma targeting and biodistribution properties of the radiolabeled conjugates. Two novel lactam bridge-cyclized alpha-MSH peptide analogues, DOTA-CycMSH (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]) and DOTA-GlyGlu-CycMSH (DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]), were synthesized and radiolabeled with (111)In. The internalization and efflux of (111)In-labeled CycMSH peptides were examined in B16/F1 melanoma cells. The melanoma targeting properties, pharmacokinetics, and SPECT/CT imaging of (111)In-labeled CycMSH peptides were determined in B16/F1 melanoma-bearing C57 mice. Both (111)In-DOTA-CycMSH and (111)In-DOTA-GlyGlu-CycMSH exhibited fast internalization and extended retention in B16/F1 cells. The tumor uptake values of (111)In-DOTA-CycMSH and (111)In-DOTA-GlyGlu-CycMSH were 9.53+/-1.41% injected dose/gram (% ID/g) and 10.40+/-1.40% ID/g at 2 h postinjection, respectively. Flank melanoma tumors were clearly visualized with (111)In-DOTA-CycMSH and (111)In-DOTA-GlyGlu-CycMSH by SPECT/CT images at 2 h postinjection. Whole-body clearance of the peptides was fast, with greater than 90% of the radioactivities cleared through urinary system by 2 h postinjection. There was low radioactivity (<0.8% ID/g) accumulated in blood and normal organs except kidneys at all time points investigated. Introduction of a negatively charged linker (-Gly-Glu-) into the peptide sequence decreased the renal uptake by 44% without affecting the tumor uptake at 4 h postinjection. High receptor-mediated melanoma uptakes coupled with fast whole-body clearance in B16/F1 melanoma-bearing C57 mice demonstrated the feasibility of using (111)In-labeled lactam bridge-cyclized alpha-MSH peptide analogues as a novel class of imaging probes for receptor-targeting melanoma imaging.
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Mirabella, S; Fibbi, G; Matassini, C; Faggi, C; Goti, A; Cardona, F
2017-11-07
A dual synthetic strategy to afford 2-substituted trihydroxypiperidines is disclosed. The procedure involved Grignard addition either to a carbohydrate-derived aldehyde or to a nitrone derived thereof, and took advantage of an efficient ring-closure reductive amination strategy in the final cyclization step. An opposite diastereofacial preference was demonstrated in the nucleophilic attack to the two electrophiles, which would finally produce the same piperidine diastereoisomer as the major product. However, use of a suitable Lewis acid in the Grignard addition to the nitrone allowed reversing the selectivity, giving access to 2-substituted piperidines with the opposite configuration at C-2.
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Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Zhao, Hui; Wang, Hong-Jiang; Ye, Qing; Zhu, Shun-Ya; Qiu, Yang; Zhou, Xi; Qin, E-De; Qin, Cheng-Feng
2013-06-01
cis-Acting elements in the viral genome RNA (vRNA) are essential for the translation, replication, and/or encapsidation of RNA viruses. In this study, a novel conserved cis-acting element was identified in the capsid-coding region of mosquito-borne flavivirus. The downstream of 5' cyclization sequence (5'CS) pseudoknot (DCS-PK) element has a three-stem pseudoknot structure, as demonstrated by structure prediction and biochemical analysis. Using dengue virus as a model, we show that DCS-PK enhances vRNA replication and that its function depends on its secondary structure and specific primary sequence. Mutagenesis revealed that the highly conserved stem 1 and loop 2, which are involved in potential loop-helix interactions, are crucial for DCS-PK function. A predicted loop 1-stem 3 base triple interaction is important for the structural stability and function of DCS-PK. Moreover, the function of DCS-PK depends on its position relative to the 5'CS, and the presence of DCS-PK facilitates the formation of 5'-3' RNA complexes. Taken together, our results reveal that the cis-acting element DCS-PK enhances vRNA replication by regulating genome cyclization, and DCS-PK might interplay with other cis-acting elements to form a functional vRNA cyclization domain, thus playing critical roles during the flavivirus life cycle and evolution.
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Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Zhao, Hui; Wang, Hong-Jiang; Ye, Qing; Zhu, Shun-Ya; Qiu, Yang; Zhou, Xi; Qin, E-De
2013-01-01
cis-Acting elements in the viral genome RNA (vRNA) are essential for the translation, replication, and/or encapsidation of RNA viruses. In this study, a novel conserved cis-acting element was identified in the capsid-coding region of mosquito-borne flavivirus. The downstream of 5′ cyclization sequence (5′CS) pseudoknot (DCS-PK) element has a three-stem pseudoknot structure, as demonstrated by structure prediction and biochemical analysis. Using dengue virus as a model, we show that DCS-PK enhances vRNA replication and that its function depends on its secondary structure and specific primary sequence. Mutagenesis revealed that the highly conserved stem 1 and loop 2, which are involved in potential loop-helix interactions, are crucial for DCS-PK function. A predicted loop 1-stem 3 base triple interaction is important for the structural stability and function of DCS-PK. Moreover, the function of DCS-PK depends on its position relative to the 5′CS, and the presence of DCS-PK facilitates the formation of 5′-3′ RNA complexes. Taken together, our results reveal that the cis-acting element DCS-PK enhances vRNA replication by regulating genome cyclization, and DCS-PK might interplay with other cis-acting elements to form a functional vRNA cyclization domain, thus playing critical roles during the flavivirus life cycle and evolution. PMID:23576500
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Coiled-Coil Hydrogels. Effect of Grafted Copolymer Composition and Cyclization on Gelation
Dušek, Karel; Dušková-Smrčková, Miroslava; Yang, Jiyuan; Kopeček, Jindřich
2009-01-01
A mean-field theoretical approach was developed to model gelation of solutions of hydrophilic polymers with grafted peptide motifs capable of forming associates of coiled-coil type. The model addresses the competition between associates engaged in branching and cyclization. It results in relative concentrations of intra- and intermolecular associates in dependence on associate strength and motif concentration. The cyclization probability is derived from the model of equivalent Gaussian chain and takes into account all possible paths connecting the interacting motifs. Examination of the association-dissociation equilibria, controlled by the equilibrium constant for association taken as input information, determines the fractions of inter- and intramolecularly associated motifs. The gelation model is based on the statistical theory of branching processes and in combination with the cyclization model predicts the critical concentration delimiting the regions of gelled and liquid states of the system. A comparison between predictions of the model and experimental data available for aqueous solutions of poly[N-(2-hydroxypropyl)methacrylamide] grafted with oppositely charged pentaheptad peptides, CCE and CCK, indicates that the association constant of grafted motifs by four orders of magnitude lower than that of free motifs. It is predicted that at the critical concentration of each motif of about 6×10−7 mol/cm3, about half of motifs in associated state is engaged in intramolecular bonds. PMID:20160932
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Ito, Tadashi; Nishiuchi, Emi; Fukuhara, Gaku; Inoue, Yoshihisa; Mori, Tadashi
2011-09-01
A series of 4-aryl-1,1-dicyanobutenes (1a-1f) with different substituents were synthesized to control the intramolecular donor-acceptor or charge-transfer (C-T) interactions in the ground state. Photoexcitation of these C-T substrates led to competitive cyclization and rearrangement, the ratio being critically controlled by various environmental factors, such as solvent polarity, temperature and static pressure, and also by excitation wavelength and supramolecular confinement (polyethylene voids). In non-polar solvents, the rearrangement was dominant (>10 : 1) for all examined substrates, while the cyclization was favoured in polar solvents, in particular at low temperatures. Selective excitation at the C-T band further enhanced the cyclization up to >50 : 1 ratios. More importantly, the cyclization/rearrangement ratio was revealed to be a linear function of the C-T transition energy. However, the substrates with a sterically demanding or highly electron-donating substituent failed to give the cyclization product.
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Hansmann, Max M; Rudolph, Matthias; Rominger, Frank; Hashmi, A Stephen K
2013-02-25
The other side of the mountain: Changing the framework of diyne systems opens up new cyclization modes for dual gold catalysis. Instead of a 5-endo cyclization and gold vinylidenes a 6-endo cyclization gives rise to gold-stabilized carbenes as key intermediates for selective C-H insertions. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Cyclization of 5-hexynoic acid to 3-alkoxy-2-cyclohexenones
Hylden, Anne T; Uzelac, Eric J; Ostojic, Zeljko; Wu, Ting-Ting; Sacry, Keely L; Sacry, Krista L; Xi, Lin
2011-01-01
Summary The one-pot cyclization of 5-hexynoic acid to produce 3-alkoxy-2-cyclohexenones proceeds in good yields (58–90%). 3-Hexynoic acid was converted to its acyl chloride with the aid of oxalyl chloride and was cyclized to 3-chloro-2-cyclohexenone upon addition of indium(III) chloride. Subsequent addition of alcohol nucleophiles led to the desired 3-alkoxy-2-cyclohexenones. PMID:22043242
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The structure of SpnF a standalone enzyme that catalyzes [4 + 2] cycloaddition
Fage, Christopher D.; Isiorho, Eta A.; Liu, Yungnan; ...
2015-03-02
In the biosynthetic pathway of the spinosyn insecticides, the tailoring enzyme SpnF performs a [4 + 2] cycloaddition on a 22-membered macrolactone to forge an embedded cyclohexene ring. To learn more about this reaction, which could potentially proceed through a Diels-Alder mechanism, in this paper we determined the 1.50-Å-resolution crystal structure of SpnF bound to S-adenosylhomocysteine. Finally, this sets the stage for advanced experimental and computational studies to determine the precise mechanism of SpnF-mediated cyclization.
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Intramolecular addition of benzylic radicals onto ketenimines. Synthesis of 2-alkylindoles.
Alajarín, Mateo; Vidal, Angel; Ortín, María-Mar
2003-12-07
The inter- and intramolecular addition of free radicals onto ketenimines is studied. All the attempts to add intermolecularly several silicon, oxygen or carbon centered radicals to N-(4-methylphenyl)-C,C-diphenyl ketenimine were unsuccessful. In contrast, the intramolecular addition of benzylic radicals, generated from xanthates, onto the central carbon of a ketenimine function with its N atom linked to the ortho position of the aromatic ring occurred under a variety of reaction conditions. These intramolecular cyclizations provide a novel radical-mediated synthesis of 2-alkylindoles.
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Jung, Hyung Hoon; Floreancig, Paul E.
2009-01-01
A series of monodeuterated benzylic and allylic ethers were subjected to oxidative carbon–hydrogen bond cleavage to determine the impact of structural variation on intramolecular kinetic isotope effects in DDQ-mediated cyclization reactions. These values are compared to the corresponding intermolecular kinetic isotope effects that were accessed through subjecting mixtures of non-deuterated and dideuterated substrates to the reaction conditions. The results indicate that carbon–hydrogen bond cleavage is rate determining and that a radical cation is most likely a key intermediate in the reaction mechanism. PMID:20640173
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Tayu, Masanori; Ishizaki, Takako; Higuchi, Kazuhiro; Kawasaki, Tomomi
2015-04-07
The cross-coupling of tryptamine with substituted aniline to access C3a-nitrogen-linked pyrroloindolines has been developed via the consecutive cyclization of tryptamine with DMSO/Tf2O and the substitution of 3a-pyrroloindolylthionium intermediate with aniline. The use of 2,3-dihydrotryptamine instead of aniline enabled easy access to 3a-(1-indolyl)pyrroloindoline and the concise synthesis of C3a-N1'-linked pyrroloindoline alkaloid (±)-psychotriasine was accomplished.
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Bornemann, Holger; Wentrup, Curt
2005-07-22
The energy surface connecting oxazinium olates 9, several possible conformers of ketenes 10 and 11, and the final cyclization products 12, 13 and 14, as well as the isomeric 1,3-oxazine-6-ones 15, ring opening of the latter to N-acylimidoylketenes 16, and subsequent rearrangement of 16 to oxoketenimines 17, azetinones 18, and the cyclization products 19 and 20 are evaluated computationally at the B3LYP/6-31G and B3LYP/6-311+G//B3LYP/6-31G levels. The cyclizations of ketenes to oxazinium olates 9 and oxazines 15 have the characteristics of pseudopericyclic reactions. Plots of the energy vs internal reaction coordinate for the cyclization of transoid acylketenes such as 10 to 9 (via TS1) and 16 to 15 (via TS7) feature two inflection points and indicate that the part of the energy surface above the lower inflection points describe internal rotation of the acyl function in the ketene moiety, and the part below this point describes the cyclization of the cisoid ketene to the planar mesoionic oxazinium olate 9 or oxazinone 15. The 1,3-shifts of the OR group that interconvert ketenes 16 and ketenimines 17 via four-membered cyclic transition states TS8 behave similarly, the first portion (from the ketenimine side) of the activation barrier being due largely to internal rotation of substituents, and the top part being due to the 1,3-shift proper.
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Ynamides in Ring Forming Transformations
WANG, XIAO-NA; YEOM, HYUN-SUK; FANG, LI-CHAO; HE, SHUZHONG; MA, ZHI-XIONG; KEDROWSKI, BRANT L.; HSUNG, RICHARD P.
2013-01-01
Conspectus The ynamide functional group activates carbon-carbon triple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years. This Account surveys and assesses new organic transformations involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides. This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within, or in close proximity to, a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides. PMID:24164363
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Xu, Wenqing; Wang, Wei; Wang, Xiang
2015-08-10
A gold-catalyzed desilylative cyclization was developed for facile synthesis of bridged tetracyclic indolenines, a common motif in many natural indole alkaloids. An antimicrobial screen of the cyclization products identified one compound which selectively potentiates β-lactam antibiotics in methicillin-resistant S. aureus (MRSA), and re-sensitizes a variety of MRSA strains to β-lactams. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Rhenium(VII) Catalysis of Prins Cyclization Reactions
Tadpetch, Kwanruthai; Rychnovsky, Scott D.
2009-01-01
The rhenium(VII) complex O3ReOSiPh3 are particularly effective catalyst for Prins cyclizations using aromatic and α,β-unsaturated aldehydes. The reaction conditions are mild and the highly substituted 4-hydroxy tetrahydropyran products are formed stereoselectively. Rhenium(VII) complexes appear to spontaneously form esters with alcohols and to directly activate electron rich alcohols for solvolysis. Re2O7 and perrhenic acid were equally effective in catalyzing these cyclizations. PMID:18816133
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He, Wei; Herrick, Ildiko R; Atesin, Tulay A; Caruana, Patrick A; Kellenberger, Colleen A; Frontier, Alison J
2008-01-23
The impact of dienone substitution on the Nazarov cyclization has been examined in detail. Substrates bearing different substituents at each of four positions on the dienone backbone were systematically probed in order to identify trends leading to higher reactivity and better selectivity. Desymmetrization of the pentadienyl cation and oxyallyl cation intermediates through placement of polarizing groups at both the C-2 and C-4 positions was found to be particularly effective. These modifications allowed cyclizations to occur in the presence of catalytic amounts of mild Lewis acids. It was also found that stereoconvergent cyclization of mixtures of E and Z isomers of alkylidene beta-ketoesters occurred via an efficient isomerization process that occurred under the reaction conditions.
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Rim-Differentiated C5-Symmetric Tiara-Pillar[5]arenes
2017-01-01
The synthesis of “rim-differentiated” C5-symmetric pillar[5]arenes, whose two rims are decorated with different chemical functionalities, has remained a challenging task. This is due to the inherent statistical nature of the cyclization of 1,4-disubstituted alkoxybenzenes with different substituents, which leads to four constitutional isomers with only 1/16th being rim-differentiated. Herein, we report a “preoriented” synthetic protocol based on FeCl3-catalyzed cyclization of asymmetrically substituted 2,5-dialkoxybenzyl alcohols. This yields an unprecedented 55% selectivity of the C5-symmetric tiara-like pillar[5]arene isomer among four constitutional isomers. Based on this new method, a series of functionalizable tiara-pillar[5]arene derivatives with C5-symmetry was successfully synthesized, isolated, and fully characterized in the solid state. PMID:29220153
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Directing-Group-mediated C-H-Alkynylations.
Caspers, Lucien D; Nachtsheim, Boris J
2018-05-18
C-C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal-catalyzed alkynylation of C-H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG-mediated C(sp 2 )-H and C(sp 3 )-H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo- and heterocycles and modifications of the DG in the presence of the alkyne. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Fleming, Fraser F.; Gudipati, Subramanyham
2013-01-01
Metalated nitriles are nucleophilic chameleons whose precise identity is determined by the nature of the metal, the solvent, the temperature, and the structure of the nitrile. The review surveys the different structural types and their cyclization trajectories to show how to selectively tune the metalated nitrile geometry for stereoselective cyclizations to a variety of cis or trans hydrindanes, decalins, and bicyclo[4.3.0]undecanes. PMID:24260015
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2015-01-01
Advances in metabolomics, particularly for research on cancer, have increased the demand for accurate, highly sensitive methods for measuring glutamine (Gln) and glutamic acid (Glu) in cell cultures and other biological samples. N-terminal Gln and Glu residues in proteins or peptides have been reported to cyclize to pyroglutamic acid (pGlu) during liquid chromatography (LC)-mass spectrometry (MS) analysis, but cyclization of free Gln and Glu to free pGlu during LC-MS analysis has not been well-characterized. Using an LC-MS/MS protocol that we developed to separate Gln, Glu, and pGlu, we found that free Gln and Glu cyclize to pGlu in the electrospray ionization source, revealing a previously uncharacterized artifact in metabolomic studies. Analysis of Gln standards over a concentration range from 0.39 to 200 μM indicated that a minimum of 33% and maximum of almost 100% of Gln was converted to pGlu in the ionization source, with the extent of conversion dependent on fragmentor voltage. We conclude that the sensitivity and accuracy of Gln, Glu, and pGlu quantitation by electrospray ionization-based mass spectrometry can be improved dramatically by using (i) chromatographic conditions that adequately separate the three metabolites, (ii) isotopic internal standards to correct for in-source pGlu formation, and (iii) user-optimized fragmentor voltage for acquisition of the MS spectra. These findings have immediate impact on metabolomics and metabolism research using LC-MS technologies. PMID:24892977
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Purwaha, Preeti; Silva, Leslie P; Hawke, David H; Weinstein, John N; Lorenzi, Philip L
2014-06-17
Advances in metabolomics, particularly for research on cancer, have increased the demand for accurate, highly sensitive methods for measuring glutamine (Gln) and glutamic acid (Glu) in cell cultures and other biological samples. N-terminal Gln and Glu residues in proteins or peptides have been reported to cyclize to pyroglutamic acid (pGlu) during liquid chromatography (LC)-mass spectrometry (MS) analysis, but cyclization of free Gln and Glu to free pGlu during LC-MS analysis has not been well-characterized. Using an LC-MS/MS protocol that we developed to separate Gln, Glu, and pGlu, we found that free Gln and Glu cyclize to pGlu in the electrospray ionization source, revealing a previously uncharacterized artifact in metabolomic studies. Analysis of Gln standards over a concentration range from 0.39 to 200 μM indicated that a minimum of 33% and maximum of almost 100% of Gln was converted to pGlu in the ionization source, with the extent of conversion dependent on fragmentor voltage. We conclude that the sensitivity and accuracy of Gln, Glu, and pGlu quantitation by electrospray ionization-based mass spectrometry can be improved dramatically by using (i) chromatographic conditions that adequately separate the three metabolites, (ii) isotopic internal standards to correct for in-source pGlu formation, and (iii) user-optimized fragmentor voltage for acquisition of the MS spectra. These findings have immediate impact on metabolomics and metabolism research using LC-MS technologies.
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Doubleday, Charles; Boguslav, Mayla; Howell, Caronae; Korotkin, Scott D; Shaked, David
2016-06-22
An unusual H/D kinetic isotope effect (KIE) is described, in which isotopic selectivity arises primarily from nonstatistical dynamics in the product. In DFT-based quasiclassical trajectories of Bergman cyclization of (Z)-3-hexen-1,5-diyne (1) at 470 K, the new CC bond retains its energy, and 28% of nascent p-benzyne recrosses back to the enediyne on a vibrational time scale. The competing process of intramolecular vibrational redistribution (IVR) in p-benzyne is too slow to prevent this. Deuteration increases the rate of IVR, which decreases the fraction of recrossing and increases the yield of statistical (trapable) p-benzyne, 2. Trapable yields for three isotopomers of 2 range from 72% to 86%. The resulting KIEs for Bergman cyclization differ substantially from KIEs predicted by transition state theory, which suggests that IVR in this reaction can be studied by conventional KIEs. Leakage of vibrational zero point energy (ZPE) into the reaction coordinate was probed by trajectories in which initial ZPE in the CH/CD stretching modes was reduced by 25%. This did not change the predicted KIEs.
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Porcine CD38 exhibits prominent secondary NAD(+) cyclase activity.
Ting, Kai Yiu; Leung, Christina F P; Graeff, Richard M; Lee, Hon Cheung; Hao, Quan; Kotaka, Masayo
2016-03-01
Cyclic ADP-ribose (cADPR) mobilizes intracellular Ca(2+) stores and activates Ca(2+) influx to regulate a wide range of physiological processes. It is one of the products produced from the catalysis of NAD(+) by the multifunctional CD38/ADP-ribosyl cyclase superfamily. After elimination of the nicotinamide ring by the enzyme, the reaction intermediate of NAD(+) can either be hydrolyzed to form linear ADPR or cyclized to form cADPR. We have previously shown that human CD38 exhibits a higher preference towards the hydrolysis of NAD(+) to form linear ADPR while Aplysia ADP-ribosyl cyclase prefers cyclizing NAD(+) to form cADPR. In this study, we characterized the enzymatic properties of porcine CD38 and revealed that it has a prominent secondary NAD(+) cyclase activity producing cADPR. We also determined the X-ray crystallographic structures of porcine CD38 and were able to observe conformational flexibility at the base of the active site of the enzyme which allow the NAD(+) reaction intermediate to adopt conformations resulting in both hydrolysis and cyclization forming linear ADPR and cADPR respectively. © 2016 The Protein Society.
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The role of structural parameters in DNA cyclization
Alexandrov, Ludmil B.; Bishop, Alan R.; Rasmussen, Kim O.; ...
2016-02-04
The intrinsic bendability of DNA plays an important role with relevance for myriad of essential cellular mechanisms. The flexibility of a DNA fragment can be experimentally and computationally examined by its propensity for cyclization, quantified by the Jacobson-Stockmayer J factor. In this paper, we use a well-established coarse-grained three-dimensional model of DNA and seven distinct sets of experimentally and computationally derived conformational parameters of the double helix to evaluate the role of structural parameters in calculating DNA cyclization.
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Copper-catalyzed domino reactions for the synthesis of cyclic compounds.
Liao, Qian; Yang, Xianghua; Xi, Chanjuan
2014-09-19
Copper-catalyzed domino reactions are one of the most useful strategies for the construction of various cyclic compounds. In this Synopsis, we mainly focus on the latest advances in copper-catalyzed cross-coupling or addition-initiated domino reactions in the synthesis of cyclic compounds, including double alkenylation of N- or S-nucleophiles, alkenylation or alkynlation followed by cyclization of amides or amines, addition and cyclization of heteroallenes affording heterocycles, and coupling and cyclization of 1,3-dicarbonyl compounds toward heterocycles.
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Photochemically Induced Intramolecular Radical Cyclization Reactions with Imines.
Lefebvre, Corentin; Michelin, Clément; Martzel, Thomas; Djou'ou Mvondo, Vaneck; Bulach, Véronique; Abe, Manabu; Hoffmann, Norbert
2018-02-16
The photochemically induced intramolecular hydrogen abstraction or hydrogen atom transfer in cyclic imines 8a,b followed by a cyclization is investigated. Two types of products are observed, one resulting from the formation of a C-C bond, the other from the formation of a C-N bond. A computational study reveals that hydrogen is exclusively transferred to the imine nitrogen leading to a triplet diradical intermediate. After intersystem crossing, the resulting zwitterionic intermediate undergoes cyclization leading to the final product.
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Porphinogen Formation from the Co-Oligomerization of Formaldehyde and Pyrrole: Free Energy Pathways.
Kua, Jeremy; Loli, Helen
2017-10-26
We have investigated the nonoxidative stepwise co-oligomerization of formaldehyde and pyrrole to form porphinogen using density functional theory calculations that include free energy corrections. While the addition of formaldehyde to the pyrrole nitrogen is kinetically favored, thermodynamics suggest that this reaction is reversible in aqueous solution. The more thermodynamically favorable addition of formaldehyde to the ortho-carbon of pyrrole begins a stepwise process, forming dipyrromethane via an azafulvene intermediate. Subsequent additions of formaldehyde and pyrrole lead to bilanes (linear tetrapyrroles), which favorably cyclize to form porphinogen. Porphinogen is a precursor to porphin, the simplest unsubstituted porphyrin that could have played a role in primitive metabolism at the origin of life.
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Molecularly imprinted cavities template the macrocyclization of tetrapeptides.
Tai, Dar-Fu; Lin, Yee-Fung
2008-11-21
Cavities formed using cyclic tetrapeptides (CTPs) or heat-induced conformers act as templates for cyclization; the cavities bind to linear tetrapeptides and enforce turn conformations to enhance cyclization to constrained CTPs.
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Massive glutamine cyclization to pyroglutamic acid in human serum discovered using NMR spectroscopy.
Nagana Gowda, G A; Gowda, Yashas N; Raftery, Daniel
2015-04-07
Glutamine is one of the most abundant metabolites in blood and is a precursor as well as end product central to numerous important metabolic pathways. A number of surprising and unexpected roles for glutamine, including cancer cell glutamine addiction discovered recently, stress the importance of accurate analysis of glutamine concentrations for understanding its role in health and numerous diseases. Utilizing a recently developed NMR approach that offers access to an unprecedented number of quantifiable blood metabolites, we have identified a surprising glutamine cyclization to pyroglutamic acid that occurs during protein removal. Intact, ultrafiltered and protein precipitated samples from the same pool of human serum were comprehensively investigated using (1)H NMR spectroscopy at 800 MHz to detect and quantitatively evaluate the phenomenon. Interestingly, although glutamine cyclization occurs in both ultrafiltered and protein precipitated serum, the cyclization was not detected in intact serum. Strikingly, due to cyclization, the apparent serum glutamine level drops by up to 75% and, concomitantly, the pyroglutamic acid level increases proportionately. Further, virtually under identical conditions, the magnitude of cyclization is vastly different for different portions of samples from the same pool of human serum. However, the sum of glutamine and pyroglutamic acid concentrations in each sample remains the same for all portions. These unexpected findings indicate the importance of considering the sum of apparent glutamine and pyroglutamic acid levels, obtained from the contemporary analytical methods, as the actual blood glutamine level for biomarker discovery and biological interpretations.
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Vazdar, Katarina; Vojta, Danijela; Margetić, Davor; Vazdar, Mario
2017-03-20
4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are biologically important reactive aldehydes formed during oxidative stress in phospholipid bilayers. They are highly reactive species due to presence of several reaction centers and can react with amino acids in peptides and proteins, as well as phosphoethanolamine (PE) lipids, thus modifying their biological activity. The aim of this work is to study in a molecular detail the reactivity of HNE and ONE toward PE lipids in a simplified system containing only lipids and reactive aldehydes in dichloromethane as an inert solvent. We use a combination of quantum chemical calculations, 1 H NMR measurements, FT-IR spectroscopy, and mass spectrometry experiments and show that for both reactive aldehydes two types of chemical reactions are possible: formation of Michael adducts and Schiff bases. In the case of HNE, an initially formed Michael adduct can also undergo an additional cyclization step to a hemiacetal derivative, whereas no cyclization occurs in the case of ONE and a Michael adduct is identified. A Schiff base product initially formed when HNE is added to PE lipid can also further cyclize to a pyrrole derivative in contrast to ONE, where only a Schiff base product is isolated. The suggested reaction mechanism by quantum-chemical calculations is in a qualitative agreement with experimental yields of isolated products and is also additionally investigated by 1 H NMR measurements, FT-IR spectroscopy, and mass spectrometry experiments.
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Structural and Chemical Biology of Terpenoid Cyclases
2017-01-01
The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can be used to reprogram the cyclization cascade to generate alternative and commercially important products. Here, I review key advances in terpenoid cyclase structural and chemical biology, focusing mainly on terpenoid cyclases and related prenyltransferases for which X-ray crystal structures have informed and advanced our understanding of enzyme structure and function. PMID:28841019
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A new method to synthesize creatine derivatives.
Garbati, Patrizia; Salis, Annalisa; Adriano, Enrico; Galatini, Andrea; Damonte, Gianluca; Balestrino, Maurizio; Millo, Enrico
2013-10-01
Creatine is an amino acid that has a pivotal role in energy metabolism of cells. Creatine acts as an "ATP shuttle", carrying ATP to the sites where it is utilized, through its reversible phosphorylation by creatine kinase. Moreover, the creatine-phosphocreatine system delays ATP depletion during anoxia or ischemia, thus exerting a neuroprotective role during those pathological conditions. Thus, its administration has been advocated as a treatment or prevention of several conditions involving the central nervous system. However, creatine crosses poorly the blood-brain barrier and the cell plasma membrane, thus its administration has but a limited effect. The use of more lipophilic creatine derivatives has thus been suggested. However, such a synthesis is complicated by the intrinsic characteristics of the creatine molecule that hardly reacts with other molecules and easily cyclizes to creatinine. We obtained amide derivatives from creatine starting from a new protected creatine molecule synthesized by us, the so-called (Boc)2-creatine. We used a temporary protection only on the creatine guanidine group while allowing a good reactivity on the carboxylic group. This temporary protection ensured efficient creatine dissolution in organic solvents and offered simultaneous protection of creatine toward intramolecular cyclization to creatinine. In this manner, it was possible to selectively conjugate molecules on the carboxylic group. The creatine guanidine group was easily released from the protection at the end of the reaction, thus obtaining the desired creatine derivative.
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Julian, Lisa D.; Hartwig, John F.
2010-01-01
We report a rhodium catalyst that exhibits high reactivity for the hydroamination of primary aminoalkenes that are unbiased toward cyclization and that possess functional groups that would not be tolerated in hydroaminations catalyzed by more electrophilic systems. This catalyst contains an unusual diaminophosphine ligand that binds to rhodium in a κ3-P,O,P mode. The reactions catalyzed by this complex typically proceed at mild temperatures (room temperature to 70 °C), occur with primary aminoalkenes lacking substituents on the alkyl chain that bias the system toward cyclization, occur with primary aminoalkenes containing chloride, ester, ether, enolizable ketone, nitrile, and unprotected alcohol functionality, and occur with primary aminoalkenes containing internal olefins. Mechanistic data imply that these reactions occur with a turnover-limiting step that is different from that of reactions catalyzed by late transition metal complexes of Pd, Pt, and Ir. This change in the turnover-limiting step and resulting high activity of the catalyst stem from favorable relative rates for protonolysis of the M-C bond to release the hydroamination product vs reversion of the aminoalkyl intermediate to regenerate the acyclic precursor. Probes for the origin of the reactivity of the rhodium complex of L1 imply that the aminophosphine groups lead to these favorable rates by effects beyond steric demands and simple electron donation to the metal center. PMID:20839807
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Direct Synthesis of Medium-Bridged Twisted Amides via a Transannular Cyclization Strategy
Szostak, Michal; Aubé, Jeffrey
2009-01-01
The sequential RCM to construct a challenging medium-sized ring followed by a transannular cyclization across a medium-sized ring delivers previously unattainable twisted amides from simple acyclic precursors. PMID:19708701
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Ren, Ji-Wei; Wang, Jing; Xiao, Jun-An; Li, Jun; Xiang, Hao-Yue; Chen, Xiao-Qing; Yang, Hua
2017-06-16
Hydrogen-bonding organocatalysts L-pyroglutamic sulphonamides were readily synthesized for the first time by fully exploiting the potentials of L-pyroglutamic acid. The newly designed catalyst was successfully applied in catalyzing asymmetric Diels-Alder cyclization of methyleneindolinones with 2-vinyl-1H-indoles to efficiently assemble carbazolespirooxindoles in excellent stereoselectivity (up to 99% ee, >20:1 dr) and yields (up to 99%). Mechanistic studies disclosed that the well-designed hydrogen-bonding modes between L-pyroglutamic sulphonamide and substrates were crucial for stereocontrol in the cyclization.
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A Highly Reactive Dicationic Iridium(III) Catalyst for Polarized Nazarov Cyclization
Vaidya, Tulaza; Atesin, Abdurrahman C.; Herrick, Ildiko R.; Frontier, Alison J.; Eisenberg, Richard
2010-01-01
Pushing the Nazarov Envelope A new electrophilic complex [IrBr(CO)(diethylisopropylidene malonate)((R)-(+)-BINAP)](SbF6)2 (2) exhibits unusual activity in the catalysis of polarized Nazarov cyclization. Aryl vinyl ketones that show poor reactivity with well-known catalysts such as [Ir(CH3)(CO)(1,2-diiodobenzene)(dppe)](B(Arf)4−)2 (1), Sc(OTf)3 + LiClO4 and Cu(ClO4)2, can be cyclized with 2 + AgSbF6 (1:1) under mild conditions with concurrent AgBr precipitation. PMID:20358570
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Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2'-Prins Cyclization.
Scoccia, Jimena; Pérez, Sixto J; Sinka, Victoria; Cruz, Daniel A; López-Soria, Juan M; Fernández, Israel; Martín, Víctor S; Miranda, Pedro O; Padrón, Juan I
2017-09-15
A new, direct, and diastereoselective synthesis of activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an S N 2'-Prins cyclization tandem process leading to the creation of three new stereocenters in one single step. These activated tetrahydro-2H-pyran units are easily derivatizable through CuAAC conjugations in order to generate multifunctionalized complex molecules. DFT calculations support the in situ S N 2' reaction as a preliminary step in the Prins cyclization.
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Enantioselective Copper-Catalyzed Carboetherification of Unactivated Alkenes**
Bovino, Michael T.; Liwosz, Timothy W.; Kendel, Nicole E.; Miller, Yan; Tyminska, Nina
2014-01-01
Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein is reported a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols that terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition state calculations support a cis-oxycupration stereochemistry-determining step. PMID:24798697
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Stepanov, A A; Gornostaev, L M; Vasilevsky, S F; Arnold, E V; Mamatyuk, V I; Fadeev, D S; Gold, B; Alabugin, I V
2011-11-04
The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.
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NASA Astrophysics Data System (ADS)
Terranova, U.; Nifosı`, R.
2010-05-01
Spontaneous chromophore formation is probably the key feature for the remarkable success of GFPs (Green Fluorescent Proteins) and related proteins in fluorescence microscopy. Though a quantitative analysis of the involved energetics still remains elusive, substantial progress has been made in identifying the steps of chromophore biosynthesis and the contribution of individual residues and surrounding protein matrix. The latter clearly enforces a peculiar configuration of the pre-cyclized chromophore-forming tripeptide. However, it is debated whether a mechanical compression is also at play in triggering backbone cyclization. Here, by molecular dynamics and potential of mean force calculations, we estimate the contribution of the protein scaffold in promoting the proximity of reacting atoms- and hence backbone cyclization - by a sort of compression mechanism. Comparing several mutants we highlight the role of some surrounding residues. Finally, we analyze the case of HAL (Histidine Ammonia-Lyase) active site, which undergoes an analogous cyclization reaction.
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Lebœuf, David; Ciesielski, Jennifer
2012-01-01
Highly functionalized cyclopentenones can be generated stereospecifically by a chemoselective copper(II)-mediated Nazarov/Wagner-Meerwein rearrangement sequence of divinyl ketones. A detailed investigation of this sequence is described including a study of substrate scope and limitations. After the initial 4π electrocyclization, this reaction proceeds via two different sequential [1,2]-shifts, with selectivity that depends upon either migratory ability or the steric bulkiness of the substituents at C1 and C5. This methodology allows the creation of vicinal stereogenic centers, including adjacent quaternary centers. This sequence can also be achieved by using a catalytic amount of copper(II) in combination with NaBAr4f, a weak Lewis acid. During the study of the scope of the reaction, a partial or complete E / Z isomerization of the enone moiety was observed in some cases prior to the cyclization, which resulted in a mixture of diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the isomerization, allowing high diastereoselectivity to be obtained in all substrate types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent with the proposed sequences observed, including E / Z isomerizations and chemoselective Wagner-Meerwein shifts. PMID:22471833
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Baron, Alice; Verdié, Pascal; Martinez, Jean; Lamaty, Frédéric
2011-02-04
A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.
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Enantioselective copper-catalyzed carboetherification of unactivated alkenes.
Bovino, Michael T; Liwosz, Timothy W; Kendel, Nicole E; Miller, Yan; Tyminska, Nina; Zurek, Eva; Chemler, Sherry R
2014-06-16
Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols which terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry-determining step. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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On-surface formation of one-dimensional polyphenylene through Bergman cyclization.
Sun, Qiang; Zhang, Chi; Li, Zhiwen; Kong, Huihui; Tan, Qinggang; Hu, Aiguo; Xu, Wei
2013-06-12
On-surface fabrication of covalently interlinked conjugated nanostructures has attracted significant attention, mainly because of the high stability and efficient electron transport ability of these structures. Here, from the interplay of scanning tunneling microscopy imaging and density functional theory calculations, we report for the first time on-surface formation of one-dimensional polyphenylene chains through Bergman cyclization followed by radical polymerization on Cu(110). The formed surface nanostructures were further corroborated by the results for the ex situ-synthesized molecular product after Bergman cyclization. These findings are of particular interest and importance for the construction of molecular electronic nanodevices on surfaces.
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Zhang, Lin; Sun, Ge; Bi, Xihe
2016-11-07
The first cyclization reaction between vinyl azides and N-sulfonyl-1,2,3-triazoles is reported. A Rh/Ag binary metal catalyst system proved to be necessary for the successful cyclization. By varying the structure of vinyl azides, such reaction allows the divergent synthesis of pyrroles and 2H-pyrazines. The cyclization reactions feature a broad substrate scope, good functional group tolerance, high reaction efficiency, and good to high product yields. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Cao, Tian-Jun; Huang, Xing-Qi; Qu, Yuan-Yuan; Zhuang, Zhong; Deng, Yin-Yin; Lu, Shan
2017-04-11
Lycopene cyclases cyclize the open ends of acyclic lycopene (ψ,ψ-carotene) into β- or ε-ionone rings in the crucial bifurcation step of carotenoid biosynthesis. Among all carotenoid constituents, β-carotene (β,β-carotene) is found in all photosynthetic organisms, except for purple bacteria and heliobacteria, suggesting a ubiquitous distribution of lycopene β-cyclase activity in these organisms. In this work, we isolated a gene ( BfLCYB ) encoding a lycopene β-cyclase from Bangia fuscopurpurea , a red alga that is considered to be one of the primitive multicellular eukaryotic photosynthetic organisms and accumulates carotenoid constituents with both β- and ε-rings, including β-carotene, zeaxanthin, α-carotene (β,ε-carotene) and lutein. Functional complementation in Escherichia coli demonstrated that BfLCYB is able to catalyze cyclization of lycopene into monocyclic γ-carotene (β,ψ-carotene) and bicyclic β-carotene, and cyclization of the open end of monocyclic δ-carotene (ε,ψ-carotene) to produce α-carotene. No ε-cyclization activity was identified for BfLCYB. Sequence comparison showed that BfLCYB shares conserved domains with other functionally characterized lycopene cyclases from different organisms and belongs to a group of ancient lycopene cyclases. Although B. fuscopurpurea also synthesizes α-carotene and lutein, its enzyme-catalyzing ε-cyclization is still unknown.
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Kawakami, Takashi; Ogawa, Koji; Hatta, Tomohisa; Goshima, Naoki; Natsume, Tohru
2016-06-17
N-alkyl amino acids are useful building blocks for the in vitro display evolution of ribosomally synthesized peptides because they can increase the proteolytic stability and cell permeability of these peptides. However, the translation initiation substrate specificity of nonproteinogenic N-alkyl amino acids has not been investigated. In this study, we screened various N-alkyl amino acids and nonamino carboxylic acids for translation initiation with an Escherichia coli reconstituted cell-free translation system (PURE system) and identified those that efficiently initiated translation. Using seven of these efficiently initiating acids, we next performed in vitro display evolution of cyclized peptidomimetics against an arbitrarily chosen model human protein (β-catenin) cell-free expressed from its cloned cDNA (HUPEX) and identified a novel β-catenin-binding cyclized peptoid-peptide chimera. Furthermore, by a proteomic approach using direct nanoflow liquid chromatography-tandem mass spectrometry (DNLC-MS/MS), we successfully identified which protein-β-catenin interaction is inhibited by the chimera. The combination of in vitro display evolution of cyclized N-alkyl peptidomimetics and in vitro expression of human proteins would be a powerful approach for the high-speed discovery of diverse human protein-targeted cyclized N-alkyl peptidomimetics.
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Catalytic, Enantioselective, Intramolecular Sulfenofunctionalization of Alkenes with Phenols
2017-01-01
The catalytic, enantioselective, cyclization of phenols with electrophilic sulfenophthalimides onto isolated or conjugated alkenes affords 2,3-disubstituted benzopyrans and benzoxepins. The reaction is catalyzed by a BINAM-based phosphoramide Lewis base catalyst which assists in the highly enantioselective formation of a thiiranium ion intermediate. The influence of nucleophile electron density, alkene substitution pattern, tether length and Lewis base functional groups on the rate, enantio- and site-selectivity for the cyclization is investigated. The reaction is not affected by the presence of substituents on the phenol ring. In contrast, substitutions around the alkene strongly affect the reaction outcome. Sequential lengthening of the tether results in decreased reactivity, which necessitated increased temperatures for reaction to occur. Sterically bulky aryl groups on the sulfenyl moiety prevented erosion of enantiomeric composition at these elevated temperatures. Alcohols and carboxylic acids preferentially captured thiiranium ions in competition with phenolic hydroxyl groups. An improved method for the selective C(2) allylation of phenols is also described. PMID:28257203
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Blackmond, Donna G; Moran, Antonio; Hughes, Matthew; Armstrong, Alan
2010-06-09
An intriguing reversal in product enantioselectivity accompanied by a change in the kinetic profile is observed in the alpha-amination of aldehydes catalyzed by proline in the presence of organic bases. Implications for the prevailing stereochemical models for proline and related aminocatalytic transformations are discussed.
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Cheng, Y D; Lin, S Y
2000-03-01
A novel Fourier transform infrared (FT-IR) microspectrophotometer equipped with differential scanning calorimetry (DSC) was used to investigate the kinetics of intramolecular cyclization of aspartame (APM) sweetener in the solid state under isothermal conditions. The thermal-dependent changes in the peak intensity of IR spectra at 1543, 1283, and 1259 cm(-1) were examined to explore the reaction. The results support that the intramolecular cyclization process in APM proceeded in three steps: the methoxyl group of ester was first thermolyzed to release methanol, then an acyl cation was attacked by the lone pair of electrons available on nitrogen by an S(N)1 pathway, and finally ring-closure occurred. The intramolecular cyclization of APM determined by this microscopic FT-IR/DSC system was found to follow zero-order kinetics after a brief induction period. The bond cleavage energy (259.38 kJ/mol) of thermolysis for the leaving group of -OCH(3), the bond conversion energy (328.88 kJ/mol) for the amide II NH band to DKP NH band, and the CN bond formation energy (326.93 kJ/mol) of cyclization for the DKP in the APM molecule were also calculated from the Arrhenius equation. The total activation energy of the DKP formation via intramolecular cyclization was 261.33 kJ/mol, calculated by the above summation of the bond energy of cleavage, conversion, and formation, which was near to the value determined by the DSC or TGA method. This indicates that the microscopic FT-IR/DSC system is useful as a potential tool not only to investigate the degradation mechanism of drugs in the solid state but also to directly predict the bond energy of the reaction.
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Graeff, R M; Walseth, T F; Fryxell, K; Branton, W D; Lee, H C
1994-12-02
Cyclic nucleotides such as cAMP and cGMP are second messengers subserving various signaling pathways. Cyclic ADP-ribose (cADPR), a recently discovered member of the family, is derived from NAD+ and is a mediator of Ca2+ mobilization in various cellular systems. The synthesis and degradation of cADPR are, respectively, catalyzed by ADP-ribosyl cyclase and cADPR hydrolase. CD38, a differentiation antigen of B lymphocytes, has recently been shown to be a bifunctional enzyme catalyzing both the formation and hydrolysis of cADPR. The overall reaction catalyzed by CD38 is the formation of ADP-ribose and nicotinamide from NAD+, identical to that catalyzed by NADase. The difficulties in detecting the formation of cADPR have led to frequent identification of CD38 as a classical NADase. In this study, we show that both ADP-ribosyl cyclase and CD38, but not NADase, can cyclize nicotinamide guanine dinucleotide (NGD+) producing a new nucleotide. Analyses by high performance liquid chromatography and mass spectroscopy indicate the product is cyclic GDP-ribose (cGDPR) with a structure similar to cADPR except with guanine replacing adenine. Compared to cADPR, cGDPR is a more stable compound showing 2.8 times more resistance to heat-induced hydrolysis. These results are consistent with a catalytic scheme for CD38 where the cyclization of the substrate precedes the hydrolytic reaction. Spectroscopic analyses show that cGDPR is fluorescent and has an absorption spectrum different from both NGD+ and GDPR, providing a very convenient way for monitoring its enzymatic formation. The use of NGD+ as substrate for assaying the cyclization reaction was found to be applicable to pure enzymes as well as crude tissue extracts making it a useful diagnostic tool for distinguishing CD38-like enzymes from degradative NADases.
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Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants.
Degenhardt, Jörg; Köllner, Tobias G; Gershenzon, Jonathan
2009-01-01
The multitude of terpene carbon skeletons in plants is formed by enzymes known as terpene synthases. This review covers the monoterpene and sesquiterpene synthases presenting an up-to-date list of enzymes reported and evidence for their ability to form multiple products. The reaction mechanisms of these enzyme classes are described, and information on how terpene synthase proteins mediate catalysis is summarized. Correlations between specific amino acid motifs and terpene synthase function are described, including an analysis of the relationships between active site sequence and cyclization type and a discussion of whether specific protein features might facilitate multiple product formation.
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Microwave-assisted synthesis of medicinally relevant indoles.
Patil, S A; Patil, R; Miller, D D
2011-01-01
Indoles represent an important structural class in medicinal chemistry with broad spectrum of biological activities. The synthesis of indoles, therefore, has attracted enormous attention from synthetic chemists. Microwave methods for the preparation of indole analogs have been developed to speed up the synthesis, therefore, microwave assisted organic synthesis (MAOS) in controlled conditions is an invaluable technique for medicinal chemistry. In this review, indole forming classical reactions such as Fischer, Madelung, Bischler-Mohlau, Batcho-Leimgruber, Hemetsberger-Knittel, Graebe-Ullmann, Diels-Alder and Wittig type reactions using microwave radiation has been summarized. In addition, metal mediated cyclizations along with solid phase synthesis of indoles have been discussed. © 2011 Bentham Science Publishers Ltd.
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NASA Astrophysics Data System (ADS)
Nguyen, John D.; D'Amato, Erica M.; Narayanam, Jagan M. R.; Stephenson, Corey R. J.
2012-10-01
Radical reactions are a powerful class of chemical transformations. However, the formation of radical species to initiate these reactions has often required the use of stoichiometric amounts of toxic reagents, such as tributyltin hydride. Recently, the use of visible-light-mediated photoredox catalysis to generate radical species has become popular, but the scope of these radical precursors has been limited. Here, we describe the identification of reaction conditions under which photocatalysts such as fac-Ir(ppy)3 can be utilized to form radicals from unactivated alkyl, alkenyl and aryl iodides. The generated radicals undergo reduction via hydrogen atom abstraction or reductive cyclization. The reaction protocol utilizes only inexpensive reagents, occurs under mild reaction conditions, and shows exceptional functional group tolerance. Reaction efficiency is maintained upon scale-up and decreased catalyst loading, and the reaction time can be significantly shortened when the reaction is performed in a flow reactor.
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Gold(I)-catalyzed tandem cyclization approach to tetracyclic indolines.
Liu, Yongxiang; Xu, Wenqing; Wang, Xiang
2010-04-02
Two highly stereoselective cationic gold(I)-catalyzed tandem cyclization reactions of alkynylindoles are described. These reactions demonstrated a novel and general strategy to rapidly construct highly functionalized polycyclic indolines. This approach was successfully employed for a formal synthesis of the akuammiline alkaloid minfiensine.
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Hassan, Fathy M.; Batmaz, Rasim; Li, Jingde; ...
2015-10-26
Silicon has the potential to revolutionize the energy storage capacities of lithium-ion batteries to meet the ever increasing power demands of next generation technologies. To avoid the operational stability problems of silicon-based anodes, we propose synergistic physicochemical alteration of electrode structures during their design. This capitalizes on covalent interaction of Si nanoparticles with sulfur-doped graphene and with cyclized polyacrylonitrile to provide a robust nanoarchitecture. This hierarchical structure stabilized the solid electrolyte interphase leading to superior reversible capacity of over 1,000 mAh g -1 for 2,275 cycles at 2 A g -1. Furthermore, the nanoarchitectured design lowered the contact of themore » electrolyte to the electrode leading to not only high coulombic efficiency of 99.9% but also maintaining high stability even with high electrode loading associated with 3.4 mAh cm -2. As a result, the excellent performance combined with the simplistic, scalable and non-hazardous approach render the process as a very promising candidate for Li-ion battery technology.« less
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Callies, Oliver; Sánchez-Cañete, María P; Gamarro, Francisco; Jiménez, Ignacio A; Castanys, Santiago; Bazzocchi, Isabel L
2016-03-10
P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2-82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxicity, and potency to reverse daunomycin and vinblastine resistances. Analogues 6, 24, 28, 59, and 66 were identified as having higher potency than compound 1 and verapamil, a first-generation P-gp modulator. SAR analysis revealed the size of the aliphatic chains and presence of nitrogen atoms are important structural characteristics to modulate reversal activity. The present study highlights the potential of these analogues as modulators of P-gp mediated MDR in cancer cells.
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Yang, Haozhe; Mei, Hui; Seela, Frank
2015-07-06
Reverse Watson-Crick DNA with parallel-strand orientation (ps DNA) has been constructed. Pyrrolo-dC (PyrdC) nucleosides with phenyl and pyridinyl residues linked to the 6 position of the pyrrolo[2,3-d]pyrimidine base have been incorporated in 12- and 25-mer oligonucleotide duplexes and utilized as silver-ion binding sites. Thermal-stability studies on the parallel DNA strands demonstrated extremely strong silver-ion binding and strongly enhanced duplex stability. Stoichiometric UV and fluorescence titration experiments verified that a single (2py) PyrdC-(2py) PyrdC pair captures two silver ions in ps DNA. A structure for the PyrdC silver-ion base pair that aligns 7-deazapurine bases head-to-tail instead of head-to-head, as suggested for canonical DNA, is proposed. The silver DNA double helix represents the first example of a ps DNA structure built up of bidentate and tridentate reverse Watson-Crick base pairs stabilized by a dinuclear silver-mediated PyrdC pair. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Hebert, Sebastien P.; Cha, Jin K.; Brash, Alan R.; Schlegel, H. Bernhard
2016-01-01
The cyclopentane core is ubiquitous among a large number of biologically relevant natural products. Cyclopentenones have been shown to be versatile intermediates for the stereoselective preparation of highly substituted cyclopentane derivatives. Allene oxides are oxygenated fatty acids which are involved in the pathways of cyclopentenone biosynthesis in plants and marine invertebrates; however, their cyclization behavior is not well understood. Recent work by Brash and co-workers (J. Biol. Chem. 2013, 288, 20797) revealed an unusual cyclization property of the 9(S)-HPODE-derived allene oxides: the previously unreported 10Z-isomer cyclizes to a cis-dialkylcyclopentenone in hexane/isopropyl alcohol (100:3,v/v), but the known 10E-isomer does not yield cis-cyclopentenone under the same conditions. The mechanism for cyclization has been investigated for unsubstituted and methyl substituted vinyl allene oxide using a variety of methods including CASSCF, ωB97xD, and CCSD(T) and basis sets up to cc-pVTZ. The lowest energy pathway proceeds via homolytic cleavage of the epoxide ring, formation of an oxyallyl diradical, which closes readily to a cyclopropanone intermediate. The cyclopropanone opens to the requisite oxyallyl which closes to the experimentally observed product, cis-cyclopentenone. The calculations show that the open shell, diradical pathway is lower in energy than the closed shell reactions of allene oxide to cyclopropanone, and cyclopropanone to cyclopentenone. PMID:26976802
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Huang, En; Yang, Xu; Zhang, Liwen; Moon, Sun Hee; Yousef, Ahmed E
2017-04-01
A new bacterial isolate, Paenibacillus sp. OSY-N, showed potent antimicrobial activity against Gram-negative and Gram-positive bacteria. Antimicrobials produced by this strain were purified by reverse-phase high-performance liquid chromatography. Structural analysis, using mass spectrometry, of a single active HPLC fraction revealed two known cyclic lipopeptides (BMY-28160 and permetin A), a new cyclic lipopeptide, and the linear counterparts of these cyclic compounds. The latter were designated as paenipeptins A, B and C, respectively. The paenipeptins have not been reported before as naturally occurring products. Paenipeptins B and C differ at the acyl side chain; paenipeptin C contains a C8-, instead of C7-fatty acyl side chain. To demonstrate unequivocally the antimicrobial activity of the linear forms of this family of cyclic lipopeptides, analogs of the paenipeptins were synthesized chemically and their antimicrobial activity was tested individually. The synthetic linear lipopeptide with an octanoic acid side chain (designated as paenipeptin C΄) showed potent antimicrobial activity with minimum inhibitory concentrations of 0.5-4.0 μg/mL for Gram-negative and 0.5-32 μg/mL for Gram-positive bacteria. Findings demonstrated that peptide cyclization in this lipopeptide family is not essential for their antimicrobial activity. Most importantly, linear lipopeptides are more accessible than their cyclic counterparts through chemical synthesis. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Aldrich, Jane V; Kulkarni, Santosh S; Senadheera, Sanjeewa N; Ross, Nicolette C; Reilley, Kate J; Eans, Shainnel O; Ganno, Michelle L; Murray, Thomas F; McLaughlin, Jay P
2011-09-05
An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Bretón-Romero, Rosa; Wang, Na; Palmisano, Joseph; Larson, Martin G; Vasan, Ramachandran S; Mitchell, Gary F; Benjamin, Emelia J; Vita, Joseph A; Hamburg, Naomi M
2016-12-01
Experimental studies link oscillatory flow accompanied by flow reversal to impaired endothelial cell function. The relation of flow reversal with vascular function and arterial stiffness remains incompletely defined. We measured brachial diastolic flow patterns along with vasodilator function in addition to tonometry-based central and peripheral arterial stiffness in 5708 participants (age 47±13 years, 53% women) in the Framingham Heart Study Offspring and Third Generation cohorts. Brachial artery diastolic flow reversal was present in 35% of the participants. In multivariable regression models, the presence of flow reversal was associated with lower flow-mediated dilation (3.9±0.2 versus 5.0±0.2%; P<0.0001) and reactive hyperemic flow velocity (50±0.99 versus 57±0.93 cm/s; P<0.0001). The presence of flow reversal (compared with absence) was associated with higher central aortic stiffness (carotid-femoral pulse wave velocity 9.3±0.1 versus 8.9±0.1 m/s), lower muscular artery stiffness (carotid-radial pulse wave velocity 9.6±0.1 versus 9.8±0.1 m/s), and higher forearm vascular resistance (5.32±0.03 versus 4.66±0.02 log dyne/s/cm 5 ; P<0.0001). The relations of diastolic flow velocity with flow-mediated dilation, aortic stiffness, and forearm vascular resistance were nonlinear, with a steeper decline in vascular function associated with increasing magnitude of flow reversal. In our large, community-based sample, brachial artery flow reversal was common and associated with impaired vasodilator function and higher aortic stiffness. Our findings are consistent with the concept that flow reversal may contribute to vascular dysfunction. © 2016 American Heart Association, Inc.
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Cyclization improves membrane permeation by antimicrobial peptoids
Andreev, Konstantin; Martynowycz, Michael W.; Ivankin, Andrey; ...
2016-10-28
The peptidomimetic approach has emerged as a powerful tool for overcoming the inherent limitations of natural antimicrobial peptides, where the therapeutic potential can be improved by increasing the selectivity and bioavailability. Restraining the conformational flexibility of a molecule may reduce the entropy loss upon its binding to the membrane. Experimental findings demonstrate that the cyclization of linear antimicrobial peptoids increases their bactericidal activity against Staphylococcus aureus while maintaining high hemolytic concentrations. Surface X-ray scattering shows that macrocyclic peptoids intercalate into Langmuir monolayers of anionic lipids with greater efficacy than for their linear analogues. Lastly, it is suggested that cyclization maymore » increase peptoid activity by allowing the macrocycle to better penetrate the bacterial cell membrane.« less
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Cyclization improves membrane permeation by antimicrobial peptoids
DOE Office of Scientific and Technical Information (OSTI.GOV)
Andreev, Konstantin; Martynowycz, Michael W.; Ivankin, Andrey
The peptidomimetic approach has emerged as a powerful tool for overcoming the inherent limitations of natural antimicrobial peptides, where the therapeutic potential can be improved by increasing the selectivity and bioavailability. Restraining the conformational flexibility of a molecule may reduce the entropy loss upon its binding to the membrane. Experimental findings demonstrate that the cyclization of linear antimicrobial peptoids increases their bactericidal activity against Staphylococcus aureus while maintaining high hemolytic concentrations. Surface X-ray scattering shows that macrocyclic peptoids intercalate into Langmuir monolayers of anionic lipids with greater efficacy than for their linear analogues. Lastly, it is suggested that cyclization maymore » increase peptoid activity by allowing the macrocycle to better penetrate the bacterial cell membrane.« less
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Ohshima, Takashi; Xu, Youjun; Takita, Ryo; Shimizu, Satoshi; Zhong, Dafang; Shibasaki, Masakatsu
2002-12-11
The enantioselective total synthesis of (-)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol % of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99% ee) as well as a tandem cyclization that simultaneously constructed B- and D-rings (>77% yield). Moreover, newly developed reaction conditions for thionium ion cyclization, NaBH3CN reduction of the imine moiety in the presence of Lewis acid to prevent ring opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids.
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Alonso, José Miguel; Muñoz, María Paz
2018-04-16
Heterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt-Au heterobimetallic catalyst system for the synthesis of a family of multi-heteroaromatic structures through tandem cyclization/C-X coupling reaction. Au-catalyzed 6-endo-cyclization takes place as the first fast step. Pt-Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer-sphere mechanism by hybrid homogeneous-heterogeneous catalysis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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González-Rodríguez, Carlos; Suárez, José Ramón; Varela, Jesús A; Saá, Carlos
2015-02-23
A new ruthenium-catalyzed cyclization of ortho-(alkynyloxy)benzylamines to dihydro-1,3-benzoxazines is reported. The cyclization is thought to take place via the vinyl ruthenium carbene intermediates which are easily formed from [Cp*RuCl(cod)] and N2 CHSiMe3 . The mild reaction conditions and the efficiency of the procedure allow the easy preparation of a broad range of new 2-vinyl-2-substituted 1,3-benzoxazine derivatives. Rearrangement of an internal C(sp) in the starting material into a tetrasubstituted C(sp(3) ) atom in the final 1,3-benzoxazine is highly remarkable. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Xie, Ming; Piper, Daniela Molina; Tian, Miao; Clancey, Joel; George, Steven M; Lee, Se-Hee; Zhou, Yun
2015-09-11
Doped Si nanoparticles (SiNPs) with conformal carbon coating and cyclized-polyacrylonitrile (PAN) network displayed capacities of 3500 and 3000 mAh g(-1) at C/20 and C/10, respectively. At 1 C, the electrode preserves a specific discharge capacity of ∼1500 mAh g(-1) for at least 60 cycles without decay. Al2O3 atomic layer deposition (ALD) helps improve the initial Coulombic efficiency (CE) to 85%. The dual coating of conformal carbon and cyclized-PAN help alleviate volume change and facilitate charge transfer. Ultra-thin Al2O3 ALD layers help form a stable solid electrolyte interphase interface.
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2015-01-01
The 1,6-conjugate addition of nucleophiles to dienyl diketones produces either cyclopentenone or 2H-pyran products with high selectivity through either Nazarov (4π) or 6π electrocyclization, respectively. The outcome of the reaction is dependent upon the nature of the nucleophile used. Nucleophiles that are anionic or easily deprotonated exclusively produce cyclopentenones via Nazarov cyclization, whereas the neutral nucleophile DABCO promotes 6π cyclization to afford 2H-pyrans. Experimental evidence is presented for both retro-4π and -6π electrocyclization in these systems, lending support to the bifurcated mechanistic hypothesis proposed for these cyclizations. PMID:25325706
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Wu, Bin; Liu, Guo-Gui; Li, Mei-Qiu; Zhang, Yong; Zhang, Shao-Yun; Qiu, Jun-Ru; Xu, Xiao-Ping; Ji, Shun-Jun; Wang, Xing-Wang
2011-04-07
Thiourea-modified cinchona alkaloids as bifunctional catalysts and a base could catalyze a stepwise [5+1] cyclization of divinyl ketones with nitromethane via double Michael additions, furnishing optically active 4-nitro-cyclohexanones with good yields, excellent diastereoselectivities (>20 : 1) and high enantiomeric ratios (up to 97 : 3).
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Gao, Yang; Huang, Yubing; Wu, Wanqing; Huang, Kefan; Jiang, Huanfeng
2014-08-07
An efficient Pd-catalyzed oxidative cyclization reaction for the synthesis of functionalized indolines by direct C-H activation of acetanilide has been developed. The norbornylpalladium species formed via direct ortho C-H activation of acetanilides is supposed to be a key intermediate in this transformation.
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Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization.
Lyapunova, Anna G; Danilkina, Natalia A; Rumyantsev, Andrey M; Khlebnikov, A F; Chislov, Mikhail V; Starova, Galina L; Sambuk, Elena V; Govdi, Anastasia I; Bräse, Stefan; Balova, Irina A
2018-03-02
To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.
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1,7-Cyclization of 1-diazo-2,4-pentadiene and its heteroanalogues: DFT study
NASA Astrophysics Data System (ADS)
Subbotina, Julia O.; Bakulev, V. A.; Herges, R.; Fabian, W. M. F.
1,7-Dipolar cyclizations of 1-diazo-2,4-pentadiene 1a and its heteroanalogues 1b,c and 4c were studied using density functional theory (DFT). Although the heteroanalogue 1c has an appropriate electronic structure to allow for pseudopericyclic cyclization, natural bond order (NBO) analysis has provided evidence for the electrocyclic ring closure. Magnetic criteria (anisotropy of the induced current density [ACID], nucleus-independent chemical shifts [NICS]) confirmed the pericyclic character of the located transition states 2a,c and 5c. The activation barriers for the cyclization of 1-diazo-2,4-pentadiene 1a and its aza analogues 1c, 4c are 3.3, 8.2, and 12.3 kcal/mol at the B3LYP/6-31G(d) level, respectively. The higher barrier of the 1c?3c and 4c?3c reactions compared with 1a?3a is in line with the Hammond postulate. The out-of-plane distorted geometry of the cyclic product is an additional factor arguing against a pseudopericyclic mechanism.
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Synthesis of a ketone analogue of biotin via the intramolecular Pauson-Khand reaction.
McNeill, Eric; Chen, Irwin; Ting, Alice Y
2006-09-28
We report an improved synthesis of 5-(5-oxohexahydrocyclopenta[c]thiophen-1-yl)pentanoic acid (ketone biotin, 1) based on the intramolecular Pauson-Khand cyclization. The synthesis proceeds in eight steps and in 2.7% overall yield from cyclohexene.
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Richelle, Gaston J J; Ori, Sumeet; Hiemstra, Henk; van Maarseveen, Jan H; Timmerman, Peter
2018-01-08
We report a one-pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties. These react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 1 and T4 2 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 3 and T4 4 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other way round. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Hirte, Max; Meese, Nicolas; Mertz, Michael; Fuchs, Monika; Brück, Thomas B
2018-01-01
Diterpene synthases catalyze complex, multi-step C-C coupling reactions thereby converting the universal, aliphatic precursor geranylgeranyl diphosphate into diverse olefinic macrocylces that form the basis for the structural diversity of the diterpene natural product family. Since catalytically relevant crystal structures of diterpene synthases are scarce, homology based biomolecular modeling techniques offer an alternative route to study the enzyme's reaction mechanism. However, precise identification of catalytically relevant amino acids is challenging since these models require careful preparation and refinement techniques prior to substrate docking studies. Targeted amino acid substitutions in this protein class can initiate premature quenching of the carbocation centered reaction cascade. The structural characterization of those alternative cyclization products allows for elucidation of the cyclization reaction cascade and provides a new source for complex macrocyclic synthons. In this study, new insights into structure and function of the fungal, bifunctional Aphidicolan-16-ß-ol synthase were achieved using a simplified biomolecular modeling strategy. The applied refinement methodologies could rapidly generate a reliable protein-ligand complex, which provides for an accurate in silico identification of catalytically relevant amino acids. Guided by our modeling data, ACS mutations lead to the identification of the catalytically relevant ACS amino acid network I626, T657, Y658, A786, F789, and Y923. Moreover, the ACS amino acid substitutions Y658L and D661A resulted in a premature termination of the cyclization reaction cascade en-route from syn-copalyl diphosphate to Aphidicolan-16-ß-ol. Both ACS mutants generated the diterpene macrocycle syn-copalol and a minor, non-hydroxylated labdane related diterpene, respectively. Our biomolecular modeling and mutational studies suggest that the ACS substrate cyclization occurs in a spatially restricted location of the enzyme's active site and that the geranylgeranyl diphosphate derived pyrophosphate moiety remains in the ACS active site thereby directing the cyclization process. Our cumulative data confirm that amino acids constituting the G-loop of diterpene synthases are involved in the open to the closed, catalytically active enzyme conformation. This study demonstrates that a simple and rapid biomolecular modeling procedure can predict catalytically relevant amino acids. The approach reduces computational and experimental screening efforts for diterpene synthase structure-function analyses.
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NASA Astrophysics Data System (ADS)
Hirte, Max; Meese, Nicolas; Mertz, Michael; Fuchs, Monika; Brück, Thomas B.
2018-04-01
Diterpene synthases catalyze complex, multi-step C-C coupling reactions thereby converting the universal, aliphatic precursor geranylgeranyl diphosphate into diverse olefinic macrocylces that form the basis for the structural diversity of the diterpene natural product family. Since catalytically relevant crystal structures of diterpene synthases are scarce, homology based biomolecular modelling techniques offer an alternative route to study the enzyme’s reaction mechanism. However, precise identification of catalytically relevant amino acids is challenging since these models require careful preparation and refinement techniques prior to substrate docking studies. Targeted amino acid substitutions in this protein class can initiate premature quenching of the carbocation centered reaction cascade. The structural characterization of those alternative cyclization products allows for elucidation of the cyclization reaction cascade and provides a new source for complex macrocyclic synthons. In this study, new insights into structure and function of the fungal, bifunctional Aphidicolan-16-ß-ol synthase were achieved using a simplified biomolecular modelling strategy. The applied refinement methodologies could rapidly generate a reliable protein-ligand complex, which provides for an accurate in silico identification of catalytically relevant amino acids. Guided by our modelling data, ACS mutations lead to the identification of the catalytically relevant ACS amino acid network I626, T657, Y658, A786, F789 and Y923. Moreover, the ACS amino acid substitutions Y658L and D661A resulted in a premature termination of the cyclization reaction cascade en-route from syn-copalyl diphosphate to Aphidicolan-16-ß-ol. Both ACS mutants generated the diterpene macrocycle syn-copalol and a minor, non-hydroxylated labdane related diterpene, respectively. Our biomolecular modelling and mutational studies suggest that the ACS substrate cyclization occurs in a spatially restricted location of the enzyme’s active site and that the geranylgeranyl diphosphate derived pyrophosphate moiety remains in the ACS active site thereby directing the cyclization process. Our cumulative data confirm that amino acids constituting the G-loop of diterpene synthases are involved in the open to the closed, catalytically active enzyme conformation. This study demonstrates that a simple and rapid biomolecular modelling procedure can predict catalytically relevant amino acids. The approach reduces computational and experimental screening efforts for diterpene synthase structure-function analyses.
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2009-01-01
The α,β-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and trans-4-hydroxynonenal (4-HNE) are products of endogenous lipid peroxidation, arising as a consequence of oxidative stress. The addition of enals to dG involves Michael addition of the N2-amine to give N2-(3-oxopropyl)-dG adducts, followed by reversible cyclization of N1 with the aldehyde, yielding 1,N2-dG exocyclic products. The 1,N2-dG exocyclic adducts from acrolein, crotonaldehyde, and 4-HNE exist in human and rodent DNA. The enal-induced 1,N2-dG lesions are repaired by the nucleotide excision repair pathway in both Escherichia coli and mammalian cells. Oligodeoxynucleotides containing structurally defined 1,N2-dG adducts of acrolein, crotonaldehyde, and 4-HNE were synthesized via a postsynthetic modification strategy. Site-specific mutagenesis of enal adducts has been carried out in E. coli and various mammalian cells. In all cases, the predominant mutations observed are G→T transversions, but these adducts are not strongly miscoding. When placed into duplex DNA opposite dC, the 1,N2-dG exocyclic lesions undergo ring opening to the corresponding N2-(3-oxopropyl)-dG derivatives. Significantly, this places a reactive aldehyde in the minor groove of DNA, and the adducted base possesses a modestly perturbed Watson−Crick face. Replication bypass studies in vitro indicate that DNA synthesis past the ring-opened lesions can be catalyzed by pol η, pol ι, and pol κ. It also can be accomplished by a combination of Rev1 and pol ζ acting sequentially. However, efficient nucleotide insertion opposite the 1,N2-dG ring-closed adducts can be carried out only by pol ι and Rev1, two DNA polymerases that do not rely on the Watson−Crick pairing to recognize the template base. The N2-(3-oxopropyl)-dG adducts can undergo further chemistry, forming interstrand DNA cross-links in the 5′-CpG-3′ sequence, intrastrand DNA cross-links, or DNA−protein conjugates. NMR and mass spectrometric analyses indicate that the DNA interstand cross-links contain a mixture of carbinolamine and Schiff base, with the carbinolamine forms of the linkages predominating in duplex DNA. The reduced derivatives of the enal-mediated N2-dG:N2-dG interstrand cross-links can be processed in mammalian cells by a mechanism not requiring homologous recombination. Mutations are rarely generated during processing of these cross-links. In contrast, the reduced acrolein-mediated N2-dG peptide conjugates can be more mutagenic than the corresponding monoadduct. DNA polymerases of the DinB family, pol IV in E. coli and pol κ in human, are implicated in error-free bypass of model acrolein-mediated N2-dG secondary adducts, the interstrand cross-links, and the peptide conjugates. PMID:19397281
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Liu, Zhong-Yu; Yu, Jiu-Yang; Huang, Xing-Yao; Fan, Hang; Li, Xiao-Feng; Deng, Yong-Qiang; Ji, Xue; Cheng, Meng-Li; Ye, Qing; Zhao, Hui; Han, Jian-Feng; An, Xiao-Ping; Jiang, Tao; Zhang, Bo; Tong, Yi-Gang; Qin, Cheng-Feng
2017-11-01
Zika virus (ZIKV) has caused significant outbreaks and epidemics in the Americas recently, raising global concern due to its ability to cause microcephaly and other neurological complications. A stable and efficient infectious clone of ZIKV is urgently needed. However, the instability and toxicity of flavivirus cDNA clones in Escherichia coli hosts has hindered the development of ZIKV infectious clones. Here, using a novel self-splicing ribozyme-based strategy, we generated a stable infectious cDNA clone of a contemporary ZIKV strain imported from Venezuela to China in 2016. The constructed clone contained a modified version of the group II self-splicing intron P.li.LSUI2 near the junction between the E and NS1 genes, which were removed from the RNA transcripts by an easy-to-establish in vitro splicing reaction. Transfection of the spliced RNAs into BHK-21 cells led to the production of infectious progeny virus that resembled the parental virus. Finally, potential cis -acting RNA elements in ZIKV genomic RNA were identified based on this novel reverse genetics system, and the critical role of 5'-SLA promoter and 5'-3' cyclization sequences were characterized by a combination of different assays. Our results provide another stable and reliable reverse genetics system for ZIKV that will help study ZIKV infection and pathogenesis, and the novel self-splicing intron-based strategy could be further expanded for the construction of infectious clones from other emerging and reemerging flaviviruses. IMPORTANCE The ongoing Zika virus (ZIKV) outbreaks have drawn global concern due to the unexpected causal link to fetus microcephaly and other severe neurological complications. The infectious cDNA clones of ZIKV are critical for the research community to study the virus, understand the disease, and inform vaccine design and antiviral screening. A panel of existing technologies have been utilized to develop ZIKV infectious clones. Here, we successfully generated a stable infectious clone of a 2016 ZIKV strain using a novel self-splicing ribozyme-based technology that abolished the potential toxicity of ZIKV cDNA clones to the E. coli host. Moreover, two crucial cis -acting replication elements (5'-SLA and 5'-CS) of ZIKV were first identified using this novel reverse genetics system. This novel self-splicing ribozyme-based reverse genetics platform will be widely utilized in future ZIKV studies and provide insight for the development of infectious clones of other emerging viruses. Copyright © 2017 American Society for Microbiology.
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Liu, Zhong-Yu; Yu, Jiu-Yang; Huang, Xing-Yao; Fan, Hang; Li, Xiao-Feng; Deng, Yong-Qiang; Ji, Xue; Cheng, Meng-Li; Ye, Qing; Zhao, Hui; Han, Jian-Feng; An, Xiao-Ping; Jiang, Tao; Zhang, Bo; Tong, Yi-Gang
2017-01-01
ABSTRACT Zika virus (ZIKV) has caused significant outbreaks and epidemics in the Americas recently, raising global concern due to its ability to cause microcephaly and other neurological complications. A stable and efficient infectious clone of ZIKV is urgently needed. However, the instability and toxicity of flavivirus cDNA clones in Escherichia coli hosts has hindered the development of ZIKV infectious clones. Here, using a novel self-splicing ribozyme-based strategy, we generated a stable infectious cDNA clone of a contemporary ZIKV strain imported from Venezuela to China in 2016. The constructed clone contained a modified version of the group II self-splicing intron P.li.LSUI2 near the junction between the E and NS1 genes, which were removed from the RNA transcripts by an easy-to-establish in vitro splicing reaction. Transfection of the spliced RNAs into BHK-21 cells led to the production of infectious progeny virus that resembled the parental virus. Finally, potential cis-acting RNA elements in ZIKV genomic RNA were identified based on this novel reverse genetics system, and the critical role of 5′-SLA promoter and 5′-3′ cyclization sequences were characterized by a combination of different assays. Our results provide another stable and reliable reverse genetics system for ZIKV that will help study ZIKV infection and pathogenesis, and the novel self-splicing intron-based strategy could be further expanded for the construction of infectious clones from other emerging and reemerging flaviviruses. IMPORTANCE The ongoing Zika virus (ZIKV) outbreaks have drawn global concern due to the unexpected causal link to fetus microcephaly and other severe neurological complications. The infectious cDNA clones of ZIKV are critical for the research community to study the virus, understand the disease, and inform vaccine design and antiviral screening. A panel of existing technologies have been utilized to develop ZIKV infectious clones. Here, we successfully generated a stable infectious clone of a 2016 ZIKV strain using a novel self-splicing ribozyme-based technology that abolished the potential toxicity of ZIKV cDNA clones to the E. coli host. Moreover, two crucial cis-acting replication elements (5′-SLA and 5′-CS) of ZIKV were first identified using this novel reverse genetics system. This novel self-splicing ribozyme-based reverse genetics platform will be widely utilized in future ZIKV studies and provide insight for the development of infectious clones of other emerging viruses. PMID:28814522
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Use of Lantibiotic Synthetases for the Preparation of Bioactive Constrained Peptides
Levengood, Matthew R.
2008-01-01
Stabilization of biologically active peptides is a major goal in peptide-based drug design. Cyclization is an often-used strategy to enhance resistance of peptides towards protease degradation and simultaneously improve their affinity for targets by restricting their conformational flexibility. Amongst the various cyclization strategies, the use of thioether crosslinks has been successful for various peptides including enkephalin. The synthesis of these thioethers can be arduous, especially for longer peptides. Described herein is an enzymatic strategy taking advantage of the lantibiotic synthetase LctM that dehydrates Ser and Thr residues to the corresponding dehydroalanine and dehydrobutyrine residues and catalyzes the Michael-type addition of Cys residues to form thioether crosslinks. The use of LctM to prepare thioether containing analogs of enkephalin, contryphan, and inhibitors of human tripeptidyl peptidase II and spider venom epimerase is demonstrated. PMID:18294843
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Synthesis of a ketone analog of biotin via the intramolecular Pauson-Khand reaction
McNeill, Eric; Chen, Irwin; Ting, Alice Y.
2008-01-01
We report an improved synthesis of 5-(5-oxohexahydrocyclopenta[c]thiophen-1-yl)pentanoic acid (ketone biotin, 1) based on the intramolecular Pauson-Khand cyclization. The synthesis proceeds in 8 steps and in 2.7% overall yield from cyclohexene. PMID:16986958
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Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst
2015-01-01
A heterogeneous gold catalyst with remarkable activity for promoting the electrophilic reactions of aryl vinyl ketones and aryl dienyl ketones is described. The catalyst is easy to prepare, is robust, and can be recycled. Low loadings are effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts. PMID:24432741
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Lebœuf, David; Theiste, Eric; Gandon, Vincent; Daifuku, Stephanie L.; Neidig, Michael L.
2013-01-01
The discovery and elucidation of a novel Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described, which constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways. PMID:23436470
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Yue, Dawei; Yao, Tuanli; Larock, Richard C
2006-01-06
[reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields.
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Reverse electron transport effects on NADH formation and metmyoglobin reduction.
Belskie, K M; Van Buiten, C B; Ramanathan, R; Mancini, R A
2015-07-01
The objective was to determine if NADH generated via reverse electron flow in beef mitochondria can be used for electron transport-mediated reduction and metmyoglobin reductase pathways. Beef mitochondria were isolated from bovine hearts (n=5) and reacted with combinations of succinate, NAD, and mitochondrial inhibitors to measure oxygen consumption and NADH formation. Mitochondria and metmyoglobin were reacted with succinate, NAD, and mitochondrial inhibitors to measure electron transport-mediated metmyoglobin reduction and metmyoglobin reductase activity. Addition of succinate and NAD increased oxygen consumption, NADH formation, electron transport-mediated metmyoglobin reduction, and reductase activity (p<0.05). Addition of antimycin A prevented electron flow beyond complex III, therefore, decreasing oxygen consumption and electron transport-mediated metmyoglobin reduction. Addition of rotenone prevented reverse electron flow, increased oxygen consumption, increased electron transport-mediated metmyoglobin reduction, and decreased NADH formation. Succinate and NAD can generate NADH in bovine tissue postmortem via reverse electron flow and this NADH can be used by both electron transport-mediated and metmyoglobin reductase pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Mancuso, Raffaella; Pomelli, Christian C; Malafronte, Francesco; Maner, Asif; Marino, Nadia; Chiappe, Cinzia; Gabriele, Bartolo
2017-06-07
The regiochemical outcome of the iodolactonization of 2-alkynylbenzoic acids, carried out at 100 °C in ionic liquids (ILs) as unconventional solvents and with molecular iodine as the iodine source, in the absence of external bases, was found to be strongly dependent on the nature of the IL medium. In particular, while the use of N-ethyl-N-methylmorpholinium dicyanamide (Mor 1,2 N(CN) 2 ) promoted the stereoselective formation of (E)-3-(iodomethylene)isobenzofuran-1(3H)-ones, through an anti-5-exo-dig cyclization route, the use of 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO 4 ) tended to favor the 6-endo-dig cyclization mode, with preferential or selective formation of 4-iodo-1H-isochromen-1-ones. In any case, the IL solvent could be easily recycled after extraction of the product from the reaction mixture with diethyl ether. DFT calculations have been carried out to clarify the role of the IL's nature in favoring either the anti-5-exo-dig cyclization route or the 6-endo-dig mode. In the case of iodocyclization of 2-ethynylbenzoic acid, only the 5-exo-dig mode was observed in both EmimEtSO 4 and Mor 1,2 N(CN) 2 solvents. The structures of two representative products have been confirmed by X-ray diffraction analysis.
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Evaluating the role of coherent delocalized phonon-like modes in DNA cyclization
Alexandrov, Ludmil B.; Rasmussen, Kim Ã.; Bishop, Alan R.; ...
2017-08-29
The innate flexibility of a DNA sequence is quantified by the Jacobson-Stockmayer’s J-factor, which measures the propensity for DNA loop formation. Recent studies of ultra-short DNA sequences revealed a discrepancy of up to six orders of magnitude between experimentally measured and theoretically predicted J-factors. These large differences suggest that, in addition to the elastic moduli of the double helix, other factors contribute to loop formation. We develop a new theoretical model that explores how coherent delocalized phonon-like modes in DNA provide single-stranded ”flexible hinges” to assist in loop formation. We also combine the Czapla-Swigon-Olson structural model of DNA with ourmore » extended Peyrard-Bishop-Dauxois model and, without changing any of the parameters of the two models, apply this new computational framework to 86 experimentally characterized DNA sequences. Our results demonstrate that the new computational framework can predict J-factors within an order of magnitude of experimental measurements for most ultra-short DNA sequences, while continuing to accurately describe the J-factors of longer sequences. Furthermore, we demonstrate that our computational framework can be used to describe the cyclization of DNA sequences that contain a base pair mismatch. Overall, our results support the conclusion that coherent delocalized phonon-like modes play an important role in DNA cyclization.« less
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A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations
Mousseau, James J.; Morten, Christopher J.
2013-01-01
Ladder polyether natural products are a class of natural products denoted by their high functional group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogues with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases they provide near complete endo to exo selectivity in the cyclization of epoxy alcohols, thereby strongly favouring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template. PMID:23775936
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Tanner, N K; Cech, T R
1985-01-01
The intervening sequence (IVS) excised from the rRNA precursor of Tetrahymena thermophila is converted to a covalently closed circular RNA in the absence of proteins in vitro. This self-catalyzed cyclization reaction is inhibited by the intercalating dye methidiumpropyl.EDTA (MPE; R.P. Hertzberg and P.B. Dervan (1982) J. Am. Chem. Soc. 104, 313-315). The MPE binding sites have been localized by mapping the sites of MPE.Fe(II) cleavage of the IVS RNA. There are three major binding sites within the 414 nucleotide IVS RNA. Two of these sites coincide with the A.B and 9L.2 pairings. These are structural elements that are conserved in all group I introns and are implicated as being functionally important for splicing. We propose that interaction of MPE with these sites is responsible for dye inhibition of cyclization. The reactions of MPE.Fe(II) with an RNA of known structure, tRNAPhe, and with the IVS RNA were studied as a function of temperature, ionic strength and ethidium concentration. Based on the comparison of the reaction with these two RNAs, we conclude that the dye is a very useful probe for structural regions of large RNAs, while it provides more limited structural information about the small, compact tRNA molecule. Images PMID:2415924
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Ariyawutthiphan, Orapin; Ose, Toyoyuki; Minami, Atsushi; Shinde, Sandip; Sinde, Sandip; Tsuda, Muneya; Gao, Yong-Gui; Yao, Min; Oikawa, Hideaki; Tanaka, Isao
2012-11-01
In the typical isoprenoid-biosynthesis pathway, condensation of the universal C(5)-unit precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) occurs via the common intermediates prenyl pyrophosphates (C(10)-C(20)). The diversity of isoprenoids reflects differences in chain length, cyclization and further additional modification after cyclization. In contrast, the biosynthesis of 2-methylisonorneol (2-MIB), which is responsible for taste and odour problems in drinking water, is unique in that it primes the enzymatic methylation of geranyl pyrophosphate (GPP) before cyclization, which is catalyzed by an S-adenosyl-L-methionine-dependent methyltransferase (GPPMT). The substrate of GPPMT contains a nonconjugated olefin and the reaction mechanism is expected to be similar to that of the steroid methyltransferase (SMT) family. Here, structural analysis of GPPMT in complex with its cofactor and substrate revealed the mechanisms of substrate recognition and possible enzymatic reaction. Using the structures of these complexes, methyl-group transfer and the subsequent proton-abstraction mechanism are discussed. GPPMT and SMTs contain a conserved glutamate residue that is likely to play a role as a general base. Comparison with the reaction mechanism of the mycolic acid cyclopropane synthase (MACS) family also supports this result. This enzyme represented here is the first model of the enzymatic C-methylation of a nonconjugated olefin in the isoprenoid-biosynthesis pathway. In addition, an elaborate system to avoid methylation of incorrect substrates is proposed.
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Evaluating the role of coherent delocalized phonon-like modes in DNA cyclization
DOE Office of Scientific and Technical Information (OSTI.GOV)
Alexandrov, Ludmil B.; Rasmussen, Kim Ã.; Bishop, Alan R.
The innate flexibility of a DNA sequence is quantified by the Jacobson-Stockmayer’s J-factor, which measures the propensity for DNA loop formation. Recent studies of ultra-short DNA sequences revealed a discrepancy of up to six orders of magnitude between experimentally measured and theoretically predicted J-factors. These large differences suggest that, in addition to the elastic moduli of the double helix, other factors contribute to loop formation. We develop a new theoretical model that explores how coherent delocalized phonon-like modes in DNA provide single-stranded ”flexible hinges” to assist in loop formation. We also combine the Czapla-Swigon-Olson structural model of DNA with ourmore » extended Peyrard-Bishop-Dauxois model and, without changing any of the parameters of the two models, apply this new computational framework to 86 experimentally characterized DNA sequences. Our results demonstrate that the new computational framework can predict J-factors within an order of magnitude of experimental measurements for most ultra-short DNA sequences, while continuing to accurately describe the J-factors of longer sequences. Furthermore, we demonstrate that our computational framework can be used to describe the cyclization of DNA sequences that contain a base pair mismatch. Overall, our results support the conclusion that coherent delocalized phonon-like modes play an important role in DNA cyclization.« less
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Molecular structure impacts on secondary organic aerosol formation from glycol ethers
NASA Astrophysics Data System (ADS)
Li, Lijie; Cocker, David R.
2018-05-01
Glycol ethers, a class of widely used solvents in consumer products, are often considered exempt as volatile organic compounds based on their vapor pressure or boiling points by regulatory agencies. However, recent studies found that glycol ethers volatilize at ambient conditions nearly as rapidly as the traditional high-volatility solvents indicating the potential of glycol ethers to form secondary organic aerosol (SOA). This is the first work on SOA formation from glycol ethers. The impact of molecular structure, specifically -OH, on SOA formation from glycol ethers and related ethers are investigated in the work. Ethers with and without -OH, with methyl group hindrance on -OH and with -OH at different location are studied in the presence of NOX and under "NOX free" conditions. Photooxidation experiments under different oxidation conditions confirm that the processing of ethers is a combination of carbonyl formation, cyclization and fragmentation. Bulk SOA chemical composition analysis and oxidation products identified in both gas and particle phase suggests that the presence and location of -OH in the carbon bond of ethers determine the occurrence of cyclization mechanism during ether oxidation. The cyclization is proposed as a critical SOA formation mechanism to prevent the formation of volatile compounds from fragmentation during the oxidation of ethers. Glycol ethers with -CH2-O-CH2CH2OH structure is found to readily form cyclization products, especially with the presence of NOx, which is more relevant to urban atmospheric conditions than without NOx. Glycol ethers are evaluated as dominating SOA precursors among all ethers studied. It is estimated that the contribution of glycol ethers to anthropogenic SOA is roughly 1% of the current organic aerosol from mobile sources. The contribution of glycol ethers to anthropogenic SOA is roughly 1% of the current organic aerosol from mobile sources and will play a more important role in future anthropogenic SOA formation.
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Zong, Xiaojuan; Wang, Wenwen; Wei, Hairong; Wang, Jiawei; Chen, Xin; Xu, Li; Zhu, Dongzi; Tan, Yue; Liu, Qingzhong
2014-11-01
Prunus necrotic ringspot virus (PNRSV) has seriously reduced the yield of Prunus species worldwide. In this study, a highly efficient and specific two-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) was developed to detect PNRSV. Total RNA was extracted from sweet cherry leaf samples using a commercial kit based on a magnetic nanoparticle technique. Transcripts were used as the templates for the assay. The results of this assay can be detected using agarose gel electrophoresis or by assessing in-tube fluorescence after adding SYBR Green I. The assay is highly specific for PNRSV, and it is more sensitive than reverse-transcription polymerase chain reaction (RT-PCR). Restriction enzyme digestion verified further the reliability of this RT-LAMP assay. To our knowledge, this is the first report of the application of RT-LAMP to PNRSV detection in Prunus species. Copyright © 2014 Elsevier B.V. All rights reserved.
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Lee, Hang Wai; Chan, Albert S C; Kwong, Fuk Yee
2007-07-07
A rhodium-(S)-xyl-BINAP complex-catalyzed tandem formate decarbonylation and [2 + 2 + 1] carbonylative cyclization is described; this cooperative process utilizes formate as a condensed CO source, and the newly developed cascade protocol can be extended to its enantioselective version, providing up to 94% ee of the cyclopentenone adducts.
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Yang, Zhi-Jun; Liu, Chuan-Zhuo; Hu, Bo-Lun; Deng, Chen-Liang; Zhang, Xing-Guo
2014-12-04
A novel one-pot strategy for the synthesis of 3-trifluoromethylquinoxalines from N-aryl enamines and nitromethane was developed. The tandem reaction is achieved through nitrosation of alkenes, tautomerization and cyclization, which can be applicable to a wide range of enamines with excellent functional group tolerance and afford quinoxalines in moderate to good yields.
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Nie, Jing; Zhu, Hong-Wei; Cui, Han-Feng; Hua, Ming-Qing; Ma, Jun-An
2007-08-02
A new catalytic stereoselective tandem transformation via Nazarov cyclization/electrophilic fluorination has been accomplished. This sequence is efficiently catalyzed by a Cu(II) complex to afford fluorine-containing 1-indanone derivatives with two new stereocenters with high diastereoselectivity (trans/cis up to 49/1). Three examples of catalytic enantioselective tandem transformation are presented.
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Canterbury, Daniel P.; Herrick, Ildiko R.; Um, Joann; Houk, K. N.; Frontier, Alison J.
2009-01-01
A mild, convenient reaction sequence for the synthesis of Nazarov cyclization substrates is described. The [3+2] dipolar cycloaddition of a nitrone and an electron-deficient alkyne gives an isolable isoxazoline intermediate, which upon oxidation undergoes stereoselective extrusion of nitrosomethane to give aryl vinyl or divinyl ketones. PMID:20161228
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Justribó, Valeria; Pellegrinet, Silvina C; Colombo, María I
2007-05-11
Studies have been conducted to investigate the reactivity of several bicyclic delta-hydroxynitriles with triflic anhydride in dichloromethane. The reactions of the analogues derived from 1-indanone and 1-tetralone lead to annulated enones. These products arise from an initial elimination reaction that generates an alkene, followed by the addition of the carbon-carbon double bond to the activated cyano group. The intramolecular cyclization of the derivative obtained from 1-benzosuberone unexpectedly followed a different path, giving a cyclic imidate as the major product. In this case, the activated cyano group is directly attacked by the hydroxyl group of the starting delta-hydroxynitrile. Theoretical calculations provide a rationale for the observed reactivity pattern. Both the formation of the triflate via its protonated form, its subsequent ionization to the carbocation, and the cyclization of the resulting alkene to the enone become less favorable when the size of the ring increases due to conformational effects. The opposite trend is observed for the competing Pinner-type cyclization to the imidate. An alternative mechanism for the formation of the lactams from the cyclic imidates under acid-catalyzed conditions has also been proposed.
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Widjaja, Effendi; Tan, Wei Jian
2008-08-01
The solid-state intramolecular cyclization of lisinopril to diketopiperazine was investigated by in situ Fourier transform infrared (FT-IR) microscopy. Using a controllable heating cell, the isothermal transformation was monitored in situ at 147.5, 150, 152.5, 155, and 157.5 degrees C. The collected time-dependent FT-IR spectra at each isothermal temperature were preprocessed and analyzed using a multivariate chemometric approach. The pure component spectra of the observable component (lisinopril and diketopiperazine) were resolved and their time-dependent relative contributions were also determined. Model-free and various model fitting methods were implemented in the kinetic analysis to estimate the activation energy of the intramolecular cyclization reaction. Arrhenius plots indicate that the activation energy is circa 327 kJ/mol.
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Tess, D A; Cole, R O; Toler, S M
1995-12-15
A simple and highly sensitive reversed-phase fluorimetric HPLC method for the quantitation of droloxifene from rat, monkey, and human plasma as well as human serum is described. This assay employs solid-phase extraction and has a dynamic range of 25 to 10,000 pg/ml. Sample extraction (efficiencies > 86%) was accomplished using a benzenesulfonic acid (SCX) column with water and methanol rinses. Droloxifene and internal standard were eluted with 1 ml of 3.5% (v/v) ammonium hydroxide (30%) in methanol. Samples were quantitated using post-column UV-photochemical cyclization coupled with fluorimetric detection with excitation and emission wavelengths of 260 nm and 375 nm, respectively. Relative ease of sample extraction and short run times allow for the analysis of approximately 100 samples per day.
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Satoh, Tetsuya; Kouroki, Seiya; Ogawa, Keita; Tanaka, Yorika; Matsumura, Kazutoshi; Iwase, Susumu
2018-04-25
Identifying body fluids from forensic samples can provide valuable evidence for criminal investigations. Messenger RNA (mRNA)-based body fluid identification was recently developed, and highly sensitive parallel identification using reverse transcription polymerase chain reaction (RT-PCR) has been described. In this study, we developed reverse transcription loop-mediated isothermal amplification (RT-LAMP) as a simple, rapid assay for identifying three common forensic body fluids, namely blood, semen, and saliva, and evaluated its specificity and sensitivity. Hemoglobin beta (HBB), transglutaminase 4 (TGM4), and statherin (STATH) were selected as marker genes for blood, semen, and saliva, respectively. RT-LAMP could be performed in a single step including both reverse transcription and DNA amplification under an isothermal condition within 60 min, and detection could be conveniently performed via visual fluorescence. Marker-specific amplification was performed in each assay, and no cross-reaction was observed among five representative forensically relevant body fluids. The detection limits of the assays were 0.3 nL, 30 nL, and 0.3 μL for blood, semen, and saliva, respectively, and their sensitivities were comparable with those of RT-PCR. Furthermore, RT-LAMP assays were applicable to forensic casework samples. It is considered that RT-LAMP is useful for body fluid identification.
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In Situ Cyclization of Native Proteins: Structure-Based Design of a Bicyclic Enzyme.
Pelay-Gimeno, Marta; Bange, Tanja; Hennig, Sven; Grossmann, Tom N
2018-05-30
Increased tolerance of enzymes towards thermal and chemical stress is required for many applications and can be achieved by macrocyclization of the enzyme resulting in the stabilizing of its tertiary structure. So far, macrocyclization approaches utilize a very limited structural diversity which complicates the design process. Here, we report an approach that enables cyclization via the installation of modular crosslinks into native proteins composed entirely of proteinogenic amino acids. Our stabilization procedure involves the introduction of three surface exposed cysteines which are reacted with a triselectrophile resulting in the in situ cylization of the protein (INCYPRO). A bicyclic version of Sortase A was designed exhibiting increased tolerance towards thermal as well as chemical denaturation, and proved efficient in protein labeling under denaturing conditions. In addition, we applied INCYPRO to the KIX domain resulting in up to 24 °C increased thermal stability. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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The neural basis of reversal learning: An updated perspective
Izquierdo, Alicia; Brigman, Jonathan L.; Radke, Anna K.; Rudebeck, Peter H.; Holmes, Andrew
2016-01-01
Reversal learning paradigms are among the most widely used tests of cognitive flexibility and have been used as assays, across species, for altered cognitive processes in a host of neuropsychiatric conditions. Based on recent studies in humans, non-human primates, and rodents, the notion that reversal learning tasks primarily measure response inhibition, has been revised. In this review, we describe how cognitive flexibility is measured by reversal learning and discuss new definitions of the construct validity of the task that are serving as an heuristic to guide future research in this field. We also provide an update on the available evidence implicating certain cortical and subcortical brain regions in the mediation of reversal learning, and an overview of the principle neurotransmitter systems involved. PMID:26979052
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Di Stefano, Stefano; Ercolani, Gianfranco
2017-01-26
An extension of the Jacobson-Stockmayer theory is presented to include the reversible formation of [2]catenanes in a ring-chain system under thermodynamic control. The extended theory is based on the molar catenation constant, measuring the ease of catenation of two ring oligomers, whose expression was obtained in a previous work. Two scenarios have been considered: that of "thick" (hydrocarbon-like) chains and that of "thin" (DNA-like) chains. In the case of "thick" chains, the formation of catenanes can be neglected, unless in the unlikely case of a very large value of the equilibrium constant for linear propagation (K ≈ 10 8 mol -1 L, or larger). For K tending to infinity, the system becomes a chain-free system where only ring-catenane equilibria occur. Under this condition, there is a critical concentration below which only rings are present at equilibrium and above which the ring fraction remains constant, and the excess monomer is converted only into catenanes. In the case of "thin" chains, the formation of catenanes cannot be neglected even for values of K as low as 10 2 mol -1 L, thus justifying the use of the extended theory.
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Radical oxidative cyclization of spiroacetals to bis-spiroacetals: an overview.
Brimble, Margaret A
2004-05-31
The use of iodobenzene diacetate and iodine under photolytic conditions provides and efficient method for the oxidative cyclization of spiroacetals bearing an hydroxyalkyl side chain to bis-spiroacetals. An overview is provided of the use of this reaction for the synthesis of several bis-spiroacetal containing natural products such as the polyether antibiotics salinomycin and CP44,161 and the shellfish toxins, the spirolides.
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Xu, Yongjin; Yin, Zhiping; Lin, Xinglong; Gan, Zubao; He, Yanyang; Gao, Lu; Song, Zhenlei
2015-04-17
A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted Z-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively.
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Zhang, Heyi; Cheng, Biao; Lu, Zhan
2018-06-20
A newly designed thiazoline iminopyridine ligand for enantioselective cobalt-catalyzed sequential Nazarov cyclization/electrophilic fluorination was developed. Various chiral α-fluorocyclopentenones were prepared with good yields and diastereo- and enantioselectivities. Further derivatizations could be easily carried out to provide chiral cyclopentenols with three contiguous stereocenters. Furthermore, a direct deesterification of fluorinated products could afford chiral α-single fluorine-substituted cyclopentenones.
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Kang, Bubwoong; Wang, Yinli; Kuwano, Satoru; Yamaoka, Yousuke; Takasu, Kiyosei; Yamada, Ken-Ichi
2017-04-18
A highly site-selective N-heterocyclic carbene (NHC)-catalyzed benzoin-type cyclization of unsymmetrical dialdoses is developed to enable a divergent cyclitol synthesis. The choice of chiral NHCs and protecting groups affects the site-selectivity. The resulting inososes are converted into epi-, muco- and myo-inositols, and their chiral protected derivatives are formed in good yields.
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Lebœuf, David; Theiste, Eric; Gandon, Vincent; Daifuku, Stephanie L; Neidig, Michael L; Frontier, Alison J
2013-04-08
The discovery and elucidation of a new Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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2015-01-01
The class I terpenoid cyclase epi-isozizaene synthase (EIZS) utilizes the universal achiral isoprenoid substrate, farnesyl diphosphate, to generate epi-isozizaene as the predominant sesquiterpene cyclization product and at least five minor sesquiterpene products, making EIZS an ideal platform for the exploration of fidelity and promiscuity in a terpenoid cyclization reaction. The hydrophobic active site contour of EIZS serves as a template that enforces a single substrate conformation, and chaperones subsequently formed carbocation intermediates through a well-defined mechanistic sequence. Here, we have used the crystal structure of EIZS as a guide to systematically remold the hydrophobic active site contour in a library of 26 site-specific mutants. Remolded cyclization templates reprogram the reaction cascade not only by reproportioning products generated by the wild-type enzyme but also by generating completely new products of diverse structure. Specifically, we have tripled the overall number of characterized products generated by EIZS. Moreover, we have converted EIZS into six different sesquiterpene synthases: F96A EIZS is an (E)-β-farnesene synthase, F96W EIZS is a zizaene synthase, F95H EIZS is a β-curcumene synthase, F95M EIZS is a β-acoradiene synthase, F198L EIZS is a β-cedrene synthase, and F96V EIZS and W203F EIZS are (Z)-γ-bisabolene synthases. Active site aromatic residues appear to be hot spots for reprogramming the cyclization cascade by manipulating the stability and conformation of critical carbocation intermediates. A majority of mutant enzymes exhibit only relatively modest 2–100-fold losses of catalytic activity, suggesting that residues responsible for triggering substrate ionization readily tolerate mutations deeper in the active site cavity. PMID:24517311
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Jez, Joseph M; Noel, Joseph P
2002-01-11
Chalcone isomerase (CHI) catalyzes the intramolecular cyclization of bicyclic chalcones into tricyclic (S)-flavanones. The activity of CHI is essential for the biosynthesis of flavanone precursors of floral pigments and phenylpropanoid plant defense compounds. We have examined the spontaneous and CHI-catalyzed cyclization reactions of 4,2',4',6'-tetrahydroxychalcone, 4,2',4'-trihydroxychalcone, 2',4'-dihydroxychalcone, and 4,2'-dihydroxychalcone into the corresponding flavanones. The pH dependence of flavanone formation indicates that both the non-enzymatic and enzymatic reactions first require the bulk phase ionization of the substrate 2'-hydroxyl group and subsequently on the reactivity of the newly formed 2'-oxyanion during C-ring formation. Solvent viscosity experiments demonstrate that at pH 7.5 the CHI-catalyzed cyclization reactions of 4,2',4',6'-tetrahydroxychalcone, 4,2',4'-trihydroxychalcone, and 2',4'-dihydroxychalcone are approximately 90% diffusion-controlled, whereas cyclization of 4,2'-dihydroxychalcone is limited by a chemical step that likely reflects the higher pK(a) of the 2'-hydroxyl group. At pH 6.0, the reactions with 4,2',4',6'-tetrahydroxychalcone and 4,2',4'-trihydroxychalcone are approximately 50% diffusion-limited, whereas the reactions of both dihydroxychalcones are limited by chemical steps. Comparisons of the 2.1-2.3 A resolution crystal structures of CHI complexed with the products 7,4'-dihydroxyflavanone, 7-hydroxyflavanone, and 4'-hydroxyflavanone show that the 7-hydroxyflavanones all share a common binding mode, whereas 4'-hydroxyflavanone binds in an altered orientation at the active site. Our functional and structural studies support the proposal that CHI accelerates the stereochemically defined intramolecular cyclization of chalcones into biologically active (2S)-flavanones by selectively binding an ionized chalcone in a conformation conducive to ring closure in a diffusion-controlled reaction.
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Giblin, Michael F.; Wang, Nannan; Hoffman, Timothy J.; Jurisson, Silvia S.; Quinn, Thomas P.
1998-01-01
α-Melanocyte stimulating hormone (α-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind α-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, d-Phe7–α-MSH4-13 analog. Structural analysis of the Re–peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate–metal–thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re–peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re–α-MSH analog. Characterization of the second-generation Re–peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of α-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties. PMID:9788997
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Recent advances in heterobimetallic catalysis across a "transition metal-tin" motif.
Das, Debjit; Mohapatra, Swapna Sarita; Roy, Sujit
2015-06-07
Heterobimetallic catalysts, bearing a metal-metal bond between a transition metal (TM) and a tin atom, are very promising due to their ability in mediating a wide variety of organic transformations. Indeed the utilization of such catalysts is a challenging and evolving area in the field of homogeneous catalysis. Catalysis across a 'TM-Sn' motif is an emerging area in the broader domain of multimetallic catalysis. The present review apprises the chemists' community of the past, present and future scope of this versatile catalytic motif. The TM-Sn catalyzed reactions presented include, among others, Friedel-Crafts alkylation, carbonylation, polymerization, cyclization, olefin metathesis, Heck coupling, hydroarylation Michael addition and tandem coupling. The mechanistic aspects of the reactions have been highlighted as well.
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NASA Astrophysics Data System (ADS)
Zhang, Yunfei; Liu, Zonglun; Yang, Kui; Zhang, Yi; Xu, Yongqian; Li, Hongjuan; Wang, Chaoxia; Lu, Aiping; Sun, Shiguo
2015-02-01
Copper ions play a vital role in a variety of fundamental physiological processes not only in human beings and plants, but also for extensive insects and microorganisms. In this paper, a novel water-soluble ruthenium(II) complex as a turn-on copper(II) ions luminescent sensor based on o-(phenylazo)aniline was designed and synthesized. The azo group would undergo a specific oxidative cyclization reaction with copper(II) ions and turn into high luminescent benzotriazole, triggering significant luminescent increasements which were linear to the concentrations of copper(II) ions. The sensor distinguished by its high sensitivity (over 80-fold luminescent switch-on response), good selectivity (the changes of the emission intensity in the presence of other metal ions or amino acids were negligible) and low detection limit (4.42 nM) in water. Moreover, the copper(II) luminescent sensor exhibited good photostability under light irradiation. Furthermore, the applicability of the proposed sensor in biological samples assay was also studied and imaged copper(II) ions in living pea aphids successfully.
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Salmon, Melissa; Thimmappa, Ramesha B.; Minto, Robert E.; Melton, Rachel E.; O’Maille, Paul E.; Hemmings, Andrew M.; Osbourn, Anne
2016-01-01
Triterpenes are structurally complex plant natural products with numerous medicinal applications. They are synthesized through an origami-like process that involves cyclization of the linear 30 carbon precursor 2,3-oxidosqualene into different triterpene scaffolds. Here, through a forward genetic screen in planta, we identify a conserved amino acid residue that determines product specificity in triterpene synthases from diverse plant species. Mutation of this residue results in a major change in triterpene cyclization, with production of tetracyclic rather than pentacyclic products. The mutated enzymes also use the more highly oxygenated substrate dioxidosqualene in preference to 2,3-oxidosqualene when expressed in yeast. Our discoveries provide new insights into triterpene cyclization, revealing hidden functional diversity within triterpene synthases. They further open up opportunities to engineer novel oxygenated triterpene scaffolds by manipulating the precursor supply. PMID:27412861
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2014-01-01
Conspectus Selective syntheses are now available for compounds of many classes, based on C-centered radicals, exploiting a diverse range of mechanisms. The prospect for chemistry based around N- and O-centered radicals is probably more favorable because of the importance of heterocycles as biologically active materials. Heteroradical chemistry is still comparatively underdeveloped due to the need for safe and easy ways of generating them. Oxime esters appeared promising candidates to meet this need because literature reports and our EPR spectroscopic examinations showed they readily dissociated on photolysis with production of a pair of N- and O-centered radicals. It soon became apparent that a whole suite of benign oxime-containing molecules could be pressed into service. The bimodality of the oxime motif meant that by suitable choice of functionality the reactions could be directed to yield selectively products from either the N-centered radicals or from the O-centered radicals. We found that on one hand photolyses of acetophenone oxime esters of carboxylic acids yielded alicyclics. On the other hand, aromatic and heteroaromatic acyl oximes (as well as dioxime oxalates) afforded good yields of phenanthridines and related heterocycles. Easily prepared oxime oxalate amides released carbamoyl radicals, and pleasingly, β-lactams were thereby obtained. Oxime carbonates and oxime carbamates, available via our novel 1,1'-carbonyldiimidazole (CDI)-based preparations, were accessible alternatives for iminyl radicals and hence for phenanthridine preparations. In their second modes, these compounds proved their value as precursors for exotic alkoxycarbonyloxyl and carbamoyloxyl radicals. Microwave-assistance was shown to be a particularly convenient procedure with O-phenyl oxime ethers. The iminyl radicals generated from such precursors with alkene, alkyne, and aromatic acceptor substituents furnished pyrrole, quinoline, phenanthridine, benzonaphthiridine, indolopyridine, and other systems. Microwave irradiations with 2-(aminoaryl)alkanone O-phenyl oximes enabled either dihydroquinazolines or quinazolines to be obtained in very good yields. The fine quality of the EPR spectra, acquired during photolyses of all the O-carbonyl oxime types, marked this as an important complement to existing ways of obtaining such spectra in solution. Quantifications enabled SARs to be obtained for key reaction types of N- and O-centered radicals, thus putting mechanistic chemistry in this area on a much firmer footing. Surprises included the inverse gem-dimethyl effect in 5-exo-cyclizations of iminyls and the interplay of spiro- with ortho-cyclization onto aromatics. Insights into unusual 4-exo-cyclizations of carbamoyl radicals showed the process to be more viable than pent-4-enyl 4-exo-ring closure. Another surprise was the magnitude of the difference in CO2 loss rate from alkoxycarbonyloxyl radicals as compared with acyloxyl radicals. Their rapid 5-exo-cyclization was charted, as was their preferred spiro-cyclization onto aromatics. The first evidence that N-monosubstituted carbamoyloxyls had finite lifetimes was also forthcoming. It is evident that oxime derivatives have excellent credentials as reagents for radical generation and that there is ample room to extend their applications to additional radical types and for further heterocycle syntheses. There is also clear scope for the development of preparative procedures based around the alkoxyl and aminyl radicals that emerge downstream from oxime carbonate and oxime carbamate dissociations. PMID:24654991
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Fukuda, Shinji; Sasaki, Yukie; Seno, Masato
2008-01-01
We developed a two-step isothermal amplification assay system, which achieved the detection of norovirus (NoV) genomes in oysters with a sensitivity similar to that of reverse transcription-seminested PCR. The time taken for the amplification of NoV genomes from RNA extracts was shortened to about 3 h. PMID:18456857
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Call, Zachary; Suchewski, Meagan; Bradley, Christopher A
2017-03-20
A reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that derive from initial 2-bromo-2-butene lithiation followed by acid mediated dienol cyclization. The revised synthesis and purification of the ligand avoids the use of mechanical stirring while still permitting access to significant quantities (39 g) of Cp*H in good yield (58%). The procedure offers other additional benefits, including a more controlled quench of excess lithium during the production of the intermediate heptadienols and a simplified isolation of Cp*H of sufficient purity for metallation with transition metals. The ligand was subsequently used to synthesize [Cp*MCl2]2 complexes of both iridium and ruthenium to demonstrate the utility of the Cp*H prepared and purified by our method. The procedure outlined herein affords substantial quantities of a ubiquitous ancillary ligand support used in organometallic chemistry while minimizing the need for specialized laboratory equipment, thus providing a simpler and more accessible entry point into the chemistry of 1,2,3,4,5-pentamethylcyclopentadiene.
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Álvarez-Pérez, Andrea; González-Rodríguez, Carlos; García-Yebra, Cristina; Varela, Jesús A; Oñate, Enrique; Esteruelas, Miguel A; Saá, Carlos
2015-11-02
A novel osmium-catalyzed cyclization of o-alkynyl phenethylamines to give 3-benzazepines is reported. The procedure allows the straightforward preparation of a broad range of dopaminergic 3-benzazepine derivatives. Mechanistic investigations revealed that the process takes place via osmacyclopropene intermediates, which were isolated and characterized by X-ray crystallography. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Sivanesam, Kalkena; Shu, Irene; Huggins, Kelly N. L.; Tatarek-Nossol, Marianna; Kapurniotu, Aphrodite; Andersen, Niels H.
2016-01-01
Versions of a previously discovered β-hairpin peptide inhibitor of IAPP aggregation that are stabilized in that conformation, or even forced to remain in the hairpin conformation by a backbone cyclization constraint, display superior activity as inhibitors. The cyclized hairpin, cyclo-WW2, displays inhibitory activity at sub-stoichiometric concentrations relative to this amyloidogenic peptide. The hairpin binding hypothesis stands confirmed. PMID:27317951
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Mayo, Muhammad Shareef; Yu, Xiaoqiang; Zhou, Xiaoyu; Feng, Xiujuan; Yamamoto, Yoshinori; Bao, Ming
2014-02-07
Brønsted acid catalyzed cyclization reactions of 2-amino thiophenols/anilines with β-diketones under oxidant-, metal-, and radiation-free conditions are described. Various 2-substituted benzothiazoles/benzimidazoles are obtained in satisfactory to excellent yields. Different groups such as methyl, chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.
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Yang, Peng; Wang, Xiao; Chen, Feng; Zhang, Zheng-Bing; Chen, Chao; Peng, Lin; Wang, Li-Xin
2017-04-07
The first organocatalytic enantioselective Michael/cyclization domino reaction between 3-amideoxindoles and α,β-unsaturated aldehydes is described. After sequential oxidation with pyridinium chlorochromate, a direct and one-pot preparation of highly sterically hindered spirocyclic oxindole-γ-lactams was achieved in 51-81% yields with 75-97% ee and ≤80/20 dr.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Wen, Jiangwei; Shi, Wenyan; Zhang, Fan
An,electrooxidative direct arylsulfonlylation of yones sulfintc acids via a radical tandem cyclization strategy has been developed for the construction of sulfonated ilicIenones:under oxidant, free conditions. This method provides a simple and efficient approach to prepare various sulfonylindenones in good to,excellent:Tyidds,, demonstrating the tremendous prospect of utilizing electrocatalysis in oxidative coupling, Notably, this reaction could Be easily scaled up with good, efficiency.
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Ratushnyy, Maxim; Parasram, Marvin; Wang, Yang; Gevorgyan, Vladimir
2018-03-01
A novel mild, visible-light-induced palladium-catalyzed hydrogen atom translocation/atom-transfer radical cyclization (HAT/ATRC) cascade has been developed. This protocol involves a 1,5-HAT process of previously unknown hybrid vinyl palladium radical intermediates, thus leading to iodomethyl carbo- and heterocyclic structures. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Development of the Vinylogous Pictet-Spengler Cyclization and Total Synthesis of (±)-Lundurine A.
Nash, Aaron; Qi, Xiangbing; Maity, Pradip; Owens, Kyle; Tambar, Uttam K
2018-04-16
A novel vinylogous Pictet-Spengler cyclization has been developed for the generation of indole-annulated medium-sized rings. The method enables the synthesis of tetrahydroazocinoindoles with a fully substituted carbon center, a prevalent structural motif in many biologically active alkaloids. The strategy has been applied to the total synthesis of (±)-lundurine A. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Three-Step Synthesis of Chiral Spirocyclic Oxaphospholenes.
Berton, Jan K E T; Salemi, Hadi; Pirat, Jean-Luc; Virieux, David; Stevens, Christian V
2017-12-01
Chiral spirocylic oxaphospholenes were prepared in a three-step sequence from chiral pool terpenoid ketones. After addition of a metal acetylide, the resulting propargyl alcohols were converted stereoselectively into their allenylphosphonate counterparts. In the last step, they were conveniently cyclized into spirooxaphospholenes with one equivalent of iodine without purification. When starting from sterically hindered terpenes, allenylphosphonates were also easily obtained but showed to be unreactive or rearranged under these cyclization conditions.
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Wei, Lai; Zhang, Junliang
2012-03-07
The first example of Yb(OTf)(3)-catalyzed tandem ring opening/Friedel-Crafts cyclization of oxiranyl and aziridinyl ketones via selective C-C bond cleavage under mild conditions was developed. Isochromanones and isoquinolines are formed in reasonable yields, which often serve as building blocks for complex chemical synthesis. This journal is © The Royal Society of Chemistry 2012
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Chain elongation and cyclization in type III PKS DpgA.
Wu, Hai-Chen; Li, Yi-San; Liu, Yu-Chen; Lyu, Syue-Yi; Wu, Chang-Jer; Li, Tsung-Lin
2012-04-16
Chain elongation and cyclization of precursors of dihydroxyphenylacetyl-CoA (DPA-CoA) catalyzed by the bacterial type III polyketide synthase DpgA were studied. Two labile intermediates, di- and tri-ketidyl-CoA (DK- and TK-CoA), were proposed and chemically synthesized. In the presence of DpgABD, each of these with [(13)C(3)]malonyl-CoA (MA-CoA) was able to form partially (13)C-enriched DPA-CoA. By NMR and MS analysis, the distribution of (13)C atoms in the partially (13)C-enriched DPA-CoA shed light on how the polyketide chain elongates and cyclizes in the DpgA-catalyzed reaction. Polyketone intermediates elongate in a manner different from that which had been believed: two molecules of DK-CoA, or one DK-CoA plus one acetoacetyl-CoA (AA-CoA), but not two molecules of AA-CoA can form one molecule of DPA-CoA. As a result, polyketidyl-CoA serves as both the starter and extender, whereas polyketone-CoA without the terminal carboxyl group can only act as an extender. The terminal carboxyl group is crucial for the cyclization that likely takes place on CoA. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Alabugin, Igor V; Timokhin, Vitaliy I; Abrams, Jason N; Manoharan, Mariappan; Abrams, Rachel; Ghiviriga, Ion
2008-08-20
Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C-C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years. This work reports a remarkable increase in the efficiency of this process upon beta-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes. Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes. Although reactions of Br atoms generated through photochemical Ts-Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of addition/elimination reactions at the exocyclic double bond. Discovery of a relatively efficient radical 5-endo-dig closure, accompanied by a C-C bond formation, provides further support to stereoelectronic considerations at the heart of the Baldwin rules and fills one of the last remaining gaps in the arsenal of radical cyclizations.
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Song, Weihong; Yan, Peipei; Shen, Dan; Chen, Zhangtao; Zeng, Xiaofei; Zhong, Guofu
2017-04-21
An efficient catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN has been developed under mild conditions. This strategy provides an elusive and rapid access to a wide range of cyano-containing phenanthridine derivatives in good yields via a one-pot alkylation/cyclization radical-cascade process. The mild reaction conditions together with no need of any catalyst, base, or oxidant make this protocol environmentally benign and practical.
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Biomimetic syntheses of phenols from polyketones.
Evans, G E; Garson, M J; Griffin, D A; Leeper, F J; Stauton, J
1978-01-01
As a result of speculation that many enzymes control polyketone cyclization in vivo by converting a key carbonyl group to a cis-enol ether derivative, we describe two novel biomimetic cyclizations. The first involves condensation of two C6 units derived from triacetic lactone to form an arylpyrone related to aloenin. In the second a naphthapyrone of the rubrofusarin type is formed by condensation of an orsellinic acid derivative with the ether of triacetic lactone.
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Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer.
Bovino, Michael T; Chemler, Sherry R
2012-04-16
Problem solved: the title reaction was used for the synthesis of chiral 2-bromo, chloro, and iodomethyl indolines and 2-iodomethyl pyrrolidines. Stereocenter formation is believed to occur by enantioselective cis aminocupration and C-X bond formation is believed to occur by atom transfer. The ultility of the products as versatile synthetic intermediates was demonstrated, as was a radical cascade cyclization sequence. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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DeKorver, Kyle A.; Hsung, Richard P.; Lohse, Andrew G.; Zhang, Yu
2010-01-01
A fascinating mechanistic study of ynamido-palladium-π-allyl complexes is described that features isolation of a unique silyl-ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles, and a novel cyclopentenimine formation via a palladium catalyzed aza-Rautenstrauch-type cyclization pathway. PMID:20337418
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Tan, Wei Wen; Yoshikai, Naohiko
2016-07-01
We report herein copper(II)-catalyzed cyclization reactions of silyl enol ethers derived from methyl ketones with α-diazo-β-ketoesters or α-diazoketones to afford 2-siloxy-2,3-dihydrofuran derivatives or 2,3,5-trisubstituted furans, respectively, under mild conditions. The former cyclization products serve as versatile 1,4-diketone surrogates, allowing facile preparation of 2,3,5-trisubstituted furans, pyrroles, and thiophenes.
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Sivanesam, Kalkena; Shu, Irene; Huggins, Kelly N L; Tatarek-Nossol, Marianna; Kapurniotu, Aphrodite; Andersen, Niels H
2016-08-01
Versions of a previously discovered β-hairpin peptide inhibitor of IAPP aggregation that are stabilized in that conformation, or even forced to remain in the hairpin conformation by a backbone cyclization constraint, display superior activity as inhibitors. The cyclized hairpin, cyclo-WW2, displays inhibitory activity at substoichiometric concentrations relative to this amyloidogenic peptide. The hairpin-binding hypothesis stands confirmed. © 2016 Federation of European Biochemical Societies.
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Pedrosa, Rafael; Andrés, Celia; Mendiguchía, Pilar; Nieto, Javier
2006-11-10
Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.
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Method for forming pyrrone molding powders and products of said method
NASA Technical Reports Server (NTRS)
Hughes, C. T.; Mchenry, R. J. (Inventor)
1972-01-01
The formation of pyrrone resins of the ladder or semiladder structure is described. The technique involves initial formation of fully cyclized prepolymers having an average degree of polymerization of about 1.5, one with acidic terminal groups, another with amine terminal groups. Thereafter the prepolymers are intimately admixed on a 1:1 stoichiometric basis. The resulting powder mixture is molded at elevated pressures and temperatures to form a fully cyclized resin.
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Redden, Alison; Perkins, Robert J; Moeller, Kevin D
2013-12-02
Construction of new ring systems: Oxidative cyclizations (see picture; RVC=reticulated vitreous carbon) have been conducted that use two separate intramolecular nucleophiles to trap an enol ether-derived radical cation intermediate. The reactions provide a means for rapidly trapping the radical cation intermediate in a manner that avoids competitive decomposition reactions. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Non-enzymatic cyclization of creatine ethyl ester to creatinine.
Giese, Matthew W; Lecher, Carl S
2009-10-16
Creatine ethyl ester was incubated at 37 degrees C in both water and phosphate-buffered saline and the diagnostic methylene resonances in the (1)H NMR spectrum were used to identify the resultant products. It was found that mild aqueous conditions result in the cyclization of creatine ethyl ester to provide inactive creatinine as the exclusive product, and this transformation becomes nearly instantaneous as the pH approaches 7.4. This study demonstrates that mild non-enzymatic conditions are sufficient for the cyclization of creatine ethyl ester into creatinine, and together with previous results obtained under enzymatic conditions suggests that there are no physiological conditions that would result in the production of creatine. It is concluded that creatine ethyl ester is a pronutrient for creatinine rather than creatine under all physiological conditions encountered during transit through the various tissues, thus no ergogenic effect is to be expected from supplementation.
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Bergman cyclization in polymer chemistry and material science.
Xiao, Yuli; Hu, Aiguo
2011-11-01
Bergman cyclization of enediynes, regarded as a promising strategy for anticancer drugs, now finds its own niche in the area of polymer chemistry and material science. The highly reactive aromatic diradicals generated from Bergman cyclization can undergo polymerization acting as either monomers or initiators of other vinyl monomers. The former, namely homopolymerization, leads to polyphenylenes and polynaphthalenes with excellent thermal stability, good solubility, and processability. The many remarkable properties of these aromatic polymers have further endowed them to be manufactured into carbon-rich materials, e.g., glassy carbons and carbon nanotubes. Whereas used as initiators, enediynes provide a novel resource for high molecular weight polymers with narrow polydispersities. The aromatic diradicals are also useful for introducing oligomers or polymers onto pristine carbonous nanomaterials, such as carbon nano-onions and carbon nanotubes, to improve their dispersibility in organic solvents and polymer solutions. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization.
Johnston, Craig P; Kothari, Abhishek; Sergeieva, Tetiana; Okovytyy, Sergiy I; Jackson, Kelvin E; Paton, Robert S; Smith, Martin D
2014-02-01
5-Endo-trig cyclizations are generally considered to be kinetically unfavourable, as described by Baldwin's rules. Consequently, observation of this mode of reaction under kinetic control is rare. This is usually ascribed to challenges in achieving appropriate approach trajectories for orbital overlap in the transition state. Here, we describe a highly enantio- and diastereoselective route to complex indanes bearing all-carbon quaternary stereogenic centres via a 5-endo-trig cyclization catalysed by a chiral ammonium salt. Through computation, the preference for the formally disfavoured 5-endo-trig Michael reaction over the formally favoured 5-exo-trig Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group, which outweigh the importance of the approach trajectory as embodied by Baldwin's rules. Our experimental and theoretical findings demonstrate that geometric and stereoelectronic constraints may not be decisive in the observed outcome of irreversible ring-closing reactions.
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Gao, Xue; Jiang, Wei; Jiménez-Osés, Gonzalo; Choi, Moon Seok; Houk, Kendall N.; Tang, Yi; Walsh, Christopher T.
2013-01-01
The bimodular 276 kDa nonribosomal peptide synthetase AspA from Aspergillus alliaceus, heterologously expressed in Saccharomyces cerevisiae, converts tryptophan and two molecules of the aromatic β-amino acid anthranilate (Ant) into a pair of tetracyclic peptidyl alkaloids asperlicin C and D in a ratio of 10:1. The first module of AspA activates and processes two molecules of Ant iteratively to generate a tethered Ant-Ant-Trp-S-enzyme intermediate on module two. Release is postulated to involve tandem cyclizations, in which the first step is the macrocyclization of the linear tripeptidyl-S-enzyme, by the terminal condensation (CT) domain to generate the regioisomeric tetracyclic asperlicin scaffolds. Computational analysis of the transannular cyclization of the 11-membered macrocyclic intermediate shows that asperlicin C is the kinetically favored product due to the high stability of a conformation resembling the transition state for cyclization, while asperlicin D is thermodynamically more stable. PMID:23890005
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Uncaria alkaloids reverse ABCB1-mediated cancer multidrug resistance
Huang, Bao-Yuan; Zeng, Yu; Li, Ying-Jie; Huang, Xiao-Jun; Hu, Nan; Yao, Nan; Chen, Min-Feng; Yang, Zai-Gang; Chen, Zhe-Sheng; Zhang, Dong-Mei; Zeng, Chang-Qing
2017-01-01
The overexpression of ATP-binding cassette (ABC) transporters is the main cause of cancer multidrug resistance (MDR), which leads to chemotherapy failure. Uncaria alkaloids are the major active components isolated from uncaria, which is a common Chinese herbal medicine. In this study, the MDR-reversal activities of uncaria alkaloids, including rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine (Icory), hirsutine and hirsuteine, were screened; they all exhibited potent reversal efficacy when combined with doxorubicin. Among them, Icory significantly sensitized ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to vincristine, doxorubicin and paclitaxel, but not to the non-ABCB1 substrate cisplatin. Noteworthy, Icory selectively reversed ABCB1-overexpressing MDR cancer cells but not ABCC1- or ABCG2-mediated MDR. Further mechanistic study revealed that Icory increased the intracellular accumulation of doxorubicin in ABCB1-overexpressing cells by blocking the efflux function of ABCB1. Instead of inhibiting ABCB1 expression and localization, Icory acts as a substrate of the ABCB1 transporter by competitively binding to substrate binding sites. Collectively, these results indicated that Icory reversed ABCB1-mediated MDR by suppressing its efflux function, and it would be beneficial to increase the efficacy of these types of uncaria alkaloids and develop them to be selective ABCB1-mediated MDR-reversal agents. PMID:28534954
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Shao, Yutian; Yang, Chao; Gui, Weijun; Liu, Yang; Xia, Wujiong
2012-04-11
Irradiation of terminal aromatic γ,δ-epoxy ketones with a 450 W UV lamp led to Norrish type II cyclization/semi-pinacol rearrangement cascade reaction which formed the benzocyclobutanones containing a full-carbon quaternary center, whereas irradiation of substituted aromatic γ,δ-epoxy ketones led to the indanones through a photochemical epoxy rearrangement and 1,5-biradicals cyclization tandem reaction. This journal is © The Royal Society of Chemistry 2012
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Masuda, Kengo; Sakiyama, Norifumi; Tanaka, Rie; Noguchi, Keiichi; Tanaka, Ken
2011-05-11
It has been established that a cationic rhodium(I)/(R)-H(8)-BINAP or (R)-Segphos complex catalyzes two modes of enantioselective cyclizations of γ-alkynylaldehydes with acyl phosphonates via C-P or C-H bond cleavage. The ligands of the Rh(I) complexes and the substitutents of both γ-alkynylaldehydes and acyl phosphonates control these two different pathways. © 2011 American Chemical Society
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Nieto, Javier; Andrés, Celia; Pérez-Encabo, Alfonso
2015-09-14
Enantiopure 1,4-oxazepane derivatives have been prepared by selenocyclofunctionalization of chiral 3-prenyl- and 3-cinnamyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The 7-endo-cyclization occurs in high yields and diastereoselection. The regio- and stereochemistry of the cyclization products was dependent on the substitution pattern of the double bond, the nature of the hydroxyl group and the experimental conditions.
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Structural Insights into the Role of the Cyclic Backbone in a Squash Trypsin Inhibitor*
Daly, Norelle L.; Thorstholm, Louise; Greenwood, Kathryn P.; King, Gordon J.; Rosengren, K. Johan; Heras, Begoña; Martin, Jennifer L.; Craik, David J.
2013-01-01
MCoTI-II is a head-to-tail cyclic peptide with potent trypsin inhibitory activity and, on the basis of its exceptional proteolytic stability, is a valuable template for the design of novel drug leads. Insights into inhibitor dynamics and interactions with biological targets are critical for drug design studies, particularly for protease targets. Here, we show that the cyclization and active site loops of MCoTI-II are flexible in solution, but when bound to trypsin, the active site loop converges to a single well defined conformation. This finding of reduced flexibility on binding is in contrast to a recent study on the homologous peptide MCoTI-I, which suggested that regions of the peptide are more flexible upon binding to trypsin. We provide a possible explanation for this discrepancy based on degradation of the complex over time. Our study also unexpectedly shows that the cyclization loop, not present in acyclic homologues, facilitates potent trypsin inhibitory activity by engaging in direct binding interactions with trypsin. PMID:24169696
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Mancuso, Raffaella; Mehta, Saurabh; Gabriele, Bartolo; Salerno, Giuseppe; Jenks, William S.; Larock, Richard C.
2010-01-01
A variety of iodo-substituted isochromenes, dihydroisobenzofurans, and pyranopyridines are readily prepared in good to excellent yields under mild conditions by the iodocyclization of readily available 2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxymethyl)pyridines. Reactions are carried out in MeCN at 15 °C using 3 equiv of I2 as the iodine source and NaHCO3 (3 equiv) as the base. The regiochemical outcome of the reaction strongly depends on the substitution pattern of the starting material. In particular, the 5-exo-dig cyclization mode, leading to dihydroisobenzofurans, is observed in the case of substrates bearing a tertiary alcoholic group, owing to the gem-dialkyl effect, while the 6-endo-dig cyclization mode, leading to isochromene or pyranopyridines, is the usually preferred pathway in the case of substrates bearing a primary or secondary alcoholic group PMID:20043652
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NASA Astrophysics Data System (ADS)
Zhang, Xuekai; Lu, Gang; Sun, Meng; Mahankali, Madhu; Ma, Yanfei; Zhang, Mingming; Hua, Wangde; Hu, Yuting; Wang, Qingbing; Chen, Jinghuo; He, Gang; Qi, Xiangbing; Shen, Weijun; Liu, Peng; Chen, Gong
2018-05-01
New methods capable of effecting cyclization, and forming novel three-dimensional structures while maintaining favourable physicochemical properties are needed to facilitate the development of cyclic peptide-based drugs that can engage challenging biological targets, such as protein-protein interactions. Here, we report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalysed intramolecular C(sp3)-H arylation reactions. Easily accessible linear peptide precursors of simple and versatile design can be selectively cyclized at the side chains of either aromatic or modified non-aromatic amino acid units to form various cyclophane-braced peptide cycles. This strategy provides a powerful tool to address the long-standing challenge of size- and composition-dependence in peptide macrocyclization, and generates novel peptide macrocycles with uniquely buttressed backbones and distinct loop-type three-dimensional structures. Preliminary cell proliferation screening of the pilot library revealed a potent lead compound with selective cytotoxicity toward proliferative Myc-dependent cancer cell lines.
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Synthesis of Benzo[a]carbazoles and an Indolo[2,3-a]carbazole from 3-Aryltetramic Acids.
Truax, Nathanyal J; Banales Mejia, Fernando; Kwansare, Deborah O; Lafferty, Megan M; Kean, Maeve H; Pelkey, Erin T
2016-08-05
A simple and flexible approach to 3-pyrrolin-2-one fused carbazoles is disclosed. The key step involves the BF3-mediated electrophilic substitution of indoles with N-alkyl-substituted 3-aryltetramic acids, which provides access to indole-substituted 3-pyrrolin-2-ones. Scholl-type oxidative cyclizations of these materials led to the formation of the corresponding 3-pyrrolin-2-one-fused benzo[a]carbazoles and indolo[2,3-a]carbazoles. This work represents the first synthesis of the benzo[a]pyrrolo[3,4-c]carbazol-3(8H)-one ring system, while the indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one ring system is found in a number of biologically active compounds including the protein kinase C (PKC) inhibitor, staurosporine.
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Li, Lei; Zhao, Yu-Long; Wang, He; Li, Yi-Jin; Xu, Xianxiu; Liu, Qun
2014-06-21
We report here that polysubstituted dihydroisoquinolones and isoquinolones can be constructed by the one-pot reaction of the readily available acyclic α,β-unsaturated carbonyl precursors and dialkyl glutaconates under mild basic conditions (1-45 min for the former vs. 1-6 h for the latter) via the domino process involving [3+3] annulation/intramolecular aza-cyclization.
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Cofacial porphyrin-ferrocene dyads and a new class of conjugated porphyrin.
Cammidge, Andrew N; Scaife, Peter J; Berber, Gûlen; Hughes, David L
2005-08-04
A porphyrin-ferrocene dyad has been synthesized in which there is close face-to-face contact between the two aromatic systems, providing a model for heterobimetallic polymers based on the same repeating unit. Attempts to synthesize the 2:1 adduct instead led to a remarkable intramolecular Heck-type cyclization which planarizes the system and extends the conjugation. [structure: see text
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Aging Affects Acquisition and Reversal of Reward-Based Associative Learning
ERIC Educational Resources Information Center
Weiler, Julia A.; Bellebaum, Christian; Daum, Irene
2008-01-01
Reward-based associative learning is mediated by a distributed network of brain regions that are dependent on the dopaminergic system. Age-related changes in key regions of this system, the striatum and the prefrontal cortex, may adversely affect the ability to use reward information for the guidance of behavior. The present study investigated the…
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Kluskens, Leon D; Kuipers, Anneke; Rink, Rick; de Boef, Esther; Fekken, Susan; Driessen, Arnold J M; Kuipers, Oscar P; Moll, Gert N
2005-09-27
Post-translationally introduced dehydroamino acids often play an important role in the activity and receptor specificity of biologically active peptides. In addition, a dehydroamino acid can be coupled to a cysteine to yield a cyclized peptide with increased biostability and resistance against proteolytic degradation and/or modified specificity. The lantibiotic nisin is an antimicrobial peptide produced by Lactococcus lactis. Its post-translational enzymatic modification involves NisB-mediated dehydration of serines and threonines and NisC-catalyzed coupling of cysteines to dehydroresidues, followed by NisT-mediated secretion. Here, we demonstrate that a L. lactis strain containing the nisBTC genes effectively dehydrates and secretes a wide range of medically relevant nonlantibiotic peptides among which variants of adrenocorticotropic hormone, vasopressin, an inhibitor of tripeptidyl peptidase II, enkephalin, luteinizing hormone-releasing hormone, angiotensin, and erythropoietin. For most of these peptides, ring formation was demonstrated. These data show that lantibiotic enzymes can be applied for the modification of peptides, thereby enabling the biotechnological production of dehydroresidue-containing and/or thioether-bridged therapeutic peptides with enhanced stability and/or modulated activities.
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Choo, Ken-Loon; Lautens, Mark
2018-03-02
A rhodium-catalyzed conjugate alkynylation/aldol cyclization cascade was developed. Densely functionalized cyclic α-propargyl-β-hydroxyketones were synthesized with simultaneous formation of a C(sp)-C(sp 3 ) bond, a C(sp 3 )-C(sp 3 ) bond, as well as three new contiguous stereocenters. The transformation was achieved with excellent enantio- and diastereoselectivities using BINAP as the ligand. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations.
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Gold(I)-Catalyzed Cascade Cyclization of Allenyl Epoxides
Tarselli, Michael A.; Lucas Zuccarello, J
2009-01-01
Cationic gold(I) phosphite catalysts activate allenes for epoxide cascade reactions. The system is tolerant of numerous functional groups (sulfones, esters, ethers, sulfonamides) and proceeds at room temperature in dichloromethane. The cyclization pathway is sensitive to the substitution pattern of the epoxide, and the backbone structure of the A-ring. It is capable of producing medium-ring ethers, fused 6-5 bicyclic, and linked pyran-furan structures. The resulting cycloisomers are reminiscent of structures found in numerous polyether natural products. PMID:19588972
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Yamakado, Ryohei; Matsuoka, Shin-ichi; Suzuki, Masato; Takeuchi, Daisuke; Masu, Hyuma; Azumaya, Isao; Takagi, Koji
2015-04-04
The diastereoselective cyclization of 2,5-dibromo-4-hexylaminobenzoic acid was achieved by the microwave-assisted condensation using SiCl4. Moreover, the triple-stranded helical structure of bis(phenylethynyl)benzene units embedded in the cyclic tri(benzamide) scaffold was obtained by a Sonogashira-Hagihara coupling reaction. Two optically active enantiomers that do not racemize even at the elevated temperature were separated by chiral HPLC. The chiral helical topology was revealed by the spectroscopic data and theoretical calculation.
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Qian, Wenyuan; Wang, Hao; Allen, Jennifer
2013-10-11
A cat of all trades: A single copper catalyst promoted up to three reaction steps with separate catalytic cycles in a domino sequence (azide-alkyne cycloaddition/Goldberg amidation/Camps cyclization/(CH arylation)) for the rapid construction of complex heterocycles from three simple components under mild conditions. Facile cleavage of the triazole ring enables further elaboration of the condensation products. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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2008-01-01
surrogate” acrolein, which was synthesized from vinyl acetate (Scheme 11, upper equation )31. This mild method was an improvement over their previous work...11, lower equation ). Both cyclizations were facile with N,S-acetals bearing strongly activating groups on aniline. The resulting 2-methylthio...kinetic studies of the MS rearrangement.144 Using a combination of Hammett analysis of substituent effects and solvent isotope effects, Edens concluded
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Xu, Guangyang; Zhu, Chenghao; Gu, Weijin; Li, Jian; Sun, Jiangtao
2015-01-12
An unprecedented gold-catalyzed ligand-controlled cross-coupling of diazo compounds by sequential selective denitrogenation and cyclization affords N-substituted pyrazoles in a position-switchable mode. This novel transformation features selective decomposition of one diazo moiety and simultaneous preservation of the other one from two substrates. Notably, the choice of the ancillary ligand to the gold complex plays a pivotal role on the chemo- and regioselectivity of the reactions. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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NASA Technical Reports Server (NTRS)
Rosser, R. W.; Korus, R. A. (Inventor)
1980-01-01
Crosslinking elastomeric polytriazines are prepared by a 4 step procedure which consists of (1) forming a poly(imidoylamidine) by the reaction, under reflux conditions, of anhydrous ammonia with certain perfluorinated alkyl or alkylether dinitriles; (2) forming a linear polytriazine by cyclizing the imidoylamidine linkages by reaction with certain perfluorinated alkyl or alkylether acid anhydrides or halides; (3) extending the linear polytriazine chain by further refluxing in anhydrous ammonia; and (4) heating to cyclize the new imidoylamidine and thereby crosslink the polymer.
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Tsetsarkin, Konstantin A.; Liu, Guangping; Shen, Kui; Pletnev, Alexander G.
2016-01-01
Insertion of microRNA target sequences into the flavivirus genome results in selective tissue-specific attenuation and host-range restriction of live attenuated vaccine viruses. However, previous strategies for miRNA-targeting did not incorporate a mechanism to prevent target elimination under miRNA-mediated selective pressure, restricting their use in vaccine development. To overcome this limitation, we developed a new approach for miRNA-targeting of tick-borne flavivirus (Langat virus, LGTV) in the duplicated capsid gene region (DCGR). Genetic stability of viruses with DCGR was ensured by the presence of multiple cis-acting elements within the N-terminal capsid coding region, including the stem-loop structure (5′SL6) at the 3′ end of the promoter. We found that the 5′SL6 functions as a structural scaffold for the conserved hexanucleotide motif at its tip and engages in a complementary interaction with the region present in the 3′ NCR to enhance viral RNA replication. The resulting kissing-loop interaction, common in tick-borne flaviviruses, supports a single pair of cyclization elements (CYC) and functions as a homolog of the second pair of CYC that is present in the majority of mosquito-borne flaviviruses. Placing miRNA targets into the DCGR results in superior attenuation of LGTV in the CNS and does not interfere with development of protective immunity in immunized mice. PMID:26850640
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Liu, Yang; Huang, Liping; Xie, Fuchun; Hu, Youhong
2010-09-17
A base-promoted one-pot tandem reaction has been developed from 3-(1-alkynyl)chromones with various acetonitriles to afford functionalized amino-substituted xanthones 3 under microwave irradiation. This tandem process involves multiple reactions, such as Michael addition/cyclization/1,2-addition, without a transition metal catalyst. This method provides an efficient approach to build up natural product-like diversified amino-substituted xanthone scaffolds rapidly.
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Hata, Takeshi; Sujaku, Shiro; Hirone, Naoki; Nakano, Kirihiro; Imoto, Junsuke; Imade, Haduki; Urabe, Hirokazu
2011-12-16
Treatment of ethyl (E)-5,5-bis[(benzyloxy)methyl]-8-(N,N-diethylcarbamoyl)-2-octen-7-ynoate with an iron reagent generated from FeCl(2) and tBuMgCl in a ratio of 1:4 (abbreviated as FeCl(2)/4 tBuMgCl) afforded ethyl [4,4-bis[(benzyloxy)methyl]-2-[(E)-(N,N-diethylcarbamoyl)methylene]cyclopent-1-yl]acetate in good yield. Deuteriolysis of an identical reaction mixture afforded the bis-deuterated product ethyl [4,4-bis[(benzyloxy)methyl]-2-[(E)-(N,N-diethylcarbamoyl)deuteriomethylene]cyclopent-1-yl]deuterioacetate, thus confirming the existence of the corresponding dimetalated intermediate. The latter intermediate can react with halogens or aldehydes to facilitate further synthetic transformations. The amount of FeCl(2) was reduced to catalytic levels (10 mol % relative to enyne), and catalytic cyclizations of this sort proceeded with yields comparable to those of the aforementioned stoichiometric reactions. The cyclization of diethyl (E,E)-2,7-nonadienedioate with a stoichiometric amount of FeCl(2)/4 tBuMgCl, followed by the addition of sBuOH as a proton source, afforded a mixture of 2-(ethoxycarbonyl)-3-bicyclo[3.3.0]octanone and its enol form in good yield. The use of aldehyde or ketone in place of sBuOH afforded 2-(ethoxycarbonyl)-3-bicyclo[3.3.0]octanone, which has an additional hydroxyalkyl side chain. Additionally, the metalation of a carbon-carbon unsaturated bond in N,N-diethyl-5,5-bis[(benzyloxy)methyl]-7,8-epoxy-2-octynamide or (E)-3,3-dimethyl-6-(N,N-diethylcarbamoyl)-5-hexenyl p-toluenesulfonate with FeCl(2)/4 tBuMgCl or FeCl(2)/4 PhMgBr was followed by an intramolecular alkylation with an epoxide or alkyl p-toluenesulfonate to afford 5,5-bis[(benzyloxy)methyl]-3-[(E)-(N,N-diethylcarbamoyl)methylene]-1-cyclohexanol or N,N-diethyl(3,3-dimethylcyclopentyl)acetamide after hydrolysis. In both cases, the remaining metalated portion α to the amide group was confirmed by deuteriolysis and could be utilized for an alkylation with methyl iodide. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Role of hydrogen bonds in the reaction mechanism of chalcone isomerase.
Jez, Joseph M; Bowman, Marianne E; Noel, Joseph P
2002-04-23
In flavonoid, isoflavonoid, and anthocyanin biosynthesis, chalcone isomerase (CHI) catalyzes the intramolecular cyclization of chalcones into (S)-flavanones with a second-order rate constant that approaches the diffusion-controlled limit. The three-dimensional structures of alfalfa CHI complexed with different flavanones indicate that two sets of hydrogen bonds may possess critical roles in catalysis. The first set of interactions includes two conserved amino acids (Thr48 and Tyr106) that mediate a hydrogen bond network with two active site water molecules. The second set of hydrogen bonds occurs between the flavanone 7-hydroxyl group and two active site residues (Asn113 and Thr190). Comparison of the steady-state kinetic parameters of wild-type and mutant CHIs demonstrates that efficient cyclization of various chalcones into their respective flavanones requires both sets of contacts. For example, the T48A, T48S, Y106F, N113A, and T190A mutants exhibit 1550-, 3-, 30-, 7-, and 6-fold reductions in k(cat) and 2-3-fold changes in K(m) with 4,2',4'-trihydroxychalcone as a substrate. Kinetic comparisons of the pH-dependence of the reactions catalyzed by wild-type and mutant enzymes indicate that the active site hydrogen bonds contributed by these four residues do not significantly alter the pK(a) of the intramolecular cyclization reaction. Determinations of solvent kinetic isotope and solvent viscosity effects for wild-type and mutant enzymes reveal a change from a diffusion-controlled reaction to one limited by chemistry in the T48A and Y106F mutants. The X-ray crystal structures of the T48A and Y106F mutants support the assertion that the observed kinetic effects result from the loss of key hydrogen bonds at the CHI active site. Our results are consistent with a reaction mechanism for CHI in which Thr48 polarizes the ketone of the substrate and Tyr106 stabilizes a key catalytic water molecule. Hydrogen bonds contributed by Asn113 and Thr190 provide additional stabilization in the transition state. Conservation of these residues in CHIs from other plant species implies a common reaction mechanism for enzyme-catalyzed flavanone formation in all plants.
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Miller; Lammi; Prathapan; Holten; Lindsey
2000-10-06
We have prepared a linear array of chromophores consisting of a perylene input unit, a bis(free base porphyrin) transmission unit, and a free base phthalocyanine output unit for studies in artificial photosynthesis and molecular photonics. The synthesis involved four stages: (1) a rational synthesis of trans-AB2C-porphyrin building blocks each bearing one meso-unsubstituted position, (2) oxidative, meso,meso coupling of the zinc porphyrin monomers to afford a bis(zinc porphyrin) bearing one phthalonitrile group and one iodophenyl group, (3) preparation of a bis(porphyrin)-phthalocyanine array via a mixed cyclization involving the bis(free base porphyrin) and 4-tert-butylphthalonitrile, and (4) Pd-mediated coupling of an ethynylperylene to afford a perylene-bis(porphyrin)-phthalocyanine linear array. The perylene-bis(porphyrin)-phthalocyanine array absorbs strongly across the visible spectrum. Excitation at 490 nm, where the perylene absorbs preferentially, results in fluorescence almost exclusively from the phthalocyanine (phi(f) = 0.78). The excited phthalocyanine forms with time constants of 2 ps (90%) and 13 ps (10%). The observed time constants resemble those of corresponding phenylethyne-linked dyads, including a perylene-porphyrin (< or = 0.5 ps) and a porphyrin-phthalocyanine (1.1 ps (70%) and 8 ps (30%)). The perylene-bis(porphyrin)-phthalocyanine architecture exhibits efficient light-harvesting properties and rapid funneling of energy in a cascade from perylene to bis(porphyrin) to phthalocyanine.
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Spangenberg, Arnaud; Piedras Perez, Jose Alejandro; Patra, Abhijit; Piard, Jonathan; Brosseau, Arnaud; Métivier, Rémi; Nakatani, Keitaro
2010-02-01
Quantification of the relative composition of the isomers in a photochromic system at any irradiation time interval is a critical issue in determining absolute quantum yields. For this purpose, we have developed a simple and convenient protocol involving combination of UV-visible and infra-red absorption spectroscopy. Photochromic cyclization reaction of cis-l,2-dicyano-l,2-bis(2,4,5-trimethyl-3-thieny1)ethene (CMTE) is analyzed to demonstrate the efficiency of the proposed methodology. This approach is based on the fact that the two isomers show distinctive infra-red bands. Detailed investigations of the UV-visible and infra-red spectra of the mixture obtained at different irradiation times in CCl(4) supported by quantum chemical computations lead to the unambiguous estimation of molar absorption coefficients of the closed isomer (epsilon(CF) = 4650 L mol(-1) cm(-1) at 512 nm). It facilitates the first determination of absolute quantum yields of this reversible photochromic reaction in CCl(4) by fitting the UV-visible spectral data (Phi(OF-->CF) = 0.41 +/- 0.05 and Phi(CF-->OF) = 0.12 +/- 0.02 at 405 nm and 546 nm, respectively).
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Gel Point Suppression in RAFT Polymerization of Pure Acrylic Cross-Linker Derived from Soybean Oil.
Yan, Mengguo; Huang, Yuerui; Lu, Mingjia; Lin, Fang-Yi; Hernández, Nacú B; Cochran, Eric W
2016-08-08
Here we report the reversible addition-fragmentation chain transfer (RAFT) polymerization of acrylated epoxidized soybean oil (AESO), a cross-linker molecule, to high conversion (>50%) and molecular weight (>100 kDa) without macrogelation. Surprisingly, gelation is suppressed in this system far beyond the expectations predicated both on Flory-Stockmeyer theory and multiple other studies of RAFT polymerization featuring cross-linking moieties. By varying AESO and initiator concentrations, we show how intra- versus intermolecular cross-linking compete, yielding a trade-off between the degree of intramolecular linkages and conversion at gel point. We measured polymer chain characteristics, including molecular weight, chain dimensions, polydispersity, and intrinsic viscosity, using multidetector gel permeation chromatography and NMR to track polymerization kinetics. We show that not only the time and conversion at macrogelation, but also the chain architecture, is largely affected by these reaction conditions. At maximal AESO concentration, the gel point approaches that predicted by the Flory-Stockmeyer theory, and increases in an exponential fashion as the AESO concentration decreases. In the most dilute solutions, macrogelation cannot be detected throughout the entire reaction. Instead, cyclization/intramolecular cross-linking reactions dominate, leading to microgelation. This work is important, especially in that it demonstrates that thermoplastic rubbers could be produced based on multifunctional renewable feedstocks.
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Ravi, Manjula; Allu, Srinivasarao; Swamy, K C Kumara
2017-03-03
An efficient Rh(III)-catalyzed ortho-alkylation of phenoxy substrates with diazo compounds has been achieved for the first time using pyrimidine or pyridine as the directing group. Furthermore, bis-alkylation has also been achieved using para-substituted phenoxypyrimidine and 3 mol equiv of the diazo ester. The ortho-alkylated derivatives of phenoxy products possessing the ester functionality undergo decarboxylative pyrimidine/pyridine migratory cyclization (rather than deprotection of pyrimidine/pyridine group) using 20% NaOEt in EtOH affording a novel class of 3-(pyrimidin-2(1H)-ylidene)benzofuran-2(3H)-ones and 6-methyl-3-(pyridin-2(1H)-ylidene)benzofuran-2(3H)-one. The ortho-alkylated phenoxypyridine possessing ester functionality also undergoes decarboxylative pyridine migratory cyclization using MeOTf/NaOMe in toluene providing 6-methyl-3-(1-methylpyridin-2(1H)-ylidene)benzofuran-2(3H)-one.
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Lewis super-acid catalyzed cyclizations: a new route to fragrance compounds.
Coulombel, Lydie; Grau, Fanny; Weïwer, Michel; Favier, Isabelle; Chaminade, Xavier; Heumann, Andreas; Bayón, J Carles; Aguirre, Pedro A; Duñach, Elisabet
2008-06-01
This review deals with the application of Lewis super acids such as Al(III), In(III), and Sn(IV) triflates and triflimidates as catalysts in the synthesis of fragrance materials. Novel catalytic reactions involving C-C and C-heteroatom bond-forming reactions, as well as cycloisomerization processes are presented. In particular, Sn(IV) and Al(III) triflates were employed as catalysts in the selective cyclization of unsaturated alcohols to cyclic ethers, as well as in the cyclization of unsaturated carboxylic acids to lactones. The addition of thiols and thioacids to non-activated olefins, both in intra- and intermolecular versions, was efficiently catalyzed by In(III) derivatives. Sn(IV) Triflimidates catalyzed the cycloisomerization of highly substituted 1,6-dienes to gem-dimethyl-substituted cyclohexanes bearing an isopropylidene substituent. The hydroformylation of these unsaturated substrates, catalyzed by a Rh(I) complex with a bulky phosphite ligand, selectively afforded the corresponding linear aldehydes. The olfactory evaluation of selected heterocycles, carbocycles, and aldehydes synthesized is also discussed.
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NASA Astrophysics Data System (ADS)
Newland, B.; Aied, A.; Pinoncely, A. V.; Zheng, Y.; Zhao, T.; Zhang, H.; Niemeier, R.; Dowd, E.; Pandit, A.; Wang, W.
2014-06-01
The purpose of this study was to develop a platform transfection technology, for applications in the brain, which could transfect astrocytes without requiring cell specific functionalization and without the common cause of toxicity through high charge density. Here we show that a simple and scalable preparation technique can be used to produce a ``knot'' structured cationic polymer, where single growing chains can crosslink together via disulphide intramolecular crosslinks (internal cyclizations). This well-defined knot structure can thus ``untie'' under reducing conditions, showing a more favorable transfection profile for astrocytes compared to 25 kDa-PEI (48-fold), SuperFect® (39-fold) and Lipofectamine®2000 (18-fold) whilst maintaining neural cell viability at over 80% after four days of culture. The high transfection/lack of toxicity of this knot structured polymer in vitro, combined with its ability to mediate luciferase transgene expression in the adult rat brain, demonstrates its use as a platform transfection technology which should be investigated further for neurodegenerative disease therapies.The purpose of this study was to develop a platform transfection technology, for applications in the brain, which could transfect astrocytes without requiring cell specific functionalization and without the common cause of toxicity through high charge density. Here we show that a simple and scalable preparation technique can be used to produce a ``knot'' structured cationic polymer, where single growing chains can crosslink together via disulphide intramolecular crosslinks (internal cyclizations). This well-defined knot structure can thus ``untie'' under reducing conditions, showing a more favorable transfection profile for astrocytes compared to 25 kDa-PEI (48-fold), SuperFect® (39-fold) and Lipofectamine®2000 (18-fold) whilst maintaining neural cell viability at over 80% after four days of culture. The high transfection/lack of toxicity of this knot structured polymer in vitro, combined with its ability to mediate luciferase transgene expression in the adult rat brain, demonstrates its use as a platform transfection technology which should be investigated further for neurodegenerative disease therapies. Electronic supplementary information (ESI) available: 1H NMR spectroscopy data and gel permeation chromatography data. See DOI: 10.1039/c3nr06737h
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Ashok, Aditya; Vijayaraghavan, S N; Unni, Gautam E; Nair, Shantikumar V; Shanmugam, Mariyappan
2018-04-27
The present study elucidates dispersive electron transport mediated by surface states in tin oxide (SnO 2 ) nanoparticle-based dye sensitized solar cells (DSSCs). Transmission electron microscopic studies on SnO 2 show a distribution of ∼10 nm particles exhibiting (111) crystal planes with inter-planar spacing of 0.28 nm. The dispersive transport, experienced by photo-generated charge carriers in the bulk of SnO 2 , is observed to be imposed by trapping and de-trapping processes via SnO 2 surface states present close to the band edge. The DSSC exhibits 50% difference in performance observed between the forward (4%) and reverse (6%) scans due to the dispersive transport characteristics of the charge carriers in the bulk of the SnO 2 . The photo-generated charge carriers are captured and released by the SnO 2 surface states that are close to the conduction band-edge resulting in a very significant variation; this is confirmed by the hysteresis observed in the forward and reverse scan current-voltage measurements under AM1.5 illumination. The hysteresis behavior assures that the charge carriers are accumulated in the bulk of electron acceptor due to the trapping, and released by de-trapping mediated by surface states observed during the forward and reverse scan measurements.
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Auffenberg, Eva; Jurik, Angela; Mattusch, Corinna; Stoffel, Rainer; Genewsky, Andreas; Namendorf, Christian; Schmid, Roland M.; Rammes, Gerhard; Biel, Martin; Uhr, Manfred; Moosmang, Sven; Michalakis, Stylianos; Wotjak, Carsten T.; Thoeringer, Christoph K.
2016-01-01
Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research. PMID:26757616
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NASA Astrophysics Data System (ADS)
Ashok, Aditya; Vijayaraghavan, S. N.; Unni, Gautam E.; Nair, Shantikumar V.; Shanmugam, Mariyappan
2018-04-01
The present study elucidates dispersive electron transport mediated by surface states in tin oxide (SnO2) nanoparticle-based dye sensitized solar cells (DSSCs). Transmission electron microscopic studies on SnO2 show a distribution of ˜10 nm particles exhibiting (111) crystal planes with inter-planar spacing of 0.28 nm. The dispersive transport, experienced by photo-generated charge carriers in the bulk of SnO2, is observed to be imposed by trapping and de-trapping processes via SnO2 surface states present close to the band edge. The DSSC exhibits 50% difference in performance observed between the forward (4%) and reverse (6%) scans due to the dispersive transport characteristics of the charge carriers in the bulk of the SnO2. The photo-generated charge carriers are captured and released by the SnO2 surface states that are close to the conduction band-edge resulting in a very significant variation; this is confirmed by the hysteresis observed in the forward and reverse scan current-voltage measurements under AM1.5 illumination. The hysteresis behavior assures that the charge carriers are accumulated in the bulk of electron acceptor due to the trapping, and released by de-trapping mediated by surface states observed during the forward and reverse scan measurements.
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Faraldos, Juan A.; Zhao, Yuxin; O'Maille, Paul E.; Noel, Joseph P.; Coates, Robert M.
2009-01-01
Tobacco 5-epi-aristolochene synthase (TEAS) catalyzes the MgII-dependent cyclizations and rearrangements of (E,E)-farnesyl diphosphate (PP) to the bicyclic sesquiterpene hydrocarbon via a tightly bound (+)-germacrene A as a deprotonated intermediate. With the native enzyme, only a few percent of the putative germacrene A intermediate is released from the active site during the catalytic cycle. 6-Fluorofarnesyl PP was designed and synthesized with the aim of arresting the cyclization-rearrangement mechanism en route to 5-epi-aristolochene. Indeed, incubation of (2E,6Z)-6-fluorofarnesyl PP with recombinant TEAS afforded (-)-1-fluororogermacrene A as the sole product in 58% yield. Steady-state kinetic experiments with farnesyl PP and the 6-fluoro analogue showed that the overall catalytic efficiencies (kcat/Km) are essentially the same for both substrates. 1-Fluorogermacrene A was characterized by chromatographic properties (TLC, GC), MS, optical rotation, UV, IR and 1H NMR data, and by heat-induced Cope rearrangement to (+)-1-fluoro-β-elemene. 1H NMR spectra at room temperature revealed that this (E,E)-configured fluorocyclodecadiene exists in solution as a 7:3 mixture of UU and UD conformers. 1-Fluorogermacrene A underwent trifluoroacetic acid-catalyzed cyclization to give three 1α-fluoroselinene isomers at a rate estimated to be about 1000 times slower than that of the similar cyclization of (+)-germacrene A to the parent selinenes. PMID:17886322
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Kelly, Christopher B; Patel, Niki R; Primer, David N; Jouffroy, Matthieu; Tellis, John C; Molander, Gary A
2017-03-01
Visible-light-activated photoredox catalysts provide synthetic chemists with the unprecedented capability to harness reactive radicals through discrete, single-electron transfer (SET) events. This protocol describes the synthesis of two transition metal complexes, [Ir{dF(CF 3 ) 2 ppy} 2 (bpy)]PF 6 (1a) and [Ru(bpy) 3 ](PF 6 ) 2 (2a), that are activated by visible light. These photoredox catalysts are SET agents that can be used to facilitate transformations ranging from proton-coupled electron-transfer-mediated cyclizations to C-C bond constructions, dehalogenations, and H-atom abstractions. These photocatalysts have been used in the synthesis of medicinally relevant compounds for drug discovery, as well as the degradation of biological polymers to access fine chemicals. These catalysts are prepared from IrCl 3 and RuCl 3 , respectively, in three chemical steps. These steps can be described as a series of two ligand modifications followed by an anion metathesis. Using the cost-effective, scalable procedures described here, the ruthenium-based photocatalyst 2a can be synthesized in a 78% overall yield (∼8.1 g), and the iridium-based photocatalyst 1a can be prepared in a 56% overall yield (∼4.4 g). The total time necessary for the complete protocols ranges from ∼2 d for 2a to 5-7 d for 1a. Procedures for applying each catalyst in representative photoredox/Ni cross-coupling to form C sp 3-C sp 2 bonds using the appropriate radical precursor-organotrifluoroborates with 1a and bis(catecholato)alkylsilicates with 2a-are described. In addition, more traditional photoredox-mediated transformations are included as diagnostic tests for catalytic activity.
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Reversal in the Size Dependence of Grain Rotation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Zhou, Xiaoling; Tamura, Nobumichi; Mi, Zhongying
The conventional belief, based on the Read-Shockley model for the grain rotation mechanism, has been that smaller grains rotate more under stress due to the motion of grain boundary dislocations. However, in our high-pressure synchrotron Laue x-ray microdiffraction experiments, 70 nm nickel particles are found to rotate more than any other grain size. We infer that the reversal in the size dependence of the grain rotation arises from the crossover between the grain boundary dislocation-mediated and grain interior dislocation-mediated deformation mechanisms. The dislocation activities in the grain interiors are evidenced by the deformation texture of nickel nanocrystals. This new findingmore » reshapes our view on the mechanism of grain rotation and helps us to better understand the plastic deformation of nanomaterials, particularly of the competing effects of grain boundary and grain interior dislocations.« less
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Reversal in the Size Dependence of Grain Rotation
Zhou, Xiaoling; Tamura, Nobumichi; Mi, Zhongying; ...
2017-03-01
The conventional belief, based on the Read-Shockley model for the grain rotation mechanism, has been that smaller grains rotate more under stress due to the motion of grain boundary dislocations. However, in our high-pressure synchrotron Laue x-ray microdiffraction experiments, 70 nm nickel particles are found to rotate more than any other grain size. We infer that the reversal in the size dependence of the grain rotation arises from the crossover between the grain boundary dislocation-mediated and grain interior dislocation-mediated deformation mechanisms. The dislocation activities in the grain interiors are evidenced by the deformation texture of nickel nanocrystals. This new findingmore » reshapes our view on the mechanism of grain rotation and helps us to better understand the plastic deformation of nanomaterials, particularly of the competing effects of grain boundary and grain interior dislocations.« less
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Lowell, Andrew N; DeMars, Matthew D; Slocum, Samuel T; Yu, Fengan; Anand, Krithika; Chemler, Joseph A; Korakavi, Nisha; Priessnitz, Jennifer K; Park, Sung Ryeol; Koch, Aaron A; Schultz, Pamela J; Sherman, David H
2017-06-14
Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification. Synthetic chemistry was employed to generate the tylactone hexaketide chain elongation intermediate that was accepted by the juvenimicin (Juv) ketosynthase of the penultimate JuvEIV PKS module. The hexaketide is processed through two complete modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and functionalization of two ketide units followed by cyclization of the resulting octaketide into tylactone. After macrolactonization, a combination of in vivo glycosylation, selective in vitro cytochrome P450-mediated oxidation, and chemical oxidation was used to complete the scalable construction of a series of macrolide natural products in as few as 15 linear steps (21 total) with an overall yield of 4.6%.
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Extensible Ontological Modeling Framefork for Subject Mediation
NASA Astrophysics Data System (ADS)
Kalinichenko, L. A.; Skvortsov, N. A.
An approach for extensible ontological model construction in a mediation environment intended for heterogeneous information sources integration in various subject domains is presented. A mediator ontological language (MOL) may depend on a subject domain and is to be defined at the mediator consolidation phase. On the other hand, for different information sources different ontological models (languages) can be used to define their own ontologies. Reversible mapping of the source ontological models into MOL is needed for information sources registration at the mediator. An approach for such reversible mapping is demonstrated for a class of the Web information sources. It is assumed that such sources apply the DAML+OIL ontological model. A subset of the hybrid object-oriented and semi-structured canonical mediator data model is used for the core of MOL. Construction of a reversible mapping of DAML+OIL into an extension of the core of MOL is presented in the paper. Such mapping is a necessary pre-requisite for contextualizing and registration of information sources at the mediator. The mapping shows how extensible MOL can be constructed. The approach proposed is oriented on digital libraries where retrieval is focused on information content, rather than on information entities.
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Choi, Isaac; Chung, Hyunho; Park, Jang Won; Chung, Young Keun
2016-11-04
A cobalt-rhodium heterobimetallic nanoparticle-catalyzed reductive cyclization of 2-(2-nitroaryl)acetonitriles to indoles has been achieved. The tandem reaction proceeds without any additives under the mild conditions (1 atm H 2 and 25 °C). This procedure could be scaled up to the gram scale. The catalytic system is significantly stable under these reaction conditions and could be reused more than ten times without loss of catalytic activity.
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NASA Astrophysics Data System (ADS)
Tittal, Ram Kumar
2018-03-01
CuCl/TMEDA-promoted halogen atom transfer radical cyclization (HATRC) of dichloroacetic acid 1-(3-methyl-but-2-enyl)-naphthalen-2-yl ester in refluxing DCE gave chlorine containing 7-member lactone 3-Chloro-2-(1-chloro-1-methyl-ethyl)-2,3-dihydro-1H-naphtho[2,1-b]oxepin-4-one via 7-exo trig radical cyclization reaction. The structure of the Lactone was confirmed by X-ray diffraction data.
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Hart-Cooper, William M.; Zhao, Chen; Triano, Rebecca M.; ...
2014-11-28
The effect of host structure on the selectivity and mechanism of intramolecular Prins reactions is evaluated using K 12Ga 4L 6 tetrahedral catalysts. The host structure was varied by modifying the structure of the chelating moieties and the size of the aromatic spacers. While variation in chelator substituents was generally observed to affect changes in rate but not selectivity, changing the host spacer afforded differences in efficiency and product diastereoselectivity. An extremely high number of turnovers (up to 840) was observed. Maximum rate accelerations were measured to be on the order of 10 5, which numbers among the largest magnitudesmore » of transition state stabilization measured with a synthetic host-catalyst. Host/guest size effects were observed to play an important role in host-mediated enantioselectivity.« less
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Oyaizu, Kenichi; Hayo, Noriko; Sasada, Yoshito; Kato, Fumiaki; Nishide, Hiroyuki
2013-12-07
Electrochemical reversibility and fast bimolecular exchange reaction found for VO(salen) gave rise to a highly efficient redox mediation to enhance the photocurrent of a dye-sensitized solar cell, leading to an excellent photovoltaic performance with a conversion efficiency of 5.4%. A heterogeneous electron-transfer rate constant at an electrode (k0) and a second-order rate constant for an electron self-exchange reaction (k(ex)) were proposed as key parameters that dominate the charge transport property, which afforded a novel design concept for the mediators based on their kinetic aspects.
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Wang, Jun; Ma, Yan; Li, Wen-Xue; Jiang, Ren-Wang; Cai, Shao-Hui
2016-01-01
Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is a major cause of cancer therapy failure. In this study, we identified a novel C21 steroidal glycoside, asclepiasterol, capable of reversing P-gp-mediated MDR. Asclepiasterol (2.5 and 5.0μM) enhanced the cytotoxity of P-gp substrate anticancer drugs in MCF-7/ADR and HepG-2/ADM cells. MDR cells were more responsive to paclitaxel in the presence of asclepiasterol, and colony formation of MDR cells was only reduced upon treatment with a combination of asclepiasterol and doxorubicin. Consistent with these findings, asclepiasterol treatment increased the intracellular accumulation of doxorubicin and rhodamine 123 (Rh123) in MDR cells. Asclepiasterol decreased expression of P-gp protein without stimulating or suppressing MDR1 mRNA levels. Asclepiasterol-mediated P-gp suppression caused inhibition of ERK1/2 phosphorylation in two MDR cell types, and EGF, an activator of the MAPK/ERK pathway, reversed the P-gp down-regulation, implicating the MAPK/ERK pathway in asclepiasterol-mediated P-gp down-regulation. These results suggest that asclepiasterol could be developed as a modulator for reversing P-gp-mediated MDR in P-gp-overexpressing cancer variants. PMID:27129170
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Yuan, Wei-Qi; Zhang, Rong-Rong; Wang, Jun; Ma, Yan; Li, Wen-Xue; Jiang, Ren-Wang; Cai, Shao-Hui
2016-05-24
Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is a major cause of cancer therapy failure. In this study, we identified a novel C21 steroidal glycoside, asclepiasterol, capable of reversing P-gp-mediated MDR. Asclepiasterol (2.5 and 5.0μM) enhanced the cytotoxity of P-gp substrate anticancer drugs in MCF-7/ADR and HepG-2/ADM cells. MDR cells were more responsive to paclitaxel in the presence of asclepiasterol, and colony formation of MDR cells was only reduced upon treatment with a combination of asclepiasterol and doxorubicin. Consistent with these findings, asclepiasterol treatment increased the intracellular accumulation of doxorubicin and rhodamine 123 (Rh123) in MDR cells. Asclepiasterol decreased expression of P-gp protein without stimulating or suppressing MDR1 mRNA levels. Asclepiasterol-mediated P-gp suppression caused inhibition of ERK1/2 phosphorylation in two MDR cell types, and EGF, an activator of the MAPK/ERK pathway, reversed the P-gp down-regulation, implicating the MAPK/ERK pathway in asclepiasterol-mediated P-gp down-regulation. These results suggest that asclepiasterol could be developed as a modulator for reversing P-gp-mediated MDR in P-gp-overexpressing cancer variants.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Alam, T.M.; Carpenter, J.P.; Dorhout, P.K.
1999-01-04
Intramolecular cyclizations during acid-catalyzed, sol-gel polymerizations of ct,co- bis(tietioxysilyl)aWmes substintidly lengtien gelties formonomers witietiylene- (l), propylene- (2), and butylene-(3)-bridging groups. These cyclizations reactions were found, using mass spectrometry and %i NMR spectroscopy, to lead preferentially to monomeric and dimeric products based on six and seven membered disilsesquioxane rings. 1,2- Bis(triethoxysilyl)ethane (1) reacts under acidic conditions to give a bicyclic drier (5) that is composed of two annelated seven membered rings. Under the same conditions, 1,3- bis(triethoxysilyl)propane (2), 1,4-bis(triethoxysilyl)butane (3), and z-1,4- bis(triethoxysilyl)but-2-ene (10) undergo an intramolecular condensation reaction to give the six membemd and seven membered cyclic disilsesquioxanes 6, 7,more » and 11. Subsequently, these cyclic monomers slowly react to form the tricyclic dirners 8,9 and 12. With NaOH as polymerization catalyst these cyclic silsesquioxanes readily ~aeted to afford gels that were shown by CP MAS z%i NMR and infr=d spectroscopes to retain some cyclic structures. Comparison of the porosity and microstructwe of xerogels prepared from the cyclic monomers 6 and 7 with gels prepared directly from their acyclic precursors 2 and 3, indicate that the final pore structure of the xerogels is markedly dependent on the nature of the precursor. In addition, despite the fact that the monomeric cyclic disilsesquioxane species can not be isolated from 1-3 under basic conditions due to their rapid rate of gelation, spectroscopic techniques also detected the presence of the cyclic structures in the resulting polymeric gels.« less
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Yamamura, Yoshimi; Taguchi, Yukari; Ichitani, Kei; Umebara, Io; Ohshita, Ayako; Kurosaki, Fumiya; Lee, Jung-Bum
2018-03-01
Gibberellins (GAs) are ubiquitous diterpenoids in higher plants, whereas some higher plants produce unique species-specific diterpenoids. In GA biosynthesis, ent-kaurene synthase (KS) and ent-kaurene oxidase (KO) are key players which catalyze early step(s) of the cyclization and oxidation reactions. We have studied the functional characterization of gene products of a KS (SdKS) and two KOs (SdKO1 and SdKO2) involved in GA biosynthesis in Scoparia dulcis. Using an in vivo heterologous expression system of Escherichia coli, we found that SdKS catalyzed a cyclization reaction from ent-CPP to ent-kaurene and that the SdKOs oxidized ent-kaurene to ent-kaurenoic acid after modification of the N-terminal region for adaptation to the E. coli expression system. The real-time PCR results showed that the SdKS, SdKO1 and SdKO2 genes were mainly expressed in the root and lateral root systems, which are elongating tissues. Based on these results, we suggest that these three genes may be responsible for the metabolism of GAs in S. dulcis.
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Non-Markovian closure kinetics of flexible polymers with hydrodynamic interactions.
Levernier, N; Dolgushev, M; Bénichou, O; Blumen, A; Guérin, T; Voituriez, R
2015-11-28
This paper presents a theoretical analysis of the closure kinetics of a polymer with hydrodynamic interactions. This analysis, which takes into account the non-Markovian dynamics of the end-to-end vector and relies on the preaveraging of the mobility tensor (Zimm dynamics), is shown to reproduce very accurately the results of numerical simulations of the complete nonlinear dynamics. It is found that Markovian treatments based on a Wilemski-Fixman approximation significantly overestimate cyclization times (up to a factor 2), showing the importance of memory effects in the dynamics. In addition, this analysis provides scaling laws of the mean first cyclization time (MFCT) with the polymer size N and capture radius b, which are identical in both Markovian and non-Markovian approaches. In particular, it is found that the scaling of the MFCT for large N is given by T ∼ N(3/2)ln(N/b(2)), which differs from the case of the Rouse dynamics where T ∼ N(2). The extension to the case of the reaction kinetics of a monomer of a Zimm polymer with an external target in a confined volume is also presented.
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Zhao, Xia; Zhang, Lipeng; Lu, Xiaoyu; Li, Tianjiao; Lu, Kui
2015-03-06
An efficient, metal-free protocol used to synthesize aryl benzo[b]furan thioethers based on the I2-catalyzed cross-coupling of benzo[b]furans as well as the electrophilic cyclization of 2-alkynylphenol derivatives with aryl sulfonyl hydrazides was developed. Various 2-aryl and 3-aryl benzo[b]furan thioethers were obtained in moderate to good yields.
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Sanjeeva, Shilpa Kammaradi; Korrapati, Swathi; Nair, Chandrasekhar B; Rao, P V Subba; Pullela, Phani Kumar; Vijayalakshmi, U; Siva, Ramamoorthy
2014-07-01
Donor-linker-acceptor (DSSA) is a concept in fluorescence chemistry with acceptor being a fluorescent compound (FRET) or quencher. The DSSA probes used to measure thiol levels in vitro and in vivo. The reduction potential of these dyes are in the range of -0.60 V, much lower than the best thiol reductant reported in literature, the DTT (-0.33 V). DSSA disulphide having an unusually low reduction potential compared to the typical thiol reductants is a puzzle. Secondly, DSSA probes have a cyclized rhodamine ring as acceptor which does not have any spectral overlap with fluorescein, but quenches its absorbance and fluorescence. To understand the structural features of DSSA probes, we have synthesized DSSANa and DSSAOr. The calculated reduction potential of these dyes suggest that DSSA probes have an alternate mechanism from the FRET based quenching, namely hydrophobic interaction or dye to dye quenching. The standard reduction potential change with increasing complexity and steric hindrance of the molecule is small, suggesting that ultra- low Eo' has no contribution from the disulphide linker and is based on structural interactions between fluorescein and cyclized rhodamine. Our results help to understand the DSSA probe quenching mechanism and provide ways to design fluorescent probes.
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Shichijo, Yoshihiro; Migita, Akira; Oguri, Hiroki; Watanabe, Mami; Tokiwano, Tetsuo; Watanabe, Kenji; Oikawa, Hideaki
2008-09-17
Polyether metabolites are an important class of natural products. Although their biosynthesis, especially construction of polyether skeletons, attracted organic chemists for many years, no experimental data on the enzymatic polyether formation has been obtained. In this study, a putative epoxide hydrolase gene lsd19 found on the biosynthetic gene cluster of an ionophore polyether lasalocid was cloned and successfully overexpressed in Escherichia coli. Using the purified Lsd19, a proposed substrate, bisepoxyprelasalocid, and its synthesized analogue were successfully converted into lasalocid A and its derivative via a 6-endo-tet cyclization mode. On the other hand, treatment of the bisepoxide with trichloroacetic acid gave isolasalocid A via a 5-exo-tet cyclization mode. Therefore, the enzymatic conversion observed in this study unambiguously showed that the bisepoxyprelasalocid is an intermediate of the lasalocid biosynthesis and that Lsd19 catalyzes the sequential cyclic ether formations involving an energetically disfavored 6-endo-tet cyclization. This is the first example of the enzymatic epoxide-opening reactions leading to a polyether natural product.
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Bisht, Rajesh; Singh, Saumya; Krishnamoorthy, Kothandam; Nithyanandhan, Jayaraj
2018-05-25
3',5'-Dimethoxybenzoin esters are important photoremovable protecting groups which form 2-phenylbenzofuran derivatives upon photo-release. We utilized a similar concept to test a photochemical method of installing a benzofuran moiety to the conjugated backbone by subjecting O-acetylated (3',5'-dimethylphenyl)heteroaryl acyloin derivatives through direct photo irradiation and a photo-induced electron transfer reaction. These photochemical methods were explored for a variety of heteroaromatic substrates appended on the ketone part of the O-acetylated cross-acyloin derivatives. The furan, thiophene and bithiophene derivatives led to the expected cyclized (benzofuran capped) products but the derivatives with extended conjugation decomposed under direct irradiation. However, under irradiation in the presence of an electron donor such as triethylamine, the extended acyloin derivatives afforded both cyclized and deacetoxylated products. The semiconducting nature of the extended cyclized products was also explored and tested for solution-processed organic field effect transistors, providing a maximum hole mobility of 1.3 × 10-6 cm2 V-1 s-1.
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NASA Astrophysics Data System (ADS)
Šoral, Michal; Markus, Jozef; Doháňošová, Jana; Šoralová, Stanislava; Dvoranová, Dana; Chyba, Andrej; Moncol, Ján; Berkeš, Dušan; Liptaj, Tibor
2017-01-01
Acid-catalyzed cyclization of spirocyclic 1‧-benzyl-2‧-(prop-2-en-1-yl)spiro[indole-3,3‧-pyrrolidine]-5‧-one (1) was performed. The pentacyclic product of Povarov-like imino-Diels-Alder reaction was isolated in high yield instead of expected tetracyclic aza-Prins intermediate. The unusual exotic alkaloid-type structure of the resulting molecule 2 was unambiguously confirmed by a detailed NMR analysis using a set of 2D NMR spectra including an INADEQUATE experiment. The relative configuration of 2 was predicted from the synthesis mechanism and DFT geometry calculations and independently confirmed using NOESY and residual dipolar coupling (RDC) assisted NMR analysis in stretched crosslinked polystyrene gels. The reversibility of the cycloaddition in aprotic solvents was observed. A new reaction pathway yielding a rare 6-5-5-5 tetracyclic spiroindoline 3 was suggested. The relative configuration within the tetracyclic framework was ultimately proved using Single-crystal X-ray diffraction analysis of compound 4.
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Selvakumar, Karuthapandi; Shah, Poonam; Singh, Harkesh B; Butcher, Ray J
2011-11-04
The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Hsu, Kean J; Beard, Courtney; Rifkin, Lara; Dillon, Daniel G; Pizzagalli, Diego A; Björgvinsson, Thröstur
2015-12-01
Deficits in attentional control have been hypothesized to cause rumination, suggesting that the relationships between attentional control and clinical symptoms may be mediated in part by rumination. However, to date, no clinical study has examined these constructs transdiagnostically in a path analysis model. Fifty-one adults presenting for treatment completed measures of self-reported attentional control, rumination, and depression and anxiety symptoms. A bias-corrected path analysis-based approach was employed to test whether indirect (i.e., mediating) effects of rumination were significantly associated with the direct effects of attentional control on depression and anxiety symptoms. Separate models for depression and anxiety symptoms were tested along with reverse models using attentional control as a proposed mediator. The relationship between attentional control and clinical symptomatology (i.e., both depression and anxiety symptoms) was mediated by rumination. Poor attentional control was associated with more rumination and consequently more severe symptoms of depression and anxiety. The reverse relationship (i.e., attentional control mediating the relationship between rumination and depression or anxiety symptoms) was not significant. Study design did not allow testing of temporal precedence for the mediation models. All constructs were assessed via self-report. Attentional control appears to impact depression and anxiety symptoms through rumination. The pathway between poor attentional control and emotion dysregulation via rumination suggests that interventions targeting attentional control may decrease maladaptive ruminative processes, leading to improved emotion regulation and reduced clinical symptomatology. Future studies should examine the stability of this mediational relationship over time (and in the face of targeted interventions). Copyright © 2015 Elsevier B.V. All rights reserved.
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Ng, Hooi Hooi; Leo, Chen Huei; Prakoso, Darnel; Qin, Chengxue; Ritchie, Rebecca H.; Parry, Laura J.
2017-01-01
Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis. PMID:28067255
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USDA-ARS?s Scientific Manuscript database
A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for detecting Sugarcane mosaic virus (SCMV) and Sorghum mosaic virus (SrMV) in sugarcane. Six sets of four primers corresponding to the conserved coat protein gene were designed for each virus and their succ...
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Weighting-Based Sensitivity Analysis in Causal Mediation Studies
ERIC Educational Resources Information Center
Hong, Guanglei; Qin, Xu; Yang, Fan
2018-01-01
Through a sensitivity analysis, the analyst attempts to determine whether a conclusion of causal inference could be easily reversed by a plausible violation of an identification assumption. Analytic conclusions that are harder to alter by such a violation are expected to add a higher value to scientific knowledge about causality. This article…
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Foster, Robert W; Tame, Christopher J; Hailes, Helen C; Sheppard, Tom D
2013-01-01
(Cyclooctadiene)(pentamethylcyclopentadiene)ruthenium chloride [Cp*RuCl(cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products. PMID:24124414
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Ito, Ryousuke; Nakada, Chika; Hoshino, Tsutomu
2017-01-18
Correction for 'β-Amyrin synthase from Euphorbia tirucalli L. functional analyses of the highly conserved aromatic residues Phe413, Tyr259 and Trp257 disclose the importance of the appropriate steric bulk, and cation-π and CH-π interactions for the efficient catalytic action of the polyolefin cyclization cascade' by Ryousuke Ito et al., Org. Biomol. Chem., 2017, 15, 177-188.
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Li, Yi; Xu, Ming-Hua
2014-05-16
The first Rh-catalyzed asymmetric tandem cyclization of nitrogen- or oxygen-bridged 5-alkynones with arylboronic acids was achieved. The simple catalytic system involving a rhodium(I) complex with readily available chiral BINAP ligand promotes the reaction to proceed in a highly stereocontrolled manner. This protocol provides a very reliable and practical access to a variety of chiral heterocyclic tertiary allylic alcohols possessing a tetrasubstituted carbon stereocenter and an all-carbon tetrasubstituted olefin functionality in good yields with great enantioselectivities up to 99% ee.
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Davies, Stephen G; Mujtaba, Nadeam; Roberts, Paul M; Smith, Andrew D; Thomson, James E
2009-05-07
Condensation of tert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide initiates a tandem conjugate addition/cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield. Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-N-alpha-methylbenzyl protecting groups without compromise of the diastereo- or enantiopurity.
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Wong, Fong T; Hotta, Kinya; Chen, Xi; Fang, Minyi; Watanabe, Kenji; Kim, Chu-Young
2015-01-14
Biosynthesis of some polyether natural products involves a kinetically disfavored epoxide-opening cyclic ether formation, a reaction termed anti-Baldwin cyclization. One such example is the biosynthesis of lasalocid A, an ionophore antibiotic polyether. During lasalocid A biosynthesis, an epoxide hydrolase, Lsd19, converts the bisepoxy polyketide intermediate into the tetrahydrofuranyl-tetrahydropyran product. We report the crystal structure of Lsd19 in complex with lasalocid A. The structure unambiguously shows that the C-terminal domain of Lsd19 catalyzes the intriguing anti-Baldwin cyclization. We propose a general mechanism for epoxide selection by ionophore polyether epoxide hydrolases.
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de Borba, Luana; Villordo, Sergio M; Iglesias, Nestor G; Filomatori, Claudia V; Gebhard, Leopoldo G; Gamarnik, Andrea V
2015-03-01
The dengue virus genome is a dynamic molecule that adopts different conformations in the infected cell. Here, using RNA folding predictions, chemical probing analysis, RNA binding assays, and functional studies, we identified new cis-acting elements present in the capsid coding sequence that facilitate cyclization of the viral RNA by hybridization with a sequence involved in a local dumbbell structure at the viral 3' untranslated region (UTR). The identified interaction differentially enhances viral replication in mosquito and mammalian cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Magnetization reversal assisted by half antivortex states in nanostructured circular cobalt disks
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lara, A.; Aliev, F. G., E-mail: farkhad.aliev@uam.es; Dobrovolskiy, O. V.
2014-11-03
The half antivortex, a fundamental topological structure which determines magnetization reversal of submicron magnetic devices with domain walls, has been suggested also to play a crucial role in spin torque induced vortex core reversal in circular disks. Here, we report on magnetization reversal in circular disks with nanoholes through consecutive metastable states with half antivortices. In-plane anisotropic magnetoresistance and broadband susceptibility measurements accompanied by micromagnetic simulations reveal that cobalt (Co) disks with two and three linearly arranged nanoholes directed at 45° and 135° with respect to the external magnetic field show reproducible step-like changes in the anisotropic magnetoresistance and magneticmore » permeability due to transitions between different intermediate states mediated by vortices and half antivortices confined to the dot nanoholes and edges, respectively. Our findings are relevant for the development of multi-hole based spintronic and magnetic memory devices.« less
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Mylne, Joshua S.; Chan, Lai Yue; Chanson, Aurelie H.; Daly, Norelle L.; Schaefer, Hanno; Bailey, Timothy L.; Nguyencong, Philip; Cascales, Laura; Craik, David J.
2012-01-01
The cyclic miniprotein Momordica cochinchinensis Trypsin Inhibitor II (MCoTI-II) (34 amino acids) is a potent trypsin inhibitor (TI) and a favored scaffold for drug design. We have cloned the corresponding genes and determined that each precursor protein contains a tandem series of cyclic TIs terminating with the more commonly known, and potentially ancestral, acyclic TI. Expression of the precursor protein in Arabidopsis thaliana showed that production of the cyclic TIs, but not the terminal acyclic TI, depends on asparaginyl endopeptidase (AEP) for maturation. The nature of their repetitive sequences and the almost identical structures of emerging TIs suggest these cyclic peptides evolved by internal gene amplification associated with recruitment of AEP for processing between domain repeats. This is the third example of similar AEP-mediated processing of a class of cyclic peptides from unrelated precursor proteins in phylogenetically distant plant families. This suggests that production of cyclic peptides in angiosperms has evolved in parallel using AEP as a constraining evolutionary channel. We believe this is evolutionary evidence that, in addition to its known roles in proteolysis, AEP is especially suited to performing protein cyclization. PMID:22822203
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Stapleton, P C; Dobson, A D W
2003-04-25
Cellobiose dehydrogenase (CDH) production in Trametes versicolor is induced in the presence of cellulose, but decreases when additional carbon sources such as glucose and maltose are added to the fungal cultures. Using T. versicolor-specific cdh primers in a reverse transcription-polymerase chain reaction-based approach, it appears that this repression in CDH production is being mediated at the level of gene transcription. When a 1.6-kb upstream region of the T. versicolor cdh gene was cloned and sequenced, a number of putative CreA-like binding sites were observed. We propose that these sites may be involved in mediating this repressive effect, based on their similarity to the consensus [5'-SYGGRGG-3'] site for binding of the CreA and Cre1 repressor proteins.
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Frazier, Brenda A; Williams, Valerie A; Wolczanski, Peter T; Bart, Suzanne C; Meyer, Karsten; Cundari, Thomas R; Lobkovsky, Emil B
2013-03-18
Molecular orbital analysis depicts the CNC(nb) backbone of the smif (1,3-di-(2-pyridyl)-2-azaallyl) ligand as having singlet diradical and/or ionic character where electrophilic or nucleophilic attack is plausible. Reversible dimerization of (smif)Fe{N(SiMe3)2} (1) to [{(Me3Si)2N}Fe]2(μ-κ(3),κ(3)-N,py2-smif,smif) (2) may be construed as diradical coupling. A proton transfer within the backbone-methylated, and o-pyridine-methylated smif of putative ((b)Me2(o)Me2smif)FeN(SiMe3)2 (8) provides a route to [{(Me3Si)2N}Fe]2(μ-κ(4),κ(4)-N,py2,C-((b)Me,(b)CH2,(o)Me2(smif)H))2 (9). A 3 + 2 cyclization of ditolyl-acetylene occurs with 1, leading to the dimer [{2,5-di(pyridin-2-yl)-3,4-di-(p-tolyl-2,5-dihydropyrrol-1-ide)}FeN(SiMe3)2]2 (11), and the collateral discovery of alkyne cyclotrimerization led to a brief study that identified Fe(N(SiMe3)2(THF) as an effective catalyst. Nucleophilic attack by (smif)2Fe (13) on (t)BuNCO and (2,6-(i)Pr2C6H3)NCO afforded (RNHCO-smif)2Fe (14a, R = (t)Bu; 14b, 2,6-(i)PrC6H3). Calculations suggested that (dpma)2Fe (15) would favorably lose dihydrogen to afford (smif)2Fe (13). H2-transfer to alkynes, olefins, imines, PhN═NPh, and ketones was explored, but only stoichiometric reactions were affected. Some physical properties of the compounds were examined, and X-ray structural studies on several dinuclear species were conducted.
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Moni, Lisa; Banfi, Luca; Basso, Andrea; Brambilla, Alice
2014-01-01
Summary An operationally simple protocol for the synthesis of 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones, based on an Ugi reaction of an ortho-(benzyloxy)benzylamine, glycolic acid, an isocyanide and an aldehyde, followed by an intramolecular Mitsunobu substitution was developed. The required ortho-(benzyloxy)benzylamines have been in situ generated from the corresponding azides, in turn prepared in high yields from salicylic derivatives. PMID:24605140
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John; Krohn; Florke; Aust; Draeger; Schulz
1999-09-01
Two known (1 and 2) and four new (3-6) diterpenes named oidiolactones A-F, respectively, and the antibiotic cladosporin were isolated from the fungus Oidiodendron truncata. The structure determination was mainly based on 1D and 2D NMR spectroscopy. The structures of compound 4, displaying an equilibrium between open-chain and cyclized form, and of cladosporin were confirmed by X-ray analysis.
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Fang, Zhongxue; Liu, Ying; Barry, Badru-Deen; Liao, Peiqiu; Bi, Xihe
2015-02-20
An atom-economic route to benzo[f]-1-indanone frameworks has been developed starting from the readily available gem-dialkylthio trienynes by intramolecular annulations. The chemoselectivity of the intramolecular cyclizations can be regulated by both the base and the type of gas atmosphere used in the reaction, thus allowing the divergent synthesis of the corresponding functionalized benzo[f]-1-indanones in good to excellent yields.
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Surface contact stimulates the just-in-time deployment of bacterial adhesins.
Li, Guanglai; Brown, Pamela J B; Tang, Jay X; Xu, Jing; Quardokus, Ellen M; Fuqua, Clay; Brun, Yves V
2012-01-01
The attachment of bacteria to surfaces provides advantages such as increasing nutrient access and resistance to environmental stress. Attachment begins with a reversible phase, often mediated by surface structures such as flagella and pili, followed by a transition to irreversible attachment, typically mediated by polysaccharides. Here we show that the interplay between pili and flagellum rotation stimulates the rapid transition between reversible and polysaccharide-mediated irreversible attachment. We found that reversible attachment of Caulobacter crescentus cells is mediated by motile cells bearing pili and that their contact with a surface results in the rapid pili-dependent arrest of flagellum rotation and concurrent stimulation of polar holdfast adhesive polysaccharide. Similar stimulation of polar adhesin production by surface contact occurs in Asticcacaulis biprosthecum and Agrobacterium tumefaciens. Therefore, single bacterial cells respond to their initial contact with surfaces by triggering just-in-time adhesin production. This mechanism restricts stable attachment to intimate surface interactions, thereby maximizing surface attachment, discouraging non-productive self-adherence, and preventing curing of the adhesive. © 2011 Blackwell Publishing Ltd.
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Kumar, K Shiva; Rambabu, D; Prasad, Bagineni; Mujahid, Mohammad; Krishna, G Rama; Rao, M V Basaveswara; Reddy, C Malla; Vanaja, G R; Kalle, Arunasree M; Pal, Manojit
2012-06-28
Regioselective construction of a fused 2-ylidene chromene ring was achieved for the first time by using AlCl(3)-induced C-C bond formation followed by Pd/C-Cu mediate coupling-cyclization strategy. A number of chromeno[4,3-b]quinoxaline derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound e.g. 6-(2,2-dimethylpropylidene)-4-methyl-6H-chromeno[4,3-b]quinoxalin-3-ol confirmed the presence of an exocyclic C-C double bond with Z-geometry. The crystal structure analysis and hydrogen bonding patterns of the same compound along with its structure elaboration via propargylation followed by Sonogashira coupling of the resulting terminal alkyne is presented. A probable mechanism for the formation of 2-ylidene chromene ring is discussed. Some of the compounds synthesized showed anticancer properties when tested in vitro.
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The role of ligand covalency in the selective activation of metalloenediynes for Bergman cyclization
Porter, Meghan R.; Zaleski, Jeffrey M.
2017-01-01
One of the key concerns with the development of radical-generating reactive therapeutics is the ability to control the activation event within a biological environment. To that end, a series of quinoline-metal-loenediynes of the form M(QuiED)·2Cl (M = Cu(II), Fe(II), Mg(II), or Zn(II)) and their independently synthesized cyclized analogs have been prepared in an effort to elucidate Bergman cyclization (BC) reactivity differences in solution. HRMS(ESI) establishes a solution stoichiometry of 1:1 metal to ligand with coordination of one chloride counter ion to the metal center. EPR spectroscopy of Cu(QuiED)·2Cl and Cu (QuiBD)·2Cl denotes an axially-elongated tetragonal octahedron (g║ > g⊥ > 2.0023) with a dx2–y2 ground state, while the electronic absorption spectrum reveals a pπ Cl→Cu(II) LMCT feature at 19,000 cm −1, indicating a solution structure with three nitrogens and a chloride in the equatorial plane with the remaining quinoline nitrogen and solvent in the axial positions. Investigations into the BC activity reveal formation of the cyclized product from the Cu(II) and Fe(II) complexes after 12 h at 45 °C in solution, while no product is observed for the Mg(II) or Zn(II) complexes under identical conditions. The basis of this reactivity difference has been found to be a steric effect leading to metal–ligand bond elongation and thus, a retardation of solution reactivity. These results demonstrate how careful consideration of ligand and complex structure may allow for a degree of control and selective activation of these reactive agents. PMID:28931964
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Porter, Meghan R; Zaleski, Jeffrey M
2016-01-08
One of the key concerns with the development of radical-generating reactive therapeutics is the ability to control the activation event within a biological environment. To that end, a series of quinoline-metal-loenediynes of the form M( QuiED )·2Cl (M = Cu(II), Fe(II), Mg(II), or Zn(II)) and their independently synthesized cyclized analogs have been prepared in an effort to elucidate Bergman cyclization (BC) reactivity differences in solution. HRMS(ESI) establishes a solution stoichiometry of 1:1 metal to ligand with coordination of one chloride counter ion to the metal center. EPR spectroscopy of Cu( QuiED )·2Cl and Cu ( QuiBD )·2Cl denotes an axially-elongated tetragonal octahedron ( g ║ > g ⊥ > 2.0023) with a d x 2 - y 2 ground state, while the electronic absorption spectrum reveals a pπ Cl→Cu(II) LMCT feature at 19,000 cm -1 , indicating a solution structure with three nitrogens and a chloride in the equatorial plane with the remaining quinoline nitrogen and solvent in the axial positions. Investigations into the BC activity reveal formation of the cyclized product from the Cu(II) and Fe(II) complexes after 12 h at 45 °C in solution, while no product is observed for the Mg(II) or Zn(II) complexes under identical conditions. The basis of this reactivity difference has been found to be a steric effect leading to metal-ligand bond elongation and thus, a retardation of solution reactivity. These results demonstrate how careful consideration of ligand and complex structure may allow for a degree of control and selective activation of these reactive agents.
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Poth, Aaron G; Colgrave, Michelle L; Philip, Reynold; Kerenga, Bomai; Daly, Norelle L; Anderson, Marilyn A; Craik, David J
2011-04-15
Cyclotides are plant proteins whose defining structural features are a head-to-tail cyclized backbone and three interlocking disulfide bonds, which in combination are known as a cyclic cystine knot. This unique structural motif confers cyclotides with exceptional resistance to proteolysis. Their endogenous function is thought to be as plant defense agents, associated with their insecticidal and larval growth-inhibitory properties. However, in addition, an array of pharmaceutically relevant biological activities has been ascribed to cyclotides, including anti-HIV, anthelmintic, uterotonic, and antimicrobial effects. So far, >150 cyclotides have been elucidated from members of the Rubiaceae, Violaceae, and Cucurbitaceae plant families, but their wider distribution among other plant families remains unclear. Clitoria ternatea (Butterfly pea) is a member of plant family Fabaceae and through its usage in traditional medicine to aid childbirth bears similarity to Oldenlandia affinis, from which many cyclotides have been isolated. Using a combination of nanospray and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) analyses, we examined seed extracts of C. ternatea and discovered cyclotides in the Fabaceae, the third-largest family of flowering plants. We characterized 12 novel cyclotides, thus expanding knowledge of cyclotide distribution and evolution within the plant kingdom. The discovery of cyclotides containing novel sequence motifs near the in planta cyclization site has provided new insights into cyclotide biosynthesis. In particular, MS analyses of the novel cyclotides from C. ternatea suggest that Asn to Asp variants at the cyclization site are more common than previously recognized. Moreover, this study provides impetus for the examination of other economically and agriculturally significant species within Fabaceae, now the largest plant family from which cyclotides have been described.
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Park, Hyeon; Kang, Eun-Hye; Müller, Laura; Choi, Tae-Lim
2016-02-24
Tandem ring-opening/ring-closing metathesis (RO/RCM) results in extremely fast living polymerization; however, according to previous reports, only monomers containing certain combinations of cycloalkenes, terminal alkynes, and nitrogen linkers successfully underwent tandem polymerization. After examining the polymerization pathways, we proposed that the relatively slow intramolecular cyclization might lead to competing side reactions such as intermolecular cross metathesis reactions to form inactive propagating species. Thus, we developed two strategies to enhance tandem polymerization efficiency. First, we modified monomer structures to accelerate tandem RO/RCM cyclization by enhancing the Thorpe-Ingold effect. This strategy increased the polymerization rate and suppressed the chain transfer reaction to achieve controlled polymerization, even for challenging syntheses of dendronized polymers. Alternatively, reducing the reaction concentration facilitated tandem polymerization, suggesting that the slow tandem RO/RCM cyclization step was the main reason for the previous failure. To broaden the monomer scope, we used monomers containing internal alkynes and observed that two different polymer units with different ring sizes were produced as a result of nonselective α-addition and β-addition on the internal alkynes. Thorough experiments with various monomers with internal alkynes suggested that steric and electronic effects of the alkyne substituents influenced alkyne addition selectivity and the polymerization reactivity. Further polymerization kinetics studies revealed that the rate-determining step of monomers containing certain internal alkynes was the six-membered cyclization step via β-addition, whereas that for other monomers was the conventional intermolecular propagation step, as observed in other chain-growth polymerizations. This conclusion agrees well with all those polymerization results and thus validates our strategies.
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Exploring the Influence of Domain Architecture on the Catalytic Function of Diterpene Synthases.
Pemberton, Travis A; Chen, Mengbin; Harris, Golda G; Chou, Wayne K W; Duan, Lian; Köksal, Mustafa; Genshaft, Alex S; Cane, David E; Christianson, David W
2017-04-11
Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as α, β, and γ. Catalysis by class I terpenoid synthases occurs exclusively in the α domain, which is found with α, αα, αβ, and αβγ domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, αβγ), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (αα) 6 ), and ophiobolin F synthase from Aspergillus clavatus (AcOS, αα). We show that the cyclization fidelity and catalytic efficiency of the α domain of TbTS are severely compromised by deletion of the βγ domains; however, retention of the β domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one α domain similarly influences catalysis by the other α domain [ Chen , M. , Chou , W. K. W. , Toyomasu , T. , Cane , D. E. , and Christianson , D. W. ( 2016 ) ACS Chem. Biol. 11 , 889 - 899 ]. Here, we show that the hexameric quaternary structure of PaFS enables cluster channeling. We also show that the α domains of PaFS and AcOS can be swapped so as to make functional chimeric αα synthases. Notably, both cyclization fidelity and catalytic efficiency are altered in all chimeric synthases. Twelve newly formed and uncharacterized C 20 diterpene products and three C 25 sesterterpene products are generated by these chimeras. Thus, engineered αβγ and αα terpenoid cyclases promise to generate chemodiversity in the greater family of terpenoid natural products.
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Sheinbaum, Tamara; Bifulco, Antonia; Ballespí, Sergi; Mitjavila, Mercè; Kwapil, Thomas R; Barrantes-Vidal, Neus
2015-01-01
Insecure attachment styles have received theoretical attention and some initial empirical support as mediators between childhood adverse experiences and psychotic phenomena; however, further specificity needs investigating. The present interview study aimed to examine (i) whether two forms of poor childhood care, namely parental antipathy and role reversal, were associated with subclinical positive and negative symptoms and schizophrenia-spectrum personality disorder (PD) traits, and (ii) whether such associations were mediated by specific insecure attachment styles. A total of 214 nonclinical young adults were interviewed for subclinical symptoms (Comprehensive Assessment of At-Risk Mental States), schizophrenia-spectrum PDs (Structured Clinical Interview for DSM-IV Axis II Disorders), poor childhood care (Childhood Experience of Care and Abuse Interview), and attachment style (Attachment Style Interview). Participants also completed the Beck Depression Inventory-II and all the analyses were conducted partialling out the effects of depressive symptoms. Both parental antipathy and role reversal were associated with subclinical positive symptoms and with paranoid and schizotypal PD traits. Role reversal was also associated with subclinical negative symptoms. Angry-dismissive attachment mediated associations between antipathy and subclinical positive symptoms and both angry-dismissive and enmeshed attachment mediated associations of antipathy with paranoid and schizotypal PD traits. Enmeshed attachment mediated associations of role reversal with paranoid and schizotypal PD traits. Attachment theory can inform lifespan models of how adverse developmental environments may increase the risk for psychosis. Insecure attachment provides a promising mechanism for understanding the development of schizophrenia-spectrum phenomenology and may offer a useful target for prophylactic intervention.
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Lu, Shun; Wang, Jing; Ye, Jixing; Zou, Yulong; Zhu, Yunxiao; Wei, Qiang; Wang, Xin; Tang, Shengli; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Farina, Evan M; Mohammed, Maryam M; Song, Dongzhe; Liao, Junyi; Huang, Jiayi; Guo, Dan; Lu, Minpeng; Liu, Feng; Liu, Jianxiang; Li, Li; Ma, Chao; Hu, Xue; Lee, Michael J; Reid, Russell R; Ameer, Guillermo A; Zhou, Dongsheng; He, Tongchuan
2016-01-01
Regenerative medicine and bone tissue engineering using mesenchymal stem cells (MSCs) hold great promise as an effective approach to bone and skeletal reconstruction. While adipose tissue harbors MSC-like progenitors, or multipotent adipose-derived cells (MADs), it is important to identify and characterize potential biological factors that can effectively induce osteogenic differentiation of MADs. To overcome the time-consuming and technically challenging process of isolating and culturing primary MADs, here we establish and characterize the reversibly immortalized mouse multipotent adipose-derived cells (iMADs). The isolated mouse primary inguinal MAD cells are reversibly immortalized via the retrovirus-mediated expression of SV40 T antigen flanked with FRT sites. The iMADs are shown to express most common MSC markers. FLP-mediated removal of SV40 T antigen effectively reduces the proliferative activity and cell survival of iMADs, indicating the immortalization is reversible. Using the highly osteogenic BMP9, we find that the iMADs are highly responsive to BMP9 stimulation, express multiple lineage regulators, and undergo osteogenic differentiation in vitro upon BMP9 stimulation. Furthermore, we demonstrate that BMP9-stimulated iMADs form robust ectopic bone with a thermoresponsive biodegradable scaffold material. Collectively, our results demonstrate that the reversibly immortalized iMADs exhibit the characteristics of multipotent MSCs and are highly responsive to BMP9-induced osteogenic differentiation. Thus, the iMADs should provide a valuable resource for the study of MAD biology, which would ultimately enable us to develop novel and efficacious strategies for MAD-based bone tissue engineering.
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Raman spectroscopic approach to monitor the in vitro cyclization of creatine → creatinine
NASA Astrophysics Data System (ADS)
Gangopadhyay, Debraj; Sharma, Poornima; Singh, Sachin Kumar; Singh, Pushkar; Tarcea, Nicolae; Deckert, Volker; Popp, Jürgen; Singh, Ranjan K.
2015-01-01
The creatine → creatinine cyclization, an important metabolic phenomenon has been initiated in vitro at acidic pH and studied through Raman spectroscopic and DFT approach. The equilibrium composition of neutral, zwitterionic and protonated microspecies of creatine has been monitored with time as the reaction proceeds. Time series Raman spectra show clear signature of creatinine formation at pH 3 after ∼240 min at room temperature and reaction is faster at higher temperature. The spectra at pH 1 and pH 5 do not show such signature up to 270 min implying faster reaction rate at pH 3.
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Mothia, Begum; Appleyard, Antony N; Wadman, Sjoerd; Tabor, Alethea B
2011-08-19
A methodology for the solid-phase synthesis of the overlapping lanthionine bridges found in many lantibiotics has been developed. A novel Teoc/TMSE-protected lanthionine derivative has been synthesized, and this lanthionine, and an Aloc/allyl-protected lanthionine derivative, have been incorporated into a linear peptide using solid-phase peptide synthesis. Selective deprotection of the silyl protecting groups, followed by sequential cyclization, deprotection of the allyl protecting groups, and further cyclization, enabled the regioselective formation of an analogue of rings D and E of nisin. © 2011 American Chemical Society
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Warner, Andrew J.; Churn, Anna; McGough, John S.
2016-01-01
Abstract BCl3‐induced borylative cyclization of aryl‐alkynes possessing ortho‐EMe (E=S, O) groups represents a simple, metal‐free method for the formation of C3‐borylated benzothiophenes and benzofurans. The dichloro(heteroaryl)borane primary products can be protected to form synthetically ubiquitous pinacol boronate esters or used in situ in Suzuki–Miyaura cross couplings to generate 2,3‐disubstituted heteroarenes from simple alkyne precursors in one pot. In a number of cases alkyne trans‐haloboration occurs alongside, or instead of, borylative cyclization and the factors controlling the reaction outcome are determined. PMID:27897368
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Oonishi, Yoshihiro; Yokoe, Takayuki; Hosotani, Akihito; Sato, Yoshihiro
2014-01-20
Rhodium(I)-catalyzed cyclization of allenynes with a tethered carbonyl group was investigated. An unusual insertion of a CO bond into the C(sp(2) )-rhodium bond of a rhodacycle intermediate occurs via a highly strained transition state. Direct reductive elimination from the obtained rhodacyle intermediate proceeds to give a tricyclic product containing an 8-oxabicyclo[3.2.1]octane skeleton, while β-hydride elimination from the same intermediate gives products that contain fused five- and seven-membered rings in high yields. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Ohmiya, Hirohisa; Tsuji, Takashi; Yorimitsu, Hideki; Oshima, Koichiro
2004-11-05
Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.
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An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function.
Li, Hao; Wang, Xu; Rukina, Daria; Huang, Qingyao; Lin, Tao; Sorrentino, Vincenzo; Zhang, Hongbo; Bou Sleiman, Maroun; Arends, Danny; McDaid, Aaron; Luan, Peiling; Ziari, Naveed; Velázquez-Villegas, Laura A; Gariani, Karim; Kutalik, Zoltan; Schoonjans, Kristina; Radcliffe, Richard A; Prins, Pjotr; Morgenthaler, Stephan; Williams, Robert W; Auwerx, Johan
2018-01-24
Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server (systems-genetics.org) to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipid metabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Increasing the sensitivity of reverse phase protein arrays by antibody-mediated signal amplification
2010-01-01
Background Reverse phase protein arrays (RPPA) emerged as a useful experimental platform to analyze biological samples in a high-throughput format. Different signal detection methods have been described to generate a quantitative readout on RPPA including the use of fluorescently labeled antibodies. Increasing the sensitivity of RPPA approaches is important since many signaling proteins or posttranslational modifications are present at a low level. Results A new antibody-mediated signal amplification (AMSA) strategy relying on sequential incubation steps with fluorescently-labeled secondary antibodies reactive against each other is introduced here. The signal quantification is performed in the near-infrared range. The RPPA-based analysis of 14 endogenous proteins in seven different cell lines demonstrated a strong correlation (r = 0.89) between AMSA and standard NIR detection. Probing serial dilutions of human cancer cell lines with different primary antibodies demonstrated that the new amplification approach improved the limit of detection especially for low abundant target proteins. Conclusions Antibody-mediated signal amplification is a convenient and cost-effective approach for the robust and specific quantification of low abundant proteins on RPPAs. Contrasting other amplification approaches it allows target protein detection over a large linear range. PMID:20569466
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Enantioselective cyclization of racemic supramolecular polymers.
ten Cate, A Tessa; Dankers, Patricia Y W; Kooijman, Huub; Spek, Anthony L; Sijbesma, Rint P; Meijer, E W
2003-06-11
Homochiral hydrogen-bonded cyclic assemblies are formed in dilute solutions of racemic supramolecular polymers based on the quadruple hydrogen bonding 2-ureido-4[1H]-pyrimidinone unit, as observed by 1H NMR and SEC experiments. Preorganization of the monomers and the combined binding strength of the eight hydrogen bonds result in a very high stability of the cyclic aggregates with pronounced selectivity between homochiral and heterochiral cyclic species, usually only observed in crystalline or liquid crystalline phases.
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Sexual and somatic development of wood frog tadpoles along a thermal gradient.
Lambert, Max R; Smylie, Meredith S; Roman, Amber J; Freidenburg, L Kealoha; Skelly, David K
2018-02-01
All amphibian species are known to have genetic sex determination. However, a variety of environmental conditions can moderate sexual differentiation, in some cases leading to sex reversal and skewed sex ratios. While there has been a recent focus on chemically-induced sex reversal in amphibians, temperature can also influence sexual differentiation. Building upon a classic 1929 study by Emil Witschi, we assessed temperature-mediated sex reversal. Witschi found that the wood frog sex ratio is 100% male at a high temperature (32°C) compared to a 50:50 sex ratio at 20°C. This pattern is consistent with multiple models of environmentally mediated sexual differentiation in vertebrates. To better understand thermally mediated sex reversal, we raised wood frogs at temperature increments of ∼1°C between 19 and 34°C. Mirroring earlier findings, wood frog metamorph sex ratios are indistinguishable from 50:50 at the lowest temperature and entirely male at the highest temperatures. In between, sex ratios become increasingly male-dominated as temperatures increase, implying a steadily increasing tendency toward female-to-male sex reversal in warmer environments. There was no evidence of a threshold temperature effect on reversal patterns. We also show that, compared to males, females metamorphose larger and later in cooler conditions but earlier and smaller under warmer conditions. While the ecological relevance in this species is unknown, these results conform to the Charnov-Bull model of sex determination (in which female-to-male sex reversal can increase fitness to genetic females at higher temperatures), suggesting the system would reward further study. © 2018 Wiley Periodicals, Inc.
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Huang, Mei-Han; Shen, Ai-Yu; Wang, Trey-Shy; Wu, Hui-Ming; Kang, Ya-Fei; Chen, Chia-Tai; Hsu, Tai-I; Chen, Bing-Shuo; Wu, Sheng-Nan
2011-02-04
Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH₃ pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH₃ cells bathed in a high-K(+), Ca(2+)-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K(+) current (I(K(erg))). Mtd suppressed the amplitude of I(K(erg)) in a concentration-dependent manner with an IC(50) value of 10.4 μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on I(K(erg)) was estimated with a dissociation constant of 8.2 μM. Mtd tended to increase the rate of I(K(erg)) deactivation in a voltage-dependent fashion. EDDP (10 μM) had no effect on I(K(erg)), while EMDP (10μM) slightly suppressed it. In GH₃ cells incubated with naloxone (30 μM), the Mtd-induced inhibition of I(K(erg)) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress I(K(erg)) in differentiated NG108-15 cells; dynorphin A(1-13) did not reverse Mtd-induced inhibition of I(K(erg)). This study shows that Mtd has a depressant effect on I(K(erg)), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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Discrimination Reversal Learning in Capuchin Monkeys ("Cebus apella")
ERIC Educational Resources Information Center
Beran, Michael J.; Klein, Emily D.; Evans, Theodore A.; Chan, Betty; Flemming, Timothy M.; Harris, Emily H.; Washburn, David A.; Rumbaugh, Duane M.
2008-01-01
Learning styles in capuchin monkeys were assessed with a computerized reversal-learning task called the mediational paradigm. First, monkeys were trained to respond with 90% accuracy on a two-choice discrimination (A+B-). Then the authors examined differences in performance on three different types of reversal trials (A-B+, A-C+, B+C-), each of…
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Siva Reddy, Alla; Kumara Swamy, K C
2015-06-19
A novel and efficient [Cu]-catalyzed one-pot regio- and stereospecific synthesis of benzo[1,4,2]dithiazine 1,1-dioxides and benzo[1,4,2]thiaselenazine 1,1-dioxides by cyclization of functionalized ynamides with elemental sulfur/selenium has been developed. Its generality is elegantly illustrated by extension to benzodithiazepines and benzothiaselenazepines. Involvement of water in the reaction is demonstrated by the incorporation of (2)D at the olefinic site by using D2O in place of water. Selective oxidation at sulfur in benzo[1,4,2]dithiazine 1,1-dioxide by using mCPBA as the oxidizing agent is also described.
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Design strategies of fluorescent probes for selective detection among biothiols.
Niu, Li-Ya; Chen, Yu-Zhe; Zheng, Hai-Rong; Wu, Li-Zhu; Tung, Chen-Ho; Yang, Qing-Zheng
2015-10-07
Simple thiol derivatives, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play key roles in biological processes, and the fluorescent probes to detect such thiols in vivo selectively with high sensitivity and fast response times are critical for understanding their numerous functions. However, the similar structures and reactivities of these thiols pose considerable challenges to the development of such probes. This review focuses on various strategies for the design of fluorescent probes for the selective detection of biothiols. We classify the fluorescent probes for discrimination among biothiols according to reaction types between the probes and thiols such as cyclization with aldehydes, conjugate addition-cyclization with acrylates, native chemical ligation, and aromatic substitution-rearrangement.
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Yao, Po-Hsin Eric; Kumar, Sunil; Liu, Yu-Li; Fang, Chiu-Ping; Liu, Chia-Chen; Sun, Chung-Ming
2017-04-10
Diversity-oriented synthesis of coumarin-linked benzimidazoles from N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded benzimidazoles which subsequently underwent a Knoevenagel condensation of the 2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole in acidic condition. Among the synthesized compounds, some were found to be promising inhibitors of porcine kidney d-amino acid oxidase (pkDAO).
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Warner, Andrew J; Churn, Anna; McGough, John S; Ingleson, Michael J
2017-01-02
BCl 3 -induced borylative cyclization of aryl-alkynes possessing ortho-EMe (E=S, O) groups represents a simple, metal-free method for the formation of C3-borylated benzothiophenes and benzofurans. The dichloro(heteroaryl)borane primary products can be protected to form synthetically ubiquitous pinacol boronate esters or used in situ in Suzuki-Miyaura cross couplings to generate 2,3-disubstituted heteroarenes from simple alkyne precursors in one pot. In a number of cases alkyne trans-haloboration occurs alongside, or instead of, borylative cyclization and the factors controlling the reaction outcome are determined. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Levitz, M; Perlman, D; Bogert, M T
1939-08-04
(1) Spirocyclohexane-1,1-indanone (VI) has been found among the oxidation products of the hydrocarbon mixture which results when 1-beta-phenylethylcyclohexanol-1 is dehydrated, or when 1-beta-phenylethylcyclohexene is cyclized by aluminum trichloride, and its constitution has been proved by synthesis (2) Its oxime melts at 137-137.8 degrees (corr.). The oxime of m.p. 187.5 degrees , reported by Cook et al. therefore must be derived from some other ketone, perhaps the trans-ketoöctahydrophenanthrene, since we were unable to isolate any oxime of m.p. 177 degrees , the figure which they reported for this compound.
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Wu, Long; Xu, Jun; Yuan, Weiqi; Wu, Baojian; Wang, Hao; Liu, Guangquan; Wang, Xiaoxiong; Du, Jun; Cai, Shaohui
2014-01-01
P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound. The in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer's instructions. 3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied. We demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells.
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Yuan, Weiqi; Wu, Baojian; Wang, Hao; Liu, Guangquan; Wang, Xiaoxiong; Du, Jun; Cai, Shaohui
2014-01-01
Purpose P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound. Methods The in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer’s instructions. Results 3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied. Conclusion We demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells. PMID:25372840
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Zhou, Xiaorong; Fan, Zili; Zhang, Zhiyin; Lu, Ping; Wang, Yanguang
2016-09-16
A cobalt(III)-catalyzed cross-coupling reaction of 1-(pyrimidin-2-yl)-1H-indoles with ketenimines is reported. The reaction provided 2-enaminylated indole derivatives in moderate to excellent yields with a broad substrate scope. The prepared 2-enaminylated indoles could be conveniently converted into pyrrolo[1,2-a]indoles, which are an important class of compounds in medicinal chemistry.
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Exploration of a Novel Persistent Reversal of Pathological Pain: Mechanisms and Mediators
2015-04-01
ability of a single IT ATL313 dose to reverse neuropathic pain from traumatic peripheral neuropathy . Milestone 2 is complete. We determined that 1 pmol...cord injury; to prevent and reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ...ATL313 can reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ) injections. We also
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Ying, Hanxiao; Wang, Jing; Shi, Ting; Zhao, Yilei; Wang, Xin; Ouyang, Pingkai; Chen, Kequan
2018-01-01
Lysine cyclodeaminase (LCD) catalyzes the piperidine ring formation in macrolide-pipecolate natural products metabolic pathways from a lysine substrate through a combination of cyclization and deamination. This enzyme belongs to a unique enzyme class, which uses NAD + as the catalytic prosthetic group instead of as the co-substrate. To understand the molecular details of NAD + functions in lysine cyclodeaminase, we have determined four ternary crystal structure complexes of LCD-NAD + with pipecolic acid (LCD-PA), lysine (LCD-LYS), and an intermediate (LCD-INT) as ligands at 2.26-, 2.00-, 2.17- and 1.80 Å resolutions, respectively. By combining computational studies, a NAD + -mediated "gate keeper" function involving NAD + /NADH and Arg49 that control the binding and entry of the ligand lysine was revealed, confirming the critical roles of NAD + in the substrate access process. Further, in the gate opening form, a substrate delivery tunnel between ε-carboxyl moiety of Glu264 and the α-carboxyl moiety of Asp236 was observed through a comparison of four structure complexes. The LCD structure details including NAD + -mediated "gate keeper" and substrate tunnel may assist in the exploration the NAD + function in this unique enzyme class, and in regulation of macrolide-pipecolate natural product synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.
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Inverted stereocontrol of iridoid synthase in snapdragon.
Kries, Hajo; Kellner, Franziska; Kamileen, Mohamed Omar; O'Connor, Sarah E
2017-09-01
The natural product class of iridoids, found in various species of flowering plants, harbors astonishing chemical complexity. The discovery of iridoid biosynthetic genes in the medicinal plant Catharanthus roseus has provided insight into the biosynthetic origins of this class of natural product. However, not all iridoids share the exact five- to six-bicyclic ring scaffold of the Catharanthus iridoids. For instance, iridoids in the ornamental flower snapdragon ( Antirrhinum majus , Plantaginaceae family) are derived from the C7 epimer of this scaffold. Here we have cloned and characterized the iridoid synthase enzyme from A. majus (AmISY), the enzyme that is responsible for converting 8-oxogeranial into the bicyclic iridoid scaffold in a two-step reduction-cyclization sequence. Chiral analysis of the reaction products reveals that AmISY reduces C7 to generate the opposite stereoconfiguration in comparison with the Catharanthus homologue CrISY. The catalytic activity of AmISY thus explains the biosynthesis of 7-epi-iridoids in Antirrhinum and related genera. However, although the stereoselectivity of the reduction step catalyzed by AmISY is clear, in both AmISY and CrISY, the cyclization step produces a diastereomeric mixture. Although the reduction of 8-oxogeranial is clearly enzymatically catalyzed, the cyclization step appears to be subject to less stringent enzyme control. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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El-Awaad, Islam; Bocola, Marco; Beuerle, Till; Liu, Benye; Beerhues, Ludger
2016-01-01
Xanthones are natural products present in plants and microorganisms. In plants, their biosynthesis starts with regioselective cyclization of 2,3′,4,6-tetrahydroxybenzophenone to either 1,3,5- or 1,3,7-trihydroxyxanthones, catalysed by cytochrome P450 (CYP) enzymes. Here we isolate and express CYP81AA-coding sequences from Hypericum calycinum and H. perforatum in yeast. Microsomes catalyse two consecutive reactions, that is, 3′-hydroxylation of 2,4,6-trihydroxybenzophenone and C–O phenol coupling of the resulting 2,3′,4,6-tetrahydroxybenzophenone. Relative to the inserted 3′-hydroxyl, the orthologues Hc/HpCYP81AA1 cyclize via the para position to form 1,3,7-trihydroxyxanthone, whereas the paralogue HpCYP81AA2 directs cyclization to the ortho position, yielding the isomeric 1,3,5-trihydroxyxanthone. Homology modelling and reciprocal mutagenesis reveal the impact of S375, L378 and A483 on controlling the regioselectivity of HpCYP81AA2, which is converted into HpCYP81AA1 by sextuple mutation. However, the reciprocal mutations in HpCYP81AA1 barely affect its regiospecificity. Product docking rationalizes the alternative C–O phenol coupling reactions. Our results help understand the machinery of bifunctional CYPs. PMID:27145837
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El-Awaad, Islam; Bocola, Marco; Beuerle, Till; Liu, Benye; Beerhues, Ludger
2016-05-05
Xanthones are natural products present in plants and microorganisms. In plants, their biosynthesis starts with regioselective cyclization of 2,3',4,6-tetrahydroxybenzophenone to either 1,3,5- or 1,3,7-trihydroxyxanthones, catalysed by cytochrome P450 (CYP) enzymes. Here we isolate and express CYP81AA-coding sequences from Hypericum calycinum and H. perforatum in yeast. Microsomes catalyse two consecutive reactions, that is, 3'-hydroxylation of 2,4,6-trihydroxybenzophenone and C-O phenol coupling of the resulting 2,3',4,6-tetrahydroxybenzophenone. Relative to the inserted 3'-hydroxyl, the orthologues Hc/HpCYP81AA1 cyclize via the para position to form 1,3,7-trihydroxyxanthone, whereas the paralogue HpCYP81AA2 directs cyclization to the ortho position, yielding the isomeric 1,3,5-trihydroxyxanthone. Homology modelling and reciprocal mutagenesis reveal the impact of S375, L378 and A483 on controlling the regioselectivity of HpCYP81AA2, which is converted into HpCYP81AA1 by sextuple mutation. However, the reciprocal mutations in HpCYP81AA1 barely affect its regiospecificity. Product docking rationalizes the alternative C-O phenol coupling reactions. Our results help understand the machinery of bifunctional CYPs.
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Inverted stereocontrol of iridoid synthase in snapdragon
Kries, Hajo; Kellner, Franziska; Kamileen, Mohamed Omar; O'Connor, Sarah E.
2017-01-01
The natural product class of iridoids, found in various species of flowering plants, harbors astonishing chemical complexity. The discovery of iridoid biosynthetic genes in the medicinal plant Catharanthus roseus has provided insight into the biosynthetic origins of this class of natural product. However, not all iridoids share the exact five- to six-bicyclic ring scaffold of the Catharanthus iridoids. For instance, iridoids in the ornamental flower snapdragon (Antirrhinum majus, Plantaginaceae family) are derived from the C7 epimer of this scaffold. Here we have cloned and characterized the iridoid synthase enzyme from A. majus (AmISY), the enzyme that is responsible for converting 8-oxogeranial into the bicyclic iridoid scaffold in a two-step reduction–cyclization sequence. Chiral analysis of the reaction products reveals that AmISY reduces C7 to generate the opposite stereoconfiguration in comparison with the Catharanthus homologue CrISY. The catalytic activity of AmISY thus explains the biosynthesis of 7-epi-iridoids in Antirrhinum and related genera. However, although the stereoselectivity of the reduction step catalyzed by AmISY is clear, in both AmISY and CrISY, the cyclization step produces a diastereomeric mixture. Although the reduction of 8-oxogeranial is clearly enzymatically catalyzed, the cyclization step appears to be subject to less stringent enzyme control. PMID:28701463
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Halim, Rosliana; Brimble, Margaret A; Merten, Jörn
2006-04-07
The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.
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Trzeciakiewicz, Anna; Fortin, Sébastien; Moreau, Emmanuel; C-Gaudreault, René; Lacroix, Jacques; Chambon, Christophe; Communal, Yves; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bouchon, Bernadette; Degoul, Françoise
2011-05-01
The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous N-phenyl-N'-(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEU subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G₂/M or G₁/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, N-phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two- to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results will be useful for the design of new prodrugs for cancer chemotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.
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Maiti, Dilip K; Debnath, Sudipto; Nawaz, Sk Masum; Dey, Bapi; Dinda, Enakhi; Roy, Dipanwita; Ray, Sudipta; Mallik, Abhijit; Hussain, Syed A
2017-10-17
A metal-free three component cyclization reaction with amidation is devised for direct synthesis of DFT-designed amido-phenazine derivative bearing noncovalent gluing interactions to fabricate organic nanomaterials. Composition-dependent organic nanoelectronics for nonvolatile memory devices are discovered using mixed phenazine-stearic acid (SA) nanomaterials. We discovered simultaneous two different types of nonmagnetic and non-moisture sensitive switching resistance properties of fabricated devices utilizing mixed organic nanomaterials: (a) sample-1(8:SA = 1:3) is initially off, turning on at a threshold, but it does not turn off again with the application of any voltage, and (b) sample-2 (8:SA = 3:1) is initially off, turning on at a sharp threshold and off again by reversing the polarity. No negative differential resistance is observed in either type. These samples have different device implementations: sample-1 is attractive for write-once-read-many-times memory devices, such as novel non-editable database, archival memory, electronic voting, radio frequency identification, sample-2 is useful for resistive-switching random access memory application.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Manna, Kuntal
The research presented and discussed in this dissertation involves the synthesis of transition metal complexes of oxazolinylboranes and cyclopentadienyl-bis(oxazolinyl)borates, and their application in catalytic enantioselective olefin hydroamination and acceptorless alcohol decarbonylation. Neutral oxazolinylboranes are excellent synthetic intermediates for preparing new borate ligands and also developing organometallic complexes. Achiral and optically active bis(oxazolinyl)phenylboranes are synthesized by reaction of 2-lithio-2-oxazolide and 0.50 equiv of dichlorophenylborane. These bis(oxazolinyl)phenylboranes are oligomeric species in solid state resulting from the coordination of an oxazoline to the boron center of another borane monomer. The treatment of chiral bis(oxazolinyl)phenylboranes with sodium cyclopentadienide provide optically active cyclopentadienyl-bis(oxazolinyl)borates H[PhB(C 5Hmore » 5)(Ox R) 2] [Ox R = Ox 4S-iPr,Me2, Ox 4R-iPr,Me2, Ox 4S-tBu]. These optically active proligands react with an equivalent of M(NMe 2) 4 (M = Ti, Zr, Hf) to afford corresponding cyclopentadienyl-bis(oxazolinyl)borato group 4 complexes {PhB(C 5H 4)(Ox R) 2}M(NMe 2) 2 in high yields. These group 4 compounds catalyze cyclization of aminoalkenes at room temperature or below, providing pyrrolidine, piperidine, and azepane with enantiomeric excesses up to 99%. Our mechanistic investigations suggest a non-insertive mechanism involving concerted C-N/C-H bond formation in the turnover limiting step of the catalytic cycle. Among cyclopentadienyl-bis(oxazolinyl)borato group 4 catalysts, the zirconium complex {PhB(C 5H 4)(Ox4 S-iPr,Me2) 2}Zr(NMe 2) 2 ({S-2}Zr(NMe 2) 2) displays highest activity and enantioselectivity. Interestingly, S-2Zr(NMe 2) 2 also desymmetrizes olefin moieties of achiral non-conjugated aminodienes and aminodiynes during cyclization. The cyclization of aminodienes catalyzed by S-2Zr(NMe 2) 2 affords diastereomeric mixture of cis and trans cylic amines with high diasteromeric ratios and excellent enantiomeric excesses. Similarly, the desymmetrization of alkyne moieties in S-2Zr(NMe 2) 2-catalyzed cyclization of aminodiynes provides corresponding cyclic imines bearing quaternary stereocenters with enantiomeric excesses up to 93%. These stereoselective desymmetrization reactions are significantly affected by concentration of the substrate, temperature, and the presence of a noncyclizable primary amine. In addition, both the diastereomeric ratios and enantiomeric excesses of the products are markedly enhanced by N-deuteration of the substrates. Notably, the cationic zirconium-monoamide complex [ S-2Zr(NMe 2)][B(C 6F 5) 4] obtained from neutral S-2Zr(NMe 2) 2 cyclizes primary aminopentenes providing pyrrolidines with S-configuration; whereas S-2Zr(NMe 2) 2 provides R-configured pyrrolidines. The yttrium complex S-2YCH 2SiMe 3 also affords S-configured pyrrolidines by cyclization of aminopentenes, however the enantiomeric excesses of products are low. An alternative optically active yttrium complex {PhB(C 5H 4)(Ox 4S-tBu) 2}YCH 2SiMe 3 ({S-3}YCH 2SiMe 3) is synthesized, which displays highly enantioselective in the cyclization of aminoalkenes at room temperature affording S-configured cyclic amines with enantiomeric excesses up to 96%. A noninsertive mechanism involving a six-membered transition state by a concerted C-N bond formation and N-H bond cleavage is proposed for {S-3}YCH 2SiMe 3 system based on the kinetic, spectroscopic, and stereochemical features. In the end, a series of bis- and tris(oxazolinyl)borato iridium and rhodium complexes are synthesized with bis(oxazolinyl)phenylborane [PhB(Ox Me2) 2] n, tris(oxazolinyl)borane [B(Ox M) 3]n, and tris(4,4-dimethyl-2-oxazolinyl)phenylborate [To M] -. All these new and other known rhodium and iridium complexes were examined in acceptorless dehydrogenative decarbonylation of primary alcohols. The catalysts survey shows that the compound To MIr(η 4- C 8H 12) is the most active for the conversion of primary alcohols into alkane, H 2, and CO at 180 °C in toluene. Several aliphatic and aromatic primary alcohols are decarbonylated in the catalytic conditions. Furthermore, To MIr(η 4-C 8H 12) is also able to decarbonylate polyols such as ethylene glycol and glycerol to syngas (H 2 and CO) at 180 °C.« less
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Liu, Xinyu; Walsh, Christopher T
2009-09-15
The fungal neurotoxin alpha-cyclopiazonic acid (CPA), a nanomolar inhibitor of Ca2+-ATPase, has a pentacyclic indole tetramic acid scaffold that arises from one molecule of tryptophan, acetyl-CoA, malonyl-CoA, and dimethylallyl pyrophosphate by consecutive action of three enzymes, CpaS, CpaD, and CpaO. CpaS is a hybrid, two module polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) that makes and releases cyclo-acetoacetyl-L-tryptophan (cAATrp), the tetramic acid that serves as substrate for subsequent prenylation and oxidative cyclization to the five ring CPA scaffold. The NRPS module in CpaS has a predicted four-domain organization of condensation, adenylation, thiolation, and reductase* (C-A-T-R*), where R* lacks the critical Ser-Tyr-Lys catalytic triad of the short chain dehydrogenase/reductase (SDR) superfamily. By heterologous overproduction in Escherichia coli of the 56 kDa Aspergillus flavus CpaS TR* didomain and the single T and R* domains, we demonstrate that CpaS catalyzes a Dieckmann-type cyclization on the N-acetoacetyl-Trp intermediate bound in thioester linkage to the phosphopantetheinyl arm of the T domain to form and release cAATrp. This occurs without any participation of NAD(P)H, so R* does not function as a canonical SDR family member. Use of the T and R* domains in in trans assays enabled multiple turnovers and evaluation of specific mutants. Mutation of the D3803 residue in the R* domain, conserved in other fungal tetramate synthetases, abolished activity both in in trans and in cis (TR*) activity assays. It is likely that cyclization of beta-ketoacylaminoacyl-S-pantetheinyl intermediates to released tetramates represents a default cyclization/release route for redox-incompetent R* domains embedded in NRPS assembly lines.
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Assessing activity of Hepatitis A virus 3C protease using a cyclized luciferase-based biosensor.
Zhou, Junwei; Wang, Dang; Xi, Yongqiang; Zhu, Xinyu; Yang, Yuting; Lv, Mengting; Luo, Chuanzhen; Chen, Jiyao; Ye, Xu; Fang, Liurong; Xiao, Shaobo
2017-07-08
Hepatitis A is an acute infection caused by Hepatitis A virus (HAV), which is widely distributed throughout the world. The HAV 3C cysteine protease (3C pro ), an important nonstructural protein, is responsible for most cleavage within the viral polyprotein and is critical for the processes of viral replication. Our group has previously demonstrated that HAV 3C pro cleaves human NF-κB essential modulator (NEMO), a kinase required in interferon signaling. Based on this finding, we generated four luciferase-based biosensors containing the NEMO sequence (PVLKAQ↓ADIYKA) that is cleaved by HAV 3C pro and/or the Nostoc punctiforme DnaE intein, to monitor the activity of HAV 3C pro in human embryonic kidney cells (HEK-293T). Western blotting showed that HAV 3C pro recognized and cleaved the NEMO cleavage sequence incorporated in the four biosensors, whereas only one cyclized luciferase-based biosensor (233-DnaE-HAV, 233DH) showed a measurable and reliable increase in firefly luciferase activity, with very low background, in the presence of HAV 3C pro . With this biosensor (233DH), we monitored HAV 3C pro activity in HEK-293T cells, and tested it against a catalytically deficient mutant HAV 3C pro and other virus-encoded proteases. The results showed that the activity of this luciferase biosensor is specifically dependent on HAV 3C pro . Collectively, our data demonstrate that the luciferase biosensor developed here might provide a rapid, sensitive, and efficient evaluation of HAV 3C pro activity, and should extend our better understanding of the biological relevance of HAV 3C pro . Copyright © 2017 Elsevier Inc. All rights reserved.
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Direct CRISPR spacer acquisition from RNA by a natural reverse-transcriptase-Cas1 fusion protein
Sidote, David J.; Markham, Laura M.; Sanchez-Amat, Antonio; Bhaya, Devaki; Lambowitz, Alan M.; Fire, Andrew Z.
2016-01-01
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) systems mediate adaptive immunity in diverse prokaryotes. CRISPR-associated Cas1 and Cas2 proteins have been shown to enable adaptation to new threats in Type I and II CRISPR systems by the acquisition of short segments of DNA (“spacers”) from invasive elements. In several Type III CRISPR systems, Cas1 is naturally fused to a reverse transcriptase (RT). In the marine bacterium Marinomonas mediterranea (MMB-1), we show that an RT-Cas1 fusion enables the acquisition of RNA spacers in vivo in an RT-dependent manner. In vitro, the MMB-1 RT-Cas1 and Cas2 proteins catalyze ligation of RNA segments into the CRISPR array, followed by reverse transcription. These observations outline a host-mediated mechanism for reverse information flow from RNA to DNA. PMID:26917774
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Tauzin, Sebastien; Starnes, Taylor W; Becker, Francisco Barros; Lam, Pui-ying; Huttenlocher, Anna
2014-12-08
Tissue damage induces early recruitment of neutrophils through redox-regulated Src family kinase (SFK) signaling in neutrophils. Redox-SFK signaling in epithelium is also necessary for wound resolution and tissue regeneration. How neutrophil-mediated inflammation resolves remains unclear. In this paper, we studied the interactions between macrophages and neutrophils in response to tissue damage in zebrafish and found that macrophages contact neutrophils and induce resolution via neutrophil reverse migration. We found that redox-SFK signaling through p22phox and Yes-related kinase is necessary for macrophage wound attraction and the subsequent reverse migration of neutrophils. Importantly, macrophage-specific reconstitution of p22phox revealed that macrophage redox signaling is necessary for neutrophil reverse migration. Thus, redox-SFK signaling in adjacent tissues is essential for coordinated leukocyte wound attraction and repulsion through pathways that involve contact-mediated guidance. © 2014 Tauzin et al.
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One- and two-photon states for quantum information
NASA Astrophysics Data System (ADS)
Peters, Nicholas A.
To find expression stability among transgenic lines, the Recombinase Mediated Transgene Integration (RMTI) technology using the Cre/ lox-mediated site-specific gene integration system was used. The objectives were to develop an efficient method of site-specific transgene integration and to test the effectiveness of this method by assaying transgene expression in the RMTI lines. The RMTI technology allows the precise integration of a transgene in a previously placed target genomic location containing a lox site. The efficiency of CRE-mediated site-specific integration in rice by particle bombardment was found to vary from 3 to 28% in nine different experiments. Some hemizygous site-specific integration plants that were derived from homozygous target locus were found to undergo CRE-mediated reversion of the integration locus. No reversion was observed in callus; however, reverting cells may have been excluded due to selection pressure. The expression of the transgene gus was studied in all 40 callus lines, 12 regenerated T0 plants and the T1 and T2 progenies of 5 lines. The isogenic SC lines had an average expression level based on the activity of beta-glucuronidase of 158 +/- 9 units/mg protein (mean +/- SEM; n=3; variance within SC lines are expressed as standard error of the mean SEM) indicating a significantly higher level of expression, as compared to MC lines that had a much lower expression level 44 +/- 8 units/mg protein (mean +/- SEM; n=3) and the imprecise lines that had 22 +/- 8 units/mg protein (mean +/- SEM; n=3). Transgene expression in the callus cells of precise single copy lines varied by ˜3 fold, whereas that in multi-copy lines varied by ˜30 fold. Furthermore, precise single copy lines, on an average, contained ˜3.5 fold higher expression than multi-copy lines. Transgene expression in the plants of precise single-copy lines was highly variable, which was found to be due to the loss of the integration because of CRE-mediated reversion in the locus. (Abstract shortened by UMI.)
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ERIC Educational Resources Information Center
Dodge, Tonya; Jaccard, James
2002-01-01
Compared sexual risk behavior of female athletes and nonathletes. Examined mediation, reverse mediation, spurious effects, and moderated causal models, using as potential mediators physical development, educational aspirations, self-esteem, attitudes toward pregnancy, involvement in a romantic relationship, age, ethnicity, and social class. Found…
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Identification and Characterization of Daurichromenic Acid Synthase Active in Anti-HIV Biosynthesis.
Iijima, Miu; Munakata, Ryosuke; Takahashi, Hironobu; Kenmoku, Hiromichi; Nakagawa, Ryuichi; Kodama, Takeshi; Asakawa, Yoshinori; Abe, Ikuro; Yazaki, Kazufumi; Kurosaki, Fumiya; Taura, Futoshi
2017-08-01
Daurichromenic acid (DCA) synthase catalyzes the oxidative cyclization of grifolic acid to produce DCA, an anti-HIV meroterpenoid isolated from Rhododendron dauricum We identified a novel cDNA encoding DCA synthase by transcriptome-based screening from young leaves of R. dauricum The gene coded for a 533-amino acid polypeptide with moderate homologies to flavin adenine dinucleotide oxidases from other plants. The primary structure contained an amino-terminal signal peptide and conserved amino acid residues to form bicovalent linkage to the flavin adenine dinucleotide isoalloxazine ring at histidine-112 and cysteine-175. In addition, the recombinant DCA synthase, purified from the culture supernatant of transgenic Pichia pastoris , exhibited structural and functional properties as a flavoprotein. The reaction mechanism of DCA synthase characterized herein partly shares a similarity with those of cannabinoid synthases from Cannabis sativa , whereas DCA synthase catalyzes a novel cyclization reaction of the farnesyl moiety of a meroterpenoid natural product of plant origin. Moreover, in this study, we present evidence that DCA is biosynthesized and accumulated specifically in the glandular scales, on the surface of R. dauricum plants, based on various analytical studies at the chemical, biochemical, and molecular levels. The extracellular localization of DCA also was confirmed by a confocal microscopic analysis of its autofluorescence. These data highlight the unique feature of DCA: the final step of biosynthesis is completed in apoplastic space, and it is highly accumulated outside the scale cells. © 2017 American Society of Plant Biologists. All Rights Reserved.
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Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase).
Rice, Amy J; Lei, Hao; Santarsiero, Bernard D; Lee, Hyun; Johnson, Michael E
2016-10-01
Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Müller, Thomas J J; Lessing, Timo; van Mark, Hauke
2018-05-04
Substituted 1H-1,2,3-triazol-4-yl-pyrrolo[2,3-b]pyridines are efficiently prepared by a one-pot coupling-cyclization-desilylation-CuAAC-sequence in the sense of a consecutive three-component fashion. The key feature of this novel de novo formation of azole and triazole anellation is the sequentially Pd/Cu-catalyzed process employing tri(iso-propyl)silylbutadiyne (TIPS-butadiyne) as a four-carbon building block. In addition, the sequence can be expanded in a four-component fashion also employing the in situ formation of the require azides. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Muldoon, Jake A; Varga, Balázs R; Deegan, Meaghan M; Chapp, Timothy W; Eördögh, Ádám M; Hughes, Russell P; Glueck, David S; Moore, Curtis E; Rheingold, Arnold L
2018-04-23
Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (S N 2) or racemization (S N 1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P-stereogenic syn-phosphiranes. DFT studies suggested that the novel stereochemistry results from acid-promoted tosylate dissociation to yield an intermediate phosphenium-bridged cation, which undergoes syn-selective cyclization. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Zirconium(IV)-Catalyzed Ring Opening of on-DNA Epoxides in Water.
Fan, Lijun; Davie, Christopher P
2017-05-04
DNA-encoded library technology (ELT) has spurred wide interest in the pharmaceutical industry as a powerful tool for hit and lead generation. In recent years a number of "DNA-compatible" chemical modifications have been published and used to synthesize vastly diverse screening libraries. Herein we report a newly developed, zirconium tetrakis(dodecyl sulfate) [Zr(DS) 4 ] catalyzed ring-opening of on-DNA epoxides in water with amines, including anilines. Subsequent cyclization of the resulting on-DNA β-amino alcohols leads to a variety of biologically interesting, nonaromatic heterocycles. Under these conditions, a library of 137 million on-DNA β-amino alcohols and their cyclization products was assembled. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Saadi, Jakub; Bentz, Christoph; Redies, Kai; Lentz, Dieter; Zimmer, Reinhold
2016-01-01
Summary Starting from γ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally defined the structure of crucial cyclization products. The relative configuration of the precursor compounds is essentially transferred to that of the products and the formed hydroxy group in the newly generated cyclohexane ring is consistently in trans-arrangement with respect to the methoxycarbonyl group. A transition-state model is proposed to explain the observed stereochemical outcome. This palladium-catalyzed Barbier-type reaction requires a reduction of palladium(II) back to palladium(0) which is apparently achieved by the present triethylamine. PMID:27559374
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Ichio, Hiroaki; Murakami, Hidetoshi; Chen, Yen-Chou; Takahashi, Tamotsu; Ogasawara, Masamichi
2017-07-21
A palladium-catalyzed reaction for preparing various endocyclic allenes was developed. The substrates for the reaction were readily available ω-(pronucleophile-tethered)-3-bromo-1,3-alkadienes, and a palladium-catalyst facilitated their unimolecular S N 2'-cyclization in the presence of potassium tert-butoxide to give the corresponding 9- to 16-membered endocyclic allenes in fair yields of up to 67% together with the dimeric 16- to 32-membered endocyclic bis-allenes and other oligomeric/polymeric intermolecular reaction products. For higher yields of the monomeric endocyclic allenes, the reaction needed to be conducted under high-dilution conditions. Using a chiral palladium catalyst, axially chiral endocyclic allenes were obtained in up to 70% ee.
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Boultwood, Tom; Affron, Dominic P.; Bull, James A.
2014-01-01
The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °Cin the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 °C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control. Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by 1H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by 1H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity. PMID:24893769
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Sahli, Rihab; Fave, Claire; Raouafi, Noureddine; Boujlel, Khaled; Schöllhorn, Bernd; Limoges, Benoît
2013-04-30
An in situ and real-time electrochemical method has been devised for quantitatively monitoring the self-assembly of a ferrocene-labeled cyclic disulfide derivative (i.e., a thioctic acid derivative) on a polycrystalline gold electrode under electrode polarization. Taking advantage of the high sensitivity, specificity, accuracy, and temporal resolution of this method, we were able to demonstrate an unexpectedly facilitated formation of the redox-active SAM when the electrode was held at a moderate cathodic potential (-0.4 V vs SCE in CH3CN), affording a saturated monolayer from only micromolar solutions in less than 10 min, and a totally impeded SAM growth when the electrode was polarized at a slightly anodic potential (+0.5 V vs SCE in CH3CN). This method literally allows for switching on/off the formation of SAMs under "soft" conditions. Moreover the cyclic disulfide-based SAM was completely desorbed at this potential contrary to the facilitated deposition of a ferrocene-labeled alkanethiol. Such a strikingly contrasting behavior could be explained by an energetically favored release of the thioctic-based SAM through homolytic cleavage of the Au-S bond followed by intramolecular cyclization of the generated thiyl diradicals. Moreover, the absence of a discernible transient faradaic current response during the potential-assisted adsorption/desorption of the redox-labeled cyclic disulfide led us to conclude in a potential-dependent reversible surface reaction where no electron is released or consumed. These results provide new insights into the formation of disulfide-based SAMs on gold but also raise some fundamental questions about the intimate mechanism involved in the facilitated adsorption/desorption of SAMs under electrode polarization. Finally, the possibility to easily and selectively address the formation/removal of thioctic-based SAMs on gold by applying a moderate cathodic/anodic potential offers another degree of freedom in tailoring their properties and in controlling their self-assembly, nanostructuration, and/or release.
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The neural bases of the effects of item-nonspecific proactive interference in working memory
POSTLE, BRADLEY R.; BRUSH, LAUREN N.
2005-01-01
We reanalyzed the behavioral and fMRI data from seven previously published studies of working memory in order to assess the behavioral and neural effects of item-nonspecific proactive interference (PI; attributable to the accrual of antecedent information independent of the repetition of particular items). We hypothesized that item-nonspecific PI, implicated in age-related declines in working memory performance, is mediated by the same mechanism(s) that mediate item-specific PI (occurring when an invalid memory probe matches a memorandum from the previous trial). Reaction time increased across trials as a function of position within the block, a trend that reversed across the duration of each multiblock experiment. The fMRI analyses revealed sensitivity to item-nonspecific PI during the probe epoch in the left anterior inferior frontal gyrus and the left dorsolateral prefrontal cortex (PFC). They also revealed a negative trend, across trials, in the transient probe-evoked component of the global signal. A common PFC-based mechanism may mediate many forms of PI. PMID:15535173
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The neural bases of the effects of item-nonspecific proactive interference in working memory.
Postle, Bradley R; Brush, Lauren N
2004-09-01
We reanalyzed the behavioral and fMRI data from seven previously published studies of working memory in order to assess the behavioral and neural effects of item-nonspecific proactive interference (PI; attributable to the accrual of antecedent information independent of the repetition of particular items). We hypothesized that item-nonspecific PI, implicated in age-related declines in working memory performance, is mediated by the same mechanism(s) that mediate item-specific PI (occurring when an invalid memory probe matches a memorandum from the previous trial). Reaction time increased across trials as a function of position within the block, a trend that reversed across the duration of each multiblock experiment. The fMRI analyses revealed sensitivity to item-nonspecific PI during the probe epoch in the left anterior inferior frontal gyrus and the left dorsolateral prefrontal cortex(PFC). They also revealed a negative trend, across trials, in the transient probe-evoked component of the global signal. A common PFC-based mechanism may mediate many forms of PI.
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Chen, Xi; Yip, Ngai Yin
2018-02-20
Current practice of using thermally driven methods to treat hypersaline brines is highly energy-intensive and costly. While conventional reverse osmosis (RO) is the most efficient desalination technique, it is confined to purifying seawater and lower salinity sources. Hydraulic pressure restrictions and elevated energy demand render RO unsuitable for high-salinity streams. Here, we propose an innovative cascading osmotically mediated reverse osmosis (COMRO) technology to overcome the limitations of conventional RO. The innovation utilizes the novel design of bilateral countercurrent reverse osmosis stages to depress the hydraulic pressure needed by lessening the osmotic pressure difference across the membrane, and simultaneously achieve energy savings. Instead of the 137 bar required by conventional RO to desalinate 70 000 ppm TDS hypersaline feed, the highest operating pressure in COMRO is only 68.3 bar (-50%). Furthermore, up to ≈17% energy saving is attained by COMRO (3.16 kWh/m 3 , compared to 3.79 kWh/m 3 with conventional RO). When COMRO is employed to boost the recovery of seawater desalination to 70% from the typical 35-50%, energy savings of up to ≈33% is achieved (2.11 kWh/m 3 , compared to 3.16 kWh/m 3 with conventional RO). Again, COMRO can operate at a moderate hydraulic pressure of 80 bar (25% lower than 113 bar of conventional RO). This study highlights the encouraging potential of energy-efficient COMRO to access unprecedented high recovery rates and treat hypersaline brines at moderate hydraulic pressures, thus extending the capabilities of membrane-based technologies for high-salinity desalination.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Napper, Scott; Prasad, Lata; Delbaere, Louis T.J.
2008-09-08
Aspartates and asparagines can spontaneously cyclize with neighboring main-chain amides to form succinimides. These succinimides hydrolyze to a mixture of isoaspartate and aspartate products. Phosphorylation of aspartates is a common mechanism of protein regulation and increases the propensity for succinimide formation. Although typically regarded as a form of protein damage, we hypothesize succinimides could represent an effective mechanism of phosphoaspartate autophosphatase activity, provided hydrolysis is limited to aspartate products. We previously reported the serendipitous creation of a protein, His15Asp histidine-containing protein (HPr), which undergoes phosphorylation-catalyzed formation of a succinimide whose hydrolysis is seemingly exclusive for aspartate formation. Here, through themore » high-resolution structure of postsuccinimide His15Asp HPr, we confirm the absence of isoaspartate residues and propose mechanisms for phosphorylation-catalyzed succinimide formation and its directed hydrolysis to aspartate. His15Asp HPr represents the first characterized protein example of an isoaspartate-free succinimide and lends credence to the hypothesis that intramolecular cyclization could represent a physiological mechanism of autophosphatase activity. Furthermore, this indicates that current strategies for succinimide evaluation, based on isoaspartate detection, underestimate the frequencies of these reactions. This is considerably significant for evaluation of protein stability and integrity.« less
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Template-constrained macrocyclic peptides prepared from native, unprotected precursors
Lawson, Kenneth V.; Rose, Tristan E.; Harran, Patrick G.
2013-01-01
Peptide–protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. PMID:24043790
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NASA Astrophysics Data System (ADS)
Kugel, Susann; Baunach, Martin; Baer, Philipp; Ishida-Ito, Mie; Sundaram, Srividhya; Xu, Zhongli; Groll, Michael; Hertweck, Christian
2017-06-01
Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.
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Electric-Field-Induced Magnetization Reversal in a Ferromagnet-Multiferroic Heterostructure
NASA Astrophysics Data System (ADS)
Heron, J. T.; Trassin, M.; Ashraf, K.; Gajek, M.; He, Q.; Yang, S. Y.; Nikonov, D. E.; Chu, Y.-H.; Salahuddin, S.; Ramesh, R.
2011-11-01
A reversal of magnetization requiring only the application of an electric field can lead to low-power spintronic devices by eliminating conventional magnetic switching methods. Here we show a nonvolatile, room temperature magnetization reversal determined by an electric field in a ferromagnet-multiferroic system. The effect is reversible and mediated by an interfacial magnetic coupling dictated by the multiferroic. Such electric-field control of a magnetoelectric device demonstrates an avenue for next-generation, low-energy consumption spintronics.
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Electric-field-induced magnetization reversal in a ferromagnet-multiferroic heterostructure.
Heron, J T; Trassin, M; Ashraf, K; Gajek, M; He, Q; Yang, S Y; Nikonov, D E; Chu, Y-H; Salahuddin, S; Ramesh, R
2011-11-18
A reversal of magnetization requiring only the application of an electric field can lead to low-power spintronic devices by eliminating conventional magnetic switching methods. Here we show a nonvolatile, room temperature magnetization reversal determined by an electric field in a ferromagnet-multiferroic system. The effect is reversible and mediated by an interfacial magnetic coupling dictated by the multiferroic. Such electric-field control of a magnetoelectric device demonstrates an avenue for next-generation, low-energy consumption spintronics.
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Kleijn, Huub J; Zollinger, Daniel P; van den Heuvel, Michiel W; Kerbusch, Thomas
2011-01-01
AIMS An integrated population pharmacokinetic–pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic–pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODS Data (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTS Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg−1 3 min after rocuronium, sugammadex 4 mg kg−1 during deep neuromuscular blockade and sugammadex 2 mg kg−1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONS Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min. PMID:21535448
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A highly selective fluorescent probe based on coumarin for the imaging of N2H4 in living cells
NASA Astrophysics Data System (ADS)
Chen, Song; Hou, Peng; Wang, Jing; Liu, Lei; Zhang, Qi
2017-02-01
A turn-on fluorescence probe for highly sensitive and selective detection of N2H4 was developed based on hydrazine-triggered a substitution- cyclization-elimination cascade. Upon the treatment with N2H4, probe 1, 4-methyl-coumarin-7-yl bromobutanoate, displayed a remarkable fluorescence enhancement (25-fold) with a maximum at 450 nm. This probe can quantitatively detect N2H4 with a extremely low detection limit as 7 × 10- 8 M. Moreover, cell imaging experiments have indicated that probe 1 has potential ability to detect and image N2H4 in biological systems.
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Kurosaki, Yohei; Magassouba, N’Faly; Oloniniyi, Olamide K.; Cherif, Mahamoud S.; Sakabe, Saori; Takada, Ayato; Hirayama, Kenji; Yasuda, Jiro
2016-01-01
Given the current absence of specific drugs or vaccines for Ebola virus disease (EVD), rapid, sensitive, and reliable diagnostic methods are required to stem the transmission chain of the disease. We have developed a rapid detection assay for Zaire ebolavirus based on reverse transcription-loop-mediated isothermal amplification (RT-LAMP) and coupled with a novel portable isothermal amplification and detection platform. The RT-LAMP assay is based on primer sets that target the untranscribed trailer region or nucleoprotein coding region of the viral RNA. The test could specifically detect viral RNAs of Central and West African Ebola virus strains within 15 minutes with no cross-reactivity to other hemorrhagic fever viruses and arboviruses, which cause febrile disease. The assay was evaluated using a total of 100 clinical specimens (serum, n = 44; oral swab, n = 56) collected from suspected EVD cases in Guinea. The specificity of this diagnostic test was 100% for both primer sets, while the sensitivity was 100% and 97.9% for the trailer and nucleoprotein primer sets, respectively, compared with a reference standard RT-PCR test. These observations suggest that our diagnostic assay is useful for identifying EVD cases, especially in the field or in settings with insufficient infrastructure. PMID:26900929
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Kurosaki, Yohei; Magassouba, N'Faly; Oloniniyi, Olamide K; Cherif, Mahamoud S; Sakabe, Saori; Takada, Ayato; Hirayama, Kenji; Yasuda, Jiro
2016-02-01
Given the current absence of specific drugs or vaccines for Ebola virus disease (EVD), rapid, sensitive, and reliable diagnostic methods are required to stem the transmission chain of the disease. We have developed a rapid detection assay for Zaire ebolavirus based on reverse transcription-loop-mediated isothermal amplification (RT-LAMP) and coupled with a novel portable isothermal amplification and detection platform. The RT-LAMP assay is based on primer sets that target the untranscribed trailer region or nucleoprotein coding region of the viral RNA. The test could specifically detect viral RNAs of Central and West African Ebola virus strains within 15 minutes with no cross-reactivity to other hemorrhagic fever viruses and arboviruses, which cause febrile disease. The assay was evaluated using a total of 100 clinical specimens (serum, n = 44; oral swab, n = 56) collected from suspected EVD cases in Guinea. The specificity of this diagnostic test was 100% for both primer sets, while the sensitivity was 100% and 97.9% for the trailer and nucleoprotein primer sets, respectively, compared with a reference standard RT-PCR test. These observations suggest that our diagnostic assay is useful for identifying EVD cases, especially in the field or in settings with insufficient infrastructure.
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Hasanin, Tamer H A; Okamoto, Yasuaki; Fujiwara, Terufumi
2016-02-01
A rapid and sensitive flow method, based on the combination of on-line solvent extraction with reversed micellar mediated chemiluminescence (CL) detection using rhodamine B (RB), was investigated for the selective determination of Au(III) and Ga(III) in aqueous solutions. 2.0 M HCl was the optimum for extracting Au(III) while a 5.0M HCl solution containing 2.5M LiCl was selected as an optimum acidic medium for extraction of Ga(III). The Au(III) and Ga(III) chloro-complex anions were extracted from the above aqueous acidic solutions into toluene as their ion-pair complexes with the protonated RBH(+) ion followed by membrane phase separation in a flow system. In a flow cell of a detector, the extract was mixed with the reversed micellar solution of cetyltrimethylammonium chloride (CTAC) in 1-hexanol-cyclohexane/water (1.0M HCl) containing 0.10 M cerium(IV) and 0.05 M lithium sulfate. Then uptake of the ion-pair by the CTAC reversed micelles and the subsequent CL oxidation of RB with Ce(IV) occurred easily and the CL signals produced were recorded. Using a flow injection system, a detection limit (DL) of 0.4 μM Au(III) and 0.6 μM Ga(III), and linear calibration graphs with dynamic ranges from the respective DLs to 10 μM for Au(III) and Ga(III) were obtained under the optimized experimental conditions. The relative standard deviations (n=6) obtained at 2.0 µM Au(III) and 4.0 µM Ga(III) were 3.0% and 2.4%, respectively. The presented CL methodology has been applied for the determination of Au(III) and Ga(III) in water and industrial samples with satisfactory results. Copyright © 2015 Elsevier B.V. All rights reserved.
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Guo, Xu-Guang; Zhou, Yong-Zhuo; Li, Qin; Wang, Wei; Wen, Jin-Zhou; Zheng, Lei; Wang, Qian
2018-04-18
To detect Zika virus more rapidly and accurately, we developed a novel method that utilized a real-time fluorescence reverse transcription loop-mediated isothermal amplification (LAMP) technique. The NS5 gene was amplified by a set of six specific primers that recognized six distinct sequences. The amplification process, including 60 min of thermostatic reaction with Bst DNA polymerase following real-time fluorescence reverse transcriptase using genomic Zika virus standard strain (MR766), was conducted through fluorescent signaling. Among the six pairs of primers that we designate here, NS5 was the most efficient with a high sensitivity of up to 3.3 ng/μl and reproducible specificity on eight pathogen samples that were used as negative controls. The real-time fluorescence reverse transcription LAMP detection process can be completed within 35 min. Our study demonstrated that real-time fluorescence reverse transcription LAMP could be highly beneficial and convenient clinical application to detect Zika virus due to its high specificity and stability.
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HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal
Wu, Guoxin; Swanson, Michael; Talla, Aarthi; Graham, Donald; Strizki, Julie; Gorman, Daniel; Barnard, Richard J.O.; Blair, Wade; Søgaard, Ole S.; Tolstrup, Martin; Østergaard, Lars; Rasmussen, Thomas A.; Sekaly, Rafick-Pierre; Archin, Nancie M.; Hazuda, Daria J.; Howell, Bonnie J.
2017-01-01
Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3 bispecific antibody. These findings extend beyond classical nucleic acid endpoints, which are confounded by the predominance of mutated, defective proviruses and, of paramount importance, enable assessment of cells making HIV protein that can now be targeted by immunological approaches. PMID:28814661
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NASA Technical Reports Server (NTRS)
Behringer, F. J.; Lomax, T. L.
1999-01-01
The lz-2 mutation in tomato (Lycopersicon esculentum) causes conditional reversal of shoot gravitropism by light. This response is mediated by phytochrome. To further elicit the mechanism by which phytochrome regulates the lz-2 phenotype, phytochrome-deficient lz-2 plants were generated. Introduction of au alleles, which severely block chromophore biosynthesis, eliminated the reversal of hypocotyl gravitropism in continuous red and far-red light. The fri1 and tri1 alleles were introduced to specifically deplete phytochromes A and B1, respectively. In dark-grown seedlings, phytochrome A was necessary for response to high-irradiance far-red light, a complete response to low fluence red light, and also mediated the effects of blue light in a far-red reversible manner. Loss of phytochrome B1 alone did not significantly affect the behaviour of lz-2 plants under any light treatment tested. However, dark-grown lz-2 plants lacking both phytochrome A and B1 exhibited reduced responses to continuous red and were less responsive to low fluence red light and high fluence blue light than plants that were deficient for phytochrome A alone. In high light, full spectrum greenhouse conditions, lz-2 plants grew downward regardless of the phytochrome deficiency. These results indicate that phytochromes A and B1 play significant roles in mediating the lz-2 phenotype and that at least one additional phytochrome is involved in reversing shoot gravitropism in this mutant.
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Shibahara, Fumitoshi; Kobayashi, Shun-ichiro; Maruyama, Toshifumi; Murai, Toshiaki
2013-01-02
Addition reactions of thioamide dianions that were derived from N-arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N-thioacyl-1,2-diamines in a highly diastereoselective manner in good-to-excellent yields. The diastereomeric purity of these N-thioacyl-1,2-diamines could be enriched by simple recrystallization. The reduction of N-thioacyl-1,2-diamines with LiAlH(4) gave their corresponding 1,2-diamines in moderate-to-good yields with retention of their stereochemistry. The oxidative-desulfurization/cyclization of an N-thioacyl-1,2-diamine in CuCl(2)/O(2) and I(2)/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N-tosylaziridines gave the addition products of N-thioacyl-1,3-diamines with low diastereoselectivity but high regioselectivity and in good-to-excellent yields. The use of AlMe(3) as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X-ray diffraction. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Wang, Jinpeng; Wei, Ren; Tian, Yaoqi; Yang, Na; Xu, Xueming; Zimmermann, Wolfgang; Jin, Zhengyu
2015-05-20
Large-ring cyclodextrins (LR-CDs) have a number of intriguing properties for potential use in pharmaceutical and food industry. To date, no colorimetric method has been reported for LR-CD content quantification. In this study, triple wavelength colorimetry (TWC) and orthogonal-function spectrophotometry (OFS) have been successfully applied to determine ingredient concentrations in a mixture of amylose and LR-CDs. Both TWC and OFS yielded precise amylose content data in good agreement with expected values. For quantification of LR-CD content, OFS provided a higher accuracy than TWC, which resulted in a slight over-determination. As a comparison, single-wavelength colorimetry performed at the corresponding absorption maximum led to a significant over-determination of both amylose and LR-CD contents. The validity of TWC and OFS allowed their application for discriminative detection of the cyclization and total activity of a 4-α-glucanotransferase (4 αGTase) from Thermus aquaticus regarding the synthesis of LR-CDs and the conversion of amylose to small molecules, respectively. High pressure size exclusion chromatography analysis of the post-reaction mixtures following 4 αGTase-catalyzed conversion of amylose revealed the presence of linear malto-oligosaccharides in the LR-CD fraction. By introduction of a correction factor, the interference caused by linear malto-oligosaccharides was eliminated for a more accurate determination of LR-CD cyclization activity. Copyright © 2015 Elsevier Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Cheng, Ai-Xia; Zhang, Xuebin; Han, Xiao-Juan
Flavonoids ubiquitously distribute to the terrestrial plants and chalcone isomerase (CHI)- catalyzed intramolecular and stereospecific cyclization of chalcones is a committed step in the production of flavonoids. However, so far the bona fide CHIs are found only in vascular plants, and their origin and evolution remains elusive. We conducted transcriptomic and/or genomic sequence search, subsequent phylogenetic analysis, and detailed biochemical and genetic characterization to explore the potential existence of CHI proteins in the basal bryophyte liverwort species and the lycophyte Selaginella moellendorffii. We found that both liverwort and Selaginella species possess canonical CHI-fold proteins that cluster with their corresponding highermore » plant counterparts. Among them, some members exhibited bona fide CHI activity, which catalyze stereospecific cyclization of both 60- hydroxychalcone and 60-deoxychalcone, yielding corresponding 5-hydroxy and 5- deoxyflavanones, resembling the typical type II CHIs currently known to be ‘specific’ for legume plants. Expressing those primitive bona fide CHIs in the Arabidopsis chi mutant restores the seed coat transparent testa phenotype and the accumulation of flavonoids. These findings, in contrast to our current understanding of the evolution of enzymatic CHIs, suggest that emergence of the bona fide type II CHIs is an ancient evolution event that occurred before the divergence of liverwort lineages.« less
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Cheng, Ai-Xia; Zhang, Xuebin; Han, Xiao-Juan; ...
2017-10-30
Flavonoids ubiquitously distribute to the terrestrial plants and chalcone isomerase (CHI)- catalyzed intramolecular and stereospecific cyclization of chalcones is a committed step in the production of flavonoids. However, so far the bona fide CHIs are found only in vascular plants, and their origin and evolution remains elusive. We conducted transcriptomic and/or genomic sequence search, subsequent phylogenetic analysis, and detailed biochemical and genetic characterization to explore the potential existence of CHI proteins in the basal bryophyte liverwort species and the lycophyte Selaginella moellendorffii. We found that both liverwort and Selaginella species possess canonical CHI-fold proteins that cluster with their corresponding highermore » plant counterparts. Among them, some members exhibited bona fide CHI activity, which catalyze stereospecific cyclization of both 60- hydroxychalcone and 60-deoxychalcone, yielding corresponding 5-hydroxy and 5- deoxyflavanones, resembling the typical type II CHIs currently known to be ‘specific’ for legume plants. Expressing those primitive bona fide CHIs in the Arabidopsis chi mutant restores the seed coat transparent testa phenotype and the accumulation of flavonoids. These findings, in contrast to our current understanding of the evolution of enzymatic CHIs, suggest that emergence of the bona fide type II CHIs is an ancient evolution event that occurred before the divergence of liverwort lineages.« less
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Burov, Sergey; Moskalenko, Yulia; Dorosh, Marina; Shkarubskaya, Zoya; Panarin, Evgeny
2009-11-01
N-terminal modification of peptides by unnatural amino acids significantly affects their enzymatic stability, conformational properties and biological activity. Application of N-amidino-amino acids, positively charged under physiological conditions, can change peptide conformation and its affinity to the corresponding receptor. In this article, we describe synthesis of short peptides, containing a new building block-N-amidino-pyroglutamic acid. Although direct guanidinylation of pyroglutamic acid and oxidation of N-amidino-proline using RuO(4) did not produce positive results, N-amidino-Glp-Phe-OH was synthesized on Wang polymer by cyclization of alpha-guanidinoglutaric acid residue. In the course of synthesis, it was found that literature procedure of selective Boc deprotection using TMSOTf/TEA reagent is accompanied by concomitant side reaction of triethylamine alkylation by polymer linker fragment. It should be mentioned that independently from cyclization time and coupling agent (DIC or HCTU), the lactam formation was incomplete. Separation of the cyclic product from the linear precursor was achieved by HPLC in ammonium formate buffer at pH 6. HPLC analysis showed N-amidino-Glp-Phe-OH stability at acidic and physiological pH and fast ring opening in water solution at pH 9. The suggested method of N-amidino-Glp residue formation can be applied in the case of short peptide chains, whereas synthesis of longer ones will require fragment condensation approach.
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A reverse transcriptase-dependent mechanism plays central roles in fundamental biological processes.
Spadafora, Corrado
2008-01-01
This review summarizes emerging evidence that LINE-1 (Long Interspersed Nuclear Elements) -encoded reverse transcriptase (RT) regulates fundamental biological processes. Earlier studies showed that sperm cells can be used as vectors of both exogenous DNA and RNA molecules in sperm-mediated gene transfer assays. During these studies, a sperm endogenous RT activity was identified, which can reverse-transcribe exogenous RNA directly, or DNA molecules through sequential transcription and reverse transcription. Resulting cDNA copies generated in sperm cells can be delivered to embryos at fertilization, further propagated in tissues as low-copy extrachromosomal structures and transmitted to the progeny in a non-mendelian fashion. Being transcriptionally competent, they can induce phenotypic variations in positive tissues. An RT activity is also present in preimplantation embryos, and its inhibition causes developmental arrest in early preimplantation stages, paralleled by an extensive reprogramming of gene expression. In analogy with this, drug-mediated inhibition of RT activity, or RNA interference-mediated silencing of human LINE-1, reduce cell proliferation and induce differentiation in a variety of cancer cell lines. Furthermore, RT inhibition in vivo antagonizes the growth of human tumors in animal models. As a whole, these data implicate a RT-dependent machinery in the genesis of new genetic information in spermatozoa and in normal and pathological developmental processes.
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Wu, Xinghai; Chen, Chanfa; Xiao, Xizhi; Deng, Ming Jun
2016-11-01
A protocol for the reverse transcription-helicase-dependent amplification (RT-HDA) of isothermal DNA was developed for the detection of tomato spotted wilt virus (TSWV). Specific primers, which were based on the highly conserved region of the N gene sequence in TSWV, were used for the amplification of virus's RNA. The LOD of RT-HDA, reverse transcriptase-loop-mediated isothermal amplification (RT-LAMP), and reverse transcriptase-polymerase chain reaction (RT-PCR) assays were conducted using 10-fold serial dilution of RNA eluates. TSWV sensitivity in RT-HDA and RT-LAMP was 4 pg RNA compared with 40 pg RNA in RT-PCR. The specificity of RT-HDA for TSWV was high, showing no cross-reactivity with other tomato and Tospovirus viruses including cucumber mosaic virus (CMV), tomato black ring virus (TBRV), tomato mosaic virus (ToMV), or impatiens necrotic spot virus (INSV). The RT-HDA method is effective for the detection of TSWV in plant samples and is a potential tool for early and rapid detection of TSWV.
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Li, Wenke; Wayne, Gregory S; Lallaman, John E; Chang, Sou-Jen; Wittenberger, Steven J
2006-02-17
Ketoester 1 is cyclized to give pyran-3,5-dione 2 in 78% yield using a parallel addition of ketoester 1 and base NaO(t)Bu in refluxing THF. Compared to the previously reported procedures, these optimized conditions have significantly increased the yield of this transformation and the quality of pyran 2 and prove to be suitable for large-scale preparation. An application of 2 to the synthesis of ABT-598, a potassium channel opener, is demonstrated.
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ten Cate, A Tessa; Dankers, Patricia Y W; Sijbesma, Rint P; Meijer, E W
2005-07-22
Stereoselective cyclization of cystine-based bifunctional 2-ureido-4[1H]-pyrimidinone derivatives in CDCl(3) solutions was demonstrated by (1)H NMR spectroscopy. Thiolate-catalyzed disulfide exchange in solution led to the equilibration of different diastereomers of 1. At low concentrations, where formation of cyclic assemblies is the dominant mode of association, the molecules act as their own template. At these concentrations the meso diastereomer is formed preferentially, indicating a higher stability of its cyclic assemblies under the applied conditions, in comparison to the other diastereomers.
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On the synthesis of protopine alkaloids.
Wada, Yasuhiro; Kaga, Harumi; Uchiito, Shiho; Kumazawa, Eri; Tomiki, Miho; Onozaki, Yu; Kurono, Nobuhito; Tokuda, Masao; Ohkuma, Takeshi; Orito, Kazuhiko
2007-09-14
For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of indeno[2,1-a][3]benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by Bischler-Napieralski cyclization of alkoxy-substituted 1-(2-bromobenzyl)-3-benzazepin-2-ones. Steric effects of the substituents in this synthesis were examined.
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Joo, Jung Min; David, Ramoncito A.; Yuan, Yu; Lee, Chulbom
2010-01-01
The total synthesis of the erythrina alkaloid 3–demethoxyerythratidinone has been achieved via a strategy based on combined rhodium catalysis. The catalytic tandem cyclization effected by the interplay of alkynyl and vinylidene rhodium species allows for efficient access to the A and B rings of the tetracyclic erythrinane skeleton in a single step. The synthesis also features rapid preparation of the requisite precursor for the double ring closure and thus has been completed in only 7 total steps in 41% overall yield. PMID:21090648
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A nickel catalyst for the addition of organoboronate esters to ketones and aldehydes.
Bouffard, Jean; Itami, Kenichiro
2009-10-01
A Ni(cod)(2)/IPr catalyst promotes the intermolecular 1,2-addition of arylboronate esters to unactivated aldehydes and ketones. Diaryl, alkyl aryl, and dialkyl ketones show good reactivity under mild reaction conditions (< or = 80 degrees C, nonpolar solvents, no strong base or acid additives). A dramatic ligand effect favors either carbonyl addition (IPr) or C-OR cross-coupling (PCy(3)) with aryl ether substrates. A Ni(0)/Ni(II) catalytic cycle initiated by the oxidative cyclization of the carbonyl substrate is proposed.
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Pechey, Rachel; Monsivais, Pablo
2016-07-01
Investigations of the contribution of food costs to socioeconomic inequalities in diet quality may have been limited by the use of estimated (vs. actual) food expenditures, not accounting for where individuals shop, and possible reverse mediation between food expenditures and healthiness of food choices. This study aimed to explore the extent to which food expenditure mediates socioeconomic inequalities in the healthiness of household food choices. Observational panel data on take-home food and beverage purchases, including expenditure, throughout 2010 were obtained for 24,879 UK households stratified by occupational social class. Purchases of (1) fruit and vegetables and (2) less-healthy foods/beverages indicated healthiness of choices. Supermarket choice was determined by whether households ever visited market-defined high-price and/or low-price supermarkets. Results showed that higher occupational social class was significantly associated with greater food expenditure, which was in turn associated with healthier purchasing. In mediation analyses, 63% of the socioeconomic differences in choices of less-healthy foods/beverages were mediated by expenditure, and 36% for fruit and vegetables, but these figures were reduced to 53% and 31% respectively when controlling for supermarket choice. However, reverse mediation analyses were also significant, suggesting that 10% of socioeconomic inequalities in expenditure were mediated by healthiness of choices. Findings suggest that lower food expenditure is likely to be a key contributor to less-healthy food choices among lower socioeconomic groups. However, the potential influence of cost may have been overestimated previously if studies did not account for supermarket choice or explore possible reverse mediation between expenditure and healthiness of choices. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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Theory and modeling of particles with DNA-mediated interactions
NASA Astrophysics Data System (ADS)
Licata, Nicholas A.
2008-05-01
In recent years significant attention has been attracted to proposals which utilize DNA for nanotechnological applications. Potential applications of these ideas range from the programmable self-assembly of colloidal crystals, to biosensors and nanoparticle based drug delivery platforms. In Chapter I we introduce the system, which generically consists of colloidal particles functionalized with specially designed DNA markers. The sequence of bases on the DNA markers determines the particle type. Due to the hybridization between complementary single-stranded DNA, specific, type-dependent interactions can be introduced between particles by choosing the appropriate DNA marker sequences. In Chapter II we develop a statistical mechanical description of the aggregation and melting behavior of particles with DNA-mediated interactions. In Chapter III a model is proposed to describe the dynamical departure and diffusion of particles which form reversible key-lock connections. In Chapter IV we propose a method to self-assemble nanoparticle clusters using DNA scaffolds. A natural extension is discussed in Chapter V, the programmable self-assembly of nanoparticle clusters where the desired cluster geometry is encoded using DNA-mediated interactions. In Chapter VI we consider a nanoparticle based drug delivery platform for targeted, cell specific chemotherapy. In Chapter VII we present prospects for future research: the connection between DNA-mediated colloidal crystallization and jamming, and the inverse problem in self-assembly.
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Pastuzyn, Elissa D; Chapman, David E; Wilcox, Karen S; Keefe, Kristen A
2012-01-01
Methamphetamine (METH) causes partial depletion of central monoamine systems and cognitive dysfunction in rats and humans. We have previously shown and now further show that the positive correlation between expression of the immediate-early gene Arc (activity-regulated, cytoskeleton-associated) in the dorsomedial (DM) striatum and learning on a response reversal task is lost in rats with METH-induced striatal dopamine loss, despite normal behavioral performance and unaltered N-methyl--aspartate (NMDA) receptor-mediated excitatory post-synaptic currents, suggesting intact excitatory transmission. This discrepancy suggests that METH-pretreated rats may no longer be using the dorsal striatum to solve the reversal task. To test this hypothesis, male Sprague–Dawley rats were pretreated with a neurotoxic regimen of METH or saline. Guide cannulae were surgically implanted bilaterally into the DM striatum. Three weeks after METH treatment, rats were trained on a motor response version of a T-maze task, and then underwent reversal training. Before reversal training, the NMDA receptor antagonist -2-amino-5-phosphonopentanoic acid (AP5) or an Arc antisense oligonucleotide was infused into the DM striatum. Acute disruption of DM striatal function by infusion of AP5 impaired reversal learning in saline-, but not METH-, pretreated rats. Likewise, acute disruption of Arc, which is implicated in consolidation of long-term memory, disrupted retention of reversal learning 24 h later in saline-, but not METH-, pretreated rats. These results highlight the critical importance of Arc in the striatum in consolidation of basal ganglia-mediated learning and suggest that long-term toxicity induced by METH alters the cognitive strategies/neural circuits used to solve tasks normally mediated by dorsal striatal function. PMID:22071872
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Pastuzyn, Elissa D; Chapman, David E; Wilcox, Karen S; Keefe, Kristen A
2012-03-01
Methamphetamine (METH) causes partial depletion of central monoamine systems and cognitive dysfunction in rats and humans. We have previously shown and now further show that the positive correlation between expression of the immediate-early gene Arc (activity-regulated, cytoskeleton-associated) in the dorsomedial (DM) striatum and learning on a response reversal task is lost in rats with METH-induced striatal dopamine loss, despite normal behavioral performance and unaltered N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic currents, suggesting intact excitatory transmission. This discrepancy suggests that METH-pretreated rats may no longer be using the dorsal striatum to solve the reversal task. To test this hypothesis, male Sprague-Dawley rats were pretreated with a neurotoxic regimen of METH or saline. Guide cannulae were surgically implanted bilaterally into the DM striatum. Three weeks after METH treatment, rats were trained on a motor response version of a T-maze task, and then underwent reversal training. Before reversal training, the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) or an Arc antisense oligonucleotide was infused into the DM striatum. Acute disruption of DM striatal function by infusion of AP5 impaired reversal learning in saline-, but not METH-, pretreated rats. Likewise, acute disruption of Arc, which is implicated in consolidation of long-term memory, disrupted retention of reversal learning 24 h later in saline-, but not METH-, pretreated rats. These results highlight the critical importance of Arc in the striatum in consolidation of basal ganglia-mediated learning and suggest that long-term toxicity induced by METH alters the cognitive strategies/neural circuits used to solve tasks normally mediated by dorsal striatal function.
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Green Chemistry Challenge: 2017 Greener Synthetic Pathways Award
Green Chemistry Challenge 2017 award winners, Merck, developed a novel asymmetric aza-Michael cyclization, employing a chemically stable and fully recyclable organocatalyst to make Letermovir, an antiviral drug
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Proximity vs. strain in intramolecular ring-closing reactions
NASA Astrophysics Data System (ADS)
Karaman, Rafik
2010-07-01
The DFT and ab initio calculation results for ring-closing reactions of eight different ω-bromoalkanecarboxylate anions (1-8) reveal that the activation energy (ΔG ‡) for the intramolecular cyclization process is strongly correlated with both (i) the experimental intramolecular cyclization rate (log k intra) and (ii) the distance between the two reactive centres, whereas the slope values of the change in enthalpy (ΔH) vs. the attack angle (α) and the distance between the two reacting centres (r) were found to correlate strongly with the experimental strain energy of the cycle being formed (E s Exp). These results assist in designing pro-prodrug systems that can be utilized to improve the overall biopharmaceutical profile of current medications in order to enhance their effectiveness and ease their utility.
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Photocyclization Reactions of Diarylethenes via the Excited Triplet State.
Murata, Ryutaro; Yago, Tomoaki; Wakasa, Masanobu
2015-11-12
Cyclization reactions of three diarylethene derivatives, 1,2-bis(2-methyl-3-benzothienyl)perfluorocyclopentene (BT), 1,2-bis(2-hexyl-3-benzothienyl)perfluorocyclopentene (BTHex), and 1,2-bis(2-isopropyl-3-benzothienyl)perfluorocyclopentene (BTiPr), via their excited triplet states were studied by means of steady-state and nanosecond transient absorption spectroscopy. The excited triplet states of BT, BTHex, and BTiPr were generated by energy transfer from the photoexcited triplet states of sensitizers such as xanthone, phenanthrene, and pyrene. The single-step quantum yields of the cyclization reactions from the excited triplet states of BT, BTHex, and BTiPr were determined to be 0.34, 0.53, and 0.65, respectively. The triplet energies of these three BTs were estimated to be 190-200 kJ mol(-1).
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Total synthesis and structural revision of the marine macrolide neopeltolide.
Custar, Daniel W; Zabawa, Thomas P; Scheidt, Karl A
2008-01-23
The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (1H, 13C, HRMS, IR, NOESY, [alpha]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.
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Alcaide, Benito; Almendros, Pedro; Lázaro-Milla, Carlos; Delgado-Martínez, Patricia
2018-04-06
Functionalized ynones can be activated by Tf 2 C=CH 2 , which was generated in situ, to form zwitterionic species. These species were trapped in an intramolecular fashion by several nucleophiles to generate two major types of triflones in a divergent manner. Through fine-tuning of the reaction temperature, bis(triflyl)-6-membered- or (triflyl)-5-membered-fused-heterocycles were achieved in reasonable yields in a totally selective manner. In this way, bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones, (triflyl)benzothienopyrans, (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and (triflyl)pyranoindoles were constructed. Conceivable mechanistic pathways were suggested on the basis of the isolation of several intermediates and the results from control experiments. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Overman, Larry E; Tanis, Paul S
2010-01-15
Polycyclic products containing the 12-oxatricyclo[6.3.1.0(2,7)]dodecane moiety having either the trans (8a-e) or cis (9a-e) relative configuration of the oxacyclic bridge and the cis angular substituents are formed stereospecifically by Prins-pinacol cyclizations of unsaturated alpha-dithianyl acetals 14a-e or 15a-e. These results show that the topography (boat or chair) of the Prins cyclization of the sulfur-stabilized oxocarbenium ions generated from acetals 14a-e or 15a-e is controlled by the stereoelectronic influence of the allylic substituents, with steric effects playing a minor role. A complex molecular rearrangement that is terminated by a thio-Prins-pinacol reaction is also identified.
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Mendive-Tapia, Lorena; Bertran, Alexandra; García, Jesús; Acosta, Gerardo; Albericio, Fernando; Lavilla, Rodolfo
2016-09-05
A series of short tryptophan-phenylalanine peptides containing an iodo substituent on the phenyl ring was subjected to Pd-catalyzed CH activation reactions to give the corresponding aryl-indole coupled products. Two types of adducts were generated: cyclomonomer and cyclodimeric peptides; no evidence of oligo- or polymerization products was detected. Contrary to standard peptide macrocyclizations, the factors controlling the fate of the reaction are the number of amino acids between the aromatic residues and the regiochemistry of the parent iodo derivative, independent of both the concentration and the cyclization mode. The method is general and allows access to novel biaryl peptidic topologies, which have been fully characterized. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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NASA Astrophysics Data System (ADS)
Ding, S.; Xu, Y.; Wang, Y.; He, Y.; Hou, J.; Chen, L.; He, J.-S.
2015-06-01
The methylation index of branched tetraethers (MBT) and cyclization ratio of branched tetraethers (CBT) based on the distribution of branched glycerol dialkyl glycerol tetraethers (brGDGT) are useful proxies for the reconstruction of mean annual air temperature (MAT) and soil pH. Recently, a series of 6-methyl brGDGTs were identified which were previously co-eluted with 5-methyl brGDGTs. However, little is known about 6-methyl brGDGTs in the Qinghai-Tibetan Plateau (QTP), a critical region of the global climate system. Here, we analyze 30 surface soils covering a large area of the QTP, among which 6-methyl brGDGTs were the most abundant components (average 53 ± 17% of total brGDGT). The fractional abundance of 6-methyl brGDGTs showed a good correlation with soil pH, while the global MBT'5ME calibration overestimates MAT in the QTP. We therefore proposed a MBT5/6 index including both 5- and 6-methyl brGDGTs, presenting a strong correlation with MAT in QTP: MAT = -20.14 + 39.51 × MBT5/6 (n = 27, r2 = 0.82; RMSE = 1.3 °C). Another index, namely IBT (isomerization of branched tetraether), based on carbon skeleton isomerization of the 5-methyl to 6-methyl brGDGTs, is dependent on soil pH: pH = 6.77 - 1.56 × IBT (n = 27; r2 = 0.74, RMSE = 0.32). Our study suggests that changing the position of methyl group of brGDGTs may be another mechanism for some soil bacteria to adapt to the ambient pH change in addition to the well-known cyclization.
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Zhang, Xiao-Yu; Zhang, Yun-Kai; Wang, Yi-Jun; Gupta, Pranav; Zeng, Leli; Xu, Megan; Wang, Xiu-Qi; Yang, Dong-Hua; Chen, Zhe-Sheng
2016-09-15
In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [³H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.
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Domain walls and ferroelectric reversal in corundum derivatives
NASA Astrophysics Data System (ADS)
Ye, Meng; Vanderbilt, David
2017-01-01
Domain walls are the topological defects that mediate polarization reversal in ferroelectrics, and they may exhibit quite different geometric and electronic structures compared to the bulk. Therefore, a detailed atomic-scale understanding of the static and dynamic properties of domain walls is of pressing interest. In this work, we use first-principles methods to study the structures of 180∘ domain walls, both in their relaxed state and along the ferroelectric reversal pathway, in ferroelectrics belonging to the family of corundum derivatives. Our calculations predict their orientation, formation energy, and migration energy and also identify important couplings between polarization, magnetization, and chirality at the domain walls. Finally, we point out a strong empirical correlation between the height of the domain-wall-mediated polarization reversal barrier and the local bonding environment of the mobile A cations as measured by bond-valence sums. Our results thus provide both theoretical and empirical guidance for future searches for ferroelectric candidates in materials of the corundum derivative family.
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Domain walls and ferroelectric reversal in corundum derivatives
NASA Astrophysics Data System (ADS)
Ye, Meng; Vanderbilt, David
Domain walls are the topological defects that mediate polarization reversal in ferroelectrics, and they may exhibit quite different geometric and electronic structures compared to the bulk. Therefore, a detailed atomic-scale understanding of the static and dynamic properties of domain walls is of pressing interest. In this work, we use first-principles methods to study the structures of 180° domain walls, both in their relaxed state and along the ferroelectric reversal pathway, in ferroelectrics belonging to the family of corundum derivatives. Our calculations predict their orientation, formation energy, and migration energy, and also identify important couplings between polarization, magnetization, and chirality at the domain walls. Finally, we point out a strong empirical correlation between the height of the domain-wall mediated polarization reversal barrier and the local bonding environment of the mobile A cations as measured by bond valence sums. Our results thus provide both theoretical and empirical guidance to further search for ferroelectric candidates in materials of the corundum derivative family. The work is supported by ONR Grant N00014-12-1-1035.
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Ube, Hitoshi; Yasuda, Yoshihiro; Sato, Hiroyasu; Shionoya, Mitsuhiko
2017-02-08
Metal ions can serve as a centre of molecular motions due to their coordination geometry, reversible bonding nature and external stimuli responsiveness. Such essential features of metal ions have been utilized for metal-mediated molecular machines with the ability to motion switch via metallation/demetallation or coordination number variation at the metal centre; however, motion switching based on the change in coordination geometry remain largely unexplored. Herein, we report a Pt II -centred molecular gear that demonstrates control of rotor engagement and disengagement based on photo- and thermally driven cis-trans isomerization at the Pt II centre. This molecular rotary motion transmitter has been constructed from two coordinating azaphosphatriptycene rotators and one Pt II ion as a stator. Isomerization between an engaged cis-form and a disengaged trans-form is reversibly driven by ultraviolet irradiation and heating. Such a photo- and thermally triggered motional interconversion between engaged/disengaged states on a metal ion would provide a selector switch for more complex interlocking systems.
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Wu, Yuxiang; Pan, Miaobo; Dai, Yuxuan; Liu, Baomin; Cui, Jian; Shi, Wei; Qiu, Qianqian; Huang, Wenlong; Qian, Hai
2016-05-15
A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Paraiso, Kim H T; Das Thakur, Meghna; Fang, Bin; Koomen, John M; Fedorenko, Inna V; John, Jobin K; Tsao, Hensin; Flaherty, Keith T; Sondak, Vernon K; Messina, Jane L; Pasquale, Elena B; Villagra, Alejandro; Rao, Uma N; Kirkwood, John M; Meier, Friedegund; Sloot, Sarah; Gibney, Geoffrey T; Stuart, Darrin; Tawbi, Hussein; Smalley, Keiran S M
2015-03-01
Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy. This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. ©2014 American Association for Cancer Research.
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Liu, Yong-Nan; Lu, Xiao-Xiao; Chen, Dai; Lu, Ya-Ping; Ren, Ang; Shi, Liang; Zhu, Jing; Jiang, Ai-Liang; Yu, Han-Shou; Zhao, Ming-Wen
2017-11-01
Phospholipid-mediated signal transduction plays a key role in responses to environmental changes, but little is known about the role of phospholipid signalling in microorganisms. Heat stress (HS) is one of the most important environmental factors. Our previous study found that HS could induce the biosynthesis of the secondary metabolites, ganoderic acids (GA). Here, we performed a comprehensive mass spectrometry-based analysis to investigate HS-induced lipid remodelling in Ganoderma lucidum. In particular, we observed a significant accumulation of phosphatidic acid (PA) on HS. Further genetic tests in which pld-silencing strains were constructed demonstrated that the accumulation of PA is dependent on HS-activated phospholipase D (PLD) hydrolysing phosphatidylethanolamine. Furthermore, we determined the role of PLD and PA in HS-induced secondary metabolism in G. lucidum. Exogenous 1-butanol, which decreased PLD-mediated formation of PA, reverses the increased GA biosynthesis that was elicited by HS. The pld-silenced strains partly blocked HS-induced GA biosynthesis, and this block can be reversed by adding PA. Taken together, our results suggest that PLD and PA are involved in the regulation of HS-induced secondary metabolism in G. lucidum. Our findings provide key insights into how microorganisms respond to heat stress and then consequently accumulate secondary metabolites by phospholipid remodelling. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.
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Pulp Inflammation Diagnosis from Clinical to Inflammatory Mediators: A Systematic Review.
Zanini, Marjorie; Meyer, Elisabeth; Simon, Stéphane
2017-07-01
Similar to other tissues, the dental pulp mounts an inflammatory reaction as a way to eliminate pathogens and stimulate repair. Pulp inflammation is prerequisite for dentin pulp complex repair and regeneration; otherwise, chronic disease or pulp necrosis occurs. Evaluation of pulp inflammation severity is necessary to predict the clinical success of maintaining pulp vitality. Clinical limitations to evaluating in situ inflammatory status are well-described. A molecular approach that aids clinical distinction between reversible and irreversible pulpitis could improve the success rate of vital pulp therapy. The aim of this article is to review inflammatory mediator expression in the context of clinical diagnosis. We searched PubMed and Cochrane databases for articles published between 1970 and December 2016. Only published studies of inflammatory mediator expression related to clinical diagnosis were eligible for inclusion and analysis. Thirty-two articles were analyzed. Two molecular approaches were described by study methods, protein expression analysis and gene expression analysis. Our review indicates that interleukin-8, matrix metalloproteinase 9, tumor necrosis factor-α, and receptor for advanced glycation end products expression increase at both the gene and protein levels during inflammation. Clinical irreversible pulpitis is related to specific levels of inflammatory mediator expression. The difference in expression between reversible and irreversible disease is both quantitative and qualitative. On the basis of our analysis, in situ quantification of inflammatory mediators may aid in the clinical distinction between reversible and irreversible pulpitis. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.
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Nature: A Box of Physical, Chemical, and Biological Tricks
NASA Astrophysics Data System (ADS)
Heinhorst, Sabine; Cannon, Gordon C.
2008-03-01
This article summarizes scientific breakthroughs, originally reported in the journal Nature, in the development of wet-dry adhesives, pain-selective anesthetics, enantioselective cyclizations and mechanical stress-induced chemical reactions.
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Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Prossnitz, Eric R; Sklar, Larry A; Miao, Yubin
2009-11-01
The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the alpha-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of 111In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (111In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-111In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-111In exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.
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Monoamines stimulate sex reversal in the saddleback wrasse.
Larson, Earl T; Norris, David O; Gordon Grau, E; Summers, Cliff H
2003-02-15
Monoamine neurotransmitters (norepinephrine, dopamine, and serotonin) play an important role in reproduction and sexual behavior throughout the vertebrates. They are the first endogenous chemical signals in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis. In teleosts with behavioral sex determination, much is known about behavioral cues that induce sex reversal. The cues are social, processed via the visual system and depend on the ratio of females to males in the population. The mechanisms by which these external behavioral cues are converted to an internal chemical regulatory process are largely unknown. The protogynous Hawaiian saddleback wrasse, Thalassoma duperrey, was used to investigate the biological pathway mediating the conversion of a social cue into neuroendocrine events regulating sex reversal. Because monoamines play an important role in the regulation of the HPG axis, they were selected as likely candidates for such a conversion. To determine if monoamines could affect sex reversal, drugs affecting monoamines were used in an attempt to either induce sex reversal under non-permissive conditions, or prevent sex reversal under permissive conditions. Increasing norepinephrine or blocking dopamine or serotonin lead to sex reversal in experimental animals under non-permissive conditions. Increasing serotonin blocked sex reversal under permissive conditions, while blocking dopamine or norepinephrine retarded the process. The results presented here demonstrate that monoamines contribute significantly to the control sex reversal. Norepinephrine stimulates initiation and completion of gonadal sex of reversal as well as color change perhaps directly via its effects on the HPG axis. Dopamine exercises inhibitory action on the initiation of sex reversal while 5-HT inhibits both initiation and completion of sex reversal. The serotonergic system appears to be an integral part of the pathway mediating the conversion of a social cue into a neuroendocrine event. The complex organization of neurochemical events controlling the psychosocial, physiological, and anatomical events that constitute reversal of sexual identity includes monoamine neurotransmitters. Copyright 2003 Elsevier Science (USA)
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2011-01-01
Background Fused heterocyclic 1,2,4-triazoles have acquired much importance because of their interesting biological properties. Although a number of methods have been reported in the literature which includes oxidation with phosphorus oxychloride, lead tetraacetate, bromine, etc., hypervalent iodine reagents have emerged as reagents of choice for various synthetically useful transformations due to their low toxicity, ready availability and ease of handling. Results A series of new 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines 4 has been conveniently synthesized by oxidative cyclization of 2-(3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-1-(pyridin-2-yl)hydrazines 3 promoted with iodobenzene diacetate under mild conditions (up to 90% isolated yields). All the new compounds were tested in vitro for their antimicrobial activity. Conclusions Iodine(III)-mediated oxidative approach has offered an easy access to new 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridines 4. The antibacterial and antifungal activities of newly synthesized compounds have proved them potent antimicrobial agents. PMID:22373059
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Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; ...
2016-06-23
Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE 2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE 2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.
Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE 2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE 2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.« less
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Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library
Moura-Letts, Gustavo; DiBlasi, Christine M.; Bauer, Renato A.; Tan, Derek S.
2011-01-01
Alkaloid and terpenoid natural products display an extensive array of chemical frameworks and biological activities. However such scaffolds remain underrepresented in current screening collections and are, thus, attractive targets for the synthesis of natural product-based libraries that access underexploited regions of chemical space. Recently, we reported a systematic approach to the stereoselective synthesis of multiple alkaloid/terpenoid-like scaffolds using transition metal-mediated cycloaddition and cyclization reactions of enyne and diyne substrates assembled on a tert-butylsulfinamide lynchpin. We report herein the synthesis of a 190-membered library of alkaloid/terpenoid-like molecules using this synthetic approach. Translation to solid-phase synthesis was facilitated by the use of a tert-butyldiarylsilyl (TBDAS) linker that closely mimics the tert-butyldiphenysilyl protecting group used in the original solution-phase route development work. Unexpected differences in stereoselectivity and regioselectivity were observed in some reactions when carried out on solid support. Further, the sulfinamide moiety could be hydrolyzed or oxidized efficiently without compromising the TBDAS linker to provide additional amine and sulfonamide functionalities. Principal component analysis of the structural and physicochemical properties of these molecules confirmed that they access regions of chemical space that overlap with bona fide natural products and are distinct from areas addressed by conventional synthetic drugs and drug-like molecules. The influences of scaffolds and substituents were also evaluated, with both found to have significant impacts on location in chemical space and three-dimensional shape. Broad biological evaluation of this library will provide valuable insights into the abilities of natural product-based libraries to access similarly underexploited regions of biological space. PMID:21451137
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Direct and reverse pollen-mediated gene flow between GM rice and red rice weed
Serrat, X.; Esteban, R.; Peñas, G.; Català, M. M.; Melé, E.; Messeguer, J.
2013-01-01
Potential risks of genetically modified (GM) crops must be identified before their commercialization, as happens with all new technologies. One of the major concerns is the proper risk assessment of adventitious presence of transgenic material in rice fields due to cross-pollination. Several studies have been conducted in order to quantify pollen-mediated gene flow from transgenic rice (Oryza sativa) to both conventional rice and red rice weed (O. sativa f. spontanea) under field conditions. Some of these studies reported GM pollen-donor rice transferring GM traits to red rice. However, gene flow also occurs in the opposite direction, in a phenomenon that we have called reverse gene flow, resulting in transgenic seeds that have incorporated the traits of wild red rice. We quantified reverse gene flow using material from two field trials. A molecular analysis based on amplified fragment length polymorphisms was carried out, being complemented with a phenotypic identification of red rice traits. In both field trials, the reverse gene flow detected was greater than the direct gene flow. The rate of direct gene flow varied according to the relative proportions of the donor (GM rice) and receptor (red rice) plants and was influenced by wind direction. The ecological impact of reverse gene flow is limited in comparison with that of direct gene flow because non-shattered and non-dormant seeds would be obtained in the first generation. Hybrid seed would remain in the spike and therefore most of it would be removed during harvesting. Nevertheless, this phenomenon must be considered in fields used for elite seed production and in developing countries where farmers often keep some seed for planting the following year. In these cases, there is a higher risk of GM red rice weed infestation increasing from year to year and therefore a proper monitoring plan needs to be established.
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Establishment and characterization of the reversibly immortalized mouse fetal heart progenitors.
Li, Mi; Chen, Yuan; Bi, Yang; Jiang, Wei; Luo, Qing; He, Yun; Su, Yuxi; Liu, Xing; Cui, Jing; Zhang, Wenwen; Li, Ruidong; Kong, Yuhan; Zhang, Jiye; Wang, Jinhua; Zhang, Hongyu; Shui, Wei; Wu, Ningning; Zhu, Jing; Tian, Jie; Yi, Qi-Jian; Luu, Hue H; Haydon, Rex C; He, Tong-Chuan; Zhu, Gao-Hui
2013-01-01
Progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart. Although cardiomyogenic differentiation has been reported for a variety of progenitor cell types, the biological factors that regulate effective cardiomyogenesis remain largely undefined. Primary cardiomyogenic progenitors (CPs) have a limited life span in culture, hampering the CPs' in vitro and in vivo studies. The objective of this study is to investigate if primary CPs isolated from fetal mouse heart can be reversibly immortalized with SV40 large T and maintain long-term cell proliferation without compromising cardiomyogenic differentiation potential. Primary cardiomyocytes were isolated from mouse E15.5 fetal heart, and immortalized retrovirally with the expression of SV40 large T antigen flanked with loxP sites. Expression of cardiomyogenic markers were determined by quantitative RT-PCR and immunofluorescence staining. The immortalization phenotype was reversed by using an adenovirus-mediated expression of the Cre reconbinase. Cardiomyogenic differentiation induced by retinoids or dexamethasone was assessed by an α-myosin heavy chain (MyHC) promoter-driven reporter. We demonstrate that the CPs derived from mouse E15.5 fetal heart can be efficiently immortalized by SV40 T antigen. The conditionally immortalized CPs (iCP15 clones) exhibit an increased proliferative activity and are able to maintain long-term proliferation, which can be reversed by Cre recombinase. The iCP15 cells express cardiomyogenic markers and retain differentiation potential as they can undergo terminal differentiate into cardiomyctes under appropriate differentiation conditions although the iCP15 clones represent a large repertoire of CPs at various differentiation stages. The removal of SV40 large T increases the iCPs' differentiation potential. Thus, the iCPs not only maintain long-term cell proliferative activity but also retain cardiomyogenic differentiation potential. Our results suggest that the reported reversible SV40 T antigen-mediated immortalization represents an efficient approach for establishing long-term culture of primary cardiomyogenic progenitors for basic and translational research.
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Enzymetically regulating the self-healing of protein hydrogels with high healing efficiency.
Gao, Yuzhou; Luo, Quan; Qiao, Shanpeng; Wang, Liang; Dong, Zeyuan; Xu, Jiayun; Liu, Junqiu
2014-08-25
Enzyme-mediated self-healing of dynamic covalent bond-driven protein hydrogels was realized by the synergy of two enzymes, glucose oxidase (GOX) and catalase (CAT). The reversible covalent attachment of glutaraldehyde to lysine residues of GOX, CAT, and bovine serum albumin (BSA) led to the formation and functionalization of the self-healing protein hydrogel system. The enzyme-mediated protein hydrogels exhibit excellent self-healing properties with 100% recovery. The self-healing process was reversible and effective with an external glucose stimulus at room temperature. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Ibuprofen-Mediated Reversal of Fluconazole Resistance in Clinical Isolates of Candida
Sharma, Monika; Kotwal, Aarti; Thakuria, Bhaskar; Kakati, Barnali; Chauhan, Bhupendra Singh; Patras, Abhishek
2015-01-01
Introduction: In view of the increasing prevalence of invasive Candidiasis in today’s health-care scenario and the emergence of fluconazole resistance among clinical isolates of Candida, we sought to determine if Ibuprofen could elicit a reversal of fluconazole resistance and thereby offer a potential therapeutic breakthrough in fluconazole-resistant Candidiasis. Materials and Methods: We selected 69 clinical isolates of Candida, which demonstrated an MIC of >32 μg/ml for fluconazole, and subjected them to broth microdilution in presence and absence of Ibuprofen. Results: Forty two of the 69 isolates (60.9%) demonstrated reversal of Fluconazole resistance with concomitant use of Ibuprofen. This was characterized by significant species-wise variation (p=0.00008), with all the C. albicans isolates and none of the C. glabrata isolates demonstrating such reversal. Only 22.2% and 37.7% of C. krusei and C. tropicalis isolates respectively showed Ibuprofen-mediated reversal of Fluconazole resistance. Conclusion: Since Ibuprofen is a known efflux pump inhibitor, our findings hint at the possible mechanism of Fluconazole resistance in most of our Candida isolates and suggest a potential therapeutic alternative that could be useful in the majority of Fluconazole-resistant clinical isolates of Candida. PMID:25737988
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Mikkelsen, Jacob Giehm; Lund, Anders H.; Dybkær, Karen; Duch, Mogens; Pedersen, Finn Skou
1998-01-01
We have previously demonstrated recombinational rescue of primer binding site (PBS)-impaired Akv murine leukemia virus-based vectors involving initial priming on endogenous viral sequences and template switching during cDNA synthesis to obtain PBS complementarity in second-strand transfer of reverse transcription (Mikkelsen et al., J. Virol. 70:1439–1447, 1996). By use of the same forced recombination system, we have now found recombinant proviruses of different structures, suggesting that PBS knockout vectors may be rescued through initial priming on endogenous virus RNA, read-through of the mutated PBS during minus-strand synthesis, and subsequent second-strand transfer mediated by the R-U5 complementarity of the plus strand and the extended minus-strand DNA acceptor template. Mechanisms for R-U5-mediated second-strand transfer and its possible role in retrovirus replication and evolution are discussed. PMID:9499117
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Currentless reversal of Néel vector in antiferromagnets
NASA Astrophysics Data System (ADS)
Semenov, Yuriy; Li, Xilai; Kim, Ki Wook
The bias driven perpendicular magnetic anisotropy is a magneto-electric effect that can realize 900 magnetization rotation and even 1800 flip along the easy axis in the ferromagnets with a minimal energy consumption. This study theoretically demonstrates a similar phenomenon of the Néel vector reversal via a short electrical pulse that can mediate perpendicular magnetic anisotropy in the antiferromagnets. The analysis based on the dynamical equations as well as the micromagnetic simulations reveals the important role of the inertial behavior in the antiferromagnets that facilitates the Néel vector to overcome the barrier between two free-energy minima of the bistable states along the easy axis. In contrast to the ferromagnets, this Néel vector reversal does not accompany angular moment transfer to the environment, leading to acceleration in the dynamical response by a few orders of magnitude. Further, a small switching energy requirement of a few attojoules illustrates an added advantage of the phenomenon in low-power spintronic applications.
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Techathuvanan, Chayapa; Draughon, Frances Ann; D'Souza, Doris Helen
2011-02-01
Novel rapid Salmonella detection assays without the need for sophisticated equipment or labor remain in high demand. Real-time reverse transcriptase PCR (RT-PCR) assays, though rapid and sensitive, require expensive thermocyclers, while a novel RT loop-mediated isothermal amplification (RT-LAMP) method requires only a simple water bath. Our objective was to compare the detection sensitivity of Salmonella Typhimurium from the pork processing environment by RT-LAMP, RT-PCR, and culture-based assays. Carcass and surface swabs and carcass rinses were obtained from a local processing plant. Autoclaved carcass rinses (500 ml) were spiked with Salmonella Typhimurium and filtered. Filters were placed in stomacher bags containing tetrathionate broth (TTB) and analyzed with or without 10-h enrichment at 37 °C. Natural swabs were stomached with buffered peptone water, and natural carcass rinses were filtered, preenriched, and further enriched in TTB. Serially-diluted enriched samples were enumerated by spread plating on xylose lysine Tergitol 4 agar. RNA was extracted from 5 ml of enriched TTB with TRIzol. RT-LAMP assay using previously described invA primers was conducted at 62 °C for 90 min in a water bath with visual detection and by gel electrophoresis. SYBR Green I-based-real-time RT-PCR was carried out with invA primers followed by melt temperature analysis. The results of RT-LAMP detection for spiked carcass rinses were comparable to those of RT-PCR and cultural plating, with detection limits of 1 log CFU/ml, although they were obtained significantly faster, within 24 h including preenrichment and enrichment. RT-LAMP showed 4 of 12 rinse samples positive, while RT-PCR showed 1 of 12 rinse samples positive. For swabs, 6 of 27 samples positive by RT-LAMP and 5 of 27 by RT-PCR were obtained. This 1-day RT-LAMP assay shows promise for routine Salmonella screening by the pork industry. Copyright ©, International Association for Food Protection
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Recent advances in the synthesis of thiophene derivatives by cyclization of functionalized alkynes.
Mancuso, Raffaella; Gabriele, Bartolo
2014-09-29
This review is intended to highlight some recent and particularly interesting examples of the synthesis of thiophene derivatives by heterocyclization of readily available S-containing alkyne substrates.
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Synthesis of enantiopure antiobesity drug lorcaserin.
Smilovic, Ivana Gazic; Cluzeau, Jerome; Richter, Frank; Nerdinger, Sven; Schreiner, Erwin; Laus, Gerhard; Schottenberger, Herwig
2018-05-15
Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Electrical current mediated interconversion between graphene oxide to reduced grapene oxide
NASA Astrophysics Data System (ADS)
Teoh, H. F.; Tao, Y.; Tok, E. S.; Ho, G. W.; Sow, C. H.
2011-04-01
In this work, we demonstrate that graphene oxide (GO) can be reversibly converted to reduced-graphene-oxide (rGO) through the use of electric current. Strong electric field could cause ionization of water molecules in air to generate H+ ions at cathode, causing GO to be reduced. When the bias is reversed, the same electrode becomes positive and OH- ions are produced. According to Le Chatelier Principle, it then favors the reverse reaction, converting rGO back to GO, GO+2H++2e-=>rGO+H2O. X-ray spectroscopy and Raman spectroscopy were carried to verify the conversion reversibility in the reversed process.
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Cui, Jiayue; Chai, David I.; Miller, Christopher; Hao, Jason; Thomas, Christopher; Wang, JingQi; Scheidt, Karl A.; Kozmin, Sergey A.
2013-01-01
We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity. PMID:22860634
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Yang, Linan; Bekele, Tefsit; Lipton, Mark A; Kenttämaa, Hilkka I
2013-04-01
A negatively charged biradical intermediate was successfully generated in the gas phase via cyclization of the deprotonated bicyclo[8.3.0]trideca-12-ene-2,7-diyn-1-one precursor. The inherent negative charge of this biradical allows its characterization via collision-activated dissociation and reactions with a variety of neutral substrates in an FT-ICR mass spectrometer. Although the biradical is unreactive toward reagents that usually react rapidly with positively charged biradicals, such as dimethyl disulfide, it reacts with the halogen-containing substrates carbon tetrachloride, carbon tetrabromide, and bromotrichloromethane via bromine or chlorine atom abstraction, which supports its biradical structure. The results presented in this study indicate that cyclizations commonly used in solution to form biradical intermediates from enediyne compounds may also occur in the gas phase.
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Yang, Linan; Bekele, Tefsit; Lipton, Mark A.
2013-01-01
A negatively charged biradical intermediate was successfully generated in the gas phase via cyclization of the deprotonated bicyclo[8.3.0]trideca-12-ene-2,7-diyn-1-one precursor. The inherent negative charge of this biradical allows its characterization via collision-activated dissociation and reactions with a variety of neutral substrates in an FT-ICR mass spectrometer. Although the biradical is unreactive toward reagents that usually react rapidly with positively charged biradicals, such as dimethyl disulfide, it reacts with the halogen-containing substrates carbon tetrachloride, carbon tetrabromide and bromotrichloromethane via bromine or chlorine atom abstraction, which supports its biradical structure. The results presented in this study indicate that cyclizations commonly used in solution to form biradical intermediates from enediyne compounds may also occur in the gas phase. PMID:23512422
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A practical synthesis of (+)-biotin from L-cysteine.
Seki, Masahiko; Hatsuda, Masanori; Mori, Yoshikazu; Yoshida, Shin-ichi; Yamada, Shin-ichi; Shimizu, Toshiaki
2004-11-19
Alpha-amino aldehyde 4, which is readily derived from L-cysteine through cyclization and elaboration of the carboxy group, was subjected to the Strecker reaction, which, via sodium bisulfite adduct 16, afforded alpha-amino nitrile 5 with high diastereoselectivity (syn/anti=11:1) and in high yield. Amide 6, derived from 5, was converted to thiolactone 8, a key intermediate in the synthesis of (+)-biotin (1), by a novel S,N-carbonyl migration and cyclization reaction. The Fukuyama coupling reaction of 8 with the zinc reagent 21, which has an ester group, in the presence of a heterogeneous Pd/C catalyst allowed the efficient installation of the 4-carboxybutyl chain to provide 9. Compound 9 was hydrogenated and the protecting groups removed to furnish 1 in 10 steps and in 34 % overall yield from L-cysteine.
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Studies on a Total Synthesis of the Microbial Immunosuppresive Agent FR901483
Kropf, Jeffrey E.; Meigh, Ivona C.; Bebbington, Magnus W.P.; Weinreb, Steven M.
2008-01-01
A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo[3.3.1]nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixure of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated towards annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43. PMID:16496992
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Webber, Peter; Krische, Michael J.
2010-01-01
Concise stereoselective syntheses of (±)-quinine and (±)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of N-protecting groups provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (±)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. A formal synthesis of (±)-quinine is achieved upon deoxygenation of the N-Cbz-protected allylic acetate 22 to provide olefin 23, which previously has been converted to quinine. Thus, (±)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal, making this route the most concise approach to quinine, to date. PMID:18989927
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Zerbe, Philipp; Chiang, Angela; Yuen, Macaire; Hamberger, Björn; Hamberger, Britta; Draper, Jason A.; Britton, Robert; Bohlmann, Jörg
2012-01-01
The labdanoid diterpene alcohol cis-abienol is a major component of the aromatic oleoresin of balsam fir (Abies balsamea) and serves as a valuable bioproduct material for the fragrance industry. Using high-throughput 454 transcriptome sequencing and metabolite profiling of balsam fir bark tissue, we identified candidate diterpene synthase sequences for full-length cDNA cloning and functional characterization. We discovered a bifunctional class I/II cis-abienol synthase (AbCAS), along with the paralogous levopimaradiene/abietadiene synthase and isopimaradiene synthase, all of which are members of the gymnosperm-specific TPS-d subfamily. The AbCAS-catalyzed formation of cis-abienol proceeds via cyclization and hydroxylation at carbon C-8 of a postulated carbocation intermediate in the class II active site, followed by cleavage of the diphosphate group and termination of the reaction sequence without further cyclization in the class I active site. This reaction mechanism is distinct from that of synthases of the isopimaradiene- or levopimaradiene/abietadiene synthase type, which employ deprotonation reactions in the class II active site and secondary cyclizations in the class I active site, leading to tricyclic diterpenes. Comparative homology modeling suggested the active site residues Asp-348, Leu-617, Phe-696, and Gly-723 as potentially important for the specificity of AbCAS. As a class I/II bifunctional enzyme, AbCAS is a promising target for metabolic engineering of cis-abienol production. PMID:22337889
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Vadola, Paul A; Carrera, Ignacio; Sames, Dalibor
2012-08-17
We here report a study of the intramolecular amination of sp(3) C-H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to N-toluenesulfonamide in the presence of BF(3)·OEt(2) to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp(3) C-H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C-H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.
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NASA Astrophysics Data System (ADS)
Zekavat, Behrooz; Miladi, Mahsan; Al-Fdeilat, Abdullah H.; Somogyi, Arpad; Solouki, Touradj
2014-02-01
To date, only a limited number of reports are available on structural variants of multiply-charged b-fragment ions. We report on observed bimodal gas-phase hydrogen/deuterium exchange (HDX) reaction kinetics and patterns for substance P b10 2+ that point to presence of isomeric structures. We also compare HDX reactions, post-ion mobility/collision-induced dissociation (post-IM/CID), and sustained off-resonance irradiation-collision induced dissociation (SORI-CID) of substance P b10 2+ and a cyclic peptide with an identical amino acid (AA) sequence order to substance P b10. The observed HDX patterns and reaction kinetics and SORI-CID pattern for the doubly charged head-to-tail cyclized peptide were different from either of the presumed isomers of substance P b10 2+, suggesting that b10 2+ may not exist exclusively as a head-to-tail cyclized structure. Ultra-high mass measurement accuracy was used to assign identities of the observed SORI-CID fragment ions of substance P b10 2+; over 30 % of the observed SORI-CID fragment ions from substance P b10 2+ had rearranged (scrambled) AA sequences. Moreover, post-IM/CID experiments revealed the presence of two conformer types for substance P b10 2+, whereas only one conformer type was observed for the head-to-tail cyclized peptide. We also show that AA sequence scrambling from CID of doubly-charged b-fragment ions is not unique to substance P b10 2+.
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Zekavat, Behrooz; Miladi, Mahsan; Al-Fdeilat, Abdullah H; Somogyi, Arpad; Solouki, Touradj
2014-02-01
To date, only a limited number of reports are available on structural variants of multiply-charged b-fragment ions. We report on observed bimodal gas-phase hydrogen/deuterium exchange (HDX) reaction kinetics and patterns for substance P b10(2+) that point to presence of isomeric structures. We also compare HDX reactions, post-ion mobility/collision-induced dissociation (post-IM/CID), and sustained off-resonance irradiation-collision induced dissociation (SORI-CID) of substance P b10(2+) and a cyclic peptide with an identical amino acid (AA) sequence order to substance P b10. The observed HDX patterns and reaction kinetics and SORI-CID pattern for the doubly charged head-to-tail cyclized peptide were different from either of the presumed isomers of substance P b10(2+), suggesting that b10(2+) may not exist exclusively as a head-to-tail cyclized structure. Ultra-high mass measurement accuracy was used to assign identities of the observed SORI-CID fragment ions of substance P b10(2+); over 30% of the observed SORI-CID fragment ions from substance P b10(2+) had rearranged (scrambled) AA sequences. Moreover, post-IM/CID experiments revealed the presence of two conformer types for substance P b10(2+), whereas only one conformer type was observed for the head-to-tail cyclized peptide. We also show that AA sequence scrambling from CID of doubly-charged b-fragment ions is not unique to substance P b10(2+).
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Garcia, Maria Fernanda; Zhang, Xiuli; Gallazzi, Fabio; Fernandez, Marcelo; Moreno, Maria; Gambini, Juan Pablo; Porcal, Williams; Cabral, Pablo; Quinn, Thomas P
2015-01-01
Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with (99m) via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with (99m)Tc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that (99m)Tc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than (99m)Tc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of (99m)Tc labeled lactam cyclized MSH molecules as melanoma imaging agents.
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The formation of pyrrolid-2-one-5-carboxylic acid at the N-terminus of immunoglobulin G heavy chain
Stott, D. I.; Munro, A. J.
1972-01-01
We propose that pyrrolid-2-one-5-carboxyl-tRNA is not involved in the initiation of protein synthesis in eukaryotic cells and that the N-terminal pyrrolid-2-one-5-carboxylic acid group of an IgG (immunoglobulin G) (that secreted by the mouse plasmacytoma Adj PC5) is formed by the enzymic cyclization of the N-terminal glutamine of the heavy chain of the completed IgG molecule and that the cyclization takes place inside the cell. We base these conclusions on the following evidence. (1) Pyrrolidonecarboxyl-tRNA was not found in incorporation experiments with rat liver preparations and [U-14C]-pyrrolidonecarboxylic acid, glutamic acid and glutamine, even though an incorporation extent of less than 2% of the total products could have been detected. (2) Double-labelling experiments showed that less than 8% of the nascent peptides of heavy chains (those obtained by precipitation by the antibody to Fc fragment) began with pyrrolidonecarboxylic acid. (3) Further double-labelling experiments showed that 60–66% of the heavy chains of the completed intracellular IgG molecule began with pyrrolidonecarboxylic acid after both 1 and 5h of labelling. (4) The IgG, after secretion by plasmacytoma Adj PC5, was found to have the sequence [unk]Glu- Val-Gln-Leu- at the N-termini of the heavy chains. PMID:4674626
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Jiang, Chunyan; Wang, Hougen; Kang, Qianjin; Liu, Jing
2012-01-01
Salinomycin is widely used in animal husbandry as a food additive due to its antibacterial and anticoccidial activities. However, its biosynthesis had only been studied by feeding experiments with isotope-labeled precursors. A strategy with degenerate primers based on the polyether-specific epoxidase sequences was successfully developed to clone the salinomycin gene cluster. Using this strategy, a putative epoxidase gene, slnC, was cloned from the salinomycin producer Streptomyces albus XM211. The targeted replacement of slnC and subsequent trans-complementation proved its involvement in salinomycin biosynthesis. A 127-kb DNA region containing slnC was sequenced, including genes for polyketide assembly and release, oxidative cyclization, modification, export, and regulation. In order to gain insight into the salinomycin biosynthesis mechanism, 13 gene replacements and deletions were conducted. Including slnC, 7 genes were identified as essential for salinomycin biosynthesis and putatively responsible for polyketide chain release, oxidative cyclization, modification, and regulation. Moreover, 6 genes were found to be relevant to salinomycin biosynthesis and possibly involved in precursor supply, removal of aberrant extender units, and regulation. Sequence analysis and a series of gene replacements suggest a proposed pathway for the biosynthesis of salinomycin. The information presented here expands the understanding of polyether biosynthesis mechanisms and paves the way for targeted engineering of salinomycin activity and productivity. PMID:22156425
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Zhang, Guohua; Chen, Wenling; Marvizón, Juan Carlos G.
2010-01-01
GABAB, μ-opioid, and adrenergic α2 receptors inhibit substance P release from primary afferent terminals in the dorsal horn. Studies in cell expression systems suggest that μ-opioid and GABAB receptors inhibit transmitter release from primary afferents by activating Src family kinases (SFKs), which then phosphorylate and inhibit voltage-gated calcium channels. This study investigated whether SFKs mediate the inhibition of substance P release by these three receptors. Substance P release was measured as neurokinin 1 receptor (NK1R) internalization in spinal cord slices and in vivo. In slices, NK1R internalization induced by high frequency dorsal root stimulation was inhibited by the μ-opioid agonist DAMGO and the GABAB agonist baclofen. This inhibition was reversed by the SFK inhibitor PP1. NK1R internalization induced by low frequency stimulation was also inhibited by DAMGO, but PP1 did not reverse this effect. In vivo, NK1R internalization induced by noxious mechanical stimulation of the hind paw was inhibited by intrathecal DAMGO and baclofen. This inhibition was reversed by intrathecal PP1, but not by the inactive PP1 analog PP3. PP1 produced no effect by itself. The α2 adrenergic agonists medetomidine and guanfacine produced a small but statistically significant inhibition of NK1R internalization induced by low frequency dorsal root stimulation. PP1 did not reverse the inhibition by guanfacine. These results show that SFKs mediate the inhibition of substance P release by μ-opioid and GABAB receptors, but not by α2 receptors, which is probably mediated by the binding of G protein βγ subunits to calcium channels. PMID:20726886
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The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats.
Zhang, Hong-Hai; Zhang, Xiao-Qin; Xue, Qing-Sheng; Yan-Luo; Huang, Jin-Lu; Zhang, Su; Shao, Hai-Jun; Lu, Han; Wang, Wen-Yuan; Yu, Bu-Wei
2014-01-01
Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats. Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.
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Dambrun, Michaël; Duarte, Sandra; Guimond, Serge
2004-06-01
Arguing from a sociobiological perspective, Sidanius and Pratto (1999) have shown that the male/female difference in social dominance orientation (SDO) is largely invariant across cultural, situational and contextual boundaries. The main objective of this study was to test the validity of Social Dominance Theory (SDT) by contrasting it with a model derived from Social Identity Theory (SIT). More specifically, while SIT predicts that gender identification mediates the effect of gender on SDO, SDT predicts the reverse. According to SDT, the degree to which men and women endorse status legitimizing ideology should determine to what extent they identify with their gender group. Using structural equation modelling, the results provide strong support for the SIT model and no support for SDT predictions. Implications of these results for social dominance theory and its sociobiologically based invariance hypothesis are discussed.
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Yogic exercises and health--a psycho-neuro immunological approach.
Kulkarni, D D; Bera, T K
2009-01-01
Relaxation potential of yogic exercises seems to play a vital role in establishing psycho-physical health in reversing the psycho-immunology of emotions under stress based on breath and body awareness. However, mechanism of yogic exercises for restoring health and fitness components operating through psycho-neuro-immunological pathways is unknown. Therefore, a hybrid model of human information processing-psycho-neuroendocrine (HIP-PNE) network has been proposed to reveal the importance of yogic information processing. This study focuses on two major pathways of information processing involving cortical and hypothalamo-pituitary-adrenal axis (HPA) interactions with a deep reach molecular action on cellular, neuro-humoral and immune system in reversing stress mediated diseases. Further, the proposed HIP-PNE model has ample of experimental potential for objective evaluation of yogic view of health and fitness.
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NASA Astrophysics Data System (ADS)
Zeng, Han; Huo, Wen-Shan; Zhao, Shu-Xian; Zhang, Yu-He
2017-11-01
Amino group surface tailored multi-wall carbon nano-tubes were covalently tethered to the gold disk electrode and Laccase molecules were covalently coupled to nano-tubes to prepare Lac-based electrode. Derivative of 3-ferrocenyl dihydropyrazole (FDPFFP) was proposed to be electron mediator for mediated oxygen reduction reaction. Investigation in electro-chemical behavior and catalytic performance to enzymatic reaction of FDPFFP indicated that it displayed quasi-reversible characteristics of electro-chemical reaction with rapid dynamics of electron shuttle and had apparent catalytic effect in oxygen reduction (onset potential for catalysis at 450 mV vs NHE). This enzymatic catalysis was restrained by the step in diffusion of substrate.
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Anderson, Ethan M; Wissman, Anne Marie; Chemplanikal, Joyce; Buzin, Nicole; Guzman, Daniel; Larson, Erin B; Neve, Rachael L; Nestler, Eric J; Cowan, Christopher W; Self, David W
2017-08-29
Chronic cocaine use is associated with prominent morphological changes in nucleus accumbens shell (NACsh) neurons, including increases in dendritic spine density along with enhanced motivation for cocaine, but a functional relationship between these morphological and behavioral phenomena has not been shown. Here we show that brain-derived neurotrophic factor (BDNF) signaling through tyrosine kinase B (TrkB) receptors in NACsh neurons is necessary for cocaine-induced dendritic spine formation by using either localized TrkB knockout or viral-mediated expression of a dominant negative, kinase-dead TrkB mutant. Interestingly, augmenting wild-type TrkB expression after chronic cocaine self-administration reverses the sustained increase in dendritic spine density, an effect mediated by TrkB signaling pathways that converge on extracellular regulated kinase. Loss of TrkB function after cocaine self-administration, however, leaves spine density intact but markedly enhances the motivation for cocaine, an effect mediated by specific loss of TrkB signaling through phospholipase Cgamma1 (PLCγ1). Conversely, overexpression of PLCγ1 both reduces the motivation for cocaine and reverses dendritic spine density, suggesting a potential target for the treatment of addiction in chronic users. Together, these findings indicate that BDNF-TrkB signaling both mediates and reverses cocaine-induced increases in dendritic spine density in NACsh neurons, and these morphological changes are entirely dissociable from changes in addictive behavior.
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Jami, Mohammad-Saeid; Salehi-Najafabadi, Zahra; Ahmadinejad, Fereshteh; Hoedt, Esthelle; Chaleshtori, Morteza Hashemzadeh; Ghatrehsamani, Mahdi; Neubert, Thomas A; Larsen, Jan Petter; Møller, Simon Geir
2015-11-01
Neuronal cell death, in neurodegenerative disorders, is mediated through a spectrum of biological processes. Excessive amounts of free radicals, such as reactive oxygen species (ROS), has detrimental effects on neurons leading to cell damage via peroxidation of unsaturated fatty acids in the cell membrane. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been used for neurological recovery in several countries, including Japan and China, and it has been suggested that Edaravone may have cytoprotective effects in neurodegeneration. Edaravone protects nerve cells in the brain by reducing ROS and inhibiting apoptosis. To gain further insight into the cytoprotective effects of Edaravone against oxidative stress condition we have performed comparative two-dimensional gel electrophoresis (2DE)-based proteomic analyses on SH-SY5Y neuroblastoma cells exposed to oxidative stress and in combination with Edaravone. We showed that Edaravone can reverse the cytotoxic effects of H2O2 through its specific mechanism. We observed that oxidative stress changes metabolic pathways and cytoskeletal integrity. Edaravone seems to reverse the H2O2-mediated effects at both the cellular and protein level via induction of Peroxiredoxin-2. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Jami, Mohammad-Saeid; Salehi-Najafabadi, Zahra; Ahmadinejad, Fereshteh; Hoedt, Esthelle; Chaleshtori, Morteza Hashemzadeh; Neubert, Thomas A.; Larsen, Jan Petter; Møller, Simon Geir
2015-01-01
Neuronal cell death, in neurodegenerative disorders, is mediated through a spectrum of biological processes. Excessive amounts of free radicals, such as reactive oxygen species (ROS), has detrimental effects on neurons leading to cell damage via peroxidation of unsaturated fatty acids in the cell membrane. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been used for neurological recovery in several countries, including Japan and China, and it has been suggested that Edaravone may have cytoprotective effects in neurodegeneration. Edaravone protects nerve cells in the brain by reducing ROS and inhibiting apoptosis. To gain further insight into the cytoprotective effects of Edaravone against oxidative stress condition we have performed comparative two-dimensional gel electrophoresis (2DE)-based proteomic analyses on SH-SY5Y neuroblastoma cells exposed to oxidative stress and in combination with Edaravone. We showed that Edaravone can reverse the cytotoxic effects of H2O2 through its specific mechanism. We observed that oxidative stress changes metabolic pathways and cytoskeletal integrity. Edaravone seems to reverse the H2O2-mediated effects at both the cellular and protein level via induction of Peroxiredoxin-2. PMID:26232623
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Li, Da-wei; Sun, Jing-yi; Wang, Kun; Zhang, Shuai; Hou, Ya-jun; Yang, Ming-feng; Fu, Xiao-yan; Zhang, Zong-yong; Mao, Lei-lei; Yuan, Hui; Fang, Jie; Fan, Cun-dong; Zhu, Mei-jia; Sun, Bao-liang
2015-10-01
Cisplatin-based chemotherapy in clinic is severely limited by its adverse effect, including neurotoxicity. Oxidative damage contributes to cisplatin-induced neurotoxicity, but the mechanism remains unclearly. Cyanidin, a natural flavonoid compound, exhibits powerful antioxidant activity. Hence, we investigated the protective effects of cyanidin on PC12 cells against cisplatin-induced neurotoxicity and explored the underlying mechanisms. The results showed that cisplatin-induced cytotoxicity was completely reversed by cyanidin through inhibition of PC12 cell apoptosis, as proved by the attenuation of Sub-G1 peak, PARP cleavage, and caspases-3 activation. Mechanistically, cyanidin significantly inhibited reactive oxygen species (ROS)-induced DNA damage in cisplatin-treated PC12 cells. Our findings revealed that cyanidin as an apoptotic inhibitor effectively blocked cisplatin-induced neurotoxicity through inhibition of ROS-mediated DNA damage and apoptosis, predicating its therapeutic potential in prevention of chemotherapy-induced neurotoxicity. Cisplatin caused DNA damage, activated p53, and subsequently induced PC12 cells apoptosis by triggering ROS overproduction. However, cyanidin administration effectively inhibited DNA damage, attenuated p53 phosphorylation, and eventually reversed cisplatin-induced PC12 cell apoptosis through inhibition ROS accumulation.
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Rhodium Catalyzed Intramolecular C-H Insertion of α-Aryl-α-diazo Ketones
Taber, Douglass F.; Tian, Weiwei
2011-01-01
Direct diazo transfer proceeds smoothly with α-aryl ketones. The derived α-aryl-α-diazo ketones cyclize efficiently with Rh catalysis to give the corresponding α-aryl cyclopentanones. PMID:17385917
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Reverse Stroop Effects with Untranslated Responses
ERIC Educational Resources Information Center
Blais, Chris; Besner, Derek
2006-01-01
Translation accounts have argued that the presence of a Stroop effect in the context of a nonvocal untranslated response is caused by verbal mediation. In its simplest form, color-labeled buttons are translated into a verbal code that interferes with color responses. On this logic, in the reverse Stroop task (identify the word; ignore the color),…
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Obenhaus, Horst A; Rozov, Andrei; Bertocchi, Ilaria; Tang, Wannan; Kirsch, Joachim; Betz, Heinrich; Sprengel, Rolf
2016-01-01
The causal interrogation of neuronal networks involved in specific behaviors requires the spatially and temporally controlled modulation of neuronal activity. For long-term manipulation of neuronal activity, chemogenetic tools provide a reasonable alternative to short-term optogenetic approaches. Here we show that virus mediated gene transfer of the ivermectin (IVM) activated glycine receptor mutant GlyRα1 (AG) can be used for the selective and reversible silencing of specific neuronal networks in mice. In the striatum, dorsal hippocampus, and olfactory bulb, GlyRα1 (AG) promoted IVM dependent effects in representative behavioral assays. Moreover, GlyRα1 (AG) mediated silencing had a strong and reversible impact on neuronal ensemble activity and c-Fos activation in the olfactory bulb. Together our results demonstrate that long-term, reversible and re-inducible neuronal silencing via GlyRα1 (AG) is a promising tool for the interrogation of network mechanisms underlying the control of behavior and memory formation.
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Kurosaki, Yohei; Magassouba, N'Faly; Bah, Hadja Aïssatou; Soropogui, Barré; Doré, Amadou; Kourouma, Fodé; Cherif, Mahamoud Sama; Keita, Sakoba; Yasuda, Jiro
2016-10-15
To strengthen the laboratory diagnostic capacity for Ebola virus disease (EVD) in the remote areas of Guinea, we deployed a mobile field laboratory and implemented reverse transcription loop-mediated isothermal amplification (RT-LAMP) for postmortem testing. We tested 896 oral swab specimens and 21 serum samples, using both RT-LAMP and reverse transcription-polymerase chain reaction (RT-PCR). Neither test yielded a positive result, and the results from RT-LAMP and RT-PCR were consistent. More than 95% of the samples were tested within 2 days of sample collection. These results highlight the usefulness of the RT-LAMP assay as an EVD diagnostic testing method in the field or remote areas. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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Eib, Constanze; Bernhard-Oettel, Claudia; Magnusson Hanson, Linda L; Leineweber, Constanze
2018-03-05
Organizational justice perceptions are considered a predictor of health and well-being. To date, empirical evidence about whether organizational justice perceptions predict health or health predicts organizational justice perceptions is mixed. Furthermore, the processes underlying these relationships are largely unknown. In this article, we study whether bidirectional relationships can be explained by 2 different mediation mechanisms. First, based on the allostatic load model, we suggest that the relationships between organizational justice perceptions and different health indicators are mediated through mental preoccupation with work. Second, based on the affective perception and affective reaction assumption, we investigate if the relationships between different health indicators and organizational justice perceptions are mediated by social support at work. Using a large-scale Swedish panel study (N = 3,236), we test the bidirectional mediating relationships between procedural justice perceptions and self-rated health, depressive symptoms, and sickness absence with a cross-lagged design with 3 waves of data. Significant lagged effects from procedural justice to health were found for models predicting depressive symptoms and sickness absence. Mental preoccupation with work was not found to mediate the longitudinal relationship between procedural justice perceptions and indicators of health. Significant lagged effects from health indicators to procedural justice were found for models involving self-rated health, depressive symptoms, and sickness absence. Social support mediated the longitudinal relationships between all 3 health indicators and procedural justice. Results are discussed in light of previous studies and implications for theory and practice are outlined. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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Almasi, Mohammad Amin; Almasi, Galavizh
2017-02-01
Sugar beet can be infected by many different viruses that can reduce yield; beet necrotic yellow vein virus (BNYVV) is one of the most economically important viruses of this crop plant. This report describes a new reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for identification of BNYVV. In addition, a novel immunocapture (IC) RT-LAMP assay for rapid and easy detection (without RNA extraction) of BNYVV was developed here and compared with DAS-ELISA and RT-LAMP assays. Our results show that the IC-RT-LAMP assay is a highly reliable alternative assay for identification of BNYVV.
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Nkere, Chukwuemeka K; Oyekanmi, Joshua O; Silva, Gonçalo; Bömer, Moritz; Atiri, Gabriel I; Onyeka, Joseph; Maroya, Norbert G; Seal, Susan E; Kumar, P Lava
2018-04-01
A closed-tube reverse transcription loop-mediated isothermal amplification (CT-RT-LAMP) assay was developed for the detection of yam mosaic virus (YMV, genus Potyvirus) infecting yam (Dioscorea spp.). The assay uses a set of six oligonucleotide primers targeting the YMV coat protein region, and the amplification products in YMV-positive samples are visualized by chromogenic detection with SYBR Green I dye. The CT-RT-LAMP assay detected YMV in leaf and tuber tissues of infected plants. The assay is 100 times more sensitive in detecting YMV than standard RT-PCR, while maintaining the same specificity.
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Huang, Ying; Zitta, Karina; Bein, Berthold; Steinfath, Markus; Albrecht, Martin
2013-01-01
SUMMARY Ischemia-reperfusion injury and tissue hypoxia are of high clinical relevance because they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms causing cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. The aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia-mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia-inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions in the culture medium. Hydrogen peroxide assays, glucose measurements and western blotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert-based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium. Glucose concentrations gradually decreased, whereas levels of hydrogen peroxide were not altered. Moreover, a rapid and reversible (onoff) generation of hypoxia could be performed by the addition and subsequent removal of the enzyme-containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of lactate dehydrogenase (a biochemical marker of cell damage). Hypoxic conditions also increased the amounts of cellular procaspase-3 and catalase as well as phosphorylation of the pro-survival kinase Akt, but not Erk1/2 or STAT5. In summary, we present a novel framework for investigating hypoxia-mediated mechanisms at the cellular level. We claim that the model, the first of its kind, enables researchers to rapidly and reversibly induce hypoxic conditions in vitro without unwanted interference of the hypoxia-inducing agent on the cultured cells. The system could help to further unravel hypoxia-associated mechanisms that are clinically relevant in various tissues and organs. PMID:24046359
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MICROWAVE-ACCELERATED MULTICOMPONENT REACTIONS UNDER SOLVENT-FREE CONDITIONS
The application of microwave-accelerated solventless synthetic protocols in multicomponent (MCC) reactions will be exemplified by several condensation and cyclization reactions including the rapid one-pot assembly of valuable heterocyclic compounds from in situ generated intermed...
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Formal Synthesis of (±)-Roseophilin
Bitar, Abdallah Y.; Frontier, Alison J.
2009-01-01
A formal synthesis of (±)-roseophilin is described. Scandium(III)-catalyzed Nazarov cyclization of 2,5-disubstituted N-tosylpyrrole 19 gives a 5,5’-fused ketopyrrole, and ansa-bridge formation via π-allyl palladium macrocyclization gives 21. PMID:19053717
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Mechanisms of nitric oxide-mediated inhibition of EMT in cancer
Baritaki, Stavroula; Huerta-Yepez, Sara; Sahakyan, Anna; Karagiannides, Iordanis; Bakirtzi, Kyriaki; Jazirehi, Ali R
2010-01-01
The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressors Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NFκB and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NFκB activity, may also inhibit Snail, induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts treated with DETANONOate. The present findings show, for the first time, the novel role of high, yet, subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis. PMID:21150329
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Shukla, Suneet; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J.; Robey, Robert W.; Zhang, Li; Yang, Dong-Hua; Talele, Tanaji T.; Bates, Susan E.; Ambudkar, Suresh V.; Chen, Zhe-Sheng
2014-01-01
ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients. PMID:24980828
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Wang, De-Shen; Patel, Atish; Shukla, Suneet; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J; Robey, Robert W; Zhang, Li; Yang, Dong-Hua; Talele, Tanaji T; Bates, Susan E; Ambudkar, Suresh V; Xu, Rui-Hua; Chen, Zhe-Sheng
2014-06-30
ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
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Song, Ming-Yu; Cao, Chen-Yu; He, Qiu-Rui; Dong, Qing-Miao; Li, Ding; Tang, Jiang-Jiang; Gao, Jin-Ming
2017-10-15
[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc) 3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC 50 value of 0.47μM, and compound 5p exhibted highest activity on HeLa cells with IC 50 vaule of 2.32µM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly. Immunohistochemistry studies and cell cycle distribution analysis indicated that 6g severely disrupted microtubule network and significantly arrested most cells in the G2/M phase of the cell cycle in PC-3 cells. In addition, molecular docking studies showed that two chiral isomers of 6g can bind efficiently and similarly at colchicine binding site of tubulin. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Clevenger, Kenneth D; Ye, Rosa; Bok, Jin Woo; Thomas, Paul M; Islam, Md Nurul; Miley, Galen P; Robey, Matthew T; Chen, Cynthia; Yang, KaHoua; Swyers, Michael; Wu, Edward; Gao, Peng; Wu, Chengcang C; Keller, Nancy P; Kelleher, Neil L
2018-03-20
The benzodiazepine benzomalvin A/D is a fungally derived specialized metabolite and inhibitor of the substance P receptor NK1, biosynthesized by a three-gene nonribosomal peptide synthetase cluster. Here, we utilize fungal artificial chromosomes with metabolomic scoring (FAC-MS) to perform molecular genetic pathway dissection and targeted metabolomics analysis to assign the in vivo role of each domain in the benzomalvin biosynthetic pathway. The use of FAC-MS identified the terminal cyclizing condensation domain as BenY-C T and the internal C-domains as BenZ-C 1 and BenZ-C 2 . Unexpectedly, we also uncovered evidence suggesting BenY-C T or a yet to be identified protein mediates benzodiazepine formation, representing the first reported benzodiazepine synthase enzymatic activity. This work informs understanding of what defines a fungal C T domain and shows how the FAC-MS platform can be used as a tool for in vivo analyses of specialized metabolite biosynthesis and for the discovery and dissection of new enzyme activities.
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Beemelmanns, Christine; Reissig, Hans-Ulrich
2015-06-01
This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI2 allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI2 -induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Murai, Masahito; Takeuchi, Yutaro; Yamauchi, Kanae; Kuninobu, Yoichiro; Takai, Kazuhiko
2016-04-18
Mechanistic insight into the construction of quaternary silicon chiral centers by rhodium-catalyzed synthesis of spiro-9-silabifluorenes through dehydrogenative silylation is reported. The C2 -symmetric bisphosphine ligand, BINAP, was effective in controlling enantioselectivity, and axially chiral spiro-9-silabifluorenes were obtained in excellent yields with high enantiomeric excess. Monitoring of the reaction revealed the presence of a monohydrosilane intermediate as a mixture of two constitutional isomers. The reaction proceeded through two consecutive dehydrogenative silylations, and the absolute configuration was determined in the first silylative cyclization. Competitive reactions with electron-rich and electron-deficient dihydrosilanes indicated that the rate of silylative cyclization increased with decreasing electron density on the silicon atom of the starting dihydrosilane. Further investigation disclosed a rare interconversion between the two constitutional isomers of the monohydrosilane intermediate with retention of the absolute configuration. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Tuneable enhancement of the salt and thermal stability of polymeric micelles by cyclized amphiphiles
Honda, Satoshi; Yamamoto, Takuya; Tezuka, Yasuyuki
2013-01-01
Cyclic molecules provide better stability for their aggregates. Typically in nature, the unique cyclic cell membrane lipids allow thermophilic archaea to inhabit extreme conditions. By mimicking the biological design, the robustness of self-assembled synthetic nanostructures is expected to be improved. Here we report topology effects by cyclized polymeric amphiphiles against their linear counterparts, demonstrating a drastic enhancement in the thermal, as well as salt stability of self-assembled micelles. Furthermore, through coassembly of the linear and cyclic amphiphiles, the stability was successfully tuned for a wide range of temperatures and salt concentrations. The enhanced thermal/salt stability was exploited in a halogen exchange reaction to stimulate the catalytic activity. The mechanism for the enhancement was also investigated. These topology effects by the cyclic amphiphiles offer unprecedented opportunities in polymer materials design unattainable by traditional means. PMID:23481382