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Sample records for backbone metal cyclization

  1. Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase

    PubMed Central

    Harris, Karen S.; Durek, Thomas; Kaas, Quentin; Poth, Aaron G.; Gilding, Edward K.; Conlan, Brendon F.; Saska, Ivana; Daly, Norelle L.; van der Weerden, Nicole L.; Craik, David J.; Anderson, Marilyn A.

    2015-01-01

    Cyclotides are diverse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express OaAEP1b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, OaAEP1b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant OaAEP1b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired. PMID:26680698

  2. Changing the topology of protein backbone: the effect of backbone cyclization on the structure and dynamics of a SH3 domain

    NASA Astrophysics Data System (ADS)

    Schumann, Frank; Varadan, Ranjani; Tayakuniyil, Praveen; Grossman, Jennifer; Camarero, Julio; Fushman, David

    2015-04-01

    Understanding of the effects of the backbone cyclization on the structure and dynamics of a protein is essential for using protein topology engineering to alter protein stability and function. Here we have determined, for the first time, the structure and dynamics of the linear and various circular constructs of the N-SH3 domain from protein c-Crk. These constructs differ in the length and amino acid composition of the cyclization region. The backbone cyclization was carried out using intein-mediated intramolecular chemical ligation between the juxtaposed N- and the C-termini. The structure and backbone dynamics studies were performed using solution NMR. Our data suggest that the backbone cyclization has little effect on the overall three-dimensional structure of the SH3 domain: besides the termini, only minor structural changes were found in the proximity of the cyclization region. In contrast to the structure, backbone dynamics are significantly affected by the cyclization. On the subnanosecond time scale, the backbone of all circular constructs on average appears more rigid than that of the linear SH3 domain; this effect is observed over the entire backbone and is not limited to the cyclization site. The backbone mobility of the circular constructs becomes less restricted with increasing length of the circularization loop. In addition, significant conformational exchange motions (on the sub-millisecond time scale) were found in the N-Src loop and in the adjacent β-strands in all circular constructs studied in this work. These effects of backbone cyclization on protein dynamics have potential implications for the stability of the protein fold and for ligand binding.

  3. Metalated Nitriles: Cation-Controlled Cyclizations

    PubMed Central

    Fleming, Fraser F.; Wei, Yunjing; Liu, Wang; Zhang, Zhiyu

    2008-01-01

    Judicious choice of cation allows the selective cyclization of substituted γ-hydroxynitriles to trans- or cis-decalins and trans- or cis-bicyclo[5.4.0]-undecanes. The stereoselectivities are consistent with deprotonations generating two distinctly different metalated nitriles: an internally coordinated nitrile anion with BuLi, and a C-magnesiated nitrile with i-PrMgCl. Employing cations to control the geometry of metalated nitriles permits stereodivergent cyclizations with complete control over the stereochemistry of the quaternary, nitrile-bearing carbon. PMID:17579448

  4. Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer.

    PubMed

    Wu, Xiaosa; Huang, Yen-Hua; Kaas, Quentin; Harvey, Peta J; Wang, Conan K; Tae, Han-Shen; Adams, David J; Craik, David J

    2017-08-28

    Conotoxin GeXIVA inhibits the α9α10 nicotinic acetylcholine receptor (nAChR) and is analgesic in animal models of pain. α-conotoxins have four cysteines, which can have three possible disulfide connectivities: globular (CysI-CysIII and CysII-CysIV); ribbon (CysI-CysIV and CysII-CysIII) or bead (CysI-CysII and CysIII-CysIV). Native α-conotoxins preferably adopt the globular connectivity, and previous studies of α-conotoxins have focused on the globular isomers as the ribbon and bead isomers typically have lower potency at nAChRs than the globular form. A recent report showed that the bead and ribbon isomers of GeXIVA are more potent than the globular isomer, with low nanomolar half maximal inhibitory concentrations (IC50s). Despite this high potency, the therapeutic potential of GeXIVA is limited because, like most peptides, it is susceptible to proteolytic degradation and is challenging to synthesize in high yield. Here we used backbone cyclization as a strategy to improve the folding yield as well as increase the serum stability of ribbon GeXIVA while preserving activity at the α9α10 nAChR. Specifically, cyclization of ribbon GeXIVA with a two-residue linker maintained the biological activity at the human α9α10 nAChR and improved stability in human serum. Short linkers led to selective formation of the ribbon disulfide isomer without requiring orthogonal protection. Overall, this study highlights the value of backbone cyclization in directing folding, improving yields and stabilizing conotoxins with therapeutic potential. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

  5. Understanding GFP chromophore biosynthesis: controlling backbone cyclization and modifying post-translational chemistry.

    PubMed

    Barondeau, David P; Kassmann, Carey J; Tainer, John A; Getzoff, Elizabeth D

    2005-02-15

    The Aequorea victoria green fluorescent protein (GFP) undergoes a remarkable post-translational modification to create a chromophore out of its component amino acids S65, Y66, and G67. Here, we describe mutational experiments in GFP designed to convert this chromophore into a 4-methylidene-imidazole-5-one (MIO) moiety similar to the post-translational active-site electrophile of histidine ammonia lyase (HAL). Crystallographic structures of GFP variant S65A Y66S (GFPhal) and of four additional related site-directed mutants reveal an aromatic MIO moiety and mechanistic details of GFP chromophore formation and MIO biosynthesis. Specifically, the GFP scaffold promotes backbone cyclization by (1) favoring nucleophilic attack by close proximity alignment of the G67 amide lone pair with the pi orbital of the residue 65 carbonyl and (2) removing enthalpic barriers by eliminating inhibitory main-chain hydrogen bonds in the precursor state. GFP R96 appears to induce structural rearrangements important in aligning the molecular orbitals for ring cyclization, favor G67 nitrogen deprotonation through electrostatic interactions with the Y66 carbonyl, and stabilize the reduced enolate intermediate. Our structures and analysis also highlight negative design features of the wild-type GFP architecture, which favor chromophore formation by destabilizing alternative conformations of the chromophore tripeptide. By providing a molecular basis for understanding and controlling the driving force and protein chemistry of chromophore creation, this research has implications for expansion of the genetic code through engineering of modified amino acids.

  6. Evaluation of backbone-cyclized HER2-binding 2-helix affibody molecule for in vivo molecular imaging.

    PubMed

    Honarvar, Hadis; Jokilaakso, Nima; Andersson, Karl; Malmberg, Jennie; Rosik, Daniel; Orlova, Anna; Karlström, Amelie Eriksson; Tolmachev, Vladimir; Järver, Peter

    2013-04-01

    Affibody molecules, small scaffold proteins, have demonstrated an appreciable potential as imaging probes. Affibody molecules are composed of three alpha-helices. Helices 1 and 2 are involved in molecular recognition, while helix 3 provides stability. The size of Affibody molecules can be reduced by omitting the third alpha-helix and cross-linking the two remaining, providing a smaller molecule with better extravasation and quicker clearance of unbound tracer. The goal of this study was to develop a novel 2-helix Affibody molecule based on backbone cyclization by native chemical ligation (NCL). The HER2-targeting NCL-cyclized Affibody molecule ZHER2:342min has been designed, synthesized and site-specifically conjugated with a DOTA chelator. DOTA-ZHER2:342min was labeled with (111)In and (68)Ga. The binding affinity of DOTA-ZHER2:342min was evaluated in vitro. The targeting properties of (111)In- and (68)Ga-DOTA-ZHER2:342min were evaluated in mice bearing SKOV-3 xenografts and compared with the properties of (111)In- and (68)Ga-labeled PEP09239, a DOTA-conjugated 2-helix Affibody analogue cyclized by a homocysteine disulfide bridge. The dissociation constant (KD) for DOTA-ZHER2:342min binding to HER2 was 18nM according to SPR measurements. DOTA-ZHER2:342min was labeled with (111)In and (68)Ga. Both conjugates demonstrated bi-phasic binding kinetics to HER2-expressing cells, with KD1 in low nanomolar range. Both variants demonstrated specific uptake in HER2-expressing xenografts. Tumor-to-blood ratios at 2h p.i. were 6.1±1.3 for (111)In- DOTA-ZHER2:342min and 4.6±0.7 for (68)Ga-DOTA-ZHER2:342min. However, the uptake of DOTA-ZHER2:342min in lung, liver and spleen was appreciably higher than the uptake of PEP09239-based counterparts. Native chemical ligation enables production of a backbone-cyclized HER2-binding 2-helix Affibody molecule (ZHER2:342min) with low nanomolar target affinity and specific tumor uptake. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the α-conotoxin MII

    PubMed Central

    Clark, Richard J.; Fischer, Harald; Dempster, Louise; Daly, Norelle L.; Rosengren, K. Johan; Nevin, Simon T.; Meunier, Frederic A.; Adams, David J.; Craik, David J.

    2005-01-01

    Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the α-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine. PMID:16162671

  8. Enantioselective Cyclizations of Silyloxyenynes Catalyzed by Cationic Metal Phosphine Complexes

    PubMed Central

    Brazeau, Jean-François; Zhang, Suyan; Colomer, Ignacio; Corkey, Britton K.; Toste, F. Dean

    2012-01-01

    The discovery of complementary methods for enantioselective transition-metal-catalyzed cyclization with silyloxyenynes has been accomplished using chiral phosphine ligands. Under palladium catalysis, 1,6-silyloxyenynes bearing a terminal alkyne led to the desired 5-membered ring with high enantioselectivities (up to 91% ee). As for reactions under cationic gold catalysis, 1,6- and 1,5-silyloxyenynes bearing an internal alkyne furnished the chiral cyclopentane derivatives with excellent enantiomeric excess (up to 94% ee). Modification of the substrate by incorporating an α,β-unsaturation led to the discovery of a tandem cyclization. Remarkably, using silyloxy-1,3-dien-7-ynes under gold catalysis conditions provided the bicyclic derivatives with excellent diastereo- and enantioselectivities (up to >20:1 dr and 99% ee). PMID:22296571

  9. Intein-mediated backbone cyclization of VP1 protein enhanced protection of CVB3-induced viral myocarditis

    PubMed Central

    Qi, Xingmei; Xiong, Sidong

    2017-01-01

    CVB3 is a common human pathogen to be highly lethal to newborns and causes viral myocarditis and pancreatitis in adults. However, there is no vaccine available for clinical use. CVB3 capsid protein VP1 is an immunodominant structural protein, containing several B- and T-cell epitopes. However, immunization of mice with VP1 protein is ineffective. Cyclization of peptide is commonly used to improve their in vivo stability and biological activity. Here, we designed and synthesizd cyclic VP1 protein by using engineered split Rma DnaB intein and the cyclization efficiency was 100% in E. coli. As a result, the cyclic VP1 was significantly more stable against irreversible aggregation upon heating and against carboxypeptidase in vitro and the degradation rate was more slowly in vivo. Compared with linear VP1, immunization mice with circular VP1 significantly increased CVB3-specific serum IgG level and augmented CVB3-specific cellular immune responses, consequently afforded better protection against CVB3-induced viral myocarditis. The cyclic VP1 may be a novel candidate protein vaccine for preventing CVB3 infection and similar approaches could be employed to a variety of protein vaccines to enhance their protection effect. PMID:28148910

  10. Green chemistry: solvent- and metal-free Prins cyclization. Application to sequential reactions.

    PubMed

    Clarisse, Damien; Pelotier, Béatrice; Piva, Olivier; Fache, Fabienne

    2012-01-04

    Prins cyclization between a homoallylic alcohol and an aldehyde, promoted by trimethylsilyl halide, afforded 4-halo-tetrahydropyrans with good to excellent yields. Thanks to the absence of the solvent and metal, the THP thus obtained have been implicated without purification in several other reactions, in a sequential way, affording in particular new indole derivatives.

  11. Selective synthesis of indazoles and indoles via triazene-alkyne cyclization switched by different metals.

    PubMed

    Fang, Yan; Wang, Chengming; Su, Shengqin; Yu, Haizhu; Huang, Yong

    2014-02-21

    We described two orthogonal heterocycle syntheses, where an arene bearing both an alkyne and a triazene functionality underwent two distinct cyclization pathways mediated by different transition metals. Starting from the same substrates, a synthesis of 2H-indazole was accomplished by a Cu(II) salt promoted oxidative cyclization, while 2-substituted indoles could be accessed via a Ag(I) salt mediated N-N bond cleavage. This method represents the first synthesis of indoles from alkynyl triazenes. Computational analysis was performed for both reaction pathways, supporting a Lewis acid role for Cu and a π-acid catalysis for Ag.

  12. Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination.

    PubMed

    Giblin, M F; Wang, N; Hoffman, T J; Jurisson, S S; Quinn, T P

    1998-10-27

    alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-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-alpha-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-alpha-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 alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.

  13. Design and characterization of α-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination

    PubMed Central

    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

  14. Template-induced diverse metal-organic materials as catalysts for the tandem acylation-Nazarov cyclization.

    PubMed

    Huang, Chao; Ding, Ran; Song, Chuanjun; Lu, Jingjing; Liu, Lu; Han, Xiao; Wu, Jie; Hou, Hongwei; Fan, Yaoting

    2014-12-01

    In our continuing quest to develop a metal-organic framework (MOF)-catalyzed tandem pyrrole acylation-Nazarov cyclization reaction with α,β-unsaturated carboxylic acids for the synthesis of cyclopentenone[b]pyrroles, which are key intermediates in the synthesis of natural product (±)-roseophilin, a series of template-induced Zn-based (1-3) metal-organic frameworks (MOFs) have been solvothermally synthesized and characterized. Structural conversions from non-porous MOF 1 to porous MOF 2, and back to non-porous MOF 3 arising from the different concentrations of template guest have been observed. The anion-π interactions between the template guests and ligands could affect the configuration of ligands and further tailor the frameworks of 1-3. Futhermore, MOFs 1-3 have shown to be effective heterogeneous catalysts for the tandem acylation-Nazarov cyclization reaction. In particular, the unique structural features of 2, including accessible catalytic sites and suitable channel size and shape, endow 2 with all of the desired features for the MOF-catalyzed tandem acylation-Nazarov cyclization reaction, including heterogeneous catalyst, high catalytic activity, robustness, and excellent selectivity. A plausible mechanism for the catalytic reaction has been proposed and the structure-reactivity relationship has been further clarified. Making use of 2 as a heterogeneous catalyst for the reaction could greatly increase the yield of total synthesis of (±)-roseophilin. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Metal-induced cyclization of thiosemicarbazones derived from beta-keto amides and beta-keto esters: open-chain and cyclized ligands in zinc(II) complexes.

    PubMed

    Casas, José S; Castaño, María V; Castellano, Eduardo E; Ellena, Javier; García-Tasende, María S; Gato, Angeles; Sánchez, Agustín; Sanjuán, Luisa M; Sordo, José

    2002-03-25

    The reactions of Zn(OAc)(2) with acetoacetanilide, methyl acetoacetate, o-acetoacetanisidide, and ethyl 2-methylacetoacetate thiosemicarbazones (HTSC(1), HTSC(2), HTSC(3), and HTSC(4), respectively) were explored in methanol. With HTSC(1), HTSC(2), and HTSC(3), following isolation of the corresponding zinc(II) thiosemicarbazonates [Zn(TSC(x))(2)] (x = 1, 2, 3), the mother liquors afforded pyrazolonate complexes [ZnL(1)(2)(H(2)O)] (HL(1) = 2,5-dihydro-3-methyl-5-oxo-1H-pyrazole-1-carbothioamide) that had been formed by cyclization of the corresponding TSC(-). The reaction of HTSC(4) with zinc(II) acetate gave only the pyrazolonate complex [ZnL(2)(2)(H(2)O)] (HL(2) = 2,5-dihydro-3,4-dimethyl-5-oxo-1H-pyrazole-1-carbothioamide). All compounds were studied by IR and NMR spectroscopy, and HTSC(3), [Zn(TSC(3))(2)] x DMSO, [ZnL(1)(2)(H(2)O)] x 2DMSO, and [ZnL(2)(2)(H(2)O)] x 2DMSO were also studied by X-ray diffractometry, giving a thorough picture of the cyclization process. In preliminary tests of the effects of HL(1) and [ZnL(1)(2)(H(2)O)] on rat paw inflammatory edema induced by carrageenan, HL(1) showed antiinflammatory activity.

  16. The Construction of Metal-Organic Framework with Active Backbones by the Utilization of Reticular Chemistry

    NASA Astrophysics Data System (ADS)

    Choi, Eunwoo

    With the principles of reticular chemistry, metal-organic frameworks with ultra-high porosity, chiral-recognition unit as a chiral stationary phase, metalloporhyrins for enhanced hydrogen adsorption and an intrinsic conductivity to form porous conductors, have been prepared. This dissertation presents how the principles of reticular chemistry were utilized to achieve in the preparations of metal-organic frameworks with a large surface area and active backbones. Through the simple isoreticular (having the same framework topology) expansion from MOF-177 composed with 1,3,5-tris(4'-carboxyphenyl-)benzene (BTB3-) as the strut; MOF-200 was prepared with 4,4',4"-(benzene-1,3,5-triyl-tris(benzene-4,1-diy1))tribenzoic acid an extension from BTB3- by a phenylene unit to yield one of the most porous MOFs with a Langmuir surface area of 10,400 m2. and the lowest density of 0.22 cm3.g-1. A successful thermal polymerization reaction at 325 °C inside of the pores of highly porous MOF, MOF-177, was performed and verified the integrity of the MOF structure even after the thermal reaction. 1,4-Diphenylbutadiyne that is known to polymerize upon heating to form a conjugated backbone was impregnated via solution-diffusion into MOF-177 and then subsequently polymerized by heat to form polymer impregnated MOF-177. Characterization was carried out using powder X-ray diffraction and volumetric sorption analyzer. MOF-1020 with a linear quaterphenyl dicarboxylate-based strut was designed to contain a chiral bisbinaphthyl crown-ether moiety for alkyl ammonium resolution was precisely placed into a Zn4O(CO2)6-based cubic MOF structure. Unfortunately, the chiral resolution was not achieved due to the sensitivity and the pore environment of MOF-1020. However, an interesting phenomenon was observed, where the loss of crystallinity occurs upon solvent removal while the crystallites remain shiny and crystalline, but it readily is restored upon re-solvation of the crystallites. This rare

  17. Hydride-induced anionic cyclization: an efficient method for the synthesis of 6-H-phenanthridines via a transition-metal-free process.

    PubMed

    Chen, Wei-Lin; Chen, Chun-Yuan; Chen, Yan-Fu; Hsieh, Jen-Chieh

    2015-03-20

    A novel procedure for hydride-induced anionic cyclization has been developed. It includes the reduction of a biaryl bromo-nitrile with a nucleophilic aromatic substitution (S(N)Ar). A range of polysubstituted 6-H-phenanthridines were so obtained in moderate to good yield with good substrate tolerance. This method involves a concise transition-metal-free process and was applied to synthesize natural alkaloids.

  18. Comparative experimental investigation on the actuation mechanisms of ionic polymer–metal composites with different backbones and water contents

    SciTech Connect

    Zhu, Zicai; Chang, Longfei; Wang, Yanjie; Chen, Hualing; Asaka, Kinji; Zhao, Hongxia; Li, Dichen

    2014-03-28

    Water-based ionic polymer–metal composites (IPMCs) exhibit complex deformation properties, especially when the water content changes. To explore the general actuation mechanisms, both Nafion and Flemion membranes are used as the polymer backbones. IPMC deformation includes three stages: fast anode deformation, relaxation deformation, and slow anode deformation, which is mainly dependent on the water content and the backbone. When the water content decreases from 21 to 14 wt. %, Nafion–IPMC exhibits a large negative relaxation deformation, zero deformation, a positive relaxation deformation, and a positive steady deformation without relaxation in sequence. Despite the slow anode deformation, Flemion–IPMC also shows a slight relaxation deformation, which disappears when the water content is less than 13 wt. %. The different water states are investigated at different water contents using nuclear magnetic resonance spectroscopy. The free water, which decreases rapidly at the beginning through evaporation, is proven to be critical for relaxation deformation. For the backbone, indirect evidence from the steady current response is correlated with the slow anode deformation of Flemion-IPMC. The latter is explained by the secondary dissociation of the weak acid group –COOH. Finally, we thoroughly explain not only the three deformations by swelling but also their evolvement with decreasing water content. A fitting model is also presented based on a multi-diffusion equation to reveal the deformation processes more clearly, the results from which are in good agreement with the experimental results.

  19. A 7-Step Formal Asymmetric Total Synthesis of Strictamine via an Asymmetric Propargylation and Metal-Mediated Cyclization.

    PubMed

    Smith, Myles W; Zhou, Zhiyao; Gao, Alison X; Shimbayashi, Takuya; Snyder, Scott A

    2017-03-03

    Herein is shown how a novel catalytic asymmetric propargylation of 3,4-dihydro-β-carboline, followed by a designed Au(I)/Ag(I)-mediated 6-endo-dig cyclization, can directly deliver the indolenine-fused methanoquinolizidine core of the akuammiline alkaloid strictamine in its native oxidation state, ultimately achieving a 7-step formal asymmetric total synthesis. Also demonstrated are how the cyclization products can rearrange into vincorine-type skeletons and a further use for the developed propargylation with the first catalytic asymmetric total synthesis of decarbomethoxydihydrogambirtannine.

  20. Synthesis of 3-carboxylated indoles through a tandem process involving cyclization of 2-ethynylanilines followed by CO2 fixation in the absence of transition metal catalysts.

    PubMed

    Inamoto, Kiyofumi; Asano, Narumi; Nakamura, Yuka; Yonemoto, Misato; Kondo, Yoshinori

    2012-05-18

    In this study, a facile synthesis of 3-carboxylated indoles involving a tandem-type cyclization of 2-ethynylanilines and subsequent CO2 fixation at the 3-position of the indole ring is realized. The reaction proceeds efficiently at 65 °C under 10 atm of CO2, giving rise to variously substituted 3-carboxylated indoles, generally in high yields. An inorganic base, such as K2CO3, is the only reagent required, and the addition of transition metal catalysts is not necessary. The method provides a novel, simple, and promising strategy for CO2 fixation in the research field of heterocyclic chemistry.

  1. Differentiating between fluorescence-quenching metal ions with polyfluorophore sensors built on a DNA backbone.

    PubMed

    Tan, Samuel S; Kim, Su Jeong; Kool, Eric T

    2011-03-02

    A common problem in detecting metal ions with fluorescentchemosensors is the emission-suppressing effects of fluorescence-quenching metal ions. This quenching tendency makes it difficult to design sensors with turn-on signal, and differentiate between several metal ions that may yield a strong quenching response. To address these challenges, we investigate a new sensor design strategy, incorporating fluorophores and metal ligands as DNA base replacements in DNA-like oligomers, for generating a broader range of responses for quenching metal ions. The modular molecular design enabled rapid synthesis and discovery of sensors from libraries on PEG-polystyrene beads. Using this approach, water-soluble sensors 1-5 were identified as strong responders to a set of eight typically quenching metal ions (Co(2+), Ni(2+), Cu(2+), Hg(2+), Pb(2+), Ag(+), Cr(3+), and Fe(3+)). They were synthesized and characterized for sensing responses in solution. Cross-screening with the full set of metal ions showed that they have a wide variety of responses, including emission enhancements and red- and blue-shifts. The diversity of sensor responses allows as few as two sensors (1 and 2) to be used together to successfully differentiate these eight metals. As a test, a set of unknown metal ion solutions in blind studies were also successfully identified based on the response pattern of the sensors. The modular nature of the sensor design strategy suggests a broadly applicable approach to finding sensors for differentiating many different cations by pattern-based recognition, simply by varying the sequence and composition of ligands and fluorophores on a DNA synthesizer.

  2. C-C bond formation and related reactions at the CNC backbone in (smif)FeX (smif = 1,3-di-(2-pyridyl)-2-azaallyl): dimerizations, 3 + 2 cyclization, and nucleophilic attack; transfer hydrogenations and alkyne trimerization (X = N(TMS)2, dpma = (di-(2-pyridyl-methyl)-amide)).

    PubMed

    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.

  3. Synthesis and structural characterization of one- and two-dimensional coordination polymers based on platinum-silver metallic backbones.

    PubMed

    Liu, Fenghui; Chen, Wanzhi; Wang, Daqi

    2006-06-28

    Seven Pt-Ag coordination polymers [Pt(NH3)2(NHCO(t)Bu)2Ag(H2O)](ClO4) (1), [Pt2(dap)2(NHCO(t)Bu)4Ag2(NO3)(ClO4)] (dap = 1,2-diaminopropane, 2), [Pt2(en)2(NHCO(t)Bu)4Ag2(m-C6H4(CO2)2)].3H2O (en = ethylenediamine, 3), [Pt2(NH3)2(NHCO(t)Bu)2Ag2(p-C6H4(CO2)2)].2H2O (4), [Pt3(en)3(NHCO(t)Bu)6Ag2(p-C6H4(CO2)2)(1.5)].6H2O (5), [Pt(NH3)2(NHCO(t)Bu)4Ag(4-C5H4NCO2)2].10H2O (6), and [Pt2(en)2(NHCO(t)Bu)4Ag2(4-C5H4NCO2)](ClO4) (7) were synthesized from the corresponding [Pt(RNH2)2(NHCO(t)Bu)2] and Ag salts, respectively, and their structures were determined by X-ray crystallography. The Pt and Ag units aggregate into one-dimensional chains based on Pt-Ag backbones. Compounds 1, 2, and 6 possess an extended zigzag Pt-Ag chain motif, and the metallic chains arrange in a parallel fashion into layered structures. Compounds 3-5, and 7 form 2-D brick wall sheets due to the coordination of the bifunctional anions to the Ag+ ions of the neighboring chains. These polymers are constructed based on the Pt-Ag interactions and the coordination of amidate oxygen atoms to Ag ions. There are three kinds of short Pt-Ag bonds observed in the structures of these compounds. The Pt-Ag metallic backbone is formed by the stacking unsupported Pt-Ag bonds, the amidate doubly bridged Pt-Ag bonds, and the amidate singly bridged Pt-Ag bonds. In the chains, the Pt-Ag bond distances are quite short, and appear in the range of 2.78-2.97 A, which are comparable to known Pt-Ag dative bonds.

  4. Samarium(II) induced asymmetric reductive cyclizations: The total synthesis of (-)-C{sub 10} desmethyl arteannuin B

    SciTech Connect

    Schwaebe, M.K.; Little, R.D.

    1995-12-31

    Arteannuin B is a member of the qinghaosu family, a novel class of sesquiterpenes that exhibit powerful antimalarial activity even against chloroquinine resistant strains. It is readily convertible to qinghaosu in several high yielding steps and has potential antitumor activity. Several approaches to the construction of the cis-decalin backbone have involved the use of electrochemical and metal promoted reductions as well as alkylations. We report a short convenient total synthesis of (-)-C{sub 10} desmethyl arteannuin B utilizing an asymmetric reductive cyclization with samarium (II) iodide which selectively forms the cis-decalin ring structure while setting the trans relationship between the subunits of the {gamma}-hydroxy ester.

  5. Allene ether Nazarov cyclization.

    PubMed

    Tius, Marcus A

    2014-05-07

    The ease of synthesis and the exceptional reactivity of alkoxyallenes has led to their use in a large number of highly diverse applications. This Report describes their use in various versions of the allene ether Nazarov cyclization. Following a brief introduction to the Nazarov cyclization (Section 1), the oxidative cyclization of vinyl alkoxyallenes is discussed first (Section 2). Nazarov cyclizations of α-alkoxyallenyl vinyl ketones and of α-alkoxyallenyl vinyl tertiary carbinols are covered (Section 3). The discovery and the subsequent rational design of acetals that serve as chiral auxiliaries on the allene in highly enantioselective Nazarov cyclizations is explained (Section 4). Interrupted Nazarov cyclizations of alkoxyallenes that are generated in situ from the isomerization of propargyl ethers on solid supports are discussed, including the evolution of a highly diastereoselective, chiral auxiliary controlled version of the reaction. Some applications of the methodology to natural products total synthesis have been included so as to provide the reader with benchmarks with which to judge the utility of the methodology.

  6. [Formula: see text]-mediated amination/cyclization of ketones with 2-aminopyridines under high-speed ball milling: solvent- and metal-free synthesis of 2,3-substituted imidazo[1,2-a]pyridines and zolimidine.

    PubMed

    Wang, Fang-Jian; Xu, Hui; Xin, Ming; Zhang, Ze

    2016-08-01

    Under solvent-free high-speed ball milling, an I[Formula: see text]-promoted condensation/cyclization of easily available methyl ketones or 1,3-dicarbonyl compounds with 2-aminopyridines has been developed, which allows the quick assembly of 2,3-substituted imidazo[1,2-a]pyridines (IPs) with broad molecular diversity, including the antiulcer drug zolimidine. The advantages of high yields, good functional group compatibility, short reaction time (within 90 min), free use of heating, solvent and metal, employment of cheap starting materials, and simple work-up procedure make this protocol a very efficient alternative to traditional synthesis of IPs.

  7. Synthesis of functionalized β-lactams and pyrrolidine-2,5-diones through a metal-free sequential Ugi-4CR/cyclization reaction.

    PubMed

    Ghabraie, Elmira; Balalaie, Saeed; Mehrparvar, Saber; Rominger, Frank

    2014-09-05

    An efficient approach for the synthesis of functionalized β-lactams and pyrrolidine-2,5-diones was achieved through a sequential Ugi-4CR/cyclization reaction. Diversity-oriented synthesis, good to high yields, easy workup, and short reaction times are advantages of this procedure.

  8. Non-Innocent Behavior of Substrate Backbone Esters in Metal-Catalyzed Carbocyclizations and Friedel-Crafts Reactions of Enynes and Arenynes.

    PubMed

    Michelet, Bastien; Thiery, Guillaume; Bour, Christophe; Gandon, Vincent

    2015-11-06

    On the basis of DFT computations and experimental results, we show that the presence of the ester group in the backbone of organic substrates can influence the mechanism of metal-catalyzed carbocyclization reactions. The non-innocent role of the ester functionality in lowering the activation barrier of the key step of the gallium- and indium-catalyzed cycloisomerization of 1,6-enynes is revealed. In the case of the gallium-catalyzed hydroarylation of arenynes, the esters in the tether can deprotonate the Wheland intermediate, thus avoiding more energetically demanding [1,3]- or [1,2]/[1,2]-H shifts. As for the gallium-catalyzed Friedel-Crafts alkylation, an unusual concerted SEAr mechanism involving the esters has been calculated. Lastly, computations evidence that the ester group of methyl propiolates enables a divergent mechanism in the platinum-catalyzed intramolecular hydroarylation.

  9. Cyclization in opioid peptides.

    PubMed

    Piekielna, Justyna; Perlikowska, Renata; Gach, Katarzyna; Janecka, Anna

    2013-06-01

    Endogenous opioid peptides have been studied extensively as potential therapeutics for the treatment of pain. The major problems of using natural opioid peptides as drug candidates are their poor receptor specificity, metabolic instability and inability to reach the brain after systemic administration. A lot of synthetic efforts have been made to opioid analogs with improved pharmacological properties. One important structural modification leading to such analogs is cyclization of linear sequences. Intramolecular cyclization has been shown to improve biological properties of various bioactive peptides. Cyclization reduces conformational freedom responsible for the simultaneous activation of two or more receptors, increases metabolic stability and lipophilicity which may result in a longer half-life and easier penetration across biological membranes. This review deals with various strategies that have been employed to synthesize cyclic analogs of opioid peptides. Discussed are such bridging bonds as amide and amine linkages, sulfur-containing bonds, including monosulfide, disulfide and dithioether bridges, bismethylene bonds, monosulfide bridges of lanthionine and, finally, carbonyl and guanidine linkages. Opioid affinities and activities of cyclic analogs are given and compared with linear opioid peptides. Analgesic activities of analogs evaluated in the in vivo pain tests are also discussed.

  10. Crosslinking metal nanoparticles into the polymer backbone of hydrogels enables preparation of soft, magnetic field-driven actuators with muscle-like flexibility.

    PubMed

    Fuhrer, Roland; Athanassiou, Evagelos Kimon; Luechinger, Norman Albert; Stark, Wendelin Jan

    2009-03-01

    The combination of force and flexibility is at the core of biomechanics and enables virtually all body movements in living organisms. In sharp contrast, presently used machines are based on rigid, linear (cylinders) or circular (rotator in an electrical engine) geometries. As a potential bioinspired alternative, magnetic elastomers can be realized through dispersion of micro- or nanoparticles in polymer matrices and have attracted significant interest as soft actuators in artificial organs, implants, and devices for controlled drug delivery. At present, magnetic particle loss and limited actuator strength have restricted the use of such materials to niche applications. We describe the direct incorporation of metal nanoparticles into the backbone of a hydrogel and application as an ultra-flexible, yet strong magnetic actuator. Covalent bonding of the particles prevents metal loss or leaching. Since metals have a far higher saturation magnetization and higher density than oxides, the resulting increased force/volume ratio afforded significantly stronger magnetic actuators with high mechanical stability, elasticity, and shape memory effect.

  11. Semienzymatic cyclization of disulfide-rich peptides using Sortase A.

    PubMed

    Jia, Xinying; Kwon, Soohyun; Wang, Ching-I Anderson; Huang, Yen-Hua; Chan, Lai Y; Tan, Chia Chia; Rosengren, K Johan; Mulvenna, Jason P; Schroeder, Christina I; Craik, David J

    2014-03-07

    Disulfide-rich cyclic peptides have generated great interest in the development of peptide-based therapeutics due to their exceptional stability toward chemical, enzymatic, or thermal attack. In particular, they have been used as scaffolds onto which bioactive epitopes can be grafted to take advantage of the favorable biophysical properties of disulfide-rich cyclic peptides. To date, the most commonly used method for the head-to-tail cyclization of peptides has been native chemical ligation. In recent years, however, enzyme-mediated cyclization has become a promising new technology due to its efficiency, safety, and cost-effectiveness. Sortase A (SrtA) is a bacterial enzyme with transpeptidase activity. It recognizes a C-terminal penta-amino acid motif, LPXTG, and cleaves the amide bond between Thr and Gly to form a thioacyl-linked intermediate. This intermediate undergoes nucleophilic attack by an N-terminal poly-Gly sequence to form an amide bond between the Thr and N-terminal Gly. Here, we demonstrate that sortase A can successfully be used to cyclize a variety of small disulfide-rich peptides, including the cyclotide kalata B1, α-conotoxin Vc1.1, and sunflower trypsin inhibitor 1. These peptides range in size from 14 to 29 amino acids and contain three, two, or one disulfide bond, respectively, within their head-to-tail cyclic backbones. Our findings provide proof of concept for the potential broad applicability of enzymatic cyclization of disulfide-rich peptides with therapeutic potential.

  12. Base-mediated synthesis of quinazolines: Cyclization reaction between 2-nitrobenzylalcohol and benzylamine

    NASA Astrophysics Data System (ADS)

    Li, Xiaowei; Mu, Wanlu; Wang, Longfei; Chen, Yong; Li, Huijing

    2017-08-01

    A transition-metal-catalyst free, base-mediated cyclization reaction of 2-nitrobenzyl alcohol with benzylamine for the construction of quinazolines has been demonstrated. The reaction provides an intramolecular redox process, which is readily synthesized in a one-step process subsequent base-mediated cyclization.

  13. Oxidative Dearomatization of 4,5,6,7-Tetrahydro-1H-indoles Obtained by Metal- and Solvent-Free Thermal 5-endo-dig Cyclization: The Route to Erythrina and Lycorine Alkaloids.

    PubMed

    Andreev, Ivan A; Ratmanova, Nina K; Novoselov, Anton M; Belov, Dmitry S; Seregina, Irina F; Kurkin, Alexander V

    2016-05-17

    A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Nazarov-like cyclization reactions.

    PubMed

    Di Grandi, Martin J

    2014-08-07

    The Nazarov cyclization, a well-known method for the formation of cyclopentenones, mechanistically involves the 4π electrocyclization of a 1,4-pentadienyl cation, generated from cross-conjugated divinyl ketones. Recently, advances related to this cyclization, such as the incorporation of heteroatoms as well as the use of cyclopropanes as double bond equivalents have extended the scope of the original reaction. The modifications discussed in this review, which covers the years 2009-2013, have allowed the realization of both heteroatom- and homo-Nazarov cyclizations.

  15. In vitro structure-activity relationship of Re-cyclized octreotide analogues.

    PubMed

    Dannoon, Shorouk F; Bigott-Hennkens, Heather M; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R; Jurisson, Silvia S

    2010-07-01

    Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Various octreotide analogue sequences and coordination systems (e.g., S(2)N(2) and S(3)N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with (111)In-DOTA-Tyr(3)-octreotide in AR42J rat pancreatic tumor cells yielded IC(50) values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr(3)-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr(3)-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS(3) and N(2)S(2) coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of (99m)Tc-cyclized analogue 4. Copyright 2010 Elsevier Inc. All rights reserved.

  16. In Vitro Structure-Activity Relationship of Re-cyclized Octreotide Analogues

    PubMed Central

    Dannoon, Shorouk F.; Bigott-Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.

    2010-01-01

    Introduction Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with non-radioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of somatostatin receptor affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue’s pharmacophore. Results Only two of the eleven Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal-cyclization of octreotide analogues via NS3 and N2S2 coordination forming 5- and 6- membered chelate rings. In vivo biodistribution studies are underway of 99m Tc- cyclized analogue 4. PMID:20610157

  17. Racemization in Prins Cyclization Reactions

    PubMed Central

    Jasti, Ramesh

    2008-01-01

    Isotopic labeling experiments were performed in order to elucidate a new mechanism for racemization in Prins cyclization reactions. The loss in optical activity for these reactions was shown to occur by 2-oxonia-Cope rearrangements by way of a (Z)-oxocarbenium ion intermediate. Reaction conditions such as solvent, temperature, and the nucleophile employed played a critical role in whether an erosion in enantiomeric excess was observed. Additionally, certain structural features of Prins cyclization precursors were also shown to be important for preserving optical purity in these reactions. PMID:17031979

  18. Thermal and metal-catalyzed cyclization of 1-substituted 3,5-dien-1-ynes via a [1,7]-hydrogen shift: development of a tandem aldol condensation-dehydration and aromatization catalysis between 3-en-1-yn-5-al units and cyclic ketones.

    PubMed

    Lian, Jian-Jou; Lin, Chung-Chang; Chang, Hsu-Kai; Chen, Po-Chiang; Liu, Rai-Shung

    2006-08-02

    This work investigates the feasibility of thermal and catalytic cyclization of 6,6-disubstituted 3,5-dien-1-ynes via a 1,7-hydrogen shift. Our strategy began with an understanding of a structural correlation of 3,5-dien-1-ynes with their thermal cyclization efficiency. Thermal cyclization proceeded only with 3,5-dien-1-ynes bearing an electron-withdrawing C(1)-phenyl or C(6)-carbonyl substituent, but the efficiencies were generally low (20-40% yields). On the basis of this structure-activity relationship, we conclude that such a [1,7]-hydrogen shift is characterized by a "protonic" hydrogen shift, which should be catalyzed by pi-alkyne activators. We prepared various 6,6-disubstituted 3,5-dien-1-ynes bearing either a phenyl or a carbonyl group, and we found their thermal cyclizations to be greatly enhanced by RuCl(3), PtCl(2), and TpRuPPh(3)(CH(3)CN)(2)PF(6) catalysts to confirm our hypothesis: the C(7)-H acidity of 3,5-dien-1-ynes is crucial for thermal cyclization. To achieve the atom economy, we have developed a tandem aldol condensation-dehydration and aromatization catalysis between cycloalkanones and special 3-en-1-yn-5-als using the weakly acidic catalyst CpRu(PPh(3))(2)Cl, which provided complex 1-indanones and alpha-tetralones with yields exceeding 65% in most cases. The deuterium-labeling experiments reveal two operable pathways for the metal-catalyzed [1,7]-hydrogen shift of 3,5-dien-1-ynes. Formation of alpha-tetralones d(4)-56 arises from a concerted [1,7]-hydrogen shift, whereas benzene derivative d(4)-9 proceeds through a proton dissociation and reprotonation process.

  19. Polarizing the Nazarov cyclization: the impact of dienone substitution pattern on reactivity and selectivity.

    PubMed

    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.

  20. Butelase-mediated cyclization and ligation of peptides and proteins.

    PubMed

    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.

  1. Semienzymatic Cyclization of Disulfide-rich Peptides Using Sortase A*

    PubMed Central

    Jia, Xinying; Kwon, Soohyun; Wang, Ching-I Anderson; Huang, Yen-Hua; Chan, Lai Y.; Tan, Chia Chia; Rosengren, K. Johan; Mulvenna, Jason P.; Schroeder, Christina I.; Craik, David J.

    2014-01-01

    Disulfide-rich cyclic peptides have generated great interest in the development of peptide-based therapeutics due to their exceptional stability toward chemical, enzymatic, or thermal attack. In particular, they have been used as scaffolds onto which bioactive epitopes can be grafted to take advantage of the favorable biophysical properties of disulfide-rich cyclic peptides. To date, the most commonly used method for the head-to-tail cyclization of peptides has been native chemical ligation. In recent years, however, enzyme-mediated cyclization has become a promising new technology due to its efficiency, safety, and cost-effectiveness. Sortase A (SrtA) is a bacterial enzyme with transpeptidase activity. It recognizes a C-terminal penta-amino acid motif, LPXTG, and cleaves the amide bond between Thr and Gly to form a thioacyl-linked intermediate. This intermediate undergoes nucleophilic attack by an N-terminal poly-Gly sequence to form an amide bond between the Thr and N-terminal Gly. Here, we demonstrate that sortase A can successfully be used to cyclize a variety of small disulfide-rich peptides, including the cyclotide kalata B1, α-conotoxin Vc1.1, and sunflower trypsin inhibitor 1. These peptides range in size from 14 to 29 amino acids and contain three, two, or one disulfide bond, respectively, within their head-to-tail cyclic backbones. Our findings provide proof of concept for the potential broad applicability of enzymatic cyclization of disulfide-rich peptides with therapeutic potential. PMID:24425873

  2. Advances in the Nazarov cyclization.

    PubMed

    Nakanishi, Waka; West, Frederick G

    2009-11-01

    Advances in synthetic methodology using the Nazarov reaction, particularly those published since 2005, are reviewed. Three principal subtopics are considered: stereocontrol (both relative and absolute), domino or cascade reactions initiated by the Nazarov cyclization (the 'interrupted Nazarov reaction'), and alternative substrates (including versions of the 'metallo-Nazarov' reaction).

  3. SpyRing interrogation: analyzing how enzyme resilience can be achieved with phytase and distinct cyclization chemistries

    PubMed Central

    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

  4. Salen promoted enantioselective Nazarov cyclizations of activated and unactivated dienones.

    PubMed

    Hutson, Gerri E; Türkmen, Yunus E; Rawal, Viresh H

    2013-04-03

    A novel class of chiral 5,5'-di(2,4,6-trialkyl)aryl salen-metal complexes have been developed and shown to catalyze highly enantioselective Nazarov cyclization reactions, giving rise to cyclopentenoids in 90:10-98:2 er. Significantly, the catalysts also promote, for the first time, highly enantioselective Nazarov reactions of "unactivated" dienones, producing hydrindenone products having in place three contiguous chiral centers.

  5. Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence.

    PubMed

    Petersen, Rico; Cohrt, A Emil; Petersen, Michael Åxman; Wu, Peng; Clausen, Mads H; Nielsen, Thomas E

    2015-06-01

    Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.

  6. Coarctate cyclization reactions: a primer.

    PubMed

    Young, Brian S; Herges, Rainer; Haley, Michael M

    2012-10-04

    The cleavage of five-membered heterocycles possessing an exocyclic carbene or nitrene to form conjugated ene-ene-yne systems has been documented for over 40 years; however, the reverse reaction, using a conjugated "ene-ene-yne" precursor to form a heterocycle is a relatively new approach. Over the past decade, the Haley and Herges groups have studied computationally and experimentally the cyclization of the "hetero-ene-ene-yne" motif via an unusual class of concerted reactions known as coarctate reactions. This feature article details our synthetic and mechanistic work involving triazene-arene-alkynes and structurally-related systems to generate heterocycles using coarctate chemistry.

  7. Reactions of thiosemicarbazones derived from beta-keto amides and beta-keto esters with Zn(II) and Cd(II) acetates: influence of metal, substitution, reagent ratio and temperature on metal-induced cyclization.

    PubMed

    Casas, José S; Castaño, María V; García-Tasende, María S; Rodríguez-Castellón, Enrique; Sánchez, Agustín; Sanjuán, Luisa M; Sordo, José

    2004-07-07

    Zinc(II) and cadmium(II) acetates were reacted in methanol under various experimental conditions with thiosemicarbazones derived from beta-keto amides or beta-keto esters (HTSC). Some of these reactions afforded thiosemicarbazonate complexes [M(TSC)2] with IR and NMR spectra compatible with N,S-coordination, but most gave complexes [ML2], where HL is a substituted 2,5-dihydro-5-oxo-1H-pyrazole-1-carbothioamide resulting from cyclization of the HTSC. Some of these pyrazolonates and two of the HL ligands were studied by X-ray diffractometry, and their structures are discussed. Surprisingly, the reactions of zinc(II) acetate with HTSC in 1:1 mol ratio usually gave a third, previously unreported type of complex with a dideprotonated ligand, [Zn(L-H)], which was also formed when [ZnL2] and Zn(OAc)2 interacted at room temperature in 1:1 mol ratio. These L-H complexes are highly insoluble in all common solvents, which hinders their characterization but suggests that they are polymeric in nature.

  8. Protein-induced bending and DNA cyclization.

    PubMed

    Kahn, J D; Crothers, D M

    1992-07-15

    We have applied T4 ligase-mediated DNA cyclization kinetics to protein-induced bending in DNA. The presence and direction of a static bend can be inferred from J factors for cyclization of 150- to 160-base-pair minicircles, which include a catabolite activator protein binding site phased against a sequence-directed bend. We demonstrate a quasi-thermodynamic linkage between cyclization and protein binding; we find that properly phased DNAs bind catabolite activator protein approximately 200-fold more tightly as circles than as linear molecules. The results unambiguously distinguish DNA bends from isotropically flexible sites and can explain cooperative binding by proteins that need not contact each other.

  9. Chiral Bidentate NHC Ligands Based on the 1,1'-Binaphthyl Scaffold: Synthesis and Application in Transition-Metal-Catalyzed Asymmetric Reactions.

    PubMed

    Xu, Qin; Gu, Peng; Jiang, Hanchun; Wei, Yin; Shi, Min

    2016-12-01

    The use of the chiral 1,1'-binaphthyl scaffold to construct chiral ligands can be traced back for a long time. However, the development of bidentate NHC ligands based on the same backbone has only appeared recently. In this account, we describe the design and synthesis of a new family of chiral NHC ligands based on the 1,1'-binaphthyl scaffold and demonstrate the applications of these chiral NHC-metal complexes in the catalyzed oxidative kinetic resolution of secondary alcohols, asymmetric carbon-carbon bond formations, hydrosilylations, and cyclizations of 1,6-enynes. The chiral NHC ligands containing the 1,1'-binaphthyl backbone can be synthesized in good yields from enantiomerically pure 1,1'-binaphthyl-2,2'-diamine. These transition metals coordinated with chiral bidentate NHC ligands exhibit high catalytic activities and good enantioselectivities for a wide range of metal-catalyzed asymmetric reactions.

  10. Robust, Chiral, and Porous BINAP-Based Metal–Organic Frameworks for Highly Enantioselective Cyclization Reactions

    SciTech Connect

    Sawano, Takahiro; Thacker, Nathan C.; Lin, Zekai; McIsaac, Alexandra R.; Lin, Wenbin

    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) 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.

  11. Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems.

    PubMed

    Itoh, Toshiyuki; Nokami, Toshiki; Kawatsura, Motoi

    2016-06-01

    Nazarov cyclization is an important and versatile method for the synthesis of five-membered carbocycles, and extensive studies have been conducted to optimize the reaction. Among recent studies, several trends are recognized. One is the combination of different reactions with Nazarov cyclization in a one-pot reaction system which enables the preparation of unique cyclization products. The second is the use of a transition-metal catalyst, though Lewis or Brønsted acids have generally been used for the reaction. The third is the realization of the asymmetric Nazarov cyclization. The fourth is the base-catalyzed Nazarov cyclization. Furthermore, several useful protocols for realizing Nazarov cyclization have also been developed. The recent progress on Nazarov cyclizations is summarized in Section 2. Section 3 is our chronicle in this field. We focused on the use of iron as the catalyst in Nazarov cyclizations and ionic liquids as solvents: Nazarov cyclization of thiophene derivatives using FeCl3 as the catalyst was accomplished and we succeeded in demonstrating the first example of an iron-catalyzed asymmetric Nazarov reaction. We next established Nazarov cyclization of pyrrole or indole derivatives using Fe(ClO4 )3 ·Al2 O3 as the catalyst with high trans selectivities in excellent yields. Since the cyclized product was reacted with a vinyl ketone in the presence of the same iron salt, the system allowed realization of the sequential type of Nazarov/Michael reaction of pyrrole derivatives. Furthermore, we demonstrated the recyclable use of the iron catalyst and obtained the desired Nazarov/Michael reaction products in good yields for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2 ], as the solvent. We expect that the iron-catalyzed Nazarov cyclization, in particular, in an ionic liquid solvent might become a useful method to synthesize functional molecules that include cycloalkene moieties. © 2016 The

  12. Reversible Bergman cyclization by atomic manipulation.

    PubMed

    Schuler, Bruno; Fatayer, Shadi; Mohn, Fabian; Moll, Nikolaj; Pavliček, Niko; Meyer, Gerhard; Peña, Diego; Gross, Leo

    2016-03-01

    The Bergman cyclization is one of the most fascinating rearrangements in chemistry, with important implications in organic synthesis and pharmacology. Here we demonstrate a reversible Bergman cyclization for the first time. We induced the on-surface transformation of an individual aromatic diradical into a highly strained ten-membered diyne using atomic manipulation and verified the products by non-contact atomic force microscopy with atomic resolution. The diyne and diradical were stabilized by using an ultrathin NaCl film as the substrate, and the diyne could be transformed back into the diradical. Importantly, the diradical and the diyne exhibit different reactivity, electronic, magnetic and optical properties associated with the changes in the bond topology, and spin multiplicity. With this reversible, triggered Bergman cyclization we demonstrated switching on demand between the two reactive intermediates by means of selective C-C bond formation or cleavage, which opens up the field of radical chemistry for on-surface reactions by atomic manipulation.

  13. Reversible Bergman cyclization by atomic manipulation

    NASA Astrophysics Data System (ADS)

    Schuler, Bruno; Fatayer, Shadi; Mohn, Fabian; Moll, Nikolaj; Pavliček, Niko; Meyer, Gerhard; Peña, Diego; Gross, Leo

    2016-03-01

    The Bergman cyclization is one of the most fascinating rearrangements in chemistry, with important implications in organic synthesis and pharmacology. Here we demonstrate a reversible Bergman cyclization for the first time. We induced the on-surface transformation of an individual aromatic diradical into a highly strained ten-membered diyne using atomic manipulation and verified the products by non-contact atomic force microscopy with atomic resolution. The diyne and diradical were stabilized by using an ultrathin NaCl film as the substrate, and the diyne could be transformed back into the diradical. Importantly, the diradical and the diyne exhibit different reactivity, electronic, magnetic and optical properties associated with the changes in the bond topology, and spin multiplicity. With this reversible, triggered Bergman cyclization we demonstrated switching on demand between the two reactive intermediates by means of selective C-C bond formation or cleavage, which opens up the field of radical chemistry for on-surface reactions by atomic manipulation.

  14. Germacrene D Cyclization: An Ab Initio Investigation

    PubMed Central

    Setzer, William N.

    2008-01-01

    Essential oils that contain large concentrations of germacrene D are typically accompanied by cadinane sesquiterpenoids. The acid-catalyzed cyclization of germacrene D to give cadinane and selinane sesquiterpenes has been computationally investigated using both density functional (B3LYP/6-31G*) and post Hartree-Fock (MP2/6-31G* *) ab initio methods. The calculated energies are in general agreement with experimentally observed product distributions, both from acid-catalyzed cyclizations as well as distribution of the compounds in essential oils. PMID:19325722

  15. Polarizing the Nazarov cyclization: efficient catalysis under mild conditions.

    PubMed

    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.

  16. ANSS Backbone Station Quality Assessment

    NASA Astrophysics Data System (ADS)

    Leeds, A.; McNamara, D.; Benz, H.; Gee, L.

    2006-12-01

    In this study we assess the ambient noise levels of the broadband seismic stations within the United States Geological Survey's (USGS) Advanced National Seismic System (ANSS) backbone network. The backbone consists of stations operated by the USGS as well as several regional network stations operated by universities. We also assess the improved detection capability of the network due to the installation of 13 additional backbone stations and the upgrade of 26 existing stations funded by the Earthscope initiative. This assessment makes use of probability density functions (PDF) of power spectral densities (PSD) (after McNamara and Buland, 2004) computed by a continuous noise monitoring system developed by the USGS- ANSS and the Incorporated Research Institutions in Seismology (IRIS) Data Management Center (DMC). We compute the median and mode of the PDF distribution and rank the stations relative to the Peterson Low noise model (LNM) (Peterson, 1993) for 11 different period bands. The power of the method lies in the fact that there is no need to screen the data for system transients, earthquakes or general data artifacts since they map into a background probability level. Previous studies have shown that most regional stations, instrumented with short period or extended short period instruments, have a higher noise level in all period bands while stations in the US network have lower noise levels at short periods (0.0625-8.0 seconds), high frequencies (8.0- 0.125Hz). The overall network is evaluated with respect to accomplishing the design goals set for the USArray/ANSS backbone project which were intended to increase broadband performance for the national monitoring network.

  17. Catalytic formal Homo-Nazarov cyclization.

    PubMed

    De Simone, Filippo; Andrès, Julien; Torosantucci, Riccardo; Waser, Jérôme

    2009-02-19

    The first catalytic method for the cyclization of vinyl-cyclopropyl ketones (formal homo-Nazarov reaction) is reported. Starting from activated cyclopropanes, heterocyclic, and carbocyclic compounds were obtained under mild conditions using Brønsted acid catalysts. Preliminary investigation of the reaction mechanism indicated a stepwise process.

  18. Polycyclic Aromatic Triptycenes: Oxygen Substitution Cyclization Strategies

    PubMed Central

    VanVeller, Brett; Schipper, Derek J.; Swager, Timothy M.

    2012-01-01

    The cyclization and planarization of polycyclic aromatic hydrocarbons with concomitant oxygen substitution was achieved through acid catalyzed transetherification and oxygen-radical reactions. The triptycene scaffold enforces proximity of the alcohol and arene reacting partners and confers significant rigidity to the resulting π system, expanding the tool set of iptycenes for materials applications. PMID:22510100

  19. Oxazolidinone-promoted, torquoselective Nazarov cyclizations.

    PubMed

    Kerr, Daniel J; Miletic, Michael; Chaplin, Jason H; White, Jonathan M; Flynn, Bernard L

    2012-04-06

    Oxazolidinones are powerful promoters of the Nazarov reaction, enabling the cyclization of conventionally resistant substrates to be achieved under mild conditions. They exert excellent regio- and torquoselective control in both the conventional Nazarov reaction giving cyclopentenones and in the "interrupted" Nazarov reaction, giving more highly substituted multistereocenter containing products.

  20. Interrupting the Nazarov Cyclization with Bromine.

    PubMed

    Schatz, Devon J; Kwon, Yonghoon; Scully, Thomas W; West, F G

    2016-12-16

    The generation of dibrominated cyclopentenones via an interrupted Nazarov cyclization is reported. The installation of two bromine atoms occurs at the α and α' positions of the cyclopentenyl scaffold via successive nucleophilic and electrophilic bromination of the 2-oxidocyclopentenyl cation and its resulting enolate. Notably, the reaction proceeds with good diastereoselectivity, favoring the symmetrical product.

  1. Knottin cyclization: impact on structure and dynamics

    PubMed Central

    Heitz, Annie; Avrutina, Olga; Le-Nguyen, Dung; Diederichsen, Ulf; Hernandez, Jean-François; Gracy, Jérôme; Kolmar, Harald; Chiche, Laurent

    2008-01-01

    Background Present in various species, the knottins (also referred to as inhibitor cystine knots) constitute a group of extremely stable miniproteins with a plethora of biological activities. Owing to their small size and their high stability, knottins are considered as excellent leads or scaffolds in drug design. Two knottin families contain macrocyclic compounds, namely the cyclotides and the squash inhibitors. The cyclotide family nearly exclusively contains head-to-tail cyclized members. On the other hand, the squash family predominantly contains linear members. Head-to-tail cyclization is intuitively expected to improve bioactivities by increasing stability and lowering flexibility as well as sensitivity to proteolytic attack. Results In this paper, we report data on solution structure, thermal stability, and flexibility as inferred from NMR experiments and molecular dynamics simulations of a linear squash inhibitor EETI-II, a circular squash inhibitor MCoTI-II, and a linear analog lin-MCoTI. Strikingly, the head-to-tail linker in cyclic MCoTI-II is by far the most flexible region of all three compounds. Moreover, we show that cyclic and linear squash inhibitors do not display large differences in structure or flexibility in standard conditions, raising the question as to why few squash inhibitors have evolved into cyclic compounds. The simulations revealed however that the cyclization increases resistance to high temperatures by limiting structure unfolding. Conclusion In this work, we show that, in contrast to what could have been intuitively expected, cyclization of squash inhibitors does not provide clear stability or flexibility modification. Overall, our results suggest that, for squash inhibitors in standard conditions, the circularization impact might come from incorporation of an additional loop sequence, that can contribute to the miniprotein specificity and affinity, rather than from an increase in conformational rigidity or protein stability

  2. Influence of backbone on the charge transport properties of G4-DNA molecules: a model-based calculation.

    PubMed

    Guo, Ai-Min; Yang, Zhi; Zhu, Hong-Jun; Xiong, Shi-Jie

    2010-02-17

    We put forward a model Hamiltonian to describe the influence of backbone energetics on charge transport through guanine-quadruplex DNA (G4-DNA) molecules. Our analytical results show that an energy gap can be produced in the energy spectrum of G4-DNA by hybridization effects between the backbone and the base and by on-site energy difference of the backbone from the base. The environmental effects are investigated by introducing different types of disorder into the backbone sites. Our numerical results suggest that the localization length of G4-DNA can be significantly enhanced by increasing the backbone disorder degree when the environment-induced disorder is sufficiently large. There exists a backbone disorder-induced semiconducting-metallic transition in short G4-DNA molecules, where G4-DNA behaves as a semiconductor if the backbone disorder is weak and behaves as a conductor if the backbone disorder degree surpasses a critical value.

  3. The backbone of a city

    NASA Astrophysics Data System (ADS)

    Scellato, S.; Cardillo, A.; Latora, V.; Porta, S.

    2006-03-01

    Recent studies have revealed the importance of centrality measures to analyze various spatial factors affecting human life in cities. Here we show how it is possible to extract the backbone of a city by deriving spanning trees based on edge betweenness and edge information. By using as sample cases the cities of Bologna and San Francisco, we show how the obtained trees are radically different from those based on edge lengths, and allow an extended comprehension of the “skeleton” of most important routes that so much affects pedestrian/vehicular flows, retail commerce vitality, land-use separation, urban crime and collective dynamical behaviours.

  4. Cyclization improves membrane permeation by antimicrobial peptoids

    DOE PAGES

    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

  5. Cyclization improves membrane permeation by antimicrobial peptoids

    SciTech Connect

    Andreev, Konstantin; Martynowycz, Michael W.; Ivankin, Andrey; Huang, Mia L.; Kuzmenko, Ivan; Meron, Mati; Lin, Binhua; Kirshenbaum, Kent; Gidalevitz, David

    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 may increase peptoid activity by allowing the macrocycle to better penetrate the bacterial cell membrane.

  6. Iridium-Catalyzed Arylative Cyclization of Alkynones by 1,4-Iridium Migration**

    PubMed Central

    Partridge, Benjamin M; Solana González, Jorge; Lam, Hon Wai

    2014-01-01

    1,4-Metal migrations enable the remote functionalization of C—H bonds, and have been utilized in a wide variety of valuable synthetic methods. The vast majority of existing examples involve the 1,4-migration of palladium or rhodium. Herein, the stereoselective synthesis of complex polycycles by the iridium-catalyzed arylative cyclization of alkynones with arylboronic acids is described. To our knowledge, these reactions involve the first reported examples of 1,4-iridium migration. PMID:24842318

  7. Silica gel-promoted tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates.

    PubMed

    Ding, Qiuping; Cao, Banpeng; Zong, Zhenzhen; Peng, Yiyuan

    2010-05-10

    Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates promoted by silica gel are described. This reaction proceeds smoothly at 80 degrees C under metal- and solvent-free conditions, which provides an efficient and practical route for the generation of 2,4-dihydro-1H-benzo[d][1,3]thiazines. The recovered silica gel could be reused for several times.

  8. Synthesis of benzimidazoles by potassium tert-butoxide-promoted intermolecular cyclization reaction of 2-iodoanilines with nitriles.

    PubMed

    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.

  9. An efficient synthesis of pyrido[1,2-a]indoles through aza-Nazarov type cyclization.

    PubMed

    Karthikeyan, Iyyanar; Arunprasath, Dhanarajan; Sekar, Govindasamy

    2015-01-31

    Transition metal free Brønsted acid mediated synthesis of biologically important pyrido[1,2-a]indole scaffolds through aza-Nazarov type cyclization of readily available diaryl(2-pyridyl)methanol using formic acid has been developed. This methodology has been successfully extended to synthesize atropisomers.

  10. Synthesis and in vitro evaluation of a rhenium-cyclized somatostatin derivative series.

    PubMed

    Bigott-Hennkens, Heather M; Junnotula, Sulochana; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R; Jurisson, Silvia S

    2008-03-13

    The structure-activity relationships of a series of rhenium (Re)-cyclized octreotide derivatives are described. The effects of changes in the peptide sequence, N-terminus, and C-terminus on metal cyclization, as well as binding to the somatostatin receptor, were investigated. Each peptide complex was found to have an integrated Re(V) core with a single metal oxo group, two coordination sites filled by the cysteine sulfhydryls, and another by the amide nitrogen of Phe (3)/Tyr (3). The final coordination site was determined by the peptide N-terminus: the N-terminal amine coordinated for N-NH 2 peptides and the amide nitrogen of Thr (6) for peptides with acetylated N-termini. Re-cyclization of the octreotide derivatives led to structural perturbations of the somatostatin receptor-binding sequence relative to the Re-free disulfide analogues, resulting in reduced binding affinities. The findings presented herein demonstrate the importance of understanding the consequences of structural modifications when designing metal-peptide complexes for somatostatin receptor targeting.

  11. Cyclization of farnesyl pyrophosphate to the sesquiterpene olefins humulene and caryophyllene by an enzyme system from sage (Salvia officinalis)

    SciTech Connect

    Croteau, R.; Gundy, A.

    1984-09-01

    A soluble enzyme preparation obtained from sage (Salvia officinalis) leaves was shown to catalyze the divalent metal-ion dependent cyclization of trans, trans-farnesyl pyrophosphate to the macrocyclic sesquiterpene olefins humulene and caryophyllene. The identities of the biosynthetic products were confirmed by radiochromatographic analysis and by preparation of crystalline derivatives, and the specificity of labeling in the cyclization reaction was established by chemical degradation of the olefins derived enzymatically from (1-3H2)farnesyl pyrophosphate. These results constitute the first report on the cyclization of farnesyl pyrophosphate to humulene and caryophyllene, two of the most common sesquiterpenes in nature, and the first description of a soluble sesquiterpene cyclase to be isolated from leaves of a higher plant.

  12. Dearomatizing Radical Cyclizations and Cyclization Cascades Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls.

    PubMed

    Huang, Huan-Ming; Procter, David J

    2017-02-01

    Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electron transfer to amide-type carbonyls by SmI2-H2O-LiBr, provide efficient access to unprecedented spirocyclic scaffolds containing up to five stereocenters with high diastereocontrol. The first dearomatizing radical cyclizations involving radicals derived from amide carbonyls by single electron transfer take place under mild conditions and engage a range of aromatic and heteroaromatic systems present in the barbiturate substrates. The radical cyclizations deliver new polycyclic hemiaminals or enamines selectively, depending on the conditions employed, that are based on a medicinally proven scaffold and can be readily manipulated.

  13. Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation.

    PubMed

    Qvit, Nir; Kornfeld, Opher S

    2016-01-26

    Protein-protein interactions (PPIs) are intimately involved in almost all biological processes and are linked to many human diseases. Therefore, there is a major effort to target PPIs in basic research and in the pharmaceutical industry. Protein-protein interfaces are usually large, flat, and often lack pockets, complicating the discovery of small molecules that target such sites. Alternative targeting approaches using antibodies have limitations due to poor oral bioavailability, low cell-permeability, and production inefficiency. Using peptides to target PPI interfaces has several advantages. Peptides have higher conformational flexibility, increased selectivity, and are generally inexpensive. However, peptides have their own limitations including poor stability and inefficiency crossing cell membranes. To overcome such limitations, peptide cyclization can be performed. Cyclization has been demonstrated to improve peptide selectivity, metabolic stability, and bioavailability. However, predicting the bioactive conformation of a cyclic peptide is not trivial. To overcome this challenge, one attractive approach it to screen a focused library to screen in which all backbone cyclic peptides have the same primary sequence, but differ in parameters that influence their conformation, such as ring size and position. We describe a detailed protocol for synthesizing a library of backbone cyclic peptides targeting specific parasite PPIs. Using a rational design approach, we developed peptides derived from the scaffold protein Leishmania receptor for activated C-kinase (LACK). We hypothesized that sequences in LACK that are conserved in parasites, but not in the mammalian host homolog, may represent interaction sites for proteins that are critical for the parasites' viability. The cyclic peptides were synthesized using microwave irradiation to reduce reaction times and increase efficiency. Developing a library of backbone cyclic peptides with different ring sizes facilitates a

  14. A Radical Cyclization Approach to Isoindolobenzazepines. Synthesis of Lennoxamine.

    PubMed

    Rodríguez, Gema; Cid, M. Magdalena; Saá, Carlos; Castedo, Luis; Domínguez, Domingo

    1996-04-19

    The alkaloid lennoxamine (1) was synthesized by transannular cyclization of a 10-membered lactam obtained by intramolecular addition of an aryl radical to a (trimethylsilyl)acetylene. The isoindolo[1,2-b][3]benzazepine skeleton present in lennoxamine was also obtained by means of regioselective 7-endo-trig radical cyclization of methylenephthalimidines.

  15. Flexible backbone aromatic polyimide adhesives

    NASA Technical Reports Server (NTRS)

    Progar, Donald J.; St. Clair, Terry L.

    1989-01-01

    Continuing research at Langley Research Center on the synthesis and development of new inexpensive flexible aromatic polyimides as adhesives has resulted in a material identified as LARC-F-SO2 with similarities to polyimidesulfone, PISO2, and other flexible backbone polyimides recently reported by Progar and St. Clair. Also prepared and evaluated was an endcapped version of PISO2. These two polymers were compared with LARC-TPI and LARC-STPI, polyimides research in our laboratory and reported in the literature. The adhesive evaluation, primarily based on lap shear strength (LSS) tests at RT, 177 C and 204 C, involved preparing adhesive tapes, conducting bonding studies and exposing lap shear specimens to 204 C air for up to 1000 hrs and to a 72-hour water boil. The type of adhesive failure as well as the Tg was determined for the fractured specimens. The results indicate that LARC-TPI provides the highest LSSs. LARC-F-SO2, LARC-TPI and LARC-STPI all retain their strengths after thermal exposure for 1000 hrs and PISO2 retains greater than 80 percent of its control strengths. After a 72-hr water boil exposure, most of the four adhesive systems showed reduced strengths for all test temperatures although still retaining a high percentage of their original strength (greater than 60 percent) except for one case. The predominant failure type was cohesive with no significant change in the Tgs.

  16. Flexible backbone aromatic polyimide adhesives

    NASA Technical Reports Server (NTRS)

    Progar, Donald J.; St.clair, Terry L.

    1988-01-01

    Continuing research at Langley Research Center on the synthesis and development of new inexpensive flexible aromatic polyimides as adhesives has resulted in a material identified as LARC-F-SO2 with similarities to polyimidesulfone, PISO2, and other flexible backbone polyimides recently reported by Progar and St. Clair. Also prepared and evaluated was an endcapped version of PISO2. These two polymers were compared with LARC-TPI and LARC-STPI, polyimides research in our laboratory and reported in the literature. The adhesive evaluation, primarily based on lap shear strength (LSS) tests at RT, 177 C and 204 C, involved preparing adhesive tapes, conducting bonding studies and exposing lap shear specimens to 204 C air for up to 1000 hrs and to a 72-hour water boil. The type of adhesive failure as well as the Tg was determined for the fractured specimens. The results indicate that LARC-TPI provides the highest LSSs. LARC-F-SO2, LARC-TPI and LARC-STPI all retain their strengths after thermal exposure for 1000 hrs and PISO2 retains greater than 80 percent of its control strengths. After a 72-hr water boil exposure, most of the four adhesive systems showed reduced strengths for all test temperatures although still retaining a high percentage of their original strength (greater than 60 percent) except for one case. The predominant failure type was cohesive with no significant change in the Tgs.

  17. Flexible backbone aromatic polyimide adhesives

    NASA Technical Reports Server (NTRS)

    Progar, Donald J.; St. Clair, Terry L.

    1989-01-01

    Continuing research at Langley Research Center on the synthesis and development of new inexpensive flexible aromatic polyimides as adhesives has resulted in a material identified as LARC-F-SO2 with similarities to polyimidesulfone, PISO2, and other flexible backbone polyimides recently reported by Progar and St. Clair. Also prepared and evaluated was an endcapped version of PISO2. These two polymers were compared with LARC-TPI and LARC-STPI, polyimides research in our laboratory and reported in the literature. The adhesive evaluation, primarily based on lap shear strength (LSS) tests at RT, 177 C and 204 C, involved preparing adhesive tapes, conducting bonding studies and exposing lap shear specimens to 204 C air for up to 1000 hrs and to a 72-hour water boil. The type of adhesive failure as well as the Tg was determined for the fractured specimens. The results indicate that LARC-TPI provides the highest LSSs. LARC-F-SO2, LARC-TPI and LARC-STPI all retain their strengths after thermal exposure for 1000 hrs and PISO2 retains greater than 80 percent of its control strengths. After a 72-hr water boil exposure, most of the four adhesive systems showed reduced strengths for all test temperatures although still retaining a high percentage of their original strength (greater than 60 percent) except for one case. The predominant failure type was cohesive with no significant change in the Tgs.

  18. External Tank - The Structure Backbone

    NASA Technical Reports Server (NTRS)

    Welzyn, Kenneth; Pilet, Jeffrey C.; Diecidue-Conners, Dawn; Worden, Michelle; Guillot, Michelle

    2011-01-01

    The External Tank forms the structural backbone of the Space Shuttle in the launch configuration. Because the tank flies to orbital velocity with the Space Shuttle Orbiter, minimization of weight is mandatory, to maximize payload performance. Choice of lightweight materials both for structure and thermal conditioning was necessary. The tank is large, and unique manufacturing facilities, tooling, handling, and transportation operations were required. Weld processes and tooling evolved with the design as it matured through several block changes, to reduce weight. Non Destructive Evaluation methods were used to assure integrity of welds and thermal protection system materials. The aluminum-lithium alloy was used near the end of the program and weld processes and weld repair techniques had to be refined. Development and implementation of friction stir welding was a substantial technology development incorporated during the Program. Automated thermal protection system application processes were developed for the majority of the tank surface. Material obsolescence was an issue throughout the 40 year program. The final configuration and tank weight enabled international space station assembly in a high inclination orbit allowing international cooperation with the Russian Federal Space Agency. Numerous process controls were implemented to assure product quality, and innovative proof testing was accomplished prior to delivery. Process controls were implemented to assure cleanliness in the production environment, to control contaminants, and to preclude corrosion. Each tank was accepted via rigorous inspections, including non-destructive evaluation techniques, proof testing, and all systems testing. In the post STS-107 era, the project focused on ascent debris risk reduction. This was accomplished via stringent process controls, post flight assessment using substantially improved imagery, and selective redesigns. These efforts were supported with a number of test programs to

  19. Cervical Exercise: The Backbone of Spine Treatment

    MedlinePlus

    Cervical Exercise: The Backbone of Spine Treatment How important is it? What can be done? North American Spine Society Public Education Series ... flow comes to the area to help repair injury. Your ability to function in your daily activities ...

  20. Cervical Exercise: The Backbone of Spine Treatment

    MedlinePlus

    Cervical Exercise: The Backbone of Spine Treatment How important is it? What can be done? North American Spine Society ... you should see your physician before starting any exercises. The Importance of Exercise for the Neck Spine ...

  1. New modes for the osmium-catalyzed oxidative cyclization.

    PubMed

    Donohoe, Timothy J; Lindsay-Scott, Peter J; Parker, Jeremy S; Callens, Cedric K A

    2010-03-05

    The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes is an effective method for the construction of pyrrolidines, utilizing a novel reoxidant (4-nitropyridine N-oxide = NPNO). The cyclization of enantiopure syn- and anti-amino alcohols gives rise to enantiopure cis- and trans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of bis-homoallylic amines bearing an exocyclic chelating group is shown to be a complementary method for trans-pyrrolidine formation.

  2. Cyclization Cascades Initiated by 1,6-Conjugate Addition

    PubMed Central

    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

  3. "Click"-cyclized (68)Ga-labeled peptides for molecular imaging and therapy: synthesis and preliminary in vitro and in vivo evaluation in a melanoma model system.

    PubMed

    Martin, Molly E; Sue O'Dorisio, M; Leverich, Whitney M; Kloepping, Kyle C; Walsh, Susan A; Schultz, Michael K

    2013-01-01

    Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disulfide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In the work described in this chapter, new α-melanocyte stimulating hormone (α-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition "click" chemistry techniques. The α-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represent a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor-bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) for MC1R on melanoma cells in vitro, high stability in human serum, and produced high-contrast PET/CT images of tumor xenografts. (68)Ga-labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor-mediated tumor accumulation of up to 16 ± 5% ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radio metals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy.

  4. Transition-metal-free synthesis of imidazo[2,1-b]thiazoles and thiazolo[3,2-a]benzimidazoles via an S-propargylation/5-exo-dig cyclization/isomerization sequence using propargyl tosylates as substrates.

    PubMed

    Omar, Mohamed A; Frey, Wolfgang; Conrad, Jürgen; Beifuss, Uwe

    2014-11-07

    A transition-metal-free route for the synthesis of several N-fused heterocycles, including thiazolo[3,2-a]benzimidazoles and imidazo[2,1-b]thiazoles, is reported. The reaction between propargyl tosylates and 2-mercaptobenzimidazoles under basic conditions results in 3-substituted thiazolo[3,2-a]benzimidazoles, in yields up to 92% in a single synthesis step. With 2-mercaptoimidazoles as the substrate, the corresponding imidazo[2,1-b]thiazoles were exclusively obtained. The transformation is considered to proceed as an intermolecular S-propargylation that is followed by 5-exo-dig ring closure and double-bond isomerization.

  5. Extended weak bonding interactions in DNA: pi-stacking (base-base), base-backbone, and backbone-backbone interactions.

    PubMed

    Matta, Chérif F; Castillo, Norberto; Boyd, Russell J

    2006-01-12

    We report on several weak interactions in nucleic acids, which, collectively, can make a nonnegligible contribution to the structure and stability of these molecules. Fragments of DNA were obtained from previously determined accurate experimental geometries and their electron density distributions calculated using density functional theory (DFT). The electron densities were analyzed topologically according to the quantum theory of atoms in molecules (AIM). A web of closed-shell bonding interactions is shown to connect neighboring base pairs in base-pair duplexes and in dinuleotide steps. This bonding underlies the well-known pi-stacking interaction between adjacent nucleic acid bases and is characterized topologically for the first time. Two less widely appreciated modes of weak closed-shell interactions in nucleic acids are also described: (i) interactions between atoms in the bases and atoms belonging to the backbone (base-backbone) and (ii) interactions among atoms within the backbone itself (backbone-backbone). These interactions include hydrogen bonding, dihydrogen bonding, hydrogen-hydrogen bonding, and several other weak closed-shell X-Y interactions (X, Y = O, N, C). While each individual interaction is very weak and typically accompanied by perhaps 0.5-3 kcal/mol, the sum total of these interactions is postulated to play a role in stabilizing the structure of nucleic acids. The Watson-and-Crick hydrogen bonding is also characterized in detail at the experimental geometries as a prelude to the discussion of the modes of interactions listed in the title.

  6. Rhenium(VII) Catalysis of Prins Cyclization Reactions

    PubMed Central

    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

  7. Structural determinants of reductive terpene cyclization in iridoid biosynthesis

    PubMed Central

    Stevenson, Clare E. M.; Kamileen, Mohammed O.; Sherden, Nathaniel H.; Geu-Flores, Fernando; Lawson, David M.; O’Connor, Sarah E.

    2015-01-01

    The carbon skeleton of ecologically and pharmacologically important iridoid monoterpenes is formed in a reductive cyclization reaction unrelated to canonical terpene cyclization. Here we report the crystal structure of the recently discovered iridoid cyclase (Catharanthus roseus) bound to a mechanism-inspired inhibitor that illuminates substrate binding and catalytic function of the enzyme. Key features that distinguish iridoid synthase from its close homologue, progesterone 5β-reductase, are highlighted. PMID:26551396

  8. Oxidative cyclization of alkenols with oxone using a miniflow reactor.

    PubMed

    Yamada, Yoichi M A; Torii, Kaoru; Uozumi, Yasuhiro

    2009-04-29

    A miniflow system for oxidative cyclization of alkenols with Oxone was developed. Thus, the oxidative cyclization of (Z)- and (E)-alkenols in i-PrOH with an aqueous solution of Oxone proceeded smoothly and safely in a PTFE tube without any exogenous catalytic species, and was subsequently quenched in a flow-reaction manner to afford the corresponding furanyl and pyranyl carbinols quantitatively within 5 or 10 min of residence time.

  9. Oxidative cyclization of alkenols with Oxone using a miniflow reactor

    PubMed Central

    Yamada, Yoichi M A; Torii, Kaoru

    2009-01-01

    Summary A miniflow system for oxidative cyclization of alkenols with Oxone was developed. Thus, the oxidative cyclization of (Z)- and (E)-alkenols in i-PrOH with an aqueous solution of Oxone proceeded smoothly and safely in a PTFE tube without any exogenous catalytic species, and was subsequently quenched in a flow-reaction manner to afford the corresponding furanyl and pyranyl carbinols quantitatively within 5 or 10 min of residence time. PMID:19513188

  10. A Light-Induced Vinylogous Nazarov-Type Cyclization.

    PubMed

    Pusch, Stefan; Schollmeyer, Dieter; Opatz, Till

    2016-07-01

    The first examples of a photochemically induced vinylogous Nazarov-type cyclization forming a cycloheptadienone core are described. The reaction can be included in a three-step cascade consisting of a photochemical isoxazole-azirine ring contraction, cobalt(II)-catalyzed ring expansion, and the photochemical cyclization. Furthermore, the first representative of the hitherto unknown 1-azatricyclo[2.2.0.0(2,6)]hexanes has been identified as a side product of the azirine formation.

  11. Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative.

    PubMed

    Huang, Yu-Wen; Frontier, Alison J

    2015-06-03

    Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation.

  12. Cetalox and analogues: synthesis via acid-mediated polyene cyclizations.

    PubMed

    Snowden, Roger L

    2008-06-01

    Using a novel, acid-mediated cyclization methodology, a direct access to Cetalox ((+/-)-1; a commercially important ambergris-type odorant) and various structurally related didehydro (i.e., 19, 26, and 30) and tetradehydro (i.e., 28 and 37/38) analogues is described. Treatment of either (E,E)-14 or (E)-15 with an excess of FSO(3)H in 2-nitropropane at -90 degrees stereospecifically afforded (+/-)-1 in 40 and 42% yield, respectively. Under similar conditions, cyclization of (E)-18 or 20 furnished 19 in 60 and 64% yield, respectively. Analogously, using an excess of ClSO(3)H in CH(2)Cl(2) at -80 degrees, 26 is formed with high stereoselectivity by cyclization of either (E)-24 or (Z)-25 (52 and 31% yield, resp.); in the same manner, 28 was prepared from 27 (22% yield). The same principle was applied to the synthesis of racemic Superambrox (30), via cyclization of 35, but only with poor selectivity (22%) and low yield (7%). Another approach via cyclization of (E)-40 under solvolysis conditions (excess TFA in CH(2)Cl(2) at -10 degrees) gave a higher yield (15%) with improved selectivity (43%). Finally, cyclization of 34 (1:1 diastereoisomer mixture) afforded 37/38 (10:1) in 27% yield. The qualitative organoleptic properties of 19, 26, 28, 30, and 37/38 (10:1) are briefly discussed.

  13. Understanding traffic dynamics at a backbone POP

    NASA Astrophysics Data System (ADS)

    Taft, Nina; Bhattacharyya, Supratik; Jetcheva, Jorjeta; Diot, Christophe

    2001-07-01

    Spatial and temporal information about traffic dynamics is central to the design of effective traffic engineering practices for IP backbones. In this paper we study backbone traffic dynamics using data collected at a major POP on a tier-1 IP backbone. We develop a methodology that combines packet-level traces from access links in the POP and BGP routing information to build components of POP-to-POP traffic matrices. Our results show that there is wide disparity in the volume of traffic headed towards different egress POPs. At the same time, we find that current routing practices in the backbone tend to constrain traffic between ingress-egress POP pairs to a small number of paths. As a result, there is a wide variation in the utilization level of links in the backbone. Frequent capacity upgrades of the heavily used links are expensive; the need for such upgrades can be reduced by designing load balancing policies that will route more traffic over less utilized links. We identify traffic aggregates based on destination address prefixes and find that this set of criteria isolates a few aggregates that account for an overwhelmingly large portion of inter-POP traffic. We also demonstrate that these aggregates exhibit stability throughout the day on per-hour time scales, and thus they form a natural basis for splitting traffic over multiple paths in order to improve load balancing.

  14. Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β-Alkynyl Hydrazines under Kinetic Resolution Conditions**

    PubMed Central

    Maity, Pradip; Lepore, Salvatore D.

    2013-01-01

    Cyclic addition of a hydrazine nitrogen to unactivated alkynes catalyzed by non-metals. Starting from readily accessible γ-silyl allenyl esters, β-alkynyl hydrazines are prepared in one step and subsequently undergo unprecedented cyclization reactions in the presence of ammonium and phosphonium catalysts leading to dehydro-azaproline products. These heterocycles are also produced in high enantiomeric excesses using chiral ammonium phase transfer catalysts via a kinetic resolution pathway. PMID:21766401

  15. Utilizing redox-mediated Bergman cyclization toward the development of dual-action metalloenediyne therapeutics.

    PubMed

    Lindahl, Sarah E; Park, Hyunsoo; Pink, Maren; Zaleski, Jeffrey M

    2013-03-13

    Reaction of 2 equiv of 1,2-bis((diphenylphosphino)ethynyl)benzene (dppeb, 1) with Pt(cod)Cl2 followed by treatment with N2H4 yields the reduced Pt(0) metalloenediyne, Pt(dppeb)2, 2. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of 2 with 1 equiv of I2 in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the cis-Bergman-cyclized, diiodo product 3 ((31)P: δ = 41 ppm, J(Pt-P) = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate ((31)P: δ = -33 ppm). In contrast, addition of 2 equiv of I2 in the absence of additional radical trap instantaneously forms a metastable Pt(dppeb)2(2+) intermediate species, 4, that is characterized by δ = 51 ppm in the (31)P NMR (J(Pt-P) = 3171 Hz) and ν(C≡C) = 2169 cm(-1) in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, 4 undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt(dppnap-I2)I2 (dppnap-I2 = (1,4-diiodonaphthalene-2,3-diyl)bis(diphenylphosphine)), 5, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate 4: one where the phosphine core has migrated to a trans-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two cis-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt-P bond lengths (>2.4 Å), indicating that nucleophilic ligand substitution by I(-) is on the reaction trajectory to the cyclized product 5. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and

  16. “Click” cyclized gallium-68 labeled peptides for molecular imaging and therapy: Synthesis and preliminary in vitro and in vivo evaluation in a melanoma model system

    PubMed Central

    Martin, Molly E.; O'Dorisio, M. Sue; Leverich, Whitney M.; Kloepping, Kyle C.; Schultz, Michael K.

    2013-01-01

    Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disufide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In this chapter, new α-melanocyte stimulating hormone (α-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition “click” chemistry techniques. The α-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represents a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) MC1R to melanoma cells in vitro, high stability in human serum, and produced high contrast PET/CT images of tumor xenografts. Gallium-68 labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor mediated tumor accumulation of up to 16±5 %ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radiometals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy. PMID:22918759

  17. Air- and water-stable catalysts for hydroamination/cyclization. Synthesis and application of CCC-NHC pincer complexes of Rh and Ir.

    PubMed

    Bauer, Eike B; Andavan, G T Senthil; Hollis, T Keith; Rubio, Ramel J; Cho, Joon; Kuchenbeiser, Glenn R; Helgert, Theodore R; Letko, Christopher S; Tham, Fook S

    2008-03-20

    The scope of CCC-NHC pincer complex synthetic methodology by metalation/transmetalation has been extended to Ir. Structural characterization revealed that it is isomorphous with the Rh complex. Both Rh and Ir complexes are efficient catalysts for the hydroamination/cyclization of secondary amines in the presence of air and/or water.

  18. Stereoselective Synthesis of cis-2,5-Disubstituted Pyrrolidines via Wacker-Type Aerobic Oxidative Cyclization of Alkenes with tBu-Sulfinamide Nucleophiles

    PubMed Central

    Redford, Joanne E.; McDonald, Richard I.; Rigsby, Matthew L.; Wiensch, Joshua D.

    2012-01-01

    Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes. PMID:22352383

  19. Computational protein design with backbone plasticity

    PubMed Central

    MacDonald, James T.; Freemont, Paul S.

    2016-01-01

    The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the de novo design of artificial enzymes. The majority of these designs have reused naturally occurring protein structures as ‘scaffolds’ onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increased search space, but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process. PMID:27911735

  20. FeCl3-diorganyl dichalcogenides promoted cyclization of 2-organochalcogen-3-alkynylthiophenes: synthesis of chalcogenophene[2,3-b]thiophenes.

    PubMed

    Stein, André L; Bilheri, Filipe N; Rosário, Alisson R; Zeni, Gilson

    2013-05-14

    We report here our results on the FeCl3-diorganyl dichalcogenides intramolecular cyclization of 2-organochalcogen-3-alkynylthiophenes. The cyclization reaction proceeded cleanly under mild reaction conditions giving the (S)-Se-, (S)-S- and (S)-Te-heterocycles in good yields. In addition, the obtained chalcogenophenes were readily transformed into more complex products using the palladium cross-coupling reaction with boronic acids. Conversely, using a metal-halogen exchange reaction with n-BuLi, the chalcogenophenes produced the lithium-intermediate which was trapped with aldehyde furnishing the desired secondary alcohol in good yield.

  1. Iron-catalyzed, hydrogen-mediated reductive cyclization of 1,6-enynes and diynes: evidence for bis(imino)pyridine ligand participation.

    PubMed

    Sylvester, Kevin T; Chirik, Paul J

    2009-07-01

    The bis(imino)pyridine iron dinitrogen complex (((i)Pr)PDI)Fe(N(2))(2) catalyzes the hydrogen-mediated reductive cyclization of enynes and diynes with turnover frequencies comparable to those of established precious metal catalysts. Amino, oxygenated, and carbon-based substrates are readily cyclized to the corresponding hetero- and carbocycles with 5 mol % iron and 4 atm H(2) at 23 degrees C. Stoichiometric reactions between selected substrates and the iron compound under a N(2) atmosphere established transfer dehydrogenation from an isopropyl aryl substituent to either the enyne or diyne substrate. In situ monitoring of the catalytic reaction by (1)H NMR spectroscopy coupled with deuterium labeling experiments established rapid cyclization followed by turnover-limiting hydrogenation.

  2. ExScal Backbone Network Architecture

    DTIC Science & Technology

    2005-01-01

    802.11 battery powered nodes was laid over the sensor network. We adopted the Stargate platform for the backbone tier to serve as the basis for...its head. XSS Hardware and Network: XSS stands for eXtreme Scaling Stargate . A stargate is a linux-based single board computer. It has a 400 MHz

  3. Discovery of cyclotides in the fabaceae plant family provides new insights into the cyclization, evolution, and distribution of circular proteins.

    PubMed

    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.

  4. Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives accelerated by microwave irradiation.

    PubMed

    Bachu, Prabhakar; Akiyama, Takahiko

    2009-07-15

    The Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives was developed. Microwave irradiation accelerated the Nazarov cyclization significantly at 40 degrees C to give cyclopenta[b]pyrrole derivatives in excellent yields with high trans selectivity.

  5. Cyclization of conotoxins to improve their biopharmaceutical properties.

    PubMed

    Clark, Richard J; Akcan, Muharrem; Kaas, Quentin; Daly, Norelle L; Craik, David J

    2012-03-15

    Conotoxins are disulfide-rich peptides from the venoms of marine cone snails that are used in prey capture. Due to their exquisite potency and selectivity for different ion channels, receptors and transporters they have attracted much interest as leads in drug design. This article gives a brief background on conotoxins, describes their structures and highlights methods for synthetic cyclization to improve their biopharmaceutical properties. The proximity of the N and C termini of many conotoxins makes them particularly suitable for cyclization with linkers of on average five to seven amino acids. By linking the ends of conotoxins it is possible to significantly decrease their susceptibility to proteolysis without loss of their intrinsic biological activity. Here, the principles of conotoxin cyclization are illustrated with applications to the α- and χ- conotoxin classes, which have been implicated as leads for the treatment of pain and a range of other disorders including neuroprotection, schizophrenia, depression and cancer.

  6. The cyclization of arabinosyladenine-5-prime-phosphorimidazolide

    NASA Technical Reports Server (NTRS)

    Harada, Kazuo; Orgel, Leslie E.

    1991-01-01

    When arabinosyladenine-5-prime-phosphorimidazolide is allowed to decompose in aqueous solution at room temperature and pH 7.2, depending on the buffer, 5-24 percent is converted to the 2-prime,5-prime-cyclic phosphate (V). Although the extent of cyclization is much greater than for adenosine-5-prime-phosphorimidazolide, cyclization is less efficient than hydrolysis and so would not substantially decrease the efficiency of condensation reactions in aqueous solution. The significance of this result for prebiotic chemistry is discussed.

  7. The role of structural parameters in DNA cyclization

    SciTech Connect

    Alexandrov, Ludmil B.; Bishop, Alan R.; Rasmussen, Kim O.; Alexandrov, Boian S.

    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.

  8. The role of structural parameters in DNA cyclization

    DOE PAGES

    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.

  9. The cyclization of arabinosyladenine-5-prime-phosphorimidazolide

    NASA Technical Reports Server (NTRS)

    Harada, Kazuo; Orgel, Leslie E.

    1991-01-01

    When arabinosyladenine-5-prime-phosphorimidazolide is allowed to decompose in aqueous solution at room temperature and pH 7.2, depending on the buffer, 5-24 percent is converted to the 2-prime,5-prime-cyclic phosphate (V). Although the extent of cyclization is much greater than for adenosine-5-prime-phosphorimidazolide, cyclization is less efficient than hydrolysis and so would not substantially decrease the efficiency of condensation reactions in aqueous solution. The significance of this result for prebiotic chemistry is discussed.

  10. Constructing backbone network by using tinker algorithm

    NASA Astrophysics Data System (ADS)

    He, Zhiwei; Zhan, Meng; Wang, Jianxiong; Yao, Chenggui

    2017-01-01

    Revealing how a biological network is organized to realize its function is one of the main topics in systems biology. The functional backbone network, defined as the primary structure of the biological network, is of great importance in maintaining the main function of the biological network. We propose a new algorithm, the tinker algorithm, to determine this core structure and apply it in the cell-cycle system. With this algorithm, the backbone network of the cell-cycle network can be determined accurately and efficiently in various models such as the Boolean model, stochastic model, and ordinary differential equation model. Results show that our algorithm is more efficient than that used in the previous research. We hope this method can be put into practical use in relevant future studies.

  11. ANSS Backbone Station Installation and Site Characterization

    NASA Astrophysics Data System (ADS)

    Meremonte, M.; Leeds, A.; Overturf, D.; McMillian, J.; Allen, J.; McNamara, D.

    2004-12-01

    During 2004 several new broadband seismic stations have been deployed as a part of the USGS's Advanced National Seismic System (ANSS) backbone and regional networks. New stations include: ERPA, MNTX, OGLA, AMTX, NATX, KCCO, BMO, MARC, TZTN, LAO, DGMT, REDW, KSU1, MOOW, TPAW, LOHW, RAMW. Permanent station locations were chosen to minimize the local noise conditions by recording continuous data and using a quantitative analysis of the statistical distribution of noise power estimates. For each one-hour segment of continuous data, a power spectral density (PSD) is estimated and smoothed in full octave averages at 1/8 octave intervals. Powers for each 1/8 period interval were then accumulated in one dB power bins. A statistical analysis of power bins yields probability density functions (PDFs) as a function of noise power for each of the octave bands at each station and component. Examination of earthquake signal, artifacts related to station operation and episodic cultural noise in the PDFs allow us to estimate both the overall station quality and the level of earth noise at each potential backbone site. The main function of a seismic network, such as the ANSS, is to provide high quality data for earthquake monitoring, source studies, and Earth structure research. The utility of seismic data is greatly increased when noise levels are reduced. A good quantification and understanding of seismic noise is a first step at reducing noise levels in seismic data and improving overall data quality from the ANSS backbone network.

  12. Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction.

    PubMed

    Peng, Qian; Paton, Robert S

    2016-05-17

    catalyst structures for enantioselective cycloisomerizations. Calculations have revealed that stepwise C-C bond formation and proton transfer dictate the exclusive endo diastereoselectivity of the intramolecular Michael addition to form 2-azabicyclo[3.3.1]nonane skeletons catalyzed by primary amines. These insights have led to development of a highly enantioselective catalyst with higher atom economy than previous generations. This Account also explores transition-metal-catalyzed cycloisomerizations, where our theoretical investigations have uncovered an unexpected reaction pathway in the [5 + 2] cycloisomerization of ynamides. This has led to the design of new phosphoramidite ligands to enable double-stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings. Computational understanding of the factors responsible for the regio-, enantio-, and diasterocontrol is shown to generate tangible predictions leading to an acceleration of catalyst development for selective cyclizations.

  13. Cyclic Graft Copolymer Unimolecular Micelles: Effects of Cyclization on Particle Morphology and Thermoresponsive Behavior

    PubMed Central

    2016-01-01

    The synthesis of cyclic amphiphilic graft copolymers with a hydrophobic polycarbonate backbone and hydrophilic poly(N-acryloylmorpholine) (PNAM) side arms via a combination of ring-opening polymerization (ROP), cyclization via copper-catalyzed azide–alkyne cycloaddition (CuAAC), and reversible addition–fragmentation chain transfer (RAFT) polymerization is reported. The ability of these cyclic graft copolymers to form unimolecular micelles in water is explored using a combination of light scattering, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryoTEM) analyses, where particle size was found to increase with increasing PNAM arm length. Further analysis revealed differences in the solution conformations, loading capabilities, and morphologies of the cyclic graft copolymers in comparison to equivalent linear graft copolymer unimolecular micelle analogues. Furthermore, the cyclic and linear graft copolymers were found to exhibit significantly different cloud point temperatures. This study highlights how subtle changes in polymer architecture (linear graft copolymer versus cyclic graft copolymer) can dramatically influence a polymer’s nanostructure and its properties. PMID:27175037

  14. Indole alkaloids synthesis via a selective cyclization of aminocyclopropanes.

    PubMed

    De Simone, Filippo; Waser, Jérôme

    2012-01-01

    The continuous progress in medicinal chemistry requires more versatile synthetic strategies for the generation of large libraries of active compounds and their analogues. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. In 2008 we developed the first catalytic formal homo-Nazarov reaction starting from activated cyclopropanes. Herein we report the extension of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations were obtained via an acyliminium intermediate generated through opening of the cyclopropane. An excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners was achieved. The utility of the developed methodology was demonstrated by the generation of the polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate. Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an extended range of vinyl-cyclopropyl ketones with cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane.

  15. Catalytic enantioselective cyclization and C3-fluorination of polyenes.

    PubMed

    Cochrane, Nikki A; Nguyen, Ha; Gagne, Michel R

    2013-01-16

    (Xylyl-phanephos)Pt(2+) in combination with XeF(2) mediates the consecutive diastereoselective cation-olefin cyclization/fluorination of polyene substrates. Isolated yields were typically in the 60-69% range while enantioselectivities reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P(2)Pt-alkyl cation intermediate.

  16. Catalytic Enantioselective Cyclization and C3-Fluorination of Polyenes

    PubMed Central

    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

  17. Cyclization of nucleotide analogues as an obstacle to polymerization

    NASA Technical Reports Server (NTRS)

    Hill, A. R. Jr; Nord, L. D.; Orgel, L. E.; Robins, R. K.

    1988-01-01

    Cyclization of activated nucleotide analogues by intramolecular phosphodiester-bond formation is likely to compete very effectively with template-directed condensation except in the cases of ribo- and arabinonucleotides. This could have excluded derivatives of most sugars from growing polyribonucleotide chains and thus reduced chain-termination in prebiotic polynucleotide synthesis.

  18. Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst

    PubMed Central

    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

  19. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization.

    PubMed

    Crawford, Jason M; Korman, Tyler P; Labonte, Jason W; Vagstad, Anna L; Hill, Eric A; Kamari-Bidkorpeh, Oliver; Tsai, Shiou-Chuan; Townsend, Craig A

    2009-10-22

    Polyketides are a class of natural products with diverse structures and biological activities. The structural variability of aromatic products of fungal nonreducing, multidomain iterative polyketide synthases (NR-PKS group of IPKSs) results from regiospecific cyclizations of reactive poly-beta-keto intermediates. How poly-beta-keto species are synthesized and stabilized, how their chain lengths are determined, and, in particular, how specific cyclization patterns are controlled have been largely inaccessible and functionally unknown until recently. A product template (PT) domain is responsible for controlling specific aldol cyclization and aromatization of these mature polyketide precursors, but the mechanistic basis is unknown. Here we present the 1.8 A crystal structure and mutational studies of a dissected PT monodomain from PksA, the NR-PKS that initiates the biosynthesis of the potent hepatocarcinogen aflatoxin B(1) in Aspergillus parasiticus. Despite having minimal sequence similarity to known enzymes, the structure displays a distinct 'double hot dog' (DHD) fold. Co-crystal structures with palmitate or a bicyclic substrate mimic illustrate that PT can bind both linear and bicyclic polyketides. Docking and mutagenesis studies reveal residues important for substrate binding and catalysis, and identify a phosphopantetheine localization channel and a deep two-part interior binding pocket and reaction chamber. Sequence similarity and extensive conservation of active site residues in PT domains suggest that the mechanistic insights gleaned from these studies will prove general for this class of IPKSs, and lay a foundation for defining the molecular rules controlling NR-PKS cyclization specificity.

  20. Backbone cyclised peptides from plants show molluscicidal activity against the rice pest Pomacea canaliculata (golden apple snail).

    PubMed

    Plan, Manuel Rey R; Saska, Ivana; Cagauan, Arsenia G; Craik, David J

    2008-07-09

    Golden apple snails ( Pomacea canaliculata) are serious pests of rice in South East Asia. Cyclotides are backbone cyclized peptides produced by plants from Rubiaceae and Violaceae. In this study, we investigated the molluscicidal activity of cyclotides against golden apple snails. Crude cyclotide extracts from both Oldenlandia affinis and Viola odorata plants showed molluscicidal activity comparable to the synthetic molluscicide metaldehyde. Individual cyclotides from each extract demonstrated a range of molluscicidal activities. The cyclotides cycloviolacin O1, kalata B1, and kalata B2 were more toxic to golden apple snails than metaldehyde, while kalata B7 and kalata B8 did not cause significant mortality. The toxicity of the cyclotide kalata B2 on a nontarget species, the Nile tilapia ( Oreochromis niloticus), was three times lower than the common piscicide rotenone. Our findings suggest that the existing diversity of cyclotides in plants could be used to develop natural molluscicides.

  1. Pyridoxamine Protects Protein Backbone from Oxidative Fragmentation

    PubMed Central

    Chetyrkin, Sergei; Mathis, Missy; McDonald, W. Hayes; Shackelford, Xavier; Hudson, Billy; Voziyan, Paul

    2011-01-01

    Oxidative damage to proteins is one of the major pathogenic mechanisms in many chronic diseases. Therefore, inhibition of this oxidative damage can be an important part of therapeutic strategies. Pyridoxamine (PM), a prospective drug for treatment of diabetic nephropathy, has been previously shown to inhibit several oxidative and glycoxidative pathways, thus protecting amino acid side chains of the proteins from oxidative damage. Here, we demonstrated that PM can also protect protein backbone from fragmentation induced via different oxidative mechanisms including autoxidation of glucose. This protection was due to hydroxyl radical scavenging by PM and may contribute to PM therapeutic effects shown in clinical trials. PMID:21763683

  2. Telephone wire is backbone of security system

    SciTech Connect

    Brede, K.; Rackson, L.T.

    1995-09-01

    Video provides a variety of low-cost, high-quality solutions in today`s security environment. Cost-conscious managers of power generation stations, casinos, prison facilities, military bases and office buildings are considering using regular telephone wire (unshielded twisted pair-UTP) within their existing systems as the backbone of a video to the PC, personal and video-conferencing and training are other areas where phone wire in a building can save money and provide an alternative to coax or fiber for video. More and more, businesses and government agencies are meeting their needs efficiently by using telephone wires for more than just telephones.

  3. Advanced routing in interplanetary backbone network

    NASA Astrophysics Data System (ADS)

    Xu, Ge; Sheng, Min; Wu, Chengke

    2007-11-01

    Interplanetary (IPN) Internet is a communication infrastructure providing communication services for scientific data delivery and navigation services for the explorer spacecrafts and orbiters of the future deep space missions. The interplanetary backbone network has the unique characteristics hence routing through the backbone network present many challenges that are not presented in traditional networks. Some routing algorithms have been proposed, in which, LPDB integrates the shortest path algorithm and the directional broadcast method to guarantee fast and reliable message delivery. Through this mutipath routing strategy, unpredictable link failures is addressed, but additional network overhead is introduced. In this paper, we propose an improvement of the LPDB named ALPDB in which the source could adaptively decide the next-hop nodes according to the link condition, hence reduce the network overhead. We model this algorithm on the network simulation platform of OPNET and compare it with other applicable algorithms in data passing ratio, data delay and network overhead. The result indicates that the ALPDB algorithm could not only guarantee reliable message delivery, but also decrease the cost significantly.

  4. Nonlinear backbone torsional pair correlations in proteins

    NASA Astrophysics Data System (ADS)

    Long, Shiyang; Tian, Pu

    2016-10-01

    Protein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions, and occur on widely different and relatively longer time scales. In contrast, correlations between backbone torsions in stable α helices and β strands are mainly linear and spatially short-ranged, and are more likely to associate with harmonic local torsional motion. Further analysis revealed that the direct cause of nonlinear contributions are heterogeneous linear correlations. These findings implicate a general search strategy for novel allosteric modulation sites of protein activities.

  5. Nonlinear backbone torsional pair correlations in proteins

    PubMed Central

    Long, Shiyang; Tian, Pu

    2016-01-01

    Protein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions, and occur on widely different and relatively longer time scales. In contrast, correlations between backbone torsions in stable α helices and β strands are mainly linear and spatially short-ranged, and are more likely to associate with harmonic local torsional motion. Further analysis revealed that the direct cause of nonlinear contributions are heterogeneous linear correlations. These findings implicate a general search strategy for novel allosteric modulation sites of protein activities. PMID:27708342

  6. Mechanical Manipulation of Chemical Reactions: Reactivity Switching of Bergman Cyclizations.

    PubMed

    Krupička, Martin; Sander, Wolfram; Marx, Dominik

    2014-03-06

    Photoswitches incorporated into molecular frameworks have been used since a long time to trigger chemical processes on demand. Here, it is shown how mechanophores can be used as switches in order to drastically change the reactivity of a neighboring functional group as a function of external stress. The reactivities of cyclic enediynes, which are highly toxic agents when undergoing Bergman cyclization, roughly correlate with the distance between the bond-forming carbons in many cases. It is demonstrated how this distance, and thus enediyne reactivity, can be tuned upon applying mechanical stress. Depending on suitable substitution patterns, chemically inert species can be turned into highly reactive ones and vice versa, thus extending the concept of photoswitching to mechanoswitching. Moreover, depending on the derivative, it is found that C1-C5 cyclization becomes energetically preferred over the Bergman (C1-C6) pathway at nano-Newton forces, thus leading to a force-induced switch in selectivity in such cases.

  7. Bergman cyclization in polymer chemistry and material science.

    PubMed

    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.

  8. Iridium-catalyzed reductive nitro-Mannich cyclization.

    PubMed

    Gregory, Alex W; Chambers, Alan; Hawkins, Alison; Jakubec, Pavol; Dixon, Darren J

    2015-01-02

    A new chemoselective reductive nitro-Mannich cyclization reaction sequence of nitroalkyl-tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)-catalyzed reduction of lactams to the corresponding enamine, subsequent nitro-Mannich cyclization of tethered nitroalkyl functionality provides direct access to important alkaloid natural-product-like structures in yields up to 81 % and in diastereoselectivities that are typically good to excellent. An in-depth understanding of the reaction mechanism has been gained through NMR studies and characterization of reaction intermediates. The new methodology has been applied to the total synthesis of (±)-epi-epiquinamide in four steps. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Survey of 2,11-cyclized cembranoids from Caribbean sources.

    PubMed

    Cóbar, Oscar M

    2009-01-01

    This review covers the literature published since the report of the first compound to December 2006, for marine natural 2,11-cyclized cembranoids isolated from Caribbean sources, with 30 citations, most of them from 2000 to 2006, referring to compounds isolated from the Caribbean gorgonian octocorals Briareum asbestinum, Briareum polyanthes, and Erithropodiun caribaeorum. The emphasis is on all of these natural compounds isolated to date, with an overview of their biogenetic pathway and relevant biological activity.

  10. Rational reprogramming of fungal polyketide first-ring cyclization

    PubMed Central

    Xu, Yuquan; Zhou, Tong; Zhou, Zhengfu; Su, Shiyou; Roberts, Sue A.; Montfort, William R.; Zeng, Jia; Chen, Ming; Zhang, Wei; Lin, Min; Zhan, Jixun; Molnár, István

    2013-01-01

    Resorcylic acid lactones and dihydroxyphenylacetic acid lactones represent important pharmacophores with heat shock response and immune system modulatory activities. The biosynthesis of these fungal polyketides involves a pair of collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1,3-benzenediol moiety bridged by a macrolactone. Biosynthesis of unreduced polyketides requires the sequestration and programmed cyclization of highly reactive poly-β-ketoacyl intermediates to channel these uncommitted, pluripotent substrates to defined subsets of the polyketide structural space. Catalyzed by product template (PT) domains of the fungal nrPKSs and discrete aromatase/cyclase enzymes in bacteria, regiospecific first-ring aldol cyclizations result in characteristically different polyketide folding modes. However, a few fungal polyketides, including the dihydroxyphenylacetic acid lactone dehydrocurvularin, derive from a folding event that is analogous to the bacterial folding mode. The structural basis of such a drastic difference in the way a PT domain acts has not been investigated until now. We report here that the fungal vs. bacterial folding mode difference is portable on creating hybrid enzymes, and we structurally characterize the resulting unnatural products. Using structure-guided active site engineering, we unravel structural contributions to regiospecific aldol condensations and show that reshaping the cyclization chamber of a PT domain by only three selected point mutations is sufficient to reprogram the dehydrocurvularin nrPKS to produce polyketides with a fungal fold. Such rational control of first-ring cyclizations will facilitate efforts to the engineered biosynthesis of novel chemical diversity from natural unreduced polyketides. PMID:23509261

  11. Synthesis of 1,2,4-Triazolo[4,3-a]pyridines and Related Heterocycles by Sequential Condensation and Iodine-Mediated Oxidative Cyclization.

    PubMed

    Li, Ertong; Hu, Zhiyuan; Song, Lina; Yu, Wenquan; Chang, Junbiao

    2016-07-25

    A facile and efficient approach to access 1,2,4-triazolo[4,3-a]pyridines and related heterocycles has been accomplished through condensation of readily available aryl hydrazines with corresponding aldehydes followed by iodine-mediated oxidative cyclization. This transition-metal-free synthetic process is broadly applicable to a variety of aromatic, aliphatic, and α,β-unsaturated aldehydes, and can be conveniently conducted on the gram scale.

  12. Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation-cyclization reaction using atmospheric carbon dioxide.

    PubMed

    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.

  13. Cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of 3-aza-1,5-enynes to synthesize 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines.

    PubMed

    Xin, Xiaoyi; Wang, Dongping; Wu, Fan; Li, Xincheng; Wan, Boshun

    2013-04-19

    Metal-free cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of readily available 3-aza-1,5-enynes have been developed. The reactions selectively give 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines involving an aza-Claisen rearrangement and a 6π-electrocyclization step. Furthermore, the reaction could be carried out in 10 g scale for the synthesis of 1,2-dihydropyridines.

  14. Sofosbuvir as backbone of interferon free treatments.

    PubMed

    Bourlière, Marc; Oules, Valèrie; Ansaldi, Christelle; Adhoute, Xavier; Castellani, Paul

    2014-12-15

    Sofosbuvir is the first-in-class NS5B nucleotide analogues to be launched for hepatitis C virus (HCV) treatment. Its viral potency, pangenotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Recent data demonstrated that sofosbuvir either with ribavirin alone or in combination with other direct-acting antivirals (DAAs) as daclatasvir, ledipasvir or simeprevir are able to cure HCV in at least 90% or over of patients. Treatment experienced genotype 3 population may remain the most difficult to treat population, but ongoing DAA combination studies will help to fill this gap. Safety profile of sofosbuvir or combination with other DAAs is good. Resistance to sofosbuvir did not appear as a significant issue. The rationale for using this class of drug and the available clinical data are reviewed. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  15. Structural basis for antibody catalysis of a cationic cyclization reaction.

    PubMed

    Zhu, Xueyong; Heine, Andreas; Monnat, Frédéric; Houk, K N; Janda, Kim D; Wilson, Ian A

    2003-05-23

    Antibody 4C6 efficiently catalyzes a cationic cyclization reaction. Crystal structures of the antibody 4C6 Fab in complex with benzoic acid and in complex with its eliciting hapten were determined to 1.30A and 2.45A resolution, respectively. These crystal structures, together with computational analysis, have elucidated a possible mechanism for the monocyclization reaction. The hapten complex revealed a combining site pocket with high shape complementarity to the hapten. This active site cleft is dominated by aromatic residues that shield the highly reactive carbocation intermediates from solvent and stabilize the carbocation intermediates through cation-pi interactions. Modeling of an acyclic olefinic sulfonate ester substrate and the transition state (TS) structures shows that the chair-like transition state is favored, and trapping by water directly produces trans-2-(dimethylphenylsilyl)-cyclohexanol, whereas the less favored boat-like transition state leads to cyclohexene. The only significant change observed upon hapten binding is a side-chain rotation of Trp(L89), which reorients to form the base of the combining site. Intriguingly, a benzoic acid molecule was sequestered in the combining site of the unliganded antibody. The 4C6 active site was compared to that observed in a previously reported tandem cyclization antibody 19A4 hapten complex. These cationic cyclization antibodies exhibit convergent structural features with terpenoid cyclases that appear to be important for catalysis.

  16. Tissue-Specific Expression of Head-to-Tail Cyclized Miniproteins in Violaceae and Structure Determination of the Root Cyclotide Viola hederacea root cyclotide1W⃞

    PubMed Central

    Trabi, Manuela; Craik, David J.

    2004-01-01

    The plant cyclotides are a family of 28 to 37 amino acid miniproteins characterized by their head-to-tail cyclized peptide backbone and six absolutely conserved Cys residues arranged in a cystine knot motif: two disulfide bonds and the connecting backbone segments form a loop that is penetrated by the third disulfide bond. This knotted disulfide arrangement, together with the cyclic peptide backbone, renders the cyclotides extremely stable against enzymatic digest as well as thermal degradation, making them interesting targets for both pharmaceutical and agrochemical applications. We have examined the expression patterns of these fascinating peptides in various Viola species (Violaceae). All tissue types examined contained complex mixtures of cyclotides, with individual profiles differing significantly. We provide evidence for at least 57 novel cyclotides present in a single Viola species (Viola hederacea). Furthermore, we have isolated one cyclotide expressed only in underground parts of V. hederacea and characterized its primary and three-dimensional structure. We propose that cyclotides constitute a new family of plant defense peptides, which might constitute an even larger and, in their biological function, more diverse family than the well-known plant defensins. PMID:15295104

  17. Tissue-specific expression of head-to-tail cyclized miniproteins in Violaceae and structure determination of the root cyclotide Viola hederacea root cyclotide1.

    PubMed

    Trabi, Manuela; Craik, David J

    2004-08-01

    The plant cyclotides are a family of 28 to 37 amino acid miniproteins characterized by their head-to-tail cyclized peptide backbone and six absolutely conserved Cys residues arranged in a cystine knot motif: two disulfide bonds and the connecting backbone segments form a loop that is penetrated by the third disulfide bond. This knotted disulfide arrangement, together with the cyclic peptide backbone, renders the cyclotides extremely stable against enzymatic digest as well as thermal degradation, making them interesting targets for both pharmaceutical and agrochemical applications. We have examined the expression patterns of these fascinating peptides in various Viola species (Violaceae). All tissue types examined contained complex mixtures of cyclotides, with individual profiles differing significantly. We provide evidence for at least 57 novel cyclotides present in a single Viola species (Viola hederacea). Furthermore, we have isolated one cyclotide expressed only in underground parts of V. hederacea and characterized its primary and three-dimensional structure. We propose that cyclotides constitute a new family of plant defense peptides, which might constitute an even larger and, in their biological function, more diverse family than the well-known plant defensins.

  18. PIFA-BF3·OEt2 mediated intramolecular regioselective domino cyclization of ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H)-ones.

    PubMed

    Ieawsuwan, Winai; Ruchirawat, Somsak

    2017-06-01

    The transition metal-free intramolecular regioselective domino cyclization of N-Boc protected ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-ones in moderate to good yields. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Cyclization strategies to polyenes using Pd(II)-catalyzed couplings of pinacol vinylboronates.

    PubMed

    Iafe, Robert G; Chan, Daniel G; Kuo, Jonathan L; Boon, Byron A; Faizi, Darius J; Saga, Tomomi; Turner, Jonathan W; Merlic, Craig A

    2012-08-17

    As a complement to Pd(0)-catalyzed cyclizations, seven Pd(II)-catalyzed cyclization strategies are reported. α,ω-Diynes are selectively hydroborated to bis(boronate esters), which cyclize under Pd(II)-catalysis producing a diverse array of small, medium, and macrocyclic polyenes with controlled E,E, Z,Z, or E,Z stereochemistry. Various functional groups are tolerated including aryl bromides, and applications are illustrated.

  20. Efficient catalysis of Nazarov cyclization using a cationic iridium complex possessing adjacent labile coordination sites.

    PubMed

    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.

  1. A general method for the catalytic nazarov cyclization of heteroaromatic compounds.

    PubMed

    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].

  2. Evaluation of impact of backbone outages in IP networks

    NASA Astrophysics Data System (ADS)

    Kogan, Yaakov; Choudhury, Gagan L.; Tarapore, Percy

    2004-09-01

    Nationwide IP networks typically include nodes in major cities and the following elements: customer equipment, access routers, backbone routers, peering routers, access links connecting customer equipment to access routers, access routers to backbone routers, and backbone links interconnecting backbone routers. The part of this network consisting of backbone routers and related interconnecting links is referred to as the "backbone". We develop a new approach for accurately computing the Availability measure of IP networks by directly simulating each type of backbone outage event and its impact on traffic loss. We use this approach to quantify availability improvement as a result of introducing various technological changes in the network such as IGP tuning, high availability router architecture, MPLS-TE and Fast Reroute. A situation, where operational backbone links do not have enough spare capacity to carry additional traffic during the outage time, is referred to as bandwidth loss. We concentrate on one unidirectional backbone link and derive asymptotic approximations for the expected bandwidth loss in the framework of generalized Erlang and Engset models when the total number of resource units and request arrival rates are proportionally large. Simulation results demonstrate good accuracy of the approximations.

  3. Improving the Binding Affinity of in-Vitro-Evolved Cyclic Peptides by Inserting Atoms into the Macrocycle Backbone.

    PubMed

    Wilbs, Jonas; Middendorp, Simon J; Heinis, Christian

    2016-12-14

    Cyclic peptides binding to targets of interest can be generated efficiently with powerful in vitro display techniques, such as phage display or mRNA display. The cyclic peptide libraries screened with these methods are generated by altering in a combinatorial fashion the amino acid sequence of the peptides, the number of amino acids in the macrocycle rings, and the cyclization chemistry. A structural element that cannot easily be varied in the cyclic peptides is the backbone, which is built from amino acids, each of which contributes three atoms to the macrocyclic ring structure. Here, we proposed to improve the affinity of a phage-selected bicyclic peptide inhibitor of coagulation factor XII (FXII) by screening variants with one or two carbon atoms inserted into different positions of the backbone, and thus tapping into a structural space that was not sampled by phage display. Two mutants showed 4.7- and 2.5-fold improved Ki values. The better one blocked FXII with a Ki of 1.5±0.1 nm and inhibited activation of the intrinsic coagulation pathway (EC2x 1.7 μm). The strategy of ring size variation by one or several atoms should be generally applicable for the affinity maturation of in-vitro-evolved cyclic peptides. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization.

    PubMed

    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

  5. High Speed Fibre Optic Backbone LAN

    NASA Astrophysics Data System (ADS)

    Tanimoto, Masaaki; Hara, Shingo; Kajita, Yuji; Kashu, Fumitoshi; Ikeuchi, Masaru; Hagihara, Satoshi; Tsuzuki, Shinji

    1987-09-01

    Our firm has developed the SUMINET-4100 series, a fibre optic local area network (LAN), to serve the communications system trunk line needs for facilities, such as steel refineries, automobile plants and university campuses, that require large transmission capacity, and for the backbone networks used in intelligent building systems. The SUMINET-4100 series is already in service in various fields of application. Of the networks available in this series, the SUMINET-4150 has a trunk line speed of 128 Mbps and the multiplexer used for time division multiplexing (TDM) was enabled by designing an ECL-TTL gate array (3000 gates) based custom LSI. The synchronous, full-duplex V.24 and V.3.5 interfaces (SUMINET-2100) are provided for use with general purpose lines. And the IBM token ring network, the SUMINET-3200, designed for heterogeneous PCs and the Ethernet can all be connected to sub loops. Further, the IBM 3270 TCA and 5080 CADAM can be connected in the local mode. Interfaces are also provided for the NTT high-speed digital service, the digital PBX systems, and the Video CODEC system. The built-in loop monitor (LM) and network supervisory processor (NSP) provide management of loop utilization and send loop status signals to the host CPU's network configuration and control facility (NCCF). These built-in functions allow both the computer system and LAN to be managed from a single source at the host. This paper outlines features of the SUMINET-4150 and provides an example of its installation.

  6. Free backbone carbonyls mediate rhodopsin activation

    PubMed Central

    Kimata, Naoki; Pope, Andreyah; Sanchez-Reyes, Omar B.; Eilers, Markus; Opefi, Chikwado A.; Ziliox, Martine; Reeves, Philip J.; Smith, Steven O.

    2016-01-01

    Conserved prolines in the transmembrane helices of G protein-coupled receptors (GPCRs) are often considered to function as hinges that divide the helix into two segments capable of independent motion. Depending on their potential to hydrogen-bond, the free C=O groups associated with these prolines can facilitate conformational flexibility, conformational switching or stabilize receptor structure. To address the role of conserved prolines in family A GPCRs, we focus on bovine rhodopsin, a GPCR in the visual receptor subfamily, using solid-state NMR spectroscopy. The free backbone C=O groups on helices H5 and H7 are found to stabilize the inactive rhodopsin structure through hydrogen-bonds to residues on adjacent helices. In response to light-induced isomerization of the retinal chromophore, hydrogen-bonding interactions involving these C=O groups are released facilitating H5 and H7 repacking onto the transmembrane core of the receptor. These results provide insights into the multiple structural and functional roles prolines play in membrane proteins. PMID:27376589

  7. Extracting the Information Backbone in Online System

    PubMed Central

    Zhang, Qian-Ming; Zeng, An; Shang, Ming-Sheng

    2013-01-01

    Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity) of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such “less can be more” feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency. PMID:23690946

  8. The Backbone of the Climate Networks

    NASA Astrophysics Data System (ADS)

    Zou, Y.; Donges, J. F.; Marwan, N.; Kurths, J.

    2009-12-01

    We propose a method to reconstruct and analyze a complex network from data generated by a spatio-temporal dynamical system, relying on the nonlinear mutual information of time series analysis and betweenness centrality of complex network theory. We show, that this approach reveals a rich internal structure in complex climate networks constructed from reanalysis and model surface air temperature data. Our novel method uncovers peculiar wave-like structures of high energy flow, that we relate to global surface ocean currents. This points to a major role of the oceanic surface circulation in coupling and stabilizing the global temperature field in the long term mean (140 years for the model run and 60 years for reanalysis data). We find that these results cannot be obtained using classical linear methods of multivariate data analysis. Furthermore, we introduce significance tests to quantify the robustness of measured network properties to uncertainties. References: [1] J.F. Donges, Y. Zou, N. Marwan, and J. Kurths. Complex networks in climate dynamics -- -- Comparing linear and nonlinear network construction methods. European Physical Journal -- Special Topics, 174, 157-179, 2009. [2] J.F. Donges, Y. Zou, N. Marwan, and J. Kurths. Backbone of the climate network. Europhysics Letters, in press, 2009.

  9. Detecting the Significant Flux Backbone of Escherichia coli metabolism.

    PubMed

    Güell, Oriol; Sagués, Francesc; Serrano, M Ángeles

    2017-04-09

    The heterogeneity of computationally predicted reaction fluxes in metabolic networks within a single flux state can be exploited to detect their significant flux backbone. Here, we disclose the backbone of Escherichia coli, and compare it with the backbones of other bacteria. We find that, in general, the core of the backbones is mainly composed of reactions in energy metabolism corresponding to ancient pathways. In E. coli, the synthesis of nucleotides and the metabolism of lipids form smaller cores which rely critically on energy metabolism. Moreover, the consideration of different media leads to the identification of pathways sensitive to environmental changes. The metabolic backbone of an organism is thus useful for tracing, simultaneously, both its evolution and adaptation fingerprints. This article is protected by copyright. All rights reserved.

  10. Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with αα Domain Architecture That Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence.

    PubMed

    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

    2015-12-08

    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 Mg(2+) 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 three Mg(2+) 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 on the basis of ∼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.

  11. Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with Alpha-Alpha Domain Architecture that Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence

    PubMed Central

    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

  12. Cyclization cascade of allenyl azides: A dual mechanism

    PubMed Central

    López, Carlos Silva; Faza, Olalla Nieto; Feldman, Ken S.; Iyer, Malliga R.; Hester, D. Keith

    2008-01-01

    A density functional theory based computational approach to describing the mechanistic course of the allene azide cycloaddition cascade sequence has been developed. The results of these calculations permit characterization of key reactive intermediates (diradicals and/or indolidenes), and explain the different behaviour observed in the experimental studies between conjugated and non-conjugated species. Furthermore, computational analysis of certain intermediates offer insight into issues of regioselectivity and stereoselectivity in cases where different reaction channels are in competition, suggesting suitable substitutions to achieve a single regioisomer in the indole synthesis via azide-allene cyclization. PMID:17530848

  13. Gas-Phase Intramolecular Cyclization of Argentinated N-Allylbenzamides

    NASA Astrophysics Data System (ADS)

    Sun, Hezhi; Chai, Yunfeng; Jin, Zhe; Sun, Cuirong; Pan, Yuanjiang

    2015-05-01

    The fragmentations of argentinated N-allylbenzamides have been exhaustively studied through collision-induced dissociation and through deuterium labeling. The intriguing elimination of AgOH is certified as the consequence of intramolecular cyclization between terminal olefin and carbonyl carbon following proton transfer to carbonyl oxygen, rather than simple enolization of amide. Linear free energy correlations and density functional theory (DFT) calculations were performed to understand the competitive relationship between AgOH loss and AgH loss, which results from the 1,2-elimination of α-hydrogen (to the amido nitrogen) with the silver.

  14. Intramolecular donor-acceptor cyclopropane ring-opening cyclizations.

    PubMed

    Cavitt, Marchello A; Phun, Lien H; France, Stefan

    2014-02-07

    Cyclization reactions of donor-acceptor (D-A) cyclopropanes are recognized as versatile methods for construction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular reactivity of donor-acceptor cyclopropanes is widely reported, reviews that center on their intramolecular chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor-acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D-A acceptor cyclopropanes as reactive subunits in natural product synthesis is underscored.

  15. Alkyldisulfanium Salts: Isolable, Electrophilic Sulfur Reagents Competent for Polyene Cyclizations.

    PubMed

    Schevenels, Florian T; Shen, Minxing; Snyder, Scott A

    2017-01-06

    Tools that can effect electrophilic sulfur-promoted cation-π cyclizations are generally lacking, especially using alkylsulfide-based reagents. Herein we report that combining three different 1,2-dithioethers with Cl2 and SbCl5 generates isolable alkyldisulfanium salts that can effect such reactions. These new reagents can install -SMe, -SEt, and -SCH2CH2CF3 in modest, moderate, or good yield on diverse frameworks, including polyenes that terminate with electron-deficient groups. We also show that reagents such as dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) can accomplish similar chemistry.

  16. Enantioselective palladium(0)-catalyzed Nazarov-type cyclization.

    PubMed

    Kitamura, Kei; Shimada, Naoyuki; Stewart, Craig; Atesin, Abdurrahman C; Ateşin, Tülay A; Tius, Marcus A

    2015-05-18

    A Pd(0)-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity. It is noteworthy that the reaction does not require that substrates should be activated by aryl substituents. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Ultrasonic-assisted synthesis of flavones by oxidative cyclization of 2'-hydroxychalcones using iodine monochloride.

    PubMed

    Lahyani, Achraf; Trabelsi, Mahmoud

    2016-07-01

    This paper presents an efficient methodology for the synthesis of flavones via the oxidative cyclization of 2'-hydroxychalcones in the presence of iodine monochloride with DMSO under ultrasound irradiation. Ultrasonic irradiation enhances the cyclization reaction and leads to reduced reaction time at lower reaction temperatures while generating flavones with high yields.

  18. Enantioselective Synthesis of 4- and 6-Azaindolines by a Cation-Directed Cyclization

    PubMed Central

    2016-01-01

    Functionalized 4- and 6-azaindolines are accessible with high levels of enantioselectivity by the cation-directed cyclization of aminopyridine-derived imines via phase-transfer catalysis. The extension of this methodology to diastereoselective cyclizations is also described. PMID:27709963

  19. Nazarov cyclization initiated by peracid oxidation: the total synthesis of (+/-)-rocaglamide.

    PubMed

    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.

  20. Peptide backbone circularization enhances antifreeze protein thermostability.

    PubMed

    Stevens, Corey A; Semrau, Joanna; Chiriac, Dragos; Litschko, Morgan; Campbell, Robert L; Langelaan, David N; Smith, Steven P; Davies, Peter L; Allingham, John S

    2017-10-01

    Antifreeze proteins (AFPs) are a class of ice-binding proteins that promote survival of a variety of cold-adapted organisms by decreasing the freezing temperature of bodily fluids. A growing number of biomedical, agricultural, and commercial products, such as organs, foods, and industrial fluids, have benefited from the ability of AFPs to control ice crystal growth and prevent ice recrystallization at subzero temperatures. One limitation of AFP use in these latter contexts is their tendency to denature and irreversibly lose activity at the elevated temperatures of certain industrial processing or large-scale AFP production. Using the small, thermolabile type III AFP as a model system, we demonstrate that AFP thermostability is dramatically enhanced via split intein-mediated N- and C-terminal end ligation. To engineer this circular protein, computational modeling and molecular dynamics simulations were applied to identify an extein sequence that would fill the 20-Å gap separating the free ends of the AFP, yet impose little impact on the structure and entropic properties of its ice-binding surface. The top candidate was then expressed in bacteria, and the circularized protein was isolated from the intein domains by ice-affinity purification. This circularized AFP induced bipyramidal ice crystals during ice growth in the hysteresis gap and retained 40% of this activity even after incubation at 100°C for 30 min. NMR analysis implicated enhanced thermostability or refolding capacity of this protein compared to the noncyclized wild-type AFP. These studies support protein backbone circularization as a means to expand the thermostability and practical applications of AFPs. © 2017 The Protein Society.

  1. Identical repeated backbone of the human genome

    PubMed Central

    2010-01-01

    Background Identical sequences with a minimal length of about 300 base pairs (bp) have been involved in the generation of various meiotic/mitotic genomic rearrangements through non-allelic homologous recombination (NAHR) events. Genomic disorders and structural variation, together with gene remodelling processes have been associated with many of these rearrangements. Based on these observations, we identified and integrated all the 100% identical repeats of at least 300 bp in the NCBI version 36.2 human genome reference assembly into non-overlapping regions, thus defining the Identical Repeated Backbone (IRB) of the reference human genome. Results The IRB sequences are distributed all over the genome in 66,600 regions, which correspond to ~2% of the total NCBI human genome reference assembly. Important structural and functional elements such as common repeats, segmental duplications, and genes are contained in the IRB. About 80% of the IRB bp overlap with known copy-number variants (CNVs). By analyzing the genes embedded in the IRB, we were able to detect some identical genes not previously included in the Ensembl release 50 annotation of human genes. In addition, we found evidence of IRB gene copy-number polymorphisms in raw sequence reads of two diploid sequenced genomes. Conclusions In general, the IRB offers new insight into the complex organization of the identical repeated sequences of the human genome. It provides an accurate map of potential NAHR sites which could be used in targeting the study of novel CNVs, predicting DNA copy-number variation in newly sequenced genomes, and improve genome annotation. PMID:20096123

  2. Strategies to control alkoxy radical-initiated relay cyclizations for the synthesis of oxygenated tetrahydrofuran motifs.

    PubMed

    Zhu, Hai; Leung, Joe C T; Sammis, Glenn M

    2015-01-16

    Radical relay cyclizations initiated by alkoxy radicals are a powerful tool for the rapid construction of substituted tetrahydrofurans. The scope of these relay cyclizations has been dramatically increased with the development of two strategies that utilize an oxygen atom in the substrate to accelerate the desired hydrogen atom transfer (HAT) over competing pathways. This has enabled a chemoselective 1,6-HAT over a competing 1,5-HAT. Furthermore, this allows for a chemoselective 1,5-HAT over competing direct cyclizations and β-fragmentations. Oxygen atom incorporation leads to a general increase in cyclization diastereoselectivity over carbon analogues. This chemoselective relay cyclization strategy was utilized in the improved synthesis of the tetrahydrofuran fragment in (−)-amphidinolide K.

  3. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    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...

  4. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    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...

  5. Radiation safety system (RSS) backbones: Design, engineering, fabrication and installation

    SciTech Connect

    Wilmarth, J.E.; Sturrock, J.C.; Gallegos, F.R.

    1998-12-01

    The Radiation Safety System (RSS) Backbones are part of an electrical/electronic/mechanical system insuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS Backbones control the safety fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low energy beam transport. The Backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the Backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two Linac Backbone segments and experimental area segments form a continuous cable plant over 3,500 feet from beam plugs to the tip on the longest tail. The Backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  6. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    SciTech Connect

    Wilmarth, J.E.; Sturrock, J.C.; Gallegos, F.R.

    1998-12-01

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely. {copyright} {ital 1998 American Institute of Physics.}

  7. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    SciTech Connect

    Wilmarth, J. E.; Sturrock, J. C.; Gallegos, F. R.

    1998-12-10

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  8. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    NASA Astrophysics Data System (ADS)

    Wilmarth, J. E.; Sturrock, J. C.; Gallegos, F. R.

    1998-12-01

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  9. Nazarov Cyclization/Internal Redox Cyclization Sequence for the Synthesis of N-Heterocyclic Bridged Ring Systems.

    PubMed

    Huang, Yu-Wen; Frontier, Alison J

    2016-10-07

    A 1,6 conjugate addition/Nazarov electrocyclization/internal redox cyclization sequence was developed. Various 5-hydroxycyclopentenones were made through the 1,6-conjugate addition initiated Nazarov reaction with excellent diastereoselectivities. Under thermal conditions, these underwent a through-space 1,5-hydride-transfer/ring-closure reaction to form bridged bicyclic N-heterocyclic compounds with up to four stereogenic centers. It was also possible to convert simple acyclic dienyl diketones into the bicyclo[3.2.1] products in a one-pot process (with a solvent switch).

  10. A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

    PubMed Central

    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

  11. Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

    SciTech Connect

    McCulloch, Kathryn M.; McCranie, Emilianne K.; Smith, Jarrod A.; Sarwar, Maruf; Mathieu, Jeannette L.; Gitschlag, Bryan L.; Du, Yu; Bachmann, Brian O.; Iverson, T. M.

    2015-08-03

    Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. In this paper, we have identified a conserved group of nonheme iron, α-ketoglutarate–dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Finally, our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.

  12. Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

    PubMed Central

    McCulloch, Kathryn M.; McCranie, Emilianne K.; Smith, Jarrod A.; Sarwar, Maruf; Mathieu, Jeannette L.; Gitschlag, Bryan L.; Du, Yu; Bachmann, Brian O.; Iverson, T. M.

    2015-01-01

    Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate–dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics. PMID:26240321

  13. Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

    DOE PAGES

    McCulloch, Kathryn M.; McCranie, Emilianne K.; Smith, Jarrod A.; ...

    2015-08-03

    Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. In this paper, we have identified a conserved group of nonheme iron, α-ketoglutarate–dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases ofmore » everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Finally, our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.« less

  14. A backbone lever-arm effect enhances polymer mechanochemistry.

    PubMed

    Klukovich, Hope M; Kouznetsova, Tatiana B; Kean, Zachary S; Lenhardt, Jeremy M; Craig, Stephen L

    2013-02-01

    Mechanical forces along a polymer backbone can be used to bring about remarkable reactivity in embedded mechanically active functional groups, but little attention has been paid to how a given polymer backbone delivers that force to the reactant. Here, single-molecule force spectroscopy was used to directly quantify and compare the forces associated with the ring opening of gem-dibromo and gem-dichlorocyclopropanes affixed along the backbone of cis-polynorbornene and cis-polybutadiene. The critical force for isomerization drops by about one-third in the polynorbornene scaffold relative to polybutadiene. The root of the effect lies in more efficient chemomechanical coupling through the polynorbornene backbone, which acts as a phenomenological lever with greater mechanical advantage than polybutadiene. The experimental results are supported computationally and provide the foundation for a new strategy by which to engineer mechanochemical reactivity.

  15. A backbone lever-arm effect enhances polymer mechanochemistry

    NASA Astrophysics Data System (ADS)

    Klukovich, Hope M.; Kouznetsova, Tatiana B.; Kean, Zachary S.; Lenhardt, Jeremy M.; Craig, Stephen L.

    2013-02-01

    Mechanical forces along a polymer backbone can be used to bring about remarkable reactivity in embedded mechanically active functional groups, but little attention has been paid to how a given polymer backbone delivers that force to the reactant. Here, single-molecule force spectroscopy was used to directly quantify and compare the forces associated with the ring opening of gem-dibromo and gem-dichlorocyclopropanes affixed along the backbone of cis-polynorbornene and cis-polybutadiene. The critical force for isomerization drops by about one-third in the polynorbornene scaffold relative to polybutadiene. The root of the effect lies in more efficient chemomechanical coupling through the polynorbornene backbone, which acts as a phenomenological lever with greater mechanical advantage than polybutadiene. The experimental results are supported computationally and provide the foundation for a new strategy by which to engineer mechanochemical reactivity.

  16. Inter- versus intra-molecular cyclization of tripeptides containing tetrahydrofuran amino acids: a density functional theory study on kinetic control.

    PubMed

    Kumar, N V Suresh; Priyakumar, U Deva; Singh, Harjinder; Roy, Saumya; Chakraborty, Tushar Kanti

    2012-07-01

    Density functional B3LYP method was used to investigate the preference of intra- and inter-molecular cyclizations of linear tripeptides containing tetrahydrofuran amino acids. Two distinct model pathways were conceived for the cyclization reaction, and all possible transition states and intermediates were located. Analysis of the energetics indicate intermolecular cyclization being favored by both thermodynamic and kinetic control. Geometric and NBO analyses were performed to explain the trends obtained along both the reaction pathways. Conceptual density functional theory-based reactive indices also show that reaction pathways leading to intermolecular cyclization of the tripeptides are relatively more facile compared to intramolecular cyclization.

  17. Side-chain and backbone ordering in a polypeptide.

    PubMed

    Wei, Yanjie; Nadler, Walter; Hansmann, Ulrich H E

    2006-10-28

    We report results from multicanonical simulations of polyglutamic acid chains of length of ten residues. For this simple polypeptide we observe a decoupling of backbone and side-chain ordering in the folding process. While the details of the two transitions vary between the peptide in gas phase and in an implicit solvent, our results indicate that, independent of the specific surroundings, upon continuously lowering the temperature side-chain ordering occurs only after the backbone topology is completely formed.

  18. Sequential Norrish type II photoelimination and intramolecular aldol cyclization of α-diketones: synthesis of polyhydroxylated cyclopentitols by ring contraction of hexopyranose carbohydrate derivatives.

    PubMed

    Alvarez-Dorta, Dimitri; León, Elisa I; Kennedy, Alan R; Martín, Angeles; Pérez-Martín, Inés; Riesco-Fagundo, Concepción; Suárez, Ernesto

    2013-07-29

    The excitation of the innermost carbonyl of nono-2,3-diulose derivatives by irradiation with visible-light initiates a sequential Norrish type II photoelimination and aldol cyclization process that finally gives polyfunctionalized cyclopentitols. The rearrangement has been confirmed by the isolation of stable acyclic photoenol intermediates that can be independently cyclized by a thermal 5-(enolexo)-exo-trig uncatalyzed aldol reaction with high diastereoselectivity. In this last step, the large deuterium kinetic isotope effect found for the 1,5-hydrogen atom transfer seems to indicate that the aldol reaction runs through a concerted pericyclic mechanism. Owing to the ready availability of pyranose sugars of various configurations, this protocol has been used to study the influence of pyranose ring-substituents on the diastereoselectivity of the aldol cyclization reaction. In contrast with other pyranose ring contraction methodologies no transition-metal reagents are needed and the sequential rearrangement occurs simply by using visible light and moderate heating (0 to 60 °C).

  19. Constructing optimal backbone segments for joining fixed DNA base pairs.

    PubMed Central

    Mazur, J; Jernigan, R L; Sarai, A

    1996-01-01

    A method is presented to link a sequence of space-fixed base pairs by the sugar-phosphate segments of single nucleotides and to evaluate the effects in the backbone caused by this positioning of the bases. The entire computational unit comprises several nucleotides that are energy-minimized, subject to constraints imposed by the sugar-phosphate backbone segments being anchored to space-fixed base pairs. The minimization schemes are based on two stages, a conjugate gradient method followed by a Newton-Raphson algorithm. Because our purpose is to examine the response, or relaxation, of an artificially stressed backbone, it is essential to be able to obtain, as closely as possible, a lowest minimum energy conformation of the backbone segment in conformational space. For this purpose, an algorithm is developed that leads to the generation of an assembly of many local energy minima. From these sets of local minima, one conformation corresponding to the one with the lowest minimum is then selected and designated to represent the backbone segment at its minimum. The effective electrostatic potential of mean force is expressed in terms of adjustable parameters that incorporate solvent screening action in the Coulombic interactions between charged backbone atoms; these parameters are adjusted to obtain the best fit of the nearest-neighbor phosphorous atoms in an x-ray structure. PMID:8874023

  20. Large-scale measurement and modeling of backbone Internet traffic

    NASA Astrophysics Data System (ADS)

    Roughan, Matthew; Gottlieb, Joel

    2002-07-01

    There is a brewing controversy in the traffic modeling community concerning how to model backbone traffic. The fundamental work on self-similarity in data traffic appears to be contradicted by recent findings that suggest that backbone traffic is smooth. The traffic analysis work to date has focused on high-quality but limited-scope packet trace measurements; this limits its applicability to high-speed backbone traffic. This paper uses more than one year's worth of SNMP traffic data covering an entire Tier 1 ISP backbone to address the question of how backbone network traffic should be modeled. Although the limitations of SNMP measurements do not permit us to comment on the fine timescale behavior of the traffic, careful analysis of the data suggests that irrespective of the variation at fine timescales, we can construct a simple traffic model that captures key features of the observed traffic. Furthermore, the model's parameters are measurable using existing network infrastructure, making this model practical in a present-day operational network. In addition to its practicality, the model verifies basic statistical multiplexing results, and thus sheds deep insight into how smooth backbone traffic really is.

  1. Triazine-Based Sequence-Defined Polymers with Side-Chain Diversity and Backbone-Backbone Interaction Motifs.

    PubMed

    Grate, Jay W; Mo, Kai-For; Daily, Michael D

    2016-03-14

    Sequence control in polymers, well-known in nature, encodes structure and functionality. Here we introduce a new architecture, based on the nucleophilic aromatic substitution chemistry of cyanuric chloride, that creates a new class of sequence-defined polymers dubbed TZPs. Proof of concept is demonstrated with two synthesized hexamers, having neutral and ionizable side chains. Molecular dynamics simulations show backbone-backbone interactions, including H-bonding motifs and pi-pi interactions. This architecture is arguably biomimetic while differing from sequence-defined polymers having peptide bonds. The synthetic methodology supports the structural diversity of side chains known in peptides, as well as backbone-backbone hydrogen-bonding motifs, and will thus enable new macromolecules and materials with useful functions.

  2. Branching Reaction in Melanogenesis: The Effect of Intramolecular Cyclization on Thiol Binding

    NASA Astrophysics Data System (ADS)

    Kishida, Ryo; Kasai, Hideaki; Aspera, Susan Meñez; Arevalo, Ryan Lacdao; Nakanishi, Hiroshi

    2017-01-01

    With the aid of density functional theory-based first principles calculations, we investigated energetics and electronic structure changes in reactions involving dopaquinone to give insights into the branching behaviors in melanogenesis. The reactions we investigated are the intramolecular cyclization and thiol binding, which are competing with each other. It was found that, in order to accomplish thiol binding, charge transfer of around one electron from thiol to dopaquinone occurs. Furthermore, intramolecular cyclization of dopaquinone increases the lowest unnoccupied molecular orbital level substantially. This result clearly shows prevention of the binding of thiol by intramolecular cyclization.

  3. Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates

    PubMed Central

    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

  4. Autocatalytic cyclization of an excised intervening sequence RNA is a cleavage-ligation reaction.

    PubMed

    Zaug, A J; Grabowski, P J; Cech, T R

    The intervening sequence (IVS) of the Tetrahymena ribosomal RNA precursor is excised as a linear RNA molecule which subsequently cyclizes itself in a protein-independent reaction. Cyclization involves cleavage of the linear IVS RNA 15 nucleotides from its 5' end and formation of a phosphodiester bond between the new 5' phosphate and the original 3'-hydroxyl terminus of the IVS. This recombination mechanism is analogous to that by which splicing of the precursor RNA is achieved. The circular molecules appear to have no direct function in RNA splicing, and we propose the cyclization serves to prevent unwanted RNA from driving the splicing reactions backwards.

  5. Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates.

    PubMed

    Spencer, William T; Vaidya, Tulaza; Frontier, Alison J

    2013-06-01

    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.

  6. A Pd(0)-Mediated Indole (Macro)cyclization Reaction

    PubMed Central

    Breazzano, Steven P.; Poudel, Yam B.; Boger, Dale L.

    2013-01-01

    Herein, we report a systematic study of the Larock indole annulation designed to explore the scope and define the generality of its use in macrocyclization reactions, its use in directly accessing the chloropeptin I versus II DEF ring system as well as key unnatural isomers, its utility for both peptide-derived and more conventional carbon-chain based macrocycles, and its extension to intramolecular cyclizations with formation of common ring sizes. The studies define a powerful method complementary to the Stille or Suzuki cross-coupling reactions for the synthesis of cyclic or macrocyclic ring systems containing an embedded indole, tolerating numerous functional groups and incorporating various (up to 28-membered) ring sizes. As a result of the efforts to expand the usefulness and scope of the reaction, we also disclose a catalytic variant of the reaction along with a powerful Pd2(dba)3 derived catalyst system, and an examination of the factors impacting reactivity and catalysis. PMID:23298368

  7. Samarium(II)-mediated linker cleavage-cyclization in fluorous synthesis: reactions of samarium enolates.

    PubMed

    James, Karen M; Willetts, Nigel; Procter, David J

    2008-03-20

    SmI2 has been used to cleave a sulfur linker and trigger cyclizations in strategies for the traceless fluorous synthesis of N-heterocycles. The studies give further insights into the reactivity of samarium enolates.

  8. Total Synthesis of (±)–Rocaglamide via Oxidation-Initiated Nazarov Cyclization

    PubMed Central

    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

  9. Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

    PubMed Central

    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

  10. SpyTag/SpyCatcher Cyclization Enhances the Thermostability of Firefly Luciferase

    PubMed Central

    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

  11. Total synthesis of (±)-rocaglamide via oxidation-initiated Nazarov cyclization.

    PubMed

    Malona, John A; Cariou, Kevin; Spencer, William T; Frontier, Alison J

    2012-02-17

    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.

  12. Powdered KOH in DMSO: an efficient base for asymmetric cyclization via memory of chirality at ambient temperature.

    PubMed

    Kawabata, Takeo; Moriyama, Katsuhiko; Kawakami, Shimpei; Tsubaki, Kazunori

    2008-03-26

    Enolate chemistry has been extensively used for stereoselective C-C bond formation, in which metal amide bases are frequently employed in strictly anhydrous solvents at low temperatures. However, we found that asymmetric intramolecular C-C bond formation via axially chiral enolate intermediates proceeded in up to 99% ee at 20 degrees C using powdered KOH in dry or wet DMSO as a base. The enantioselectivity was even higher than that of the corresponding reactions with potassium hexamethyldisilazide in DMF at -60 degrees C. The racemization barrier of the axially chiral enolate intermediate was estimated to be approximately 15.5 kcal/mol. On the basis of the barrier, the chiral enolate intermediate was supposed to undergo cyclization within approximately 10(-3) sec at 20 degrees C after it is generated to give the product in >or=99% ee. Thus, enolates generated with powdered KOH in DMSO were expected to be extremely reactive.

  13. Syntheses, thermal reactivities, and computational studies of aryl-fused quinoxalenediynes: effect of extended benzannelation on Bergman cyclization energetics.

    PubMed

    Spence, John D; Rios, Andro C; Frost, Megan A; McCutcheon, Claire M; Cox, Christopher D; Chavez, Sonia; Fernandez, Ramiro; Gherman, Benjamin F

    2012-11-16

    A series of [b]-fused 6,7-diethynylquinoxaline derivatives have been synthesized through an imine condensation strategy to examine the effect of extended benzannelation on the thermal reactivity of enediynes. Absorption and emission spectra of the highly conjugated quinoxalenediynes were red-shifted approximately 100-200 nm relative to those of 1,2-diethynylbenzene. Strong exotherms indicative of enediyne cyclization were observed by differential scanning calorimetry, while solution cyclizations in the presence of 1,4-cyclohexadiene confirmed C(1)-C(6) Bergman cyclization. To provide further insight into Bergman cyclization energetics, computational studies were performed to compare changes in the cyclization enthalpy barrier, reaction enthalpy, and barrier of retro-Bergman ring-opening. Extension of benzannelation from 1,2-diethynylbenzene to either 2,3-diethynylnaphthalene or the 6,7-diethynylquinoxalines had a minimal effect on the cyclization barrier. In comparison, the enthalpies of cyclization were increased upon linearly extended benzannelation, which resulted in reduced barriers to retro-Bergman ring-opening. In addition, the orientation of extended benzannelation was found to have a significant effect on the cyclization endothermicity. In particular, 5,6-diethynylquinoxaline exhibited a 6.9 kcal/mol decrease in cyclization enthalpy compared to 6,7-diethynylquinoxaline due to increased aromatic stabilization energy in the respective angularly versus linearly fused azaacene cyclized products.

  14. A Raney Cobalt Mediated Reductive Cyclization Route to the Uleine Alkaloid Gilbertine.

    PubMed

    Tang, Fei; Banwell, Martin G; Willis, Anthony C

    2016-11-04

    Reductive cyclization of the 2,4,5-trisubstituted cyclohexenone 16 using dihydogen in the presence of Raney cobalt afforded compound 17 (60%) that could be elaborated over a further five steps, including one involving a cationic cyclization process, into the racemic modification of the unusual uleine alkaloid gilbertine. Single-crystal X-ray analyses of compounds (±)-1, 16, and a derivative of 17 are reported.

  15. Synthesis of tyrocidine A and its analogues by spontaneous cyclization in aqueous solution.

    PubMed

    Bu, Xianzhang; Wu, Xiaoming; Xie, Guiyang; Guo, Zhihong

    2002-08-22

    [reaction: see text] Head-to-tail cyclization of peptides is a multistep process involving tedious C-terminal activation and side chain protection. Here we report a facile, quantitative cyclization method in aqueous ammonia solution for the total syntheses of the cyclic decapeptide antibiotic Tyrocidine A and its analogues from their fully deprotected linear thioester precursors on a solid support. This novel aqueous method is conformation-dependent and may be applicable to syntheses of other natural cyclic peptides.

  16. A catalytic homo-Nazarov cyclization protocol for the synthesis of heteroaromatic ring-fused cyclohexanones.

    PubMed

    Phun, Lien H; Patil, Dadasaheb V; Cavitt, Marchello A; France, Stefan

    2011-04-15

    A general protocol for the catalytic homo-Nazarov cyclization of cyclopropyl heteroaryl ketones has been developed, which employs indium triflate as the promoter. A range of heteroaromatic ring-fused cyclohexanones was synthesized in 56-91% yield using this protocol. An example of a tandem cyclopropanation/homo-Nazarov cyclization is also reported in which the one-pot yield is greater than the overall yield of the two individual steps. © 2011 American Chemical Society

  17. Organic Photocatalytic Cyclization of Polyenes: A Visible-Light-Mediated Radical Cascade Approach.

    PubMed

    Yang, Zhongbo; Li, Han; Zhang, Long; Zhang, Ming-Tian; Cheng, Jin-Pei; Luo, Sanzhong

    2015-10-12

    A visible-light-mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosin Y as photocatalyst in hexafluoro-2-propanol. The catalyst system is also suitable for 1,3-dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols.

  18. Vinyl dihydropyrans and dihydrooxazines: cyclizations of catalytic ruthenium carbenes derived from alkynals and alkynones.

    PubMed

    Cambeiro, Fermín; López, Susana; Varela, Jesús A; Saá, Carlos

    2014-06-02

    A novel synthesis of 2-vinyldihydropyrans and dihydro-1,4-oxazines (morpholine derivatives) from alkynals and alkynones has been developed. The cyclizations require a mild generation of catalytic ruthenium carbenes from terminal alkynes and (trimethylsilyl)diazomethane followed by trapping with carbonyl nucleophiles. Mechanistic aspects of the new cyclizations are discussed. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis.

    PubMed

    Svennebring, Andreas; Nilsson, Peter; Larhed, Mats

    2007-07-20

    A number of new spiro[cyclohexane-1,1'-isobenzofuran]-based compounds was synthesized by palladium(0)-catalyzed 5-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of aryl iodide 6, 2-(2-iodobenzyloxy)cyclohex-2-enyl acetate, proceeded selectively without involvement of the allylic acetate functionality.

  20. Structural dependencies of protein backbone 2JNC' couplings.

    PubMed

    Juranić, Nenad; Dannenberg, J J; Cornilescu, Gabriel; Salvador, Pedro; Atanasova, Elena; Ahn, Hee-Chul; Macura, Slobodan; Markley, John L; Prendergast, Franklyn G

    2008-04-01

    Protein folding can introduce strain in peptide covalent geometry, including deviations from planarity that are difficult to detect, especially for a protein in solution. We have found dependencies in protein backbone (2)J(NC') couplings on the planarity and the relative orientation of the sequential peptide planes. These dependences were observed in experimental (2)J(NC') couplings from seven proteins, and also were supported by DFT calculations for a model tripeptide. Findings indicate that elevated (2)J(NC') couplings may serve as reporters of structural strain in the protein backbone imposed by protein folds. Such information, supplemented with the H-bond strengths derived from (h3)J(NC') couplings, provides useful insight into the overall energy profile of the protein backbone in solution.

  1. Structural dependencies of protein backbone 2JNC′ couplings

    PubMed Central

    Juranić, Nenad; Dannenberg, J.J.; Cornilescu, Gabriel; Salvador, Pedro; Atanasova, Elena; Ahn, Hee-Chul; Macura, Slobodan; Markley, John L.; Prendergast, Franklyn G.

    2008-01-01

    Protein folding can introduce strain in peptide covalent geometry, including deviations from planarity that are difficult to detect, especially for a protein in solution. We have found dependencies in protein backbone 2JNC′ couplings on the planarity and the relative orientation of the sequential peptide planes. These dependences were observed in experimental 2JNC′ couplings from seven proteins, and also were supported by DFT calculations for a model tripeptide. Findings indicate that elevated 2JNC′ couplings may serve as reporters of structural strain in the protein backbone imposed by protein folds. Such information, supplemented with the H-bond strengths derived from h3JNC′ couplings, provides useful insight into the overall energy profile of the protein backbone in solution. PMID:18305196

  2. Cyclization strategies of meditopes: affinity and diffraction studies of meditope–Fab complexes

    SciTech Connect

    Bzymek, Krzysztof P.; Ma, Yuelong; Avery, Kendra A.; Horne, David A.; Williams, John C.

    2016-05-23

    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. 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.

  3. Structural studies of intermediates along the cyclization pathway of Aplysia ADP-ribosyl cyclase.

    PubMed

    Kotaka, Masayo; Graeff, Richard; Chen, Zhe; Zhang, Li He; Lee, Hon Cheung; Hao, Quan

    2012-01-20

    Cyclic ADP-ribose (cADPR) is a calcium messenger that can mobilize intracellular Ca²⁺ stores and activate Ca²⁺ influx to regulate a wide range of physiological processes. Aplysia cyclase is the first member of the ADP-ribosyl cyclases identified to catalyze the cyclization of NAD⁺ into cADPR. The catalysis involves a two-step reaction, the elimination of the nicotinamide ring and the cyclization of the intermediate resulting in the covalent attachment of the purine ring to the terminal ribose. Aplysia cyclase exhibits a high degree of leniency towards the purine base of its substrate, and the cyclization reaction takes place at either the N1- or the N7-position of the purine ring. To decipher the mechanism of cyclization in Aplysia cyclase, we used a crystallization setup with multiple Aplysia cyclase molecules present in the asymmetric unit. With the use of natural substrates and analogs, not only were we able to capture multiple snapshots during enzyme catalysis resulting in either N1 or N7 linkage of the purine ring to the terminal ribose, we were also able to observe, for the first time, the cyclized products of both N1 and N7 cyclization bound in the active site of Aplysia cyclase.

  4. SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme.

    PubMed

    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.

  5. T4 DNA ligase is more than an effective trap of cyclized dsDNA.

    PubMed

    Yuan, Chongli; Lou, Xiong Wen; Rhoades, Elizabeth; Chen, Huimin; Archer, Lynden A

    2007-01-01

    T4 DNA ligase is used in standard cyclization assays to trap double-stranded DNA (dsDNA) in low-probability, cyclic or highly bent conformations. The cyclization probability, deduced from the relative yield of cyclized product, can be used in conjunction with statistical mechanical models to extract the bending stiffness of dsDNA. By inserting the base analog 2-aminopurine (2-AP) at designated positions in 89 bp and 94 bp dsDNA fragments, we find that T4 DNA ligase can have a previously unknown effect. Specifically, we observe that addition of T4 ligase to dsDNA in proportions comparable to what is used in the cyclization assay leads to a significant increase in fluorescence from 2-AP. This effect is believed to originate from stabilization of local base-pair opening by formation of transient DNA-ligase complexes. Non-specific binding of T4 ligase to dsDNA is also confirmed using fluorescence correlation spectroscopy (FCS) experiments, which reveal a systematic reduction of dsDNA diffusivity in the presence of ligase. ATP competes with regular DNA for non-covalent binding to the T4 ligase and is found to significantly reduce DNA-ligase complexation. For short dsDNA fragments, however, the population of DNA-ligase complexes at typical ATP concentrations used in DNA cyclization studies is determined to be large enough to dominate the cyclization reaction.

  6. Aminoacyl-tRNA Substrate and Enzyme Backbone Atoms Contribute to Translational Quality Control by YbaK

    PubMed Central

    Kumar, Sandeep; Das, Mom; Hadad, Christopher M.; Musier-Forsyth, Karin

    2012-01-01

    Amino acids are covalently attached to their corresponding tRNAs by aminoacyl-tRNA synthetases. Proofreading mechanisms exist to ensure that high fidelity is maintained in this key step in protein synthesis. Prolyl-tRNA synthetase (ProRS) can misacylate cognate tRNAPro with Ala and Cys. The cis-editing domain of ProRS (INS) hydrolyzes Ala-tRNAPro, whereas Cys-tRNAPro is hydrolyzed by a single domain editing protein, YbaK, in trans. Previous studies have proposed a model of substrate-binding by bacterial YbaK and elucidated a substrate-assisted mechanism of catalysis. However, the microscopic steps in this mechanism have not been investigated. In this work, we carried out biochemical experiments together with a detailed hybrid quantum mechanics/molecular mechanics study to investigate the mechanism of catalysis by Escherichia coli YbaK. The results support a mechanism wherein cyclization of the substrate Cys results in cleavage of the Cys-tRNA ester bond. Protein side chains do not play a significant role in YbaK catalysis. Instead, protein backbone atoms play crucial roles in stabilizing the transition state, while the product is stabilized by the 2'-OH of the tRNA. PMID:23185990

  7. Two-dimensional NMR spectroscopy reveals cation-triggered backbone degradation in polysulfone-based anion exchange membranes

    PubMed Central

    Arges, Christopher G.; Ramani, Vijay

    2013-01-01

    Anion exchange membranes (AEMs) find widespread applications as an electrolyte and/or electrode binder in fuel cells, electrodialysis stacks, flow and metal-air batteries, and electrolyzers. AEMs exhibit poor stability in alkaline media; their degradation is induced by the hydroxide ion, a potent nucleophile. We have used 2D NMR techniques to investigate polymer backbone stability (as opposed to cation stability) of the AEM in alkaline media. We report the mechanism behind a peculiar, often-observed phenomenon, wherein a demonstrably stable polysulfone backbone degrades rapidly in alkaline solutions upon derivatization with alkaline stable fixed cation groups. Using COSY and heteronuclear multiple quantum correlation spectroscopy (2D NMR), we unequivocally demonstrate that the added cation group triggers degradation of the polymer backbone in alkaline via quaternary carbon hydrolysis and ether hydrolysis, leading to rapid failure. This finding challenges the existing perception that having a stable cation moiety is sufficient to yield a stable AEM and emphasizes the importance of the often ignored issue of backbone stability. PMID:23335629

  8. Chiral Lewis base-assisted Brønsted acid (LBBA)-catalyzed enantioselective cyclization of 2-geranylphenols.

    PubMed

    Sakakura, Akira; Sakuma, Masayuki; Ishihara, Kazuaki

    2011-06-17

    Chiral Lewis base-assisted Brønsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective cyclization. A salt of a chiral phosphonous acid diester with FSO(3)H catalyzes the enantioselective cyclization of 2-geranylphenols to give the desired trans-fused cyclized products with high diastereo- and enantioselectivities (up to 98:2 dr and 93% ee). © 2011 American Chemical Society

  9. Gold-Catalyzed Cyclization Processes: Pivotal Avenues for Organic Synthesis.

    PubMed

    Kumar, Amit; Singh, Sukhdev; Sharma, Sunil K; Parmar, Virinder S; Van der Eycken, Erik V

    2016-02-01

    Over the years, gold catalysis has materialized as an incredible synthetic approach among the scientific community. Due to the trivial reaction conditions and great functional compatibility, these progressions are synthetically expedient, because practitioners can implement them to build intricate architectures from readily amassed building blocks with high bond forming indices. The incendiary growth of gold catalysts in organic synthesis has been demonstrated as one of the most prevailing soft Lewis acids for electrophilic activation of carbon-carbon multiple bonds towards a great assortment of nucleophiles. Nowadays, organic chemists consistently employ gold catalysts to carry out a diverse array of organic transformations to build unprecedented molecular architectures. Despite all these achievements and a plethora of reports, many vital challenges remain. In this account, we describe the reactivity of various gold catalysts towards cyclization processes developed over the years. These protocols give access to a wide scope of polyheterocyclic structures, containing different medium-sized ring skeletons. This is interesting, as the quest for highly selective reactions to assemble diversely functionalized products has attracted much attention. We envisage that these newly developed chemo-, regio-, and diastereoselective protocols could provide an expedient route to architecturally cumbersome heterocycles of importance for the pharmaceutical industry.

  10. Degradation of Hole Transport Materials via Exciton-Driven Cyclization.

    PubMed

    Bell, Bruce M; Clark, Michael B; Devore, David D; De Vries, Timothy S; Froese, Robert D; Gray, Kaitlyn C; Jackson, David H K; Kuech, T F; Na, Hong-Yeop; Kearns, Kenneth L; Lee, Kyung-Joo; Mukhopadhyay, Sukrit; Rachford, Aaron A; Spencer, Liam P; Woodward, W H Hunter

    2017-04-19

    Organic light-emitting diode (OLED) displays have been an active and intense area of research for well over a decade and have now reached commercial success for displays from cell phones to large format televisions. A more thorough understanding of the many different potential degradation modes which cause OLED device failure will be necessary to develop the next generation of OLED materials, improve device lifetime, and to ultimately improve the cost vs performance ratio. Each of the different organic layers in an OLED device can be susceptible to unique decomposition pathways, however stability toward excitons is critical for emissive layer (EML) materials as well as any layer near the recombination zone. This study will specifically focus on degradation modes within the hole transport layer (HTL) with the goal being to identify the general decomposition paths occurring in an operating device and use this information to design new derivatives which can block these pathways. Through post-mortem analyses of several aged OLED devices, an apparently common intramolecular cyclization pathway has been identified that was not previously reported for arylamine-containing HTL materials and that operates parallel to but faster than the previously described fragmentation pathways.

  11. Theoretical studies of chromophore maturation in the wild-type green fluorescent protein: ONIOM(DFT:MM) investigation of the mechanism of cyclization.

    PubMed

    Ma, Yingying; Sun, Qiao; Li, Zhen; Yu, Jian-Guo; Smith, Sean C

    2012-02-02

    The availability of a gene encoding green fluorescence immediately stimulates interest in the puzzle of autocatalytic formation of the green fluorescent protein (GFP) chromophore. Numerous experimental and theoretical studies have indicated that cyclization is the first and most important step in the maturation process of the GFP. In our previous paper based on cluster models [J. Phys. Chem. B2010, 114, 9698-9705], two possible mechanisms have been investigated with the conclusion that the backbone condensation initiated by deprotonation of the Gly67 amide nitrogen is easier than deprotonation of the Tyr66 α-carbon. However, the impact of the protein environment on the reaction mechanism remains to be explored. In this paper, we investigated the two possible mechanisms with inclusion of protein environmental effects by using molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) calculations. Our calculations reveal no hydrogen bonding network that would facilitate deprotonation of the amide nitrogen of Gly67, although it is the lower energy pathway in the cluster model system. Contrastingly, there is a hydrogen bonding network between Tyr66 α-carbon and Glu222, which is in good agreement with X-ray data. The ONIOM studies show that proton transfer from Tyr66 α-carbon to Glu222 is a long-distance charge transfer process. The charge distribution of the MM region has a significant perturbation to the wave function for the QM region, with the QM energy for the proton transfer product being increased under the influence of the electrostatic protein environment. The barrier for the rate-limiting step in cyclization is quite high, about 40.0 kcal/mol in the case of ONIOM-EE.

  12. Backbone fractal dimension and fractal hybrid orbital of protein structure

    NASA Astrophysics Data System (ADS)

    Peng, Xin; Qi, Wei; Wang, Mengfan; Su, Rongxin; He, Zhimin

    2013-12-01

    Fractal geometry analysis provides a useful and desirable tool to characterize the configuration and structure of proteins. In this paper we examined the fractal properties of 750 folded proteins from four different structural classes, namely (1) the α-class (dominated by α-helices), (2) the β-class (dominated by β-pleated sheets), (3) the (α/β)-class (α-helices and β-sheets alternately mixed) and (4) the (α + β)-class (α-helices and β-sheets largely segregated) by using two fractal dimension methods, i.e. "the local fractal dimension" and "the backbone fractal dimension" (a new and useful quantitative parameter). The results showed that the protein molecules exhibit a fractal behavior in the range of 1 ⩽ N ⩽ 15 (N is the number of the interval between two adjacent amino acid residues), and the value of backbone fractal dimension is distinctly greater than that of local fractal dimension for the same protein. The average value of two fractal dimensions decreased in order of α > α/β > α + β > β. Moreover, the mathematical formula for the hybrid orbital model of protein based on the concept of backbone fractal dimension is in good coincidence with that of the similarity dimension. So it is a very accurate and simple method to analyze the hybrid orbital model of protein by using the backbone fractal dimension.

  13. The Graphical Representation of the Digital Astronaut Physiology Backbone

    NASA Technical Reports Server (NTRS)

    Briers, Demarcus

    2010-01-01

    This report summarizes my internship project with the NASA Digital Astronaut Project to analyze the Digital Astronaut (DA) physiology backbone model. The Digital Astronaut Project (DAP) applies integrated physiology models to support space biomedical operations, and to assist NASA researchers in closing knowledge gaps related to human physiologic responses to space flight. The DA physiology backbone is a set of integrated physiological equations and functions that model the interacting systems of the human body. The current release of the model is HumMod (Human Model) version 1.5 and was developed over forty years at the University of Mississippi Medical Center (UMMC). The physiology equations and functions are scripted in an XML schema specifically designed for physiology modeling by Dr. Thomas G. Coleman at UMMC. Currently it is difficult to examine the physiology backbone without being knowledgeable of the XML schema. While investigating and documenting the tags and algorithms used in the XML schema, I proposed a standard methodology for a graphical representation. This standard methodology may be used to transcribe graphical representations from the DA physiology backbone. In turn, the graphical representations can allow examination of the physiological functions and equations without the need to be familiar with the computer programming languages or markup languages used by DA modeling software.

  14. Impact of template backbone heterogeneity on RNA polymerase II transcription

    PubMed Central

    Xu, Liang; Wang, Wei; Zhang, Lu; Chong, Jenny; Huang, Xuhui; Wang, Dong

    2015-01-01

    Variations in the sugar component (ribose or deoxyribose) and the nature of the phosphodiester linkage (3′-5′ or 2′-5′ orientation) have been a challenge for genetic information transfer from the very beginning of evolution. RNA polymerase II (pol II) governs the transcription of DNA into precursor mRNA in all eukaryotic cells. How pol II recognizes DNA template backbone (phosphodiester linkage and sugar) and whether it tolerates the backbone heterogeneity remain elusive. Such knowledge is not only important for elucidating the chemical basis of transcriptional fidelity but also provides new insights into molecular evolution. In this study, we systematically and quantitatively investigated pol II transcriptional behaviors through different template backbone variants. We revealed that pol II can well tolerate and bypass sugar heterogeneity sites at the template but stalls at phosphodiester linkage heterogeneity sites. The distinct impacts of these two backbone components on pol II transcription reveal the molecular basis of template recognition during pol II transcription and provide the evolutionary insight from the RNA world to the contemporary ‘imperfect’ DNA world. In addition, our results also reveal the transcriptional consequences from ribose-containing genomic DNA. PMID:25662224

  15. Cooperative UAV-Based Communications Backbone for Sensor Networks

    SciTech Connect

    Roberts, R S

    2001-10-07

    The objective of this project is to investigate the use of unmanned air vehicles (UAVs) as mobile, adaptive communications backbones for ground-based sensor networks. In this type of network, the UAVs provide communication connectivity to sensors that cannot communicate with each other because of terrain, distance, or other geographical constraints. In these situations, UAVs provide a vertical communication path for the sensors, thereby mitigating geographic obstacles often imposed on networks. With the proper use of UAVs, connectivity to a widely disbursed sensor network in rugged terrain is readily achieved. Our investigation has focused on networks where multiple cooperating UAVs are used to form a network backbone. The advantage of using multiple UAVs to form the network backbone is parallelization of sensor connectivity. Many widely spaced or isolated sensors can be connected to the network at once using this approach. In these networks, the UAVs logically partition the sensor network into sub-networks (subnets), with one UAV assigned per subnet. Partitioning the network into subnets allows the UAVs to service sensors in parallel thereby decreasing the sensor-to-network connectivity. A UAV services sensors in its subnet by flying a route (path) through the subnet, uplinking data collected by the sensors, and forwarding the data to a ground station. An additional advantage of using multiple UAVs in the network is that they provide redundancy in the communications backbone, so that the failure of a single UAV does not necessarily imply the loss of the network.

  16. Backbone flexibility of CDR3 and immune recognition of antigens.

    PubMed

    Haidar, Jaafar N; Zhu, Wei; Lypowy, Jacqueline; Pierce, Brian G; Bari, Amtul; Persaud, Kris; Luna, Xenia; Snavely, Marshall; Ludwig, Dale; Weng, Zhiping

    2014-04-03

    Conformational entropy is an important component of protein-protein interactions; however, there is no reliable method for computing this parameter. We have developed a statistical measure of residual backbone entropy in folded proteins by using the ϕ-ψ distributions of the 20 amino acids in common secondary structures. The backbone entropy patterns of amino acids within helix, sheet or coil form clusters that recapitulate the branching and hydrogen bonding properties of the side chains in the secondary structure type. The same types of residues in coil and sheet have identical backbone entropies, while helix residues have much smaller conformational entropies. We estimated the backbone entropy change for immunoglobulin complementarity-determining regions (CDRs) from the crystal structures of 34 low-affinity T-cell receptors and 40 high-affinity Fabs as a result of the formation of protein complexes. Surprisingly, we discovered that the computed backbone entropy loss of only the CDR3, but not all CDRs, correlated significantly with the kinetic and affinity constants of the 74 selected complexes. Consequently, we propose a simple algorithm to introduce proline mutations that restrict the conformational flexibility of CDRs and enhance the kinetics and affinity of immunoglobulin interactions. Combining the proline mutations with rationally designed mutants from a previous study led to 2400-fold increase in the affinity of the A6 T-cell receptor for Tax-HLAA2. However, this mutational scheme failed to induce significant binding changes in the already-high-affinity C225-Fab/huEGFR interface. Our results will serve as a roadmap to formulate more effective target functions to design immune complexes with improved biological functions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Structural basis for cyclization specificity of two Azotobacter type III polyketide synthases: a single amino acid substitution reverses their cyclization specificity.

    PubMed

    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.

  18. Structural Elucidation of Cisoid and Transoid Cyclization Pathways of a Sesquiterpene Synthase Using 2-Fluorofarnesyl Diphosphates

    PubMed Central

    2010-01-01

    Sesquiterpene skeletal complexity in nature originates from the enzyme-catalyzed ionization of (trans,trans)-farnesyl diphosphate (FPP) (1a) and subsequent cyclization along either 2,3-transoid or 2,3-cisoid farnesyl cation pathways. Tobacco 5-epi-aristolochene synthase (TEAS), a transoid synthase, produces cisoid products as a component of its minor product spectrum. To investigate the cryptic cisoid cyclization pathway in TEAS, we employed (cis,trans)-FPP (1b) as an alternative substrate. Strikingly, TEAS was catalytically robust in the enzymatic conversion of (cis,trans)-FPP (1b) to exclusively (≥99.5%) cisoid products. Further, crystallographic characterization of wild-type TEAS and a catalytically promiscuous mutant (M4 TEAS) with 2-fluoro analogues of both all-trans FPP (1a) and (cis,trans)-FPP (1b) revealed binding modes consistent with preorganization of the farnesyl chain. These results provide a structural glimpse into both cisoid and transoid cyclization pathways efficiently templated by a single enzyme active site, consistent with the recently elucidated stereochemistry of the cisoid products. Further, computational studies using density functional theory calculations reveal concerted, highly asynchronous cyclization pathways leading to the major cisoid cyclization products. The implications of these discoveries for expanded sesquiterpene diversity in nature are discussed. PMID:20175559

  19. Identification of systems containing nonlinear stiffnesses using backbone curves

    NASA Astrophysics Data System (ADS)

    Londoño, Julián M.; Cooper, Jonathan E.; Neild, Simon A.

    2017-02-01

    This paper presents a method for the dynamic identification of structures containing discrete nonlinear stiffnesses. The approach requires the structure to be excited at a single resonant frequency, enabling measurements to be made in regimes of large displacements where nonlinearities are more likely to be significant. Measured resonant decay data is used to estimate the system backbone curves. Linear natural frequencies and nonlinear parameters are identified using these backbone curves assuming a form for the nonlinear behaviour. Numerical and experimental examples, inspired by an aerospace industry test case study, are considered to illustrate how the method can be applied. Results from these models demonstrate that the method can successfully deliver nonlinear models able to predict the response of the test structure nonlinear dynamics.

  20. Fates of imine intermediates in radical cyclizations of N-sulfonylindoles and ene-sulfonamides.

    PubMed

    Zhang, Hanmo; Hay, E Ben; Geib, Stephen J; Curran, Dennis P

    2015-01-01

    Two new fates of imine intermediates formed on radical cyclizations of ene-sulfonamides have been identified, reduction and hydration/fragmentation. Tin hydride-mediated cyclizations of 2-halo-N-(3-methyl-N-sulfonylindole)anilines provide spiro[indoline-3,3'-indolones] or spiro-3,3'-biindolines (derived from imine reduction), depending on the indole C2 substituent. Cyclizations of 2-haloanilide derivatives of 3-carboxy-N-sulfonyl-2,3-dihydropyrroles also presumably form spiro-imines as primary products. However, the lactam carbonyl group facilitates the ring-opening of these cyclic imines by a new pathway of hydration and retro-Claisen-type reaction, providing rearranged 2-(2'-formamidoethyl)oxindoles.

  1. Fates of imine intermediates in radical cyclizations of N-sulfonylindoles and ene-sulfonamides

    PubMed Central

    Zhang, Hanmo; Hay, E Ben; Geib, Stephen J

    2015-01-01

    Summary Two new fates of imine intermediates formed on radical cyclizations of ene-sulfonamides have been identified, reduction and hydration/fragmentation. Tin hydride-mediated cyclizations of 2-halo-N-(3-methyl-N-sulfonylindole)anilines provide spiro[indoline-3,3'-indolones] or spiro-3,3'-biindolines (derived from imine reduction), depending on the indole C2 substituent. Cyclizations of 2-haloanilide derivatives of 3-carboxy-N-sulfonyl-2,3-dihydropyrroles also presumably form spiro-imines as primary products. However, the lactam carbonyl group facilitates the ring-opening of these cyclic imines by a new pathway of hydration and retro-Claisen-type reaction, providing rearranged 2-(2'-formamidoethyl)oxindoles. PMID:26664585

  2. Total Synthesis of (+)-Sieboldine A: Evolution of A Pinacol-Terminated Cyclization Strategy

    PubMed Central

    Canham, Stephen M.; France, David J.; Overman, Larry E.

    2013-01-01

    This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study a number of pinacol-terminated cationic cyclizations were examined to form the cis-hydrindanone core of sieboldine A. Of these, a mild Au(I)-promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor. PMID:22734821

  3. Silyl Enol Ether Prins Cyclization: Diastereoselective Formation of Substituted Tetrahydropyran-4-ones

    PubMed Central

    2015-01-01

    A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether and an aldehyde to afford substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up to 97% yield and >95:5 dr. The cyclization step forms new carbon–carbon and carbon–oxygen bonds, as well as a quaternary center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans. PMID:25200563

  4. Cyclization of squalene from both termini: identification of an onoceroid synthase and enzymatic synthesis of ambrein.

    PubMed

    Ueda, Daijiro; Hoshino, Tsutomu; Sato, Tsutomu

    2013-12-11

    The onoceroids are triterpenoids biosynthesized from squalene or (3S)-2,3-oxidosqualene by cyclization from both termini. We recently revealed that tetraprenyl-β-curcumene cyclase from Bacillus megaterium (BmeTC) is a bifunctional triterpene/sesquarterpene cyclase that converts head-to-tail tetraprenyl-β-curcumene and tail-to-tail squalene into pentacyclic and bicyclic products, respectively, in vivo. Here, we reveal that BmeTC has an unprecedented catalytic function in cyclizing squalene from both termini and is the first onoceroid synthase. We also report the first onoceroids from bacterial origin. Our discoveries suggest that symmetric and asymmetric onoceroids could be biosynthesized by a single enzyme via an intermediate cyclized at one terminus of squalene. Furthermore, the new function of BmeTC enabled the synthesis of (+)-ambrein, a major constituent of ambergris that is difficult to obtain naturally, via a mutated squalene-hopene cyclase-catalyzed reaction from easily available squalene.

  5. Hydrophobic core packing and backbone flexibility in coiled coils

    NASA Astrophysics Data System (ADS)

    Plecs, Joseph John

    1999-11-01

    An understanding of the structure and function of protein molecules requires an understanding of how their hydrophobic cores are assembled, including how the peptide backbone can adjust to accommodate different packing arrangements. Using coiled-coil molecules as a model of protein structures, we studied several cases in which the arrangement of packing groups in the hydrophobic core controls the structure of a folded molecule. First, we consider an example of a prosthetic packing group, where the addition of a hydrophobic ligand permits a new packing arrangement that incorporates the ligand, leading to a new overall structure. Second, the crystal structures of two peptides designed to adopt a novel fold, the right-handed coiled coils, reveal how a small change in core packing can discriminate between two different folds. And last, the design of heterodimers based on core-packing complementarity establishes that core packing can convey specificity of association between different molecules, as well as determining the molecular structure. The heterodimer designs also demonstrate the importance of a combination of backbone freedom and restriction in predicting the energetics of folded molecules. In this case, a parametrized coiled- coil backbone with appropriate parameters and restrictions was required to predict stabilities. We conclude that core packing can exert a great deal of control over the structure of proteins, and that many of its effects can be accurately predicted by modeling the molecular interactions in the context of a flexible overall structure.

  6. Geometry motivated alternative view on local protein backbone structures.

    PubMed

    Zacharias, Jan; Knapp, Ernst Walter

    2013-11-01

    We present an alternative to the classical Ramachandran plot (R-plot) to display local protein backbone structure. Instead of the (φ, ψ)-backbone angles relating to the chemical architecture of polypeptides generic helical parameters are used. These are the rotation or twist angle ϑ and the helical rise parameter d. Plots with these parameters provide a different view on the nature of local protein backbone structures. It allows to display the local structures in polar (d, ϑ)-coordinates, which is not possible for an R-plot, where structural regimes connected by periodicity appear disconnected. But there are other advantages, like a clear discrimination of the handedness of a local structure, a larger spread of the different local structure domains--the latter can yield a better separation of different local secondary structure motives--and many more. Compared to the R-plot we are not aware of any major disadvantage to classify local polypeptide structures with the (d, ϑ)-plot, except that it requires some elementary computations. To facilitate usage of the new (d, ϑ)-plot for protein structures we provide a web application (http://agknapp.chemie.fu-berlin.de/secsass), which shows the (d, ϑ)-plot side-by-side with the R-plot.

  7. Side-chain and backbone ordering in homopolymers.

    PubMed

    Wei, Yanjie; Nadler, Walter; Hansmann, Ulrich H E

    2007-04-26

    In order to study the relation between backbone and side-chain ordering in proteins, we have performed multicanonical simulations of deka-peptide chains with various side groups. Glu(10), Gln(10), Asp(10), Asn(10), and Lys(10) were selected to cover a wide variety of possible interactions between the side chains of the monomers. All homopolymers undergo helix-coil transitions. We found that peptides with long side chains that are capable of hydrogen bonding, i.e., Glu(10), and Gln(10), exhibit a second transition at lower temperatures connected with side-chain ordering. This occurs in the gas phase as well as in solvent, although the character of the side-chain structure is different in each case. However, in polymers with short side chains capable of hydrogen bonding, i.e., Asp(10) and Asn(10), side-chain ordering takes place over a wide temperature range and exhibits no phase transition-like character. Moreover, non-backbone hydrogen bonds show enhanced formation and fluctuations already at the helix-coil transition temperature, indicating competition between side-chain and backbone hydrogen bond formation. Again, these results are qualitatively independent of the environment. Side-chain ordering in Lys(10), whose side groups are long and polar, also takes place over a wide temperature range and exhibits no phase transition-like character in both environments. Reasons for the observed chain length threshold and consequences from these results for protein folding are discussed.

  8. Intramolecular, reductive cyclization of beta-ketoisothiocyanates promoted by using samarium diiodide.

    PubMed

    Cho, Min Seok; Lee, In Sang; Kang, Sung Ho; Kim, Yong Hae

    2005-02-18

    A novel samarium diiodide (SmI2) promoted intramolecular cyclization of beta-ketoisothiocyanate, derived from alpha,beta-unsaturated esters and ammonium thiocyanate led to alpha-hydroxythiolactams and/or thiolactams in high yields. Treatment of beta-ketoisothiocyanate with two equivalents of SmI2 gave a mixture of alpha-hydroxythiolactam and thiolactam. Four equivalents of SmI2 afforded only thiolactam in high yields. The intramolecular cyclization took place with high to complete stereoselectivity. A mechanism to explain this transformation is proposed.

  9. On-surface formation of one-dimensional polyphenylene through Bergman cyclization.

    PubMed

    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.

  10. Palladium-catalyzed tandem addition/cyclization in aqueous medium: synthesis of 2-arylindoles.

    PubMed

    Yu, Shuling; Hu, Kun; Gong, Julin; Qi, Linjun; Zhu, Jianghe; Zhang, Yetong; Cheng, Tianxing; Chen, Jiuxi

    2017-05-23

    An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles.

  11. Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space.

    PubMed

    Rolfe, Alan; Lushington, Gerald H; Hanson, Paul R

    2010-05-07

    The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic (DOS) strategy to probe chemical and biological space via a "Click, Click, Cyclize" protocol. In this DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and polar surface area (PSA) calculations.

  12. Total synthesis of (±)-sacidumlignans D and A through Ueno-Stork radical cyclization reaction.

    PubMed

    Zhang, Jian-Jian; Yan, Chang-Song; Peng, Yu; Luo, Zhen-Biao; Xu, Xiao-Bo; Wang, Ya-Wen

    2013-04-21

    Efficient synthesis of (±)-sacidumlignan D (4) has been successfully achieved employing Ueno-Stork radical cyclization of α-bromo acetal 21 as a key step. Two synthetic approaches for the symmetrical diaryl ketone 19 have been discussed in detail. Notably, sacidumlignan A (1) can be also efficiently synthesized in only 7 steps with 25% overall yield, where acid triggered tandem reaction starting from analogous Ueno-Stork cyclization product 27 played an important role. Moreover, potentially biomimetic conversion from (±)-sacidumlignan D (4) to sacidumlignan A (1) could be realized.

  13. A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization.

    PubMed

    Wang, Shao-Rong; Sánchez-Murcia, Pedro A; Gago, Federico; Fang, Wei-Shuo

    2016-01-07

    A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

  14. Conversion of Substrate Analogs Suggests a Michael Cyclization in Iridoid Biosynthesis

    PubMed Central

    Lindner, Stephanie; Geu-Flores, Fernando; Bräse, Stefan; Sherden, Nathaniel H.; O’Connor, Sarah E.

    2014-01-01

    Summary The core structure of the iridoid monoterpenes is formed by a unique cyclization reaction. The enzyme that catalyzes this reaction, iridoid synthase, is mechanistically distinct from other terpene cyclases. Here we describe the synthesis of two substrate analogs to probe the mechanism of iridoid synthase. Enzymatic assay of these substrate analogs along with clues from the product profile of the native substrate strongly suggest that iridoid synthase utilizes a Michael reaction to achieve cyclization. This improved mechanistic understanding will facilitate the exploitation of the potential of iridoid synthase to synthesize new cyclic compounds from nonnatural substrates. PMID:25444551

  15. Drawing from a pool of radicals for the design of selective enyne cyclizations.

    PubMed

    Mondal, Sayantan; Mohamed, Rana K; Manoharan, Mariappan; Phan, Hoa; Alabugin, Igor V

    2013-11-15

    Despite the possibility of intermolecular attack at four different locations, the Bu3Sn-mediated radical cyclization of aromatic enynes is surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by intermolecular Bu3Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with electrophiles.

  16. A Highly Reactive Dicationic Iridium(III) Catalyst for Polarized Nazarov Cyclization

    PubMed Central

    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

  17. “Cation-Stitching Cascade”: exquisite control of terpene cyclization in cyclooctatin biosynthesis

    NASA Astrophysics Data System (ADS)

    Sato, Hajime; Teramoto, Kazuya; Masumoto, Yui; Tezuka, Noriyuki; Sakai, Kenta; Ueda, Shota; Totsuka, Yusuke; Shinada, Tetsuro; Nishiyama, Makoto; Wang, Chao; Kuzuyama, Tomohisa; Uchiyama, Masanobu

    2015-12-01

    Terpene cyclization is orchestrated by terpene cyclases, which are involved in the biosynthesis of various cyclic natural products, but understanding the origin and mechanism of the selectivity of terpene cyclization is challenging. In this work, we describe an in-depth mechanistic study on cyclooctatin biosynthesis by means of theoretical calculations combined with experimental methods. We show that the main framework of cyclooctatin is formed through domino-type carbocation transportation along the terpene chain, which we call a “cation-stitching cascade”, including multiple hydrogen-shifts and a ring rearrangement that elegantly determine the stereoselectivity.

  18. Triaryl-Substituted Divinyl Ketones Cyclization: Nazarov Reaction versus Friedel-Crafts Electrophilic Substitution.

    PubMed

    Shirinian, Valerii Z; Lvov, Andrey G; Yadykov, Anton V; Yaminova, Liana V; Kachala, Vadim V; Markosyan, Ashot I

    2016-12-16

    The acid-catalyzed cyclization of a wide range of triaryl-substituted divinyl ketones has been studied. It was found that the reaction pathway strongly depends on the nature of the aryl substituent at the α-position to the carbonyl group. An electron-rich aromatic substituent promotes the reaction to proceed through the intramolecular Friedel-Crafts electrophilic substitution giving dihydronaphthalene derivatives. In contrast, the presence of an electron-deficient substituent is favorable for the Nazarov 4π-conrotatory cyclization yielding triaryl-substituted cyclopentenones. The electrophilic substitution reaction was applied to thiophene and thiazole derivatives.

  19. Observation of a thermally induced Bora-Nazarov cyclization at a phosphole framework.

    PubMed

    Möbus, Juri; Kehr, Gerald; Daniliuc, Constantin G; Mück-Lichtenfeld, Christian; Erker, Gerhard

    2015-10-12

    The reaction of the bis(enynyl)phosphanes 6 a,b with the electrophilic borane reagents RB(C6 F5 )2 (R=C6 F5 , CH2 CH2 Ph, CH3 ) gave phospholes cleanly in a 1,1-carboboration reaction sequence. Depending on the steric bulk, the resulting 2,5-alkenylphospholes underwent a thermally induced bora-Nazarov type cyclization. The equilibrium situation of these examples of a bora-Nazarov type cyclization was investigated in detail by NMR spectroscopy, X-ray crystal structure analysis, and DFT calculations. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Nazarov Cyclization and Tandem [4 + 2]-Cycloaddition Reactions of Donor-Acceptor Cyclopropanes.

    PubMed

    Sudhakar, Gangarajula; Mahesh, S K; Vemulapalli, S Phani Babu; Nanubolu, Jagadeesh Babu

    2017-09-01

    The development of aryl vinyl/divinyl donor-acceptor cyclopropanes (DACs) as novel Nazarov cyclization (NC) precursors is described. The 1,3-zwitterion, generated from DACs embedded in the divinyl framework, acts as a pentadienyl cation, a requisite for Nazarov cyclization. A cyclic allyl cation in the course of NC was trapped with external nucleophiles to provide an interrupted NC product. Indeed, an allyl cation in this reaction is analogous to a 1,4-zwitterion that on reaction with dipolarophiles provided an easy access to substituted pyrans with excellent yield and diastereoselectivity via NC followed by a formal [4 + 2] cycloaddition.

  1. Induced helical backbone conformations of self-organizable dendronized polymers.

    PubMed

    Rudick, Jonathan G; Percec, Virgil

    2008-12-01

    Control of function through the primary structure of a molecule presents a significant challenge with valuable rewards for nanoscience. Dendritic building blocks encoded with information that defines their three-dimensional shape (e.g., flat-tapered or conical) and how they associate with each other are referred to as self-assembling dendrons. Self-organizable dendronized polymers possess a flat-tapered or conical self-assembling dendritic side chain on each repeat unit of a linear polymer backbone. When appended to a covalent polymer, the self-assembling dendrons direct a folding process (i.e., intramolecular self-assembly). Alternatively, intermolecular self-assembly of dendrons mediated by noncovalent interactions between apex groups can generate a supramolecular polymer backbone. Self-organization, as we refer to it, is the spontaneous formation of periodic and quasiperiodic arrays from supramolecular elements. Covalent and supramolecular polymers jacketed with self-assembling dendrons self-organize. The arrays are most often comprised of cylindrical or spherical objects. The shape of the object is determined by the primary structure of the dendronized polymer: the structure of the self-assembling dendron and the length of the polymer backbone. It is therefore possible to predictably generate building blocks for single-molecule nanotechnologies or arrays of supramolecules for bottom-up self-assembly. We exploit the self-organization of polymers jacketed with self-assembling dendrons to elucidate how primary structure determines the adopted conformation and fold (i.e., secondary and tertiary structure), how the supramolecules associate (i.e., quaternary structure), and their resulting functions. A combination of experimental techniques is employed to interrogate the primary, secondary, tertiary, and quaternary structure of the self-organizable dendronized polymers. We refer to the process by which we interpolate between the various levels of structural

  2. Radiofluorinated rhenium cyclized α-MSH analogues for PET imaging of melanocortin receptor 1.

    PubMed

    Ren, Gang; Liu, Shuanlong; Liu, Hongguang; Miao, Zheng; Cheng, Zhen

    2010-12-15

    In order to accomplish in vivo molecular imaging of melanoma biomarker melanocortin 1 receptor (MC1R), several α-melanocyte-stimulating hormone (α-MSH) analogues have been labeled with N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸)F-SFB) and studied as positron emission tomography (PET) probes in our recent studies. To further pursue a radiofluorinated α-MSH peptide with high clinical translation potential, we utilized 4-nitrophenyl 2-¹⁸F-fluoropropionate (¹⁸F-NFP) to radiofluorinate the transition metal rhenium cyclized α-MSH metallopeptides for PET imaging of MC1R positive malignant melanoma. Metallopeptides Ac-d,Lys-ReCCMSH(Arg¹¹) (two isomers, namely RMSH-1 and RMSH-2) were synthesized using conventional solid phase peptide synthesis chemistry and rhenium cyclization reaction. The two isomers were then conjugated with ¹⁹F-NFP or ¹⁸F-NFP. The resulting cold or radiofluorinated metallopeptides, (¹⁸/¹⁹)F-FP-RMSH-1 and (¹⁸/¹⁹)F-FP-RMSH-2, were further evaluated for their in vitro receptor binding affinities, in vivo biodistribution, and small-animal PET imaging properties. The binding affinities of ¹⁹F-FP-RMSH-1 and ¹⁹F-FP-RMSH-2 were determined to be within low nanomolar range. In vivo studies revealed that both F-labeled metallopeptides possessed good tumor uptake in the B16F10 murine model with high MC1R expression, while possessing much lower uptake in A375M human melanoma xenografts. Moreover, ¹⁸F-FP-RMSH-1 displayed more favorable in vivo performance in terms of higher tumor uptake and much lower accumulation in the kidney and liver, when compared to that of ¹⁸F-FP-RMSH-2 at 2 h postinjection (p.i.). ¹⁸F-FP-RMSH-1 also displayed lower liver and lung uptake when compared with that of the same peptide labeled with ¹⁸F-SFB (named as ¹⁸F-FB-RMSH-1). Small animal PET imaging of ¹⁸F-FP-RMSH-1 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptake and

  3. Radiofluorinated Rhenium Cyclized α-MSH Analogs for PET Imaging of Melanocortin Receptor 1

    PubMed Central

    Ren, Gang; Liu, Shuanlong; Liu, Hongguang; Miao, Zheng; Cheng, Zhen

    2010-01-01

    In order to accomplish in vivo molecular imaging of melanoma biomarker melanocortin 1 receptor (MC1R), several alpha-melanocyte-stimulating hormone (α-MSH) analogs have been labeled with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) and studied as positron emission tomography (PET) probes in our recent studies. To further pursue a radiofluorinated α-MSH peptide with high clinical translation potential, we utilized 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP) to radiofluorinate the transition metal rhenium cyclized α-MSH metallopeptides for PET imaging of MC1R positive malignant melanoma. Methods Metallopeptides Ac-d,Lys-ReCCMSH(Arg11) (two isomers, namely RMSH-1 and RMSH-2) were synthesized using conventional solid phase peptide synthesis chemistry and rhenium cyclization reaction. The two isomers were then conjugated with 19F-NFP or 18F-NFP. The resulting cold or radiofluorinated metallopeptides, 18/19F-FP-RMSH-1 and 18/19F-FP-RMSH-2 were further evaluated for their in vitro receptor binding affinities, in vivo biodistribution and small-animal PET imaging properties. Results The binding affinities of the 19F-FP-RMSH-1 and 19F-FP-RMSH-2) were determined to be within low nM range. In vivo studies revealed that both 18F-labeled metallopeptides possessed good tumor uptake in B16F10 murine model with high MC1R expression, while much lower uptake in A375M human melanoma xenografts. Moreover, 18F-FP-RMSH-1 displayed more favorable in vivo performance in terms of higher tumor uptake and much lower accumulation in kidney and liver, when compared to 18F-FP-RMSH-2 at 2 h post-injection (p.i.). 18F-FP-RMSH-1 also displayed lower liver and lung uptake when compared with the same peptide labeled with 18F-SFB (named as 18F-FB-RMSH-1). Small animal PET imaging of 18F-FP-RMSH-1 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptake and poorer tumor/normal organs contrast were observed for A375M model than that of B16

  4. How do analogous alpha-chloroenamides and alpha-iodoenamides give different product distributions in 5-endo radical cyclizations?

    PubMed

    Curran, Dennis P; Guthrie, David B; Geib, Steven J

    2008-07-02

    5-Endo cyclizations of N-alkenyl carbamoylmethyl radicals provide gamma-lactam radicals, which in turn evolve to reduced or non-reduced (alkene) products depending on reagents and reaction conditions. Several groups have made surprising observations that chlorides are better radical precursors than iodides in such cyclizations. Here is described a detailed study of tin and silicon hydride-mediated radical cyclizations of N-benzyl-2-halo-N-cyclohex-1-enylacetamides. The ratios of directly reduced, cyclized/reduced, and cyclized/non-reduced products depend not only on the reaction conditions and reducing reagent but also on the precursor. Prior explanations for the precursor-dependent product ratios based on amide rotamer effects are ruled out. The precursor-dependent behavior is further dissected into two different effects: (1) the ratio of cyclized/reduced products to cyclized/non-reduced products depends on the ability of the radical precursor to react with the product gamma-lactam radical in competition with tin hydride (iodides can compete, chlorides cannot), and (2) the occurrence of large amounts of directly reduced (noncyclized) products in the case of iodides is attributed to a competing ionic chain reaction by which the precursor is reductively deiodinated with HI. This side reaction is not available to chlorides, thereby explaining why the chlorides are better precursors in such reactions. The ability of the iodides to provide cyclized products can be largely restored by adding base. The chlorides and iodides then become complementary precursors, with chlorides giving largely cyclized/reduced products and iodides giving largely cyclized/non-reduced products.

  5. Retrieving Backbone String Neighbors Provides Insights Into Structural Modeling of Membrane Proteins*

    PubMed Central

    Sun, Jiang-Ming; Li, Tong-Hua; Cong, Pei-Sheng; Tang, Sheng-Nan; Xiong, Wen-Wei

    2012-01-01

    Identification of protein structural neighbors to a query is fundamental in structure and function prediction. Here we present BS-align, a systematic method to retrieve backbone string neighbors from primary sequences as templates for protein modeling. The backbone conformation of a protein is represented by the backbone string, as defined in Ramachandran space. The backbone string of a query can be accurately predicted by two innovative technologies: a knowledge-driven sequence alignment and encoding of a backbone string element profile. Then, the predicted backbone string is employed to align against a backbone string database and retrieve a set of backbone string neighbors. The backbone string neighbors were shown to be close to native structures of query proteins. BS-align was successfully employed to predict models of 10 membrane proteins with lengths ranging between 229 and 595 residues, and whose high-resolution structural determinations were difficult to elucidate both by experiment and prediction. The obtained TM-scores and root mean square deviations of the models confirmed that the models based on the backbone string neighbors retrieved by the BS-align were very close to the native membrane structures although the query and the neighbor shared a very low sequence identity. The backbone string system represents a new road for the prediction of protein structure from sequence, and suggests that the similarity of the backbone string would be more informative than describing a protein as belonging to a fold. PMID:22415040

  6. Icosahedral medium-range orders and backbone formation in an amorphous alloy

    NASA Astrophysics Data System (ADS)

    Lee, Mirim; Kim, Hong-Kyu; Lee, Jae-Chul

    2010-12-01

    Analyses of metallic amorphous solids constructed using molecular dynamics (MD) simulations have demonstrated that individual short-range orders (SROs) are linked with neighboring SROs and form various medium-range orders (MROs). These MROs have been observed to have different structural stability depending on their linking patterns. On the basis of the assessment of the structural stability of various MROs, we propose new types of structural organization, namely, icosahedral medium-range orders (I-MROs) and their extended-range order that forms the backbone of amorphous solids. We also discuss why the atomic-scale structure of an amorphous alloy can be more appropriately described in terms of I-MROs, rather than by the degree of short-range ordering as characterized by the fractions of SROs.

  7. Aqueous self-assembly of hydrophobic macromolecules with adjustable rigidity of the backbone.

    PubMed

    Guan, Zhou; Liu, Dapeng; Lin, Jiaping; Wang, Xiaosong

    2017-08-02

    P(FpC3P) (Fp: CpFe(CO)2; C3P: propyl diphenyl phosphine) has a helical backbone, resulting from piano stool metal coordination geometry, which is rigid with intramolecular aromatic interaction of the phenyl groups. The macromolecule is hydrophobic, but the polarized CO groups can interact with water for aqueous self-assembly. The stiffness of P(FpC3P), which is adjustable by temperature, is an important factor influencing the morphologies of kinetically trapped assemblies. P(FpC3P)7 self-assembles in DMSO/water (10/90 by volume) into lamellae at 25 °C, vesicles at 40 °C and irregular aggregates at higher temperatures (60 and 70 °C). The colloidal stability decreases in the order of lamellae, vesicles and irregular aggregates. Dissipative particle dynamics (DPD) simulation reveals the same temperature-dependent self-assembled morphologies with an interior of hydrophobic aromatic groups covered with the metal coordination units. The rigid backbone at 25 °C accounts for the formation of the layered morphology, while the reduced rigidity of the same P(FpC3P)7 at 40 °C curves up the lamellae into vesicles. At a higher temperature (60 or 70 °C), P(FpC3P)7 behaves as a random coil without obvious amphiphilic segregation, resulting in irregular aggregates. The stiffness is, therefore, a crucial factor for the aqueous assembly of macromolecules without obvious amphiphilic segregation, which is reminiscent of the solution behavior observed for many hydrophobic biological macromolecules such as proteins.

  8. Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions.

    PubMed

    Holan, Martin; Pohl, Radek; Císařová, Ivana; Klepetářová, Blanka; Jones, Peter G; Jahn, Ullrich

    2015-06-26

    Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with α-benzylidene and α-alkylidene β-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C-C bonds and one C-O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.

  9. Construction of a Spirooxindole Amide Library through Nitrile Hydrozirconation-Acylation-Cyclization Cascade

    PubMed Central

    LaPorte, Matthew G.; Tsegay, Sammi; Hong, Ki Bum; Lu, Chunliang; Fang, Cheng; Wang, Lirong; Xie, Xiang-Qun; Floreancig, Paul E.

    2013-01-01

    A library of spirooxindoles containing varied elements of structural and stereochemical diversity has been constructed via a three step, one pot nitrile hydrozirconation-acylation-cyclization reaction sequence from common acyclic indole intermediates. The resulting library was evaluated for novelty through comparison with MLSMR and Maybridge compound collections. PMID:23731121

  10. Enantioselective Total Synthesis of (−)-Nardoaristolone B via a Gold(I)-Catalyzed Oxidative Cyclization

    PubMed Central

    2015-01-01

    The first enantioselective total synthesis of (−)-nardoaristolone B is accomplished by the implementation of an enantio- and diastereoselective copper(I)-catalyzed conjugate addition/enolate trapping sequence and a gold(I)-catalyzed oxidative cyclization (intermolecular oxidant), employed for the first time in total synthesis. PMID:25563976

  11. Highly diastereoselective samarium diiodide induced cyclizations of new 3-substituted indole derivatives.

    PubMed

    Beemelmanns, Christine; Reissig, Hans-Ulrich

    2009-11-07

    Herein, we describe the synthesis of new functionalized tricyclic and tetracyclic indole derivatives via samarium diiodide induced ketyl cyclizations. The intermediate samarium organyls were either protonated using different proton sources or alkylated with various electrophiles in a highly diastereoselective manner. The obtained products were subjected to further transformations leading to synthetically interesting building blocks.

  12. Asymmetric Cyclization of N-Sulfonyl Alkenyl Amides Catalyzed by Iridium/Chiral Diene Complexes.

    PubMed

    Nagamoto, Midori; Yanagi, Tomoyuki; Nishimura, Takahiro; Yorimitsu, Hideki

    2016-09-16

    Iridium/chiral diene complexes efficiently catalyzed the asymmetric cyclization of N-sulfonyl alkenyl amides to give the corresponding 2-pyrrolidone derivatives with high enantioselectivity. A mechanistic study revealed that the reaction proceeds via nucleophilic attack of the amide on the alkene moiety.

  13. Enantioselective Cascade Cyclization/Protodemetalation of Polyenes with N3Pt(2+) Catalysts.

    PubMed

    Nguyen, Ha; Gagné, Michel R

    2014-03-07

    The combination of the N-based pincer ligand PyBOX with Pt(2+) leads to new catalysts for the enantioselective cycloisomerization of dienyl- and trienyl-ols. The mechanistic combination of electrophilic cyclization followed by rapid protodemetalation is surprising and leads to a powerful construct for developing new reactions.

  14. Solvent-free cyclization of linear dienes using olefin metathesis and the Thorpe-Ingold effect

    SciTech Connect

    Forbees, M.D.E.; Myers, T.L.; Maynard, H.D.; Schulz, G.R. ); Patton, J.T.; Smith, D.W. Jr.; Wagener, K.B. )

    1992-12-30

    The olefin metathesis reaction is of great synthetic utility in polymer chemistry. The recent development of ring-opening (ROMP) and acyclic diene (ADMET) metathesis polymerization reactions has opened new avenues for the synthesis of novel polymeric materials. Recently the authors used ADMET to synthesize several photochemically active poly(keto olefins) using the catalyst Mo(CHCMe[sub 2]Ph)(NAr)(OCMe(CF[sub 3])[sub 2])[sub 2] (Ar = 2,6-diisopropylphenyl) (1) developed by Schrock and co-workers in 1990. In the course of that work, they discovered that neat samples of highly substituted dienes will cyclize quantitatively via metathesis to give difunctional five- and seven-membered rings instead of the expected linear polymer. Examples of substituted diene cyclizations by metathesis even in the presence of a solvent are rare. Their systematic exploitation in organic synthesis has therefore been limited to two recent studies by Fu and Grubbs, who cyclized several substituted diene ethers, amines, and amides to unsaturated oxygen and nitrogen heterocycles. Cyclization of unsubstituted dienes in various solvents has been reported, but complete conversion occurred in only a few cases. Formation of cyclic alkene oligomers from back-biting during the ROMP reaction is also known. The reactions reported here are unusual in that they are intermolecular between catalyst and substrate, yet can give 100% yield of product solely from the monomer in the absence of solvent. 13 refs.

  15. Enantioselective Michael addition/iminium ion cyclization cascades of tryptamine-derived ureas.

    PubMed

    Aillaud, Isabelle; Barber, David M; Thompson, Amber L; Dixon, Darren J

    2013-06-21

    A Michael addition/iminium ion cyclization cascade of enones with tryptamine-derived ureas under BINOL phosphoric acid (BPA) catalysis is reported. The cascade reaction tolerates a wide variety of easily synthesized tryptamine-derived ureas, including those bearing substituents on the distal nitrogen atom of the urea moiety, affording polyheterocyclic products in good yields and good to excellent enantioselectivities.

  16. endo-Cyclization of unsaturated RO2 radicals from the gas-phase ozonolysis of cyclohexadienes.

    PubMed

    Richters, Stefanie; Pfeifle, Mark; Olzmann, Matthias; Berndt, Torsten

    2017-04-06

    Unsaturated RO2 radicals from the ozonolysis of cyclodienes can readily undergo an endo-cyclization step under atmospheric conditions forming a new ring-containing RO2 radical after further O2 addition. This path represents an extension of the atmospheric autoxidation scheme forming highly oxidized multifunctional organic compounds (HOMs). HOMs play an important role for Earth's organic aerosol burden.

  17. Solid phase synthesis of hydantoins by thermal cyclization and screening of reaction conditions using APOS 1200.

    PubMed

    Karnbrock, W; Deeg, M; Gerhardt, J; Rapp, W

    1998-01-01

    A novel strategy for solid-phase synthesis of hydantoins with high optical purity is described using a thermal pH-neutral cyclization and simultaneous release from resin. Hereby even hydantoins bearing a pH-sensitive side chain (protection) are available. The reaction conditions are well screened applying the parallel organic synthesizer APOS 1200.

  18. Leveraging the micellar effect: gold-catalyzed dehydrative cyclizations in water at room temperature.

    PubMed

    Minkler, Stefan R K; Isley, Nicholas A; Lippincott, Daniel J; Krause, Norbert; Lipshutz, Bruce H

    2014-02-07

    The first examples of gold-catalyzed cyclizations of diols and triols to the corresponding hetero- or spirocycles in an aqueous medium are presented. These reactions take place within nanomicelles, where the hydrophobic effect is operating, thereby driving the dehydrations, notwithstanding the surrounding water. By the addition of simple salts such as sodium chloride, reaction times and catalyst loadings can be significantly decreased.

  19. Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization

    PubMed Central

    Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Ye, Qing; Zhao, Hui; Yu, Jiu-Yang; Qin, Cheng-Feng

    2016-01-01

    Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunable cis-acting element named 5′-UAR-flanking stem (UFS) in the flavivirus genomic 5′ terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5′ end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses. DOI: http://dx.doi.org/10.7554/eLife.17636.001 PMID:27692070

  20. An efficient route to well-defined macrocyclic polymers via "click" cyclization.

    PubMed

    Laurent, Boyd A; Grayson, Scott M

    2006-04-05

    Polystyrene macrocycles have been prepared from ATRP precursors by modification of the terminal bromide to an azide, followed by "click" cyclization with a pendant alkyne from the initiator. This route offers exceptional control over the size and polydispersity of the macrocyclic polymers, as well as providing tolerance to a number of functional groups.

  1. Diastereospecific nazarov cyclization of fully substituted dienones: generation of vicinal all-carbon-atom quaternary stereocenters.

    PubMed

    Jolit, Anais; Vazquez-Rodriguez, Saleta; Yap, Glenn P A; Tius, Marcus A

    2013-10-11

    No vacancy: Fully substituted dienones that are highly polarized by a vinylogous carbonate group were found to undergo a remarkably rapid and diastereospecific Nazarov cyclization that led to cyclopentenones with vicinal all-carbon-atom quaternary centers (see example; SEM=2-(trimethylsilyl)ethoxymethyl, Tf=trifluoromethanesulfonyl). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Nazarov cyclization of dienylaziridines: synthesis of cyclopentadienyl/hydrinedienyl/indenyl glycines.

    PubMed

    Sudhakar, Gangarajula; Reddy, Karla Janardhan; Nanubolu, Jagadesh Babu

    2015-09-07

    Cyclopentadienyl, hydrinedienyl, and indenyl glycines were synthesized using dienylaziridines as Nazarov cyclization precursors for the first time. Several substrates were synthesized to demonstrate the compatibility of this reaction. Asymmetric synthesis of these amino acids was also developed to show the additional scope of this method.

  3. Synthesis of multiply substituted 1,6-dihydropyridines through Cu(I)-catalyzed 6-endo cyclization.

    PubMed

    Mizoguchi, Haruki; Watanabe, Ryo; Minami, Shintaro; Oikawa, Hideaki; Oguri, Hiroki

    2015-06-07

    Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.

  4. Spirocyclic dihydropyridines by electrophile-induced dearomatizing cyclization of N-alkenyl pyridinecarboxamides.

    PubMed

    Senczyszyn, Jemma; Brice, Heloise; Clayden, Jonathan

    2013-04-19

    On treatment with acylating or sulfonylating agents, N-alkenyl pyridine carboxamides (N-pyridinecarbonyl enamines) undergo a dearomatizing cyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic dihydropyridines which may be further elaborated to spirocyclic heterocycles with drug-like features.

  5. Resistance of Feynman diagrams and the percolation backbone dimension.

    PubMed

    Janssen, H K; Stenull, O; Oerding, K

    1999-06-01

    We present an alternative view of Feynman diagrams for the field theory of random resistor networks, in which the diagrams are interpreted as being resistor networks themselves. This simplifies the field theory considerably as we demonstrate by calculating the fractal dimension D(B) of the percolation backbone to three loop order. Using renormalization group methods we obtain D(B)=2+epsilon/21-172epsilon(2)/9261+2epsilon(3)[-74 639+22 680zeta(3)]/4 084 101, where epsilon=6-d with d being the spatial dimension and zeta(3)=1.202 057... .

  6. Robust identification of backbone curves using control-based continuation

    NASA Astrophysics Data System (ADS)

    Renson, L.; Gonzalez-Buelga, A.; Barton, D. A. W.; Neild, S. A.

    2016-04-01

    Control-based continuation is a recently developed approach for testing nonlinear dynamic systems in a controlled manner and exploring their dynamic features as system parameters are varied. In this paper, control-based continuation is adapted to follow the locus where system response and excitation are in quadrature, extracting the backbone curve of the underlying conservative system. The method is applied to a single-degree-of-freedom oscillator under base excitation, and the results are compared with the standard resonant-decay method.

  7. Electron-impact total ionization cross sections of DNA sugar-phosphate backbone and an additivity principle

    NASA Technical Reports Server (NTRS)

    Huo, Winifred M.; Dateo, Christopher E.

    2005-01-01

    The improved binary-encounter dipole (iBED) model [W.M. Huo, Phys. Rev. A64, 042719-1 (2001)l is used to study the total ionization cross sections of the DNA sugar-phosphate backbone by electron impact. Calculations using neutral fragments found that the total ionization cross sections of C3' - and C5', -deoxyribose-phospate, two conformers of the sugar-phosphate backbone, are close to each other. Furthermore, the sum of the ionization cross sections of the separate deoxyribose and phosphate fragments is in close agreement with the C3' - and C5" -deoxyribose-phospate cross sections, differing by less than 10%. The result implies that certain properties of the-DNA, like the total singly ionization cross section, are localized properties and a building-up or additivity principle may apply. This allows us to obtain accurate properties of larger molecular systems built up from the results of smaller subsystem fragments. Calculations are underway using a negatively charged sugar-phosphate backbone with a metal counter-ion.

  8. SpyRings Declassified: A Blueprint for Using Isopeptide-Mediated Cyclization to Enhance Enzyme Thermal Resilience.

    PubMed

    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.

  9. Construction of Polyarylenes with Various Structural Features via Bergman Cyclization Polymerization.

    PubMed

    Wang, Youfu; Chen, Shudan; Hu, Aiguo

    2017-06-01

    Synthetic polymer chemistry is a fundamental part of polymer science, and highly efficient polymerization reactions are essential for the synthesis of high-performance polymers. Development of new synthetic methods for emerging polymer science is of great importance in this regard. Bergman cyclization is a chemical process in which highly reactive aryl diradicals form from enediyne precursors, having a strong impact in a number of fields including pharmaceutics, synthetic chemistry, and materials science. Diradical intermediates stemming from enediynes can cause DNA cleavage under physiological conditions, leading to the strong cytotoxicity of many naturally occurring enediyne antibiotics. Meanwhile, diradical intermediates can quickly couple with each other to construct polyarylenes, providing a novel method to synthesize these conjugated polymers with the advantages of facile and catalyst-free operation, high efficiency, and tailored structure. Moreover, conjugated polymers generated by Bergman cyclization exhibit many remarkable properties, such as excellent thermal stability and good solubility and processability, enabling their further processing into carbon-rich materials. This review presents a brief overview of the trajectory of Bergman cyclization in polymer science, followed by an introduction to research advances, mainly from our group, in developing polymerization methods based on Bergman cyclization, taking advantages of its catalyst-free, byproduct-free, in situ polymerization mechanism to synthesize new polymeric materials with various structures and morphologies. These synthetic strategies include fabrication of rod-like polymers with polyester, dendrimer, and chiral imide side chains, functionalization of carbon nanomaterials by surface-grafting conjugated polymers, formation of nanoparticles by intramolecular collapse of single polymer chains, and construction of carbon nanomembranes on the external and internal surface of inorganic nanomaterials

  10. Structural Basis for Cyclization Specificity of Two Azotobacter Type III Polyketide Synthases

    PubMed Central

    Satou, Ryutaro; Miyanaga, Akimasa; Ozawa, Hiroki; Funa, Nobutaka; Katsuyama, Yohei; Miyazono, Ken-ichi; Tanokura, Masaru; Ohnishi, Yasuo; Horinouchi, Sueharu

    2013-01-01

    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. PMID:24100027

  11. Catalytic mechanism of DNA backbone cleavage by the restriction enzyme EcoRV: a quantum mechanical/molecular mechanical analysis.

    PubMed

    Imhof, Petra; Fischer, Stefan; Smith, Jeremy C

    2009-09-29

    Endonucleases, such as the restriction enzyme EcoRV, cleave the DNA backbone at a specific recognition sequence. We have investigated the catalytic mechanism of backbone phosphodiester hydrolysis by the restriction enzyme EcoRV by means of hybrid quantum mechanical/molecular mechanical calculations. An exhaustive computation of different reaction pathways is performed, thus generating a network of pathways. Comparison of the computed (AM1d/MM) enzymatic reaction pathways with an analogous mechanism for small-molecule model systems [AM1/d and B3LYP/6-31++G(d,p)] reveals that the transition barriers for associative hydrolysis, which is more probable in the model systems, are not lowered by the enzyme. Instead, a reaction mechanism which has mostly dissociative character is more likely. The protein environment is tuned to significantly electrostatically stabilize the transition state structures. The direct catalytic impact of essential residues is determined: The magnesium metal ion activates a water molecule, thus facilitating protonation of the leaving group. A reduction of the coordination number of the magnesium metal ion from six to four upon the positioning of the attacking water molecule explains why larger metal ions, such as calcium, are not catalytically active. The nucleophile is generated by the transfer of a proton from the attacking water molecule to a carboxylic oxygen atom of aspartate 90. The catalytic effect of lysine 92 involves proper positioning of the scissile phosphate group and, more importantly, stabilization of the metaphosphate intermediate in an orientation optimal for attack of the nucleophile.

  12. Long-term forecasting of internet backbone traffic.

    PubMed

    Papagiannaki, Konstantina; Taft, Nina; Zhang, Zhi-Li; Diot, Christophe

    2005-09-01

    We introduce a methodology to predict when and where link additions/upgrades have to take place in an Internet protocol (IP) backbone network. Using simple network management protocol (SNMP) statistics, collected continuously since 1999, we compute aggregate demand between any two adjacent points of presence (PoPs) and look at its evolution at time scales larger than 1 h. We show that IP backbone traffic exhibits visible long term trends, strong periodicities, and variability at multiple time scales. Our methodology relies on the wavelet multiresolution analysis (MRA) and linear time series models. Using wavelet MRA, we smooth the collected measurements until we identify the overall long-term trend. The fluctuations around the obtained trend are further analyzed at multiple time scales. We show that the largest amount of variability in the original signal is due to its fluctuations at the 12-h time scale. We model inter-PoP aggregate demand as a multiple linear regression model, consisting of the two identified components. We show that this model accounts for 98% of the total energy in the original signal, while explaining 90% of its variance. Weekly approximations of those components can be accurately modeled with low-order autoregressive integrated moving average (ARIMA) models. We show that forecasting the long term trend and the fluctuations of the traffic at the 12-h time scale yields accurate estimates for at least 6 months in the future.

  13. A phylogenetic backbone for Bivalvia: an RNA-seq approach

    PubMed Central

    González, Vanessa L.; Andrade, Sónia C. S.; Bieler, Rüdiger; Collins, Timothy M.; Dunn, Casey W.; Mikkelsen, Paula M.; Taylor, John D.; Giribet, Gonzalo

    2015-01-01

    Bivalves are an ancient and ubiquitous group of aquatic invertebrates with an estimated 10 000–20 000 living species. They are economically significant as a human food source, and ecologically important given their biomass and effects on communities. Their phylogenetic relationships have been studied for decades, and their unparalleled fossil record extends from the Cambrian to the Recent. Nevertheless, a robustly supported phylogeny of the deepest nodes, needed to fully exploit the bivalves as a model for testing macroevolutionary theories, is lacking. Here, we present the first phylogenomic approach for this important group of molluscs, including novel transcriptomic data for 31 bivalves obtained through an RNA-seq approach, and analyse these data with published genomes and transcriptomes of other bivalves plus outgroups. Our results provide a well-resolved, robust phylogenetic backbone for Bivalvia with all major lineages delineated, addressing long-standing questions about the monophyly of Protobranchia and Heterodonta, and resolving the position of particular groups such as Palaeoheterodonta, Archiheterodonta and Anomalodesmata. This now fully resolved backbone demonstrates that genomic approaches using hundreds of genes are feasible for resolving phylogenetic questions in bivalves and other animals. PMID:25589608

  14. A phylogenetic backbone for Bivalvia: an RNA-seq approach.

    PubMed

    González, Vanessa L; Andrade, Sónia C S; Bieler, Rüdiger; Collins, Timothy M; Dunn, Casey W; Mikkelsen, Paula M; Taylor, John D; Giribet, Gonzalo

    2015-02-22

    Bivalves are an ancient and ubiquitous group of aquatic invertebrates with an estimated 10 000-20 000 living species. They are economically significant as a human food source, and ecologically important given their biomass and effects on communities. Their phylogenetic relationships have been studied for decades, and their unparalleled fossil record extends from the Cambrian to the Recent. Nevertheless, a robustly supported phylogeny of the deepest nodes, needed to fully exploit the bivalves as a model for testing macroevolutionary theories, is lacking. Here, we present the first phylogenomic approach for this important group of molluscs, including novel transcriptomic data for 31 bivalves obtained through an RNA-seq approach, and analyse these data with published genomes and transcriptomes of other bivalves plus outgroups. Our results provide a well-resolved, robust phylogenetic backbone for Bivalvia with all major lineages delineated, addressing long-standing questions about the monophyly of Protobranchia and Heterodonta, and resolving the position of particular groups such as Palaeoheterodonta, Archiheterodonta and Anomalodesmata. This now fully resolved backbone demonstrates that genomic approaches using hundreds of genes are feasible for resolving phylogenetic questions in bivalves and other animals.

  15. Radical cyclizations of cyclic ene sulfonamides occur with β-elimination of sulfonyl radicals to form polycyclic imines

    PubMed Central

    Zhang, Hanmo; Hay, E. Ben; Geib, Steven J.; Curran, Dennis P.

    2013-01-01

    Radical cyclizations of cyclic ene sulfonamides provide stable bicyclic and tricyclic aldimines and ketimines in good yields. Depending on the structure of the precursor, the cyclizations occur to provide fused and spirocyclic imines with five-, six-, and seven-membered rings. The initial radical cyclization produces an α-sulfonamidoyl radical that undergoes elimination to form the imine and a phenylsulfonyl radical. In a related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2-iodophenylsulfonyl)tetrahydroisoquinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild reductive conditions. PMID:24111991

  16. Tandem SN2' nucleophilic substitution/oxidative radical cyclization of aryl substituted allylic alcohols with 1,3-dicarbonyl compounds.

    PubMed

    Zhang, Zhen; Li, Cheng; Wang, Shao-Hua; Zhang, Fu-Min; Han, Xue; Tu, Yong-Qiang; Zhang, Xiao-Ming

    2017-03-23

    A novel and efficient tandem SN2' 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.

  17. Exploring O-stannyl ketyl and acyl radical cyclizations for the synthesis of γ-lactone-fused benzopyrans and benzofurans.

    PubMed

    Santoso, Helen; Casana, Myriam I; Donner, Christopher D

    2014-01-07

    The synthesis of a series of γ-lactone-fused benzopyrans and benzofurans, analogues of the pyranonaphthoquinone antibiotics, is reported. Preparation of the heterocycles was achieved by either O-stannyl ketyl or acyl radical cyclization of benzaldehyde precursors followed by oxidation to give the pyrano- and furanobenzoquinone systems. The observed diastereoselectivity during O-stannyl ketyl radical cyclization is influenced by aromatic substitution ortho to the aldehyde, whilst acyl radical cyclization followed by stereoselective reduction of the resulting pyranones provides a complimentary approach to forming the required γ-lactone-fused benzopyran systems.

  18. Radical cyclizations of cyclic ene sulfonamides occur with β-elimination of sulfonyl radicals to form polycyclic imines.

    PubMed

    Zhang, Hanmo; Hay, E Ben; Geib, Steven J; Curran, Dennis P

    2013-11-06

    Radical cyclizations of cyclic ene sulfonamides provide stable bicyclic and tricyclic aldimines and ketimines in good yields. Depending on the structure of the precursor, the cyclizations occur to provide fused and spirocyclic imines with five-, six-, and seven-membered rings. The initial radical cyclization produces an α-sulfonamidoyl radical that undergoes elimination to form the imine and a phenylsulfonyl radical. In a related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2-iodophenylsulfonyl)tetrahydroiso-quinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild reductive conditions.

  19. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    SciTech Connect

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  20. Backbone building from quadrilaterals: a fast and accurate algorithm for protein backbone reconstruction from alpha carbon coordinates.

    PubMed

    Gront, Dominik; Kmiecik, Sebastian; Kolinski, Andrzej

    2007-07-15

    In this contribution, we present an algorithm for protein backbone reconstruction that comprises very high computational efficiency with high accuracy. Reconstruction of the main chain atomic coordinates from the alpha carbon trace is a common task in protein modeling, including de novo structure prediction, comparative modeling, and processing experimental data. The method employed in this work follows the main idea of some earlier approaches to the problem. The details and careful design of the present approach are new and lead to the algorithm that outperforms all commonly used earlier applications. BBQ (Backbone Building from Quadrilaterals) program has been extensively tested both on native structures as well as on near-native decoy models and compared with the different available existing methods. Obtained results provide a comprehensive benchmark of existing tools and evaluate their applicability to a large scale modeling using a reduced representation of protein conformational space. The BBQ package is available for downloading from our website at http://biocomp.chem.uw.edu.pl/services/BBQ/. This webpage also provides a user manual that describes BBQ functions in detail.

  1. Visible light mediated cyclization of tertiary anilines with maleimides using nickel(II) oxide surface-modified titanium dioxide catalyst.

    PubMed

    Tang, Jian; Grampp, Günter; Liu, Yun; Wang, Bing-Xiang; Tao, Fei-Fei; Wang, Li-Jun; Liang, Xue-Zheng; Xiao, Hui-Quan; Shen, Yong-Miao

    2015-03-06

    Surface-modified titanium dioxides by highly dispersed NiO particles have an extended absorption in the visible light region and a reduced hole-electron pair recombination than unmodified TiO2. They have now been successfully applied as highly active heterogeneous photocatalysts in the visible light mediated direct cyclization of tertiary anilines with maleimides to give tetrahydroquinoline products in moderate to high yields at ambient temperature. In contrast with unmodified titanium dioxide catalysts that are conventionally used in a stoichiometric amount in combination with UVA light, only a catalytic amount (1 mol %) of the surface-modified TiO2 catalyst is needed along with visible light to efficiently catalyze the reaction. Compared with transition-metal complexes such as Ru(bpy)3Cl2 or Ir(ppy)2(dtbbpy)PF6, advantages of these surface-modified titanium dioxides as photocatalyst include high catalytic activity, low cost, ease of recovering, and being able to be used for at least nine times without significant decay of catalytic activity.

  2. Refined solution structure and backbone dynamics of HIV-1 Nef.

    PubMed Central

    Grzesiek, S.; Bax, A.; Hu, J. S.; Kaufman, J.; Palmer, I.; Stahl, S. J.; Tjandra, N.; Wingfield, P. T.

    1997-01-01

    The tendency of HIV-1 Nef to form aggregates in solution, particularly at pH values below 8, together with its large fraction of highly mobile residues seriously complicated determination of its three-dimensional structure, both for heteronuclear solution NMR (Grzesiek et al., 1996a, Nat Struct Biol 3:340-345) and for X-ray crystallography (Lee et al., 1996, Cell 85:931-942). Methods used to determine the Nef structure by NMR at pH 8 and 0.6 mM concentration are presented, together with a detailed description of Nef's secondary and tertiary structure. The described techniques have general applicability for the NMR structure determination of proteins that are aggregating and/or have limited stability at low pH values. Extensive chemical shift assignments are reported for backbone and side chain 1H, 13C, and 15N resonances of the HIV-1 Nef deletion mutants NEF delta 2-39, NEF delta 2-39, delta 159-173, and of NEF delta 2-39, delta 159-173 in complex with the SH3 domain of the Hck tyrosine protein kinase. Besides a type II polyproline helix, Nef's structure consists of three alpha-helices, a 3(10) helix, and a five-stranded anti-parallel beta-sheet. The analysis of 15N relaxation parameters of the backbone amide sites reveals that all the secondary structure elements are non-mobile on the picosecond to nanosecond and on the millisecond time scale. A large number of slowly exchanging amide protons provides evidence for the stability of the Nef core even on the time scale of hours. Significant internal motions on the ps to ns time scale are detected for residues 60 to 71 and for residues 149 to 180, which form solvent-exposed loops. The residues of the HIV-1 protease cleavage site (W57/L58) do not exhibit large amplitude motions on the sub-nanosecond time scale, and their side chains insert themselves into a hydrophobic crevice formed between the C-terminus of helix 1 and the N-terminus of helix 2. A refined structure has been determined based on additional constraints

  3. Energetics of DNA twisting. I. Relation between twist and cyclization probability.

    PubMed

    Shore, D; Baldwin, R L

    1983-11-15

    The twisting potential of DNA has been determined directly by a method that measures the cyclization probability or j-factor of EcoRI restriction fragments as a function of DNA twist. The cyclization probability is proportional to Kc, the equilibrium constant for cyclization of the restriction fragment via its cohesive ends (Shore et al., 1981). Here we vary the twist of the DNA by making small internal additions to or deletions from a 242 bp EcoRI restriction fragment. A series of 12 DNA molecules has been studied, which range in length from 237 to 254 bp. The cyclization probability is measured from the rates of covalent closure by phage T4 DNA ligase of two systems: (1) a linear restriction fragment in equilibrium with its cyclized form and (2) half molecules (cut by a blunt-end endonuclease) in equilibrium with joined half molecules. The striking result is that, in this DNA size range, the j-factor depends strongly on the fractional twist: the difference between the total helical twist and the nearest integer. Thus j depends in an oscillatory manner on DNA length between 237 and 254 bp with a period of about 10 bp. These data give the free energy of DNA twisting as a function of twist. The curve of j versus DNA length can be fitted to a harmonic twisting potential with a torsional constant of C = 2.4 X 10(-19) erg cm. This value is in reasonable agreement with different estimates of C made by Barkley & Zimm (1979: C = 1.8 X 10(-19) to 4.1 X 10(-19) erg cm) and is somewhat larger than the value obtained resulting from the kinetics of DNA twisting measured by fluorescence depolarization of ethidium intercalated into DNA (C = 1.4 X 10(-19) erg cm; Millar et al., 1982; Thomas et al., 1980) or from spin label studies (Hurley et al., 1982). Our experiments provide a direct measurement of the torsional free energy and they show that the DNA twisting potential is symmetric. Our experiments also indicate that the DNA helix is continuous, or nearly so, in a nicked circle

  4. FeCl3 mediated intramolecular olefin-cation cyclization of cinnamates for the synthesis of highly substituted indenes.

    PubMed

    Dethe, Dattatraya H; Murhade, Ganesh M

    2013-09-21

    Highly substituted indene derivatives were readily prepared in excellent yields with high regioselectivity under very mild reaction conditions by the FeCl3 mediated intramolecular olefin-cationic cyclization of cinnamates.

  5. 2,3-Heteroaromatic ring-fused cyclohexanones via heteroaromatic homo-Nazarov cyclization of donor-acceptor substituted cyclopropanes.

    PubMed

    Yadav, Veejendra K; Kumar, Naganaboina Vijaya

    2008-08-28

    Heteroaryl 2-silylmethyl-substituted cyclopropyl ketones rearrange under Lewis acid conditions via heteroaromatic homo-Nazarov cyclization to form 2,3-heteroaromatic ring fused 4-t-butyldiphenylsilylmethyl-substituted cyclohexanones.

  6. Radical-Radical Cyclization Cascades of Barbiturates Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls.

    PubMed

    Huang, Huan-Ming; Procter, David J

    2016-06-22

    Radical-radical cyclization cascades, triggered by single-electron transfer to amide-type carbonyls by SmI2-H2O, convert simple achiral barbiturates in one step to hemiaminal- or enamine-containing tricyclic scaffolds containing up to five contiguous stereocenters (including quaternary stereocenters). Furthermore, we describe the surprising beneficial effect of LiBr on the most challenging of the radical-radical cyclization cascades. An alternative fragmentation-radical cyclization sequence of related substrates allows access to bicyclic uracil derivatives. The radical-radical cyclization process constitutes the first example of a radical cascade involving ET reduction of the amide carbonyl. Products of the cascade can be readily manipulated to give highly unusual and medicinally relevant bi- and tricyclic barbiturates.

  7. Mechanics and chemistry: single molecule bond rupture forces correlate with molecular backbone structure.

    PubMed

    Frei, Michael; Aradhya, Sriharsha V; Koentopp, Max; Hybertsen, Mark S; Venkataraman, L

    2011-04-13

    We simultaneously measure conductance and force across nanoscale junctions. A new, two-dimensional histogram technique is introduced to statistically extract bond rupture forces from a large data set of individual junction elongation traces. For the case of Au point contacts, we find a rupture force of 1.4 ± 0.2 nN, which is in good agreement with previous measurements. We then study systematic trends for single gold metal-molecule-metal junctions for a series of molecules terminated with amine and pyridine linkers. For all molecules studied, single molecule junctions rupture at the Au-N bond. Selective binding of the linker group allows us to correlate the N-Au bond-rupture force to the molecular backbone. We find that the rupture force ranges from 0.8 nN for 4,4' bipyridine to 0.5 nN in 1,4 diaminobenzene. These experimental results are in excellent quantitative agreement with density functional theory based adiabatic molecular junction elongation and rupture calculations.

  8. Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO.

    PubMed

    Hudson, R; Bizier, N P; Esdale, K N; Katz, J L

    2015-02-28

    The synthesis of 2-substituted indoles and benzofurans was achieved by nucleophilic aromatic substitution, followed by subsequent 5-endo-dig cyclization between the nucleophile and an ortho acetylene. The acetylene serves the dual role of the electron withdrawing group to activate the substrate for SNAr, and the C1-C2 carbon scaffold for the newly formed 5-membered heteroaromatic ring. This method allows for the bond forming sequence of Ar-X-N/O-C1 to proceed in a single synthetic step, furnishing indoles and benzofurans in moderate to high yields. Since the method is not transition metal mediated, brominated and chlorinated substrates are tolerated, and benzofuran formation can be conducted using water or water-DMSO mixtures as solvent.

  9. A Native to Amyloidogenic Transition Regulated by a Backbone Trigger

    SciTech Connect

    Eakin,C.; Berman, A.; Miranker, A.

    2006-01-01

    Many polypeptides can self-associate into linear, aggregated assemblies termed amyloid fibers. High-resolution structural insights into the mechanism of fibrillogenesis are elusive owing to the transient and mixed oligomeric nature of assembly intermediates. Here, we report the conformational changes that initiate fiber formation by beta-2-microglobulin (beta2m) in dialysis-related amyloidosis. Access of beta2m to amyloidogenic conformations is catalyzed by selective binding of divalent cations. The chemical basis of this process was determined to be backbone isomerization of a conserved proline. On the basis of this finding, we designed a beta2m variant that closely adopts this intermediate state. The variant has kinetic, thermodynamic and catalytic properties consistent with its being a fibrillogenic intermediate of wild-type beta2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.

  10. Bioactivities of fish protein hydrolysates from defatted salmon backbones.

    PubMed

    Slizyte, Rasa; Rommi, Katariina; Mozuraityte, Revilija; Eck, Peter; Five, Kathrine; Rustad, Turid

    2016-09-01

    Bioactivities of bulk fish protein hydrolysates (FPH) from defatted salmon backbones obtained with eight different commercial enzymes and their combinations were tested. All FPH showed antioxidative activity in vitro. DPPH scavenging activity increased, while iron chelating ability decreased with increasing time of hydrolysis. All FPH showed ACE inhibiting effect which depended on type of enzyme and increased with time of hydrolysis. The highest effect was found for FPH produced with Trypsin. Bromelain + Papain hydrolysates reduced the uptake of radiolabelled glucose into CaCo-2 cells, a model of human enterocytes, indicating a potential antidiabetic effect of FPH. FPH obtained by Trypsin, Bromelain + Papain and Protamex showed the highest ACE inhibitory, cellular glucose transporter (GLUT/SGLT) inhibitory and in vitro antioxidative activities, respectively. Correlation was observed between the measured bioactivities, degree of hydrolysis and molecular weight profiles, supporting prolonged hydrolysis to obtain high bioactivities.

  11. Reconstruction of the Sunspot Group Number: The Backbone Method

    NASA Astrophysics Data System (ADS)

    Svalgaard, Leif; Schatten, Kenneth H.

    2016-11-01

    We have reconstructed the sunspot-group count, not by comparisons with other reconstructions and correcting those where they were deemed to be deficient, but by a re-assessment of original sources. The resulting series is a pure solar index and does not rely on input from other proxies, e.g. radionuclides, auroral sightings, or geomagnetic records. "Backboning" the data sets, our chosen method, provides substance and rigidity by using long-time observers as a stiffness character. Solar activity, as defined by the Group Number, appears to reach and sustain for extended intervals of time the same level in each of the last three centuries since 1700 and the past several decades do not seem to have been exceptionally active, contrary to what is often claimed.

  12. Chemical characteristics and antithrombotic effect of chondroitin sulfates from sturgeon skull and sturgeon backbone.

    PubMed

    Gui, Meng; Song, Juyi; Zhang, Lu; Wang, Shun; Wu, Ruiyun; Ma, Changwei; Li, Pinglan

    2015-06-05

    Chondroitin sulfates (CSs) were extracted from sturgeon skull and backbone, and their chemical composition, anticoagulant, anti-platelet and thrombolysis activities were evaluated. The average molecular weights of CS from sturgeon skull and backbone were 38.5kDa and 49.2kDa, respectively. Disaccharide analysis indicated that the sturgeon backbone CS was primarily composed of disaccharide monosulfated in position four of the GalNAc (37.8%) and disaccharide monosulfated in position six of the GalNAc (59.6%) while sturgeon skull CS was primarily composed of nonsulfated disaccharide (74.2%). Sturgeon backbone CS showed stronger antithrombotic effect than sturgeon skull CS. Sturgeon backbone CS could significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT), inhibited ADP-induced platelet aggregation and dissolved platelet plasma clots in vitro. The results suggested that sturgeon backbone CS can be explored as a functional food with antithrombotic function.

  13. Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-Type Alkaloids via Reductive Radical Cyclizations.

    PubMed

    Coussanes, Guilhem; Bonjoch, Josep

    2017-02-17

    A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

  14. Synthesis of each enantiomer of rocaglamide by means of a palladium(0)-catalyzed Nazarov-type cyclization.

    PubMed

    Zhou, Zhe; Tius, Marcus A

    2015-05-11

    A recently reported Pd(0)-catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (-)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Synthesis and characterization of cyclic polystyrene using copper-catalyzed alkyne-azide cycloaddition coupling - evaluation of physical properties and optimization of cyclization conditions

    NASA Astrophysics Data System (ADS)

    Elupula, Ravinder

    Polymers with a cyclic topology exhibit a range of unique and potentially useful physical properties, including reduced rates of degradation and increased rates of diffusion in bulk relative to linear analogs. However the synthesis of high purity cyclic polymers, and verification of their structural purity remains challenging. The copper-catalyzed azide-alkyne "click" cyclization route toward cyclic polymers has been used widely, due to its synthetic ease and its compatibility with diverse polymer backbones. Yet unoptimized click cyclization conditions have been observed to generate oligomeric byproducts. In order to optimize these cyclization conditions, and to better understand the structure of the higher molecular weight oligomers, these impurities have been isolated by size exclusion chromatography (SEC) and characterized by mass spectrometry (MS). Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-ToF) MS is a particularly valuable characterization tool and was used to determine that the high molecular weight impurities are predominantly cyclic oligomers. It should also be noted that the rapid analysis and small analyte requirements of this MS technique make it particularly attractive as a general tool for elucidating polymer architecture. Ability to tailor the physical properties of polymers by changing the architecture alone has garnered a lot of attention over the past few decades. Compared to their linear analogues, these novel polymer architectures behave completely different in nanoscale regime. Cyclic polymers are especially intriguing since we can compare the differences in the physical properties with that of the linear chains. One of the major physical property changes are T g-confinement effect. Using ATRP and "click chemistry" we have produced highly pure cyclic PS (c-PS) with number-average molecular weight (MW) of 3.4 kg/mol and 9.1 kg/mol. Bulk glass transition temperatures for c-PS were weakly depended on MWs

  16. Crystal Structure And Functional Analysis of Tetracenomycin Aro/Cyc: Implications for Cyclization Specificity of Aromatic Polyketides

    SciTech Connect

    Ames, B.D.; Korman, T.P.; Zhang, W.; Smith, P.; Vu, T.; Tang, Y.; Tsai, S.-C.

    2009-05-11

    Polyketides are a class of natural products with highly diverse chemical structures and pharmaceutical activities. Polyketide cyclization, promoted by the aromatase/cyclase (ARO/CYC), helps diversify aromatic polyketides. How the ARO/CYC promotes highly specific cyclization is not well understood because of the lack of a first-ring ARO/CYC structure. The 1.9 {angstrom} crystal structure of Tcm ARO/CYC reveals that the enzyme belongs to the Bet v1-like superfamily (or STAR domain family) with a helix-grip fold, and contains a highly conserved interior pocket. Docking, mutagenesis, and an in vivo assay show that the size, shape, and composition of the pocket are important to orient and specifically fold the polyketide chain for C9-C14 first-ring and C7-C16 second-ring cyclizations. Two pocket residues, R69 and Y35, were found to be essential for promoting first- and second-ring cyclization specificity. Different pocket residue mutations affected the polyketide product distribution. A mechanism is proposed based on the structure-mutation-docking results. These results strongly suggest that the regiospecific cyclizations of the first two rings and subsequent aromatizations take place in the interior pocket. The chemical insights gleaned from this work pave the foundation toward defining the molecular rules for the ARO/CYC cyclization specificity, whose rational control will be important for future endeavors in the engineered biosynthesis of novel anticancer and antibiotic aromatic polyketides.

  17. Nucleophilic addition/double cyclization cascade processes between enynyl Fischer carbene complexes and alkynyl malonates.

    PubMed

    Álvarez-Fernández, Ana; Suárez-Rodríguez, Tatiana; Suárez-Sobrino, Ángel L

    2014-07-18

    Two new selective cascade processes for enynyl Fischer carbene complexes 1 are described in their reaction with alkynyl malonates. When carbene complexes 1 react with the sodium enolate of homopropargyl malonates 3 a consecutive Michael-type addition/cyclopentannulation/6-exo cyclization takes place leading, in a regio- and stereoselective way, to n/5/6 angular tricyclic compounds 5. Furthermore, when propargylic malonates are used, a delayed protonation of the reaction mixture allows intermediate 1,4-addition adduct Ia to evolve through a 5-exo cyclization, consisting of an intramolecular nucleophilic attack from the central carbon of the allenylmetallate over the triple C-C bond. Further spontaneous cyclopentannulation of the resulting metallatriene gives rise to bicyclic and linear polycyclic compounds 6 and 7, some of them bearing a polyquinane framework.

  18. Protein cyclization enhanced thermostability and exopeptidase-resistance of green fluorescent protein.

    PubMed

    Zhao, Zhonglin; Ma, Xin; Li, Liang; Zhang, Wei; Ping, Shuzhen; Xu, Ming-Qun; Lin, Min

    2010-03-01

    A mutant of green fluorescent protein (GFPmut3*) from the jellyfish Aequorea victoria was cyclized in vitro and in vivo by the use of a naturally split intein from the dnaE gene of Synechocystis species PCC6803 (Ssp). Cyclization of GFPmut3* was confirmed by amino acid sequencing and resulted in an increased electrophoretic mobility compared with the linear GFPmut3*. The circular GFPmut3* was 5 degrees C more thermostable than the linear form and significantly more resistant to proteolysis of exopeptidase. The circular GFPmut3* also displayed increased relative fluorescence intensity. In addition, chemical stability of GFPmut3* against GdnHCl revealed more stability of the circular form compared with the linear form.

  19. Total synthesis of (-)-tubingensin B enabled by the strategic use of an aryne cyclization

    NASA Astrophysics Data System (ADS)

    Corsello, Michael A.; Kim, Junyong; Garg, Neil K.

    2017-10-01

    Tubingensin B is an indole diterpenoid that bears a daunting chemical structure featuring a disubstituted carbazole unit, five stereogenic centres—three of which are quaternary—and a decorated [3.2.2]-bridged bicycle. We describe our synthetic design toward a concise and enantiospecific total synthesis of tubingensin B, which hinges on the strategic use of a transient aryne intermediate. Although initial studies led to unexpected reaction outcomes, we ultimately implemented a sequence of carbazolyne cyclization followed by Rh-catalysed fragmentation to install the seven-membered ring and vicinal quaternary stereocentres of the natural product. Coupled with a late-stage radical cyclization to construct the [3.2.2]-bridged bicycle, these efforts have enabled the total synthesis of tubingensin B. The design and evolution of our succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

  20. Titanocene-catalyzed cascade cyclization of epoxypolyprenes: straightforward synthesis of terpenoids by free-radical chemistry.

    PubMed

    Justicia, José; Rosales, Antonio; Buñuel, Elena; Oller-López, Juan L; Valdivia, Mónica; Haïdour, Ali; Oltra, J Enrique; Barrero, Alejandro F; Cárdenas, Diego J; Cuerva, Juan M

    2004-04-02

    The titanocene-catalyzed cascade cyclization of epoxypolyenes, which are easily prepared from commercially available polyprenoids, has proven to be a useful procedure for the synthesis of C(10), C(15), C(20), and C(30) terpenoids, including monocyclic, bicyclic, and tricyclic natural products. Both theoretical and experimental evidence suggests that this cyclization takes place in a nonconcerted fashion via discrete carbon-centered radicals. Nevertheless, the termination step of the process seems to be subjected to a kind of water-dependent control, which is unusual in free-radical chemistry. The catalytic cycle is based on the use of the novel combination Me(3)SiCl/2,4,6-collidine to regenerate the titanocene catalyst. In practice this procedure has several advantages: it takes place at room temperature under mild conditions compatible with different functional groups, uses inexpensive reagents, and its end step can easily be controlled to give exocyclic double bonds by simply excluding water from the medium.

  1. An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins.

    PubMed

    Tian, Zhenhua; Sun, Peng; Yan, Yan; Wu, Zhuhua; Zheng, Qingfei; Zhou, Shuaixiang; Zhang, Hua; Yu, Futao; Jia, Xinying; Chen, Dandan; Mándi, Attila; Kurtán, Tibor; Liu, Wen

    2015-04-01

    The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.

  2. A strategy for sequence control in vinyl polymers via iterative controlled radical cyclization

    PubMed Central

    Hibi, Yusuke; Ouchi, Makoto; Sawamoto, Mitsuo

    2016-01-01

    There is a growing interest in sequence-controlled polymers toward advanced functional materials. However, control of side-chain order for vinyl polymers has been lacking feasibility in the field of polymer synthesis because of the inherent feature of chain-growth propagation. Here we show a general and versatile strategy to control sequence in vinyl polymers through iterative radical cyclization with orthogonally cleavable and renewable bonds. The proposed methodology employs a repetitive and iterative intramolecular cyclization via a radical intermediate in a one-time template with a radical-generating site at one end and an alkene end at the other, each of which is connected to a linker via independently cleavable and renewable bonds. The unique design specifically allowed control of radical addition reaction although inherent chain-growth intermediate (radical species) was used, as well as the iterative cycle and functionalization for resultant side chains, to lead to sequence-controlled vinyl polymers (or oligomers). PMID:26996881

  3. 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.

  4. Gold-catalyzed cyclizations of alkynol-based compounds: synthesis of natural products and derivatives.

    PubMed

    Alcaide, Benito; Almendros, Pedro; Alonso, José M

    2011-09-13

    The last decade has witnessed dramatic growth in the number of reactions catalyzed by gold complexes because of their powerful soft Lewis acid nature. In particular, the gold-catalyzed activation of propargylic compounds has progressively emerged in recent years. Some of these gold-catalyzed reactions in alkynes have been optimized and show significant utility in organic synthesis. Thus, apart from significant methodology work, in the meantime gold-catalyzed cyclizations in alkynol derivatives have become an efficient tool in total synthesis. However, there is a lack of specific review articles covering the joined importance of both gold salts and alkynol-based compounds for the synthesis of natural products and derivatives. The aim of this Review is to survey the chemistry of alkynol derivatives under gold-catalyzed cyclization conditions and its utility in total synthesis, concentrating on the advances that have been made in the last decade, and in particular in the last quinquennium.

  5. Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization.

    PubMed

    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.

  6. Probing the limits of ligand steric bulk: backbone C-H activation in a saturated N-heterocyclic carbene.

    PubMed

    Phillips, Nicholas; Tirfoin, Remi; Aldridge, Simon

    2014-03-24

    The consequences of extremely high steric loading have been probed for late transition metal complexes featuring the expanded ring N-heterocyclic carbene 6-Dipp. The reluctance of this ligand to form 2:1 complexes with d-block metals (rationalised on the basis of its percentage buried volume, % Vbur , of 50.8%) leads to C-H and C-N bond activation processes driven by attack at the backbone β-CH2 unit. In the presence of Ir(I) (or indeed H(+) ) the net result is the formation of an allyl formamidine fragment, while Au(I) brings about an additional ring (re-)closure step via nucleophilic attack at the coordinated alkene. The net transformation of 6-Dipp in the presence of [(6-Dipp)Au](+) represents to our knowledge the first example of backbone C-H activation of a saturated N-heterocyclic carbene, proceeding in this case via a mechanism which involves free carbene in addition to the Au(I) centre. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Synthesis of pachastrissamine from phytosphingosine: a comparison of cyclic sulfate vs an epoxide intermediate in cyclization.

    PubMed

    Lee, Taeho; Lee, Sukjin; Kwak, Young Shin; Kim, Deukjoon; Kim, Sanghee

    2007-02-01

    [reaction: see text] The syntheses of the cytotoxic natural product pachastrissamine and its unnatural 4-epi-congener were accomplished starting from a natural phytosphingosine. The relatively unstrained cyclic sulfate intermediate smoothly underwent the 5-endo cyclization to yield the 2,3,4-trisubstituted tetrahydrofuran ring system of pachastrissamine. The corresponding epoxy alcohol afforded the 4-epi-congener via a tosylate-mediated double inversion process.

  8. Polyfunctionalized pyrrolidines by Ugi multicomponent reaction followed by palladium-mediated SN2' cyclizations.

    PubMed

    Banfi, Luca; Basso, Andrea; Cerulli, Valentina; Guanti, Giuseppe; Riva, Renata

    2008-02-15

    A 4-component Ugi reaction with a suitable isocyanide, followed by a novel secondary transformation involving a Pd(II)-mediated (R5 = H) or a Pd(0)-mediated (R5 = CO2Me) SN2' cyclization to give highly functionalized N-acyl-2-vinylpyrrolidines, is reported. The overall yields are usually good and in most cases the Pd(0)-catalyzed reaction gave the final product in almost quantitative yield.

  9. First direct evidence of radical intermediates in samarium diiodide induced cyclization by ESR spectra.

    PubMed

    Sono, Masakazu; Hanamura, Shin-ichi; Furumaki, Midori; Murai, Hisao; Tori, Motoo

    2011-11-04

    The mechanism of samarium diiodide (SmI(2))-induced cyclization of α,β-unsaturated esters and ketones to bicyclic compounds was examined using ESR spectroscopy. This is the first report of direct evidence of the radical intermediates in the SmI(2) reaction. The preferential reduction of the α,β-unsaturated carbonyl part in some substrates should be recognized as a main route. © 2011 American Chemical Society

  10. Palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides: efficient access to C2-diversified oxazoles.

    PubMed

    Wang, Jian; Luo, Shuang; Huang, Jinbo; Mao, Tingting; Zhu, Qiang

    2014-08-25

    A novel procedure for the synthesis of C2-diversified oxazoles, through palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides with aryl, vinyl, alkynyl halides, or triflates, was developed. Migratory insertion of isocyanide into a Csp3-palladium(II) intermediate in a cascade process was also realized, generating alkyl-substituted oxazoles. Therefore, oxazoles functionalized at the C2 position with sp, sp(2), and sp(3) hybridized carbon atoms are accessible by applying this method.

  11. Synthesis of oxazoles by silver catalysed oxidative decarboxylation-cyclization of α-oxocarboxylates and isocyanides.

    PubMed

    Ma, Yiyang; Yan, Zhiyuan; Bian, Changliang; Li, Ke; Zhang, Xiaowen; Wang, Mengfan; Gao, Xinlong; Zhang, Heng; Lei, Aiwen

    2015-07-04

    A silver catalysed synthesis of oxazoles by the oxidative decarboxylation-cyclization of α-oxocarboxylates and isocyanides was developed. This method provided a novel strategy to construct oxazole rings compared to traditional methods. Mechanistic investigations such as operando IR, EPR and radical inhibition experiments were carefully done and confirmed the acyl cation and Ag(II) as the intermediates in this transformation, and the involvement of a radical decarboxylative process.

  12. Synthesis of derivatives of indole and quinoline by the intramolecular catalytic cyclization of allylanilines

    SciTech Connect

    Abdrakmanov, I.B.; Mustafin, A.G.; Tolstikov, G.A.; Fakhretdinov, R.N.; Dzhemilev, U.M.

    1986-09-01

    An effective method for the isolation of 3-methyl-2-ethylindole and 2,4-dimethyl-quinoline by the intramolecular cyclization of N-(1-methyl-2-butenyl)- and 2-(1-methyl-2-butenyl)anilines under the action of the catalyst PdCl/sub 2/ (DMSO)/sub n/ was developed. The influence of the nature of the solvent, the temperature, and the concentration of the catalyst on the yield and the ratio of the reaction products was investigated.

  13. Enantioselective palladium-catalyzed dearomative cyclization for the efficient synthesis of terpenes and steroids.

    PubMed

    Du, Kang; Guo, Pan; Chen, Yuan; Cao, Zhen; Wang, Zheng; Tang, Wenjun

    2015-03-02

    A novel enantioselective palladium-catalyzed dearomative cyclization has been developed for the efficient construction of a series of chiral phenanthrenone derivatives bearing an all-carbon quaternary center. The effectiveness of this method in the synthesis of terpenes and steroids was demonstrated by a highly efficient synthesis of a kaurene intermediate, the facile construction of the skeleton of the anabolic steroid boldenone, and the enantioselective total synthesis of the antimicrobial diterpene natural product (-)-totaradiol.

  14. Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes.

    PubMed

    De Simone, Filippo; Saget, Tanguy; Benfatti, Fides; Almeida, Sofia; Waser, Jérôme

    2011-12-16

    The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Indium-catalyzed homo-Nazarov cyclizations of alkenyl cyclopropyl ketones.

    PubMed

    Patil, Dadasaheb V; Phun, Lien H; France, Stefan

    2010-12-17

    Herein, an efficient Lewis acid catalyzed protocol for the homo-Nazarov cyclizations of alkenyl cyclopropyl ketones is reported. Alkenes bearing β-hydrogens (or silyl groups) provide 1.5:1 mixtures of methylene cyclohexenols and cyclohexenones. When no β-hydrogens (or silyl groups) are present, only cyclohexenones are observed. Products are rapidly formed in good to high yields (up to 93%) under mild conditions and could be readily derivatized.

  16. Hydroxyl-substituted ladder polyethers via selective tandem epoxidation/cyclization sequence.

    PubMed

    Czabaniuk, Lara C; Jamison, Timothy F

    2015-02-20

    A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity.

  17. Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

    PubMed Central

    Czabaniuk, Lara C.; Jamison, Timothy F.

    2015-01-01

    A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) iso-propoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity. PMID:25647091

  18. Synthesis of 6'-branched locked nucleic acid by a radical TEMPO-scavanged stereoselective mercury cyclization.

    PubMed

    Enderlin, Gerald; Nielsen, Poul

    2008-09-05

    A 6'(R)-hydroxymethyl derivative of the locked nucleic acid (LNA)-thymidine monomer has been synthesized by a stereoselective mercury cyclization and subsequent use of TEMPO as a radical scavenger. This compound was converted to an azide derivative, which in a Huisgen-type [3 + 2] cycloaddition afforded a double-headed nucleoside with a triazole linking an additional thymine to the 6'-position of the LNA-nucleoside monomer.

  19. A seco-catechin cyclization approach to 4→6-linked catechin dimers.

    PubMed

    Watanabe, Gen; Ohmori, Ken; Suzuki, Keisuke

    2014-11-28

    A viable route has been developed for the selective synthesis of the 4→6-linked catechin dimers, scarcely accessible from Nature and/or through synthesis. An acyclic nucleophilic catechin precursor (seco-catechin) was used for the regioselective union with an electrophilic catechin unit, and subsequent pyran cyclization gave the desired 4→6-linked dimers, i.e., procyanidin B6 and catechin-(4α→6)-gallocatechin.

  20. Catalytic Cyclization of o-Alkynyl Phenethylamines via Osmacyclopropene Intermediates: Direct Access to Dopaminergic 3-Benzazepines.

    PubMed

    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.

  1. Domino Knoevenagel condensation/intramolecular aldol cyclization route to diverse indolizines with densely functionalized pyridine units.

    PubMed

    Kim, Myungock; Jung, Youngeun; Kim, Ikyon

    2013-10-18

    A highly efficient [4 + 2] annulation route to polysubstituted indolizines is described employing a domino Knoevenagel condensation/intramolecular aldol cyclization process as a key step. Construction of pyridine rings in indolizine skeleton was rapidly achieved from several pyrrole-2-carboxaldehydes in good to excellent yields, leading to indolizines with various substituents at the 5, 6, and 7 positions depending on the reacting active methylene partners.

  2. Synthesis of Gem-Difluorinated Fused Quinolines via Visible Light-Mediated Cascade Radical Cyclization.

    PubMed

    Xiao, Tiebo; Li, Linyong; Xie, Yang; Mao, Zong-Wan; Zhou, Lei

    2016-03-04

    A facile synthesis of gem-difluorinated fused quinolines via visible light-mediated cascade radical cyclization between functionalized difluoromethyl chlorides and alkenes was developed. Various highly functionalized fused quinolines were assembled in moderate to good yields under very mild reaction conditions. The reaction extends the applications of chlorodifluoroacetic acid as the gem-difluoromethylenated building block by simple derivatization, especially in the synthesis of gem-difluorinated fused heterocyclic rings, which are difficult to access with existing methods.

  3. Reductive cyclizations of hydroxysulfinyl ketones: enantioselective access to tetrahydropyran and tetrahydrofuran derivatives.

    PubMed

    Carreño, M Carmen; Des Mazery, Renaud; Urbano, Antonio; Colobert, Françoise; Solladié, Guy

    2003-10-03

    The stereocontrolled formation of cis-2,5-disubstituted tetrahydrofurans and cis-2,6-disubstituted tetrahydropyrans is achieved from enantiopure ketosulfinyl esters by reduction, Weinreb's amide, and ketone formation, followed by the reductive cyclization (Et3SiH/TMSOTf) of the resulting hydroxysulfinyl ketones. The sulfoxide-bearing heterocycles were transformed into two natural products, (-)-centrolobine (1) and both enantiomers of cis-(6-methyltetrahydropyran-2-yl)acetic acid (2).

  4. Catalytic enantioselective Nazarov cyclization: construction of vicinal all-carbon-atom quaternary stereocenters.

    PubMed

    Jolit, Anais; Walleser, Patrick M; Yap, Glenn P A; Tius, Marcus A

    2014-06-10

    The diastereoselective asymmetric synthesis of vicinal all-carbon-atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Flow Pickering Emulsion Interfaces Enhance Catalysis Efficiency and Selectivity for Cyclization of Citronellal.

    PubMed

    Chen, Huan; Zou, Houbing; Hao, Yajuan; Yang, Hengquan

    2017-05-09

    Cyclization of citronellal is a necessary intermediate step to produce the important flavor chemical (-)-menthol. Here, a continuous-flow Pickering emulsion (FPE) strategy for selective cyclization of citronellal to (-)-isopulegol by using water droplets hosting a heteropolyacid (HPA) catalyst to fill a column reactor is demonstrated. Owing to the large liquid-liquid interface and the excellent confinement ability of droplets toward HPA, the FPE system exhibited a much higher catalysis efficiency than its batch counterpart (2-5-fold) and an excellent durability (two months). Moreover, a remarkably enhanced selectivity was observed from 34.8 % for batch reactions to 64 % for the FPE reactions. It was found that the water droplet size and the flow rate significantly impact the catalysis selectivity and efficiency. This study not only represents an unprecedented and sustainable process for the selective cyclization of citronellal but also demonstrates a new flow-interface catalysis effect that can be useful for designing innovative catalysis systems in the future. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Oxidative Cyclizations in a Nonpolar Solvent Using Molecular Oxygen and Studies on the Stereochemistry of Oxypalladation

    PubMed Central

    Trend, Raissa M.; Ramtohul, Yeeman K.; Stoltz., Brian M.

    2008-01-01

    Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a “Wacker-type” mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono- and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation. PMID:16351107

  7. Multistereocenter-Containing Cyclopentanoids from Ynamides via Oxazolidinone-Controlled Nazarov Cyclization.

    PubMed

    Manchala, Narasimhulu; Law, Hanson Y L; Kerr, Daniel J; Volpe, Rohan; Lepage, Romain J; White, Jonathan M; Krenske, Elizabeth H; Flynn, Bernard L

    2017-07-07

    Achieving ready-enantioselective access to multistereocenter-containing cyclopentyl rings is an area of great significance to organic synthesis. In this work, we describe a general protocol for accessing multistereocenter-containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated divinyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio-, and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both in the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a "coupled-torque" mechanism in which rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation, favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated lone-pair stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates, broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereo- and regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multistereocenter containing cyclopentanoids. Finally, the Ox group is readily removed and recovered or can be converted into other amine functionalities.

  8. Intramolecular Cyclization of Thiophene-Based [7]Helicenes to Quasi-[8]Circulenes

    SciTech Connect

    Rajca, Andrzej; Miyasaka, Makoto; Xiao, Shuzhang; Boratynski, Przemystaw J.; Pink, Maren; Rajca, Suchada

    2009-12-08

    Intramolecular cyclization in a series of thiophene-based dibromo[7]helicenes (4-6) with different helix structures is investigated by vacuum pyrolysis, tin- and palladium-mediated C-C bond forming reactions. The product with the cyclic structure of the annelated aromatic rings, which resembles [8]circulene devoid of an atom linkage, is referred to as quasi-[8]circulene. Vacuum pyrolysis of 4 gives insoluble, unidentified products, while 5 and 6 yield the corresponding quasi-[8]circulenes under similar conditions. Thermogravimetry (TG) and differential scanning calorimetry (DSC) analyses for 4 indicate complex reaction pathways, while those for 5 and 6 show a single process corresponding to a loss of 1 equiv of Br2 at about 330 C. Pd-mediated reductive cyclization provides quasi-[8]circulenes for all three [7]helicenes, though only 4 gives a good isolated yield. Tributyltin hydride-mediated radical cyclization of 4-6 provides quasi-[8]circulenes in excellent yields, and it is practically insensitive to the helix structure. Experimental and calculated UV-vis absorption spectra for quasi-[8]circulenes and [8]circulenes are reported. The results suggest that the lack of atom linkage in quasi-[8]circulene does not significantly affect properties and conformation, compared to those for the corresponding [8]circulenes.

  9. Synthesis of triazafluoranthenones via silver(I)-mediated nonoxidative and oxidative intramolecular palladium-catalyzed cyclizations.

    PubMed

    Koutentis, Panayiotis A; Loizou, Georgia; Lo Re, Daniele

    2011-07-15

    Silver(I) fluoride (AgF)-mediated intramolecular nonoxidative and oxidative palladium-catalyzed cyclizations of 1,3-diphenyl- and 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ones 6a (R = H) and 7a (R = I) afford a new 'alkaloid like' ring system 2-phenyl-6H-[1,2,4]triazino[5,6,1-jk]carbazol-6-one 8a (triazafluoranthenone) in 86 and 100% yields, respectively. Furthermore, these cyclization protocols were used to prepare triazafluoranthenone analogues 8b-e bearing dialkylamino, methoxy, and phenylsulfanyl substituents at C-5, which were also independently synthesized from triazafluoranthenone 8a by regioselective nucleophilic addition. Similar AgF-mediated intramolecular nonoxidative and oxidative palladium-catalyzed cyclizations of 8,10-dihydro-1-iodo-10-phenylphenazin-2(7H)-ones 13 gave the new 'alkaloid like' ring system 8H-indolo[1,2,3-mn]phenazin-8-one 14 in 80 and 18% yields, respectively.

  10. 1H, 13C, and 15N backbone, side-chain, and heme chemical shift assignments for oxidized and reduced forms of the monoheme c-type cytochrome ApcA isolated from the acidophilic metal-reducing bacterium Acidiphilium cryptum.

    SciTech Connect

    Cort, John R.; Swenson, Michael; Magnuson, Timothy S.

    2011-03-04

    We report the 1H, 13C, and 15N chemical shift assignments of both oxidized and reduced forms of an abundant periplasmic c-type cytochrome, designated ApcA, from the acidophilic gram-negative facultatively anaerobic metal-reducing alpha-proteobacterium Acidiphilium cryptum. These resonance assignments prove that ApcA is a monoheme cytochrome c2 and the product of the Acry_2099 gene. An absence of resonance peaks in the NMR spectra for the 21 N-terminal residues suggests that a predicted N-terminal signal sequence is cleaved. We also describe the preparation and purification of the protein in labeled form from laboratory cultures of A. cryptum growing on 13C- and 15N- labeled substrates.

  11. Cost-effectiveness analysis of dolutegravir plus backbone compared with raltegravir plus backbone, darunavir+ritonavir plus backbone and efavirenz/tenofovir/emtricitabine in treatment naïve and experienced HIV-positive patients.

    PubMed

    Restelli, Umberto; Rizzardini, Giuliano; Antinori, Andrea; Lazzarin, Adriano; Bonfanti, Marzia; Bonfanti, Paolo; Croce, Davide

    2017-01-01

    In January 2014, the European Medicines Agency issued a marketing authorization for dolutegravir (DTG), a second-generation integrase strand transfer inhibitor for HIV treatment. The study aimed at determining the incremental cost-effectiveness ratio (ICER) of the use of DTG+backbone compared with raltegravir (RAL)+backbone, darunavir (DRV)+ritonavir(r)+backbone and efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in HIV-positive treatment-naïve patients and compared with RAL+backbone in treatment-experienced patients, from the Italian National Health Service's point of view. A published Monte Carlo Individual Simulation Model (ARAMIS-DTG model) was used to perform the analysis. Patients pass through mutually exclusive health states (defined in terms of diagnosis of HIV with or without opportunistic infections [OIs] and cardiovascular disease [CVD]) and successive lines of therapy. The model considers costs (2014) and quality of life per monthly cycle in a lifetime horizon. Costs and quality-adjusted life years (QALYs) are dependent on OI, CVD, AIDS events, adverse events and antiretroviral therapies. In treatment-naïve patients, DTG dominates RAL; compared with DRV/r, the ICER obtained is of 38,586 €/QALY (6,170 €/QALY in patients with high viral load) and over EFV/TDF/FTC, DTG generates an ICER of 33,664 €/QALY. In treatment-experienced patients, DTG compared to RAL leads to an ICER of 12,074 €/QALY. The use of DTG+backbone may be cost effective in treatment-naïve and treatment-experienced patients compared with RAL+backbone and in treatment-naïve patients compared with DRV/r+backbone and EFV/TDF/FTC considering a threshold of 40,000 €/QALY.

  12. Computational design of high-affinity epitope scaffolds by backbone grafting of a linear epitope.

    PubMed

    Azoitei, Mihai L; Ban, Yih-En Andrew; Julien, Jean-Philippe; Bryson, Steve; Schroeter, Alexandria; Kalyuzhniy, Oleksandr; Porter, Justin R; Adachi, Yumiko; Baker, David; Pai, Emil F; Schief, William R

    2012-01-06

    Computational grafting of functional motifs onto scaffold proteins is a promising way to engineer novel proteins with pre-specified functionalities. Typically, protein grafting involves the transplantation of protein side chains from a functional motif onto structurally homologous regions of scaffold proteins. Using this approach, we previously transplanted the human immunodeficiency virus 2F5 and 4E10 epitopes onto heterologous proteins to design novel "epitope-scaffold" antigens. However, side-chain grafting is limited by the availability of scaffolds with compatible backbone for a given epitope structure and offers no route to modify backbone structure to improve mimicry or binding affinity. To address this, we report here a new and more aggressive computational method-backbone grafting of linear motifs-that transplants the backbone and side chains of linear functional motifs onto scaffold proteins. To test this method, we first used side-chain grafting to design new 2F5 epitope scaffolds with improved biophysical characteristics. We then independently transplanted the 2F5 epitope onto three of the same parent scaffolds using the newly developed backbone grafting procedure. Crystal structures of side-chain and backbone grafting designs showed close agreement with both the computational models and the desired epitope structure. In two cases, backbone grafting scaffolds bound antibody 2F5 with 30- and 9-fold higher affinity than corresponding side-chain grafting designs. These results demonstrate that flexible backbone methods for epitope grafting can significantly improve binding affinities over those achieved by fixed backbone methods alone. Backbone grafting of linear motifs is a general method to transplant functional motifs when backbone remodeling of the target scaffold is necessary.

  13. Pendant Dynamics of Ethylene-Oxide Containing Polymers with Diverse Backbones

    NASA Astrophysics Data System (ADS)

    Bartels, Joshua; Wang, Jing-Han Helen; Chen, Quan; Runt, James; Colby, Ralph

    In the last twenty years, a wide variety of ion conducting polymers have used ether oxygens to facilitate ion conduction, and it is therefore important to understand the dynamics of ether oxygens (EOs) when attached to different polymer backbones. Four different EO-containing polymer architectures are studied by dielectric spectroscopy to understand the backbone effect on the EO dipoles. Polysiloxanes, polyphosphazenes, polymethylmethacrylates, and a polyester ether are compared, with different EO pendant lengths for the siloxane and methylmethacrylate backbones. The flexible polysiloxanes and polyphosphazene backbones impart superior segmental mobility with a glass transition temperature 15 K lower than that of the organic backbone polymers. Short EO pendants are found to impart a lower static dielectric constant at comparable EO content as compared to longer EO pendants of either inorganic or organic backbones. The long-pendant polymethylmethacrylate polymers show two relaxations corresponding to fast EOs near the pendant tail end and slow EOs close to the slower backbone, whereas the long-pendant polysiloxane shows a single relaxation due to the siloxane backbone relaxing faster than the EO pendant. Supported by the NSF Division of Materials Research Polymers Program through Grants DMR-1404586 (RHC) and DMR-1505953 (JR).

  14. Backbone Assignment of the MALT1 Paracaspase by Solution NMR.

    PubMed

    Unnerståle, Sofia; Nowakowski, Michal; Baraznenok, Vera; Stenberg, Gun; Lindberg, Jimmy; Mayzel, Maxim; Orekhov, Vladislav; Agback, Tatiana

    2016-01-01

    Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a unique paracaspase protein whose protease activity mediates oncogenic NF-κB signalling in activated B cell-like diffuse large B cell lymphomas (ABC-DLBCLs). ABC-DLBCLs are aggressive lymphomas with high resistance to current chemotherapies. Low survival rate among patients emphasizes the urgent need for alternative treatment options. The characterization of the MALT1 will be an essential tool for developing new target-directed drugs against MALT1 dependent disorders. As the first step in the atomic-level NMR studies of the system, here we report, the (15)N/(13)C/(1)H backbone assignment of the apo form of the MALT1 paracaspase region together with the third immunoglobulin-like (Ig3) domain, 44 kDa, by high resolution NMR. In addition, the non-uniform sampling (NUS) based targeted acquisition procedure is evaluated as a mean of decreasing acquisition and analysis time for larger proteins.

  15. Thermogelling Biodegradable Polymers with Hydrophilic Backbones: PEG-g-PLGA

    SciTech Connect

    Jeong, Byeongmoon; Kibbey, Merinda R.; Birnbaum, Jerome C.; Won, You-Yeong; Gutowska, Anna

    2000-10-31

    The aqueous solutions of poly(ethylene glycol)grafted with poly(lactic acid-co-glycolic acid) flow freely at room temperature but form gels at higher temperature. The existence of micelles in water at low polymer concentration was confirmed by Cro-transmission electron microscopy and dye solubilization studies. The micellar diameter and critical micelle concentration are about 9 nm and 0.47 wt.% respectively. The critical gel concentration, above which a gel phase appears was 16 wt.% and sol-to-gel transition temperature was slightly affected by the concentration in the range of 16 {approx} 25 wt.%. At sol-to-gel transition, viscosity increased abruptly and C-NMR showed molecular motion of hydrophilic poly(lactic acid-co-glycolic acid) side-chains increased. The hydrogel of PEG-g-PLGA with hydrophilic backbones was transparent during degradation and remained a gel for one week, suggesting a promising material for short-term drug delivery.

  16. A New Secondary Structure Assignment Algorithm Using Cα Backbone Fragments.

    PubMed

    Cao, Chen; Wang, Guishen; Liu, An; Xu, Shutan; Wang, Lincong; Zou, Shuxue

    2016-03-11

    The assignment of secondary structure elements in proteins is a key step in the analysis of their structures and functions. We have developed an algorithm, SACF (secondary structure assignment based on Cα fragments), for secondary structure element (SSE) assignment based on the alignment of Cα backbone fragments with central poses derived by clustering known SSE fragments. The assignment algorithm consists of three steps: First, the outlier fragments on known SSEs are detected. Next, the remaining fragments are clustered to obtain the central fragments for each cluster. Finally, the central fragments are used as a template to make assignments. Following a large-scale comparison of 11 secondary structure assignment methods, SACF, KAKSI and PROSS are found to have similar agreement with DSSP, while PCASSO agrees with DSSP best. SACF and PCASSO show preference to reducing residues in N and C cap regions, whereas KAKSI, P-SEA and SEGNO tend to add residues to the terminals when DSSP assignment is taken as standard. Moreover, our algorithm is able to assign subtle helices (310-helix, π-helix and left-handed helix) and make uniform assignments, as well as to detect rare SSEs in β-sheets or long helices as outlier fragments from other programs. The structural uniformity should be useful for protein structure classification and prediction, while outlier fragments underlie the structure-function relationship.

  17. A New Secondary Structure Assignment Algorithm Using Cα Backbone Fragments

    PubMed Central

    Cao, Chen; Wang, Guishen; Liu, An; Xu, Shutan; Wang, Lincong; Zou, Shuxue

    2016-01-01

    The assignment of secondary structure elements in proteins is a key step in the analysis of their structures and functions. We have developed an algorithm, SACF (secondary structure assignment based on Cα fragments), for secondary structure element (SSE) assignment based on the alignment of Cα backbone fragments with central poses derived by clustering known SSE fragments. The assignment algorithm consists of three steps: First, the outlier fragments on known SSEs are detected. Next, the remaining fragments are clustered to obtain the central fragments for each cluster. Finally, the central fragments are used as a template to make assignments. Following a large-scale comparison of 11 secondary structure assignment methods, SACF, KAKSI and PROSS are found to have similar agreement with DSSP, while PCASSO agrees with DSSP best. SACF and PCASSO show preference to reducing residues in N and C cap regions, whereas KAKSI, P-SEA and SEGNO tend to add residues to the terminals when DSSP assignment is taken as standard. Moreover, our algorithm is able to assign subtle helices (310-helix, π-helix and left-handed helix) and make uniform assignments, as well as to detect rare SSEs in β-sheets or long helices as outlier fragments from other programs. The structural uniformity should be useful for protein structure classification and prediction, while outlier fragments underlie the structure–function relationship. PMID:26978354

  18. Backbone of complex networks of corporations: The flow of control

    NASA Astrophysics Data System (ADS)

    Glattfelder, J. B.; Battiston, S.

    2009-09-01

    We present a methodology to extract the backbone of complex networks based on the weight and direction of links, as well as on nontopological properties of nodes. We show how the methodology can be applied in general to networks in which mass or energy is flowing along the links. In particular, the procedure enables us to address important questions in economics, namely, how control and wealth are structured and concentrated across national markets. We report on the first cross-country investigation of ownership networks, focusing on the stock markets of 48 countries around the world. On the one hand, our analysis confirms results expected on the basis of the literature on corporate control, namely, that in Anglo-Saxon countries control tends to be dispersed among numerous shareholders. On the other hand, it also reveals that in the same countries, control is found to be highly concentrated at the global level, namely, lying in the hands of very few important shareholders. Interestingly, the exact opposite is observed for European countries. These results have previously not been reported as they are not observable without the kind of network analysis developed here.

  19. Data Acquisition Backbone Core DABC release v1.0

    NASA Astrophysics Data System (ADS)

    Adamczewski-Musch, J.; Essel, H. G.; Kurz, N.; Linev, S.

    2010-04-01

    The Data Acquisition Backbone Core (DABC) is a general purpose software framework designed for the implementation of a wide-range of data acquisition systems - from various small detector test beds to high performance systems. DABC consists of a compact data-flow kernel and a number of plug-ins for various functional components like data inputs, device drivers, user functional modules and applications. DABC provides configurable components for implementing event building over fast networks like InfiniBand or Gigabit Ethernet. A generic Java GUI provides the dynamic control and visualization of control parameters and commands, provided by DIM servers. A first set of application plug-ins has been implemented to use DABC as event builder for the front-end components of the GSI standard DAQ system MBS (Multi Branch System). Another application covers the connection to DAQ readout chains from detector front-end boards (N-XYTER) linked to read-out controller boards (ROC) over UDP into DABC for event building, archiving and data serving. This was applied for data taking in the September 2008 test beamtime for the CBM experiment at GSI. DABC version 1.0 is released and available from the website.

  20. Backbone of complex networks of corporations: the flow of control.

    PubMed

    Glattfelder, J B; Battiston, S

    2009-09-01

    We present a methodology to extract the backbone of complex networks based on the weight and direction of links, as well as on nontopological properties of nodes. We show how the methodology can be applied in general to networks in which mass or energy is flowing along the links. In particular, the procedure enables us to address important questions in economics, namely, how control and wealth are structured and concentrated across national markets. We report on the first cross-country investigation of ownership networks, focusing on the stock markets of 48 countries around the world. On the one hand, our analysis confirms results expected on the basis of the literature on corporate control, namely, that in Anglo-Saxon countries control tends to be dispersed among numerous shareholders. On the other hand, it also reveals that in the same countries, control is found to be highly concentrated at the global level, namely, lying in the hands of very few important shareholders. Interestingly, the exact opposite is observed for European countries. These results have previously not been reported as they are not observable without the kind of network analysis developed here.

  1. Backbone Assignment of the MALT1 Paracaspase by Solution NMR

    PubMed Central

    Unnerståle, Sofia; Nowakowski, Michal; Baraznenok, Vera; Stenberg, Gun; Lindberg, Jimmy; Mayzel, Maxim; Orekhov, Vladislav; Agback, Tatiana

    2016-01-01

    Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a unique paracaspase protein whose protease activity mediates oncogenic NF-κB signalling in activated B cell-like diffuse large B cell lymphomas (ABC-DLBCLs). ABC-DLBCLs are aggressive lymphomas with high resistance to current chemotherapies. Low survival rate among patients emphasizes the urgent need for alternative treatment options. The characterization of the MALT1 will be an essential tool for developing new target-directed drugs against MALT1 dependent disorders. As the first step in the atomic-level NMR studies of the system, here we report, the 15N/13C/1H backbone assignment of the apo form of the MALT1 paracaspase region together with the third immunoglobulin-like (Ig3) domain, 44 kDa, by high resolution NMR. In addition, the non-uniform sampling (NUS) based targeted acquisition procedure is evaluated as a mean of decreasing acquisition and analysis time for larger proteins. PMID:26788853

  2. Structure and backbone dynamics of a microcrystalline metalloprotein by solid-state NMR

    PubMed Central

    Knight, Michael J.; Pell, Andrew J.; Bertini, Ivano; Felli, Isabella C.; Gonnelli, Leonardo; Pierattelli, Roberta; Herrmann, Torsten; Emsley, Lyndon; Pintacuda, Guido

    2012-01-01

    We introduce a new approach to improve structural and dynamical determination of large metalloproteins using solid-state nuclear magnetic resonance (NMR) with 1H detection under ultrafast magic angle spinning (MAS). The approach is based on the rapid and sensitive acquisition of an extensive set of 15N and 13C nuclear relaxation rates. The system on which we demonstrate these methods is the enzyme Cu, Zn superoxide dismutase (SOD), which coordinates a Cu ion available either in Cu+ (diamagnetic) or Cu2+ (paramagnetic) form. Paramagnetic relaxation enhancements are obtained from the difference in rates measured in the two forms and are employed as structural constraints for the determination of the protein structure. When added to 1H-1H distance restraints, they are shown to yield a twofold improvement of the precision of the structure. Site-specific order parameters and timescales of motion are obtained by a Gaussian axial fluctuation (GAF) analysis of the relaxation rates of the diamagnetic molecule, and interpreted in relation to backbone structure and metal binding. Timescales for motion are found to be in the range of the overall correlation time in solution, where internal motions characterized here would not be observable. PMID:22723345

  3. Density Functional Theory-Based First Principles Calculations of Rhododendrol-Quinone Reactions: Preference to Thiol Binding over Cyclization

    NASA Astrophysics Data System (ADS)

    Kishida, Ryo; Kasai, Hideaki; Meñez Aspera, Susan; Lacdao Arevalo, Ryan; Nakanishi, Hiroshi

    2017-02-01

    Using density functional theory-based first principles calculations, we investigated the changes in the energetics and electronic structures of rhododendrol (RD)-quinone for the initial step of two important reactions, viz., cyclization and thiol binding, to give significant insights into the mechanism of the cause of cytotoxic effects. We found that RD-quinone in the electroneutral structure cannot undergo cyclization, indicating a slow cyclization of RD-quinone at neutral pH. Furthermore, using methane thiolate ion as a model thiol, we found that the oxidized form of the cyclized RD-quinone, namely RD-cyclic quinone, exhibited a reduced binding energy for thiols. However, this reduction of binding energy is clearly smaller than the case of dopaquinone, which is a molecule originally involved in the melanin synthesis. This study clearly shows that RD-quinone has a preference toward thiol bindings than cyclization compared to the case of dopaquinone. Considering that thiol bindings have been reported to induce cytotoxic effects in various ways, the preference toward thiol bindings is an important chemical property for the cytotoxicity caused by RD.

  4. Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

    PubMed Central

    Luo, Dan; Callari, Roberta; Hamberger, Britta; Wubshet, Sileshi Gizachew; Nielsen, Morten T.; Andersen-Ranberg, Johan; Hallström, Björn M.; Cozzi, Federico; Lindberg Møller, Birger; Hamberger, Björn

    2016-01-01

    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 in 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. PMID:27506796

  5. Localization of electrons in the sugar/phosphate backbone in DNA investigated via resonant Auger decay spectra

    SciTech Connect

    Baba, Yuji; Sekiguchi, Tetsuhiro; Shimoyama, Iwao; Hirao, Norie; Nath, Krishna G.

    2006-11-15

    In order to elucidate the localized nature of electrons in sugar/phosphate backbone in DNA molecules, resonant Auger decay spectra excited by soft x-rays around the inner-shell ionization thresholds have been measured for single-strand DNA. The systems investigated are thin films of DNA as well as related phosphorus compounds such as nucleotide (adenosine triphosphate, ATP), sodium phosphate, and indium phosphide. For ATP and DNA, it was observed that the resonant excitations from P 1s to valence unoccupied {pi}* orbitals are followed by spectator-type Auger decays where the excited electrons remain in valence orbitals during the core-hole decays. It was also found that the energy of the P KL{sub 2,3}L{sub 2,3} (2p{sup -1}{center_dot}{pi}*) spectator Auger peak shifts linearly with the photon energy due to the resonant Auger Raman scattering. Most of the decay channel at the core-to-valence resonant excitation is spectator-type Auger decay in DNA, which is quite different from the Auger decay processes in metallic and semiconducting materials. We conclude that the excited electrons in valence unoccupied states around the phosphates in DNA molecules are strongly localized, resulting in the insulating properties in a one-dimensional direction along sugar/phosphate backbone.

  6. Cyclization and rearrangement reactions of a(n) fragment ions of protonated peptides.

    PubMed

    Bythell, Benjamin J; Maître, Philippe; Paizs, Béla

    2010-10-27

    a(n) ions are frequently formed in collision-induced dissociation (CID) of protonated peptides in tandem mass spectrometry (MS/MS) based sequencing experiments. These ions have generally been assumed to exist as immonium derivatives (-HN(+)═CHR). Using a quadrupole ion trap mass spectrometer, MS/MS experiments have been performed and the structure of a(n) ions formed from oligoglycines was probed by infrared spectroscopy. The structure and isomerization reactions of the same ions were studied using density functional theory. Overall, theory and infrared spectroscopy provide compelling evidence that a(n) ions undergo cyclization and/or rearrangement reactions, and the resulting structure(s) observed under our experimental conditions depends on the size (n). The a(2) ion (GG sequence) undergoes cyclization to form a 5-membered ring isomer. The a(3) ion (GGG sequence) undergoes cyclization initiated by nucleophilic attack of the carbonyl oxygen of the N-terminal glycine residue on the carbon center of the C-terminal immonium group forming a 7-membered ring isomer. The barrier to this reaction is comparatively low at 10.5 kcal mol(-1), and the resulting cyclic isomer (-5.4 kcal mol(-1)) is more energetically favorable than the linear form. The a(4) ion with the GGGG sequence undergoes head-to-tail cyclization via nucleophilic attack of the N-terminal amino group on the carbon center of the C-terminal immonium ion, forming an 11-membered macroring which contains a secondary amine and three trans amide bonds. Then an intermolecular proton transfer isomerizes the initially formed secondary amine moiety (-CH(2)-NH(2)(+)-CH(2)-NH-CO-) to form a new -CH(2)-NH-CH(2)-NH(2)(+)-CO- form. This structure is readily cleaved at the -CH(2)-NH(2)(+)- bond, leading to opening of the macrocycle and formation of a rearranged linear isomer with the H(2)C═NH(+)-CH(2)- moiety at the N terminus and the -CO-NH(2) amide bond at the C terminus. This rearranged linear structure is much more

  7. Proteins of well-defined structures can be designed without backbone readjustment by a statistical model.

    PubMed

    Zhou, Xiaoqun; Xiong, Peng; Wang, Meng; Ma, Rongsheng; Zhang, Jiahai; Chen, Quan; Liu, Haiyan

    2016-12-01

    We report that using mainly a statistical energy model, protein sequence design for designable backbones can be carried out with high confidence without considering backbone relaxation. A recently-developed statistical energy function for backbone-based protein sequence design has been rationally revised to improve its accuracy. As a demonstrative example, this revised model is applied to design a de novo protein for a target backbone for which the previous model had relied on after-design directed evolution to produce a well-folded protein. The actual backbone structure of the newly designed protein agrees excellently with the corresponding target. Besides presenting a new protein design protocol with experimentally verifications on different backbone types, our study implies that with an energy model of an appropriate resolution, proteins of well-defined structures instead of molten globules can be designed without the explicit consideration of backbone variations due to side chain changes, even if the side chain changes correspond to complete sequence redesigns.

  8. SmI2-induced cyclizations and their applications in natural product synthesis.

    PubMed

    Nakata, Tadashi

    2010-06-01

    Since the isolation of brevetoxin-B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans-fused polycyclic ether ring systems have been reported. We have developed SmI(2)-induced cyclization of beta-alkoxyacrylate with aldehyde, affording 2,6-syn-2,3-trans-tetrahydropyran (THP) or 2,7-syn-2,3-trans-oxepane with complete stereoselection, as a key reaction of efficient iterative and bi-directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3-, 5-, and 6-methyl-THPs and 3,5-dimethyl-THP. The synthesis of 2-methyl- and 2,6-dimethyl-THPs was accomplished by means of a unique methyl insertion. Recently, the SmI(2)-induced cyclization was extended to similar reactions using beta-alkoxyvinyl sulfone and sulfoxide. Reaction of (E)- and (Z)-beta-alkoxyvinyl sulfone-aldehyde afforded 2,6-syn-2,3-trans- and 2,6-syn-2,3-cis- THPs, respectively. Reaction of (E)-beta-alkoxyvinyl (R)- and (S)-sulfoxides gave 2,6-anti-2,3-cis- and 2,6-syn-2,3-trans-THPs, respectively. Reaction of (Z)-beta-alkoxyvinyl (R)-sulfoxides gave 2,6-syn-2,3-cis-THP and an olefinic product, while that of (Z)-beta-alkoxyvinyl (S)-sulfoxide afforded a mixture of many products. These SmI(2)-induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin-B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced.

  9. Opposing auxiliary conformations produce the same torquoselectivity in an oxazolidinone-directed Nazarov cyclization.

    PubMed

    Flynn, Bernard L; Manchala, Narasimhulu; Krenske, Elizabeth H

    2013-06-19

    Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R(4) and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative

  10. Synthesis of anionic phosphorus-containing heterocycles by intramolecular cyclizations involving N-functionalized phosphinecarboxamides.

    PubMed

    Robinson, Thomas P; Goicoechea, Jose M

    2015-04-07

    We report that the 2-phosphaethynolate anion (PCO(-)) reacts with propargylamines in the presence of a proton source to afford novel N-derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five- and six-membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5-exo-dig or 6-endo-dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus-containing heterocylic systems that are closely related to known organic molecules with interesting bio-active properties.

  11. [6-endo-trig mode cyclization to a hydrindanone using samarium (II) iodide].

    PubMed

    Sono, Masakazu

    2003-08-01

    Samarium (II) iodide has been employed to promote the vinylogous pinacol coupling reaction of aldehyde to alpha, beta-unsaturated ketones. The diastereoselectivity of 6-endo-trig mode products was changed by the addition of a proton source and/or HMPA and by the reaction temperature. The stereochemistry of the hydrindanone was controlled by the coordinated samarium species, resulting in the cis-orientation in respect of the hydroxyl group at C-4 and the juncture proton at C-3a under mild reaction conditions. Coronafacic acid has been synthesized from a hydrindanone prepared by the cyclization reaction of the enone-aldehyde with samarium (II) iodide.

  12. Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

    PubMed Central

    Szwalbe, Agnieszka J.; Mulholland, Nicholas P.; Vincent, Jason L.; Bailey, Andrew M.; Willis, Christine L.; Simpson, Thomas J.

    2016-01-01

    Abstract Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9‐membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate‐processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine‐binding proteins. PMID:27099957

  13. Stereocontrolled synthesis of rosuvastatin calcium via iodine chloride-induced intramolecular cyclization.

    PubMed

    Xiong, Fangjun; Wang, Haifeng; Yan, Lingjie; Han, Sheng; Tao, Yuan; Wu, Yan; Chen, Fener

    2016-01-28

    A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intramolecular cyclization of chiral homoallylic carbonate to deliver the C6-formyl statin side chain with a syn-1,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. Moreover, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pitavastatin calcium and atorvastatin calcium and their related analogs.

  14. Catalysis and chemodivergence in the interrupted, formal homo-Nazarov cyclization using allylsilanes.

    PubMed

    Shenje, Raynold; Williams, Corey W; Francois, Katherine M; France, Stefan

    2014-12-19

    A chemodivergent, Lewis acid catalyzed allylsilane interrupted formal homo-Nazarov cyclization is disclosed. With catalytic amounts of SnCl4 and in the presence of allyltrimethylsilane, a formal Hosomi-Sakurai-type allylation of the oxyallyl cation intermediate is observed. A variety of functionalized donor-acceptor cyclopropanes and allylsilanes were shown to be amenable to the reaction transformation and the allyl products were formed in up to 92% yield. Under dilute reaction conditions with stoichiometric SnCl4 and at reduced temperatures, an unusual formal [3 + 2]-cycloaddition between the allylsilane and the oxyallyl cation occurred to give hexahydrobenzofuran products in up to 69% yield.

  15. The polysiloxane cyclization equilibrium constant: a theoretical focus on small and intermediate size rings.

    PubMed

    Madeleine-Perdrillat, Claire; Delor-Jestin, Florence; de Sainte Claire, Pascal

    2014-01-09

    The nonlinear dependence of polysiloxane cyclization constants (log(K(x))) with ring size (log(x)) is explained by a thermodynamic model that treats specific torsional modes of the macromolecular chains with a classical coupled hindered rotor model. Several parameters such as the dependence of the internal rotation kinetic energy matrix with geometry, the effect of potential energy hindrance, anharmonicity, and the couplings between internal rotors were investigated. This behavior arises from the competing effects of local molecular entropy that is mainly driven by the intrinsic transformation of vibrations in small cycles into hindered rotations in larger cycles and configurational entropy.

  16. New strategies for cyclization and bicyclization of oligonucleotides by click chemistry assisted by microwaves.

    PubMed

    Lietard, Jory; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, François

    2008-01-04

    The synthesis of cyclic, branched, and bicyclic oligonucleotides was performed by copper-catalyzed azide-alkyne cycloaddition assisted by microwaves in solution and on solid support. For that purpose, new phosphoramidite building blocks and new solid supports were designed to introduce alkyne and bromo functions into the same oligonucleotide by solid-phase synthesis on a DNA synthesizer. The bromine atom was then substituted by sodium azide to yield azide oligonucleotides. Cyclizations were found to be more efficient in solution than on solid support. This method allowed the efficient preparation of cyclic (6- to 20-mers), branched (with one or two dangling sequences), and bicyclic (2 x 10-mers) oligonucleotides.

  17. The direct oxidative diene cyclization and related reactions in natural product synthesis

    PubMed Central

    2016-01-01

    Summary The direct oxidative cyclization of 1,5-dienes is a valuable synthetic method for the (dia)stereoselective preparation of substituted tetrahydrofurans. Closely related reactions start from 5,6-dihydroxy or 5-hydroxyalkenes to generate similar products in a mechanistically analogous manner. After a brief overview on the history of this group of transformations and a survey on mechanistic and stereochemical aspects, this review article provides a summary on applications in natural product synthesis. Moreover, current limitations and future directions in this area of chemistry are discussed. PMID:27829917

  18. Octupolar (C3 and S4) Symmetric Cyclized Indole Derivatives: Syntheses, Structures, and NLO Properties.

    PubMed

    Wang, Lei; Fang, Qi; Lu, Qing; Zhang, Shao-jun; Jin, Ying-ying; Liu, Zhi-qiang

    2015-09-04

    Several cyclized indole derivatives have been synthesized, and their structures been determined. The C3-symmetric single-chiral N-phenyltriindole (Tr-Ph3) crystallized in the P1 space group, and the S4-symmetric saddle-like tetraindole (TTr) crystallized in the I4̅ space group. The Tr-Ph3 and TTr crystals exhibit remarkable powder SHG intensities 5 and 11 times that of KH2PO4 (KDP), respectively. TTr is a useful octupolar core to build S4-symmetric molecules and crystals for second-NLO materials.

  19. 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.

  20. Synthesis of functionalized indole- and benzo-fused heterocyclic derivatives through anionic benzyne cyclization.

    PubMed

    Barluenga, José; Fañanás, Francisco J; Sanz, Roberto; Fernández, Yolanda

    2002-05-03

    The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.

  1. Controlling both ground- and excited-state thermal barriers to Bergman cyclization with alkyne termini substitution.

    PubMed

    Nath, Mahendra; Pink, Maren; Zaleski, Jeffrey M

    2005-01-19

    The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c-e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a-d undergo zinc insertion upon treatment with Zn(OAc)2.2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a-d) in 70-92% yields. Thermal Bergman cyclization of 1a-e and 2a-d was studied in chlorobenzene and approximately 35-fold 1,4-cyclohexadiene at 120-210 degrees C. Compounds 1b and 2b with R = H react at lower temperature (120 degrees C) and produce cyclized products 3b and 4b in higher yields (65-70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the -TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 degrees C in chlorobenzene/CHD for 24 h. Photolysis (at lambda >/= 395 nm) of 1b and 2b at 10 degrees C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 degrees C in the dark. Unlike thermolysis at 125 degrees C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c: 5%; 4c: 8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 degrees C with lambda >/= 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the

  2. Approach to Merosesquiterpenes via Lewis Acid Catalyzed Nazarov-Type Cyclization: Total Synthesis of Akaol A.

    PubMed

    Kakde, Badrinath N; Kumar, Nivesh; Mondal, Pradip Kumar; Bisai, Alakesh

    2016-04-15

    A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)2 and Bi(OTf)3 in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine sesquiterpene quinol, akaol A (1a).

  3. Stereospecific Decarboxylative Nazarov Cyclization Mediated by Carbon Dioxide for the Preparation of Highly Substituted 2-Cyclopentenones.

    PubMed

    Komatsuki, Keiichi; Sadamitsu, Yuta; Sekine, Kohei; Saito, Kodai; Yamada, Tohru

    2017-09-11

    Highly substituted 2-cyclopentenones were stereospecifically and regioselectively constructed with high catalytic efficiency through Lewis-acid catalyzed decarboxylative Nazarov cyclization of the cyclic carbonate derivative, which is prepared by reacting the propargyl alcohol with carbon dioxide in the presence of a silver catalyst. The stereochemistry of the 2-cyclopentenone is strictly controlled by the geometry of the alkene in the starting material. This method is applicable for various substrates. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Catalytic Asymmetric Nazarov Cyclization of Heteroaryl Vinyl Ketones through a Crystallographically Defined Chiral Dinuclear Nickel Complex.

    PubMed

    Takeda, Takuya; Harada, Shinji; Nishida, Atsushi

    2015-11-06

    A Ni(NTf2)2 and tetradentate bisimino-bisquinoline ligand complex catalyzed the enantioselective Nazarov cyclization of heteroaryl vinyl ketones. An X-ray-quality crystal was obtained from a mixture of the Ni complex and the substrate, which was the dinuclear chiral Ni complex. From information regarding the structure of the complex, the substrate was distorted to form a helical shape, and the carbon atoms involved in bond formation were close to each other. In addition, mechanistic studies revealed that the configuration of the olefin moiety was isomerized before bond formation.

  5. Methanesulfonic acid cataylzed cyclization of 3-arylpropanoic and 4-arylbutanoic acids to 1-indanones and 1-tetralones

    SciTech Connect

    Premasagar, V.; Palaniswamy, V.A.; Eisenbraun, E.J.

    1981-07-03

    Since methanesulfonic acid (MSA), does not cause sulfonation of aromatic rings, it was used at elevated temperatures to prepare 1-indanones and 1-tetralones through cyclization of 3-arylpropanoic and 4-arylbutanoic acids. The twelve ketones which were prepared from MSA-catalyzed cyclization of 3 and 4-aryl substituted carboxylic acids are pesented in a table, along with their yields, time and temperature. Studies under a variety of temperatures, concentrations and reaction times show that 30 min. to 3 hours is needed for cyclization depending on the reactivity of the starting material. The use of neat MSA as a substitute for Friedel-Crafts catalyst was not promising. Trial studies in which m-xylene was treated with acetic acid in the presence of anhydrous MSA at 110/sup 0/C for 3 hours gave low yields of acetylation product (ca. 30%), and gas chromatography analysis of the product showed unreacted m-xylene.

  6. Rotational isomers of N-methyl-N-arylacetamides and their derived enolates: implications for asymmetric Hartwig oxindole cyclizations

    PubMed Central

    Mandel, Jérémie; Pan, Xiaohong; Ben Hay, E.; Geib, Steven J.

    2013-01-01

    The rotational preferences of N-(2-bromo-4,6-dimethylphenyl)-N-methyl 2-phenyl-propanamide were studied as a model of precursors for Hartwig asymmetric oxindole cyclizations. The atropisomers of this compound were separated by flash chromatography, then the enantiomers were resolved and the interconversions of the stereocenter and the N–Ar axis were studied. Under thermal conditions, the axis is very stable. Under the basic conditions of the Hartwig cyclization, both the stere-ocenter and the chiral axis equilibrate via enolate formation. The N–Ar rotation barrier of a 2-phenylacetamide analog was reduced from 31 kcal mol−1 in the precursor to 17 kcal mol−1 in the enolate. Reasons for this dramatic barrier reduction and implications of both N–Ar and amide C–N rotations for Hartwig cyclizations are discussed. PMID:23534372

  7. 7-endo radical cyclizations catalyzed by titanocene(III). Straightforward synthesis of terpenoids with seven-membered carbocycles.

    PubMed

    Justicia, José; Oller-López, Juan L; Campaña, Araceli G; Oltra, J Enrique; Cuerva, Juan M; Buñuel, Elena; Cárdenas, Diego J

    2005-10-26

    We describe a novel procedure for the straightforward synthesis of seven-membered carbocycles via free-radical chemistry, based on titanocene(III)-catalyzed 7-endo-dig and 7-endo-trig cyclizations. This procedure has proved to be useful for the chemical preparation of terpenoids with different skeletons containing cycloheptane rings, including the first total syntheses of dauca-4(11),8-diene (2), barekoxide (3), authentic laukarlaol (81), and a valparane diterpenoid (72), as well as a substantially improved synthesis of karahanaenone (1). We also provide theoretical and experimental evidence in support of a plausible mechanism, which may rationalize the preference for the unusual 7-endo cyclization mode shown by radicals with substitution patterns characteristic of the linalyl, nerolidyl, and geranyl linalyl systems. In light of these chemical findings, we discuss the potential involvement of radical cyclizations in the biosynthesis of some terpenoids containing seven-membered carbocycles.

  8. Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery.

    PubMed

    Reichart, Florian; Horn, Mareike; Neundorf, Ines

    2016-06-01

    In this work we report synthesis and biological evaluation of a cell-penetrating peptide (CPP), that is partly cyclized via a triazole bridge. Recently, beneficious properties have been reported for cyclized peptides concerning their metabolic stability and intracellular uptake. A CPP based on human calcitonin was used in this study, and side chain cyclization was achieved via copper catalyzed alkyne-azide click reaction. Cell viability studies in several cell-lines revealed no cytotoxic effects. Furthermore, efficient uptake in breast cancer MCF-7 cells could be determined. Moreover, preliminary studies using this novel peptide as drug transporter for daunorubicin were performed. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  9. Progress toward the syntheses of (+)-GB 13, (+)-himgaline, and himandridine. new insights into intramolecular imine/enamine aldol cyclizations.

    PubMed

    Evans, David A; Adams, Drew J; Kwan, Eugene E

    2012-05-16

    A full account of our total synthesis of the galbulimima alkaloids GB 13 and himgaline is provided. Using a strategy adapted from the proposed biosynthesis of the GB alkaloid family, a linear precursor underwent successive intramolecular Diels-Alder, Michael, and imine aldol cyclizations to form the polycyclic alkaloid core. We now show that modification of this strategy can also deliver an advanced intermediate en route to the related alkaloid himandridine. The success of the key imine aldol cyclization is acutely sensitive to substrate structure and solvent, including a case in which cyclization was spontaneous in protic solvents. A detailed computational investigation of the course of the reaction closely correlates with, and suggests a rationale for, the observed patterns of imine aldol reactivity.

  10. Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold

    SciTech Connect

    Azoitei, Mihai L.; Correia, Bruno E.; Ban, Yih-En Andrew; Carrico, Chris; Kalyuzhniy, Oleksandr; Chen, Lei; Schroeter, Alexandria; Huang, Po-Ssu; McLellan, Jason S.; Kwong, Peter D.; Baker, David; Strong, Roland K.; Schief, William R.

    2012-02-07

    The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.

  11. Uganda's National Transmission Backbone Infrastructure Project: Technical Challenges and the Way Forward

    NASA Astrophysics Data System (ADS)

    Bulega, T.; Kyeyune, A.; Onek, P.; Sseguya, R.; Mbabazi, D.; Katwiremu, E.

    2011-10-01

    Several publications have identified technical challenges facing Uganda's National Transmission Backbone Infrastructure project. This research addresses the technical limitations of the National Transmission Backbone Infrastructure project, evaluates the goals of the project, and compares the results against the technical capability of the backbone. The findings of the study indicate a bandwidth deficit, which will be addressed by using dense wave division multiplexing repeaters, leasing bandwidth from private companies. Microwave links for redundancy, a Network Operation Center for operation and maintenance, and deployment of wireless interoperability for microwave access as a last-mile solution are also suggested.

  12. Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N–O bond-forming cyclization of 2-azidobenzoic acids

    PubMed Central

    Dzhons, Daria Yu

    2016-01-01

    Summary The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions. PMID:27340478

  13. Biomimetic cationic polyannulation reaction catalyzed by Bi(OTf)3: cyclization of 1,6-dienes, 1,6,10-trienes, and aryl polyenes.

    PubMed

    Godeau, Julien; Olivero, Sandra; Antoniotti, Sylvain; Duñach, Elisabet

    2011-07-01

    Nonactivated trienes and aryltrienes were cyclized into polycyclic compounds in good to excellent yields under bismuth triflate catalysis in a biomimetic fashion. The reaction showed broad applicability and allowed for the formation of functionalized bicyclic to tetracyclic structures from simple precursors in one pot. For some specific substrates, the cyclization was followed by a methyl shift as encountered in terpenoid biosynthesis.

  14. Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N-O bond-forming cyclization of 2-azidobenzoic acids.

    PubMed

    Dzhons, Daria Yu; Budruev, Andrei V

    2016-01-01

    The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.

  15. A Synthetic HIV-1 Subtype C Backbone Generates Comparable PR and RT Resistance Profiles to a Subtype B Backbone in a Recombinant Virus Assay

    PubMed Central

    Nauwelaers, David; Van Houtte, Margriet; Winters, Bart; Steegen, Kim; Van Baelen, Kurt; Chi, Ellen; Zhou, Mimi; Steiner, Derek; Bonesteel, Rachelle; Aston, Colin; Stuyver, Lieven J.

    2011-01-01

    In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT) using In-Fusion reagents. Recombinant viruses (1 to 5 per patient sample) were produced in MT4-eGFP cells where cyto-pathogenic effect (CPE), p24 and Viral Load (VL) were monitored. The resulting HIV-1-C recombinant virus stocks (RVS) were added to MT4-eGFP cells in the presence of serial dilutions of antiretroviral drugs (PI, NNRTI, NRTI) to determine the fold-change in IC50 compared to the IC50 of wild-type HIV-1 virus. Additionally, viral RNA was extracted from the HIV-1-C RVS and the amplified GPRT products were used to generate recombinant virus in a subtype B backbone. Phenotypic resistance profiles in a subtype B and subtype C backbone were compared. The following observations were made: i) functional, infectious HIV-1 subtype C viruses were generated, confirmed by VL and p24 measurements; ii) their rate of infection was slower than viruses generated in the subtype B backbone; iii) they did not produce clear CPE in MT4 cells; and iv) drug resistance profiles generated in both backbones were very similar, including re-sensitizing effects like M184V on AZT. PMID:21629677

  16. Sesquiterpene synthases Cop4 and Cop6 from Coprinus cinereus: catalytic promiscuity and cyclization of farnesyl pyrophosphate geometric isomers.

    PubMed

    Lopez-Gallego, Fernando; Agger, Sean A; Abate-Pella, Daniel; Distefano, Mark D; Schmidt-Dannert, Claudia

    2010-05-17

    Sesquiterpene synthases catalyze with different catalytic fidelity the cyclization of farnesyl pyrophosphate (FPP) into hundreds of known compounds with diverse structures and stereochemistries. Two sesquiterpene synthases, Cop4 and Cop6, were previously isolated from Coprinus cinereus as part of a fungal genome survey. This study investigates the reaction mechanism and catalytic fidelity of the two enzymes. Cyclization of all-trans-FPP ((E,E)-FPP) was compared to the cyclization of the cis-trans isomer of FPP ((Z,E)-FPP) as a surrogate for the secondary cisoid neryl cation intermediate generated by sesquiterpene synthases, which are capable of isomerizing the C2--C3 pi bond of all-trans-FPP. Cop6 is a "high-fidelity" alpha-cuprenene synthase that retains its fidelity under various conditions tested. Cop4 is a catalytically promiscuous enzyme that cyclizes (E,E)-FPP into multiple products, including (-)-germacrene D and cubebol. Changing the pH of the reaction drastically alters the fidelity of Cop4 and makes it a highly selective enzyme. Cyclization of (Z,E)-FPP by Cop4 and Cop6 yields products that are very different from those obtained with (E,E)-FPP. Conversion of (E,E)-FPP proceeds via a (6R)-beta-bisabolyl carbocation in the case of Cop6 and an (E,E)-germacradienyl carbocation in the case of Cop4. However, (Z,E)-FPP is cyclized via a (6S)-beta-bisabolene carbocation by both enzymes. Structural modeling suggests that differences in the active site and the loop that covers the active site of the two enzymes might explain their different catalytic fidelities.

  17. Biosynthesis of monoterpenes: Stereochemistry of the coupled isomerization and cyclization of geranyl pyrophosphate to camphane and isocamphane monoterpenes

    SciTech Connect

    Croteau, R.; Gershenzon, J.; Wheeler, C.J.; Satterwhite, D.M. )

    1990-03-01

    The conversion of geranyl pyrophosphate to (+)-bornyl pyrophosphate and (+)-camphene is considered to proceed by the initial isomerization of the substrate to (-)-(3R)-linalyl pyrophosphate and the subsequent cyclization of this bound intermediate. In the case of (-)-bornyl pyrophosphate and (-)-camphene, isomerization of the substrate to the (+)-(3S)-linalyl intermediate precedes cyclization. The geranyl and linalyl precursors were shown to be mutually competitive substrates (inhibitors) of the relevant cyclization enzymes isolated from Salvia officinalis (sage) and Tanacetum vulgare (tansy) by the mixed substrate analysis method, demonstrating that isomerization and cyclization take place at the same active site. Incubation of partially purified enzyme preparations with (3R)-(1Z-3H)linalyl pyrophosphate plus (1-14C)geranyl pyrophosphate gave rise to double-labeled (+)-bornyl pyrophosphate and (+)-camphene, whereas incubation of enzyme preparations catalyzing the antipodal cyclizations with (3S)-(1Z-3H)-linalyl pyrophosphate plus (1-14C)geranyl pyrophosphate yielded double-labeled (-)-bornyl pyrophosphate and (-)-camphene. Each product was then transformed to the corresponding (+)- or (-)-camphor without change in the 3H:14C isotope ratio, and the location of the tritium label was deduced in each case by stereoselective, base-catalyzed exchange of the exo-alpha-hydrogen of the derived ketone. The finding that the 1Z-3H of the linalyl precursor was positioned at the endo-alpha-hydrogen of the corresponding camphor in all cases, coupled to the previously demonstrated retention of configuration at C1 of the geranyl substrate in these transformations, confirmed the syn-isomerization of geranyl pyrophosphate to linalyl pyrophosphate and the cyclization of the latter via the anti,endo- conformer.

  18. Sesquiterpene synthases Cop4 and Cop6 from Coprinus cinereus: Catalytic promiscuity and cyclization of farnesyl pyrophosphate geometrical isomers

    PubMed Central

    Lopez-Gallego, Fernando; Agger, Sean A.; Pella, Daniel A.; Distefano, Mark D.; Schmidt-Dannert, Claudia

    2010-01-01

    Sesquiterpene synthases catalyze with different catalytic fidelity the cyclization of farnesyl pyrophosphate (FPP) into hundreds of known compounds with diverse structures and stereochemistries. Two sesquiterpene synthases, Cop4 and Cop6, were previously isolated from Coprinus cinereus as part of a fungal genome survey. This study investigates the reaction mechanism and catalytic fidelity of the two enzymes. Cyclization of all-trans-FPP ((E,E)-FPP) was compared to the cyclization of the cis-trans isomer of FPP ((Z,E)-FPP) as a surrogate for the secondary cisoid neryl cation intermediate generated by sesquiterpene synthases capable of isomerizing the C2-C3 π bond of all-trans-FPP. Cop6 is a “high-fidelity” α-cuprenene synthase that retains its fidelity under various conditions tested. Cop4 is a catalytically promiscuous enzyme that cyclizes (E,E)-FPP into multiple products, including (−)-germacrene D and cubebol. Changing the pH of the reaction drastically alters the fidelity of Cop4 and makes it a highly selective enzyme. Cyclization of (Z,E)-FPP by Cop4 and Cop6 yields products that are very different from those obtained with (E,E)-FPP. Conversion of (E,E)-FPP proceeds via a (6R)-β-bisabolyl carbocation in the case of Cop6 and an (E,E)-germacradienyl carbocation in the case of Cop4. However, (Z,E)-FPP is cyclized via a (6S)-β-bisabolene carbocation by both enzymes. Structural modeling suggests that differences in the active site and the loop that covers the active site of the two enzymes may explain their different catalytic fidelities. PMID:20419721

  19. FeCl3-Catalyzed Tandem Prins and Friedel-Crafts Cyclization: A Highly Diastereoselective Route to Polycyclic Ring Structures.

    PubMed

    Ghosh, Arun K; Keyes, Chad; Veitschegger, Anne M

    2014-07-23

    Catalytic FeCl3 in the presence of 4Å molecular sieves has been shown to effect highly diastereoselective tandem Prins and Friedel-Crafts cyclization of substituted (E/Z)-6-phenylhex-3-en-1-ol and a variety of aldehydes to provide a range of polycyclic compounds in good to excellent yields. The reaction of an enantioenriched alcohol with an aldehyde provided the cyclization product without loss of optical activity. Furthermore, a Lewis acid catalyzed ring opening resulted in functionalized tetralin derivatives with multiple chiral centers.

  20. Modular Synthesis of 1,2-Diamine Derivatives via Palladium-Catalyzed Aerobic Oxidative Cyclization of Allylic Sulfamides**

    PubMed Central

    McDonald, Richard I.

    2010-01-01

    Allylic sulfamides undergo efficient aerobic oxidative cyclization at room temperature, mediated by a new Pd catalyst system consisting of 5% Pd(TFA)2/10% DMSO in THF. The synthetic utility of these reactions is enhanced by several features: (1) the sulfamide substrates are accessible in multi-gram scale from the corresponding allylic and primary amines, (2) the cyclic sulfamide products are readily converted to the corresponding 1,2-diamines upon treatment with LiAlH4, and (3) substrates derived from chiral allylic amines cyclize with very high levels of diastereoselectivity. PMID:21132102

  1. Modular Synthesis of 1,2-Diamine Derivatives via Palladium-Catalyzed Aerobic Oxidative Cyclization of Allylic Sulfamides**

    PubMed Central

    McDonald, Richard I.

    2012-01-01

    Allylic sulfamides undergo efficient aerobic oxidative cyclization at room temperature, mediated by a new Pd catalyst system consisting of 5% Pd(TFA)2/10% DMSO in THF. The synthetic utility of these reactions is enhanced by several features: (1) the sulfamide substrates are accessible in multi-gram scale from the corresponding allylic and primary amines, (2) the cyclic sulfamide products are readily converted to the corresponding 1,2-diamines upon treatment with LiAlH4, and (3) substrates derived from chiral allylic amines cyclize with very high levels of diastereoselectivity. PMID:20583013

  2. Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2'-Prins Cyclization.

    PubMed

    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 SN2'-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 SN2' reaction as a preliminary step in the Prins cyclization.

  3. Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to α-(Hetero)aryl Cyclohexanones.

    PubMed

    Williams, Corey W; Shenje, Raynold; France, Stefan

    2016-09-16

    The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov cyclization have been disclosed. Using SnCl4 as the catalyst, alkenyl cyclopropyl ketones undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 12:1. Regiospecific arylation occurs at the α-carbon of the oxyallyl cation due to polarization caused by the ester group.

  4. Synthesis of tri-, tetra-, and pentacarbonyl derivatives via ozonolysis of 1,4-dienes and cyclization to polyaromatic systems.

    PubMed

    Kersten, Laura; Harms, Klaus; Hilt, Gerhard

    2014-12-05

    The aim of this work was the synthesis of polyaromatic systems by cyclization of β-polycarbonyls. Useful synthons for β-polycarbonyl derivatives are branched 1,4-dienes generated by cobalt-catalyzed hydrovinylation of terminal alkenes and 2,3-dimethyl-1,3-butadiene. Thus, a series of tri-, tetra-, and pentacarbonyl synthons was successfully synthesized. Subsequently, these synthons were examined in an ozonolysis/cyclization reaction sequence. Polyaromatic derivatives were obtained in good yields and the method was applied in the synthesis of the natural product Kwanzoquinone A.

  5. The Development of a Palladium-Catalyzed Tandem Addition/Cyclization for Direct Construction of Indole Skeletons.

    PubMed

    Yu, Shuling; Qi, Linjun; Hu, Kun; Gong, Julin; Cheng, Tianxing; Wang, Qingzong; Chen, Jiuxi; Wu, Huayue

    2017-03-13

    A palladium-catalyzed tandem addition/cyclization of 2-(2-aminoaryl)acetonitriles with arylboronic acids has been developed for the first time, achieving a new strategy for direct construction of indole skeletons. This system shows good functional group tolerance and remarkable chemoselectivity. Especially, the halogen (e.g. bromo and iodo) substituents are amenable for further synthetic elaborations thereby broadening the diversity of the products. Preliminary mechanistic experiments indicate that this transformation involves sequential nucleophilic addition followed by an intramolecular cyclization.

  6. Synthetic applications of the nickel-catalyzed cyclization of alkynes combined with addition reactions in a domino process.

    PubMed

    Durandetti, Muriel; Hardou, Lucie; Lhermet, Rudy; Rouen, Mathieu; Maddaluno, Jacques

    2011-11-04

    Carbonickelations of alkynes and functionalization of the resulting vinylnickel moiety have been performed efficiently in a nickel-catalyzed domino cyclization-condensation process. This reaction, which does not require the preparation of any other organometallic reagent, proceeds only by exo-dig cyclization. This convenient and mild method constitutes a one-pot synthesis of substituted dihydrobenzofurans, chromans, isochromans, indoles, or indanes. Theses valuable products are generally obtained in good yields and high stereoselectivity. They are shown to be useful synthons for rapid access to functionalized polycyclic skeletons. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Synthesis of polyhydroxylated pyrrolidines from sugar-derived bromonitriles through a cascade addition of allylmagnesium bromide/cyclization/reduction.

    PubMed

    Malik, Michał; Jarosz, Sławomir

    2016-02-07

    The synthesis of polyhydroxylated 2-allylpyrrolidines from sugar-derived bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/reduction with Zn(BH4)2 is described. The stereochemical course of the reduction step is rationalized. Two of the obtained compounds are transformed into stereoisomers of naturally-occurring iminosugar (+)-lentiginosine. In an alternative approach, 2,2-diallylpyrrolidines are obtained from bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/addition of another equivalent of allylmagnesium bromide.

  8. Regiocontrolled intramolecular cyclizations of carboxylic acids to carbon-carbon triple bonds promoted by acid or base catalyst.

    PubMed

    Uchiyama, Masanobu; Ozawa, Hiroki; Takuma, Kazuya; Matsumoto, Yotaro; Yonehara, Mitsuhiro; Hiroya, Kou; Sakamoto, Takao

    2006-11-23

    We systematically investigated, for the first time, the relationship between regioselectivity and acid/base effects in the cyclization reactions between carboxylic acids and carbon-carbon triple bonds. We found novel acid- and base-promoted cyclizations to selectively give isocoumarin or pyran-2(2H)-one and phthalide or furan-2(5H)-one skeletons, respectively, and established a catalytic version of regioselective heterocyclic ring synthesis. Density functional theory calculations and application to a short route to thunberginol A were also described. [reaction: see text].

  9. Stereospecific Synthesis of 2-Iminothiazolidines via Domino Ring-Opening Cyclization of Activated Aziridines with Aryl- and Alkyl Isothiocyanates.

    PubMed

    Bhattacharyya, Aditya; Kavitha, C V; Ghorai, Manas K

    2016-08-05

    Lewis acid catalyzed domino ring-opening cyclization of activated aziridines with aryl and alkyl isothiocyanates has been accomplished leading to the formation of a wide variety of highly substituted and functionalized 2-iminothiazolidines with excellent diastereo- and enantiospecificity (de, ee up to >99%). The reaction proceeds via a Lewis acid catalyzed SN2-type ring-opening of the activated aziridine followed by a concomitant 5-exo-dig cyclization in a domino fashion to furnish the 2-iminothiazolidine derivative in excellent yields (up to 99%).

  10. Lewis Acid Induced Switch of Torquoselectivity in the Nazarov Cyclization of Activated Dienones Bearing a Chiral Sulfoxide.

    PubMed

    Grenet, Erwann; Martínez, Jean; Salom-Roig, Xavier J

    2016-11-14

    A Nazarov cyclization of activated dienones bearing a dihydropyran as an electron-donating group (EDG) and a chiral sulfoxide group as an electron-withdrawing group (EWG) and chiral inductor is described. The direction of the torquoselectivity depends highly on the nature of the Lewis acid promoter. This diastereodivergent strategy furnishes both trans stereoisomers from a common precursor. The potential of the Nazarov cyclization products was highlighted by further synthetic elaboration. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Modeling 15N NMR chemical shift changes in protein backbone with pressure

    NASA Astrophysics Data System (ADS)

    La Penna, Giovanni; Mori, Yoshiharu; Kitahara, Ryo; Akasaka, Kazuyuki; Okamoto, Yuko

    2016-08-01

    Nitrogen chemical shift is a useful parameter for determining the backbone three-dimensional structure of proteins. Empirical models for fast calculation of N chemical shift are improving their reliability, but there are subtle effects that cannot be easily interpreted. Among these, the effects of slight changes in hydrogen bonds, both intramolecular and with water molecules in the solvent, are particularly difficult to predict. On the other hand, these hydrogen bonds are sensitive to changes in protein environment. In this work, the change of N chemical shift with pressure for backbone segments in the protein ubiquitin is correlated with the change in the population of hydrogen bonds involving the backbone amide group. The different extent of interaction of protein backbone with the water molecules in the solvent is put in evidence.

  12. The radical cationic repair pathway of cyclobutane pyrimidine dimer: the effect of sugar-phosphate backbone.

    PubMed

    Ebrahimi, Ali; Habibi-Khorassani, Mostafa; Shahraki, Asiyeh

    2013-01-01

    Radical cationic repair process of cis-syn thymine dimer has been investigated when (1) sugar-phosphate backbones were substituted by hydrogen atoms, (2) phosphate group was substituted by two hydrogen atoms each on a sugar ring and (3) sugar-phosphate backbone was taken into account. The effect of the interactions between N1 and N1' lone pairs and the C6-C6' antibonding orbital are the most important evidences for the cleavage of the C6-C6' bond in the first step of radical cationic repair mechanism in the absence of the sugar-phosphate backbone. The impact of the N1 and N1' lone pairs on the C6-C6' bond cleavage decreases and the energy barrier of the cleavage of that bond significantly increases in the presence of the deoxynucleoside sugars and the sugar-phosphate backbone. © 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.

  13. A comprehensive library of blocked dipeptides reveals intrinsic backbone conformational propensities of unfolded proteins.

    PubMed

    Oh, Kwang-Im; Lee, Kyung-Koo; Park, Eun-Kyung; Jung, Youngae; Hwang, Geum-Sook; Cho, Minhaeng

    2012-04-01

    Despite prolonged scientific efforts to elucidate the intrinsic peptide backbone preferences of amino-acids based on understanding of intermolecular forces, many open questions remain, particularly concerning neighboring peptide interaction effects on the backbone conformational distribution of short peptides and unfolded proteins. Here, we show that spectroscopic studies of a complete library of 400 dipeptides reveal that, irrespective of side-chain properties, the backbone conformation distribution is narrow and they adopt polyproline II and β-strand, indicating the importance of backbone peptide solvation and electronic effects. By directly comparing the dipeptide circular dichroism and NMR results with those of unfolded proteins, the comprehensive dipeptides form a complete set of structural motifs of unfolded proteins. We thus anticipate that the present dipeptide library with spectroscopic data can serve as a useful database for understanding the nature of unfolded protein structures and for further refinements of molecular mechanical parameters. Copyright © 2011 Wiley Periodicals, Inc.

  14. Increasing Sequence Diversity with Flexible Backbone Protein Design: The Complete Redesign of a Protein Hydrophobic Core

    SciTech Connect

    Murphy, Grant S.; Mills, Jeffrey L.; Miley, Michael J.; Machius, Mischa; Szyperski, Thomas; Kuhlman, Brian

    2015-10-15

    Protein design tests our understanding of protein stability and structure. Successful design methods should allow the exploration of sequence space not found in nature. However, when redesigning naturally occurring protein structures, most fixed backbone design algorithms return amino acid sequences that share strong sequence identity with wild-type sequences, especially in the protein core. This behavior places a restriction on functional space that can be explored and is not consistent with observations from nature, where sequences of low identity have similar structures. Here, we allow backbone flexibility during design to mutate every position in the core (38 residues) of a four-helix bundle protein. Only small perturbations to the backbone, 12 {angstrom}, were needed to entirely mutate the core. The redesigned protein, DRNN, is exceptionally stable (melting point >140C). An NMR and X-ray crystal structure show that the side chains and backbone were accurately modeled (all-atom RMSD = 1.3 {angstrom}).

  15. Modeling (15)N NMR chemical shift changes in protein backbone with pressure.

    PubMed

    La Penna, Giovanni; Mori, Yoshiharu; Kitahara, Ryo; Akasaka, Kazuyuki; Okamoto, Yuko

    2016-08-28

    Nitrogen chemical shift is a useful parameter for determining the backbone three-dimensional structure of proteins. Empirical models for fast calculation of N chemical shift are improving their reliability, but there are subtle effects that cannot be easily interpreted. Among these, the effects of slight changes in hydrogen bonds, both intramolecular and with water molecules in the solvent, are particularly difficult to predict. On the other hand, these hydrogen bonds are sensitive to changes in protein environment. In this work, the change of N chemical shift with pressure for backbone segments in the protein ubiquitin is correlated with the change in the population of hydrogen bonds involving the backbone amide group. The different extent of interaction of protein backbone with the water molecules in the solvent is put in evidence.

  16. Enzyme-Like Catalysis of the Nazarov Cyclization by Supramolecular Encapsulation

    SciTech Connect

    Hastings, Courtney; Pluth, Michael; Bergman, Robert; Raymond, Kenneth

    2010-03-29

    A primary goal in the design and synthesis of molecular hosts has been the selective recognition and binding of a variety of guests using non-covalent interactions. Supramolecular catalysis, which is the application of such hosts towards catalysis, has much in common with many enzymatic reactions, chiefly the use of both spatially appropriate binding pockets and precisely oriented functional groups to recognize and activate specific substrate molecules. Although there are now many examples which demonstrate how selective encapsulation in a host cavity can enhance the reactivity of a bound guest, all have failed to reach the degree of increased reactivity typical of enzymes. We now report the catalysis of the Nazarov cyclization by a self-assembled coordination cage, a carbon-carbon bond-forming reaction which proceeds under mild, aqueous conditions. The acceleration in this system is over a million-fold, and represents the first example of supramolecular catalysis that achieves the level of rate enhancement comparable to that observed in several enzymes. We explain the unprecedented degree of rate increase as due to the combination of (a) preorganization of the encapsulated substrate molecule, (b) stabilization of the transition state of the cyclization by constrictive binding, and (c) increase in the basicity of the complexed alcohol functionality.

  17. Stabilization of a binary protein complex by intein-mediated cyclization.

    PubMed

    Jeffries, Cy M; Graham, Stephen C; Stokes, Philippa H; Collyer, Charles A; Guss, J Mitchell; Matthews, Jacqueline M

    2006-11-01

    The study of protein-protein interactions can be hampered by the instability of one or more of the protein complex components. In this study, we showed that intein-mediated cyclization can be used to engineer an artificial intramolecular cyclic protein complex between two interacting proteins: the largely unstable LIM-only protein 4 (LMO4) and an unstructured domain of LIM domain binding protein 1 (ldb1). The X-ray structure of the cyclic complex is identical to noncyclized versions of the complex. Chemical and thermal denaturation assays using intrinsic tryptophan fluorescence and dynamic light scattering were used to compare the relative stabilities of the cyclized complex, the intermolecular (or free) complex, and two linear versions of the intramolecular complex (in which the interacting domains of LMO4 and ldb1 were fused, via a flexible linker, in either orientation). In terms of resistance to denaturation, the cyclic complex is the most stable variant and the intermolecular complex is the least stable; however, the two linear intramolecular variants show significant differences in stability. These differences appear to be related to the relative contact order (the average distance in sequence between residues that make contacts within a structure) of key binding residues at the interface of the two proteins. Thus, the restriction of the more stable component of a complex may enhance stability to a greater extent than restraining less stable components.

  18. Positional effects of click cyclization on β-hairpin structure, stability, and function†

    PubMed Central

    Park, Jessica H.; Waters, Marcey L.

    2014-01-01

    The use of the copper (I)-assisted azide-alkyne cycloaddition (CuAAC, or “click” reaction) as a method of β-hairpin stabilization was investigated at several different positions to determine the impact on hairpin structure and function, including hydrogen bonded sites, non-hydrogen bonded sites, and at the peptide termini. The role of the turn sequence in the peptide and the chain length of the azied were also investigated. It was determined that the CuAAC reaction was a suitable method for locking in β-hairpin structure in peptides possessing either the type I’ turn, VNGO and the type II’ turn, VpGO. Moreover, all cyclic variants exhibited improved thermal stability and resistance to proteolysis as compared to the non-cyclic peptides, regardless of the position in the strand. Additionally, the function of the CuAAC cyclized peptides was not altered as exhibited by similar binding affinities for ATP as the WKWK peptide. These studies provided a comprehensive method for CuAAC cyclization of β-hairpin peptides, which could further be utilized in the inhibition of protein-protein and protein-nucleic acid interactions. PMID:23064223

  19. Thermally Induced Self-Assembly and Cyclization of l-Leucyl-l-Leucine in Solid State.

    PubMed

    Ziganshin, Marat A; Safiullina, Aisylu S; Gerasimov, Alexander V; Ziganshina, Sufia A; Klimovitskii, Alexander E; Khayarov, Khasan R; Gorbatchuk, Valery V

    2017-09-14

    Thermal treatment of oligopeptides is one of the methods for synthesis of organic nanostructures. However, heating may lead not only to self-assembly of the initial molecules, but also to chemical reactions resulting in the formation of new unexpected nanostructures or change in the properties of the existing ones. In the present work, the reaction of cyclization of dipeptide l-leucyl-l-leucine in solid state under heating was studied. The change in morphology of dipeptide thin film and formation of nanostructures after heating was visualized using atomic force microscopy. This method also was used for demonstration of differences in self-assembly of linear and cyclic dipeptides. The chemical structure of reaction product was characterized by NMR spectrometry, FTIR spectroscopy and GC-MS analysis. Kinetic parameters of cyclization were estimated within the approaches of the nonisothermal kinetics ("model-free" kinetics and linear regression methods for detection of topochemical equation). The results of present work are useful for explanation the changes in the properties of nanostructures based on short-chain oligopeptides, notably leucyl-leucine, after thermal treatment, as well as for the synthesis of cyclic oligopeptides.

  20. Origins of large rate enhancements in the Nazarov cyclization catalyzed by supramolecular encapsulation.

    PubMed

    Hastings, Courtney J; Bergman, Robert G; Raymond, Kenneth N

    2014-04-01

    The self-assembled supramolecular host [Ga4L6](12-) (1; L=N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene) catalyzes the Nazarov cyclization of 1,3-pentadienols with extremely high levels of efficiency. The catalyzed reaction proceeds at a rate over a million times faster than that of the background reaction, an increase comparable to those observed in some enzymatic systems. A detailed study was conducted to elucidate the reaction mechanism of both the catalyzed and uncatalyzed Nazarov cyclization of pentadienols. Kinetic analysis and (18)O-exchange experiments implicate a mechanism, in which encapsulation, protonation, and water loss from substrate are reversible, followed by irreversible electrocyclization. Although electrocyclization is rate determining in the uncatalyzed reaction, the barrier for water loss and for electrocyclization are nearly equal in the assembly-catalyzed reaction. Analysis of the energetics of the catalyzed and uncatalyzed reaction revealed that transition-state stabilization contributes significantly to the dramatically enhanced rate of the catalyzed reaction. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. An exhaustive survey of regular peptide conformations using a new metric for backbone handedness (h)

    PubMed Central

    2017-01-01

    The Ramachandran plot is important to structural biology as it describes a peptide backbone in the context of its dominant degrees of freedom—the backbone dihedral angles φ and ψ (Ramachandran, Ramakrishnan & Sasisekharan, 1963). Since its introduction, the Ramachandran plot has been a crucial tool to characterize protein backbone features. However, the conformation or twist of a backbone as a function of φ and ψ has not been completely described for both cis and trans backbones. Additionally, little intuitive understanding is available about a peptide’s conformation simply from knowing the φ and ψ values of a peptide (e.g., is the regular peptide defined by φ = ψ =  − 100°  left-handed or right-handed?). This report provides a new metric for backbone handedness (h) based on interpreting a peptide backbone as a helix with axial displacement d and angular displacement θ, both of which are derived from a peptide backbone’s internal coordinates, especially dihedral angles φ, ψ and ω. In particular, h equals sin(θ)d∕|d|, with range [−1, 1] and negative (or positive) values indicating left(or right)-handedness. The metric h is used to characterize the handedness of every region of the Ramachandran plot for both cis (ω = 0°) and trans (ω = 180°) backbones, which provides the first exhaustive survey of twist handedness in Ramachandran (φ, ψ) space. These maps fill in the ‘dead space’ within the Ramachandran plot, which are regions that are not commonly accessed by structured proteins, but which may be accessible to intrinsically disordered proteins, short peptide fragments, and protein mimics such as peptoids. Finally, building on the work of (Zacharias & Knapp, 2013), this report presents a new plot based on d and θ that serves as a universal and intuitive alternative to the Ramachandran plot. The universality arises from the fact that the co-inhabitants of such a plot include every possible peptide backbone including cis

  2. A simple model of backbone flexibility improves modeling of side-chain conformational variability.

    PubMed

    Friedland, Gregory D; Linares, Anthony J; Smith, Colin A; Kortemme, Tanja

    2008-07-18

    The considerable flexibility of side-chains in folded proteins is important for protein stability and function, and may have a role in mediating allosteric interactions. While sampling side-chain degrees of freedom has been an integral part of several successful computational protein design methods, the predictions of these approaches have not been directly compared to experimental measurements of side-chain motional amplitudes. In addition, protein design methods frequently keep the backbone fixed, an approximation that may substantially limit the ability to accurately model side-chain flexibility. Here, we describe a Monte Carlo approach to modeling side-chain conformational variability and validate our method against a large dataset of methyl relaxation order parameters derived from nuclear magnetic resonance (NMR) experiments (17 proteins and a total of 530 data points). We also evaluate a model of backbone flexibility based on Backrub motions, a type of conformational change frequently observed in ultra-high-resolution X-ray structures that accounts for correlated side-chain backbone movements. The fixed-backbone model performs reasonably well with an overall rmsd between computed and predicted side-chain order parameters of 0.26. Notably, including backbone flexibility leads to significant improvements in modeling side-chain order parameters for ten of the 17 proteins in the set. Greater accuracy of the flexible backbone model results from both increases and decreases in side-chain flexibility relative to the fixed-backbone model. This simple flexible-backbone model should be useful for a variety of protein design applications, including improved modeling of protein-protein interactions, design of proteins with desired flexibility or rigidity, and prediction of correlated motions within proteins.

  3. Transition-metal-free synthesis of phenanthridinones from biaryl-2-oxamic acid under radical conditions.

    PubMed

    Yuan, Ming; Chen, Li; Wang, Junwei; Chen, Shenjie; Wang, Kongchao; Xue, Yongbo; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui

    2015-01-16

    Na2S2O8-promoted decarboxylative cyclization of biaryl-2-oxamic acid for phenanthridinones has been developed. This work illustrates the first example of intramolecular decarboxylative amidation of unactivated arene under transition-metal-free conditions. Additionally, this approach provides an efficient and economical method to access biologically interesting phenanthridinones, an important structure motif in many natural products.

  4. AbDesign: an algorithm for combinatorial backbone design guided by natural conformations and sequences

    PubMed Central

    Lapidoth, Gideon D.; Baran, Dror; Pszolla, Gabriele M.; Norn, Christoffer; Alon, Assaf; Tyka, Michael D.; Fleishman, Sarel J.

    2016-01-01

    Computational design of protein function has made substantial progress, generating new enzymes, binders, inhibitors, and nanomaterials not previously seen in nature. However, the ability to design new protein backbones for function – essential to exert control over all polypeptide degrees of freedom – remains a critical challenge. Most previous attempts to design new backbones computed the mainchain from scratch. Here, instead, we describe a combinatorial backbone and sequence optimization algorithm called AbDesign, which leverages the large number of sequences and experimentally determined molecular structures of antibodies to construct new antibody models, dock them against target surfaces and optimize their sequence and backbone conformation for high stability and binding affinity. We used the algorithm to produce antibody designs that target the same molecular surfaces as nine natural, high-affinity antibodies; in six the backbone conformation at the core of the antibody binding surface is similar to the natural antibody targets, and in several cases sequence and sidechain conformations recapitulate those seen in the natural antibodies. In the case of an anti-lysozyme antibody, designed antibody CDRs at the periphery of the interface, such as L1 and H2, show a greater backbone conformation diversity than the CDRs at the core of the interface, and increase the binding surface area compared to the natural antibody, which could enhance affinity and specificity. PMID:25670500

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

    PubMed

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

    2017-03-20

    A new class of chiral C2-symmetric N-donor pincer ligands, 2,5-bis(2-oxazolinyldimethylmethyl)pyrroles (PdmBox)H, was synthesized starting from the readily available ethyl 2,2-dimethyl-3-oxobutanoate (1). The synthesis of the ligand backbone was achieved by oxidative enole coupling with CuC12 followed by Paal-Knorr-type pyrrole synthesis. The corresponding protioligands ((R)PdmBox)H (R = iPr: 5a; Ph: 5b) were obtained by condensation with amino alcohols and subsequent zinc-catalyzed cyclization. Reaction of the lithiated ligands with [NiCl2(dme)] yielded the corresponding square-planar nickel(II) complexes [((R)PdmBox)NiCl] (6a/b). Salt metathesis of 6a with the corresponding alkali or cesium salts in acetone led to the formation of air- and moisture-stable [((iPr)PdmBox)NiX] (X = F (7), X = Br (8), X = I (9), X = N3 (10), X = OAc (11). Furthermore, the conversion of [((iPr)PdmBox)NiF] (7) with hydride transfer reagents such as PhSiH3 led to the stable hydrido species [((iPr)PdmBox)NiH] (27), the stoichiometric transformations of which were studied. Treatment of 6a with organometallic reagents such as ZnEt2, PhLi, PhC≡CLi, NsLi, or ((4F)Bn)2Mg(THF)2 gave the corresponding alkyl, alkynyl, or aryl complexes. The availability of the new nonisomerizable PdmBox pincer ligands allowed the comparative study of their ligation to square-planar complexes as helically twisted spectator ligands as opposed to the enforced planar rigidity of their iso-PmBox analogues and the way this influences the reactivity of the Ni complexes.

  6. FeCl3-catalyzed cyclization of α-sulfonamido-allenes with aldehydes--the substituent effect.

    PubMed

    Cheng, Jiajia; Tang, Xinjun; Yu, Yihua; Ma, Shengming

    2012-12-25

    FeCl(3)-catalyzed aza-Prins-cyclization reaction of α-sulfonamido-allenes with aldehydes afforded 1,2,3,6-tetrahydropyridine or 2,5-dihydro-1H-pyrrole derivatives efficiently and highly selectively. The different regioselectivity is probably caused by the stabilizing effect of the phenyl group on the positively charged allylic intermediate.

  7. FeCl3-promoted carboxamidation and cyclization of aryl isonitriles with formamides toward phenanthridine-6-carboxamides.

    PubMed

    Tu, Hai-Yong; Liu, Yu-Rong; Chu, Jing-Jing; Hu, Bo-Lun; Zhang, Xing-Guo

    2014-10-17

    An iron-promoted tandem carboxamidation and cyclization between aryl isonitriles and formamides has been developed. The one-pot strategy can be applied to a wide range of 2-isocyanobiphenyls and formamides with excellent functional group tolerance for the synthesis of phenanthridine-6-carboxamides in moderate to excellent yields.

  8. Cyclizations producing hydrindanones with two methyl groups at the juncture positions mediated by samarium diiodide and electrolysis.

    PubMed

    Sono, Masakazu; Ise, Natsuko; Shoji, Tsutomu; Tori, Motoo

    2012-09-13

    One-electron reductive intramolecular cyclization of enones with ketones or aldehydes mediated by samarium diiodide and electrolysis to afford cis-trimethyl- hydrindanolones. The reactions gave selectivities ranging from 1:1 to 100:0 depending on the conditions.

  9. Asymmetric Synthesis of Tetrahydropyridines via an Organocatalytic One-Pot Multicomponent Michael/Aza-Henry/Cyclization Triple Domino Reaction

    PubMed Central

    2014-01-01

    A low loading of a quinine-derived squaramide efficiently catalyzes the triple-domino Michael/aza-Henry/cyclization reaction between 1,3-dicarbonyl compounds, β-nitroolefins, and aldimines to provide tetrahydropyridines bearing three contiguous stereogenic centers in good yields, excellent enantiomeric excesses, and up to high diastereomeric ratios. PMID:25379786

  10. Catalyst-free intramolecular oxidative cyclization of N-allylbenzamides: a new route to 2,5-substituted oxazoles.

    PubMed

    Zhou, Wei; Xie, Chen; Han, Jianlin; Pan, Yi

    2012-09-21

    A catalyst-free intramolecular oxidative cyclization reaction of N-allylbenzamides has been developed to prepare 2,5-disubstituted oxazoles with good yields. This reaction gives an efficient synthetic strategy to form an oxazole nucleus directly from easily accessible substrates under temperate conditions.

  11. Radical cation cyclization of 1,5-hexadiene to cyclohexene via the cyclohexane-2,5-diyl radical cation intermediate

    SciTech Connect

    Guo, Q.X.; Qin, X.Z.; Wang, J.T.; Williams, F.

    1988-03-16

    The classical example of a neutral carbon-centered radical cyclization reaction is the regioselective 1,5-ring closure (exocyclization) of the 5-hexenyl radical to the cyclopentylcarbinyl radical. Here the authors report the title reaction, a comparable addition process whereby an ..cap alpha.., omega-diene radical cation reacts by endocyclization and hydrogen shift(s) to produce a cycloolefin radical cation.

  12. Pd-Catalyzed C-H activation/oxidative cyclization of acetanilide with norbornene: concise access to functionalized indolines.

    PubMed

    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.

  13. Synthesis of 3,4-Disubstituted 2H-Benzopyrans Through C-C Bond Formation via Electrophilic Cyclization

    PubMed Central

    Worlikar, Shilpa A.; Kesharwani, Tanay; Yao, Tuanli; Larock, Richard C.

    2008-01-01

    The electrophilic cyclization of substituted propargylic aryl ethers by I2, ICl and PhSeBr produces 3,4-disubstituted 2H-benzopyrans in excellent yields. This methodology results in vinylic halides or selenides under mild reaction conditions, and tolerates a variety of functional groups, including methoxy, alcohol, aldehyde and nitro groups. PMID:17288382

  14. Dearomatization-induced transannular cyclization: synthesis of electron-accepting thiophene-S,S-dioxide-fused biphenylene.

    PubMed

    Fukazawa, Aiko; Oshima, Hiroya; Shimizu, Soji; Kobayashi, Nagao; Yamaguchi, Shigehiro

    2014-06-18

    The transannular cyclization of dehydroannulenes bearing several alkyne moieties in close proximity is a powerful synthetic method for producing polycyclic aromatic hydrocarbons. We report that the reactivity can be switched by the aromaticity of the ring skeletons fused with the dehydroannulene core. Thus, while thiophene-fused bisdehydro[12]annulene 1 was handled as a stable compound in the air at room temperature, the oxidation with m-chloroperbenzoic acid from the aromatic thiophene rings to the nonaromatic thiophene-S,S-dioxides induced the transannular cyclization, even at room temperature, which was completed within 1 day to produce the formal [2 + 2] cycloadduct 3. This is in stark contrast to the fact that the thermal cyclization of 1 itself required heating at 80 °C for 9 days for completion. Experimental and theoretical studies indicate that the oxidation of even one thiophene ring in 1 sufficiently decreases the activation barrier for the transannular cyclization that proceeds through the 8π and 4π electrocyclic reaction sequence. The thiophene-S,S-dioxide-fused biphenylene 3 thus produced exhibits a set of intriguing properties, such as a higher electron affinity (E1/2 = -1.17 V vs Fc and Fc(+)) and a stronger fluorescence (ΦF = 0.20) than the other relevant biphenylene derivatives, which have electron-donating and nonfluorescent characteristics.

  15. Asymmetric Synthesis of Ramariolides A and C through Bimetallic Cascade Cyclization and Z-E Isomerization Reaction.

    PubMed

    Pal, Pratik; Nanda, Samik

    2017-03-03

    A short and flexible asymmetric synthesis of ramariolides A and C was accomplished. A bimetallic catalytic system consisting of Pd-Cu-mediated cascade cyclization, unprecedented Z-E isomerization by a Ru-based metathesis catalyst, and late-stage stereoselective epoxidation are the key steps involved in the synthesis.

  16. Ruthenium-catalyzed aerobic oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes: a new route to isoquinolones.

    PubMed

    Reddy, Mallu Chenna; Manikandan, Rajendran; Jeganmohan, Masilamani

    2013-07-11

    The oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes in the presence of a catalytic amount of [{RuCl2(p-cymene)}2], Cu(OAc)2·H2O and KPF6 in acetic acid under air gave isoquinolones in good to excellent yields.

  17. Importance of cytochromes in cyclization reactions: quantum chemical study on a model reaction of proguanil to cycloguanil.

    PubMed

    Arfeen, Minhajul; Patel, Dhilon S; Abbat, Sheenu; Taxak, Nikhil; Bharatam, Prasad V

    2014-10-30

    Proguanil, an anti-malarial prodrug, undergoes cytochrome P450 catalyzed biotransformation to the pharmacologically active triazine metabolite (cycloguanil), which inhibits plasmodial dihydrofolate reductase. This cyclization is catalyzed by CYP2C19 and many anti-malarial lead compounds are being designed and synthesized to exploit this pathway. Quantum chemical calculations were performed using the model species (Cpd I for active species of cytochrome and N4-isopropyl-N6-methylbiguanide for proguanil) to elucidate the mechanism of the cyclization pathway. The overall reaction involves the loss of a water molecule, and is exothermic by approximately 55 kcal/mol, and involves a barrier of approximately 17 kcal/mol. The plausible reaction pathway involves the initial H-radical abstraction from the isopropyl group by Cpd I, followed by two alternative paths- (i) oxygen rebound to provide hydroxyl derivative and (ii) loss of additional H-radical to yield 1,3,5-triazatriene, which undergoes cyclization. This study helped in understanding the role of the active species of cytochromes in this important cyclization reaction.

  18. SYNTHESIS OF TETRAHYDROPYRAN DERIVATIVES VIA A NOVEL INDIUM TRICHLORIDE MEDIATED CROSS-CYCLIZATION BETWEEN EPOXIDES AND HOMOALLYL ALCOHOLS. (R822668)

    EPA Science Inventory

    Abstract

    A cross-cyclization between epoxides and homoallyl alcohols catalyzed by indium chloride generates tetrahydropyran derivatives in high yields.

    Graphical Abstract


    SYNTHESIS OF TETRAHYDROPYRAN DERIVATIVES VIA A NOVEL INDIUM TRICHLORIDE MEDIATED CROSS-CYCLIZATION BETWEEN EPOXIDES AND HOMOALLYL ALCOHOLS. (R822668)

    EPA Science Inventory

    Abstract

    A cross-cyclization between epoxides and homoallyl alcohols catalyzed by indium chloride generates tetrahydropyran derivatives in high yields.

    Graphical Abstract


    Efficient Nazarov cyclization/Wagner-Meerwein rearrangement terminated by a Cu(II)-promoted oxidation: synthesis of 4-alkylidene cyclopentenones.

    PubMed

    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.

  1. Efficient Nazarov Cyclization/Wagner-Meerwein Rearrangement Terminated by a Cu(II)-Promoted Oxidation: Synthesis of 4-Alkylidene Cyclopentenones

    PubMed Central

    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

  2. Enantioselective Nickel-Catalyzed anti-Carbometallative Cyclizations of Alkynyl Electrophiles Enabled by Reversible Alkenylnickel E/Z Isomerization

    PubMed Central

    2016-01-01

    Nickel-catalyzed additions of arylboronic acids to alkynes, followed by enantioselective cyclizations of the alkenylnickel species onto tethered ketones or enones, are reported. These reactions are reliant upon the formal anti-carbonickelation of the alkyne, which is postulated to occur by the reversible E/Z isomerization of an alkenylnickel species. PMID:27333360

  3. Domino Cyclization of 1,n-Enynes (n = 7, 8, 9) Giving Derivatives of Pyrane, Chromene, Fluorene, Phenanthrene and Dibenzo[7]annulene by Ruthenium Complexes.

    PubMed

    Ma, Hao-Wei; Chen, Pei-Min; Lo, Ji-Xian; Lin, Ying-Chih; Huang, Shou-Ling; Chen, Chi-Ren; Chia, Pi-Yeh

    2016-06-03

    Cyclization of the ether enyne 1 catalyzed by [Ru]NCCH3(+) ([Ru] = Cp(PPh3)2Ru) in CHCl3 generates a diastereomeric mixture of the substituted tetrahydropyran 11. Presumably, formation of an allenylidene complex is followed by a cyclization by nucleophilic addition of the olefinic group to Cγ of the ligand giving a boat-like six-membered ring. The diastereoselectivity is controlled by the 1,3-diaxial interaction. The vinylidene complex 7, a precursor of 11, is obtained from 1 and [Ru]Cl. In a mixture of MeOH/CHCl3, the domino cyclization of 1 further affords 14a, a chromene product catalytically. The second cyclization proceeds via nucleophilic addition of the resulting olefinic unit to Cα of 7. But the ether enyne 3 with a cyclopentyl ring on the olefinic unit undergoes only single cyclization due to steric effect. The propargyl alcohol and the two terminal methyl groups on the olefinic unit shape the cyclization. Thus, similar all-carbon 1,n-enynes (n = 7, 8, 9) 4-6 each with an aromatic linker undergo direct domino cyclization catalyzed by [Ru]NCCH3(+), to give derivatives of tricyclic fluorene, phenanthrene and dibenzo[7]annulene, respectively, with no intermediate observed.

  4. Gas-Phase Nazarov Cyclization of Protonated 2-Methoxy and 2-Hydroxychalcone: An Example of Intramolecular Proton-Transport Catalysis

    PubMed Central

    George, M.; Sebastian, V. S.; Reddy, P. Nagi; Srinivas, R.; Giblin, Daryl; Gross, Michael L.

    2009-01-01

    Upon CA, ESI generated [M + H]+ ions of chalcone (benzalacetophenone) and 3-phenyl-indanone both undergo losses of H2O, CO, and the elements of benzene. CA of the [M + H]+ ions of 2-methoxy and 2-hydroxychalcone, however, prompts instead a dominant loss of ketene. In addition, CA of the [M + H]+ ions of 2-methoxy-β-methylchalcone produces an analogous loss of methylketene instead. Furthermore, the [M + D]+ ion of 2-methoxychalcone upon CA eliminates only unlabeled ketene, and the resultant product, the [M + D - ketene]+ ion, yields only the benzyl-d1 cation upon CA. We propose that the 2-methoxy and 2-hydroxy (ortho) substituents facilitate a Nazarov cyclization to the corresponding protonated 3-aryl-indanones by mediating a critical proton transfer. The resultant protonated indanones then undergo a second proton transport catalysis facilitated by the same ortho substituents producing intermediates that eliminate ketene to yield 2-methoxy- or 2-hydroxyphenyl-phenyl-methylcarbocations, respectively. The basicity of the ortho substituent is important; for example, replacement of the ortho function with a chloro substituent does not provide an efficient catalyst for the proton transports. The Nazarov cyclization must compete with an alternate cyclization, driven by the protonated carbonyl group of the chalcone that results in losses of H2O and CO. The assisted proton transfer mediated by the ortho substituent shifts the competition in favor of the Nazarov cyclization. The proposed mechanisms for cyclization and fragmentation are supported by high-mass resolving power data, tandem mass spectra, deuterium labeling, and molecular orbital calculations. PMID:19230703

  5. Metal Sensing by DNA.

    PubMed

    Zhou, Wenhu; Saran, Runjhun; Liu, Juewen

    2017-06-28

    Metal ions are essential to many chemical, biological, and environmental processes. In the past two decades, many DNA-based metal sensors have emerged. While the main biological role of DNA is to store genetic information, its chemical structure is ideal for metal binding via both the phosphate backbone and nucleobases. DNA is highly stable, cost-effective, easy to modify, and amenable to combinatorial selection. Two main classes of functional DNA were developed for metal sensing: aptamers and DNAzymes. While a few metal binding aptamers are known, it is generally quite difficult to isolate such aptamers. On the other hand, DNAzymes are powerful tools for metal sensing since they are selected based on catalytic activity, thus bypassing the need for metal immobilization. In the last five years, a new surge of development has been made on isolating new metal-sensing DNA sequences. To date, many important metals can be selectively detected by DNA often down to the low parts-per-billion level. Herein, each metal ion and the known DNA sequences for its sensing are reviewed. We focus on the fundamental aspect of metal binding, emphasizing the distinct chemical property of each metal. Instead of reviewing each published sensor, a high-level summary of signaling methods is made as a separate section. In principle, each signaling strategy can be applied to many DNA sequences for designing sensors. Finally, a few specific applications are highlighted, and future research opportunities are discussed.

  6. Cyclization of 1,4-hydroxycarbonyls is not a homogenous gas phase process

    NASA Astrophysics Data System (ADS)

    Dibble, Theodore S.

    2007-10-01

    Previous studies of 1,4-hydroxycarbonyls derived from alkanes have suggested that they can cyclize to saturated furans, which can subsequently eliminate water to form the corresponding dihydrofurans. CBS-QB3 and G3 studies of 5-hydroxy-2-pentanone and 2-hydroxypentanal show that both steps have activation barriers far too large for these reactions to occur as homogenous gas phase reactions. Similar results were obtained in CBS-QB3 studies of the analogous process leading from 2- and 3-methyl-4-hydroxy-2-butenal (species posited to form in the degradation of isoprene) to 3-methylfuran. The latter two processes are much more favorable, thermodynamically, than the formation of dihydrofurans from the saturated 1,4-hydroxycarbonyls.

  7. Tuneable enhancement of the salt and thermal stability of polymeric micelles by cyclized amphiphiles

    PubMed Central

    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

  8. Synergistic effects between Lewis and Brønsted acids: application to the Prins cyclization.

    PubMed

    Breugst, Martin; Grée, René; Houk, K N

    2013-10-04

    Brønsted and Lewis acids can catalyze the Prins cyclization, an efficient method for the synthesis of tetrahydropyrans from homoallylic alcohols and carbonyl compounds. Synergistic effects between weak Brønsted and Lewis acids in these reactions have been analyzed by density functional theory [M06-L/def2-QZVP/IEFPCM(CH2Cl2)//M06-L/6-311+G(2df,2p)]. In order to characterize the reactivities of the employed Lewis acids, methyl anion and hydroxide affinities were determined. On the basis of our calculations, we found that the coordination of Lewis acids to carboxylic and sulfonic acids results in a significant increase in the Brønsted acidities of the latter.

  9. Dissociation or Cyclization: Options for a Triad of Radicals Released from Oxime Carbamates

    PubMed Central

    2013-01-01

    A set of oxime carbamates having N-alkyl and N,N-dialkyl substituents were prepared via carbonyldiimidazole intermediates. It was shown by EPR spectroscopy that they underwent clean homolysis of their N–O bonds upon UV photolysis. During photolysis of acetophenone O-allylcarbamoyl oxime, the corresponding oxazolidin-2-onylmethyl radical was detected by EPR spectroscopy, providing the first evidence that N-monosubstituted carbamoyloxyl radicals can hold their structural integrity. N,N-Disubstituted carbamoyloxyl radicals dissociated rapidly at the lowest accessible temperatures. Above room temperature, both types of oxime carbamate acted as selective new precursors for aminyl and iminyl radicals. Rate parameters were measured for 5-exo cyclization of N-benzyl-N-pent-4-enylaminyl radicals; the rate constant was smaller than for C-centered and O-centered analogues. Oxime carbamates derived from the volatile diethylamine afforded aryliminyl radicals that proved convenient for phenanthridine preparations. PMID:23600463

  10. Palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to a library of tetraphenylenes

    PubMed Central

    Zhu, Chendan; Zhao, Yue; Wang, Di; Sun, Wei-Yin; Shi, Zhuangzhi

    2016-01-01

    Aryl–aryl bond formation constitutes one of the most important subjects in organic synthesis. The recent developments in direct arylation reactions forming aryl–aryl bond have emerged as very attractive alternatives to traditional cross-coupling reactions. Here, we describe a general palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to build a library of tetraphenylenes. This transformation represents one of the very few examples of C-H activation process that involves simultaneous formation of two aryl–aryl bonds. Oxygen plays a vital role by ensuring high reactivity, with air as the promoter furnished the best results. We anticipate this ligand-free and aerobic catalytic system will simplify the synthesis of tetraphenylenes as many of the reported methods involve use of preformed organometallic reagents and will lead to the discovery of highly efficient new direct arylation process. PMID:27629701

  11. A Van Leusen deprotection-cyclization strategy as a fast entry into two imidazoquinoxaline families.

    PubMed

    De Moliner, Fabio; Hulme, Christopher

    2012-10-24

    A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency.

  12. Kinetics of hydrolysis and cyclization of ethyl 2-(aminosulfonyl)benzoate to saccharin.

    PubMed

    Di Loreto, H E; Czarnowski, J; dos Santos Afonso, M

    2002-10-01

    The cyclization of ethyl 2-(aminosulfonyl)benzoate (ASB) to give saccharin was investigated in aqueous solutions at pH between 5.2 and 9.5 and in the temperature range of 296.2-334.2 K. The initial concentration of the reactant was varied between 1.45 x 10(-5) and 3.86 x 10(-4) M. Ultraviolet spectroscopy was used to obtain the kinetic data. The reaction is acid catalyzed and follows pseudo-first-order kinetics. The experimental rate constant, k(obs), increases with temperature and pH. Its dependence on the temperature and pH is well described by: k(obs) = k1 [OH-] = [(2.52 +/- 0.9) x 10(16) exp(-20.2 +/- 1 kcalmol(-1)/RT) s(-1)][OH-] A mechanism is proposed and the half-life of ethyl ASB is calculated.

  13. Asymmetric synthesis of gem-difluoromethylenated linear triquinanes via cascade gem-difluoroalkyl radical cyclization.

    PubMed

    Thaharn, Watcharaporn; Soorukram, Darunee; Kuhakarn, Chutima; Tuchinda, Patoomratana; Pakawatchai, Chaveng; Saithong, Saowanit; Reutrakul, Vichai; Pohmakotr, Manat

    2015-01-16

    An asymmetric synthesis of gem-difluoromethylenated linear triquinanes is described exploiting the synthetic utilities of PhSCF2TMS (5) as a "(•)CF2(-)'' building block. The strategy involves fluoride-catalyzed nucleophilic addition of PhSCF2TMS (5) to chiral ketocyclopentenes 6 to provide silylated adducts 9 or alcohol derivatives 10 and 11. Subsequent cascade radical cyclization of the gem-difluoroalkyl radical generated from silylated adducts 9 or alcohols 10 and 11 afforded gem-difluoromethylenated linear triquinanes 16 as an approximate 1:1 mixture of two diastereomers (16A and 16B). Alternatively, a convenient asymmetric synthesis of gem-difluoromethylenated linear triquinanes 16A can be accomplished by oxidation of 16a (R = H) to provide ketotriquinane 17 followed by a highly stereoselective nucleophilic addition to 17 employing DIBAL, NaBH4, and various Grignard reagents.

  14. Spectral assignments and structural studies of a warfarin derivative stereoselectively formed by tandem cyclization

    NASA Astrophysics Data System (ADS)

    Velayutham Pillai, M.; Rajeswari, K.; Vidhyasagar, T.

    2015-11-01

    The structural elucidation of a Mannich condensation product of rac-Warfarin with benzaldehyde and methyl amine was carried out using IR, Mass, 1H NMR, 13C NMR, 1H-1H COSY, 1H-13C COSY, DEPT-135, HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem cyclization in the presence of methyl amine was observed. The optimized geometry and HOMO-LUMO energy gap along with other important physical parameters were found by Gaussian 09 program using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level of theory. The preferred conformation of the piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the solid state.

  15. Palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to a library of tetraphenylenes

    NASA Astrophysics Data System (ADS)

    Zhu, Chendan; Zhao, Yue; Wang, Di; Sun, Wei-Yin; Shi, Zhuangzhi

    2016-09-01

    Aryl–aryl bond formation constitutes one of the most important subjects in organic synthesis. The recent developments in direct arylation reactions forming aryl–aryl bond have emerged as very attractive alternatives to traditional cross-coupling reactions. Here, we describe a general palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to build a library of tetraphenylenes. This transformation represents one of the very few examples of C-H activation process that involves simultaneous formation of two aryl–aryl bonds. Oxygen plays a vital role by ensuring high reactivity, with air as the promoter furnished the best results. We anticipate this ligand-free and aerobic catalytic system will simplify the synthesis of tetraphenylenes as many of the reported methods involve use of preformed organometallic reagents and will lead to the discovery of highly efficient new direct arylation process.

  16. An exhaustive survey of regular peptide conformations using a new metric for backbone handedness ( h )

    DOE PAGES

    Mannige, Ranjan V.

    2017-05-16

    The Ramachandran plot is important to structural biology as it describes a peptide backbone in the context of its dominant degrees of freedom—the backbone dihedral anglesφandψ(Ramachandran, Ramakrishnan & Sasisekharan, 1963). Since its introduction, the Ramachandran plot has been a crucial tool to characterize protein backbone features. However, the conformation or twist of a backbone as a function ofφandψhas not been completely described for bothcisandtransbackbones. Additionally, little intuitive understanding is available about a peptide’s conformation simply from knowing theφandψvalues of a peptide (e.g., is the regular peptide defined byφ = ψ =  - 100°  left-handed or right-handed?). This report provides a new metric for backbone handednessmore » (h) based on interpreting a peptide backbone as a helix with axial displacementdand angular displacementθ, both of which are derived from a peptide backbone’s internal coordinates, especially dihedral anglesφ,ψandω. In particular,hequals sin(θ)d/d|, with range [-1, 1] and negative (or positive) values indicating left(or right)-handedness. The metrichis used to characterize the handedness of every region of the Ramachandran plot for bothcis(ω = 0°) and trans (ω = 180°) backbones, which provides the first exhaustive survey of twist handedness in Ramachandran (φ,ψ) space. These maps fill in the ‘dead space’ within the Ramachandran plot, which are regions that are not commonly accessed by structured proteins, but which may be accessible to intrinsically disordered proteins, short peptide fragments, and protein mimics such as peptoids. Finally, building on the work of (Zacharias & Knapp, 2013), this report presents a new plot based ondandθthat serves as a universal and intuitive alternative to the Ramachandran plot. The universality arises from the fact that the co-inhabitants of such a plot include every possible peptide backbone includingcisandtransbackbones. The intuitiveness

  17. Aromatic ring strain in arylselenenyl bromides: role in facile synthesis of selenenate esters via intramolecular cyclization.

    PubMed

    Selvakumar, K; Singh, Harkesh B; Butcher, Ray J

    2010-09-10

    The synthesis and reactivity of 2,6-disubstituted arylselenium compounds derived from 2-bromo-5-tert-butylisophthalic acid (43) are described. The syntheses of bis(5-tert-butylisophthalic acid dimethyl ester)diselenide (46) and bis(5-tert-butylisophthalic acid diisopropyl ester)diselenide (47) have been achieved by the reaction of the corresponding ester precursors with disodium diselenide. Reduction of diselenide 46 with lithium aluminum hydride affords 2,2'-bis(5-tert-butylbenzene-1,3-dimethanol)diselenide (53). Diselenides 46 and 47 exhibit intramolecular Se...O interaction. Compound 53 does not show any intramolecular Se...O interaction. The anomalous Se...O nonbonded coordination observed in the single-crystal X-ray structures of compounds 46, 47 and 53 is compared and contrasted. The corresponding selenenyl bromides 54 and 55, derived from the reaction of diselenides 46 and 47 with bromine, are quite stable in the solid state. However, they undergo hydrolysis and subsequent intramolecular cyclization upon heating or after having been kept in solution over a period of time to give the corresponding selenenate esters 56 and 57. The X-ray crystallographic study and density functional theory calculations on 54 at the B3LYP/6-31G(d) level of theory indicate a significant distortion in planarity of the aromatic ring. Glutathione peroxidase-like activities of diselenides 46 and 47 and their selenenate esters 56 and 57 have been studied both by thiophenol and bioassay methods. The very low glutathione peroxidase-like activity of the diselenides (46 and 47) and their selenenate esters (56 and 57) in the thiophenol assay is attributed to the presence of the relatively strong Se...O intramolecular interaction in the selenenyl sulfide intermediates. The interaction retards the catalytic activity through both thiol exchange and an intramolecular cyclization reaction.

  18. Subgraph "backbone" analysis of dynamic brain networks during consciousness and anesthesia.

    PubMed

    Shin, Jeongkyu; Mashour, George A; Ku, Seungwoo; Kim, Seunghwan; Lee, Uncheol

    2013-01-01

    General anesthesia significantly alters brain network connectivity. Graph-theoretical analysis has been used extensively to study static brain networks but may be limited in the study of rapidly changing brain connectivity during induction of or recovery from general anesthesia. Here we introduce a novel method to study the temporal evolution of network modules in the brain. We recorded multichannel electroencephalograms (EEG) from 18 surgical patients who underwent general anesthesia with either propofol (n = 9) or sevoflurane (n = 9). Time series data were used to reconstruct networks; each electroencephalographic channel was defined as a node and correlated activity between the channels was defined as a link. We analyzed the frequency of subgraphs in the network with a defined number of links; subgraphs with a high probability of occurrence were deemed network "backbones." We analyzed the behavior of network backbones across consciousness, anesthetic induction, anesthetic maintenance, and two points of recovery. Constitutive, variable and state-specific backbones were identified across anesthetic state transitions. Brain networks derived from neurophysiologic data can be deconstructed into network backbones that change rapidly across states of consciousness. This technique enabled a granular description of network evolution over time. The concept of network backbones may facilitate graph-theoretical analysis of dynamically changing networks.

  19. Backbone dipoles generate positive potentials in all proteins: origins and implications of the effect.

    PubMed Central

    Gunner, M R; Saleh, M A; Cross, E; ud-Doula, A; Wise, M

    2000-01-01

    Asymmetry in packing the peptide amide dipole results in larger positive than negative regions in proteins of all folding motifs. The average side chain potential in 305 proteins is 109 +/- 30 mV (2. 5 +/- 0.7 kcal/mol/e). Because the backbone has zero net charge, the non-zero potential is unexpected. The larger oxygen at the negative and smaller proton at the positive end of the amide dipole yield positive potentials because: 1) at allowed phi and psi angles residues come off the backbone into the positive end of their own amide dipole, avoiding the large oxygen; and 2) amide dipoles with their carbonyl oxygen surface exposed and amine proton buried make the protein interior more positive. Twice as many amides have their oxygens exposed than their amine protons. The distribution of acidic and basic residues shows the importance of the bias toward positive backbone potentials. Thirty percent of the Asp, Glu, Lys, and Arg are buried. Sixty percent of buried residues are acids, only 40% bases. The positive backbone potential stabilizes ionization of 20% of the acids by >3 pH units (-4.1 kcal/mol). Only 6.5% of the bases are equivalently stabilized by negative regions. The backbone stabilizes bound anions such as phosphates and rarely stabilizes bound cations. PMID:10692303

  20. Complete backbone and DENQ side chain NMR assignments in proteins from a single experiment: implications to structure-function studies.

    PubMed

    Reddy, Jithender G; Hosur, Ramakrishna V

    2014-03-01

    Resonance assignment is the first and the most crucial step in all nuclear magnetic resonance (NMR) investigations on structure-function relationships in biological macromolecules. Often, the assignment exercise has to be repeated several times when specific interactions with ligands, substrates etc., have to be elucidated for understanding the functional mechanisms. While the protein backbone serves to provide a scaffold, the side chains interact directly with the ligands. Such investigations will be greatly facilitated, if there are rapid methods for obtaining exhaustive information with minimum of NMR experimentation. In this context, we present here a pulse sequence which exploits the recently introduced technique of parallel detection of multiple nuclei, e.g. (1)H and (13)C, and results in two 3D-data sets simultaneously. These yield complete backbone resonance assignment ((1)H(N), (15)N, (13)CO, (1)Hα/(13)Cα, and (1)Hβ/(13)Cβ chemical shifts) and side chain assignment of D, E, N and Q residues. Such an exhaustive assignment has the potential of yielding accurate 3D structures using one or more of several algorithms which calculate structures of the molecules very reliably on the basis of NMR chemical shifts alone. The side chain assignments of D, E, N, and Q will be extremely valuable for interaction studies with different ligands; D and E side chains are known to be involved in majority of catalytic activities. Utility of this experiment has been demonstrated with Ca(2+) bound M-crystallin, which contains largely D, E, N and Q residues at the metal binding sites.

  1. A ruthenium(II) complex as turn-on Cu(II) luminescent sensor based on oxidative cyclization mechanism and its application in vivo

    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.

  2. A ruthenium(II) complex as turn-on Cu(II) luminescent sensor based on oxidative cyclization mechanism and its application in vivo

    PubMed Central

    Zhang, Yunfei; Liu, Zonglun; Yang, Kui; Zhang, Yi; Xu, Yongqian; Li, Hongjuan; Wang, Chaoxia; Lu, Aiping; Sun, Shiguo

    2015-01-01

    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. PMID:25640000

  3. Bis(phosphinimino)methanide rare earth amides: synthesis, structure, and catalysis of hydroamination/cyclization, hydrosilylation, and sequential hydroamination/hydrosilylation.

    PubMed

    Rastätter, Marcus; Zulys, Agustino; Roesky, Peter W

    2007-01-01

    A series of yttrium and lanthanide amido complexes [Ln{N(SiHMe(2))2}2{CH(PPh(2)NSiMe(3))2}] (Ln=Y, La, Sm, Ho, Lu) were synthesized by three different pathways. The title compounds can be obtained either from [Ln{N(SiHMe(2))2}3(thf)2] and [CH(2)(PPh(2)NSiMe(3))2] or from KN(SiHMe(2))2 and [Ln{CH(PPh(2)NSiMe(3))2}Cl(2)]2, while in a third approach the lanthanum compound was synthesized in a one-pot reaction starting from K{CH(PPh(2)NSiMe(3))2}, LaCl3, and KN(SiHMe(2))2. All the complexes have been characterized by single-crystal X-ray diffraction. The new complexes, [Ln{N(SiHMe(2))2}2{CH(PPh(2)NSiMe(3))2}], were used as catalysts for hydroamination/cyclization and hydrosilylation reactions. A clear dependence of the reaction rate on the ionic radius of the center metal was observed, showing the lanthanum compound to be the most active one in both reactions. Furthermore, a combination of both reactions--a sequential hydroamination/hydrosilylation reaction--was also investigated.

  4. Wetting of nonconserved residue-backbones: A feature indicative of aggregation associated regions of proteins.

    PubMed

    Pradhan, Mohan R; Pal, Arumay; Hu, Zhongqiao; Kannan, Srinivasaraghavan; Chee Keong, Kwoh; Lane, David P; Verma, Chandra S

    2016-02-01

    Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using "Dehydrons." "Dehydrons" are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved. Combining evolutionary conservation of residues and extent of backbone hydration allows us to distinguish regions on proteins associated with aggregation (non-conserved dehydron-residues) from other interaction interfaces (conserved dehydron-residues). This novel feature can complement the existing strategies used to investigate protein aggregation/complexation.

  5. No-Enclave Percolation Corresponds to Holes in the Cluster Backbone

    NASA Astrophysics Data System (ADS)

    Hu, Hao; Ziff, Robert M.; Deng, Youjin

    2016-10-01

    The no-enclave percolation (NEP) model introduced recently by Sheinman et al. can be mapped to a problem of holes within a standard percolation backbone, and numerical measurements of such holes give the same size-distribution exponent τ =1.82 (1 ) as found for the NEP model. An argument is given that τ =1 +dB/2 ≈1.822 for backbone holes, where dB is the backbone dimension. On the other hand, a model of simple holes within a percolation cluster yields τ =1 +df/2 =187 /96 ≈1.948 , where df is the fractal dimension of the cluster, and this value is consistent with the experimental results of gel collapse of Sheinman et al., which give τ =1.91 (6 ). This suggests that the gel clusters are of the universality class of percolation cluster holes. Both models give a discontinuous maximum hole size at pc, signifying explosive percolation behavior.

  6. Fast extraction of the backbone of projected bipartite networks to aid community detection

    NASA Astrophysics Data System (ADS)

    Liebig, J.; Rao, A.

    2016-01-01

    This paper introduces a computationally inexpensive method for extracting the backbone of one-mode networks projected from bipartite networks. We show that the edge weights in the one-mode projections are distributed according to a Poisson binomial distribution and that finding the expected weight distribution of a one-mode network projected from a random bipartite network only requires knowledge of the bipartite degree distributions. Being able to extract the backbone of a projection is highly beneficial in filtering out redundant information in large complex networks and narrowing down the information in the one-mode projection to the most relevant. We demonstrate that the backbone of a one-mode projection aids in the detection of communities.

  7. Remote Enantioselection Transmitted by an Achiral Peptide Nucleic Acid Backbone

    NASA Technical Reports Server (NTRS)

    Kozlov, Igor A.; Orgel, Leslie E.; Nielsen, Peter E.

    2000-01-01

    short homochiral segment of DNA into a PNA helix could have guaranteed that the next short segment of DNA to be incorporated would have the same handedness as the first. Once two segments of the same handedness were present, the probability that a third segment would have the same handedness would increase, and so on. Evolution could then slowly dilute out the PNA part. This scenario would ultimately allow the formation of a chiral oligonucleotide by processes that are largely resistant to enantiomeric crossinhibition. It is important to note that the ligation of homochiral dinucleotides on a nucleic acid template would probably be at least as enantiospecific as the reaction that we have studied. The disadvantage of using chiral monomers as components of a replicating system arises from the difficulty of generating a first long homochiral template from a racemic mixture of monomers, although results of experiments designed to overcome this difficulty by employing homochiral tetramers have been reported.l l The probability of obtaining a homochiral n-mer from achiral substrates is approximately 1P-I if the nontemplate-directed extension of the primer is not enantioselective. Hence, it would be very hard to get started with a homochiral 40-mer, for example. No such difficulty exists in a scenario that originates with an achiral genetic material and in which the incorporation of very few chiral monomers in this achiral background gradually progresses towards homochirality. It seems possible that some PNA sequences could act as catalysts, analogous to ribozymes, even though PNA lacks clear metal binding sites. Although such catalysts could not be enantioselective, the incorporation of as few as two chiral nucleotides could then impose chiral specificity on the system. Furthermore, such patch chimeras could help to bridge the gap in catalytic potential between PNA and RNA, while guaranteeing enantioselectivity.

  8. Metal-free oxidative hydroxyalkylarylation of activated alkenes by direct sp3 C-H functionalization of alcohols.

    PubMed

    Meng, Yuan; Guo, Li-Na; Wang, Hua; Duan, Xin-Hua

    2013-09-04

    A metal-free tandem radical addition/cyclization reaction of activated alkenes and alcohols has been developed. The process provides an efficient and atom economical access to various valuable hydroxyl-containing oxindoles through the direct sp(3) C-H functionalization of alcohols.

  9. AbDesign: An algorithm for combinatorial backbone design guided by natural conformations and sequences.

    PubMed

    Lapidoth, Gideon D; Baran, Dror; Pszolla, Gabriele M; Norn, Christoffer; Alon, Assaf; Tyka, Michael D; Fleishman, Sarel J

    2015-08-01

    Computational design of protein function has made substantial progress, generating new enzymes, binders, inhibitors, and nanomaterials not previously seen in nature. However, the ability to design new protein backbones for function--essential to exert control over all polypeptide degrees of freedom--remains a critical challenge. Most previous attempts to design new backbones computed the mainchain from scratch. Here, instead, we describe a combinatorial backbone and sequence optimization algorithm called AbDesign, which leverages the large number of sequences and experimentally determined molecular structures of antibodies to construct new antibody models, dock them against target surfaces and optimize their sequence and backbone conformation for high stability and binding affinity. We used the algorithm to produce antibody designs that target the same molecular surfaces as nine natural, high-affinity antibodies; in five cases interface sequence identity is above 30%, and in four of those the backbone conformation at the core of the antibody binding surface is within 1 Å root-mean square deviation from the natural antibodies. Designs recapitulate polar interaction networks observed in natural complexes, and amino acid sidechain rigidity at the designed binding surface, which is likely important for affinity and specificity, is high compared to previous design studies. In designed anti-lysozyme antibodies, complementarity-determining regions (CDRs) at the periphery of the interface, such as L1 and H2, show greater backbone conformation diversity than the CDRs at the core of the interface, and increase the binding surface area compared to the natural antibody, potentially enhancing affinity and specificity.

  10. Domino cyclization-alkylation protocol for the synthesis of 2,3-functionalized indoles from o-alkynylanilines and allylic alcohols.

    PubMed

    Xu, Chang; Murugan, Vinod K; Pullarkat, Sumod A

    2012-05-21

    A practical and efficient protocol for the one-pot synthesis of 2,3-substituted indoles was developed via a palladacycle catalyzed domino cyclization-alkylation reaction involving 2-alkynylanilines and allylic alcohols under mild conditions without any additives.

  11. Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization-Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding.

    PubMed

    Brooks, Joshua L; Xu, Liping; Wiest, Olaf; Tan, Derek S

    2017-01-06

    Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.

  12. A cyclization-induced emission enhancement (CIEE)-based ratiometric fluorogenic and chromogenic probe for the facile detection of a nerve agent simulant DCP.

    PubMed

    Mahapatra, Ajit Kumar; Maiti, Kalipada; Manna, Saikat Kumar; Maji, Rajkishor; Mondal, Sanchita; Das Mukhopadhyay, Chitrangada; Sahoo, Prithidipa; Mandal, Debasish

    2015-06-14

    The first ratiometric fluorescent probe for the detection of a nerve agent simulant was developed based on tandem phosphorylation and intramolecular cyclization, by which high sensitivity as well as large emission shift could be achieved.

  13. Tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization between vinyl ether boronates and vinyl halides: a concise approach to polysubstituted furans.

    PubMed

    Butkevich, Alexey N; Meerpoel, Lieven; Stansfield, Ian; Angibaud, Patrick; Corbu, Andrei; Cossy, Janine

    2013-08-02

    Polysubstituted 2-(ω-hydroxyalkyl)furans were prepared by tandem Suzuki-Miyaura coupling/acid-catalyzed cyclization starting from appropriately substituted 3-haloallylic alcohols and dihydrofuran-, dihydropyran- or glycal-derived pinacol boronates.

  14. Formal syntheses of (±)-platensimycin and (±)-platencin via a dual-mode Lewis acid induced cascade cyclization approach.

    PubMed

    Zhu, Lizhi; Zhou, Congshan; Yang, Wei; He, Shuzhong; Cheng, Gui-Juan; Zhang, Xinhao; Lee, Chi-Sing

    2013-08-16

    A mild and efficient dual-mode Lewis acid induced Diels-Alder (DA)/carbocyclization cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr2 as the dual-mode Lewis acid, a series of substituted enones and dienes underwent DA/carbocyclization cascade cyclization reaction smoothly at room temperature and provided the tricyclic cyclized products in one pot with good yields and high diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin.

  15. Electric field induced localization phenomena in a ladder network with superlattice configuration: Effect of backbone environment

    SciTech Connect

    Dutta, Paramita; Karmakar, S. N.; Maiti, Santanu K.

    2014-09-15

    Electric field induced localization properties of a tight-binding ladder network in presence of backbone sites are investigated. Based on Green's function formalism we numerically calculate two-terminal transport together with density of states for different arrangements of atomic sites in the ladder and its backbone. Our results lead to a possibility of getting multiple mobility edges which essentially plays a switching action between a completely opaque to fully or partly conducting region upon the variation of system Fermi energy, and thus, support in fabricating mesoscopic or DNA-based switching devices.

  16. Solvation thermodynamics of amino acid side chains on a short peptide backbone

    SciTech Connect

    Hajari, Timir; Vegt, Nico F. A. van der

    2015-04-14

    The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvation free energies of nonpolar and polar side chains attached to a short peptide backbone. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The observed differences are large; however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. We find that a similar compensation does not apply to the nonpolar side chains; while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side

  17. Using Excel To Study The Relation Between Protein Dihedral Angle Omega And Backbone Length

    NASA Astrophysics Data System (ADS)

    Shew, Christopher; Evans, Samari; Tao, Xiuping

    How to involve the uninitiated undergraduate students in computational biophysics research? We made use of Microsoft Excel to carry out calculations of bond lengths, bond angles and dihedral angles of proteins. Specifically, we studied protein backbone dihedral angle omega by examining how its distribution varies with the length of the backbone length. It turns out Excel is a respectable tool for this task. An ordinary current-day desktop or laptop can handle the calculations for midsized proteins in just seconds. Care has to be taken to enter the formulas for the spreadsheet column after column to minimize the computing load. Supported in part by NSF Grant #1238795.

  18. Polyolefin backbone substitution in binders for low temperature powder injection moulding feedstocks.

    PubMed

    Hausnerova, Berenika; Kuritka, Ivo; Bleyan, Davit

    2014-02-27

    This paper reports the substitution of polyolefin backbone binder components with low melting temperature carnauba wax for powder injection moulding applications. The effect of various binder compositions of Al₂O₃ feedstock on thermal degradation parameters is investigated by thermogravimetric analysis. Within the experimental framework 29 original feedstock compositions were prepared and the superiority of carnauba wax over the polyethylene binder backbone was demonstrated in compositions containing polyethylene glycol as the initial opening agent and governing the proper mechanism of the degradation process. Moreover, the replacement of synthetic polymer by the natural wax contributes to an increase of environmental sustainability of modern industrial technologies.

  19. Ebolavirus VP35 Coats the Backbone of Double-Stranded RNA for Interferon Antagonism

    PubMed Central

    Bale, Shridhar; Julien, Jean-Philippe; Bornholdt, Zachary A.; Krois, Alexander S.; Wilson, Ian A.

    2013-01-01

    Recognition of viral double-stranded RNA (dsRNA) activates interferon production and immune signaling in host cells. Crystal structures of ebolavirus VP35 show that it caps dsRNA ends to prevent sensing by pattern recognition receptors such as RIG-I. In contrast, structures of marburgvirus VP35 show that it primarily coats the dsRNA backbone. Here, we demonstrate that ebolavirus VP35 also coats the dsRNA backbone in solution, although binding to the dsRNA ends probably constitutes the initial binding event. PMID:23824825

  20. Convenient and Scalable Synthesis of Fmoc-Protected Peptide Nucleic Acid Backbone

    PubMed Central

    Feagin, Trevor A.; Shah, Nirmal I.; Heemstra, Jennifer M.

    2012-01-01

    The peptide nucleic acid backbone Fmoc-AEG-OBn has been synthesized via a scalable and cost-effective route. Ethylenediamine is mono-Boc protected, then alkylated with benzyl bromoacetate. The Boc group is removed and replaced with an Fmoc group. The synthesis was performed starting with 50 g of Boc anhydride to give 31 g of product in 32% overall yield. The Fmoc-protected PNA backbone is a key intermediate in the synthesis of nucleobase-modified PNA monomers. Thus, improved access to this molecule is anticipated to facilitate future investigations into the chemical properties and applications of nucleobase-modified PNA. PMID:22848796

  1. Room temperature copper(II)-catalyzed oxidative cyclization of enamides to 2,5-disubstituted oxazoles via vinylic C-H functionalization.

    PubMed

    Cheung, Chi Wai; Buchwald, Stephen L

    2012-09-07

    A copper(II)-catalyzed oxidative cyclization of enamides to oxazoles via vinylic C-H bond functionalization at room temperature is described. Various 2,5-disubstituted oxazoles bearing aryl, vinyl, alkyl, and heteroaryl substituents could be synthesized in moderate to high yields. This reaction protocol is complementary to our previously reported iodine-mediated cyclization of enamides to afford 2,4,5-trisubstituted oxazoles.

  2. Rh(iii)-Catalyzed bilateral cyclization of aldehydes with nitrosos toward unsymmetrical acridines proceeding with C-H functionalization enabled by a transient directing group.

    PubMed

    Hu, Weiming; Zheng, Qingheng; Sun, Song; Cheng, Jiang

    2017-06-06

    A Rh(iii)-catalyzed bilateral cyclization was developed for the efficient construction of acridines proceeding with C-H functionalization whereby in situ formation and removal of an imino transient directing group in the presence of catalytic amount of BnNH2 are achieved. In this transformation, a sequential Rh(iii)-catalyzed C-H amination, cyclization, and aromatization process was involved.

  3. Organocatalytic Asymmetric Tandem Nazarov Cyclization/Semipinacol Rearrangement: Rapid Construction of Chiral Spiro[4.4]nonane-1,6-diones.

    PubMed

    Yang, Bin-Miao; Cai, Pei-Jun; Tu, Yong-Qiang; Yu, Zhi-Xiang; Chen, Zhi-Min; Wang, Shuang-Hu; Wang, Shao-Hua; Zhang, Fu-Min

    2015-07-08

    A novel organocatalytic asymmetric tandem Nazarov cyclization/semipinacol rearrangement reaction using "unactivated" substrates has been developed, generating a series of chiral spiro[4.4]nonane-1,6-diones in up to 96% yield and 97% enantiomeric excess. Significantly, it is the first direct example for asymmetric synthesis of cyclopentanones with four stereocenters using Nazarov cyclization. DFT calculations have been applied to understand the reaction mechanism, stereochemistry, and substituent effects.

  4. Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s.

    PubMed

    Wang, Zhiming; Xu, Xingzhu; Gu, Zhanshou; Feng, Wei; Qian, Houjun; Li, Zhengyi; Sun, Xiaoqiang; Kwon, Ohyun

    2016-02-14

    The first Lewis acid-catalyzed intramolecular interrupted Nazarov cyclization of 1,4-pentadien-3-ols is described. Using FeBr3 as the catalyst, a series of new substituted cyclopenta[b]indoles was prepared-through a sequence of Nazarov cyclization, nucleophilic amination, and isomerization-with good yields and high diastereo- and regioselectivities. A similar catalytic process was also developed for the synthesis of structurally interesting spiro[indene-1,4'-quinoline]s.

  5. A Rational Entry to Cyclic Polymers via Selective Cyclization by Self-Assembly and Topology Transformation of Linear Polymers.

    PubMed

    Aoki, Daisuke; Aibara, Gouta; Uchida, Satoshi; Takata, Toshikazu

    2017-05-24

    A simple and effective synthetic route to cyclic polymers has been developed based on the following sequence: (i) selective cyclization of two self-complementary sec-ammonium-containing crown ether monomers to afford [c2] daisy-chain bifunctional initiators, (ii) living polymerization to afford the corresponding linear polymers, and (iii) a topology transformation of these linear polymers to furnish cyclic polymers. The key step in this sequence is the quantitative cyclization via self-assembly of two crown ether molecules with hydroxyl and sec-ammonium moieties. After the living polymerization, the linear polymers release the daisy-chain assembly to generate a cyclic topology. The specific advantages of the present synthetic protocol, i.e., procedural simplicity and concentration independence, are demonstrated by a gram-scale synthesis.

  6. Nucleophilic addition of amines to ruthenium carbenes: ortho-(alkynyloxy)benzylamine cyclizations towards 1,3-benzoxazines.

    PubMed

    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.

  7. Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions.

    PubMed

    Weinstein, Adam B; Ellman, Jonathan A

    2016-07-01

    The development of Rh(III)-catalyzed C-H conjugate addition/cyclization reactions that provide access to synthetically useful fused bi- and tricyclic nitrogen heterocycles is reported. A broad scope of C-H functionalization substrates and electrophilic olefin coupling partners is effective, and depending on the nature of the directing group, cyclic imide, amide, or heteroaromatic products are obtained. An efficient synthesis of a pyrrolophenanthridine alkaloid natural product, oxoassoanine, highlights the utility of this method.

  8. Coupling and cyclization of o-iodoanilines and propargylic bromides via allenes: an efficient entry to indomethacin.

    PubMed

    Zhu, Can; Ma, Shengming

    2013-06-07

    A sequential allene synthesis and cyclization has been realized in a one-pot manner. A Pd(0)-catalyzed one-pot reaction of N-Ts or -Ms 2-iodoanilines and propargylic bromides afforded indoles with pharmaceutical importance highly efficiently with diversity via sequential carbon-carbon bond coupling forming allenes and azapalladation. With this newly established methodology, an efficient approach to indomethacin, an anti-inflammatory drug (NSAID), has been accomplished.

  9. Stereoselective synthesis of 3-substituted tetrahydropyrazinoisoquinolines via intramolecular cyclization of enantiomerically enriched dihydro-2H-pyrazines.

    PubMed

    Reginato, Gianna; Catalani, Maria Pia; Pezzati, Bernardo; Di Fabio, Romano; Bernardelli, Andrea; Curcuruto, Ornella; Moro, Elisa; Pozzan, Alfonso; Mordini, Alessandro

    2015-02-06

    The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.

  10. Nazarov cyclization of divinyl and arylvinyl epoxides: application in the synthesis of resveratrol-based natural products.

    PubMed

    Sudhakar, Gangarajula; Satish, Kovela

    2015-04-20

    New variation in the Nazarov cyclization has been developed by preparing divinyl and arylvinyl epoxides as pentadienyl cation precursors for the first time. Highly substituted cyclopentadienes, hydrindienes, and indenes were synthesized to demonstrate the compatibility of this reaction with substrates bearing a variety of substitutions and having different types of epoxides. Application of this method in the synthesis of resveratrol-based natural products was also demonstrated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Silver(I)‐Catalyzed Intramolecular Cyclizations of Epoxide‐Propargylic Esters to 1,4‐Oxazine Derivatives

    PubMed Central

    Li, Peng‐Hua; Yang, Jin‐Ming; Wei, Yin

    2016-01-01

    Abstract An interesting silver(I)‐catalyzed, one‐pot intramolecular cyclization of epoxide‐propargylic esters is described. A variety of 1,4‐oxazine derivatives were obtained through a novel domino sequence, including three‐membered ring‐opening, 3,3‐sigmatropic rearrangement, 6‐exo‐cycloisomerization and subsequent intramolecular elimination in moderate yields under mild conditions. PMID:28168146

  12. Ligand bite angle-dependent palladium-catalyzed cyclization of propargylic carbonates to 2-alkynyl azacycles or cyclic dienamides.

    PubMed

    Daniels, David S B; Jones, Alison S; Thompson, Amber L; Paton, Robert S; Anderson, Edward A

    2014-02-10

    The regioselectivity of the palladium-catalyzed cyclization of propargylic carbonates with sulfonamide nucleophiles is critically dependent on the bite angle of the bidentate phosphine ligand. Ligands with small bite angles favor attack on the central carbon atom of an allenylpalladium intermediate to afford cyclic dienamide products, whereas the use of those with large bite angles leads to alkynyl azacycles, with high stereoselectivity. A computational analysis of the reaction pathway is also presented.

  13. Palladium-Catalyzed Tandem Carbene Migratory Insertion and Intramolecular Cyclization: Synthesis of Chromeno[4,3-b]chromene Compounds.

    PubMed

    Shang, Xue Song; Li, Nian Tai; Siyang, Hai Xiao; Liu, Pei Nian

    2015-05-01

    Chromeno[4,3-b]chromene is a ubiquitous structural motif found in various pharmaceuticals and biologically active compounds. A concise palladium-catalyzed reaction of vinyl iodides and salicyl N-tosylhydrazones has been achieved to afford a series of compounds containing the chromeno[4,3-b]chromene scaffold in moderate to high yield. This tandem reaction involves palladium(II) carbene migratory insertion and intramolecular cyclization assisted by an O nucleophile and tolerates various functional groups.

  14. Copper-mediated cross-coupling-cyclization-oxidation: a one-pot reaction to construct polysubstituted pyrroles.

    PubMed

    Liu, Pei; Liu, Jin-ling; Wang, Heng-shan; Pan, Ying-ming; Liang, Hong; Chen, Zhen-Feng

    2014-05-14

    A novel and efficient procedure for the synthesis of polysubstituted pyrroles has been developed in this work. The polysubsituted pyrroles were synthesized directly from terminal alkenes, amines and β-keto esters through cross-coupling-cyclization-oxidation in the presence of a catalytic amount of cuprous chloride. This method provides a one-pot synthesis route from terminal alkenes to polysubstituted pyrroles for the first time and opens a new area in cuprous catalysis.

  15. Reprogramming the Chemodiversity of Terpenoid Cyclization by Remolding the Active Site Contour of epi-Isozizaene Synthase

    PubMed Central

    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

  16. Unusual transannular cyclization products of sarcophytoxide, a 14-membered marine cembranoid: anomalous stereochemistry of epoxide-ketone rearrangement.

    PubMed

    Nii, Keiji; Tagami, Keiko; Matsuoka, Keisuke; Munakata, Tatsuo; Ooi, Takashi; Kusumi, Takenori

    2006-07-06

    [reaction: see text] Treatment of sarcophytoxide with trimethylsilyl trifluoromethanesulfonate afforded an aromatic ketone as an unusual cyclization product. The modified Mosher's method and X-ray analysis performed on the aromatic ketone revealed that it is a 4:1 mixture of 8(R)- and 8(S)-enantiomers. It also suggested that the precursor ketone has 8(R)-configuration, which is contradictory to that expected from the ordinary epoxide-ketone rearrangement.

  17. Intramolecular monomer-on-monomer (MoM) Mitsunobu cyclization for the synthesis of benzofused thiadiazepine-dioxides.

    PubMed

    Maity, Pradip K; Kainz, Quirin M; Faisal, Saqib; Rolfe, Alan; Samarakoon, Thiwanka B; Basha, Fatima Z; Reiser, Oliver; Hanson, Paul R

    2011-12-14

    The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-opening metathesis (ROM) polymerization initiated by one of three metathesis catalyst methods: (i) free metathesis catalyst, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.

  18. Mycolic Acid Containing Bacterium Stimulates Tandem Cyclization of Polyene Macrolactam in a Lake Sediment Derived Rare Actinomycete.

    PubMed

    Hoshino, Shotaro; Okada, Masahiro; Awakawa, Takayoshi; Asamizu, Shumpei; Onaka, Hiroyasu; Abe, Ikuro

    2017-09-15

    Two novel macrolactams, dracolactams A and B, were identified from a combined-culture of Micromonospora species and a mycolic-acid containing bacterium (MACB). Their structures and stereochemistries were completely assigned, based on spectroscopic analyses and chemical derivatization. Both dracolactams were probably generated from a common macrolactam precursor produced by the Micromonospora species. In this combined-culture system, MACB is likely to activate cryptic oxidase genes in the Micromonospora species and induce the downstream polyene macrolactam cyclization.

  19. Hydroxyl Radical-Mediated Novel Modification of Peptides: N-Terminal Cyclization through the Formation of α-Ketoamide.

    PubMed

    Lee, Seon Hwa; Kyung, Hyunsook; Yokota, Ryo; Goto, Takaaki; Oe, Tomoyuki

    2015-01-20

    The hydroxyl radical-mediated oxidation of peptides and proteins constitutes a large group of post-translational modifications that can result in structural and functional changes. These oxidations can lead to hydroxylation, sulfoxidation, or carbonylation of certain amino acid residues and cleavage of peptide bonds. In addition, hydroxyl radicals can convert the N-terminus of peptides to an α-ketoamide via abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. In the present study, we identified N-terminal cyclization as a novel modification mediated by a hydroxyl radical. The reaction of angiotensin (Ang) II (DRVYIHPF) and the hydroxyl radical generated by the Cu(II)/ascorbic acid (AA) system or UV/hydrogen peroxide system produced N-terminal cyclized-Ang II (Ang C) and pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The structure of Ang C was confirmed by mass spectrometry and comparison to an authentic standard. The subsequent incubation of isolated Ang P in the presence of Cu(II)/AA revealed that Ang P was the direct precursor of Ang C. The proposed mechanism involves the formation of a nitrogen-centered (aminyl) radical, which cyclizes to form a five-membered ring containing the alkoxy radical. The subsequent β-scission reaction of the alkoxyl radical results in the cleavage of the terminal CH3CO group. The initial aminyl radical can be stabilized by chelation to the Cu(II) ions. The affinity of Ang C toward the Ang II type 1 receptor was significantly lower than that of Ang II or Ang P. Ang C was not further metabolized by aminopeptidase A, which converts Ang II to Ang III. Hydroxyl radical-mediated N-terminal cyclization was also observed in other Ang peptides containing N-terminal alanine, arginine, valine, and amyloid β 1-11 (DAEFRHDSGYE).

  20. Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-Nazarov Cyclization: Access to Functionalized 2-Aminopyrroles.

    PubMed

    Shu, Chao; Wang, Yong-Heng; Shen, Cang-Hai; Ruan, Peng-Peng; Lu, Xin; Ye, Long-Wu

    2016-07-01

    A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed, allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic rationale for this tandem sequence, especially for the observed high regioselectivity, is also well supported by DFT (density functional theory) computations. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable alternative for the construction of 2-aminopyrroles.

  1. Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol.

    PubMed

    Tang, Mei-Lin; Peng, Peng; Liu, Zheng-Yu; Zhang, Jian; Yu, Jian-Ming; Sun, Xun

    2016-10-04

    The synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+)-pallidol. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Effects of Protein Stabilizing Agents on Thermal Backbone Motions: A Disulfide Trapping Study†

    PubMed Central

    Butler, Scott L.; Falke, Joseph J.

    2010-01-01

    Chemical stabilizers are widely used to enhance protein stability, both in nature and in the laboratory. Here, the molecular mechanism of chemical stabilizers is studied using a disulfide trapping assay to measure the effects of stabilizers on thermal backbone dynamics in the Escherichia coli galactose/glucose binding protein. Two types of backbone fluctuations are examined: (a) relative movements of adjacent surface α-helices within the same domain and (b) interdomain twisting motions. Both types of fluctuations are significantly reduced by all six stabilizers tested (glycerol, sucrose, trehalose, l-glucose, d-glucose, and d-galactose), and in each case larger amplitude motions are inhibited more than smaller ones. Motional inhibition does not require a high-affinity stabilizer binding site, indicating that the effects of stabilizers are nonspecific. Overall, the results support the theory that effective stabilizing agents act by favoring the most compact structure of a protein, thereby reducing local backbone fluctuations away from the fully folded state. Such inhibition of protein backbone dynamics may be a general mechanism of protein stabilization in extreme thermal or chemical environments. PMID:8718847

  3. Animals without Backbones: The Invertebrate Story. Grade Level 5-9.

    ERIC Educational Resources Information Center

    Jerome, Brian; Fuqua, Paul

    This guide, when used in tandem with the videotape "Animals Without Backbones," helps students learn about invertebrates. These materials promote hands-on discovery and learning. The guide is composed of six curriculum-based teaching units: (1) "Getting Started"; (2) "Porifera"; (3) "Cnidarians"; (4) "Worms"; (5) "Mollusks"; (6) "Arthropods"; and…

  4. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes.

    PubMed

    Sharp, Kim A; O'Brien, Evan; Kasinath, Vignesh; Wand, A Joshua

    2015-05-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O(2) NH ) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O(2) NH  < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O(2) axis . A calibration curve for backbone entropy vs. O(2) NH is developed, which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O(2) NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, for example, upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O(2) axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. © 2015 Wiley Periodicals, Inc.

  5. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes

    PubMed Central

    Sharp, Kim A.; O’Brien, Evan; Kasinath, Vignesh; Wand, A. Joshua

    2015-01-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O2NH) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O2NH < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O2axis. A calibration curve for backbone entropy vs. O2NH is developed which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O2NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, e.g. upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O2axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. PMID:25739366

  6. Graduate Education in Kinesiology: Are We Part of "America's Backbone for Competitiveness and Innovation"?

    ERIC Educational Resources Information Center

    DePauw, Karen P.

    2008-01-01

    Graduate education in the United States has been identified as being the backbone of American competitiveness and innovation in a recent report by the Council of Graduate Schools. The report provides a framework for examining the role of graduate education in partnership with business and government to advance an action agenda for achieving…

  7. Residue-Specific Side-Chain Packing Determines the Backbone Dynamics of Transmembrane Model Helices

    PubMed Central

    Quint, Stefan; Widmaier, Simon; Minde, David; Hornburg, Daniel; Langosch, Dieter; Scharnagl, Christina

    2010-01-01

    The transmembrane domains (TMDs) of membrane-fusogenic proteins contain an overabundance of β-branched residues. In a previous effort to systematically study the relation among valine content, fusogenicity, and helix dynamics, we developed model TMDs that we termed LV-peptides. The content and position of valine in LV-peptides determine their fusogenicity and backbone dynamics, as shown experimentally. Here, we analyze their conformational dynamics and the underlying molecular forces using molecular-dynamics simulations. Our study reveals that backbone dynamics is correlated with the efficiency of side-chain to side-chain van der Waals packing between consecutive turns of the helix. Leu side chains rapidly interconvert between two rotameric states, thus favoring contacts to its i±3 and i±4 neighbors. Stereochemical restraints acting on valine side chains in the α-helix force both β-substituents into an orientation where i,i±3 interactions are less favorable than i,i±4 interactions, thus inducing a local packing deficiency at VV3 motifs. We provide a quantitative molecular model to explain the relationship among chain connectivity, side-chain mobility, and backbone flexibility. We expect that this mechanism also defines the backbone flexibility of natural TMDs. PMID:20959095

  8. Automated extraction of backbone deuteration levels from amide H/2H mass spectrometry experiments

    PubMed Central

    Hotchko, Matthew; Anand, Ganesh S.; Komives, Elizabeth A.; Ten Eyck, Lynn F.

    2006-01-01

    A Fourier deconvolution method has been developed to explicitly determine the amount of backbone amide deuterium incorporated into protein regions or segments by hydrogen/deuterium (H/D) exchange with high-resolution mass spectrometry. Determination and analysis of the level and number of backbone amide exchanging in solution provide more information about the solvent accessibility of the protein than do previous centroid methods, which only calculate the average deuterons exchanged. After exchange, a protein is digested into peptides as a way of determining the exchange within a local area of the protein. The mass of a peptide upon deuteration is a sum of the natural isotope abundance, fast exchanging side-chain hydrogens (present in MALDI-TOF H/2H data) and backbone amide exchange. Removal of the components of the isotopic distribution due to the natural isotope abundances and the fast exchanging side-chains allows for a precise quantification of the levels of backbone amide exchange, as is shown by an example from protein kinase A. The deconvoluted results are affected by overlapping peptides or inconsistent mass envelopes, and evaluation procedures for these cases are discussed. Finally, a method for determining the back exchange corrected populations is presented, and its effect on the data is discussed under various circumstances. PMID:16501228

  9. Insights on chiral, backbone modified peptide nucleic acids: Properties and biological activity

    PubMed Central

    Moccia, Maria; Adamo, Mauro F A; Saviano, Michele

    2014-01-01

    PNAs are emerging as useful synthetic devices targeting natural miRNAs. In particular 3 classes of structurally modified PNAs analogs are herein described, namely α, β and γ, which differ by their backbone modification. Their mode and binding affinity for natural nucleic acids and their use in medicinal chemistry as potential miRNA binders is discussed. PMID:26752710

  10. Oligonucleotides with conjugated dihydropyrroloindole tripeptides: base composition and backbone effects on hybridization.

    PubMed Central

    Kutyavin, I V; Lukhtanov, E A; Gamper, H B; Meyer, R B

    1997-01-01

    The ability of conjugated minor groove binding (MGB) residues to stabilize nucleic acid duplexes was investigated by synthesis of oligonucleotides bearing a tethered dihydropyrroloindole tripeptide (CDPI3). Duplexes bearing one or more of these conjugated MGBs were varied by base composition (AT- or GC-rich oligonucleotides), backbone modifications (phosphodiester DNA, 2'-O-methyl phosphodiester RNA or phosphorothioate DNA) and site of attachment of the MGB moiety (5'- or 3'-end of either duplex strand). Melting temperatures of the duplexes were determined. The conjugated CDPI3 residue enhanced the stability of virtually all duplexes studied. The extent of stabilization was backbone and sequence dependent and reached a maximum value of 40-49 degrees C for d(pT)8. d(pA)8. Duplexes with a phosphorothioate DNA backbone responded similarly on CDPI3 conjugation, although they were less stable than analogous phosphodiesters. Modest stabilization was obtained for duplexes with a 2'-O-methyl RNA backbone. The conjugated CDPI3 residue stabilized GC-rich DNA duplexes, albeit to a lesser extent than for AT-rich duplexes of the same length. PMID:9278496

  11. Animals without Backbones: The Invertebrate Story. Grade Level 5-9.

    ERIC Educational Resources Information Center

    Jerome, Brian; Fuqua, Paul

    This guide, when used in tandem with the videotape "Animals Without Backbones," helps students learn about invertebrates. These materials promote hands-on discovery and learning. The guide is composed of six curriculum-based teaching units: (1) "Getting Started"; (2) "Porifera"; (3) "Cnidarians"; (4) "Worms"; (5) "Mollusks"; (6) "Arthropods"; and…

  12. Increasing Sequence Diversity with Flexible Backbone Protein Design: The Complete Redesign of a Protein Hydrophobic Core

    PubMed Central

    Murphy, Grant S.; Mills, Jeffrey L.; Miley, Michael J.; Machius, Mischa; Szyperski, Thomas; Kuhlman, Brian

    2012-01-01

    Summary Protein design tests our understanding of protein stability and structure. Successful design methods should allow the exploration of sequence space not found in nature. However, when redesigning naturally occurring protein structures most fixed backbone design algorithms return amino acid sequences that share strong sequence identity with wild-type sequences, especially in the protein core. This behavior places a restriction on functional space that can be explored and is not consistent with observations from nature, where sequences of low identity have similar structures. Here, we allow backbone flexibility during design to mutate every position in the core (38 residues) of a four-helix bundle protein. Only small perturbations to the backbone, 1-2 Å, were needed to entirely mutate the core. The redesigned protein, DRNN, is exceptionally stable (melting point > 140 °C). An NMR and X-ray crystal structure show that the side chains and backbone were accurately modeled (all-atom RMSD = 1.3 Å). PMID:22632833

  13. Graduate Education in Kinesiology: Are We Part of "America's Backbone for Competitiveness and Innovation"?

    ERIC Educational Resources Information Center

    DePauw, Karen P.

    2008-01-01

    Graduate education in the United States has been identified as being the backbone of American competitiveness and innovation in a recent report by the Council of Graduate Schools. The report provides a framework for examining the role of graduate education in partnership with business and government to advance an action agenda for achieving…

  14. Linear discrete diffraction and transverse localization of light in two-dimensional backbone lattices.

    PubMed

    Qi, Yiling; Zhang, Guoquan

    2010-09-13

    We study the linear discrete diffraction characteristics of light in two-dimensional backbone lattices. It is found that, as the refractive index modulation depth of the backbone lattice increases, high-order band gaps become open and broad in sequence, and the allowed band curves of the Floquet-Bloch modes become flat gradually. As a result, the diffraction pattern at the exit face converges gradually for both the on-site and off-site excitation cases. Particularly, when the refractive index modulation depth of the backbone lattice is high enough, for example, on the order of 0.01 for a square lattice, the light wave propagating in the backbone lattice will be localized in transverse dimension for both the on-site and off-site excitation cases. This is because only the first several allowed bands with nearly flat band curves are excited in the lattice, and the transverse expansion velocities of the Floquet-Bloch modes in these flat allowed bands approach to zero. Such a linear transverse localization of light may have potential applications in navigating light propagation dynamics and optical signal processing.

  15. Peptide-functionalized semiconductor surfaces: strong surface electronic effects from minor alterations to backbone composition.

    PubMed

    Matmor, Maayan; Lengyel, George A; Horne, W Seth; Ashkenasy, Nurit

    2017-02-22

    The use of non-canonical amino acids is a powerful way to control protein structure. Here, we show that subtle changes to backbone composition affect the ability of a dipeptide to modify solid surface electronic properties. The extreme sensitivity of the interactions to the peptide structure suggests potential applications in improving the performance of electronic devices.

  16. 7-N-(mercaptoalkyl)mitomycins: implications of cyclization for drug function.

    PubMed

    Na, Younghwa; Wang, Shuang; Kohn, Harold

    2002-05-01

    The Kyowa Hakko Kogyo and Bristol-Myers Squibb companies reported that select mitomycin C(7) aminoethylene disulfides displayed improved pharmacological profiles compared with mitomycin C (1). Mechanisms have been advanced for these mitomycins that differ from 1. Central to many of these hypotheses is the intermediate generation of 7-N-(2-mercaptoethyl)mitomycin C (5). Thiol 5 has been neither isolated nor characterized. Two efficient methods were developed for mitomycin (porfiromycin) C(7)-substituted thiols. In the first method, the thiol was produced by a thiol-mediated disulfide exchange process using an activated mixed mitomycin disulfide. In the second route, the thiol was generated by base-mediated cleavage of a porfiromycin C(7)-substituted thiol ester. We selected four thiols, 7-N-(2-mercaptoethyl)mitomycin C (5), 7-N-(2-mercaptoethyl)porfiromycin (12), 7-N-(2-mercapto-2-methylpropyl)mitomycin C (13), and 7-N-(3-mercaptopropyl)porfiromycin (14), for study. Thiols 5 and 12-14 differed in the composition of the alkyl linker that bridged the thiol with the mitomycin (porfiromycin) C(7) amino substituent. Thiol generation was documented by HPLC and spectroscopic studies and by thiol-trapping experiments. The linker affected the structure of the thiol species and the stability of the thiol. We observed that thiols 5 and 12 existed largely as their cyclic isomers. Evidence is presented that cyclization predominantly occurred at the mitomycin C(7) position. Correspondingly, alkyl linker substitution (13) or extension of the linker to three carbons (14) led to enhanced thiol stability and the predominant formation of the free thiol species. The dominant reaction of thiols 5 and 12-14 or their isomers was dimerization, and we found no evidence that thiol formation led to mitosene production and aziridine ring-opening. These findings indicated that thiol generation was not sufficient for mitomycin ring activation. The potential pharmacological advantages of

  17. Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters

    PubMed Central

    Zgarbová, Marie; Luque, F. Javier; Šponer, Jiří; Cheatham, Thomas E.; Otyepka, Michal; Jurečka, Petr

    2013-01-01

    We present a refinement of the backbone torsion parameters ε and ζ of the Cornell et al. AMBER force field for DNA simulations. The new parameters, denoted as εζOL1, were derived from quantum-mechanical calculations with inclusion of conformation-dependent solvation effects according to the recently reported methodology (J. Chem. Theory Comput. 2012, 7(9), 2886-2902). The performance of the refined parameters was analyzed by means of extended molecular dynamics (MD) simulations for several representative systems. The results showed that the εζOL1 refinement improves the backbone description of B-DNA double helices and G-DNA stem. In B-DNA simulations, we observed an average increase of the helical twist and narrowing of the major groove, thus achieving better agreement with X-ray and solution NMR data. The balance between populations of BI and BII backbone substates was shifted towards the BII state, in better agreement with ensemble-refined solution experimental results. Furthermore, the refined parameters decreased the backbone RMS deviations in B-DNA MD simulations. In the antiparallel guanine quadruplex (G-DNA) the εζOL1 modification improved the description of non-canonical α/γ backbone substates, which were shown to be coupled to the ε/ζ torsion potential. Thus, the refinement is suggested as a possible alternative to the current ε/ζ torsion potential, which may enable more accurate modeling of nucleic acids. However, long-term testing is recommended before its routine application in DNA simulations. PMID:24058302

  18. A backbone design principle for covalent organic frameworks: the impact of weakly interacting units on CO2 adsorption.

    PubMed

    Zhai, Lipeng; Huang, Ning; Xu, Hong; Chen, Qiuhong; Jiang, Donglin

    2017-03-31

    Covalent organic frameworks are designed to have backbones with different yet discrete contents of triarylamine units that interact weakly with CO2. Adsorption experiments indicate that the triarylamine units dominate the CO2 adsorption process and the CO2 uptake increases monotonically with the triarylamine content. These profound collective effects reveal a principle for designing backbones targeting for CO2 capture and separation.

  19. BF3 x Et2O-mediated cascade cyclizations: synthesis of schweinfurthins F and G.

    PubMed

    Mente, Nolan R; Neighbors, Jeffrey D; Wiemer, David F

    2008-10-17

    The total synthesis of the natural stilbene (+)-schweinfurthin G (8) has been accomplished through a sequence based on an efficient cationic cascade cyclization. This cascade process is initiated by Lewis acid promoted ring opening of an epoxide and terminated through a novel reaction with a phenolic oxygen "protected" as its MOM ether. Several Lewis acids have been examined for their ability to induce this new reaction, and BF3 x Et2O was found to be the most effective. The only major byproduct under these conditions was one where the expected secondary alcohol was found as its MOM ether derivative (e.g., 30). While this byproduct could be converted to the original target compound through hydrolysis, it also could be employed as a protected alcohol to allow preparation of a benzylic phosphonate (43) without dehydration of the secondary alcohol. The resulting phosphonate was employed in a Horner-Wadsworth-Emmons condensation with an aldehyde representing the right half of the target compounds, an approach complementary to previous studies based on condensation of a right-half phosphonate and a left-half aldehyde.

  20. Stannous chloride-mediated reductive cyclization-rearrangement of nitroarenyl ketones.

    PubMed

    Bates, Dallas K; Li, Kexue

    2002-11-29

    Cyclization products are produced in excellent yields from using standard reaction conditions for nitroarene reduction to aminoarene with SnCl2. Thus, 4-methyl-2-(2-nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treatment with SnCl2 in ethanol did not produce the expected aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-quino[3,2-b][1,4]benzothiazine (3) was produced in excellent yield, presumably via novel Sn (IV)-mediated amidine formation from the initial aniline reduction product. Under identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate (7). A novel semipinacol rearrangement is proposed to account for this extensive skeletal rearrangement. Aniline derivative (14) (from 6 treated with FeSO4.7H2O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodibenzo[b,f][1,5]thiazocine (15) upon treatment with SnCl2 in ethanol. Thiophene analogues of 6 and 14 (18 and 19, respectively) react similarly, forming the analogous thiazepine (20) and cyclic N,O-acetals (21), respectively.