Gas Sorption and Storage Properties of Calixarenes

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

Patil, Rahul S.; Banerjee, Debasis; Atwood, Jerry L.

2016-12-01

Calixarenes, a class of organic macrocyclic molecules have shown interesting gas sorption properties towards industrially important gases such as carbon di-oxide, hydrogen, methane and acetylene. These macrocycles are involved in weak van der Waals interaction to form multidimensional supramolecular frameworks. The gas-diffusion and subsequent sorption occurs due to a cooperative behavior between neighboring macrocycles. Furthermore, the flexibility at the upper rim functional group also plays a key role in the overall gas uptake of calixarene. In this book chapter, we give a brief account of interaction and diffusion of gases in calixarene and selected derivatives.

Development of inexpensive metal macrocyclic complexes for use in fuel cells

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

Doddapaneni, N.; Ingersoll, D.; Kosek, J.A.

Several metal macrocyclic complexes were synthesized for use as catalysts in fuel cells. An initial evaluation of their ability to catalyze the fuel cell reactions were completed. Based on this initial evaluation, one metal macrocyclic catalyst was selected and long-term stability testing in a fuel cell was initiated. The fuel cell employing this catalyst was operated continuously for one year with little signs of catalyst degradation. The effect of synthetic reformates on the performance of the catalyst in the fuel cell environment also demonstrated high tolerance of this catalyst for common contaminants and poisons.

Neighbor-Directed Histidine N (s)–Alkylation: A Route to Imidazolium-Containing Phosphopeptide Macrocycles-Biopolymers | Center for Cancer Research

Cancer.gov

Our recently discovered, selective, on-resin route to N(s)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently

Adaptive self-assembly and induced-fit transformations of anion-binding metal-organic macrocycles

NASA Astrophysics Data System (ADS)

Zhang, Ting; Zhou, Li-Peng; Guo, Xiao-Qing; Cai, Li-Xuan; Sun, Qing-Fu

2017-06-01

Container-molecules are attractive to chemists due to their unique structural characteristics comparable to enzymes and receptors in nature. We report here a family of artificial self-assembled macrocyclic containers that feature induced-fit transformations in response to different anionic guests. Five metal-organic macrocycles with empirical formula of MnL2n (M=Metal L=Ligand n=3, 4, 5, 6, 7) are selectively obtained starting from one simple benzimidazole-based ligand and square-planar palladium(II) ions, either by direct anion-adaptive self-assembly or induced-fit transformations. Hydrogen-bonding interactions between the inner surface of the macrocycles and the anionic guests dictate the shape and size of the product. A comprehensive induced-fit transformation map across all the MnL2n species is drawn, with a representative reconstitution process from Pd7L14 to Pd3L6 traced in detail, revealing a gradual ring-shrinking mechanism. We envisage that these macrocyclic molecules with adjustable well-defined hydrogen-bonding pockets will find wide applications in molecular sensing or catalysis.

Response of a benzoxainone derivative linked to monoaza-15-crown-5 with divalent heavy metals.

PubMed

Addleman, R S; Bennett, J; Tweedy, S H; Elshani, S; Wai, C M

1998-08-01

The response of a monoaza-15-crown-5 with an optically active aminobenzoxazinone moiety to divalent cations was investigated. The crown ether was found to undergo a strong emission shift to the blue when complexed with specific divalent metals that have ionic diameters between 1.9-2.4 A. Consequently the photoactive macrocycle is responsive to Mg(2+), Ca(2+), Ba(2+), Sr(2+), Cd(2+), and particularly responsive to Hg(2+)and Pb(2+). Macrocycle emission spectra are shown to be a function of cation concentration. Alkaline metal cations and smaller transition metals ions such as Ni(2+), Co(2+)and Zn(2+)do not cause significant changes in the macrocycle emission spectra. Emission, absorption, and complex stability constants are determined. Mechanisms of cation selectivity and spectral emission shifts are discussed. Challenges involving immobilization of the macrocycle while preserving its spectral response to cations are explored.

Enhanced liquid-liquid anion exchange using macrocyclic anion receptors: effect of receptor structure on sulphate-nitrate exchange selectivity

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

Moyer, Bruce A; Sloop Jr, Frederick; Fowler, Christopher J

2010-01-01

When certain macrocyclic anion receptors are added to a chloroform solution of the nitrate form of a lipophilic quaternary ammonium salt (methyltri-C8,10-ammonium nitrate, Aliquat 336N), the extraction of sulphate from an aqueous sodium nitrate solution via exchange with the organic-phase nitrate is significantly enhanced. Eight macrocycles were surveyed, including two derivatives of a tetraamide macrocycle, five derivatives of calix[4]pyrrole and -decafluorocalix[5]pyrrole. Under the hypothesis that the enhancement originates from sulphate binding by the anion receptors in the chloroform phase, it was possible to obtain reasonable fits to the sulphate distribution survey data based on the formation of 1:1 and 2:1more » receptor:sulphate complexes in the chloroform phase. Apparent 1:1 sulphate-binding constants obtained from the model in this system fell in the range . Comparison of the results for the various anion receptors included in this study reveals that sulphate binding is sensitive to the nature of the substituents on the parent macrocycle scaffolds in a way that does not follow straightforwardly from simple chemical expectations, such as electron-withdrawing effects on hydrogen-bond donor strength.« less

Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,⁷.1⁹,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles.

PubMed

Breslin, Henry J; Lane, Brandon M; Ott, Gregory R; Ghose, Arup K; Angeles, Thelma S; Albom, Mark S; Cheng, Mangeng; Wan, Weihua; Haltiwanger, R Curtis; Wells-Knecht, Kevin J; Dorsey, Bruce D

2012-01-12

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.

Final Technical Report: Targeting DOE-Relevant Ions with Supramolecular Strategies, DE-SC0010555

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

Bowman-James, Kristin

The effectiveness of three popular supramolecular strategies to selectively target negatively charged ions (anions) was evaluated. Ions of interest included oxo anions, particularly sulfate, that hamper nuclear waste remediation. Three objectives were pursued using a simple building block strategies and by strategically placing anion-binding sites at appropriate positions on organic host molecules. The goal of the first objective was to assess the influence of secondary, tertiary and quaternized amines on binding tetrahedral anions using mixed amide/amine macrocyclic and urea/amine hosts containing aromatic or heteroaromatic spacers. Objective 2 focused on the design of ion pair hosts, using mixed macrocyclic anion hostsmore » joined through polyether linkages. Objective 3 was to explore the synthesis of new metal-linked extended macrocyclic frameworks to leverage anion binding. Key findings were that smaller 24-membered macrocycles provided the most complementary binding for sulfate ion and mixed urea/amine chelates showed enhanced binding over amide corollaries in addition to being highly selective for SO 4 2- in the presence of small quantities of water. In addition to obtaining prototype metal-linked macrocyclic anion hosts, a new dipincer ligand was designed that can be used to link macrocyclic or other supramolecular hosts in extended frameworks. When the tetraamide-based pincers are bound to two metal ions, an interesting phenomenon occurs. Upon deprotonation of the amides, two new protons appear between adjacent carbonyl pairs on the ligand, which may modify the chemistry, and metal-metal interactions in the complexes. Gel formation occurred for some of these extended hosts, and the physical properties are currently under investigation. The new tetracarboxamide-based pincers can also provide basic frameworks for double macrocycles capable of binding ion pairs as well as for binding metal ions and exploring intermetallic interactions through the pyrazine π system. Additionally appendages capable of influencing solvation effects can be introduced, and a number of other potential applications can be realized in areas such as soft materials chemistry, catalysis, sensing, and proton switches, the latter for binding and release of targeted guests. These findings provide a better foundation for understanding the selective binding of anions by targeted placement of hydrogen binding sites, and the strengths and weaknesses of various functional groups, that will allow for more the design of more effective anion sequestering agents. Our design strategy also used simple, cost-effective building blocks for host synthesis to allow for scale-up should real-world applications be forthcoming.« less

Application of a macrocyclic compound, bambus[6]uril, in tailor-made liquid membranes for highly selective electromembrane extractions of inorganic anions.

PubMed

Šlampová, Andrea; Šindelář, Vladimír; Kubáň, Pavel

2017-01-15

A tailor-made liquid membrane consisting of a resistive organic solvent (nitrobenzene, NB) and a highly selective non-ionic macrocyclic compound (bambus[6]uril, BU6) was employed for electromembrane extraction (EME) of inorganic anions. BU6 facilitates strong host-guest interactions of its internal cavity with selected inorganic anions only and its presence in the liquid membrane ensured excellent selectivity of the EME process. EME transfers were directly related to association constants between BU6 and inorganic anions and nearly absolute selectivity was achieved for EMEs of iodide, bromide and perchlorate. Major inorganic anions (chloride, nitrate, sulphate and carbonate), which exhibit low interactions with BU6 cavity, were efficiently eliminated from the EME transfer. No interferences were observed for EMEs of target analytes from samples containing up to 100.000-fold higher concentrations of the major anions. Addition of species-specific macrocyclic modifiers to free and supported liquid membranes might thus open new directions in fine-tuning of EME selectivity. At optimized EME conditions (polypropylene hollow fiber impregnated with NB + 3% (w/w) BU6, extraction voltage 25 V, extraction time 15 min, deionized water as acceptor solution) perchlorate was selectively extracted from tap water at concentrations below the guideline value recommended by United States Environmental Protection Agency. Excellent selectivity of the tailor-made liquid membrane was further demonstrated by EME of bromide from sea water. Copyright © 2016 Elsevier B.V. All rights reserved.

Lead Diversification through a Prins-Driven Macrocyclization Strategy: Application to C13-Diversified Bryostatin Analogues.

PubMed

Wender, Paul A; Billingsley, Kelvin L

2013-01-01

The design, synthesis, and biological evaluation of a novel class of C13-diversified bryostatin analogues are described. An innovative and general strategy based on a Prins macrocyclization-nucleophilic trapping cascade was used to achieve late-stage diversification. In vitro analysis of selected library members revealed that modification at the C13 position of the bryostatin scaffold can be used as a diversification handle to regulate biological activity.

Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization.

PubMed

Shimamura, Hiroyuki; Breazzano, Steven P; Garfunkle, Joie; Kimball, F Scott; Trzupek, John D; Boger, Dale L

2010-06-09

Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration. In this instance, the complexity of the substrate and the reverse macrocyclization order did not diminish the atropodiastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with the analogous substrate used to provide the isolated DEF ring system in our first-generation approach. Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling.

The extraction of aromatic carboxylic acids by the copper complex with Curtis macrocyclic tetramine and its utilization for photometric determination of nonsteroidal anti-inflammatory drugs.

PubMed

Zseltvay, Ivan; Zheltvay, Olga; Antonovich, Valerij

2011-01-01

Copper complex with Curtis macrocyclic tetramine is offered as reagent for extraction-photometric determination of nonsteroidal anti-inflammatory drugs (NSAIDs), belonging to the class of aromatic carboxylic acids. The studies indicate that this method is suitable for quantitative determination of NSAIDs, which have the constant distribution in the system chloroform/water (log P) no less than 3 and dissolubility in chloroform (S) no less than 10 mg/mL. Under optimum conditions, there are liner relationships between the absorption of chloroform extracts and concentration of NSAID in the range of 0.2-4 mg/mL for indometacin (Ind), 0.2-3 mg/mL for mefenamic acid (Mef) and 0.5-3 mg/mL for diclofenac (Dic). The detection limits (S/N = 3) of Ind, Mef and Dic are 0.2, 0.1 and 0.15 mg/mL, respectively. With the help of calculating method (SPARC V4.2) it was predicted the possibility of utilization of this method for extractive-photometric determination of its detached specimen NSAID.

Recognition of thymine in DNA bulges by a Zn(II) macrocyclic complex.

PubMed

del Mundo, Imee Marie A; Fountain, Matthew A; Morrow, Janet R

2011-08-14

A Zn(II) macrocyclic complex with appended quinoline is a bifunctional recognition agent that uses both the Zn(II) center and the pendent aromatic group to bind to thymine in bulges with good selectivity over DNA containing G, C or A bulges. Spectroscopic studies show that the stem containing the bulge stays largely intact in a DNA hairpin with the Zn(II) complex bound to the thymine bulge. This journal is © The Royal Society of Chemistry 2011

Trimodal Control of Ion-Transport Activity on Cyclo-oligo-(1→6)-β-D-glucosamine-Based Artificial Ion-Transport Systems.

PubMed

Roy, Arundhati; Saha, Tanmoy; Gening, Marina L; Titov, Denis V; Gerbst, Alexey G; Tsvetkov, Yury E; Nifantiev, Nikolay E; Talukdar, Pinaki

2015-11-23

Cyclo-oligo-(1→6)-β-D-glucosamines functionalized with hydrophobic tails are reported as a new class of transmembrane ion-transport system. These macrocycles with hydrophilic cavities were introduced as an alternative to cyclodextrins, which are supramolecular systems with hydrophobic cavities. The transport activities of these glycoconjugates were manipulated by altering the oligomericity of the macrocycles, as well as the length and number of attached tails. Hydrophobic tails of 3 different sizes were synthesized and coupled with each glucosamine scaffold through the amide linkage to obtain 18 derivatives. The ion-transport activity increased from di- to tetrameric glucosamine macrocycles, but decreased further when flexible pentameric glucosamine was introduced. The ion-transport activity also increased with increasing length of attached linkers. For a fixed length of linkers, the transport activity decreased when the number of such tails was reduced. All glycoconjugates displayed a uniform anion-selectivity sequence: Cl(-) >Br(-) >I(-) . From theoretical studies, hydrogen bonding between the macrocycle backbone and the anion bridged through water molecules was observed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib.

PubMed

Basit, Sulman; Ashraf, Zaman; Lee, Kwangho; Latif, Muhammad

2017-07-07

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2 nd -generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3 rd -generation macrocyclic ALK-TKI that demonstrates many advantages over 2 nd -generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Neighbor-directed histidine N(τ) alkylation. A route to imidazolium-containing phosphopeptide macrocycles

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

Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert

2015-07-07

Our recently discovered, selective, on-resin route to N(τ)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. These cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Furthermore, neighbor-directed histidine N(τ)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.

Biodegradable polyester-based eco-composites containing hemp fibers modified with macrocyclic oligomers

NASA Astrophysics Data System (ADS)

Conzatti, Lucia; Utzeri, Roberto; Hodge, Philip; Stagnaro, Paola

2016-05-01

An original compatibilizing pathway for hemp fibers/poly(1,4-butylene adipate-co-terephtalate) (PBAT) eco-composites was explored exploiting the capability of macrocyclic oligomers (MCOs), obtained by cyclodepolymerization (CDP) of PBAT at high dilution, of being re-converted into linear chains by entropically-driven ring-opening polymerization (ED-ROP) that occurs simply heating the MCOS in the bulk. CDP reaction of PBAT was carried out varying solvent, catalyst and reaction time. Selected MCOs were used to adjust the conditions of the ED-ROP reaction. The best experimental conditions were then adopted to modify hemp fibers. Eco-composites based on PBAT and hemp fibers as obtained or modified with PBAT macrocyclics or oligomers were prepared by different process strategies. The best fiber-PBAT compatibility was observed when the fibers were modified with PBAT oligomers before incorporation in the polyester matrix.

Strategies for the control of Rhipicephalus microplus ticks in a world of conventional acaricide and macrocyclic lactone resistance.

PubMed

Rodriguez-Vivas, Roger I; Jonsson, Nicholas N; Bhushan, Chandra

2018-01-01

Infestations with the cattle tick, Rhipicephalus microplus, constitute the most important ectoparasite problem for cattle production in tropical and subtropical regions worldwide, resulting in major economic losses. The control of R. microplus is mostly based on the use of conventional acaricides and macrocyclic lactones. However, the intensive use of such compounds has resulted in tick populations that exhibit resistance to all major acaricide chemical classes. Consequently, there is a need for the development of alternative approaches, possibly including the use of animal husbandry practices, synergized pesticides, rotation of acaricides, pesticide mixture formulations, manual removal of ticks, selection for host resistance, nutritional management, release of sterile male hybrids, environmental management, plant species that are unfavourable to ticks, pasture management, plant extracts, essential oils and vaccination. Integrated tick management consists of the systematic combination of at least two control technologies aiming to reduce selection pressure in favour of acaricide-resistant individuals, while maintaining adequate levels of animal production. The purpose of this paper is to present a current review on conventional acaricide and macrocyclic lactone resistance for better understanding and control of resistant ticks with particular emphasis on R. microplus on cattle.

Using Gas-Phase Guest-Host Chemistry to Probe the Structures of b Ions of Peptides

NASA Astrophysics Data System (ADS)

Somogyi, Árpád; Harrison, Alex G.; Paizs, Béla

2012-12-01

Middle-sized b n ( n ≥ 5) fragments of protonated peptides undergo selective complex formation with ammonia under experimental conditions typically used to probe hydrogen-deuterium exchange in Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Other usual peptide fragments like y, a, a*, etc., and small b n ( n ≤ 4) fragments do not form stable ammonia adducts. We propose that complex formation of b n ions with ammonia is characteristic to macrocyclic isomers of these fragments. Experiments on a protonated cyclic peptide and N-terminal acetylated peptides fully support this hypothesis; the protonated cyclic peptide does form ammonia adducts while linear b n ions of acetylated peptides do not undergo complexation. Density functional theory (DFT) calculations on the proton-bound dimers of all-Ala b 4 , b 5 , and b 7 ions and ammonia indicate that the ionizing proton initially located on the peptide fragment transfers to ammonia upon adduct formation. The ammonium ion is then solvated by N+-H…O H-bonds; this stabilization is much stronger for macrocyclic b n isomers due to the stable cage-like structure formed and entropy effects. The present study demonstrates that gas-phase guest-host chemistry can be used to selectively probe structural features (i.e., macrocyclic or linear) of fragments of protonated peptides. Stable ammonia adducts of b 9 , b 9 -A, and b 9 -2A of A8YA, and b 13 of A20YVFL are observed indicating that even these large b-type ions form macrocyclic structures.

Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

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

Johnson, Ted W.; Richardson, Paul F.; Bailey, Simon

2014-06-12

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinasemore » domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.« less

Arg-Phe-Phe D-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xaa-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles.

PubMed

Ericson, Mark D; Koerperich, Zoe M; Freeman, Katie T; Fleming, Katlyn A; Haskell-Luevano, Carrie

2018-06-20

The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally-occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding D-isomer(s), generating a 14 compound library. While L-to-D inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.

Occurrence of Stachybotrys chartarum chemotype S in dried culinary herbs.

PubMed

Biermaier, Barbara; Gottschalk, Christoph; Schwaiger, Karin; Gareis, Manfred

2015-02-01

Stachybotrys (S.) chartarum is an omnipresent cellulolytic mould which produces secondary metabolites, such as the highly toxic macrocyclic trichothecenes. While it is known to occur in animal feed like hay and straw as well as in water-damaged indoor environments, there is little knowledge about the occurrence of S. chartarum and its secondary metabolites in food. The objective of the present study was to examine selected dried culinary herbs for the presence of S. chartarum chemotype S, to assess the potential risk of a contamination of foods with macrocyclic trichothecenes. In total, 50 Stachybotrys isolates from different types of culinary herbs (n=100) such as marjoram (Origanum majorana Linné (L.)), oregano (Origanum vulgare L.), thyme (Thymus vulgaris L.), and savory (Satureja hortensis L.) were examined by MTT-cell culture test (effect-based bioassay), ELISA, and by liquid chromatography tandem mass spectrometry (LC-MS/MS). Selected toxic and non-toxic isolates (n=15) were genetically characterized by PCR and sequencing. Five isolates (10%) were highly toxic in the MTT-cell culture test, and the production of macrocyclic trichothecenes was proven by ELISA and LC-MS/MS. These five isolates were genetically confirmed as S. chartarum chemotype S. To the best of our knowledge, this is the first report about a contamination of dried culinary herbs with toxigenic S. chartarum.

Aza-macrocyclic Triphenylamine Ligands for G-Quadruplex Recognition.

PubMed

García-España, Enrique Victor; Pont, Isabel; González-García, Jorge; Inclán, Mario; Reynolds, Matthew; Delgado-Pinar, Estefanía; Albelda, M Teresa; Vilar, Ramon

2018-05-16

A new series of triphenylamine-based ligands with one (TPA1PY), two (TPA2PY) or three pending aza-macrocycle(s) (TPA3PY) have been synthesised and studied by means of pH-metric titrations, UV/Vis spectroscopy and fluorescence experiments. The affinity of these ligands for G-quadruplex (G4) DNA and its selectivity over duplex DNA were investigated by FRET melting assays, fluorimetric titrations and circular dichroism (CD) spectroscopy. Interestingly, the interaction of the bi- and specially the tri-branched ligand with G4 leads to a very intense red-shifted fluorescence emission band which may be associated with intermolecular aggregation between the molecule and the DNA. This light-up effect allows the application of the ligands as fluorescence probes to selectivity detect G4. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of classic and microwave-assisted synthesis of benzo-thio crown ethers, and investigation of their ion pair extractions

NASA Astrophysics Data System (ADS)

Calisir, Umit; Çiçek, Baki

2017-11-01

Macrocyclic benzo-thio crown ethers and benzo-oxo crown ethers were prepared using an esterification-ring closing method. These compounds were synthesised using 2,2‧-dithiodibenzoyl chloride, and various glycols and dithiols, in the presence of pyridine base under a nitrogen atmosphere in chloroform. All reactions were performed under reflux condition with conventional heating and microwave (MW) irradiation. The synthesised macrocycles were characterised by FT-IR, 1H NMR, 13C NMR, LC-MS, and elemental analysis methods. Extraction studies have been performed on these original macrocycles using liquid-liquid ion-pair extraction with Li+, Na+, K+, Ni2+, Ca2+, Mg2+, Zn2+, Fe2+,Fe3+, Co3+, Pb2+, Cr3+, Ag+, and Cd2+.The KD, ext.%, ΔG and log KExt values were also calculated. While (U1-U7) ligands exhibits selectivity for Zn2+, Ag+, Ca2+, Pb2+, Fe3+, Cr3+, Co2+, Mg2+, Cd2+, and Ni2+ metal salts, they showed no selectivity for Li+, K+ and Na+ metal salts. Furthermore, Fe3+is the most selective cation for all ligands for competitive extraction. We also observed that microwave heating can have certain benefits over conventional ovens: reaction rate acceleration, milder reaction conditions, higher chemical yield, and lower energy usage. These ligands could be used as metal sensors, enzyme inhibitors, antimicrobial/antifungal agents, and in biological applications.

Mechanistics and photo-energetics of macrocycles and photodynamic therapy: An overview of aspects to consider for research.

PubMed

Horne, Tamarisk K; Cronjé, Marianne J

2017-02-01

Research within the field of photodynamic therapy has escalated over the past 20 years. The required conjunctional use of photosensitizers, particularly of the macrocycle structure, has lead to a vast repertoire of derivatives that branch classes and subclasses thereof. Each exhibits a differential range of physiochemical properties that influence their potential applications within the larger phototherapy field for use in either diagnostics, photodynamic therapy, both or none. Herein, we provide an overview of these properties as they relate to photodynamic therapy and to a lesser extent diagnostics. By summarizing the mechanistics of photodynamic therapy coupled to the photo-energetics displayed by macrocycle photosensitizers, we aimed to highlight the critical aspects any researcher should be aware of and consider when selecting and performing research for therapeutic application purposes. These include photosensitizer, photophysical and structural properties, synthesis design and subsequent attributes, main applications within research, common shortcomings exhibited and the current methods practiced to overcome them. © 2017 John Wiley & Sons A/S.

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

PubMed

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

2013-05-24

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

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability.

PubMed

Andersson, Vincent; Bergström, Fredrik; Brånalt, Jonas; Grönberg, Gunnar; Gustafsson, David; Karlsson, Staffan; Polla, Magnus; Bergman, Joakim; Kihlberg, Jan

2016-07-28

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

How Proteins Bind Macrocycles

PubMed Central

Villar, Elizabeth A.; Beglov, Dmitri; Chennamadhavuni, Spandan; Porco, John A.; Kozakov, Dima; Vajda, Sandor; Whitty, Adrian

2014-01-01

The potential utility of synthetic macrocycles as drugs, particularly against low druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of macrocycles for good target protein-binding activity or bioavailability. To address this knowledge gap we analyze the binding modes of a representative set of macrocycle-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic macrocycles libraries possessing structural and physicochemical features likely to favor strong binding to protein targets and also good bioavailability. We additionally provide evidence that large, natural product derived macrocycles can bind to targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product inspired synthetic macrocycles can expand the number of proteins that are druggable by synthetic small molecules. PMID:25038790

Concurrent treatment with a macrocyclic lactone and benzimidazole provides season long performance advantages in grazing cattle harboring macrocyclic lactone resistant nematodes.

PubMed

Edmonds, M D; Vatta, A F; Marchiondo, A A; Vanimisetti, H B; Edmonds, J D

2018-03-15

In 2013, a 118-day study was initiated to investigate the efficacy of concurrent treatment at pasture turnout with an injectable macrocyclic lactone with activity up to 28 days and an oral benzimidazole, referred to as "conventional" anthelmintics, when compared to treatment with conventional macrocyclic lactone alone or an injectable macrocyclic lactone with extended activity of 100 days or longer. A group of 210 steers were obtained from a ranch in California and transported to Idaho, USA. A total of 176 steers with the highest fecal egg counts were blocked by pre-treatment body weights and pasture location. A total of 44 pasture paddocks were assigned with 4 steers per paddock with 12 paddocks per therapeutic treatment group and 8 paddocks per controls. The four treatments were injectable doramectin (Dectomax ® , Zoetis Inc., 0.2 mg kg -1 BW, SC), injectable doramectin concurrently with oral albendazole (Valbazen ® , Zoetis Inc., 10 mg kg -1 BW, PO), extended release injectable eprinomectin (LongRange™, Merial Limited, 1 mg kg -1 BW, SC) or saline. Cattle were individually weighed and sampled for fecal egg count on Days 0, 31/32, 61, 88, and 117/118 with an additional fecal sample on Day 14. At conclusion, one steer per paddock was euthanized for nematode recovery. The results from the first 32 days found evidence of macrocyclic lactone resistance against injectable doramectin and extended release eprinomectin. During this period the concurrent therapy provided nearly 100% efficacy based on fecal egg count reduction and a 19.98% improvement in total weight gain compared to controls (P = 0.039). At the conclusion of the 118-day study and past the approved efficacy for the conventional anthelmintics, the concurrent therapy with conventional anthelmintics provided a 22.98% improvement in total weight gain compared to controls (P = 0.004). The 118-day improvement in weight gain for the extended release eprinomectin group (29.06% compared to control) was not statistically different from the concurrent therapy with conventional anthelmintics. The results indicate that concurrent treatment with a conventional macrocyclic lactone and benzimidazole may provide production benefits early in the grazing period that continue throughout the entire period for cattle harboring macrocyclic lactone resistant nematodes. By using two different anthelmintic classes together, macrocyclic lactone resistant parasites were effectively controlled early in the period. Furthermore, the use of an effective conventional anthelmintic treatment regimen without an extended period of drug release may help to promote refugia and decrease the further selection for anthelmintic resistant parasites. Copyright © 2018 Elsevier B.V. All rights reserved.

Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp(3)-rich library.

PubMed

Storr, Thomas E; Cully, Sarah J; Rawling, Michael J; Lewis, William; Hamza, Daniel; Jones, Geraint; Stockman, Robert A

2015-06-01

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library. Copyright © 2015 Elsevier Ltd. All rights reserved.

Differential protein acetylation induced by novel histone deacetylase inhibitors.

PubMed

Glaser, K B; Li, J; Pease, L J; Staver, M J; Marcotte, P A; Guo, J; Frey, R R; Garland, R B; Heyman, H R; Wada, C K; Vasudevan, A; Michaelides, M R; Davidsen, S K; Curtin, M L

2004-12-17

Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.

Lethal and sub-lethal effects of select macrocyclic lactones insecticides on forager worker honey bees under laboratory experimental conditions.

PubMed

Abdu-Allah, Gamal A M; Pittendrigh, Barry R

2018-01-01

Selective insecticide application is one important strategy for more precisely targeting harmful insects while avoiding or mitigating collateral damage to beneficial insects like honey bees. Recently, macrocyclic lactone-class insecticides have been introduced into the market place as selective bio-insecticides for controlling many arthropod pests, but how to target this selectivity only to harmful insects has yet to be achieved. In this study, the authors investigated the acute toxicity of fourmacrocyclic lactone insecticides (commercialized as abamectin, emamectin benzoate, spinetoram, and spinosad) both topically and through feeding studies with adult forager honey bees. Results indicated emamectin benzoate as topically 133.3, 750.0, and 38.3-fold and orally 3.3, 7.6, and 31.7-fold more toxic, respectively than abamectin, spinetoram and spinosad. Using Hazard Quotients for estimates of field toxicity, abamectin was measured as the safest insecticide both topically and orally for honey bees. Moreover, a significant reduction of sugar solution consumption by treatment group honey bees for orally applied emamectin benzoate and spinetoram suggests that these insecticides may have repellent properties.

Strained Cyclophane Macrocycles: Impact of Progressive Ring Size Reduction on Synthesis and Structure

PubMed Central

Bogdan, Andrew R.; Jerome, Steven V.; Houk, K. N.; James, Keith

2012-01-01

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide-alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries. These strained cyclophane macrocyclic systems provide access to spatial orientations of functionality that would not be readily available in unstrained or acyclic analogs. The most strained system prepared represents the first report of an 11-membered cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring, and establishes a limit to the ring strain that can be generated using this macrocycle synthesis methodology. PMID:22133103

Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold

NASA Astrophysics Data System (ADS)

Li, Yizhou; De Luca, Roberto; Cazzamalli, Samuele; Pretto, Francesca; Bajic, Davor; Scheuermann, Jörg; Neri, Dario

2018-03-01

In nature, specific antibodies can be generated as a result of an adaptive selection and expansion of lymphocytes with suitable protein binding properties. We attempted to mimic antibody-antigen recognition by displaying multiple chemical diversity elements on a defined macrocyclic scaffold. Encoding of the displayed combinations was achieved using distinctive DNA tags, resulting in a library size of 35,393,112. Specific binders could be isolated against a variety of proteins, including carbonic anhydrase IX, horseradish peroxidase, tankyrase 1, human serum albumin, alpha-1 acid glycoprotein, calmodulin, prostate-specific antigen and tumour necrosis factor. Similar to antibodies, the encoded display of multiple chemical elements on a constant scaffold enabled practical applications, such as fluorescence microscopy procedures or the selective in vivo delivery of payloads to tumours. Furthermore, the versatile structure of the scaffold facilitated the generation of protein-specific chemical probes, as illustrated by photo-crosslinking.

Bambus[n]urils: a new family of macrocyclic anion receptors.

PubMed

Havel, Vaclav; Svec, Jan; Wimmerova, Michaela; Dusek, Michal; Pojarova, Michaela; Sindelar, Vladimir

2011-08-05

A recently discovered anion receptor is jointed by three related macrocycles differing in the number of glycoluril units and type of substitution. The synthesis is carried out in nonpolar solvents compared to aqueous media used in the case of the original macrocycle. The size of macrocycle is controlled by a template. A hexameric macrocycle with benzyl substitution binds halide anions with an affinity exceeding 10(9) M(-1) while a tetrameric analog does not bind any of the investigated anions. © 2011 American Chemical Society

Preparation of macrocycles with high carbon content: Toward the synthesis of endohedral metal fullerene complexes

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

Parker, T.C.; Rubin, Y.

1995-12-31

This research is focused on the synthesis of macrocycles with high carbon content for the purpose of total synthesis of fullerenes or fullerene-like structures with the ultimate goal of obtaining endohedral metal complexes of fullerene C{sub 60}. Toward this goal, the authors have utilized organometallic chemistry to synthesize novel cyclophanes such as 1 which are constituted primarily of acetylenic units. The authors believe such macrocycles may be C{sub 60} precursors since studies have shown that acetylenic macrocycles form fullerenes in the gas phase. The authors have synthesized macrocycle 1 using a highly convergent route from commercially available starting materials. Themore » macrocycle 1 is produced from copper (I) catalyzed coupling of 2 which is obtained in turn by the coupling of the copper acetylide 3 with 4. The suitability of macrocycles such as 1 for fullerene precursors is currently under investigation.« less

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.

PubMed

Isidro-Llobet, Albert; Hadje Georgiou, Kathy; Galloway, Warren R J D; Giacomini, Elisa; Hansen, Mette R; Méndez-Abt, Gabriela; Tan, Yaw Sing; Carro, Laura; Sore, Hannah F; Spring, David R

2015-04-21

Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.

Macrocyclic fragrance materials--a screening-level environmental assessment using chemical categorization.

PubMed

Salvito, Daniel; Lapczynski, Aurelia; Sachse-Vasquez, Christen; McIntosh, Colin; Calow, Peter; Greim, Helmut; Escher, Beate

2011-09-01

A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 μg/L in Europe and from <0.01 to 0.03 μg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 μg/L in Europe and from <0.01 to 1.0 μg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 μg/L and for macrocyclic lactones/lactides is 2.7 μg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup. Copyright © 2011 Elsevier Inc. All rights reserved.

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

Cyclization improves membrane permeation by antimicrobial peptoids

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

Andreev, Konstantin; Martynowycz, Michael W.; Ivankin, Andrey

The peptidomimetic approach has emerged as a powerful tool for overcoming the inherent limitations of natural antimicrobial peptides, where the therapeutic potential can be improved by increasing the selectivity and bioavailability. Restraining the conformational flexibility of a molecule may reduce the entropy loss upon its binding to the membrane. Experimental findings demonstrate that the cyclization of linear antimicrobial peptoids increases their bactericidal activity against Staphylococcus aureus while maintaining high hemolytic concentrations. Surface X-ray scattering shows that macrocyclic peptoids intercalate into Langmuir monolayers of anionic lipids with greater efficacy than for their linear analogues. Lastly, it is suggested that cyclization maymore » increase peptoid activity by allowing the macrocycle to better penetrate the bacterial cell membrane.« less

Chemical Editing of Macrocyclic Natural Products and Kinetic Profiling Reveal Slow, Tight-Binding Histone Deacetylase Inhibitors with Picomolar Affinities.

PubMed

Kitir, Betül; Maolanon, Alex R; Ohm, Ragnhild G; Colaço, Ana R; Fristrup, Peter; Madsen, Andreas S; Olsen, Christian A

2017-09-26

Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical probes used to investigate the effects of HDAC enzymes are vital. We interrogated Nature's arsenal of macrocyclic nonribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogues. This furnished surprising trends in binding affinities for the various macrocycles, which were then exploited for the design of highly potent class I and IIb HDAC inhibitors. Furthermore, thorough kinetic investigation revealed unexpected inhibitory mechanisms of important tool compounds as well as the approved drug Istodax (romidepsin). This work provides novel inhibitors with varying potencies, selectivity profiles, and mechanisms of inhibition and, importantly, affords insight into known tool compounds that will improve the interpretation of their effects in biology and medicine.

Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

PubMed

Tang, Jun; Jones, Stacey A; Jeffery, Jerry L; Miranda, Sonia R; Galardi, Cristin M; Irlbeck, David M; Brown, Kevin W; McDanal, Charlene B; Han, Nianhe; Gao, Daxin; Wu, Yongyong; Shen, Bin; Liu, Chunyu; Xi, Caiming; Yang, Heping; Li, Rui; Yu, Yajun; Sun, Yufei; Jin, Zhimin; Wang, Erjuan; Johns, Brian A

2014-01-01

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design.

PubMed

Giroud, Maude; Kuhn, Bernd; Saint-Auret, Sarah; Kuratli, Christoph; Martin, Rainer E; Schuler, Franz; Diederich, François; Kaiser, Marcel; Brun, Reto; Schirmeister, Tanja; Haap, Wolfgang

2018-04-26

Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( K i values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC 50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.

Process for the extraction of strontium from acidic solutions

DOEpatents

Horwitz, E.P.; Dietz, M.L.

1994-09-06

The invention is a process for selectively extracting strontium values from aqueous nitric acid waste solutions containing these and other fission product values. The extractant solution is a macrocyclic polyether in an aliphatic hydrocarbon diluent containing a phase modifier. The process will selectively extract strontium values from nitric acid solutions which are up to 6 molar in nitric acid. 4 figs.

Process for the extraction of strontium from acidic solutions

DOEpatents

Horwitz, E. Philip; Dietz, Mark L.

1994-01-01

The invention is a process for selectively extracting strontium values from aqueous nitric acid waste solutions containing these and other fission product values. The extractant solution is a macrocyclic polyether in an aliphatic hydrocarbon diluent containing a phase modifier. The process will selectively extract strontium values from nitric acid solutions which are up to 6 molar in nitric acid.

Process for the extraction of strontium from acidic solutions

DOEpatents

Horwitz, E.P.; Dietz, M.L.

1993-01-01

The invention is a process for selectively extracting strontium values from aqueous nitric acid waste solutions containing these and other fission product values. The extractant solution is a macrocyclic polyether in an aliphatic hydrocarbon diluent containing a phase modifier. The process will selectively extract strontium values from nitric acid solutions which are up to 6 molar in nitric acid.

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds† †Electronic supplementary information (ESI) available: Experimental procedures, characterization data and details of the computational analyses. See DOI: 10.1039/c5ob00371g Click here for additional data file.

PubMed Central

Isidro-Llobet, Albert; Hadje Georgiou, Kathy; Galloway, Warren R. J. D.; Giacomini, Elisa; Hansen, Mette R.; Méndez-Abt, Gabriela; Tan, Yaw Sing; Carro, Laura; Sore, Hannah F.

2015-01-01

Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity. PMID:25778821

Can a proton be encapsulated in tetraamido/diamino quaternized macrocycles in aqueous solution and electric field?

PubMed

Jiang, Nan; Ma, Jing

2011-09-12

The proton-binding behavior of solvated tetraamido/diamino quaternized macrocyclic compounds with rigid phenyl and flexible phenyl bridges in the absence or presence of an external electric field is investigated by molecular dynamics simulation. The proton can be held through H-bonding interactions with the two carbonyl oxygen atoms in macrocycles containing rigid (phenyl) and flexible (propyl) bridges. The solute-solvent H-bonding interactions cause the macrocyclic backbones to twist to different extents, depending on the different bridges. The macrocycle with the rigid phenyl linkages folds into a cuplike shape due to π-π interaction, while the propyl analogue still maintains the ellipsoidal ringlike shape with just a slight distortion. The potential energy required for proton transfer is larger in the phenyl-containing macrocycle than in the compound with propyl units. When an external electric field with a strength of 2.5 V nm(-1) is exerted along the carbonyl oxygen atoms, a difference in proton encircling is exhibited for macrocycles with rigid and flexible bridges. In contrast to encapsulation of a proton in the propyl analogue, the intermolecular solute-solvent H-bonding and intramolecular π-π stacking between the two rigid phenyl spacers leads to loss of the proton from the highly distorted cuplike macrocycle with phenyl bridges. The competition between intra- and intermolecular interactions governs the behavior of proton encircling in macrocycles. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The macrocyclic peptide natural product CJ-15,208 is orally active and prevents reinstatement of extinguished cocaine-seeking behavior.

PubMed

Aldrich, Jane V; Senadheera, Sanjeewa N; Ross, Nicolette C; Ganno, Michelle L; Eans, Shainnel O; McLaughlin, Jay P

2013-03-22

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects.

Macrocyclic {3d-4f} SMMs as building blocks for 1D-polymers: selective bridging of 4f ions by use of an O-donor ligand.

PubMed

Dhers, Sébastien; Feltham, Humphrey L C; Rouzières, Mathieu; Clérac, Rodolphe; Brooker, Sally

2016-11-15

Crystallisation of the tetranuclear 3d-4f Single-Molecule Magnet (SMM) [CuTb III (L Et )(NO 3 ) 3 (MeOH)]·MeOH (1) with Na 2 [tpa] (tpa = terephthalate and H 6 L Et is the [3 + 3] imine macrocycle derived from 1,4-diformyl-2,3-dihydroxybenzene and 1,2-diaminoethane) gives a structurally characterised one-dimensional cationic polymer {[CuTb III (L Et )(tpa)(H 2 O) 3 ](NO 3 )·0.5H 2 O·0.25MeOH} n (2). A comparative study of the static and dynamic magnetic properties of 2 and its precursor, 1, is reported.

A Multidimensional Diversity‐Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

PubMed Central

Nie, Feilin; Kunciw, Dominique L.; Wilcke, David; Stokes, Jamie E.; Galloway, Warren R. J. D.; Bartlett, Sean; Sore, Hannah F.

2016-01-01

Abstract Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity‐oriented synthesis, and its application towards macrocycles. This enabled the step‐efficient generation of a library of 45 novel, structurally diverse, and highly‐functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza‐ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity‐generating steps of the synthesis strategy impact on molecular shape. PMID:27484830

Structural and conformational determinants of macrocycle cell permeability.

PubMed

Over, Björn; Matsson, Pär; Tyrchan, Christian; Artursson, Per; Doak, Bradley C; Foley, Michael A; Hilgendorf, Constanze; Johnston, Stephen E; Lee, Maurice D; Lewis, Richard J; McCarren, Patrick; Muncipinto, Giovanni; Norinder, Ulf; Perry, Matthew W D; Duvall, Jeremy R; Kihlberg, Jan

2016-12-01

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

Synthesis of Strained 1,3-Diene Macrocycles via Copper-Mediated Castro-Stephens Coupling/Alkyne Reduction Tandem Reactions.

PubMed

Li, Wei; Schneider, Christopher M; Georg, Gunda I

2015-08-07

A copper-mediated macrocyclization involving the reaction of a vinyl iodide and a terminal alkyne followed by an in situ reduction of the enyne intermediate is reported. The reaction generates a conjugated Z-double bond within a strained medium-size lactone, lactam, or ether macrocycle. A variety of macrocyclic compounds bearing different ring sizes and functionalities were synthesized. A complementary stepwise procedure was also developed for less strained ring systems.

Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology.

PubMed

Bogdan, Andrew R; James, Keith

2011-08-05

A new macrocyclization strategy to synthesize 12- to 31-membered 5-iodo-1,2,3-triazole-containing macrocycles is described. The macrocycles have been generated using a simple and efficient copper-catalyzed cycloaddition in flow under environmentally friendly conditions. This methodology also permits the facile, regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazole-containing macrocyles using palladium-catalyzed cross-coupling reactions. © 2011 American Chemical Society

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

2016-10-01

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules.

PubMed

Usanov, Dmitry L; Chan, Alix I; Maianti, Juan Pablo; Liu, David R

2018-07-01

DNA-encoded libraries have emerged as a widely used resource for the discovery of bioactive small molecules, and offer substantial advantages compared with conventional small-molecule libraries. Here, we have developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20 × 20 × 20 × 80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We have integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme affinity resulted in novel insulin-degrading enzyme inhibitors, including one of unusual potency and novel macrocycle stereochemistry (IC 50  = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined and cost-effective tools for bioactive small-molecule discovery.

Selectivity of bis(calix[4]diquinone) ionophores towards metal ions in solvent dimethylsulfoxide: a molecular mechanics and molecular dynamics study.

PubMed

Felix, Vitor; Drew, Michael G B; Webber, Philip R A; Beer, Paul D

2006-01-28

Molecular modelling studies have been carried out on two bis(calix[4]diquinone) ionophores, each created from two (calix[4]diquinone)arenes bridged at their bottom rims via alkyl chains (CH(2))(n), 1: n = 3, 2; n = 4, in order to understand the reported selectivity of these ligands towards different sized metal ions such as Na(+), K(+), Rb(+), and Cs(+) in dmso solution. Conformational analyses have been carried out which show that in the lowest energy conformations of the two macrocycles, the individual calix[4]diquinones exhibit a combination of partial cone, 1,3-alternate and cone conformations. The interactions of these alkali metals with the macrocycles have been studied in the gas phase and in a periodic box of solvent dmso by molecular mechanics and molecular dynamics calculations. Molecular mechanics calculations have been carried out on the mode of entry of the ions into the macrocycles and suggest that this is likely to occur from the side of the central cavity, rather than through the main axis of the calix[4]diquinones. There are energy barriers of ca. 19 kcal mol(-1) for this entry path in the gas phase, but in solution no energy barrier is found. Molecular dynamics simulations show that in both 1 and 2, though particularly in the latter macrocycle, one or two solvent molecules are bonded to the metal throughout the course of the simulation, often to the exclusion of one or more of the ether oxygen atoms. By contrast the carbonyl oxygen atoms remain bonded to the metal atoms throughout with bond lengths that remain significantly less than those to the ether oxygen atoms. Free energy perturbation studies have been carried out in dmso and indicate that for 1, the selectivity follows the order Rb(+) approximately K(+) > Cs(+) > Na(+), which is partially in agreement with the experimental results. The energy differences are small and indeed the ratio between stability constants found for Cs(+) and K(+) complexes is only 0.60, showing that has only a slight preference for K(+). For the larger receptor , which is better suited to metal complexation, the binding affinity follows the pattern Cs(+) > Rb(+) > K(+) > Na(+), with energy differences of 5.75, 2.61, 2.78 kcal mol(-1) which is perfectly consistent with experimental results.

Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

PubMed

Tran, Hai L; Lexa, Katrina W; Julien, Olivier; Young, Travis S; Walsh, Christopher T; Jacobson, Matthew P; Wells, James A

2017-02-22

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

Correlation between oxygen adsorption energy and electronic structure of transition metal macrocyclic complexes.

PubMed

Liu, Kexi; Lei, Yinkai; Wang, Guofeng

2013-11-28

Oxygen adsorption energy is directly relevant to the catalytic activity of electrocatalysts for oxygen reduction reaction (ORR). In this study, we established the correlation between the O2 adsorption energy and the electronic structure of transition metal macrocyclic complexes which exhibit activity for ORR. To this end, we have predicted the molecular and electronic structures of a series of transition metal macrocyclic complexes with planar N4 chelation, as well as the molecular and electronic structures for the O2 adsorption on these macrocyclic molecules, using the density functional theory calculation method. We found that the calculated adsorption energy of O2 on the transition metal macrocyclic complexes was linearly related to the average position (relative to the lowest unoccupied molecular orbital of the macrocyclic complexes) of the non-bonding d orbitals (d(z(2)), d(xy), d(xz), and d(yz)) which belong to the central transition metal atom. Importantly, our results suggest that varying the energy level of the non-bonding d orbitals through changing the central transition metal atom and/or peripheral ligand groups could be an effective way to tuning their O2 adsorption energy for enhancing the ORR activity of transition metal macrocyclic complex catalysts.

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

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

Ghosh, Arun K.; Sean Fyvie, W.; Brindisi, Margherita

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

The Macrocyclic Peptide Natural Product CJ-15,208 is Orally Active and Prevents Reinstatement of Extinguished Cocaine Seeking Behavior1

PubMed Central

Aldrich, Jane V.; Senadheera, Sanjeewa N.; Ross, Nicolette C.; Ganno, Michelle L.; Eans, Shainnel O.; McLaughlin, Jay P.

2013-01-01

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug seeking behavior in abstinent subjects. PMID:23327691

Solvent Extraction Separation of Trivalent Americium from Curium and the Lanthanides

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

Jensen, Mark P.; Chiarizia, Renato; Ulicki, Joseph S.

2015-02-27

The sterically constrained, macrocyclic, aqueous soluble ligand N,N'-bis[(6-carboxy-2-pyridyl)methyl]-1,10-diaza-18-crown-6 (H2BP18C6) was investigated for separating americium from curium and all the lanthanides by solvent extraction. Pairing H2BP18C6, which favors complexation of larger f-element cations, with acidic organophosphorus extractants that favor extraction of smaller f-element cations, such as bis-(2-ethylhexyl)phosphoric acid (HDEHP) or (2-ethylhexyl)phosphonic acid mono(2-ethylhexyl) ester (HEH[EHP]), created solvent extraction systems with good Cm/Am selectivity, excellent trans-lanthanide selectivity (Kex,Lu/Kex,La = 108), but poor selectivity for Am against the lightest lanthanides. However, using an organic phase containing both a neutral extractant, N,N,N’,N’-tetra(2-ethylhexyl)diglycolamide (TEHDGA), and HEH[EHP] enabled rejection of the lightest lanthanides during loading ofmore » the organic phase from aqueous nitric acid, eliminating their interference in the americium stripping stages. In addition, although it is a macrocyclic ligand, H2BP18C6 does not significantly impede the mass transfer kinetics of the HDEHP solvent extraction system« less

Improving the reactivity of phenylacetylene macrocycles toward topochemical polymerization by side chains modification

PubMed Central

Daigle, Maxime; Cantin, Katy

2014-01-01

Summary The synthesis and self-assembly of two new phenylacetylene macrocycle (PAM) organogelators were performed. Polar 2-hydroxyethoxy side chains were incorporated in the inner part of the macrocycles to modify the assembly mode in the gel state. With this modification, it was possible to increase the reactivity of the macrocycles in the xerogel state to form polydiacetylenes (PDAs), leading to a significant enhancement of the polymerization yields. The organogels and the PDAs were characterized using Raman spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). PMID:25161718

Electronic and vibrational exciton coupling in oxidized trianglimines.

PubMed

Szymkowiak, Joanna; Kwit, Marcin

2018-02-01

Readily available chiral trianglimine and their (poly)oxygenated congeners represent a unique class of macrocyclic rigid compounds optimal for testing electronic and vibrational circular dichroism exciton chirality methods. Electronic and vibrational circular dichroism spectra of such trianglimines are strongly affected by polar substituents in macrocycle skeletons. Double substitution by OH groups in each aromatic fragment of the macrocycle causes sign reversal of the exciton couplet in the region of the strongest UV absorption. On the other hand, electronic circular dichroism spectrum of the macrocycle having 2 methoxy groups shows 2 exciton couplets-the long-wavelength positive and the second of the negative sign, observed at the shorter wavelengths. VCD spectra of macrocyclic imines show vibrational exciton couplets in the region of strong C=N stretches. The signs of these couplets are positive and the opposite of the diamine chirality. For trianglimine macrocycles the interpretation of VCD spectra in terms of excitons is much more convincing than for electronic circular dichroism spectra. By contrast, trans-1,2-diaminocyclohexane-based vicinal diimines, being a one-third of the respective macrocycle, do not exhibit any vibrational exciton effect. Experimental data were confronted with DFT calculations. We observed good-to-excellent agreement between experimental and computed data. © 2017 Wiley Periodicals, Inc.

The addition of a second lanthanide ion to increase the luminescence of europium(III) macrocyclic complexes

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

Bromm, A.J. Jr.; Vallarino, L.M.; Leif, R.C.

At present, the microscopic visualization of luminescent labels containing lanthanide(III) ions, primarily europium(III), as light-emitting centers is best performed with time-gated instrumentation, which by virtually eliminating the background fluorescence results in an improved signal to noise ratio. However, the use of the europium(III) macrocycle, Quantum Dye{trademark}, in conjunction with the strong luminescence enhancing effect (cofluorescence) of yttrium(III) or gadolinium(III), can eliminate the need for such specialized instrumentation. In the presence of Gd(III), the luminescence of the Eu(III)-macrocycles can be conveniently observed with conventional fluorescence instrumentation at previously unattainable low levels. The Eu(III) {sup 5}D{sub 0} {r_arrow} {sup 7}F{sub 2} emissionmore » of the Eu(III)-macrocycles was observed as an extremely sharp band with a maximum at 619 nm and a clearly resolved characteristic pattern. At very low Eu(III)-macrocycle concentrations, another sharp emission was detected at 614 nm, arising from traces of Eu(III) present in even the purest commercially available gadolinium products. Discrimination of the resolved emissions of the Eu(III)-macrocycle and Eu(III) contaminant should provide a means to further lower the limit of detection of the Eu(III)-macrocycle.« less

Ru(II) complexes of N 4 and N 2O 2 macrocyclic Schiff base ligands: Their antibacterial and antifungal studies

NASA Astrophysics Data System (ADS)

Shanker, Kanne; Rohini, Rondla; Ravinder, Vadde; Reddy, P. Muralidhar; Ho, Yen-Peng

2009-07-01

Reactions of [RuCl 2(DMSO) 4] with some of the biologically active macrocyclic Schiff base ligands containing N 4 and N 2O 2 donor group yielded a number of stable complexes, effecting complete displacement of DMSO groups from the complex. The interaction of tetradentate ligand with [RuCl 2(DMSO) 4] gave neutral complexes of the type [RuCl 2(L)] [where L = tetradentate macrocyclic ligand]. These complexes were characterized by elemental, IR, 1H, 13C NMR, mass, electronic, thermal, molar conductance and magnetic susceptibility measurements. An octahedral geometry has been proposed for all complexes. All the macrocycles and macrocyclic Ru(II) complexes along with existing antibacterial drugs were screened for antibacterial activity against Gram +ve ( Bacillus subtilis, Staphylococcus aureus) and Gram -ve ( Escherichia coli, Klebsiella pneumonia) bacteria. All these compounds were found to be more active when compared to streptomycin and ampicillin. The representative macrocyclic Schiff bases and their complexes were also tested in vitro to evaluate their activity against fungi, namely, Aspergillus flavus and Fusarium species.

Rapid fixation of methylene chloride by a macrocyclic amine.

PubMed

Lee, Jung-Jae; Stanger, Keith J; Noll, Bruce C; Gonzalez, Carlos; Marquez, Manuel; Smith, Bradley D

2005-03-30

A simple macrocyclic amine is alkylated by methylene chloride to give a quaternary ammonium chloride salt. When methylene chloride is the solvent, the reaction exhibits pseudo-first-order kinetics, and the reaction half-life at 25.0 degrees C is 2.0 min. The reaction half-life for a structurally related, acyclic amine is approximately 50 000 times longer. Detailed calculations favor a mechanism where the methylene chloride associates with the macrocycle to form an activated prereaction complex. The macrocyclic nitrogen subsequently attacks the methylene chloride with a classic SN2 trajectory, and although the carbon-chlorine bond breaks, the chloride leaving group does not separate from the newly formed cationic macrocycle, such that the product is a tightly associated ion-pair. X-ray crystal structures of the starting amine and the product salt, as well as kinetic data, support this mechanism.

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks.

PubMed

Maurya, Sushil K; Rana, Rohit

2017-01-01

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide-alkene building blocks coupled through copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

Selective Capture of CWAs and Containment of Their Neutralization Byproducts by Porous Frameworks Presenting Self-Amplifying and Self-Regulating Reactivities

DTIC Science & Technology

2013-02-04

Intl. Symposium on Macrocyclic and Supramolecular Chemistry, June 2010, Nara, Japan (Plenary talk). O. M. Yaghi, Zeolitic imidazolate frameworks, 5th...International Zeolite Membrane Meeting, May 2010, Loutraki, Greece (Plenary talk). O. M. Yaghi, Reticular chemistry and its applications to clean energy

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

PubMed

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

2016-06-06

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

Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes.

PubMed

Davis, Tony D; Mohandas, Poornima; Chiriac, Maria I; Bythrow, Glennon V; Quadri, Luis E N; Tan, Derek S

2016-11-01

Biosynthesis of bacterial natural-product virulence factors is emerging as a promising antibiotic target. Many such natural products are produced by nonribosomal peptide synthetases (NRPS) from amino acid precursors. To develop selective inhibitors of these pathways, we have previously described aminoacyl-AMS (sulfamoyladenosine) macrocycles that inhibit NRPS amino acid adenylation domains but not mechanistically-related aminoacyl-tRNA synthetases. To improve the cell permeability of these inhibitors, we explore herein replacement of the α-amino group with an α-hydroxy group. In both macrocycles and corresponding linear congeners, this leads to decreased biochemical inhibition of the cysteine adenylation domain of the Yersina pestis siderophore synthetase HMWP2, which we attribute to loss of an electrostatic interaction with a conserved active-site aspartate. However, inhibitory activity can be regained by installing a cognate β-thiol moiety in the linear series. This provides a path forward to develop selective, cell-penetrant inhibitors of the biosynthesis of virulence factors to probe their biological functions and potential as therapeutic targets. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antitumoral activity of 1,2-diaminocyclohexane derivatives in breast, colon and skin human cancer cells.

PubMed

Morales, Fátima; Ramírez, Alberto; Morata-Tarifa, Cynthia; Navarro, Saúl A; Marchal, Juan A; Campos, Joaquín M; Conejo-García, Ana

2017-03-01

Cancer is among the leading causes of death worldwide. Medical interest has focused on macrocyclic polyamines because of their properties as antitumor agents. Results/Methodology: We have designed and synthesized a series of 1,2-diaminocyclohexane derivatives with notable in vitro antiproliferative activities against the MCF-7, HCT-116 and A375 cancer cell lines. Cell cycle and apoptosis analyses were also carried out. Our results show that all the compounds are potent cytotoxic agents, especially against the A375 cell line. The selective activity of the macrocyclic derivative against A375, via apoptosis, supposes a great advantage for future therapeutic use. This exemplifies the potential of 1,2-diaminocyclohexane derivatives to qualify as lead structures for future anticancer drug development due to their easy syntheses and noteworthy bioactivity.

Squaraine rotaxanes with boat conformation macrocycles.

PubMed

Fu, Na; Baumes, Jeffrey M; Arunkumar, Easwaran; Noll, Bruce C; Smith, Bradley D

2009-09-04

Mechanical encapsulation of fluorescent, deep-red bis(anilino)squaraine dyes inside Leigh-type tetralactam macrocycles produces interlocked squaraine rotaxanes. The surrounding macrocycles are flexible and undergo rapid exchange of chair and boat conformations in solution. A series of X-ray crystal structures show how the rotaxane co-conformational exchange process involves simultaneous lateral oscillation of the macrocycle about the center of the encapsulated squaraine thread. Rotaxane macrocycles with 1,4-phenylene sidewalls and 2,6-pyridine dicarboxamide bridging units are more likely to adopt boat conformations in the solid state than analogous squaraine rotaxane systems with isophthalamide-containing macrocycles. A truncated squaraine dye, with a secondary amine attached directly to the central C(4)O(2) core, is less electrophilic than the extended bis(anilino)squaraine analogue, but it is still susceptible to chemical and photochemical bleaching. Its stability is greatly enhanced when it is encapsulated as an interlocked squaraine rotaxane. An X-ray crystal structure of this truncated squaraine rotaxane shows the macrocycle in a boat conformation, and NMR studies indicate that the boat is maintained in solution. Encapsulation as a rotaxane increases the dye's brightness by a factor of 6. The encapsulation process appears to constrain the dye and reduce deformation of the chromophore from planarity. This study shows how mechanical encapsulation as a rotaxane can be used as a rational design parameter to fine-tune the chemical and photochemical properties of squaraine dyes.

Squaraine Rotaxanes with Boat Conformation Macrocycles

PubMed Central

Fu, Na; Baumes, Jeffrey M.; Arunkumar, Easwaran; Noll, Bruce C.; Smith, Bradley D.

2010-01-01

Mechanical encapsulation of fluorescent, deep-red bis(anilino)squaraine dyes inside Leigh-type tetralactam macrocycles produces interlocked squaraine rotaxanes. The surrounding macrocycles are flexible and undergo rapid exchange of chair and boat conformations in solution. A series of X-ray crystal structures show how the rotaxane co-conformational exchange process involves simultaneous lateral oscillation of the macrocycle about the center of the encapsulated squaraine thread. Rotaxane macrocycles with 1,4-phenylene-sidewalls and 2,6-pyridine dicarboxamide bridging units are more likely to adopt boat conformations in the solid-state than analogous squaraine rotaxane systems with isophthalamide-containing macrocycles. A truncated squaraine dye, with a secondary amine attached directly to the central C4O2 core, is less electrophilic than the extended bis(anilino)squaraine analogue, but it is still susceptible to chemical and photochemical bleaching. Its stability is greatly enhanced when it is encapsulated as an interlocked squaraine rotaxane. An X-ray crystal structure of this truncated squaraine rotaxane shows the macrocycle in a boat conformation, and NMR studies indicate that the boat is maintained in solution. Encapsulation as a rotaxane increases the dye’s brightness by a factor of six. The encapsulation process appears to constrain the dye and reduce deformation of the chromophore from planarity. This study shows how mechanical encapsulation as a rotaxane can be used as a rational design parameter to fine-tune the chemical and photochemical properties of squaraine dyes. PMID:19639940

Synthesis and Characterization of Macrocyclic Polyether N,N'-Diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6.

PubMed

Toeri, Julius; Laborie, Marie-Pierre

2016-01-29

In this study an efficient and direct production procedure for a macrocyclic polyether N,N'-diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 from the reaction of catechol and N,N-bis(2-chloroethyl)prop-2-en-1-amine in n-butanol in the presence of a strong base is reported. The synthesis involves a two-step addition of sodium hydroxide to enhance the cyclization process, and at the end of the reaction, the reaction mixture is neutralized and the solvent replaced with water in-situ through distillation to afford a relatively pure precipitate that is easily recrystallized from acetone. The yield of the macrocycle was 36%-45% and could be scaled-up to one-mole quantities. The structure and purity of this compound was verified on the basis of elemental analysis, IR, UV-Vis, ¹H-, (13)C-NMR, 2D-NMR, mass spectroscopy, and thermal analysis. The white crystalline compound has a sharp melting point of 124 °C and a crystallization temperature of 81.4 °C determined by differential scanning calorimetry. Our motivation behind the synthesis of the bibracchial lariat azacrown polyether ligand was to examine its possible applications in ion-selective polymer-supported materials.

Structural basis for precursor protein-directed ribosomal peptide macrocyclization

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

Li, Kunhua; Condurso, Heather L.; Li, Gengnan

Macrocyclization is a common feature of natural product biosynthetic pathways including the diverse family of ribosomal peptides. Microviridins are architecturally complex cyanobacterial ribosomal peptides that target proteases with potent reversible inhibition. The product structure is constructed via three macrocyclizations catalyzed sequentially by two members of the ATP-grasp family, a unique strategy for ribosomal peptide macrocyclization. Here we describe in detail the structural basis for the enzyme-catalyzed macrocyclizations in the microviridin J pathway of Microcystis aeruginosa. The macrocyclases MdnC and MdnB interact with a conserved α-helix of the precursor peptide using a novel precursor-peptide recognition mechanism. The results provide insight intomore » the unique protein–protein interactions that are key to the chemistry, suggest an origin for the natural combinatorial synthesis of microviridin peptides, and provide a framework for future engineering efforts to generate designed compounds.« less

Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling.

PubMed

Assem, Naila; Ferreira, David J; Wolan, Dennis W; Dawson, Philip E

2015-07-20

Macrocyclization is a broadly applied approach for overcoming the intrinsically disordered nature of linear peptides. Herein, it is shown that dichloroacetone (DCA) enhances helical secondary structures when introduced between peptide nucleophiles, such as thiols, to yield an acetone-linked bridge (ACE). Aside from stabilizing helical structures, the ketone moiety embedded in the linker can be modified with diverse molecular tags by oxime ligation. Insights into the structure of the tether were obtained through co-crystallization of a constrained S-peptide in complex with RNAse S. The scope of the acetone-linked peptides was further explored through the generation of N-terminus to side chain macrocycles and a new approach for generating fused macrocycles (bicycles). Together, these studies suggest that acetone linking is generally applicable to peptide macrocycles with a specific utility in the synthesis of stabilized helices that incorporate functional tags. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interference of interchromophoric energy-transfer pathways in π-conjugated macrocycles

DOE PAGES

Alfonso Hernandez, Laura; Nelson, Tammie Renee; Gelin, Maxim F.; ...

2016-11-10

The interchromophoric energy-transfer pathways between weakly coupled units in a π-conjugated phenylene–ethynylene macrocycle and its half-ring analogue have been investigated using the nonadiabatic excited-state molecular dynamics approach. To track the flow of electronic transition density between macrocycle units, we formulate a transition density flux analysis adapted from the statistical minimum flow method previously developed to investigate vibrational energy flow. Following photoexcitation, transition density is primarily delocalized on two chromophore units and the system undergoes ultrafast energy transfer, creating a localized excited state on a single unit. In the macrocycle, distinct chromophore units donate transition density to a single acceptor unitmore » but do not interchange transition density among each other. We find that energy transfer in the macrocycle is slower than in the corresponding half ring because of the presence of multiple interfering energy-transfer pathways. Finally, simulation results are validated by modeling the fluorescence anisotropy decay.« less

Direct comparison of linear and macrocyclic compound libraries as a source of protein ligands.

PubMed

Gao, Yu; Kodadek, Thomas

2015-03-09

There has been much discussion of the potential desirability of macrocyclic molecules for the development of tool compounds and drug leads. But there is little experimental data comparing otherwise equivalent macrocyclic and linear compound libraries as a source of protein ligands. In this Letter, we probe this point in the context of peptoid libraries. Bead-displayed libraries of macrocyclic and linear peptoids containing four variable positions and 0-2 fixed residues, to vary the ring size, were screened against streptavidin and the affinity of every hit for the target was measured. The data show that macrocyclization is advantageous, but only when the ring contains 17 atoms, not 20 or 23 atoms. This technology will be useful for conducting direct comparisons between many different types of chemical libraries to determine their relative utility as a source of protein ligands.

Fused tetracycles with a benzene or cyclohexadiene core: [2 + 2 + 2] cycloadditions on macrocyclic systems.

PubMed

Brun, Sandra; Garcia, Lídia; González, Iván; Torrent, Anna; Dachs, Anna; Pla-Quintana, Anna; Parella, Teodor; Roglans, Anna

2008-09-28

A series of fused tetracycles with a benzene or cyclohexadiene core (2a-h) is satisfactorily prepared by intramolecular [2 + 2 + 2] cycloadditions of triynic and enediynic macrocycles (1a-h) under RhCl(PPh3)3 catalysis; the enantioselective cycloaddition of macrocycles 1b and 1e and gives chiral tetracycles with moderate enantiomeric excess.

Corona[5]arenes Accessed by a Macrocycle-to-Macrocycle Transformation Route and a One-Pot Three-Component Reaction.

PubMed

Wu, Zhi-Chen; Guo, Qing-Hui; Wang, Mei-Xiang

2017-06-12

Corona[5]arenes, a novel type of macrocyclic compound that is composed of alternating heteroatoms and para-arylenes, were synthesized efficiently by two distinct methods. In a macrocycle-to-macrocycle transformation approach, S 6 -corona[3]arene[3]tetrazine underwent sequential S N Ar reactions with HS-C 6 H 4 -X-C 6 H 4 -SH (X=S, CH 2 , CMe 2 , SO 2 , and O) to produce the corresponding corona[3]arene[2]tetrazines. Different corona[3]arene[2]tetrazine compounds were also constructed in a straightforward manner by a one-pot three-component reaction of HS-C 6 H 4 -X-C 6 H 4 -SH (X=S, CH 2 , CMe 2 , SO 2 , and O) with diethyl 2,5-dimercaptoterephthalate and 2 equiv of 3,6-dichlorotetrazine under very mild conditions. All corona[5]arenes adopted 1,2,4-alternate conformational structures in the crystalline state yielding similar nearly regular pentagonal cavities. Both the cavity size and the electronic property of the acquired macrocycles were fine-tuned by the nature of the bridging element X. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Supramolecular Organocatalysis in Water Mediated by Macrocyclic Compounds

NASA Astrophysics Data System (ADS)

De Rosa, Margherita; La Manna, Pellegrino; Talotta, Carmen; Soriente, Annunziata; Gaeta, Carmine; Neri, Placido

2018-04-01

In the last decades many efforts have been devoted to design supramolecular organocatalysts able to work in water as the reaction medium. The use of water as solvent provides promising benefits with respect to environmental impact. In this context, macrocyclic compounds played a role of primary importance thanks to their ease of synthesis and their molecular recognition abilities toward the reactants. The aim of this review is to give an overview of the recent advances in the field of supramolecular organocatalysis in water, focusing the attention on calixarene and cyclodextrins derivatives. Calixarenes and cyclodextrins, thanks to their hydrophobic cavities, are able to host selectively the substrates isolating they from the reaction environment. In addition, the synthetic versatilities of these macrocycles permits to introduce useful functional groups in close proximity of the hydrophobic binding sites. Regarding the cyclodextrins (CDs), we have here reviewed the their most recent uses as organocatalysts for the synthesis of heterocyclic compounds, in multi-component reactions and in carbon-carbon bond forming reactions. Examples have been reported in which CD catalysts are able to drive the regiochemistry of common organic reactions. In addition, cyclodextrins bearing catalytically active chiral groups, have shown excellent enantioselectivity in the catalysis of organic reactions. Recently reported results have shown that calixarene derivatives are able to accelerate organic reaction under "on-water" conditions with a significant selectivity toward the reactants. Under "on-water conditions" the hydrophobic effect, induced by insoluble calixarene derivatives, forces the reactants and the catalyst to aggregate and thus accelerating the reaction between them thanks to an amplification of weak secondary interactions. Regarding the use of water-soluble calixarene organocatalysts, we have here reviewed their role in the acceleration of common organic reactions.

Turn on macrocyclic chemosensor for Al3+ ion with facile synthesis and application in live cell imaging

NASA Astrophysics Data System (ADS)

Ezhumalai, Dhineshkumar; Mathivanan, Iyappan; Chinnadurai, Anbuselvan

2018-06-01

An effort of a new Schiff base macrocyclic chemosensor, 14‑methyl‑2,6,8,12,14,18‑hexaaza‑1,7,13(1,2),4,10,16(1,4)‑hexabenzenacyclooctadecaphane‑2,5,8,11,14,17‑hexaene (me1) and 14,74‑dimethyl‑2,6,8,12,14,18‑hexaaza‑1,7,13(1,2),4,10,16(1,4)‑hexabenzenacyclooctadecadecaphane‑2,5,8,11,14,17‑hexaene (dm2), which enables selective sensing of Al3+ in aqueous DMF were synthesized by a simplistic one-step condensation reaction of macrocyclic compounds. The probe me1 and dm2 characterized by elemental analysis, FT-IR, 1H and 13C NMR, LC-MS spectral techniques. The compounds as mentioned above subjected to FE-SEM with EDS and elemental color mapping. On addition of Al3+, the fluorescent probe me1 and dm2 induces turn-on responses in both absorption and sensing spectra by a PET mechanism. The receptor me1 and dm2 serve highly selective, sensitive and turn-on detection of Al3+. Further, they did not interfere with other cations present in biological or environmental samples. The detection limit is found to be 3 μM and 5 μM. From the view of cytotoxic activity, the ability of these compounds me1 and dm2 to inhibit the growth of KB cell lines examined. The chelating functionality of compounds me1 and dm2 examined for their inhibitory properties of KB cell, live cell images. The compounds me1 and dm2 subjected to theoretical studies by DFT-B3LYP invoking the 6-31G level of theory. The energy of the HOMO and LUMO has been established.

Highly selective and sensitive macrocycle-based dinuclear foldamer for fluorometric and colorimetric sensing of citrate in water.

PubMed

Rhaman, Md Mhahabubur; Hasan, Mohammad H; Alamgir, Azmain; Xu, Lihua; Powell, Douglas R; Wong, Bryan M; Tandon, Ritesh; Hossain, Md Alamgir

2018-01-10

The selective detection of citrate anions is essential for various biological functions in living systems. A quantitative assessment of citrate is required for the diagnosis of various diseases in the human body; however, it is extremely challenging to develop efficient fluorescence and color-detecting molecular probes for sensing citrate in water. Herein, we report a macrocycle-based dinuclear foldamer (1) assembled with eosin Y (EY) that has been studied for anion binding by fluorescence and colorimetric techniques in water at neutral pH. Results from the fluorescence titrations reveal that the 1·EY ensemble strongly binds citrate anions, showing remarkable selectivity over a wide range of inorganic and carboxylate anions. The addition of citrate anions to the 1·EY adduct led to a large fluorescence enhancement, displaying a detectable color change under both visible and UV light in water up to 2 μmol. The biocompatibility of 1·EY as an intracellular carrier in a biological system was evaluated on primary human foreskin fibroblast (HF) cells, showing an excellent cell viability. The strong binding properties of the ensemble allow it to be used as a highly sensitive, detective probe for biologically relevant citrate anions in various applications.

A Reliable Hybrid Adsorbent for Efficient Radioactive Cesium Accumulation from Contaminated Wastewater

PubMed Central

Awual, Md. Rabiul; Yaita, Tsuyoshi; Miyazaki, Yuji; Matsumura, Daiju; Shiwaku, Hideaki; Taguchi, Tomitsugu

2016-01-01

Cesium (Cs) removal from nuclear liquid wastewater has become an emerging issue for safeguarding public health after the accident at the Fukushima Daiichi Nuclear Power Plant. A novel macrocyclic ligand of o-benzo-p-xylyl-22-crown-6-ether (OBPX22C6) was developed and successfully immobilized onto mesoporous silica for the preparation of hybrid adsorbent. The benzene ring π electron is the part of crown ether of OBPX22C6 for easy orientation of the macrocyclic compound for making the π electron donation with Cs complexation. The potential and feasibility of the hybrid adsorbent as being Cs selective was evaluated in terms of sensitivity, selectivity and reusability. The results clarified that the Cs removal process was rapid and reached saturation within a short time. Considering the effect of competitive ions, sodium (Na) did not markedly affect the Cs adsorption whereas potassium (K) was slightly affected due to the similar ionic radii. However, the oxygen in long ethylene glycol chain in OBPX22C6 was expected to show strong coordination, including Cs-π interaction with Cs even in the presence of the high amount of K and Na. Due to its high selectivity and reusability, significant volume reduction is expected as this promising hybrid adsorbent is used for Cs removal in Fukushima wastewater. PMID:26818070

A Reliable Hybrid Adsorbent for Efficient Radioactive Cesium Accumulation from Contaminated Wastewater.

PubMed

Awual, Md Rabiul; Yaita, Tsuyoshi; Miyazaki, Yuji; Matsumura, Daiju; Shiwaku, Hideaki; Taguchi, Tomitsugu

2016-01-28

Cesium (Cs) removal from nuclear liquid wastewater has become an emerging issue for safeguarding public health after the accident at the Fukushima Daiichi Nuclear Power Plant. A novel macrocyclic ligand of o-benzo-p-xylyl-22-crown-6-ether (OBPX22C6) was developed and successfully immobilized onto mesoporous silica for the preparation of hybrid adsorbent. The benzene ring π electron is the part of crown ether of OBPX22C6 for easy orientation of the macrocyclic compound for making the π electron donation with Cs complexation. The potential and feasibility of the hybrid adsorbent as being Cs selective was evaluated in terms of sensitivity, selectivity and reusability. The results clarified that the Cs removal process was rapid and reached saturation within a short time. Considering the effect of competitive ions, sodium (Na) did not markedly affect the Cs adsorption whereas potassium (K) was slightly affected due to the similar ionic radii. However, the oxygen in long ethylene glycol chain in OBPX22C6 was expected to show strong coordination, including Cs-π interaction with Cs even in the presence of the high amount of K and Na. Due to its high selectivity and reusability, significant volume reduction is expected as this promising hybrid adsorbent is used for Cs removal in Fukushima wastewater.

High Affinity Macrocycle Threading by a Near-Infrared Croconaine Dye with Flanking Polymer Chains

PubMed Central

Liu, Wenqi; Peck, Evan M.; Smith, Bradley D.

2016-01-01

Croconaine dyes have narrow and intense absorption bands at ~800 nm, very weak fluorescence, and high photostabilities, which combine to make them very attractive chromophores for absorption-based imaging or laser heating technologies. The physical supramolecular properties of croconaine dyes have rarely been investigated, especially in water. This study focuses on a molecular threading process that encapsulates a croconaine dye inside a tetralactam macrocycle in organic or aqueous solvent. Macrocycle association and rate constant data are reported for a series of croconaine structures with different substituents attached to the ends of the dye. The association constants were highest in water (Ka ~109 M−1), and the threading rate constants (kon) increased in the solvent order H2O > MeOH > CHCl3. Systematic variation of croconaine substituents located just outside the croconaine/macrocycle complexation interface hardly changed Ka but had a strong influence on kon. A croconaine dye with N-propyl groups at each end of the structure exhibited a desirable mixture of macrocycle threading properties; that is, there was rapid and quantitative croconaine/macrocycle complexation at relatively high concentrations in water, and no dissociation of the pre-assembled complex when it was diluted into a solution of fetal bovine serum, even after laser induced photothermal heating of the solution. The combination of favorable near-infrared absorption properties and tunable mechanical stability makes threaded croconaine/macrocycle complexes very attractive as molecular probes or as supramolecular composites for various applications in absorption-based imaging or photothermal therapy. PMID:26807599

Treatment of MDR1 Mutant Dogs with Macrocyclic Lactones

PubMed Central

Geyer, Joachim; Janko, Christina

2012-01-01

P-glycoprotein, encoded by the multidrug resistance gene MDR1, is an ATP-driven drug efflux pump which is highly expressed at the blood-brain barrier of vertebrates. Drug efflux of macrocyclic lactones by P-glycoprotein is highly relevant for the therapeutic safety of macrocyclic lactones, as thereby GABA-gated chloride channels, which are confined to the central nervous system in vertebrates, are protected from high drug concentrations that otherwise would induce neurological toxicity. A 4-bp deletion mutation exists in the MDR1 gene of many dog breeds such as the Collie and the Australian Shepherd, which results in the expression of a non-functional P-glycoprotein and is associated with multiple drug sensitivity. Accordingly, dogs with homozygous MDR1 mutation are in general prone to neurotoxicity by macrocyclic lactones due to their increased brain penetration. Nevertheless, treatment of these dogs with macrocyclic lactones does not inevitably result in neurological symptoms, since, the safety of treatment highly depends on the treatment indication, dosage, route of application, and the individual compound used as outlined in this review. Whereas all available macrocyclic lactones can safely be administered to MDR1 mutant dogs at doses usually used for heartworm prevention, these dogs will experience neurological toxicity following a high dose regimen which is common for mange treatment in dogs. Here, we review and discuss the neurotoxicological potential of different macrocyclic lactones as well as their treatment options in MDR1 mutant dogs. PMID:22039792

Macrocyclic Receptor for Precious Gold, Platinum, or Palladium Coordination Complexes.

PubMed

Liu, Wenqi; Oliver, Allen G; Smith, Bradley D

2018-06-06

Two macrocyclic tetralactam receptors are shown to selectively encapsulate anionic, square-planar chloride and bromide coordination complexes of gold(III), platinum(II), and palladium(II). Both receptors have a preorganized structure that is complementary to its precious metal guest. The receptors do not directly ligate the guest metal center but instead provide an array of arene π-electron donors that interact with the electropositive metal and hydrogen-bond donors that interact with the outer electronegative ligands. This unique mode of supramolecular recognition is illustrated by six X-ray crystal structures showing receptor encapsulation of AuCl 4 - , AuBr 4 - , PtCl 4 -2 , or Pd 2 Cl 6 -2 . In organic solution, the 1:1 association constants correlate with specific supramolecular features identified in the solid state. Technical applications using these receptors are envisioned in a wide range of fields that involve precious metals, including mining, recycling, catalysis, nanoscience, and medicine.

The HSP90 binding mode of a radicicol-like E-oxime from docking, binding free energy estimations, and NMR 15N chemical shifts

PubMed Central

Spichty, Martin; Taly, Antoine; Hagn, Franz; Kessler, Horst; Barluenga, Sofia; Winssinger, Nicolas; Karplus, Martin

2009-01-01

We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90. Docking poses are then evaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of back-bone 15N provides an additional evaluation criteria. As a last test we check the binding modes against available structure-activity-relationships. We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex. PMID:19482409

On-Surface Synthesis and Characterization of Honeycombene Oligophenylene Macrocycles.

PubMed

Chen, Min; Shang, Jian; Wang, Yongfeng; Wu, Kai; Kuttner, Julian; Hilt, Gerhard; Hieringer, Wolfgang; Gottfried, J Michael

2017-01-24

We report the on-surface formation and characterization of [30]-honeycombene, a cyclotriacontaphenylene, which consists of 30 phenyl rings (C 180 H 120 ) and has a diameter of 4.0 nm. This shape-persistent, conjugated, and unsubstituted hexagonal hydrocarbon macrocycle was obtained by solvent-free synthesis on a silver (111) single-crystal surface, making solubility-enhancing alkyl side groups unnecessary. Side products include strained macrocycles with square, pentagonal, and heptagonal shape. The molecules were characterized by scanning tunneling microscopy and density functional theory (DFT) calculations. On the Ag(111) surface, the macrocycles act as molecular quantum corrals and lead to the confinement of surface-state electrons inside the central cavity. The energy of the confined surface state correlates with the size of the macrocycle and is well described by a particle-in-the-box model. Tunneling spectroscopy suggests conjugation within the planar rings and reveals influences of self-assembly on the electronic structure. While the adsorbed molecules appear to be approximately planar, the free molecules have nonplanar conformation, according to DFT.

MacroEvoLution: A New Method for the Rapid Generation of Novel Scaffold-Diverse Macrocyclic Libraries.

PubMed

Saupe, Jörn; Kunz, Oliver; Haustedt, Lars Ole; Jakupovic, Sven; Mang, Christian

2017-09-04

Macrocycles are a structural class bearing great promise for future challenges in medicinal chemistry. Nevertheless, there are few flexible approaches for the rapid generation of structurally diverse macrocyclic compound collections. Here, an efficient method for the generation of novel macrocyclic peptide-based scaffolds is reported. The process, named here as "MacroEvoLution", is based on a cyclization screening approach that gives reliable access to novel macrocyclic architectures. Classification of building blocks into specific pools ensures that scaffolds with orthogonally addressable functionalities are generated, which can easily be used for the generation of structurally diverse compound libraries. The method grants rapid access to novel scaffolds with scalable synthesis (multi gram scale) and the introduction of further diversity at a late stage. Despite being developed for peptidic systems, the approach can easily be extended for the synthesis of systems with a decreased peptidic character. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Macrocycles inserted in graphene: from coordination chemistry on graphene to graphitic carbon oxide.

NASA Astrophysics Data System (ADS)

Liu, Wei; Liu, Jingyao; Miao, Maosheng

Tuning the electronic structure and the chemical properties of graphene by binding with metals has become a focus in the area of two dimension materials. Despite many interesting results and promising potentials, the approach suffers from weak binding and the high reactivity of the metal atoms. On the other hand, many macrocyclic molecules such as crown ether show strong and selective binding with metal atoms. The alliance of the two substances will largely benefit the two parallel fields: it will provide a scaffold for coordination chemistry as well as a controllable method for tuning the electronic structure of graphene through strong binding with metals. Here, using crown ether as an example, we demonstrate by first principles calculations that the embedment of macrocyclic molecules into graphene honeycomb lattice can be very thermochemically favored. The embedment of crown ether on graphene can form a family of new two-dimensional materials that possess varying band gaps and band edges. The one with highest O composition (C2O), with similar structure features as graphilic C3N4, shows strong potentials for photolysis and as true two-dimensional superconductor while binding with alkali metals. Calculations are performed on NSF-funded XSEDE resources (TG-DMR130005). This research is also supported by National Natural Science Foundation of China (Grants No. 21373098) in China.

Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.

PubMed

Huang, Yifang; Strobel, Eric D; Ho, Chih Y; Reynolds, Charles H; Conway, Kelly A; Piesvaux, Jennifer A; Brenneman, Douglas E; Yohrling, George J; Moore Arnold, H; Rosenthal, Daniel; Alexander, Richard S; Tounge, Brett A; Mercken, Marc; Vandermeeren, Marc; Parker, Michael H; Reitz, Allen B; Baxter, Ellen W

2010-05-15

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)). Copyright 2010 Elsevier Ltd. All rights reserved.

Self-assembled monolayers of shape-persistent macrocycles on graphite: interior design and conformational polymorphism.

PubMed

Vollmeyer, Joscha; Eberhagen, Friederike; Höger, Sigurd; Jester, Stefan-S

2014-01-01

Three shape-persistent naphthylene-phenylene-acetylene macrocycles of identical backbone structures and extraannular substitution patterns but different (empty, apolar, polar) nanopore fillings are self-assembled at the solid/liquid interface of highly oriented pyrolytic graphite and 1,2,4-trichlorobenzene. Submolecularly resolved images of the resulting two-dimensional (2D) crystalline monolayer patterns are obtained by in situ scanning tunneling microscopy. A concentration-dependent conformational polymorphism is found, and open and more dense packing motifs are observed. For all three compounds alike lattice parameters are found, therefore the intermolecular macrocycle distances are mainly determined by their size and symmetry. This is an excellent example that the graphite acts as a template for the macrocycle organization independent from their specific interior.

Host-guest capability of a three-dimensional heterometallic macrocycle.

PubMed

Fan, Qi-Jia; Lin, Yue-Jian; Hahn, F Ekkehardt; Jin, Guo-Xin

2018-02-13

A three-dimensional heterometallic coordination macrocycle is found to be capable of encapsulating planar pyrene (G1), coronene (G4) and non-planar corannulene (G2) guest molecules in high yields, giving rise to 1 : 1 host-guest complexes. The bowl-shaped guest corannulene is found to be significantly flattened upon inclusion within the cavity. However, macrocyclic compounds with larger cavity sizes, which form 1 : 1 stoichiometry assemblies with a naphthalene bisimide planar molecule (G3), are more inclined to form infinite sandwich structures. Furthermore, these heterometallic coordination macrocycles can be destroyed in the presence of a soft base to form hexanuclear triangular prism complexes. These structures are unambiguously revealed by single-crystal X-ray analysis.

Catalytic "active-metal" template synthesis of [2]rotaxanes, [3]rotaxanes, and molecular shuttles, and some observations on the mechanism of the cu(i)-catalyzed azide-alkyne 1,3-cycloaddition.

PubMed

Aucagne, Vincent; Berna, José; Crowley, James D; Goldup, Stephen M; Hänni, Kevin D; Leigh, David A; Lusby, Paul J; Ronaldson, Vicki E; Slawin, Alexandra M Z; Viterisi, Aurélien; Walker, D Barney

2007-10-03

A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.

Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery.

PubMed

Chen, I-Jen; Foloppe, Nicolas

2013-12-15

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the 'Drug-like', larger 'Flexible', and 'Macrocycle' compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles. Copyright © 2013 Elsevier Ltd. All rights reserved.

Structural basis of nonribosomal peptide macrocyclization in fungi.

PubMed

Zhang, Jinru; Liu, Nicholas; Cacho, Ralph A; Gong, Zhou; Liu, Zhu; Qin, Wenming; Tang, Chun; Tang, Yi; Zhou, Jiahai

2016-12-01

Nonribosomal peptide synthetases (NRPSs) in fungi biosynthesize important pharmaceutical compounds, including penicillin, cyclosporine and echinocandin. To understand the fungal strategy of forging the macrocyclic peptide linkage, we determined the crystal structures of the terminal condensation-like (C T ) domain and the holo thiolation (T)-C T complex of Penicillium aethiopicum TqaA. The first, to our knowledge, structural depiction of the terminal module in a fungal NRPS provides a molecular blueprint for generating new macrocyclic peptide natural products.

Minimum structural requirements for cell membrane leakage-mediated anti-MRSA activity of macrocyclic bis(bibenzyl)s.

PubMed

Fujii, Kana; Morita, Daichi; Onoda, Kenji; Kuroda, Teruo; Miyachi, Hiroyuki

2016-05-01

Macrocyclic bis(bibenzyl)-type phenolic natural products, found exclusively in bryophytes, exhibit potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Here, in order to identify the minimum essential structure for cell membrane leakage-mediated anti-MRSA activity of these compounds, we synthesized acyclic fragment structures and evaluated their anti-MRSA activity. The activities of all of the acyclic fragments tested exhibited similar characteristics to those of the macrocycles, i.e., anti-MRSA bactericidal activity, an enhancing effect on influx and efflux of ethidium bromide (EtBr: fluorescent DNA-binder) in Staphylococcus aureus cells, and bactericidal activity towards a Staphylococcus aureus strain resistant to 2-phenoxyphenol (4). The latter result suggests that they have a different mechanism of action from 4, which is a FabI inhibitor previously proposed to be the minimum active fragment of riccardin-type macrocycles. Thus, cyclic structure is not a necessary condition for cell membrane leakage-mediated anti-MRSA activity of macrocyclic bis(bibenzyl)s. Copyright © 2016 Elsevier Ltd. All rights reserved.

A 26-Membered Macrocycle Obtained by a Double Diels-Alder Cycloaddition Between Two 2H-Pyran-2-one Rings and Two 1,1'-(Hexane-1,6-diyl)bis (1H-pyrrole-2,5-dione)s.

PubMed

Turek, Bor Lucijan; Kočevar, Marijan; Kranjc, Krištof; Perdih, Franc

2017-12-01

With the application of a double dienophile 1,1'-(hexane-1,6-diyl)bis(1H-pyrrole-2,5-dione) for a [4+2] cycloaddition with a substituted 2H-pyran-2-one a novel 26-membered tetraaza heteromacrocyclic system 3 was prepared via a direct method under solvent-free conditions with microwave irradiation. The macrocycle prepared is composed of two units of the dienophile and two of the diene. The structure of the macrocycle was characterized on the basis of IR, 1H and 13C NMR and mass spectroscopy, as well as by the elemental analysis and melting point determination. With X-ray diffraction of a single crystal of the macrocycle we have determined that the two acetyl groups (attached to the bridging double bond of the bicyclo[2.2.2]octene fragments) are oriented towards each other (and also towards the inside of the cavity of the macrocycle), therefore, mostly filling it completely.

Catalytic reduction of pralidoxime in pharmaceuticals by macrocyclic Ni(II) compounds derived from orthophthalaldehyde.

PubMed

Reddy, P Muralidhar; Prasad, Adapa V S S; Rohini, Rondla; Ravinder, Vadde

2008-08-01

Efficient catalytic method for the reduction of pralidoxime to its amine derivative by macrocyclic Ni(II) compounds has been developed. Ten macrocyclic Schiff base Ni(II) compounds were synthesized via non-template synthesis by treating the corresponding macrocycles with nickel chloride in 1:1 ratio. The resulting compounds were characterized by elemental, IR, (1)H NMR, (13)C NMR, mass, electronic spectra, conductance, magnetic, thermal studies and their structures have been proposed. These compounds were used as catalysts for the reduction of pralidoxime to its amino derivative. The reduced pralidoxime was also characterized by spectral analysis and catalytic cycle has been established. The reduced product was determined spectrophotometrically by treating with ninhydrin reagent and the percent yields were found to be in the range of 75.12-82.36%.

Kinetic Analysis for Macrocyclizations Involving Anionic Template at the Transition State

PubMed Central

Martí-Centelles, Vicente; Burguete, M. Isabel; Luis, Santiago V.

2012-01-01

Several kinetic models for the macrocyclization of a C2 pseudopeptide with a dihalide through a SN2 reaction have been developed. These models not only focus on the kinetic analysis of the main macrocyclization reaction, but also consider the competitive oligomerization/polymerization processes yielding undesired oligomeric/polymeric byproducts. The effect of anions has also been included in the kinetic models, as they can act as catalytic templates in the transition state reducing and stabilizing the transition state. The corresponding differential equation systems for each kinetic model can be solved numerically. Through a comprehensive analysis of these results, it is possible to obtain a better understanding of the different parameters that are involved in the macrocyclization reaction mechanism and to develop strategies for the optimization of the desired processes. PMID:22666148

Advances in macrocyclic peptide-based antibiotics.

PubMed

Luther, Anatol; Bisang, Christian; Obrecht, Daniel

2018-06-01

Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fluorescence Turn-on Enantioselective Recognition of both Chiral Acidic Compounds and α-Amino Acids by a Chiral Tetraphenylethylene Macrocycle Amine.

PubMed

Feng, Hai-Tao; Zhang, Xing; Zheng, Yan-Song

2015-08-21

New chiral tetraphenylethylene (TPE) macrocycles bearing optically pure amine groups were synthesized and found to have a discriminating ability between the two enantiomers of not only chiral acidic compounds but also α-amino acids by enantioselective aggregation and aggregation-induced emission (AIE) effects. NMR spectra, including 2D-NOESY, disclosed that the host-guest interaction of the macrocycle receptor played a key role in addition to the acid-base interactions.

Aureoverticillactam, a novel 22-atom macrocyclic lactam from the marine actinomycete Streptomyces aureoverticillatus.

PubMed

Mitchell, Scott S; Nicholson, Benjamin; Teisan, Sy; Lam, Kin S; Potts, Barbara C M

2004-08-01

During the course of our screening program designed to discover novel anticancer and anti-infective agents from marine microorganisms, a strain of Streptomyces aureoverticillatus (NPS001583) isolated from a marine sediment was found to produce a novel macrocyclic lactam with cytotoxicity against various tumor cell lines. Using extensive MS, UV, and NMR spectral analyses, the structure has been established as compound 1, aureoverticillactam, a 22-atom macrocyclic lactam incorporating both triene and tetraene conjugated olefins.

Macrocycles

DOEpatents

Raymond, Kenneth N.; Xu, Jide; Pham, Tiffany A.

2016-09-13

The invention provides macrocycles useful in chelating metal ions, particularly radionuclides, to provide metal ion complexes. The invention also provides methods of using the compounds and complexes of the invention, such as in therapeutic and diagnostic applications.

Synthesis of potent G-quadruplex binders of macrocyclic heptaoxazole and evaluation of their activities.

PubMed

Tera, Masayuki; Iida, Keisuke; Shin-ya, Kazuo; Nagasawa, Kazuo

2009-01-01

Guanine-rich DNA sequences form unique three-dimensional conformation known as G-quadruplexes (G-q). G-q structures have been found in telomere and in some oncogene promoter. Recently, it was suggested that G-q showed some biological activities including telomere shortening and transcriptional regulation. In this paper, we synthesized selective G-q binders and evaluated of their biological activities.

Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Alkynes: The Transannular Pauson-Khand Reaction.

PubMed

Karabiyikoglu, Sedef; Boon, Byron A; Merlic, Craig A

2017-08-04

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2 + 2 + 1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Macrocyclic enyne and dienyne complexes were readily synthesized by palladium(II)-catalyzed oxidative macrocyclizations of bis(vinyl boronate esters) or ring-closing metathesis reactions followed by complexation with dicobalt octacarbonyl. Several reaction modalities of these macrocyclic complexes were uncovered. In addition to the first successful transannular Pauson-Khand reactions, other intermolecular and transannular cycloaddition reactions included intermolecular Pauson-Khand reactions, transannular [4 + 2] cycloaddition reactions, intermolecular [2 + 2 + 2] cycloaddition reactions, and intermolecular [2 + 2 + 1 + 1] cycloaddition reactions. The structural and reaction requirements for each process are presented.

Structural characterization of synthetic and protein-bound porphyrins in terms of the lowest-frequency normal coordinates of the macrocycle

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

Jentzen, W.; Song, X.Z.; Shelnutt, J.A.

1997-02-27

The X-ray crystal structures of synthetic and protein-bound metalloporphyrins are analyzed using a new normal structural decomposition method for classifying and quantifying their out-of-plane and in-plane distortions. These distortions are characterized in terms of equivalent displacements along the normal coordinates of the D{sub 4h}-symmetric porphyrin macrocycle (normal deformations). It is shown that the macrocyclic structure is, even in highly distorted porphyrins, accurately represented by displacements along only the lowest-frequency normal coordinates. Accordingly, the macrocyclic structure obtained from just the out-of-plane normal deformations of the saddling (sad, B{sub 2u})-, ruffling (ruf, B{sub 1u})-, doming (dom, A{sub 2u})-, waving [wav(x), wav(y); E{submore » g}]-, and propellering (pro, A{sub 1u})-type essentially simulates the out-of-plane distortion of the X-ray crystal structure. Similarly, the observed in-plane distortions are decomposed into in-plane normal deformations corresponding to the lowest-frequency vibrational modes including macrocycle stretching in the direction of the meso-carbon atoms (meso-str, B{sub 2g}), stretching in the direction of the nitrogen atoms (N-str, B{sub 1g}), x and y pyrrole translations [trn(x), trn(y); E{sub u}], macrocycle breathing (bre, A{sub 1g}), and pyrrole rotation (rot, A{sub 2g}). 71 refs., 9 figs., 4 tabs.« less

Minireview: Mode of action of meta-diamide insecticides.

PubMed

Nakao, Toshifumi; Banba, Shinichi

2015-06-01

Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor noncompetitive antagonists showing high insecticidal activity against Spodoptera litura. The mode of action of the meta-diamides was demonstrated to be distinct from that of conventional noncompetitive antagonists (NCAs) such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. It was suggested that meta-diamides act at or near G336 in the M3 region of the Drosophila RDL GABA receptor. Although the site of action of the meta-diamides appears to overlap with that of macrocyclic lactones including avermectins and milbemycins, differential effects of mutations on the actions of the meta-diamides and the macrocyclic lactones were observed. Molecular modeling studies revealed that the meta-diamides may bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor better when in the closed state, which is distinct from the NCA-binding site, which is in a channel formed by M2s. In contrast, the macrocyclic lactones were suggested to bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor when in the open state. Furthermore, mechanisms underlying the high selectivity of meta-diamides are discussed. This minireview highlights the unique features of novel meta-diamide insecticides and demonstrates why meta-diamides are anticipated to become prominent insecticides that are effective against pests resistant to cyclodienes and fipronil. Copyright © 2014 Elsevier Inc. All rights reserved.

ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs

NASA Astrophysics Data System (ADS)

Cleves, Ann E.; Jain, Ajay N.

2017-05-01

We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

Reactions of copper macrocycles with antioxidants and HOCl: potential for biological redox sensing.

PubMed

Sowden, Rebecca J; Trotter, Katherine D; Dunbar, Lynsey; Craig, Gemma; Erdemli, Omer; Spickett, Corinne M; Reglinski, John

2013-02-01

A series of simple copper N(2)S(2) macrocycles were examined for their potential as biological redox sensors, following previous characterization of their redox potentials and crystal structures. The divalent species were reduced by glutathione or ascorbate at a biologically relevant pH in aqueous buffer. A less efficient reduction was also achieved by vitamin E in DMSO. Oxidation of the corresponding univalent copper species by sodium hypochlorite resulted in only partial (~65 %) recovery of the divalent form. This was concluded to be due to competition between metal oxidation and ligand oxidation, which is believed to contribute to macrocycle demetallation. Electrospray mass spectrometry confirmed that ligand oxidation had occurred. Moreover, the macrocyclic complexes could be demetallated by incubation with EDTA and bovine serum albumin, demonstrating that they would be inappropriate for use in biological systems. The susceptibility to oxidation and demetallation was hypothesized to be due to oxidation of the secondary amines. Consequently these were modified to incorporate additional oxygen donor atoms. This modification led to greater resistance to demetallation and ligand oxidation, providing a better platform for further development of copper macrocycles as redox sensors for use in biological systems.

Broflanilide: A meta-diamide insecticide with a novel mode of action.

PubMed

Nakao, Toshifumi; Banba, Shinichi

2016-02-01

Broflanilide is a meta-diamide [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamide] that exhibits high larvicidal activity against Spodoptera litura. It has been suggested that broflanilide is metabolized to desmethyl-broflanilide and that it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of conventional noncompetitive antagonists such as fipronil. It has been proposed that the site of action for desmethyl-broflanilide is close to G336 in the M3 region of the Drosophila RDL GABA receptor. However, although the site of action for desmethyl-broflanilide appears to overlap with that of macrocyclic lactones, different modes of actions have been demonstrated for desmethyl-broflanilide and the macrocyclic lactones. The mechanisms underlying the high selectivity of meta-diamides are also discussed in this review. Broflanilide is expected to become a prominent insecticide because it is effective against pests with resistance to cyclodienes and fipronil. Copyright © 2015 Elsevier Ltd. All rights reserved.

Electrochemically Triggered Co-Conformational Switching in a [2]catenane Comprising a Non-Symmetric Calix[6]arene Wheel and a Two-Station Oriented Macrocycle.

PubMed

Zanichelli, Valeria; Dallacasagrande, Luca; Arduini, Arturo; Secchi, Andrea; Ragazzon, Giulio; Silvi, Serena; Credi, Alberto

2018-05-11

Catenanes with desymmetrized ring components can undergo co-conformational rearrangements upon external stimulation and can form the basis for the development of molecular rotary motors. We describe the design, synthesis and properties of a [2]catenane consisting of a macrocycle-the 'track' ring-endowed with two distinct recognition sites (a bipyridinium and an ammonium) for a calix[6]arene-the 'shuttle' ring. By exploiting the ability of the calixarene to thread appropriate non-symmetric axles with directional selectivity, we assembled an oriented pseudorotaxane and converted it into the corresponding oriented catenane by intramolecular ring closing metathesis. Cyclic voltammetric experiments indicate that the calixarene wheel initially surrounds the bipyridinium site, moves away from it when it is reduced, and returns in the original position upon reoxidation. A comparison with appropriate model compounds shows that the presence of the ammonium station is necessary for the calixarene to leave the reduced bipyridinium site.

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration

PubMed Central

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-01-01

Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. Conclusions and Implications The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. PMID:23425081

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration.

PubMed

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-05-01

Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Turn on macrocyclic chemosensor for Al3+ ion with facile synthesis and application in live cell imaging.

PubMed

Ezhumalai, Dhineshkumar; Mathivanan, Iyappan; Chinnadurai, Anbuselvan

2018-06-15

An effort of a new Schiff base macrocyclic chemosensor, 1 4 ‑methyl‑2,6,8,12,14,18‑hexaaza‑1,7,13(1,2),4,10,16(1,4)‑hexabenzenacyclooctadecaphane‑2,5,8,11,14,17‑hexaene (me1) and 1 4 ,7 4 ‑dimethyl‑2,6,8,12,14,18‑hexaaza‑1,7,13(1,2),4,10,16(1,4)‑hexabenzenacyclooctadecadecaphane‑2,5,8,11,14,17‑hexaene (dm2), which enables selective sensing of Al 3+ in aqueous DMF were synthesized by a simplistic one-step condensation reaction of macrocyclic compounds. The probe me1 and dm2 characterized by elemental analysis, FT-IR, 1 H and 13 C NMR, LC-MS spectral techniques. The compounds as mentioned above subjected to FE-SEM with EDS and elemental color mapping. On addition of Al 3+ , the fluorescent probe me1 and dm2 induces turn-on responses in both absorption and sensing spectra by a PET mechanism. The receptor me1 and dm2 serve highly selective, sensitive and turn-on detection of Al 3+ . Further, they did not interfere with other cations present in biological or environmental samples. The detection limit is found to be 3μM and 5μM. From the view of cytotoxic activity, the ability of these compounds me1 and dm2 to inhibit the growth of KB cell lines examined. The chelating functionality of compounds me1 and dm2 examined for their inhibitory properties of KB cell, live cell images. The compounds me1 and dm2 subjected to theoretical studies by DFT-B3LYP invoking the 6-31G level of theory. The energy of the HOMO and LUMO has been established. Copyright © 2018 Elsevier B.V. All rights reserved.

Proof of Principle: Immobilisation of Robust CuII3 TbIII -Macrocycles on Small, Suitably Pre-functionalised Gold Nanoparticles.

PubMed

Feltham, Humphrey L C; Dumas, Christophe; Mannini, Matteo; Otero, Edwige; Sainctavit, Philippe; Sessoli, Roberta; Meledandri, Carla J; Brooker, Sally

2017-02-21

In a proof-of-principle study, a soluble macrocyclic single-molecule magnet (SMM) containing a Cu II 3 Tb III magnetic core was covalently grafted onto small gold nanoparticles pre-functionalised with carboxylate-terminated tethers. A modified microemulsion method allowed production of the small and monodisperse nanoparticles (approximately 3.5 nm in diameter) for the chemisorption of a large amount of intact macrocyclic complexes in the hybrid system. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Luminescent macrocyclic lanthanide complexes

DOEpatents

Raymond, Kenneth N; Corneillie, Todd M; Xu, Jide

2014-05-20

The present invention provides a novel class of macrocyclic compounds as well as complexes formed between a metal (e.g., lanthanide) ion and the compounds of the invention. Preferred complexes exhibit high stability as well as high quantum yields of lanthanide ion luminescence in aqueous media without the need for secondary activating agents. Preferred compounds incorporate hydroxy-isophthalamide moieties within their macrocyclic structure and are characterized by surprisingly low, non-specific binding to a variety of polypeptides such as antibodies and proteins as well as high kinetic stability. These characteristics distinguish them from known, open-structured ligands.

Syntheses, solid state and solution structures of the palladium(II) complexes of malonamide-derived open-chain and macrocyclic ligands.

PubMed

Gavrish, Sergey P; Lampeka, Yaroslaw D; Pritzkow, Hans; Lightfoot, Philip

2010-09-07

The crystal structures of the palladium(II) complexes of the open-chain and macrocyclic ligands PdL(1).3H(2)O, PdL(2).6H(2)O and PdL(3).5H(2)O have been determined (H(2)L(1) = 1,4,8,11-tetraazaundecane-5,7-dione, H(2)L(2) = 1,4,8,11-tetraazacyclotetradecane-5,7-dione, H(2)L(3) = 1,4,8,11-tetraazacyclotridecane-5,7-dione). The coordination polyhedra of the palladium(II) ions in all complexes are formed by two deprotonated amide and two amine donors with Pd-N distances being similar in PdL(1) and PdL(2) and substantially shorter in PdL(3). A detailed analysis of the (1)H NMR spectra of the macrocyclic complexes supports the formation in aqueous solution of only N-meso isomers of both compounds in agreement with the X-ray data. The spectra of the palladium(II) macrocyclic complexes are shifted downfield as a whole as compared to those of the nickel(II) analogues with the shifts being essentially non-uniform. The latter feature can be related to the differences in magnetic anisotropy of the M-N bonds. The maxima of d-d absorption bands of the palladium(II) complexes demonstrate weaker dependence on the macrocycle size as compared to those of the nickel(II) analogues. Both macrocyclic compounds PdL(2).6H(2)O and PdL(3).5H(2)O are characterized by lamellar crystal structures consisting of interleaved layers formed by macrocyclic units and by water molecules with similar metal complex layers and different 2D water sheets. A columnar crystal structure is inherent for PdL(1).3H(2)O with the water molecules present as discrete (H(2)O)(3) clusters.

Zn2+ -Ion Sensing by Fluorescent Schiff Base Calix[4]arene Macrocycles.

PubMed

Ullmann, Steve; Schnorr, René; Handke, Marcel; Laube, Christian; Abel, Bernd; Matysik, Jörg; Findeisen, Matthias; Rüger, Robert; Heine, Thomas; Kersting, Berthold

2017-03-17

A macrocyclic ligand (H 2 L) containing two o,o'-bis(iminomethyl)phenol and two calix[4]arene head units has been synthesized and its coordination chemistry towards divalent Ni and Zn investigated. The new macrocycle forms complexes of composition [ML] (M=Zn, M=Ni) and [ZnL(py) 2 ], which were characterized by elemental analysis; IR, UV/Vis, and NMR spectroscopy; electrospray ionization mass spectrometry (ESI-MS); and X-ray crystallography (for [ZnL(py) 2 ] and [NiL]). H 2 L allows the sensitive optical detection of Zn 2+ among a series of biologically relevant metal ions by a dual fluorescence enhancement/quenching effect in solution. The fluorescence intensity of the macrocycle increases by a factor of ten in the presence of Zn 2+ with a detection limit in the lower nanomolar region. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Recent Advances in Macrocyclic Fluorescent Probes for Ion Sensing.

PubMed

Wong, Joseph K-H; Todd, Matthew H; Rutledge, Peter J

2017-01-25

Small-molecule fluorescent probes play a myriad of important roles in chemical sensing. Many such systems incorporating a receptor component designed to recognise and bind a specific analyte, and a reporter or transducer component which signals the binding event with a change in fluorescence output have been developed. Fluorescent probes use a variety of mechanisms to transmit the binding event to the reporter unit, including photoinduced electron transfer (PET), charge transfer (CT), Förster resonance energy transfer (FRET), excimer formation, and aggregation induced emission (AIE) or aggregation caused quenching (ACQ). These systems respond to a wide array of potential analytes including protons, metal cations, anions, carbohydrates, and other biomolecules. This review surveys important new fluorescence-based probes for these and other analytes that have been reported over the past five years, focusing on the most widely exploited macrocyclic recognition components, those based on cyclam, calixarenes, cyclodextrins and crown ethers; other macrocyclic and non-macrocyclic receptors are also discussed.

Preparation and Characterization of Organic-Inorganic Hybrid Macrocyclic Compounds: Cyclic Ladder-like Polyphenylsilsesquioxanes.

PubMed

Zhang, Wenchao; Wang, Xiaoxia; Wu, Yiwei; Qi, Zhi; Yang, Rongjie

2018-04-02

Organic-inorganic hybrid macrocyclic compounds, cyclic polyphenylsilsesquioxanes (cyc-PSQs), have been synthesized through hydrolysis and condensation reactions of phenyltrichlorosilane. Structural characterization has revealed that cyc-PSQs consist of a closed-ring double-chain siloxane inorganic backbone bearing organic phenyl groups. The cyc-PSQ molecules have been simulated and structurally optimized using the Forcite tool as implemented in Materials Studio. Structurally optimized cyc-PSQs are highly symmetrical and regular with high stereoregularity, consistent with the dimensions of their experimentally derived structures. Thermogravimetric analysis showed that these macrocyclic compounds have excellent thermal stability. In addition to these perfectly structured compounds, macrocyclic compounds with the same ring ladder structure but bearing an additional Si-OH group, cyc-PSQs-OH, have also been synthesized. A possible mechanism for the formation of the closed-ring molecular structures of cyc-PSQs and cyc-PSQs-OH is proposed.

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

Alfonso Hernandez, Laura; Nelson, Tammie Renee; Gelin, Maxim F.

The interchromophoric energy-transfer pathways between weakly coupled units in a π-conjugated phenylene–ethynylene macrocycle and its half-ring analogue have been investigated using the nonadiabatic excited-state molecular dynamics approach. To track the flow of electronic transition density between macrocycle units, we formulate a transition density flux analysis adapted from the statistical minimum flow method previously developed to investigate vibrational energy flow. Following photoexcitation, transition density is primarily delocalized on two chromophore units and the system undergoes ultrafast energy transfer, creating a localized excited state on a single unit. In the macrocycle, distinct chromophore units donate transition density to a single acceptor unitmore » but do not interchange transition density among each other. We find that energy transfer in the macrocycle is slower than in the corresponding half ring because of the presence of multiple interfering energy-transfer pathways. Finally, simulation results are validated by modeling the fluorescence anisotropy decay.« less

Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species.

PubMed

Credito, Kim L; Appelbaum, Peter C

2004-11-01

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between

Process for the recovery of strontium from acid solutions

DOEpatents

Horwitz, E. Philip; Dietz, Mark L.

1992-01-01

The invention is a process for selectively extracting strontium and technetium values from aqueous nitric acid waste solutions containing these and other fission product values. The extractant is a macrocyclic polyether in a diluent which is insoluble in water, but which will itself dissolve a small amount of water. The process will extract strontium and technetium values from nitric acid solutions which are up to 6 molar in nitric acid.

Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities.

PubMed

Si, Wen; Xin, Pengyang; Li, Zhan-Ting; Hou, Jun-Li

2015-06-16

Lipid bilayer membranes separate living cells from their environment. Membrane proteins are responsible for the processing of ion and molecular inputs and exports, sensing stimuli and signals across the bilayers, which may operate in a channel or carrier mechanism. Inspired by these wide-ranging functions of membrane proteins, chemists have made great efforts in constructing synthetic mimics in order to understand the transport mechanisms, create materials for separation, and develop therapeutic agents. Since the report of an alkylated cyclodextrin for transporting Cu(2+) and Co(2+) by Tabushi and co-workers in 1982, chemists have constructed a variety of artificial transmembrane channels by making use of either the multimolecular self-assembly or unimolecular strategy. In the context of the design of unimolecular channels, important advances have been made, including, among others, the tethering of natural gramicidin A or alamethicin and the modification of various macrocycles such as crown ethers, cyclodextrins, calixarenes, and cucurbiturils. Many of these unimolecular channels exhibit high transport ability for metal ions, particularly K(+) and Na(+). Concerning the development of artificial channels based on macrocyclic frameworks, one straightforward and efficient approach is to introduce discrete chains to reinforce their capability to insert into bilayers. Currently, this approach has found the widest applications in the systems of crown ethers and calixarenes. We envisioned that for macrocycle-based unimolecular channels, control of the arrangement of the appended chains in the upward and/or downward direction would favor the insertion of the molecular systems into bilayers, while the introduction of additional interactions among the chains would further stabilize a tubular conformation. Both factors should be helpful for the formation of new efficient channels. In this Account, we discuss our efforts in designing new unimolecular artificial channels from tubular pillar[n]arenes by extending their lengths with various ester, hydrazide, and short peptide chains. We have utilized well-defined pillar[5]arene and pillar[6]arene as rigid frameworks that allow the appended chains to afford extended tubular structures. We demonstrate that the hydrazide and peptide chains form intramolecular N-H···O═C hydrogen bonds that enhance the tubular conformation of the whole molecule. The new pillar[n]arene derivatives have been successfully applied as unimolecular channels for the selective transport of protons, water, and amino acids and the voltage-gated transport of K(+). We also show that aromatic hydrazide helices and macrocycles appended with peptide chains are able to mediate the selective transport of NH4(+).

Dynamically analyte-responsive macrocyclic host-fluorophore systems.

PubMed

Ghale, Garima; Nau, Werner M

2014-07-15

CONSPECTUS: Host-guest chemistry commenced to a large degree with the work of Pedersen, who in 1967 first reported the synthesis of crown ethers. The past 45 years have witnessed a substantial progress in the field, from the design of highly selective host molecules as receptors to their application in drug delivery and, particularly, analyte sensing. Much effort has been expended on designing receptors and signaling mechanism for detecting compounds of biological and environmental relevance. Traditionally, the design of a chemosensor comprises one component for molecular recognition, frequently macrocycles of the cyclodextrin, cucurbituril, cyclophane, or calixarene type. The second component, used for signaling, is typically an indicator dye which changes its photophysical properties, preferably its fluorescence, upon analyte binding. A variety of signal transduction mechanisms are available, of which displacement of the dye from the macrocyclic binding site is one of the simplest and most popular ones. This constitutes the working principle of indicator displacement assays. However, indicator displacement assays have been predominantly exploited in a static fashion, namely, to determine absolute analyte concentrations, or, by using combinations of several reporter pairs, to achieve a differential sensing and, thus, identification of specific food products or brands. In contrast, their use in biological systems, for example, with membranes, cells, or with enzymes has been comparably less explored, which led us to the design of the so-called tandem assays, that is, dynamically analyte-responsive host-dye systems, in which the change in analyte concentrations is induced by a biological reaction or process. This methodological variation has practical application potential, because the ability to monitor these biochemical pathways or to follow specific molecules in real time is of paramount interest for both biochemical laboratories and the pharmaceutical industry. We will begin by describing the underlying principles that govern the use of macrocycle-fluorescent dye complexes to monitor time-dependent changes in analyte concentrations. Suitable chemosensing ensembles are introduced, along with their fluorescence responses (switch-on or switch-off). This includes supramolecular tandem assays in their product- and substrate-selective variants, and in their domino and enzyme-coupled modifications, with assays for amino acid decarboxylases, diamine, and choline oxidase, proteases, methyl transferases, acetylcholineesterase (including an unpublished direct tandem assay), choline oxidase, and potato apyrase as examples. It also includes the very recently introduced tandem membrane assays in their published influx and unpublished efflux variants, with the outer membrane protein F as channel protein and protamine as bidirectionally translocated analyte. As proof-of-principle for environmental monitoring applications, we describe sensing ensembles for volatile hydrocarbons.

Self-assembled photosynthesis-inspired light harvesting material and solar cells containing the same

DOEpatents

Lindsey, Jonathan S [Raleigh, NC; Chinnasamy, Muthiah [Raleigh, NC; Fan, Dazhong [Raleigh, NC

2009-12-15

A solar cell is described that comprises: (a) a semiconductor charge separation material; (b) at least one electrode connected to the charge separation material; and (c) a light-harvesting film on the charge separation material, the light-harvesting film comprising non-covalently coupled, self-assembled units of porphyrinic macrocycles. The porphyrinic macrocycles preferably comprise: (i) an intramolecularly coordinated metal; (ii) a first coordinating substituent; and (iii) a second coordinating substituent opposite the first coordinating substituent. The porphyrinic macrocycles can be assembled by repeating intermolecular coordination complexes of the metal, the first coordinating substituent and the second coordinating substituent.

Complexes of DOTA-bisphosphonate conjugates: probes for determination of adsorption capacity and affinity constants of hydroxyapatite.

PubMed

Vitha, Tomas; Kubícek, Vojtech; Hermann, Petr; Kolar, Zvonimir I; Wolterbeek, Hubert Th; Peters, Joop A; Lukes, Ivan

2008-03-04

The adsorption on hydroxyapatite of three conjugates of a bisphosphonate and a macrocycle having C1, C2, and C3 spacers and their terbium complexes was studied by the radiotracer method using 160Tb as the label. The radiotracer-containing complex of the conjugate with the C3 spacer was used as a probe for the determination of the adsorption parameters of other bisphosphonates that lack a DOTA unit. A physicochemical model describing the competitive adsorption was successfully applied in the fitting of the obtained data. The maximum adsorption capacity of bisphosphonates containing bulky substituents is determined mainly by their size. For bisphosphonates having no DOTA moiety, the maximum adsorption capacity is determined by the electrostatic repulsion between negatively charged bisphosphonate groups. Compounds with a hydroxy or amino group attached to the alpha-carbon atom show higher affinities. Macrocyclic compounds containing a short spacer between the different bisphosphonic acid groups and the macrocyclic unit exhibit high affinities, indicating a synergic effect of the bisphosphonic and the macrocyclic groups during adsorption. The competition method described uses a well-characterized complex and allows a simple evaluation of the adsorption behavior of bisphosphonates. The application of the macrocycle-bisphosphonate conjugates allows easy radiolabeling via complexation of a suitable metal isotope.

Fabrication of reduced graphene oxide/macrocyclic cobalt complex nanocomposites as counter electrodes for Pt-free dye-sensitized solar cells

NASA Astrophysics Data System (ADS)

Tsai, Chih-Hung; Shih, Chun-Jyun; Wang, Wun-Shiuan; Chi, Wen-Feng; Huang, Wei-Chih; Hu, Yu-Chung; Yu, Yuan-Hsiang

2018-03-01

In this study, macrocyclic Co complexes were successfully grafted onto graphene oxide (GO) to produce GO/Co nanocomposites with a large surface area, high electrical conductivity, and excellent catalytic properties. The novel GO/Co nanocomposites were applied as counter electrodes for Pt-free dye-sensitized solar cells (DSSCs). Various ratios of macrocyclic Co complexes were used as the reductant to react with the GO, with which the surface functional groups of the GO were reduced and the macrocyclic ligand of the Co complexes underwent oxidative dehydrogenation, after which the conjugated macrocyclic Co systems were grafted onto the surface of the reduced GO to form GO/Co nanocomposites. The surface morphology, material structure, and composition of the GO/Co composites and their influences on the power-conversion efficiency of DSSC devices were comprehensively investigated. The results showed that the GO/Co (1:10) counter electrode (CE) exhibited an optimal power conversion efficiency of 7.48%, which was higher than that of the Pt CE. The GO/Co (1:10) CE exhibited superior electric conductivity, catalytic capacity, and redox capacity. Because GO/Co (1:10) CEs are more efficient and cheaper than Pt CEs, they could potentially be used as a replacement for Pt electrodes.

Methods and intermediates for the synthesis of dipyrrin-substituted porphyrinic macrocycles

DOEpatents

Yu, Lianhe; Muthukumaran, Kannan; Sreedharan, Prathapan; Lindsey, Jonathan S.

2010-05-25

The present invention provides dipyrrin substituted porphyrinic macrocycles, intermediates useful for making the same, and methods of making the same. Such compounds may be used for purposes including the making of molecular memory devices, solar cells and light harvesting arrays.

Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species

PubMed Central

Credito, Kim L.; Appelbaum, Peter C.

2004-01-01

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between ≤0.016 and 0.25 μg/ml. PMID:15504874

Process for the recovery of strontium from acid solutions

DOEpatents

Horwitz, E.P.; Dietz, M.L.

1992-03-31

The invention is a process for selectively extracting strontium and technetium values from aqueous nitric acid waste solutions containing these and other fission product values. The extractant is a macrocyclic polyether in a diluent which is insoluble in water, but which will itself dissolve a small amount of water. The process will extract strontium and technetium values from nitric acid solutions which are up to 6 molar in nitric acid. 5 figs.

Largazole as a Novel and Selective Anti-Breast Cancer Agent

DTIC Science & Technology

2012-10-01

while having no effect on thioester formation. E1 inhibition appears to be specific to human E1 as Largazole ketone fails to inhibit the activation of...activity relationship on p27 ubiquitination. To investigate this, Largazole ester (E), Largazole ketone (K), Largazole macrocycle (M), and seco...L), Largazole ketone (K), and Largazole ester (E) inhibited the ligation of ubiquitin onto p27; however, the M and S analogues and TSA failed to

Largazole as a Novel and Selective Anti-Breast Cancer Agent. Addendum

DTIC Science & Technology

2013-12-01

largazole ketone (K), largazole macrocycle (M), and seco-largazole (S) were tested in an in vitro p27 ubiquitination assay (Figure 2b). We also...inhibitors affect p27 ubiquitination. We observed that largazole (L), largazole ketone (K), and largazole ester (E) inhibited the ligation of...largazole is not required for inhibition, because the ketone and ester analogues were equally potent in blocking p27 ubiquitination. In addition, E1

m-Diethynylbenzene macrocycles: syntheses and self-association behavior in solution.

PubMed

Tobe, Yoshito; Utsumi, Naoto; Kawabata, Kazuya; Nagano, Atsushi; Adachi, Kiyomi; Araki, Shunji; Sonoda, Motohiro; Hirose, Keiji; Naemura, Koichiro

2002-05-15

m-Diethynylbenzene macrocycles (DBMs), buta-1,3-diyne-bridged [4(n)]metacyclophanes, have been synthesized and their self-association behaviors in solution were investigated. Cyclic tetramers, hexamers, and octamers of DBMs having exo-annular octyl, hexadecyl, and 3,6,9-trioxadecyl ester groups were prepared by intermolecular oxidative coupling of dimer units or intramolecular cyclization of the corresponding open-chain oligomers. The aggregation properties were investigated by two methods, the (1)H NMR spectra and the vapor pressure osmometry (VPO). Although some discrepancies were observed between the association constants obtained from the two methods, the qualitative view was consistent with each other. The analysis of self-aggregation by VPO revealed unique aggregation behavior of DBMs in acetone and toluene, which was not elucidated by the NMR method. Namely, the association constants for infinite association are several times larger than the dimerization constant, suggesting that the aggregation is enhanced by the formation of dimers (a nucleation mechanism). In polar solvents, DBMs aggregate more strongly than in chloroform due to the solvophobic interactions between the macrocyclic framework and the solvents. Moreover, DBMs self-associate in aromatic solvents such as toluene and o-xylene more readily than in chloroform. In particular, the hexameric DBM having a large macrocyclic cavity exhibits extremely large association constants in aromatic solvents. By comparing the aggregation properties of DBMs with the corresponding acyclic oligomers, the effect of the macrocyclic structure on the aggregation propensity was clarified. Finally, it turned out that DBMs tend to aggregate more readily than the corresponding phenylacetylene macrocycles, acetylene-bridged [2(n)]metacyclophanes, owing to the withdrawal of the electron density from the aromatic rings by the butadiyne linkages which facilitates pi-pi stacking interactions.

Probing the dynamic reversibility and generation of dynamic combinatorial libraries in the presence of bacterial model oligopeptides as templating guests of tetra-carbohydrazide macrocycles using electrospray mass spectrometry.

PubMed

Nour, Hany F; Islam, Tuhidul; Fernández-Lahore, Marcelo; Kuhnert, Nikolai

2012-12-30

Over the past few decades, bacterial resistance to antibiotics has emerged as a real threat to human health. Accordingly, there is an urgent demand for the development of innovative strategies for discovering new antibiotics. We present the first use of tetra-carbohydrazide cyclophane macrocycles in dynamic combinatorial chemistry (DCC) and molecular recognition as chiral hosts binding oligopeptides, which mimic bacterial cell wall. This study introduces an innovative application of electrospray ionisation time-of-flight mass spectrometry (ESI-TOF MS) to oligopeptides recognition using DCC. A small dynamic library composed of eight functionalised macrocycles has been generated in solution and all members were characterised by ESI-TOF MS. We also probed the dynamic reversibility and mechanism of formation of tetra-carbohydrazide cyclophanes in real-time using ESI-TOF MS. Dynamic reversibility of tetra-carbohydrazide cyclophanes is favored under thermodynamic control. The mechanism of formation of tetra-carbohydrazide cyclophanes involves key dialdehyde intermediates, which have been detected and assigned according to their high-resolution m/z values. Three members of the dynamic library bind efficiently in the gas phase to a selection of oligopeptides, unique to bacteria, allowing observation of host/guest complex ions in the gas phase. We probed the mechanism of the [2+2]-cyclocondensation reaction forming library members, proved dynamic reversibility of tetra-carbohydrazide cyclophanes and showed that complex ions formed between library members and hosts can be observed in the gas phase, allowing the solution of an important problem of biological interest. Copyright © 2012 John Wiley & Sons, Ltd.

Interpreting medium ring canonical conformers by a triangular plane tessellation of the macrocycle

NASA Astrophysics Data System (ADS)

Khalili, Pegah; Barnett, Christopher B.; Naidoo, Kevin J.

2013-05-01

Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed.

One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2.

PubMed

Shi, Yan; Challa, Sridevi; Sang, Peng; She, Fengyu; Li, Chunpu; Gray, Geoffrey M; Nimmagadda, Alekhya; Teng, Peng; Odom, Timothy; Wang, Yan; van der Vaart, Arjan; Li, Qi; Cai, Jianfeng

2017-11-22

Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (K d = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

PubMed Central

2018-01-01

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design. PMID:29652495

Templated bilayer self-assembly of fully conjugated π-expanded macrocyclic oligothiophenes complexed with fullerenes

PubMed Central

Cojal González, José D.; Iyoda, Masahiko; Rabe, Jürgen P.

2017-01-01

Fully conjugated macrocyclic oligothiophenes exhibit a combination of highly attractive structural, optical and electronic properties, and multifunctional molecular thin film architectures thereof are envisioned. However, control over the self-assembly of such systems becomes increasingly challenging, the more complex the target structures are. Here we show a robust self-assembly based on hierarchical non-covalent interactions. A self-assembled monolayer of hydrogen-bonded trimesic acid at the interface between an organic solution and graphite provides host-sites for the epitaxial ordering of Saturn-like complexes of fullerenes with oligothiophene macrocycles in mono- and bilayers. STM tomography verifies the formation of the templated layers. Molecular dynamics simulations corroborate the conformational stability and assign the adsorption sites of the adlayers. Scanning tunnelling spectroscopy determines their rectification characteristics. Current–voltage characteristics reveal the modification of the rectifying properties of the macrocycles by the formation of donor–acceptor complexes in a densely packed all-self-assembled supramolecular nanostructure. PMID:28281557

Lysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci.

PubMed

Schramma, Kelsey R; Seyedsayamdost, Mohammad R

2017-04-21

Macrocycles represent a common structural framework in many naturally occurring peptides. Several strategies exist for macrocyclization, and the enzymes that incorporate them are of great interest, as they enhance our repertoire for creating complex molecules. We recently discovered a new peptide cyclization reaction involving a crosslink between the side chains of lysine and tryptophan that is installed by a radical SAM enzyme. Herein, we characterize relatives of this metalloenzyme from the pathogens Streptococcus agalactiae and Streptococcus suis. Our results show that the corresponding enzymes, which we call AgaB and SuiB, contain multiple [4Fe-4S] clusters and catalyze Lys-Trp crosslink formation in their respective substrates. Subsequent high-resolution-MS and 2D-NMR analyses located the site of macrocyclization. Moreover, we report that AgaB can accept modified substrates containing natural or unnatural amino acids. Aside from providing insights into the mechanism of this unusual modification, the substrate promiscuity of AgaB may be exploited to create diverse macrocyclic peptides.

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

PubMed

Kamenik, Anna S; Lessel, Uta; Fuchs, Julian E; Fox, Thomas; Liedl, Klaus R

2018-05-29

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design.

Templated bilayer self-assembly of fully conjugated π-expanded macrocyclic oligothiophenes complexed with fullerenes

NASA Astrophysics Data System (ADS)

Cojal González, José D.; Iyoda, Masahiko; Rabe, Jürgen P.

2017-03-01

Fully conjugated macrocyclic oligothiophenes exhibit a combination of highly attractive structural, optical and electronic properties, and multifunctional molecular thin film architectures thereof are envisioned. However, control over the self-assembly of such systems becomes increasingly challenging, the more complex the target structures are. Here we show a robust self-assembly based on hierarchical non-covalent interactions. A self-assembled monolayer of hydrogen-bonded trimesic acid at the interface between an organic solution and graphite provides host-sites for the epitaxial ordering of Saturn-like complexes of fullerenes with oligothiophene macrocycles in mono- and bilayers. STM tomography verifies the formation of the templated layers. Molecular dynamics simulations corroborate the conformational stability and assign the adsorption sites of the adlayers. Scanning tunnelling spectroscopy determines their rectification characteristics. Current-voltage characteristics reveal the modification of the rectifying properties of the macrocycles by the formation of donor-acceptor complexes in a densely packed all-self-assembled supramolecular nanostructure.

Chiral Recognition with Macrocyclic Glycopeptides: Mechanisms and Applications

NASA Astrophysics Data System (ADS)

Berthod, Alain; Qiu, Hai Xiao; Staroverov, Sergey M.; Kuznestov, Mikhail A.; Armstrong, Daniel W.

The macrocyclic glycopeptide chiral selectors are natural molecules produced by bacterial fermentation. Purified and bonded to silica particles, they make very useful chiral stationary phases (CSP) with a broad spectrum of applicability in enantiomeric separation. The macrocyclic glycopeptide CSPs are multimodal, the same column being able to work in normal phase mode with apolar mobile phase, in reversed-phase mode, or in polar ionic mode with 100% alcoholic mobile phase of adjusted pH. The role of the carbohydrate units is described as well as the critical charge-charge docking interaction responsible for the amino acid enantiomer recognition. The complimentary phenomenon is also exposed.

New macrocyclic lactones with acaricidal and nematocidal activities from a genetically engineered strain Streptomyces bingchenggensis BCJ60.

PubMed

Li, Jian-Song; Zhang, Hui; Zhang, Shao-Yong; Wang, Hai-Yan; Zhang, Ji; Chen, An-Liang; Wang, Ji-Dong; Xiang, Wen-Sheng

2017-04-01

Two new macrocyclic lactones, 4,25-diethyl-4,25-demethyl-milbemycin β 3 (1) and 27-formaldehyde-milbemycin β 14 (2), were isolated from a genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. The acaricidal and nematocidal capacities of compounds 1 and 2 were evaluated against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, respectively. The results showed that the two new macrocyclic lactones 1 and 2 possessed potent acaricidal and nematocidal activities.

A Macrocyclic β-Iodoallenolate Intermediate is Key: Synthesis of the ABD Core of Phomactin A

PubMed Central

Ciesielski, Jennifer; Cariou, Kevin

2012-01-01

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid-triggered cyclization of a β-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor. PMID:22853449

A macrocyclic ellagitannin trimer, oenotherin T(1), from Oenothera species.

PubMed

Taniguchi, Shoko; Imayoshi, Yoko; Yabu-uchi, Ryoko; Ito, Hideyuki; Hatano, Tsutomu; Yoshida, Takashi

2002-01-01

Oenotherin T(1) was isolated from leaves of Oenothera tetraptera as a major ellagitannin. Its structure, that of a macrocyclic trimer with a new acyl group, an isodehydrovaloneoyl group, was established. This compound was also produced by callus tissues induced from O. laciniata leaves.

Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents.

PubMed

Radbruch, Alexander; Weberling, Lukas D; Kieslich, Pascal J; Hepp, Johanna; Kickingereder, Philipp; Wick, Wolfgang; Schlemmer, Heinz-Peter; Bendszus, Martin

2016-11-01

Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN-pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine. Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods. The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean ± SD, 0.0448 ± 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 ± 0.0459, P = 0.026; gadoterate meglumine: -0.0250 ± 0.0284, P = 0.011). In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease.

Photoswitchable Dihydroazulene Macrocycles for Solar Energy Storage: The Effects of Ring Strain.

PubMed

Vlasceanu, Alexandru; Frandsen, Benjamin N; Skov, Anders B; Hansen, Anne Schou; Rasmussen, Mads Georg; Kjaergaard, Henrik G; Mikkelsen, Kurt V; Nielsen, Mogens Brøndsted

2017-10-06

Efficient energy storage and release are two major challenges of solar energy harvesting technologies. The development of molecular solar thermal systems presents one approach to address these issues by tuning the isomerization reactions of photo/thermoswitches. Here we show that the incorporation of photoswitches into macrocyclic structures is a particularly attractive solution for increasing the storage time. We present the synthesis and properties of a series of macrocycles incorporating two dihydroazulene (DHA) photoswitching subunits, bridged by linkers of varying chain length. Independent of ring size, all macrocycles exhibit stepwise, light-induced, ring-opening reactions (DHA-DHA to DHA-VHF to VHF-VHF; VHF = vinylheptafulvene) with the first DHA undergoing isomerization with a similar efficiency as the uncyclized parent system while the second (DHA-VHF to VHF-VHF) is significantly slower. The energy-releasing, VHF-to-DHA, ring closures also occur in a stepwise manner and are systematically found to proceed slower in the more strained (smaller) cycles, but in all cases with a remarkably slow conversion of the second VHF to DHA. We managed to increase the half-life of the second VHF-to-DHA conversion from 65 to 202 h at room temperature by simply decreasing the ring size. A computational study reveals the smallest macrocycle to have the most energetic VHF-VHF state and hence highest energy density.

Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

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

Wilson, Justin J.; Ferrier, Maryline; Radchenko, Valery

The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope ²¹³Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi³⁺, however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L py), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L pyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L pyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L pz), were prepared by a previously reported method and investigatedmore » here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[ (R)-2-amino-3-( p-isothiocyanato-phenyl)propyl]- trans-(S,S)- cyclohexane-1,2-diamine- N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, ²⁰⁷Bi (t 1/2 = 32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi³⁺ and the generator parent ion Ac³⁺.In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi³⁺ in the presence of the parent isotope Ac³⁺. Among the four tested, L py was found to exhibit optimal Bi³⁺-binding kinetics and complex stability. L py complexes Bi³⁺ more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations corroborate the experimentally observed selectivity of these ligands for Bi³⁺ over Ac³⁺. Taken together, these data implicate L py as a valuable chelating agent for the delivery of ²¹³Bi. Its selectivity for Bi³⁺ and rapid and stable labeling properties warrant further investigation and biological studies.« less

Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

DOE PAGES

Wilson, Justin J.; Ferrier, Maryline; Radchenko, Valery; ...

2015-05-01

The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope ²¹³Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi³⁺, however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L py), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L pyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L pyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L pz), were prepared by a previously reported method and investigatedmore » here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[ (R)-2-amino-3-( p-isothiocyanato-phenyl)propyl]- trans-(S,S)- cyclohexane-1,2-diamine- N,N,N',N",N"-pentaacetic acid (CHX-A''-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, ²⁰⁷Bi (t 1/2 = 32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi³⁺ and the generator parent ion Ac³⁺.In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi³⁺ in the presence of the parent isotope Ac³⁺. Among the four tested, L py was found to exhibit optimal Bi³⁺-binding kinetics and complex stability. L py complexes Bi³⁺ more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations corroborate the experimentally observed selectivity of these ligands for Bi³⁺ over Ac³⁺. Taken together, these data implicate L py as a valuable chelating agent for the delivery of ²¹³Bi. Its selectivity for Bi³⁺ and rapid and stable labeling properties warrant further investigation and biological studies.« less

LANTHANIDE ENHANCE LUMINESCENCE (LEL) WITH ONE AND TWO PHOTON EXCITATION OF QUANTUM DYES LANTHANIDE (III) - MACROCYCLES

EPA Science Inventory

Title: Lanthanide Enhance Luminescence (LEL) with one and two photon excitation of Quantum Dyes? Lanthanide(III)-Macrocycles
Principal Author:
Robert C. Leif, Newport Instruments
Secondary Authors:
Margie C. Becker, Phoenix Flow Systems
Al Bromm, Virginia Commonw...

Metacridamides A and B, bioactive macrocycles from conidia of the entomopathogenic fungus Metarhizium acridum

USDA-ARS?s Scientific Manuscript database

Metarhizium acridum, an entomopathogenic fungus, has been commercialized and used successfully for biocontrol of grasshopper pests in Africa and Australia. Its conidia produce two novel 17-membered macrocycles, metacridamides A (1) and B (2), which consist of a Phe unit condensed with a nonaketide....

Two-Photon Porphyrin Core Dendrimers for Optical Power Limiting

DTIC Science & Technology

2006-09-30

macrocycle as compared to centro- symmetric porphyrins. Lowering of the symmetry relaxes the parity selection rules for 2PA, thus making the Soret band...collection of information is estimated to average 1 hour per response, including the time for reviewing instr* - - a 9 www, yen. .c. my anu maintaining...and polymers [2]. 3. We have completed a detailed study of 2PA in symmetrical and asymmetrical (push-pull) phthalocyanines [3,4,5]. 4. We have

Selective Anion Binding by a Cofacial Binuclear Zinc Complex of a Schiff-Base Pyrrole Macrocycle

PubMed Central

Devoille, Aline M. J.; Richardson, Patricia; Bill, Nathan; Sessler, Jonathan L.; Love, Jason B.

2011-01-01

The synthesis of the new cofacial binuclear zinc complex [Zn2(L)] of a Schiff-base pyrrole macrocycle is reported. It was discovered that the binuclear microenvironment between the two metals of [Zn2(L)] is suited for the encapsulation of anions, leading to the formation of [K(THF)6][Zn2(μ-Cl)(L)].2THF and [Bun4N][Zn2(μ-OH)(L)] which were characterized by X-ray crystallography. Unusually obtuse Zn-X-Zn angles (X=Cl: 150.54(9)° and OH: 157.4(3)°) illustrate the weak character of these interactions and the importance of the cleft pre-organization to stabilize the host. In the absence of added anion, aggregation of [Zn2(L)] was inferred and investigated by successive dilutions and by the addition of coordinating solvents to [Zn2(L)] solutions using NMR spectroscopy as well as isothermal microcalorimetry (ITC). On anion addition, evidence for de-aggregation of [Zn2(L)], combined with the formation of the 1:1 host-guest complex, was observed by NMR spectroscopy and ITC titrations. Furthermore, [Zn2(L)] binds to Cl− selectively in THF as deduced from the ITC analyses, while other halides induce only de-aggregation. These conclusions were reinforced by DFT calculations, which indicated that the binding energies of OH− and Cl− were significantly greater than for the other halides. PMID:21391550

Hybrid maize breeding with doubled haploids: I. One-stage versus two-stage selection for testcross performance.

PubMed

Longin, C Friedrich H; Utz, H Friedrich; Reif, Jochen C; Schipprack, Wolfgang; Melchinger, Albrecht E

2006-03-01

Optimum allocation of resources is of fundamental importance for the efficiency of breeding programs. The objectives of our study were to (1) determine the optimum allocation for the number of lines and test locations in hybrid maize breeding with doubled haploids (DHs) regarding two optimization criteria, the selection gain deltaG(k) and the probability P(k) of identifying superior genotypes, (2) compare both optimization criteria including their standard deviations (SDs), and (3) investigate the influence of production costs of DHs on the optimum allocation. For different budgets, number of finally selected lines, ratios of variance components, and production costs of DHs, the optimum allocation of test resources under one- and two-stage selection for testcross performance with a given tester was determined by using Monte Carlo simulations. In one-stage selection, lines are tested in field trials in a single year. In two-stage selection, optimum allocation of resources involves evaluation of (1) a large number of lines in a small number of test locations in the first year and (2) a small number of the selected superior lines in a large number of test locations in the second year, thereby maximizing both optimization criteria. Furthermore, to have a realistic chance of identifying a superior genotype, the probability P(k) of identifying superior genotypes should be greater than 75%. For budgets between 200 and 5,000 field plot equivalents, P(k) > 75% was reached only for genotypes belonging to the best 5% of the population. As the optimum allocation for P(k)(5%) was similar to that for deltaG(k), the choice of the optimization criterion was not crucial. The production costs of DHs had only a minor effect on the optimum number of locations and on values of the optimization criteria.

Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208).

PubMed

De Marco, Rossella; Bedini, Andrea; Spampinato, Santi; Cavina, Lorenzo; Pirazzoli, Edoardo; Gentilucci, Luca

2016-10-13

Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.

Selection of Wavelengths for Optimum Precision in Simultaneous Spectrophotometric Determinations.

ERIC Educational Resources Information Center

DiTusa, Michael R.; Schilt, Alfred A.

1985-01-01

Although many textbooks include a description of simultaneous determinations employing absorption spectrophotometry and treat the mathematics necessary for analytical quantitations, treatment of analytical wavelength selection has been mostly qualitative. Therefore, a general method for selecting wavelengths for optimum precision in simultaneous…

Synthesis of N₄ donor macrocyclic Schiff base ligands and their Ru (II), Pd (II), Pt (II) metal complexes for biological studies and catalytic oxidation of didanosine in pharmaceuticals.

PubMed

Ravi Krishna, E; Muralidhar Reddy, P; Sarangapani, M; Hanmanthu, G; Geeta, B; Shoba Rani, K; Ravinder, V

2012-11-01

A series of tetraaza (N(4) donor) macrocyclic ligands (L(1)-L(4)) were derived from the condensation of o-phthalaldehyde (OPA) with some substituted aromatic amines/azide, and subsequently used to synthesize the metal complexes of Ru(II), Pd(II) and Pt(II). The structures of macrocyclic ligands and their metal complexes were characterized by elemental analyses, IR, (1)H &(13)C NMR, mass and electronic spectroscopy, thermal, magnetic and conductance measurements. Both the ligands and their complexes were screened for their antibacterial activities against Gram positive and Gram negative bacteria by MIC method. Besides, these macrocyclic complexes were investigated as catalysts in the oxidation of pharmaceutical drug didanosine. The oxidized products were further treated with sulphanilic acid to develop the colored products to determine by spectrophotometrically. The current oxidation method is an environmentally friendly, simple to set-up, requires short reaction time, produces high yields and does not require co-oxidant. Copyright © 2012 Elsevier B.V. All rights reserved.

Toxicity, Spectroscopic Characterization and Electrochemical Behaviour of New Macrocclic Complexes of Lead(II) and Palladium(II) Metals

PubMed Central

Bansal, Anil; Singh, Randhir

2000-01-01

Tetraazamacrocyclie complexes of lead and palladium have been synthesized by the template process using the bis(benzil)ethylenediamine precursor. The tetradentate macrocycle (maL) reacts with PbCl2, PdCl2 and different diamines in a 1:1:1 molar ratio in methanol to give several solid complexes of the types [Pb(maL)(R)Cl2] and [Pd(maL)(R)]Cl2 (where R = 2,6-diaminopyridine or 1,2-phenylenediamine). The macrocycle and its metal complexes have been characterized by elemental analysis, molecular weight determinations, molar conductivity, IR, 1H NMR, 13C NMR, electronic, mass and electrochemical studies. The macrocyclic ligand coordinates through the four azomethine nitrogen atoms which are bridged by benzil moieties. IR spectra suggest that the pyridine nitrogen is not coordinating. The palladium complexes exhibit tetracoordinated square-planar geometry, whereas a hexacoordinated octahedral geometry is suggested for lead complexes. The macrocycle along with its complexes have been screened in vitro against a number of pathogenic fungi and bacteria to assess their growth inhibiting potential. PMID:18475947

Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage.

PubMed

Onoda, Kenji; Sawada, Hiromi; Morita, Daichi; Fujii, Kana; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

2015-07-01

We synthesized three geometrical isomers of a macrocyclic bis(bibenzyl) based on isoplagiochin, a natural product isolated from bryophytes, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The isomer containing a 1,4-linked ring (5) showed only weak activity, whereas the isomers containing a 1,3-linked (6) or 1,2-linked (7) C ring showed potent anti-MRSA activity. Molecular dynamics calculations indicated that these differences are probably due to differences in the conformational flexibility of the macrocyclic ring; the active compounds 6 and 7 were more rigid than 5. In order to understand the action mechanism of anti-MRSA activity, we investigated the cellular flux of a fluorescent DNA-binder, ethidium bromide (EtBr), in the presence and absence of these macrocycles. The active compound 6 increased the levels of EtBr inflow and outflow in S. aureus cells, as did our potent anti-MRSA riccardin derivative (4), indicating that these compounds increased the permeability of the cytoplasmic membrane. Inactive 5 had no effect on EtBr inflow or outflow. Furthermore, compound 6 abrogated the normal intracellular concentration gradients of Na(+) and K(+) in S. aureus cells, increasing the intracellular Na(+) concentration and decreasing the K(+) concentration, while 5 had no such effect. These results indicate that anti-MRSA-active macrocyclic bis(bibenzyl) derivatives directly damage the gram-positive bacterial membrane, resulting in increased permeability. Copyright © 2015 Elsevier Ltd. All rights reserved.

A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine.

PubMed

Ciardiello, J J; Stewart, H L; Sore, H F; Galloway, W R J D; Spring, D R

2017-06-01

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Electrochemical studies of DNA interaction and antimicrobial activities of MnII, FeIII, CoII and NiII Schiff base tetraazamacrocyclic complexes

NASA Astrophysics Data System (ADS)

Kumar, Anuj; Vashistha, Vinod Kumar; Tevatia, Prashant; Singh, Randhir

2017-04-01

Tetraazamacrocyclic complexes of MnII, FeIII, CoII and NiII have been synthesized by template method. These tetraazamacrocycles have been analyzed with various techniques like molar conductance, IR, UV-vis, mass spectral and cyclic voltammetric studies. On the basis of all these studies, octahedral geometry has been assigned to these tetraazamacrocyclic complexes. The DNA binding properties of these macrocyclic complexes have been investigated by electronic absorption spectra, fluorescence spectra, cyclic voltammetric and differential pulse voltammetric studies. The cyclic voltammetric data showed that ipc and ipa were effectively decreased in the presence of calf thymus DNA, which is a strong evidence for the interaction of these macrocyclic complexes with the calf thymus DNA (ct-DNA). The heterogeneous electron transfer rate constant found in the order: KCoII > KNiII > KMnII which indicates that CoII macrocyclic complex has formed a strong intercalated intermediate. The Stern-Volmer quenching constant (KSV) and voltammetric binding constant were found in the order KSV(CoII) > KSV(NiII) > KSV(MnII) and K+(CoII) > K+(NiII) > K+(MnII) which shows that CoII macrocyclic complex exhibits the high interaction affinity towards ct-DNA by the intercalation binding. Biological studies of the macrocyclic complexes compared with the standard drug like Gentamycin, have shown antibacterial activities against E. coli, P. aeruginosa, B. cereus, S. aureus and antifungal activity against C. albicans.

Coherent anti-Stokes Raman scattering (CARS) spectroscopy in Caenorhabditis elegans and Globodera pallida: evidence for an ivermectin-activated decrease in lipid stores.

PubMed

Smus, Justyna P; Ludlow, Elizabeth; Dallière, Nicolas; Luedtke, Sarah; Monfort, Tual; Lilley, Catherine; Urwin, Peter; Walker, Robert J; O'Connor, Vincent; Holden-Dye, Lindy; Mahajan, Sumeet

2017-12-01

Macrocyclic lactones are arguably the most successful chemical class with efficacy against parasitic nematodes. Here we investigated the effect of the macrocyclic lactone ivermectin on lipid homeostasis in the plant parasitic nematode Globodera pallida and provide new insight into its mode of action. A non-invasive, non-destructive, label-free and chemically selective technique called Coherent anti-Stokes Raman scattering (CARS) spectroscopy was used to study lipid stores in G. pallida. We optimised the protocol using the free-living nematode Caenorhabditis elegans and then used CARS to quantify lipid stores in the pre-parasitic, non-feeding J2 stage of G. pallida. This revealed a concentration of lipid stores in the posterior region of J2 s within 24 h of hatching which decreased to undetectable levels over the course of 28 days. We tested the effect of ivermectin on J2 viability and lipid stores. Within 24 h, ivermectin paralysed J2 s. Counterintuitively, over the same time-course ivermectin increased the rate of depletion of J2 lipid, suggesting that in ivermectin-treated J2 s there is a disconnection between the energy requirements for motility and metabolic rate. This decrease in lipid stores would be predicted to negatively impact on J2 infective potential. These data suggest that the benefit of macrocyclic lactones as seed treatments may be underpinned by a multilevel effect involving both neuromuscular inhibition and acceleration of lipid metabolism. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Coherent anti‐Stokes Raman scattering (CARS) spectroscopy in Caenorhabditis elegans and Globodera pallida: evidence for an ivermectin‐activated decrease in lipid stores

PubMed Central

Smus, Justyna P; Ludlow, Elizabeth; Dallière, Nicolas; Luedtke, Sarah; Monfort, Tual; Lilley, Catherine; Urwin, Peter; Walker, Robert J; O'Connor, Vincent

2017-01-01

Abstract BACKGROUND Macrocyclic lactones are arguably the most successful chemical class with efficacy against parasitic nematodes. Here we investigated the effect of the macrocyclic lactone ivermectin on lipid homeostasis in the plant parasitic nematode Globodera pallida and provide new insight into its mode of action. RESULTS A non‐invasive, non‐destructive, label‐free and chemically selective technique called Coherent anti‐Stokes Raman scattering (CARS) spectroscopy was used to study lipid stores in G. pallida. We optimised the protocol using the free‐living nematode Caenorhabditis elegans and then used CARS to quantify lipid stores in the pre‐parasitic, non‐feeding J2 stage of G. pallida. This revealed a concentration of lipid stores in the posterior region of J2 s within 24 h of hatching which decreased to undetectable levels over the course of 28 days. We tested the effect of ivermectin on J2 viability and lipid stores. Within 24 h, ivermectin paralysed J2 s. Counterintuitively, over the same time‐course ivermectin increased the rate of depletion of J2 lipid, suggesting that in ivermectin‐treated J2 s there is a disconnection between the energy requirements for motility and metabolic rate. This decrease in lipid stores would be predicted to negatively impact on J2 infective potential. CONCLUSION These data suggest that the benefit of macrocyclic lactones as seed treatments may be underpinned by a multilevel effect involving both neuromuscular inhibition and acceleration of lipid metabolism. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID:28834172

Structural Heterogeneity of Doubly-Charged Peptide b-Ions

NASA Astrophysics Data System (ADS)

Li, Xiaojuan; Huang, Yiqun; O'Connor, Peter B.; Lin, Cheng

2011-02-01

Performing collisionally activated dissociation (CAD) and electron capture dissociation (ECD) in tandem has shown great promise in providing comprehensive sequence information that was otherwise unobtainable by using either fragmentation method alone or in duet. However, the general applicability of this MS3 approach in peptide sequencing may be undermined by the formation of non-direct sequence ions, as sometimes observed under CAD, particularly when multiple stages of CAD are involved. In this study, varied-sized doubly-charged b-ions from three tachykinin peptides were investigated by ECD. Sequence scrambling was observed in ECD of all b-ions from neurokinin A (HKTDSFVGLM-NH2), suggesting the presence of N- and C-termini linked macro-cyclic conformers. On the contrary, none of the b-ions from eledoisin (pEPSKDAFIGLM-NH2) produced non-direct sequence ions under ECD, as it does not contain a free N-terminal amino group. ECD of several b-ions from Substance P (RPKPQQFFGLM-NH2) showed series of cm-Lys fragment ions which suggested that the macro-cyclic structure may also be formed by connecting the C-terminal carbonyl group and the ɛ-amino group of the lysine side chain. Theoretical investigation of selected Substance P b-ions revealed several low energy conformers, including both linear oxazolones and macro-ring structures, in corroboration with the experimental observation. This study showed that a b-ion may exist as a mixture of several forms, with their propensities influenced by its N-terminus, length, and certain side-chain groups. Further, the presence of several macro-cyclic structures may result in erroneous sequence assignment when the combined CAD and ECD methods are used in peptide sequencing.

Structural Heterogeneity of Doubly-Charged Peptide b-Ions

PubMed Central

Li, Xiaojuan; Huang, Yiqun; O’Connor, Peter B.; Lin, Cheng

2011-01-01

Performing collisionally activated dissociation (CAD) and electron capture dissociation (ECD) in tandem has shown great promise in providing comprehensive sequence information that was otherwise unobtainable by using either fragmentation method alone or in duet. However, the general applicability of this MS3 approach in peptide sequencing may be undermined by the formation of non-direct sequence ions, as sometimes observed under CAD, particularly when multiple stages of CAD are involved. In this study, varied-sized doubly-charged b-ions from three tachykinin peptides were investigated by ECD. Sequence scrambling was observed in ECD of all b-ions from neurokinin A (HKTDSFVGLM-NH2), suggesting the presence of N- and C-termini linked macro-cyclic conformers. On the contrary, none of the b-ions from eledoisin (pEPSKDAFIGLM-NH2) produced non-direct sequence ions under ECD, as it does not contain a free N-terminal amino group. ECD of several b-ions from Substance P (RPKPQQFFGLM-NH2) showed series of cm-Lys fragment ions which suggested that the macro-cyclic structure may also be formed by connecting the C-terminal carbonyl group and the ε-amino group of the lysine side chain. Theoretical investigation of selected Substance P b-ions revealed several low energy conformers, including both linear oxazolones and macro-ring structures, in corroboration with the experimental observation. This study showed that a b-ion may exist as a mixture of several forms, with their propensities influenced by its N-terminus, length, and certain side-chain groups. Further, the presence of several macro-cyclic structures may result in erroneous sequence assignment when the combined CAD and ECD methods are used in peptide sequencing. PMID:21472584

Simultaneous biosynthesis of putrebactin, avaroferrin and bisucaberin by Shewanella putrefaciens and characterisation of complexes with iron(III), molybdenum(VI) or chromium(V).

PubMed

Soe, Cho Zin; Telfer, Thomas J; Levina, Aviva; Lay, Peter A; Codd, Rachel

2016-09-01

Cultures of Shewanella putrefaciens grown in medium containing 10mM 1,4-diamino-2-butanone (DBO) as an inhibitor of ornithine decarboxylase and 10mM 1,5-diaminopentane (cadaverine) showed the simultaneous biosynthesis of the macrocyclic dihydroxamic acids: putrebactin (pbH 2 ), avaroferrin (avH 2 ) and bisucaberin (bsH 2 ). The level of DBO did not completely repress the production of endogenous 1,4-diaminobutane (putrescine) as the native diamine substrate of pbH 2 . The relative concentration of pbH 2 :avH 2 :bsH 2 was 1:2:1, which correlated with the substrate selection of putrescine:cadaverine in a ratio of 1:1. The macrocycles were characterised using LC-MS as free ligands and as 1:1 complexes with Fe(III) of the form [Fe(pb)] + , [Fe(av)] + or [Fe(bs)] + , with labile ancillary ligands in six-coordinate complexes displaced during ESI-MS acquisition; or with Mo(VI) of the form [Mo(O) 2 (pb)], [Mo(O) 2 (av)] or [Mo(O) 2 (bs)]. Chromium(V) complexes of the form [CrO(pb)] + were detected from solutions of Cr(VI) and pbH 2 in DMF using X-band EPR spectroscopy. Supplementation of S. putrefaciens medium with DBO and 1,3-diaminopropane, 1,6-diaminohexane or 1,4-diamino-2(Z)-butene (Z-DBE) resulted only in the biosynthesis of pbH 2 . The work has identified a native system for the simultaneous biosynthesis of a suite of three macrocyclic dihydroxamic acid siderophores and highlights both the utility of precursor-directed biosynthesis for expanding the structural diversity of siderophores, and the breadth of their coordination chemistry. Copyright © 2015 Elsevier Inc. All rights reserved.

Fabrication of novel coated pyrolytic graphite electrodes for the selective nano-level monitoring of Cd²⁺ ions in biological and environmental samples using polymeric membrane of newly synthesized macrocycle.

PubMed

Sahani, Manoj Kumar; Singh, A K; Jain, A K; Upadhyay, Anjali; Kumar, Amit; Singh, Udai P; Narang, Shikha

2015-02-20

Novel 5-amino-1,3,4-thiadiazole-2-thiol unit based macrocyclic ionophore 5,11,17-trithia-1,3,7,9,13,15,19,20,21-nonaazatetracyclo[14.2.1.1(4,7).1(10,13)]henicosa-4(20),10(21),16(19)-triene-6,12,18-trithione (M1), was synthesized and characterized. Preliminary studies on M1 have showed that it has more the affinity toward Cd(2+) ion. Thus, the macrocyclic ionophore (M1) was used as electroactive material in the fabrication of PVC-membrane electrodes such as polymeric membrane electrode (PME), coated graphite electrode (CGE) and coated pyrolytic graphite electrode (CPGE) were prepared and its performance characteristic were compared with. The electroanalytical studies performed on PME, CGE and CPGE revealed that CPGE having membrane composition M1:PVC:1-CN:NaTPB in the ratio of 7:37:54:2 exhibits the best potentiometric characteristics in terms of detection limit of 7.58×10(-9) mol L(-1), Nernstian slope of 29.6 mV decade(-1) of activity. The sensor was found to be independent of pH in the range 2.5-8.5. The sensor showed a fast response time of 10s and could be used over a period of 4 months without any significant divergence in its potentiometric characteristics. The sensor has been employed for monitoring of the Cd(2+) ion in real samples and also used as an indicator electrode in the potentiometric titration of Cd(2+) ion with EDTA. Copyright © 2014. Published by Elsevier B.V.

Phthalocyanines functionalized with 2-methyl-5-nitro-1H-imidazolylethoxy and 1,4,7-trioxanonyl moieties and the effect of metronidazole substitution on photocytotoxicity.

PubMed

Wierzchowski, Marcin; Sobotta, Lukasz; Skupin-Mrugalska, Paulina; Kruk, Justyna; Jusiak, Weronika; Yee, Michael; Konopka, Krystyna; Düzgüneş, Nejat; Tykarska, Ewa; Gdaniec, Maria; Mielcarek, Jadwiga; Goslinski, Tomasz

2013-10-01

Four novel magnesium(II) and zinc(II) phthalocyanines bearing 1,4,7-trioxanonyl, polyether and/or (2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy, heterocyclic substituents at their non-peripheral positions were synthesized and assessed in terms of physicochemical and biological properties. Magnesium phthalocyanine derivatives bearing polyether substituents (Pc-1), a mixed system of polyether and heterocyclic substituents (Pc-3), and four heterocyclic substituents (Pc-4), respectively, were synthesized following the Linstead macrocyclization reaction procedure. Zinc phthalocyanine (Pc-2) bearing polyether substituents at non-peripheral positions was synthesized following the procedure in n-pentanol with the zinc acetate, and DBU. Novel phthalocyanines were purified by flash column chromatography and characterized using NMR, MS, UV-Vis and HPLC. Moreover, two precursors in macrocyclization reaction phthalonitriles were characterized using X-ray. Photophysical properties of the novel macrocycles were evaluated, including UV-Vis spectra analysis and aggregation study. All macrocycles subjected to singlet oxygen generation and the oxidation rate constant measurements exhibited lower quantum yields of singlet oxygen generation in DMSO than in DMF. In addition, the Pc-2 molecule was found to be the most efficient singlet oxygen generator from the group of macrocycles studied. The photocytotoxicity evaluated on the human oral squamous cell carcinoma cell line, HSC-3, for Pc-3 was significantly higher than that for Pc-1, Pc-2, and Pc-4. Interestingly, Pc-3 was found to be the most active macrocycle in vitro although its ability to generate singlet oxygen was significantly lower than those of Pc-1 and Pc-2. However, attempts to encapsulate phthalocyanines Pc-1-Pc-3 in liposomal membranes were unsuccessful. The phthalocyanine-nitroimidazole conjugate, Pc-4 was encapsulated in phosphatidylglycerol:phosphatidylcholine unilamellar liposomes and subjected to photocytotoxicity study. © 2013.

Fifty years of oxacalix[3]arenes: A review

PubMed Central

Cottet, Kevin; Marcos, Paula M

2012-01-01

Summary Hexahomotrioxacalix[3]arenes, commonly called oxacalix[3]arenes, were first reported in 1962. Since then, their chemistry has been expanded to include numerous derivatives and complexes. This review describes the syntheses of the parent compounds, their derivatives, and their complexation behaviour towards cations. Extraction data are presented, as are crystal structures of the macrocycles and their complexes with guest species. Applications in fields as diverse as ion selective electrode modifiers, fluorescence sensors, fullerene separations and biomimetic chemistry are described. PMID:22423288

Entropy-driven homochiral self-sorting of a dynamic library.

PubMed

Atcher, Joan; Bujons, Jordi; Alfonso, Ignacio

2017-04-11

A dynamic mixture of stereoisomeric macrocycles derived from glutamic acid displayed a homochiral self-selection when increasing the acetonitrile content of the aqueous mixed medium. The homochiral self-sorting required the anionic form of the side chains and increased at higher temperature, implying an entropic origin. Conformational analysis (NMR and MD simulations) allowed us to explain the observed behaviour. The results show that entropy can play a role in the homochiral self-sorting in adaptive bio-inspired chemical systems.

Novel octanuclear copper(I) metallomacrocycles and their transformation into hexanuclear 2-dimensional grids of copper(i) coordination polymers containing cyclodiphosphazanes, [(micro-NtBuP)2(NC4H8X)2] (X = NMe, O).

PubMed

Suresh, D; Balakrishna, Maravanji S; Mague, Joel T

2008-07-07

Novel octanuclear copper(I) macrocyclic complexes and hexanuclear 2-dimensional grid-like polymers containing [P(micro-NR)](2) scaffold in which the anionic moieties are trapped inside the cationic macrocyclic cavities are reported.

Organic Materials as Electrodes for Li-ion Batteries

DTIC Science & Technology

2015-09-04

Various macrocycles, their synthesis, characterization and subsequent use in lithium - ion batteries were attempted. Ellagic acid, alizarin and...Various macrocycles, their synthesis, characterization and subsequent use in lithium - ion batteries were attempted. Ellagic acid, alizarin and...characterization and subsequent use in lithium - ion batteries have been attempted to. Lithium -based batteries are at the forefront of battery

Polymers containing nickel(II) complexes of Goedken's macrocycle: optimized synthesis and electrochemical characterization.

PubMed

Paquette, Joseph A; Sauvé, Ethan R; Gilroy, Joe B

2015-04-01

The synthesis and characterization of a new class of nickel-containing polymers is described. The optimized copolymerization of alkyne-bearing nickel(II) complexes of Goedken's macrocycle (4,11-dihydro-5,7,12,14-tetramethyldibenzo[b,i][1,4,8,11]tetraazacyclotetradecine) and brominated 9,9-dihexylfluorene produced polymers with potential application as functional redox-active materials. The title polymers exhibit electrochemically reversible, ligand-centered oxidation events at 0.24 and 0.73 V versus the ferrocene/ferrocenium redox couple. They also display exceptional thermal stability and interesting absorption properties due to the presence of the macrocyclic nickel(II) complexes and π-conjugated units incorporated in their backbones. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Theory of optical transitions in π-conjugated macrocycles

NASA Astrophysics Data System (ADS)

Marcus, Max; Coonjobeeharry, Jaymee; Barford, William

2016-04-01

We describe a theoretical and computational investigation of the optical properties of π-conjugated macrocycles. Since the low-energy excitations of these systems are Frenkel excitons that couple to high-frequency dispersionless phonons, we employ the quantized Frenkel-Holstein model and solve it via the density matrix renormalization group (DMRG) method. First we consider optical emission from perfectly circular systems. Owing to optical selection rules, such systems radiate via two mechanisms: (i) within the Condon approximation, by thermally induced emission from the optically allowed j = ± 1 states and (ii) beyond the Condon approximation, by emission from the j = 0 state via coupling with a totally non-symmetric phonon (namely, the Herzberg-Teller effect). Using perturbation theory, we derive an expression for the Herzberg-Teller correction and show via DMRG calculations that this expression soon fails as ħ ω/J and the size of the macrocycle increase. Next, we consider the role of broken symmetry caused by torsional disorder. In this case the quantum number j no longer labels eigenstates of angular momentum, but instead labels localized local exciton groundstates (LEGSs) or quasi-extended states (QEESs). As for linear polymers, LEGSs define chromophores, with the higher energy QEESs being extended over numerous LEGSs. Within the Condon approximation (i.e., neglecting the Herzberg-Teller correction) we show that increased disorder increases the emissive optical intensity, because all the LEGSs are optically active. We next consider the combined role of broken symmetry and curvature, by explicitly evaluating the Herzberg-Teller correction in disordered systems via the DMRG method. The Herzberg-Teller correction is most evident in the emission intensity ratio, I00/I01. In the Condon approximation I00/I01 is a constant function of curvature, whereas in practice it vanishes for closed rings and only approaches a constant in the limit of vanishing curvature. We calculate the optical spectra of a model system, cyclo-poly(para-phenylene ethynylene), for different amounts of torsional disorder within and beyond the Condon approximation. We show how broken symmetry and the Herzberg-Teller effect explain the spectral features. The Herzberg-Teller correction to the 0-1 emission vibronic peak is always significant. Finally, we note the qualitative similarities between the optical properties of conformationally disordered linear polymers and macrocycles in the limit of sufficiently large disorder, because in both cases they are determined by the optical properties of curved chromophores.

Magnetism in (Semi)Conducting Macrocycles of pi conjugated Polymers

DTIC Science & Technology

2016-12-09

wise and avoiding a break in the continuity of the macrocycle. As a first criterion we tested the continuity of the electron orbitals over the...magnesium chloride) and post polymerization functionalization by a Sonogashira coupling reaction is required (scheme 2). Scheme 2: Synthetic...Sonogashira post - polymerization chain end functionalization and B isotopic model of the different population present in the final batch

Multicomponent Macrocyclization Reactions (MCMRs) Employing Highly Reactive Acyl Ketene and Nitrile Oxide Intermediates

PubMed Central

Knapp, John M.; Fettinger, James C.; Kurth, Mark J.

2011-01-01

An efficient synthesis of spiro-fused macrolactams by a multicomponent macrocyclization reaction (MCMR) is reported. The use of highly reactive, transient intermediates in this MCMR permits short reaction times, even at high dilution. The methods employed for this MCMR were first developed as a four component strategy for the synthesis of β-ketoamide isoxazolines. PMID:21827181

Hydrolyzable tannins of tamaricaceous plants. III. Hellinoyl- and macrocyclic-type ellagitannins from Tamarix nilotica.

PubMed

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

2010-05-28

Three new hellinoyl-type ellagitannins, nilotinins M4 (7), D7 (8), and D8 (9), and a new macrocyclic-type, nilotinin D9 (10), together with eight known tannins, hirtellins B (2), C (11), and F (12), isohirtellin C (13), tamarixinin A (3), tellimagrandins I and II, and 1,2,6-tri-O-galloyl-beta-d-glucose (14), were isolated from an aqueous acetone extract of Tamarix nilotica dried leaves. Nilotinin M4 (7) is a monomeric tannin possessing a hellinoyl moiety. The structure of 8 demonstrated replacement of one of the HHDP groups at the glucose core O-4/O-6 in ordinary dimeric tannins with a galloyl moiety at O-6. This is a new structural feature among the tamaricaceous ellagitannins. On the basis of the results, reported spectroscopic assignments for 2, 3, and the macrocyclic tannins 11-13 were revised. Unusual shifts in the NMR spectra of these macrocyclic tannins are also discussed in relation to their conformations. Several tannins isolated from T. nilotica were assessed for possible cytotoxic activity against four human tumor cell lines, and nilotinin D8 (9) and hirtellin A (1) showed high cytotoxic effects.

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants.

PubMed

Chekan, Jonathan R; Estrada, Paola; Covello, Patrick S; Nair, Satish K

2017-06-20

Enzymes that can catalyze the macrocyclization of linear peptide substrates have long been sought for the production of libraries of structurally diverse scaffolds via combinatorial gene assembly as well as to afford rapid in vivo screening methods. Orbitides are plant ribosomally synthesized and posttranslationally modified peptides (RiPPs) of various sizes and topologies, several of which are shown to be biologically active. The diversity in size and sequence of orbitides suggests that the corresponding macrocyclases may be ideal catalysts for production of cyclic peptides. Here we present the biochemical characterization and crystal structures of the plant enzyme PCY1 involved in orbitide macrocyclization. These studies demonstrate how the PCY1 S9A protease fold has been adapted for transamidation, rather than hydrolysis, of acyl-enzyme intermediates to yield cyclic products. Notably, PCY1 uses an unusual strategy in which the cleaved C-terminal follower peptide from the substrate stabilizes the enzyme in a productive conformation to facilitate macrocyclization of the N-terminal fragment. The broad substrate tolerance of PCY1 can be exploited as a biotechnological tool to generate structurally diverse arrays of macrocycles, including those with nonproteinogenic elements.

The temporal distribution of directional gradients under selection for an optimum.

PubMed

Chevin, Luis-Miguel; Haller, Benjamin C

2014-12-01

Temporal variation in phenotypic selection is often attributed to environmental change causing movements of the adaptive surface relating traits to fitness, but this connection is rarely established empirically. Fluctuating phenotypic selection can be measured by the variance and autocorrelation of directional selection gradients through time. However, the dynamics of these gradients depend not only on environmental changes altering the fitness surface, but also on evolution of the phenotypic distribution. Therefore, it is unclear to what extent variability in selection gradients can inform us about the underlying drivers of their fluctuations. To investigate this question, we derive the temporal distribution of directional gradients under selection for a phenotypic optimum that is either constant or fluctuates randomly in various ways in a finite population. Our analytical results, combined with population- and individual-based simulations, show that although some characteristic patterns can be distinguished, very different types of change in the optimum (including a constant optimum) can generate similar temporal distributions of selection gradients, making it difficult to infer the processes underlying apparent fluctuating selection. Analyzing changes in phenotype distributions together with changes in selection gradients should prove more useful for inferring the mechanisms underlying estimated fluctuating selection. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Improved selectivity for Pb(II) by sulfur, selenium and tellurium analogues of 1,8-anthraquinone-18-crown-5: synthesis, spectroscopy, X-ray crystallography and computational studies.

PubMed

Mariappan, Kadarkaraisamy; Alaparthi, Madhubabu; Hoffman, Mariah; Rama, Myriam Alcantar; Balasubramanian, Vinothini; John, Danielle M; Sykes, Andrew G

2015-07-14

We report here a series of heteroatom-substituted macrocycles containing an anthraquinone moiety as a fluorescent signaling unit and a cyclic polyheteroether chain as the receptor. Sulfur, selenium, and tellurium derivatives of 1,8-anthraquinone-18-crown-5 (1) were synthesized by reacting sodium sulfide (Na2S), sodium selenide (Na2Se) and sodium telluride (Na2Te) with 1,8-bis(2-bromoethylethyleneoxy)anthracene-9,10-dione in a 1 : 1 ratio. The optical properties of the new compounds are examined and the sulfur and selenium analogues produce an intense green emission enhancement upon association with Pb(II) in acetonitrile. Selectivity for Pb(II) is markedly improved as compared to the oxygen analogue 1 which was also competitive for Ca(II) ion. UV-Visible and luminescence titrations reveal that 2 and 3 form 1 : 1 complexes with Pb(II), confirmed by single-crystal X-ray studies where Pb(II) is complexed within the macrocycle through coordinate covalent bonds to neighboring carbonyl, ether and heteroether donor atoms. Cyclic voltammetry of 2-8 showed classical, irreversible oxidation potentials for sulfur, selenium and tellurium heteroethers in addition to two one-electron reductions for the anthraquinone carbonyl groups. DFT calculations were also conducted on 1, 2, 3, 6, 6 + Pb(II) and 6 + Mg(II) to determine the trend in energies of the HOMO and the LUMO levels along the series.

Simple Syntheses of Two New Benzo-Fused Macrocycles Incorporating Chalcone Moiety

PubMed Central

Mondal, Rina; Samanta, Swati; Sarkar, Saheli; Mallik, Asok K.

2014-01-01

Simple syntheses of the benzo-fused 26-membered macrocyclic bischalcone (19E,43E)-2.11.27.36-tetroxaheptacyclo[44.4.0.04,9.012,17.021,26.029,34.037,42]pentaconta-1(46),4(9),5,7,12(17),13,15,19,21,23,25,29,31,33,37,39,41,43,47,49-icosaene-18,45-dione (3) and the benzo-fused 13-membered macrocyclic chalcone (19E)-2.11-dioxatetracyclo[19.4.0.04,9.012,17]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5) using very common starting materials and reagents are described. The compounds are new and they have been characterized from their analytical and spectral data. PMID:27379283

Simple Syntheses of Two New Benzo-Fused Macrocycles Incorporating Chalcone Moiety.

PubMed

Mondal, Rina; Samanta, Swati; Sarkar, Saheli; Mallik, Asok K

2014-01-01

Simple syntheses of the benzo-fused 26-membered macrocyclic bischalcone (19E,43E)-2.11.27.36-tetroxaheptacyclo[44.4.0.0(4,9).0(12,17).0(21,26).0(29,34).0(37,42)]pentaconta-1(46),4(9),5,7,12(17),13,15,19,21,23,25,29,31,33,37,39,41,43,47,49-icosaene-18,45-dione (3) and the benzo-fused 13-membered macrocyclic chalcone (19E)-2.11-dioxatetracyclo[19.4.0.0(4,9).0(12,17)]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5) using very common starting materials and reagents are described. The compounds are new and they have been characterized from their analytical and spectral data.

Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor.

PubMed

Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Fleming, Katlyn A; Haskell-Luevano, Carrie

2017-10-12

The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R.

Synthesis, spectroscopic, and antibacterial activity of tetraazamacrocyclic complexes of trivalent chromium, manganese, and iron.

PubMed

Singh, D P; Malik, Vandna; Kumar, Ramesh; Singh, Jitender

2009-10-01

A new series of macrocyclic complexes of type [M(TML)X]X(2), where M = Cr(III), Mn(III), or Fe(III), TML is tetradentate macrocyclic ligand, and X = Cl(-), NO(3)(-), CH(3)COO(-) for Cr(III), Fe(III) and X = CH(3)COO(-) for Mn (III), has been synthesized by condensation of benzil and succinyldihydrazide in the presence of metal salt. The complexes have been so formulated due to the 1:2 electrolytic nature of these complexes as shown by conductivity measurements. The complexes have been characterized with the help of various physicochemical techniques such as elemental analysis, molar conductance, electronic and infrared spectral studies, and magnetic susceptibility. On the basis of these studies, a five-coordinate distorted square pyramidal geometry, in which two nitrogens and two carbonyl oxygen atoms are suitably placed for coordination toward the metal ion, has been proposed for all the complexes. The complexes have been tested for their in vitro antibacterial activity. Some of the complexes show remarkable antibacterial activities against some selected bacterial strains. The minimum inhibitory concentrations shown by these complexes have been compared with those shown by some standard antibiotics such as linezolid and cefaclor.

Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction

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

Karatas, Hacer; Li, Yangbing; Liu, Liu

We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5–mixed lineage leukemia (MLL) protein–protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis formore » their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.« less

Microscale Synthesis, Reactions, and (Super 1)H NMR Spectroscopic Investigations of Square Planar Macrocyclic, Tetramido-N Co(III) Complexes Relevant to Green Chemistry

ERIC Educational Resources Information Center

Watson, Tanya T.; Uffelman, Erich S.; Lee, Daniel W., III; Doherty, Jonathan R.; Schulze, Carl; Burke, Amy L.; Bonnema, Kristen, R.

2004-01-01

The microscale preparation, characterization, and reactivity of a square planar Co(III) complex that has grown out of a program to introduce experiments of relevance to green chemistry into the undergraduate curriculum is presented. The given experiments illustrate the remarkable redox and aqueous acid-base stability that make the macrocycles very…

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

PubMed

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

2001-08-01

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

Conformational analysis of a condensed macrocyclic β-lactam by NMR and molecular dynamics calculations

NASA Astrophysics Data System (ADS)

Keserű, György M.; Vásárhelyi, Helga; Makara, Gergely

1994-09-01

The conformation of the new macrocyclic β-lactam ( 1) was investigated by NMR and molecular dynamics (MD) calculations. Restraints obtained from NOESY and ROESY experiments were introduced into MD simulations which led to well-defined conformations. The preference for the calculated minimum energy conformation was confirmed by the analysis of vicinal coupling constants. Experimental coupling constants agreed with computed values.

Organic Materials as Electrodes for Li-ion Batteries

DTIC Science & Technology

2015-09-04

given for each class of materials. Various macrocycles, their synthesis, characterization and subsequent use in lithium - ion batteries were attempted...macrocycles, their synthesis, characterization and subsequent use in lithium - ion batteries have been attempted to. Lithium -based batteries are at the...organic dye can be used for storing reversibly, both lithium and sodium ions for rechargeable battery applications. In the present study, we have

Bistable or oscillating state depending on station and temperature in three-station glycorotaxane molecular machines.

PubMed

Busseron, Eric; Romuald, Camille; Coutrot, Frédéric

2010-09-03

High-yield, straightforward synthesis of two- and three-station [2]rotaxane molecular machines based on an anilinium, a triazolium, and a mono- or disubstituted pyridinium amide station is reported. In the case of the pH-sensitive two-station molecular machines, large-amplitude movement of the macrocycle occurred. However, the presence of an intermediate third station led, after deprotonation of the anilinium station, and depending on the substitution of the pyridinium amide, either to exclusive localization of the macrocycle around the triazolium station or to oscillatory shuttling of the macrocycle between the triazolium and monosubstituted pyridinium amide station. Variable-temperature (1)H NMR investigation of the oscillating system was performed in CD(2)Cl(2). The exchange between the two stations proved to be fast on the NMR timescale for all considered temperatures (298-193 K). Interestingly, decreasing the temperature displaced the equilibrium between the two translational isomers until a unique location of the macrocycle around the monosubstituted pyridinium amide station was reached. Thermodynamic constants K were evaluated at each temperature: the thermodynamic parameters DeltaH and DeltaS were extracted from a Van't Hoff plot, and provided the Gibbs energy DeltaG. Arrhenius and Eyring plots afforded kinetic parameters, namely, energies of activation E(a), enthalpies of activation DeltaH( not equal), and entropies of activation DeltaS( not equal). The DeltaG values deduced from kinetic parameters match very well with the DeltaG values determined from thermodynamic parameters. In addition, whereas signal coalescence of pyridinium hydrogen atoms located next to the amide bond was observed at 205 K in the oscillating rotaxane and at 203 K in the two-station rotaxane with a unique location of the macrocycle around the pyridinium amide, no separation of (1)H NMR signals of the considered hydrogen atoms was seen in the corresponding nonencapsulated thread. It is suggested that the macrocycle acts as a molecular brake for the rotation of the pyridinium-amide bond when it interacts by hydrogen bonding with both the amide NH and the pyridinium hydrogen atoms at the same time.

An evaluation of alternative selection indexes for a non-linear profit trait approaching its economic optimum.

PubMed

Martin-Collado, D; Byrne, T J; Visser, B; Amer, P R

2016-12-01

This study used simulation to evaluate the performance of alternative selection index configurations in the context of a breeding programme where a trait with a non-linear economic value is approaching an economic optimum. The simulation used a simple population structure that approximately mimics selection in dual purpose sheep flocks in New Zealand (NZ). In the NZ dual purpose sheep population, number of lambs born is a genetic trait that is approaching an economic optimum, while genetically correlated growth traits have linear economic values and are not approaching any optimum. The predominant view among theoretical livestock geneticists is that the optimal approach to select for nonlinear profit traits is to use a linear selection index and to update it regularly. However, there are some nonlinear index approaches that have not been evaluated. This study assessed the efficiency of the following four alternative selection index approaches in terms of genetic progress relative to each other: (i) a linear index, (ii) a linear index updated regularly, (iii) a nonlinear (quadratic) index, and (iv) a NLF index (nonlinear index below the optimum and then flat). The NLF approach does not reward or penalize animals for additional genetic merit beyond the trait optimum. It was found to be at least comparable in efficiency to the approach of regularly updating the linear index with short (15 year) and long (30 year) time frames. The relative efficiency of this approach was slightly reduced when the current average value of the nonlinear trait was close to the optimum. Finally, practical issues of industry application of indexes are considered and some potential practical benefits of efficient deployment of a NLF index in highly heterogeneous industries (breeds, flocks and production environments) such as in the NZ dual purpose sheep population are discussed. © 2016 Blackwell Verlag GmbH.

In vivo three-dimensional molecular imaging with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) at high spatiotemporal resolution.

PubMed

Coman, Daniel; de Graaf, Robin A; Rothman, Douglas L; Hyder, Fahmeed

2013-11-01

Spectroscopic signals which emanate from complexes between paramagnetic lanthanide (III) ions (e.g. Tm(3+)) and macrocyclic chelates (e.g. 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, or DOTMA(4-)) are sensitive to physiology (e.g. temperature). Because nonexchanging protons from these lanthanide-based macrocyclic agents have relaxation times on the order of a few milliseconds, rapid data acquisition is possible with chemical shift imaging (CSI). Thus, Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from nonexchanging protons of these paramagnetic agents, but exclude water proton detection, can allow molecular imaging. Previous two-dimensional CSI experiments with such lanthanide-based macrocyclics allowed acquisition from ~12-μL voxels in rat brain within 5 min using rectangular encoding of k space. Because cubical encoding of k space in three dimensions for whole-brain coverage increases the CSI acquisition time to several tens of minutes or more, a faster CSI technique is required for BIRDS to be of practical use. Here, we demonstrate a CSI acquisition method to improve three-dimensional molecular imaging capabilities with lanthanide-based macrocyclics. Using TmDOTMA(-), we show datasets from a 20 × 20 × 20-mm(3) field of view with voxels of ~1 μL effective volume acquired within 5 min (at 11.7 T) for temperature mapping. By employing reduced spherical encoding with Gaussian weighting (RESEGAW) instead of cubical encoding of k space, a significant increase in CSI signal is obtained. In vitro and in vivo three-dimensional CSI data with TmDOTMA(-), and presumably similar lanthanide-based macrocyclics, suggest that acquisition using RESEGAW can be used for high spatiotemporal resolution molecular mapping with BIRDS. Copyright © 2013 John Wiley & Sons, Ltd.

Synthesis, characterization and anti-microbial activity of a novel macrocyclic ligand derived from the reaction of 2,6-pyridinedicarboxylic acid with homopiperazine and its Co(II), Ni(II), Cu(II), and Zn(II) complexes

NASA Astrophysics Data System (ADS)

Soleimani, Esmaiel

2011-05-01

The preparation of a novel macrocyclic ligand ( 1), N,N'-diethylhomopiperazinyl,2,6-pyridinedicarboxylate and its Co(II), Ni(II), Cu(II), and Zn(II) complexes are described. The ligand was prepared in EtOH from the reaction of dipotassium salt of 2,6-pyridinedicarboxylic acid with 1,2-dibromoethane in the presence of homopiperazine. Reaction of macrocyclic ligand ( 1) in EtOH with CoCl 2.6H 2O, NiCl 2.6H 2O, CuCl 2.2H 2O, and ZnCl 2·2H 2O yielded the complexes with the general formula [M(L)Cl 2] {where M = Co(II) ( 2), Ni(II) ( 3), Cu(II) ( 4), Zn ( 5), respectively}. The analysis of IR, 1H and 13C NMR spectral data of macrocyclic ligand ( 1) and its Zn(II) complex ( 5) together with their molar conductivity values, and the magnetic moments of the complexes suggest that the macrocyclic ligand ( 1) is bonded to metal(II) ions through two oxygen atoms of ester moiety and the two nitrogen atoms of homopiperazine ring. The electronic spectral data of these complexes in DMSO are in good agreement with the octahedral coordination of M(II) ions. The ligand field parameters for these complexes, i.e. splitting energy and Racah parameter were calculated to be 14,945 and 673 cm -1 for the Co(II) ( 2), 16,260 and 774 cm -1 for the Ni(II) ( 3) complexes respectively. The spliting energy of 17,262 cm -1 was obtained for the Cu(II) complex ( 4).

Phosphate Tether-Mediated Approach to the Formal Total Synthesis of (-)-Salicylihalamides A and B

PubMed Central

Chegondi, Rambabu; Tan, Mary M. L.; Hanson, Paul R.

2011-01-01

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4-steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol. PMID:21504150

Synthesis of Cyclic Porphyrin Trimers through Alkyne Metathesis Cyclooligomerization and Their Host–Guest Binding Study

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

Yu, Chao; Long, Hai; Jin, Yinghua

2016-06-17

Cyclic porphyrin trimers were synthesized through one-step cyclooligomerization via alkyne metathesis from diyne monomers. These macrocycles show interesting host-guest binding interactions with fullerenes, selectively binding C70 (6 x 103 M-1) over C60 and C84 (no binding observed). The fullerene-encapsulated host-guest complex can undergo guest or host exchange in the presence of another guest (2,4,6-tri(4-pyridyl)-1,3,5-triazine) or host (cage COP5) molecule with higher binding affinity.

Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy.

PubMed

Wender, Paul A; Hilinski, Michael K; Skaanderup, Philip R; Soldermann, Nicolas G; Mooberry, Susan L

2006-08-31

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

Synthetic approaches to aromatic belts: building up strain in macrocyclic polyarenes.

PubMed

Eisenberg, David; Shenhar, Roy; Rabinovitz, Mordecai

2010-08-01

This tutorial review discusses synthetic strategies towards aromatic belts, defined here as double-stranded conjugated macrocycles, such as [n]cyclacenes, [n]cyclophenacenes, Schlüter belt, and Vögtle belt. Their appeal stems, firstly, from the unique nature of their conjugation, having p orbitals oriented radially rather than perpendicular to the plane of the macrocycle. Secondly, as aromatic belts are model compounds of carbon nanotubes of different chiralities, a synthetic strategy towards the buildup of structural strain in these compounds could finally open a route towards rational chemical synthesis of carbon nanotubes. The elusiveness of these compounds has stimulated fascinating and ingenious synthetic strategies over the last decades. The various strategies are classified here by their approach to the buildup of structural strain, which is the main obstacle in the preparation of these curved polyarenes.

Laser desorption vs. electrospray of polyyne-threaded rotaxanes: Preventing covalent cross-linking and promoting noncovalent aggregation

NASA Astrophysics Data System (ADS)

Neugebauer, Thomas S.; Franz, Michael; Frankenberger, Stephanie; Tykwinski, Rik R.; Drewello, Thomas

2018-02-01

Laser-induced cross-linking of polyynes is successfully hindered when the polyyne is encapsulated as part of a rotaxane and therefore protected by a surrounding macrocycle. When the rotaxane is electrosprayed, however, noncovalent aggregate ions are efficiently formed. Aggregates of considerable size (including more than 50 rotaxane molecules with masses beyond 100k Da) and charge states (up to 13 charges and beyond) have been observed. Either protons or sodium cations act as the charge carriers. These aggregates are not formed when the individual components of the rotaxane, i.e., the macrocycle or the polyyne, are separately electrosprayed. This underlines the structural importance of the rotaxane for the aggregate formation. Straightforward force field calculations indicate that the polyyne thread hinders the folding of the macrocycles, which facilitates the bonding interaction between the two components.

Supramolecular control of transition metal complexes in water by a hydrophobic cavity: a bio-inspired strategy.

PubMed

Bistri, Olivia; Reinaud, Olivia

2015-03-14

Supramolecular chemistry in water is a very challenging research area. In biology, water is the universal solvent where transition metal ions play major roles in molecular recognition and catalysis. In enzymes, it participates in substrate binding and/or activation in the heart of a pocket defined by the folded protein. The association of a hydrophobic cavity with a transition metal ion is thus a very appealing strategy for controlling the metal ion properties in the very competitive water solvent. Various systems based on intrinsically water-soluble macrocyclic structures such as cyclodextrins, cucurbituryls, and metallo-cages have been reported. Others use calixarenes and resorcinarenes functionalized with hydrophilic substituents. One approach for connecting a metal complex to these cavities is to graft a ligand for metal ion binding at their edge. Early work with cyclodextrins has shown Michaelis-Menten like catalysis displaying enhanced kinetics and substrate-selectivity. Remarkable examples of regio- and stereo-selective transformation of substrates have been reported as well. Dynamic two-phase systems for transition metal catalysis have also been developed. They rely on either water-transfer of the metal complex through ligand embedment or synergistic coordination of a metal ion and substrate hosting. Another strategy consists in using metallo-cages, which provide a well-defined hydrophobic space, to stabilize metal complexes in water. When the cages can host simultaneously a substrate and a reactive metal complex, size- and regio-selective catalysis was obtained. Finally, construction of a polydentate coordination site closely interlocked with a calixarene or resorcinarene macrocycle has been shown to be a very fruitful strategy for obtaining metal complexes with remarkable hosting properties. For each of these systems, the synergism resulting from the biomimetic association of a hydrophobic cavity and a metal ion is discussed within the objective of developing new tools for either selective molecular recognition (with analytical perspectives) or performant catalysis, in water.

Bambus[6]uril as a novel macrocyclic receptor for the nitrate anion.

PubMed

Toman, Petr; Makrlík, Emanuel; Vanura, Petr

2013-01-01

By using quantum mechanical DFT calculations, the most probable structure of the bambus[6]uril x NO3(-) anionic complex species was derived. In this complex having C3 symmetry, the nitrate anion NO3(-), included in the macrocyclic cavity, is bound by twelve weak hydrogen bonds between methine hydrogen atoms on the convex face of glycoluril units and the considered NO3(-) ion.

Oxidative Carbocation Formation in Macrocycles: Synthesis of the Neopeltolide Macrocycle**

PubMed Central

Tu, Wangyang

2009-01-01

Processes for the functionalization of carbon–hydrogen bonds are the focus of significant attention in organic synthesis[1] in response to the need to streamline molecular assembly. As a continuation of our efforts to generate carbocations through single-electron oxidation reactions,[2] we recently reported[3] DDQ-mediated cyclization reactions of benzylic and allylic ethers (Scheme 1; DDQ =2,3-dichloro-4,5-dicyanoquinone). PMID:19455526

Two-Dimensional Nanoporous Networks Formed by Liquid-to-Solid Transfer of Hydrogen-Bonded Macrocycles Built from DNA Bases.

PubMed

Bilbao, Nerea; Destoop, Iris; De Feyter, Steven; González-Rodríguez, David

2016-01-11

We present an approach that makes use of DNA base pairing to produce hydrogen-bonded macrocycles whose supramolecular structure can be transferred from solution to a solid substrate. A hierarchical assembly process ultimately leads to two-dimensional nanostructured porous networks that are able to host size-complementary guests. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, Characterization and Antifertility Activity of New Unsymmetrical Macrocyclic Complexes of Tin(II)

PubMed Central

Sharma, Kripa; Joshi, S. C.

2000-01-01

A new series of unsymmetrical macrocyclic complexes of tin(ll) has been prepared by the template process using bis(3-oxo-2-butylidene)propane-1,3-diamine as precursor. This affords a method to synthesize these complexes with various ring sizes. The tetradentate macrocyclic precursor [N4mL] reacts with SnCl2 and different diamines in a 1:1:1 molar ratio in refluxing methanol to give complexes of the type [Sn(N4mL)Cl2]. The ring expansion has been achieved by varying the diamine between the two diacetyl amino nitrogen atoms. The macrocyclic precursor and its metal complexes have been characterized on the basis of elemental analysis, molar conductance, molecular weight determinations, IR, 1H NMR,13C NMR, 119Sn NMR and electronic spectral studies. An octahedral geometry around the metal ion is suggested for these complexes. On the basis of molecular weights and conductivity measurements, their monomeric and non-electrolytic nature has been confirmed. The precursor and complexes have been screened in vitro against a number of pathogenic fungi and bacteria to assess their growth inhibiting potential. The testicular sperm density and testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in mating trails and biochemicals parameters of reproductive organs have been examined and discussed. PMID:18475951

Sensitized terbium(III) macrocyclic-phthalimide complexes as luminescent pH switches.

PubMed

Chen, Gaoyun; Wardle, Nicholas J; Sarris, Jason; Chatterton, Nicholas P; Bligh, S W Annie

2013-10-21

Four new macrocyclic-phthalimide ligands were synthesised via the coupling of N-(3-bromopropyl)phthalimide either to cyclen (1,4,7,10-tetraazacyclododecane) itself or its carboxylate-functionalized analogues, and photophysical studies were carried out on their corresponding Tb(III) complexes in aqueous media as a function of pH. Luminescence intensities of Tb·L1a–Tb·L3a were in ‘switched off’ mode under acidic conditions (pH < 4), and were activated on progression to basic conditions as the phthalimido functions therein were hydrolysed to their corresponding phthalamates Tb·L1b–Tb·L3b. Emission of phthalamate-based macrocyclic Tb(III) complexes Tb·L1b–Tb·L3b was in ‘switched on’ mode between pH 4 and 11, exhibiting high quantum yields (Φ) and long lifetimes (τ) of the order of milliseconds at pH ~ 6. Tb(III) emissions were found to decline with increasing number of chromophores. The values of Φ and τ were 46% and 2.4 ms respectively for Tb·L1b at pH ~ 6 when activated. This is the best pH-dependent sensor based on a Tb(III) complex reported to date, benefiting from the macrocyclic architecture of the ligand.

Spectroscopic, cyclic voltammetric and biological studies of transition metal complexes with mixed nitrogen-sulphur (NS) donor macrocyclic ligand derived from thiosemicarbazide

NASA Astrophysics Data System (ADS)

Chandra, Sulekh; Gupta, Lokesh Kumar; Sangeetika

2005-11-01

The complexation of new mixed thia-aza-oxa macrocycle viz., 2,12-dithio-5,9,14,18-tetraoxo-7,16-dithia-1,3,4,10,11,13-hexaazacyclooctadecane containing thiosemicarba-zone unit with a series of transition metals Co(II), Ni(II) and Cu(II) has been investigated, by different spectroscopic techniques. The structural features of the ligand have been studied by EI-mass, 1H NMR and IR spectral techniques. Elemental analyses, magnetic moment susceptibility, molar conductance, IR, electronic, and EPR spectral studies characterized the complexes. Electronic absorption and IR spectra of the complexes indicate octahedral geometry for chloro, nitrato, thiocyanato or acetato complexes. The dimeric and neutral nature of the sulphato complexes are confirmed from magnetic susceptibility and low conductance values. Electronic spectra suggests square-planar geometry for all sulphato complexes. The redox behaviour was studied by cyclic voltammetry, show metal-centered reduction processes for all complexes. The complexes of copper show both oxidation and reduction process. The redox potentials depend on the conformation of central atom in the macrocyclic complexes. Newly synthesized macrocyclic ligand and its transition metal complexes show markedly growth inhibitory activity against pathogenic bacterias and plant pathogenic fungi under study. Most of the complexes have higher activity than that of the metal free ligand.

Synthesis, Structure, and Molecular Recognition of S6 - and (SO2 )6 -Corona[6](het)arenes: Control of Macrocyclic Conformation and Properties by the Oxidation State of the Bridging Heteroatoms.

PubMed

Guo, Qing-Hui; Zhao, Liang; Wang, Mei-Xiang

2016-05-10

We report herein the synthesis, structure, and molecular recognition of S6 - and (SO2 )6 -corona[6](het)arenes, and demonstrate a unique and efficient strategy of regulating macrocyclic conformation and properties by adjusting the oxidation state of the heteroatom linkages. The one-pot nucleophilic aromatic substitution reaction of 1,4-benzenedithiol derivatives, biphenyl-4,4'-dithiol and 9,9-dipropyl-9H-fluorene-2,7-dithiol with 3,6-dichlorotetrazine afforded S6 -corona[3]arene[3]tetrazines. These compounds underwent inverse-electron-demand Diels-Alder reaction with enamines and norbornadiene to produce S6 -corona[3]arene[3]pyridazines. Facile oxidation of sulfide linkages yielded (SO2 )6 -corona[3]arene[3]pyridazines. All corona[6](het)arenes adopted generally hexagonal macrocyclic ring structures; however, their electronic properties and conformation could be fine-tuned by altering the oxidation state of the sulfur linkages. Whereas (SO2 )6 -corona[3]arene[3]pyridazines were electron-deficient, S6 -corona[3]arene[3]pyridazines acted as electron-rich macrocyclic hosts that recognized various organic cations in both aqueous and organic solutions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Saturn-Like Complex Composed of Macrocyclic Oligothiophene and C60 Fullerene: Structure, Stability, and Photophysical Properties in Solution and the Solid State.

PubMed

Shimizu, Hideyuki; Park, Kyu Hyung; Otani, Hiroyuki; Aoyagi, Shinobu; Nishinaga, Tohru; Aso, Yoshio; Kim, Dongho; Iyoda, Masahiko

2018-03-12

A Saturn-like 1:1 complex composed of macrocyclic oligothiophene E-8T7A and C 60 fullerene (C 60 ) was synthesized to investigate the interaction between macrocyclic oligothiophenes and C 60 in solution and the solid state. Because the Saturn-like 1:1 complex E-8T7A⋅C 60 is mainly stabilized by van der Waals interactions between C 60 and the sulfur atoms of the E-8T7A macrocycle, C 60 is rather weakly incorporated inside the macro-ring in solution. However, in the solid state the Saturn-like 1:1 complex preferentially formed single crystals or nanostructured polymorphs. Interestingly, X-ray analysis and theoretical calculations exhibited hindered rotation of C 60 in the Saturn-like complex due to interactions between C 60 and the sulfur atoms. Furthermore, the photoinduced charge transfer (CT) interaction between E-8T7A and C 60 in solution was investigated by using femtosecond transient absorption (TA) spectroscopy. The ultrafast TA spectral changes in the photoinduced absorption bands were attributed to the CT process in the Saturn-like structure. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

One-Pot Approach to Organo-Phosphorus-Chalcogen Macrocycles Incorporating Double OP(S)SCn or OP(Se)SeCn Scaffolds: A Synthetic and Structural Study.

PubMed

Hua, Guoxiong; Du, Junyi; Slawin, Alexandra M Z; Woollins, J Derek

2016-06-01

The development of new methodology for the preparation of functional macrocycles with practical applications is an important research area in macromolecular science. In this study, we report a new one-pot route for the synthesis of a series of macro-heterocycles by incorporating two phosphorus atoms and two chalcogen atoms and two oxygen atoms (double OP(S)SCn or OP(Se)SeCn scaffolds). The three-component condensation reactions of 2,4-diferrocenyl-1,3,2,4-diathiadiphosphetane 2,4-disulfide (FcLR, a ferrocene analogue of Lawesson's reagent) or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (LR, Lawesson's reagent), or 2,4-diphenyl-1,3,2,4-diselenadiphosphetane 2,4-diselenide (WR, Woollins' reagent), disodium alkenyl-diols, and dihalogenated alkanes are performed, giving rise to soluble and air or moisture-stable macrocycles in good-to-excellent yields (up to 92 %). This is the first systemically preparative and readily scalable example of one-pot ring opening/ring extending reaction of three-components to prepare phosphorus-chalcogen containing macrocycles. We also provide a systematic crystallographic study. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Investigating the binding properties of porous drug delivery systems using nuclear sensors (radiotracers) and positron annihilation lifetime spectroscopy--predicting conditions for optimum performance.

PubMed

Mume, Eskender; Lynch, Daniel E; Uedono, Akira; Smith, Suzanne V

2011-06-21

Understanding how the size, charge and number of available pores in porous material influences the uptake and release properties is important for optimising their design and ultimately their application. Unfortunately there are no standard methods for screening porous materials in solution and therefore formulations must be developed for each encapsulated agent. This study investigates the potential of a library of radiotracers (nuclear sensors) for assessing the binding properties of hollow silica shell materials. Uptake and release of Cu(2+) and Co(2+) and their respective complexes with polyazacarboxylate macrocycles (dota and teta) and a series of hexa aza cages (diamsar, sarar and bis-(p-aminobenzyl)-diamsar) from the hollow silica shells was monitored using their radioisotopic analogues. Coordination chemistry of the metal (M) species, subtle alterations in the molecular architecture of ligands (Ligand) and their resultant complexes (M-Ligand) were found to significantly influence their uptake over pH 3 to 9 at room temperature. Positively charged species were selectively and rapidly (within 10 min) absorbed at pH 7 to 9. Negatively charged species were preferentially absorbed at low pH (3 to 5). Rates of release varied for each nuclear sensor, and time to establish equilibrium varied from minutes to days. The subtle changes in design of the nuclear sensors proved to be a valuable tool for determining the binding properties of porous materials. The data support the development of a library of nuclear sensors for screening porous materials for use in optimising the design of porous materials and the potential of nuclear sensors for high through-put screening of materials.

Gd-complexes of macrocyclic DTPA conjugates of 1,1'-bis(amino)ferrocenes as high relaxivity MRI blood-pool contrast agents (BPCAs).

PubMed

Kim, Hee-Kyung; Park, Ji-Ae; Kim, Kyeong Min; Nasiruzzaman, Sk Md; Kang, Duk-Sik; Lee, Jongmin; Chang, Yongmin; Kim, Tae-Jeong

2010-11-28

We report the synthesis of macrocyclic DTPA conjugates of 1,1'-bis(amino)ferrocenes (1a-b) and their Gd-complexes [Gd(L)(H(2)O)] (2a-b, L = 1a-b) for use as new MRI blood-pool contrast agents. High R(1) relaxivity in HSA as well as high thermodynamic and kinetic stabilities is observed for 2a.

Syntheses and Functionalizations of Porphyrin Macrocycles

PubMed Central

Vicente, Maria da G.H.; Smith, Kevin M.

2014-01-01

Porphyrin macrocycles have been the subject of intense study in the last century because they are widely distributed in nature, usually as metal complexes of either iron or magnesium. As such, they serve as the prosthetic groups in a wide variety of primary metabolites, such as hemoglobins, myoglobins, cytochromes, catalases, peroxidases, chlorophylls, and bacteriochlorophylls; these compounds have multiple applications in materials science, biology and medicine. This article describes current methodology for preparation of simple, symmetrical model porphyrins, as well as more complex protocols for preparation of unsymmetrically substituted porphyrin macrocycles similar to those found in nature. The basic chemical reactivity of porphyrins and metalloporphyrin is also described, including electrophilic and nucleophilic reactions, oxidations, reductions, and metal-mediated cross-coupling reactions. Using the synthetic approaches and reactivity profiles presented, eventually almost any substituted porphyrin system can be prepared for applications in a variety of areas, including in catalysis, electron transport, model biological systems and therapeutics. PMID:25484638

A new spermidine macrocyclic alkaloid isolated from Gymnosporia arenicola leaf.

PubMed

da Silva, Gustavo; Martinho, Ana; Soengas, Raquel González; Duarte, Ana Paula; Serrano, Rita; Gomes, Elsa Teixeira; Silva, Olga

2015-10-01

The isolation and structural elucidation of a macrocyclic alkaloid, characterized by the presence of a 13-membered macrolactam ring containing a spermidine unit N-linked to a benzoyl group is hereby reported. The structure of this previously unknown spermidine alkaloid isolated from Gymnosporia arenicola (Celastraceae) leaves has been elucidated by (1)H and (13)C NMR spectroscopy (including bidimensional analysis) and further characterized by high-resolution mass spectrometry and polarimetry. A route for the biosynthesis of this new bioactive macrocycle is proposed and the cytotoxicity of the compound was evaluated against two ATCC cell lines - one normal-derived (MCF10A) and one cancer-derived cell line (MCF7) - using the MTT assay. The alkaloid revealed to be non-cytotoxic against both cell lines. The IC50 values from the cells were also determined. Copyright © 2015 Elsevier B.V. All rights reserved.

Macrocyclic lactones: A versatile source for omega radiohalogenated fatty acid analogs

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

Dougan, A.H.; Lyster, D.M.; Robertson, K.A.

For each omega halogenated fatty acid there exists a potential omega hydroxy fatty acid and the corresponding macrocyclic lactone. The authors have utilized such lactones as starting materials for omega /sup 123/I fatty acid analogs intended for myocardial imaging. Macrocyclic musk lactones are industrially available; 120 analogs are described in the literature. The preparation requires saponification, tosylation, and radio-iodide substitution. Iodo-fatty acids are readily separated from tosylate fatty acids on TLC. While providing a secure source of 16-iodo-hexadecanoic acid and 17-iodo-heptadecanoic acid, the scheme allows ready access to a large number of untried fatty acid analogs. Examples presented are 16-iodo-hexadecanoicmore » acid, 16-iodo-7-hexadecanoic acid, 16-iodo-12-oxa-hexadecanoic acid, 15-iodo-pentadecanoic acid, and 15-iodo-12-keto-pentadecanoic acid. Metabolic studies are in progress in mice and dogs to assess the utility of these analogs for myocardial imaging.« less

Diels-Alder active-template synthesis of rotaxanes and metal-ion-switchable molecular shuttles.

PubMed

Crowley, James D; Hänni, Kevin D; Leigh, David A; Slawin, Alexandra M Z

2010-04-14

A synthesis of [2]rotaxanes in which Zn(II) or Cu(II) Lewis acids catalyze a Diels-Alder cycloaddition to form the axle while simultaneously acting as the template for the assembly of the interlocked molecules is described. Coordination of the Lewis acid to a multidentate endotopic 2,6-di(methyleneoxymethyl)pyridyl- or bipyridine-containing macrocycle orients a chelated dienophile through the macrocycle cavity. Lewis acid activation of the double bond causes it to react with an incoming "stoppered" diene, affording the [2]rotaxane in up to 91% yield. Unusually for an active-template synthesis, the metal binding site "lives on" in these rotaxanes. This was exploited in the synthesis of a molecular shuttle containing two different ligating sites in which the position of the macrocycle could be switched by complexation with metal ions [Zn(II) and Pd(II)] with different preferred coordination geometries.

Solar Thermal Energy Storage in a Photochromic Macrocycle.

PubMed

Vlasceanu, Alexandru; Broman, Søren L; Hansen, Anne S; Skov, Anders B; Cacciarini, Martina; Kadziola, Anders; Kjaergaard, Henrik G; Mikkelsen, Kurt V; Nielsen, Mogens Brøndsted

2016-07-25

The conversion and efficient storage of solar energy is recognized to hold significant potential with regard to future energy solutions. Molecular solar thermal batteries based on photochromic systems exemplify one possible technology able to harness and apply this potential. Herein is described the synthesis of a macrocycle based on a dimer of the dihydroazulene/vinylheptafulvene (DHA/VHF) photo/thermal couple. By taking advantage of conformational strain, this DHA-DHA macrocycle presents an improved ability to absorb and store incident light energy in chemical bonds (VHF-VHF). A stepwise energy release over two sequential ring-closing reactions (VHF→DHA) combines the advantages of an initially fast discharge, hypothetically addressing immediate energy consumption needs, followed by a slow process for consistent, long-term use. This exemplifies another step forward in the molecular engineering and design of functional organic materials towards solar thermal energy storage and release. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The interaction of amino acids with macrocyclic pH probes of pseudopeptidic nature.

PubMed

Izquierdo, M Angeles; Wadhavane, Prashant D; Vigara, Laura; Burguete, M Isabel; Galindo, Francisco; Luis, Santiago V

2017-08-09

The fluorescence quenching, by a series of amino acids, of pseudopeptidic compounds acting as probes for cellular acidity has been investigated. It has been found that amino acids containing electron-rich aromatic side chains like Trp or Tyr, as well as Met quench the emission of the probes mainly via a collisional mechanism, with Stern-Volmer constants in the 7-43 M -1 range, while other amino acids such as His, Val or Phe did not cause deactivation of the fluorescence. Only a minor contribution of a static quenching due to the formation of ground-state complexes has been found for Trp and Tyr, with association constants in the 9-24 M -1 range. For these ground-state complexes, a comparison between the macrocyclic probes and an open chain analogue reveals the existence of a moderate macrocyclic effect due to the preorganization of the probes in the more rigid structure.

Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation.

PubMed

Rojas, Anthony J; Zhang, Chi; Vinogradova, Ekaterina V; Buchwald, Nathan H; Reilly, John; Pentelute, Bradley L; Buchwald, Stephen L

2017-06-01

Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Here we detail a method for a divergent macrocyclisation of unprotected peptides by crosslinking two cysteine residues with bis-palladium organometallic reagents. These synthetic intermediates are prepared in a single step from commercially available aryl bis-halides. Two bioactive linear peptides with cysteine residues at i , i + 4 and i , i + 7 positions, respectively, were cyclised to introduce a diverse array of aryl and bi-aryl linkers. These two series of macrocyclic peptides displayed similar linker-dependent lipophilicity, phospholipid affinity, and unique volume of distributions. Additionally, one of the bioactive peptides showed target binding affinity that was predominantly affected by the length of the linker. Collectively, this divergent strategy allowed rapid and convenient access to various aryl linkers, enabling the systematic evaluation of the effect of appending unit on the medicinal properties of macrocyclic peptides.

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

Oocydin A, a chlorinated macrocyclic lactone with potent anti-oomycete activity from Serratia marcescens.

PubMed

Srobel, G; Li, J Y; Sugawara, F; Koshino, H; Harper, J; Hess, W M

1999-12-01

A unique chlorinated macrocyclic lactone, termed oocydin A, was isolated from a strain of Serratia marcescens growing as an epiphyte on Rhyncholacis pedicillata, an aquatic plant native to the Carrao river of the Venezuelan-Guyanan region of South America. The lactone has a molecular mass of 470 Da, and contains one atom of chlorine, a carboxyl group and a tetrahydrofuran ring internal to a larger macrocyclic ring. MICs of approximately 0.03 microg ml(-1) were noted for oocydin A against such phytopathogenic oomycetes as Pythium ultimum, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora citrophora. With regard to the true fungi, oocydin A had either minimal or no effect against certain Fungi Imperfecti (including several pathogens of humans), two ascomycetes and a basidiomycete. Oocydin A may have potential as an antimycotic in agricultural applications and especially for crop protection.

Macrocyclic metal complexes for metalloenzyme mimicry and sensor development.

PubMed

Joshi, Tanmaya; Graham, Bim; Spiccia, Leone

2015-08-18

Examples of proteins that incorporate one or more metal ions within their structure are found within a broad range of classes, including oxidases, oxidoreductases, reductases, proteases, proton transport proteins, electron transfer/transport proteins, storage proteins, lyases, rusticyanins, metallochaperones, sporulation proteins, hydrolases, endopeptidases, luminescent proteins, iron transport proteins, oxygen storage/transport proteins, calcium binding proteins, and monooxygenases. The metal coordination environment therein is often generated from residues inherent to the protein, small exogenous molecules (e.g., aqua ligands) and/or macrocyclic porphyrin units found, for example, in hemoglobin, myoglobin, cytochrome C, cytochrome C oxidase, and vitamin B12. Thus, there continues to be considerable interest in employing macrocyclic metal complexes to construct low-molecular weight models for metallobiosites that mirror essential features of the coordination environment of a bound metal ion without inclusion of the surrounding protein framework. Herein, we review and appraise our research exploring the application of the metal complexes formed by two macrocyclic ligands, 1,4,7-triazacyclononane (tacn) and 1,4,7,10-tetraazacyclododecane (cyclen), and their derivatives in biological inorganic chemistry. Taking advantage of the kinetic inertness and thermodynamic stability of their metal complexes, these macrocyclic scaffolds have been employed in the development of models that aid the understanding of metal ion-binding natural systems, and complexes with potential applications in biomolecule sensing, diagnosis, and therapy. In particular, the focus has been on "coordinatively unsaturated" metal complexes that incorporate a kinetically inert and stable metal-ligand moiety, but which also contain one or more weakly bound ligands, allowing for the reversible binding of guest molecules via the formation and dissociation of coordinate bonds. With regards to mimicking metallobiosites, examples are presented from our work on tacn-based complexes developed as simplified structural models for multimetallic enzyme sites. In particular, structural comparisons are made between multinuclear copper(II) complexes formed by such ligands and multicopper enzymes featuring type-2 and type-3 copper centers, such as ascorbate oxidase (AO) and laccase (Lc). Likewise, with the aid of relevant examples, we highlight the importance of cooperativity between either multiple metal centers or a metal center and a proximal auxiliary unit appended to the macrocyclic ligand in achieving efficient phosphate ester cleavage. Finally, the critical importance of the Zn(II)-imido and Zn(II)-phosphate interactions in Zn-cyclen-based systems for delivering highly sensitive electrochemical and fluorescent chemosensors is also showcased. The Account additionally highlights some of the factors that limit the performance of these synthetic nucleases and the practical application of the biosensors, and then identifies some avenues for the development of more effective macrocyclic constructs in the future.

The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase.

PubMed

Gajiwala, Ketan S; Grodsky, Neil; Bolaños, Ben; Feng, Junli; Ferre, RoseAnn; Timofeevski, Sergei; Xu, Meirong; Murray, Brion W; Johnson, Ted W; Stewart, Al

2017-09-22

The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor-binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Comparison of various error functions in predicting the optimum isotherm by linear and non-linear regression analysis for the sorption of basic red 9 by activated carbon.

PubMed

Kumar, K Vasanth; Porkodi, K; Rocha, F

2008-01-15

A comparison of linear and non-linear regression method in selecting the optimum isotherm was made to the experimental equilibrium data of basic red 9 sorption by activated carbon. The r(2) was used to select the best fit linear theoretical isotherm. In the case of non-linear regression method, six error functions namely coefficient of determination (r(2)), hybrid fractional error function (HYBRID), Marquardt's percent standard deviation (MPSD), the average relative error (ARE), sum of the errors squared (ERRSQ) and sum of the absolute errors (EABS) were used to predict the parameters involved in the two and three parameter isotherms and also to predict the optimum isotherm. Non-linear regression was found to be a better way to obtain the parameters involved in the isotherms and also the optimum isotherm. For two parameter isotherm, MPSD was found to be the best error function in minimizing the error distribution between the experimental equilibrium data and predicted isotherms. In the case of three parameter isotherm, r(2) was found to be the best error function to minimize the error distribution structure between experimental equilibrium data and theoretical isotherms. The present study showed that the size of the error function alone is not a deciding factor to choose the optimum isotherm. In addition to the size of error function, the theory behind the predicted isotherm should be verified with the help of experimental data while selecting the optimum isotherm. A coefficient of non-determination, K(2) was explained and was found to be very useful in identifying the best error function while selecting the optimum isotherm.

Unsaturated macrocyclic dihydroxamic acid siderophores produced by Shewanella putrefaciens using precursor-directed biosynthesis.

PubMed

Soe, Cho Z; Codd, Rachel

2014-04-18

To acquire iron essential for growth, the bacterium Shewanella putrefaciens produces the macrocyclic dihydroxamic acid putrebactin (pbH2; [M + H(+)](+), m/zcalc 373.2) as its native siderophore. The assembly of pbH2 requires endogenous 1,4-diaminobutane (DB), which is produced from the ornithine decarboxylase (ODC)-catalyzed decarboxylation of l-ornithine. In this work, levels of endogenous DB were attenuated in S. putrefaciens cultures by augmenting the medium with the ODC inhibitor 1,4-diamino-2-butanone (DBO). The presence in the medium of DBO together with alternative exogenous non-native diamine substrates, (15)N2-1,4-diaminobutane ((15)N2-DB) or 1,4-diamino-2(E)-butene (E-DBE), resulted in the respective biosynthesis of (15)N-labeled pbH2 ((15)N4-pbH2; [M + H(+)](+), m/zcalc 377.2, m/zobs 377.2) or the unsaturated pbH2 variant, named here: E,E-putrebactene (E,E-pbeH2; [M + H(+)](+), m/zcalc 369.2, m/zobs 369.2). In the latter system, remaining endogenous DB resulted in the parallel biosynthesis of the monounsaturated DB-E-DBE hybrid, E-putrebactene (E-pbxH2; [M + H(+)](+), m/zcalc 371.2, m/zobs 371.2). These are the first identified unsaturated macrocyclic dihydroxamic acid siderophores. LC-MS measurements showed 1:1 complexes formed between Fe(III) and pbH2 ([Fe(pb)](+); [M](+), m/zcalc 426.1, m/zobs 426.2), (15)N4-pbH2 ([Fe((15)N4-pb)](+); [M](+), m/zcalc 430.1, m/zobs 430.1), E,E-pbeH2 ([Fe(E,E-pbe)](+); [M](+), m/zcalc 422.1, m/zobs 422.0), or E-pbxH2 ([Fe(E-pbx)](+); [M](+), m/zcalc 424.1, m/zobs 424.2). The order of the gain in siderophore-mediated Fe(III) solubility, as defined by the difference in retention time between the free ligand and the Fe(III)-loaded complex, was pbH2 (ΔtR = 8.77 min) > E-pbxH2 (ΔtR = 6.95 min) > E,E-pbeH2 (ΔtR = 6.16 min), which suggests one possible reason why nature has selected for saturated rather than unsaturated siderophores as Fe(III) solubilization agents. The potential to conduct multiple types of ex situ chemical conversions across the double bond(s) of the unsaturated macrocycles provides a new route to increased molecular diversity in this class of siderophore.

Polysaccharide Nanoparticles for Efficient siRNA Targeting in Cancer Cells by Supramolecular pKa Shift

NASA Astrophysics Data System (ADS)

Zhang, Ying-Ming; Yang, Yang; Zhang, Yu-Hui; Liu, Yu

2016-07-01

Biomacromolecular pKa shifting is considered as one of the most ubiquitous processes in biochemical events, e.g., the enzyme-catalyzed reaction and protein conformational stabilization. In this paper, we report on the construction of biocompatible polysaccharide nanoparticle with targeting ability and lower toxicity by supramolecular pKa shift strategy. This was realized through a ternary assembly constructed by the dual host‒guest interactions of an adamantane-bis(diamine) conjugate (ADA) with cucurbit[6]uril (CB[6]) and a polysaccharide. The potential application of such biocompatible nanostructure was further implemented by the selective transportation of small interfering RNA (siRNA) in a controlled manner. It is demonstrated that the strong encapsulation of the ADA’s diammonium tail by CB[6] not only reduced the cytotoxicity of the nano-scaled vehicle but also dramatically enhanced cation density through an obvious positive macrocycle-induced pKa shift, which eventually facilitated the subsequent siRNA binding. With a targeted polysaccharide shell containing a cyclodextrin‒hyaluronic acid conjugate, macrocycle-incorporated siRNA polyplexes were specifically delivered into malignant human prostate PC-3 cells. The supramolecular polysaccharide nanoparticles, the formation of which was enabled and promoted by the complexation-assisted pKa shift, may be used as a versatile tool for controlled capture and release of biofunctional substrates.

Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury.

PubMed

Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R

2010-04-01

Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

On-Surface Pseudo-High-Dilution Synthesis of Macrocycles: Principle and Mechanism.

PubMed

Fan, Qitang; Wang, Tao; Dai, Jingya; Kuttner, Julian; Hilt, Gerhard; Gottfried, J Michael; Zhu, Junfa

2017-05-23

Macrocycles have attracted much attention due to their specific "endless" topology, which results in extraordinary properties compared to related linear (open-chain) molecules. However, challenges still remain in their controlled synthesis with well-defined constitution and geometry. Here, we report the successful application of the (pseudo-)high-dilution method to the conditions of on-surface synthesis in ultrahigh vacuum. This approach leads to high yields (up to 84%) of cyclic hyperbenzene ([18]-honeycombene) via an Ullmann-type reaction from 4,4″-dibromo-meta-terphenyl (DMTP) as precursor on a Ag(111) surface. The mechanism of macrocycle formation was explored in detail using scanning tunneling microscopy and X-ray photoemission spectroscopy. We propose that the dominant pathway for hyperbenzene (MTP) 6 formation is the stepwise desilverization of an organometallic (MTP-Ag) 6 macrocycle, which forms via cyclization of (MTP-Ag) 6 chains under pseudo-high-dilution conditions. The high probability of cyclization on the stage of the organometallic phase results from the reversibility of the C-Ag bond. The case is different from that in solution, in which cyclization typically occurs on the stage of a covalently bonded open-chain precursor. This difference in the cyclization mechanism on a surface compared to that in solution stems mainly from the 2D confinement exerted by the surface template, which hinders the flipping of chain segments necessary for cyclization.

Spectroscopic and electrochemical investigation with coordination stabilities: Mononuclear manganese(II) complexes derived from different constituents macrocyclic ligands

NASA Astrophysics Data System (ADS)

Kumar, Rajiv; Chnadra, S.; Mishra, Parashuram

2007-12-01

Since the manganese(II) complexes are known as having a high degree of stability, some of them may be able to play a very important role in biosystems. We prepared manganese(II) complexes with different chromospheres containing macrocyclic ligands bearing N, S and O like functional donor atoms in order to obtain different models of compounds. So these new manganese(II) complexes were derived from macrocyclic ligands by chelating them with metal ions. Thus, two macrocyclic ligands, L 1: 2,4-diphenyl-1,5-diaza-8,12-dioxo-6,7:13,14-dibenzocyclo tetradeca-1,4-diene[N 2O 2]ane; L 2: 2,4,9,11-tetraphenyl-6,13-dimethyl-1,5,8,12-traazacyclotertr-adeca-1,4,8,11-tetraene[N 4]ane; and two more different form first one viz.—L 3: 1,7-diaza-4-monothia-10,14-dioxo-8,9:15,16-cyclohexadecane[N 2O 2S]ane and L 4: 4,13-diaoxa-1,7,10,16-hexazacyclooctadecane[N 4O 2]ane were prepared and their capacity to retain the manganese(II) ion in solid as well as aqueous solution was determined from various physiochemical techniques viz: characterized by elemental analyses, molar conductance measurements, magnetic susceptibility measurements, mass, IR, electronic, ESR spectral studies and cyclic voltammetric measurements.

There is room for selection in a small local pig breed when using optimum contribution selection: a simulation study.

PubMed

Gourdine, J L; Sørensen, A C; Rydhmer, L

2012-01-01

Selection progress must be carefully balanced against the conservation of genetic variation in small populations of local breeds. Well-defined breeding programs with specified selection traits are rare in local pig breeds. Given the small population size, the focus is often on the management of genetic diversity. However, in local breeds, optimum contribution selection can be applied to control the rate of inbreeding and to avoid reduced performance in traits with high market value. The aim of this study was to assess the extent to which a breeding program aiming for improved product quality in a small local breed would be feasible. We used stochastic simulations to compare 25 scenarios. The scenarios differed in size of population, selection intensity of boars, type of selection (random selection, truncation selection based on BLUP breeding values, or optimum contribution selection based on BLUP breeding values), and heritability of the selection trait. It was assumed that the local breed is used in an extensive system for a high-meat-quality market. The simulations showed that in the smallest population (300 female reproducers), inbreeding increased by 0.8% when selection was performed at random. With optimum contribution selection, genetic progress can be achieved that is almost as great as that with truncation selection based on BLUP breeding values (0.2 to 0.5 vs. 0.3 to 0.5 genetic SD, P < 0.05), but at a considerably decreased rate of inbreeding (0.7 to 1.2 vs. 2.3 to 5.7%, P < 0.01). This confirmation of the potential utilization of OCS even in small populations is important in the context of sustainable management and the use of animal genetic resources.

Optimization of control gain by operator adjustment

NASA Technical Reports Server (NTRS)

Kruse, W.; Rothbauer, G.

1973-01-01

An optimal gain was established by measuring errors at 5 discrete control gain settings in an experimental set-up consisting of a 2-dimensional, first-order pursuit tracking task performed by subjects (S's). No significant experience effect on optimum gain setting was found in the first experiment. During the second experiment, in which control gain was continuously adjustable, high experienced S's tended to reach the previously determined optimum gain quite accurately and quickly. Less experienced S's tended to select a marginally optimum gain either below or above the experimentally determined optimum depending on initial control gain setting, although mean settings of both groups were equal. This quick and simple method is recommended for selecting control gains for different control systems and forcing functions.

A new oxomolybdate component extracted from the "virtual dynamic library" yielding the macrocyclic anion [(Mo(VI)(8)O(28))(4)(Mo(V)(2)O(2)S(2))(4)](24-).

PubMed

Korenev, Vladimir S; Boulay, Antoine G; Dolbecq, Anne; Sokolov, Maxim N; Hijazi, Akram; Floquet, Sébastien; Fedin, Vladimir P; Cadot, Emmanuel

2010-11-01

A rare isomer of the {Mo(8)O(28)}(8-) anion has been trapped from an acidified aqueous solution of molybdate by using the {Mo(2)O(2)S(2)}(2+) oxothio cation as the linker and isolated as a part of a unique macrocyclic anion, which consists of four isopolyoxomolybdate fragments {Mo(8)O(28)} bridged by four {Mo(2)O(2)S(2)} units.

Total synthesis and structure-activity investigation of the marine natural product neopeltolide.

PubMed

Custar, Daniel W; Zabawa, Thomas P; Hines, John; Crews, Craig M; Scheidt, Karl A

2009-09-02

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity.

Characterization of a potentially axially symmetric europium(III) complex of a tetraacetate,tetraaza, macrocyclic ligand by luminescence excitation, emission and lifetime spectroscopy

NASA Astrophysics Data System (ADS)

Albin, Michael; de, William; Horrocks, W., Jr.; Liotta, Frank J.

1982-01-01

The Eu(III) complex of the octadentate macrocyclic ligand, 1,4,7,10-tetraazacyclododecane-N,N',N'',N''' -tetraacetate, DOTA, has been examined by luminescence excitation, emission, and lifetime spectroscopy using pulsed dye laser techniques. The results confirm the expected axially symmetric nature of the major component in solution and reveal that 1.2 ± 0.4 water molecules arc coordinatcd to the Eu(III) ion in the complex.

Capped Mesoporous Silica Nanoparticles for the Selective and Sensitive Detection of Cyanide.

PubMed

Sayed, Sameh El; Licchelli, Maurizio; Martínez-Máñez, Ramón; Sancenón, Félix

2017-10-18

The development of easy and affordable methods for the detection of cyanide is of great significance due to the high toxicity of this anion and the potential risks associated with its pollution. Herein, optical detection of cyanide in water has been achieved by using a hybrid organic-inorganic nanomaterial. Mesoporous silica nanoparticles were loaded with [Ru(bipy) 3 ] 2+ , functionalized with macrocyclic nickel(II) complex subunits, and capped with a sterically hindering anion (hexametaphosphate). Cyanide selectively induces demetallation of nickel(II) complexes and the removal of capping anions from the silica surface, allowing the release of the dye and the consequent increase in fluorescence intensity. The response of the capped nanoparticles in aqueous solution is highly selective and sensitive towards cyanide with a limit of detection of 2 μm. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mechanochemical Cycloreversion of Cyclobutane Observed at the Single Molecule Level.

PubMed

Pill, Michael F; Holz, Katharina; Preußke, Nils; Berger, Florian; Clausen-Schaumann, Hauke; Lüning, Ulrich; Beyer, Martin K

2016-08-16

Mechanochemical cycloreversion of cyclobutane is known from ultrasound experiments. It is, however, not clear which forces are required to induce the cycloreversion. In atomic force microscopy (AFM) experiments, on the other hand, it is notoriously difficult to assign the ruptured bond. We have solved this problem through the synthesis of tailored macrocycles, in which the cyclobutane mechanophore is bypassed by an ethylene glycol chain of specific length. This macrocycle is covalently anchored between a glass substrate and an AFM cantilever by polyethylene glycol linkers. Upon mechanical stretching of the macrocycle, cycloreversion occurs, which is identified by a defined length increase of the stretched polymer. The measured length change agrees with the value calculated with the external force explicitly included (EFEI) method. By using two different lengths for the ethylene glycol safety line, the assignment becomes unambiguous. Mechanochemical cycloreversion of cyclobutane is observed at forces above 1.7 nN. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

PubMed Central

Lawson, Kenneth V.; Rose, Tristan E.; Harran, Patrick G.

2013-01-01

Peptide–protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. PMID:24043790

Synthesis, antimicrobial, antioxidant and molecular docking studies of thiophene based macrocyclic Schiff base complexes

NASA Astrophysics Data System (ADS)

Rathi, Parveen; Singh, D. P.

2015-11-01

The macrocyclic complexes of pharmaceutical importance with trivalent transition metals have been synthesized by [1 + 1] condensation of succinyldihydrazide and thiophenedicarboxaldehyde, via template method, resulting in the formation of the complex [MLX] X2; where L is (C10H10N4O2S), a macrocyclic ligand, M = Cr (III) and Fe (III) and X = Cl-, CH3COO- or NO3- . These complexes have been characterized with the help of elemental analyses, molar conductance measurements, magnetic susceptibility measurements, ultraviolet, infrared, far infrared, electron spin resonance, mass spectral studies and powder x-ray diffraction analysis. On the basis of all these studies, mononuclear complexes having 1:2 electrolytic nature with a five coordinated square pyramidal geometry have been proposed. Powder diffraction XRD indicates the presence of triclinic crystal system with p bravais lattice for the representative complex. All the metal complexes have also been explored for their in vitro antimicrobial and antioxidant activities.

Chemistry of anthracene-acetylene oligomers XXV: on-surface chirality of a self-assembled molecular network of a fan-blade-shaped anthracene-acetylene macrocycle with a long alkyl chain.

PubMed

Tsuya, Takuya; Iritani, Kohei; Tahara, Kazukuni; Tobe, Yoshito; Iwanaga, Tetsuo; Toyota, Shinji

2015-03-27

An anthracene cyclic dimer with two different linkers and a dodecyl group was synthesized by means of coupling reactions. The calculated structure had a planar macrocyclic π core and a linear alkyl chain. Scanning tunneling microscopy observations at the 1-phenyloctane/graphite interface revealed that the molecules formed a self-assembled monolayer that consisted of linear striped bright and dark bands. In each domain, the molecular network consisted of either Re or Si molecules that differed in the two-dimensional chirality about the macrocyclic faces, which led to a unique conglomerate-type self-assembly. The molecular packing mode and the conformation of the alkyl chains are discussed in terms of the intermolecular interactions and the interactions between the molecules and the graphite surface with the aid of MM3 simulations of a model system. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Utility of charge-transfer complexation for the assessment of macrocyclic polyethers: Spectroscopic, thermal and surface morphology characteristics of two highly crown ethers complexed with acido acceptors

NASA Astrophysics Data System (ADS)

Refat, Moamen S.; Adam, Abdel Majid A.; Saad, Hosam A.

2015-04-01

The study of the complexing ability of macrocyclic compounds to organic and inorganic substances is of great interest. The aim of this work is to provide basic data that can be used to the assessment of macrocyclic crown ethers quantitatively based on charge-transfer (CT) complexation. This goal was achieved by preparing CT complexes of two interesting mixed nitrogen-oxygen crown ethers with acido acceptors (chloranilic and picric acid), which were fully structurally characterized. The crown ethers are 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (HDHC) and 1,4,10-trioxa-7,13-diaza-cyclopentadecane (TDPD). The obtained complexes were structurally characterized via elemental analysis, IR, Raman, 1H NMR, and UV-visible spectroscopy. Thermal properties of these complexes were also studied, and their kinetic thermodynamic parameters were calculated. Furthermore, the microstructure properties of these complexes have also been investigated using X-ray diffraction (XRD) and scanning electron microscope (SEM).

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

Ho, I-Ting; Sessler, Jonathan L.; Gambhir, Sanjiv Sam

Chemical tools that can report radioactive isotopes would be of interest to the defense community. Here in this paper we report –250 nm polymeric nanoparticles containing porphyrinoid macrocycles with and without pre-complexed depleted uranium and demonstrate that the latter species may be detected easily and with high sensitivity via photoacoustic imaging. The porphyrinoid macrocycles used in the present study are non-aromatic in the absence of the uranyl cation, but aromatic after cation complexation. We solubilized both the freebase and metalated forms of the macrocycles in poly(lactic-co-glycolic acid) and found a peak in the photoacoustic spectrum at 910 nm excitation inmore » the case of the uranyl complex. The signal was stable for at least 15 minutes and allowed detection of uranium concentrations down to 6.2 ppb (5.7 nM) in vitro and 0.57 ppm (19 fCi; 0.52 μM) in vivo. Furthermore, to the best of our knowledge, this is the first report of a nanoparticle that detects an actinide cation via photoacoustic imaging.« less

An autonomous chemically fuelled small-molecule motor

NASA Astrophysics Data System (ADS)

Wilson, Miriam R.; Solà, Jordi; Carlone, Armando; Goldup, Stephen M.; Lebrasseur, Nathalie; Leigh, David A.

2016-06-01

Molecular machines are among the most complex of all functional molecules and lie at the heart of nearly every biological process. A number of synthetic small-molecule machines have been developed, including molecular muscles, synthesizers, pumps, walkers, transporters and light-driven and electrically driven rotary motors. However, although biological molecular motors are powered by chemical gradients or the hydrolysis of adenosine triphosphate (ATP), so far there are no synthetic small-molecule motors that can operate autonomously using chemical energy (that is, the components move with net directionality as long as a chemical fuel is present). Here we describe a system in which a small molecular ring (macrocycle) is continuously transported directionally around a cyclic molecular track when powered by irreversible reactions of a chemical fuel, 9-fluorenylmethoxycarbonyl chloride. Key to the design is that the rate of reaction of this fuel with reactive sites on the cyclic track is faster when the macrocycle is far from the reactive site than when it is near to it. We find that a bulky pyridine-based catalyst promotes carbonate-forming reactions that ratchet the displacement of the macrocycle away from the reactive sites on the track. Under reaction conditions where both attachment and cleavage of the 9-fluorenylmethoxycarbonyl groups occur through different processes, and the cleavage reaction occurs at a rate independent of macrocycle location, net directional rotation of the molecular motor continues for as long as unreacted fuel remains. We anticipate that autonomous chemically fuelled molecular motors will find application as engines in molecular nanotechnology.

Cyclic tetraureas with variable flexibility--synthesis, crystal structures and properties.

PubMed

Meshcheryakov, Denys; Arnaud-Neu, Françoise; Böhmer, Volker; Bolte, Michael; Cavaleri, Julien; Hubscher-Bruder, Véronique; Thondorf, Iris; Werner, Sabine

2008-09-21

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.

Synthesis, spectroscopic, physicochemical and structural characterization of tetrandrine-based macrocycles functionalized with acridine and anthracene groups: DNA binding and anti-proliferative activity.

PubMed

Calvillo-Páez, Viviana; Sotelo-Mundo, Rogerio R; Leyva-Peralta, Mario; Gálvez-Ruiz, Juan Carlos; Corona-Martínez, David; Moreno-Corral, Ramón; Escobar-Picos, Raymundo; Höpfl, Herbert; Juárez-Sánchez, Octavio; Lara, Karen Ochoa

2018-04-25

In this work, we report on the synthesis of two new mono-alkylated tetrandrine derivatives with acridine and anthracene units, MAcT and MAnT. The compounds were fully characterized by physicochemical techniques and single-crystal X-ray diffraction analysis. In addition, both derivatives were studied as nucleotide receptors and double-stranded DNA binders in aqueous phosphate buffer at pH = 7.2 using UV-vis and fluorescence spectroscopy. According to the molecular recognition studies, MAcT and MAnT exhibit high affinity (K ∼ 10 5  M -1 ) and selectivity for ds-DNA, presumably in an intercalation mode. Finally, the anti-proliferative effects of the tetrandrine derivatives on different cancer cell lines were explored, revealing promising activities. Particularly, the mono-anthracene tetrandrine derivative MAnT showed an IC 50 of 2.74 μg/mL on the HeLa cervical cancer cell line, representing a value 3.3 times smaller than that obtained for unsubstituted tetrandrine. Examination of the cytotoxic effects on the HeLa cell line by inverted microscopy suggests that the cell death mechanism consists basically in apoptosis. The molecular modelling of three ds-DNA-MAcT complexes, suggested that the macrocycles may use an intercalation binding mode towards DNA. MAcT is predicted to bind into the major groove of the ds-DNA providing non-covalent interactions such as electrostatic, van der Waals and hydrophobic interactions that lead to selectivity. Overall experimental data supports the mode of action of MAnT and MAcT as cytotoxic compounds against cancer cell lines via a DNA interaction mechanism. Copyright © 2018 Elsevier B.V. All rights reserved.

Maintenance of Genetic Variability under Strong Stabilizing Selection: A Two-Locus Model

PubMed Central

Gavrilets, S.; Hastings, A.

1993-01-01

We study a two locus model with additive contributions to the phenotype to explore the relationship between stabilizing selection and recombination. We show that if the double heterozygote has the optimum phenotype and the contributions of the loci to the trait are different, then any symmetric stabilizing selection fitness function can maintain genetic variability provided selection is sufficiently strong relative to linkage. We present results of a detailed analysis of the quadratic fitness function which show that selection need not be extremely strong relative to recombination for the polymorphic equilibria to be stable. At these polymorphic equilibria the mean value of the trait, in general, is not equal to the optimum phenotype, there exists a large level of negative linkage disequilibrium which ``hides'' additive genetic variance, and different equilibria can be stable simultaneously. We analyze dependence of different characteristics of these equilibria on the location of optimum phenotype, on the difference in allelic effect, and on the strength of selection relative to recombination. Our overall result that stabilizing selection does not necessarily eliminate genetic variability is compatible with some experimental results where the lines subject to strong stabilizing selection did not have significant reductions in genetic variability. PMID:8514145

Total Synthesis and Structure-Activity Investigation of the Marine Natural Product Neopeltolide

PubMed Central

Custar, Daniel W.; Zabawa, Thomas P.; Hines, John; Crews, Craig M.; Scheidt, Karl A.

2009-01-01

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity. PMID:19663512

Macrocyclic polyaminocarboxylates for stable radiometal antibody conjugates for therapy, spect and pet imaging

DOEpatents

Mease, Ronnie C.; Mausner, Leonard F.; Srivastava, Suresh C.

1997-06-17

A simple method for the synthesis of 1,4,7, 10-tetraazacyclododecane N,N'N",N'"-tetraacetic acid and 1,4,8,11-tetraazacyclotetradecane N,N',N",N'"-tetraacetic acid involves cyanomethylating 1,4,7, 10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane to form a tetranitrile and hydrolyzing the tetranitrile. These macrocyclic compounds are functionalized through one of the carboxylates and then conjugated to various biological molecules including monoclonal antibodies. The resulting conjugated molecules are labeled with radiometals for SPECT and PET imaging and for radiotherapy.

Separation of Arylenevinylene Macrocycles with a Surface-Confined Two-Dimensional Covalent Organic Framework.

PubMed

Liu, Chunhua; Park, Eunsol; Jin, Yinghua; Liu, Jie; Yu, Yanxia; Zhang, Wei; Lei, Shengbin; Hu, Wenping

2018-05-31

A two-dimensional surface covalent organic framework, prepared by a surface-confined synthesis using 4,4'-azodianiline and benzene-1,3,5-tricarbaldehyde as the precursors, was used as a host network to effectively immobilize arylenevinylene macrocycles (AVMs). Thus AVMs could be separated from their linear polymer analogues, which are the common side-products in the cyclooligomerization process. Scanning tunneling microscopy investigations revealed efficient removal of linear polymers by a simple surface binding and solvent washing process. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Host-guest complexes of local anesthetics with cucurbit[6]uril and para-sulphonatocalix[8]arene in the solid state

NASA Astrophysics Data System (ADS)

Danylyuk, Oksana; Butkiewicz, Helena; Coleman, Anthony W.; Suwinska, Kinga

2017-12-01

Here we describe the host-guest inclusion complexes of local anesthetic drugs with two macrocyclic hosts cucurbit[6]uril and para-sulphonatocalix[8]arene in the solid state. The anesthetic agents used in the co-crystallization with the supramolecular hosts are lidocaine, procaine, procainamide, prilocaine and proparacaine. Both macrocycles encapsulate the alkylammonium moieties of anestetics guests into their cavities although the mechanism of complexation, host-guest stoichiometry and geometry differ depending on the nature of the supramolecular host.

Ferrocene- and Biferrocene-Containing Macrocycles towards Single-Molecule Electronics.

PubMed

Wilson, Lucy E; Hassenrück, Christopher; Winter, Rainer F; White, Andrew J P; Albrecht, Tim; Long, Nicholas J

2017-06-06

Cyclic multiredox centered systems are currently of great interest, with new compounds being reported and developments made in understanding their behavior. Efficient, elegant, and high-yielding (for macrocyclic species) synthetic routes to two novel alkynyl-conjugated multiple ferrocene- and biferrocene-containing cyclic compounds are presented. The electronic interactions between the individual ferrocene units have been investigated through electrochemistry, spectroelectrochemistry, density functional theory (DFT), and crystallography to understand the effect of cyclization on the electronic properties and structure. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thio-,amine-,nitro-,and macrocyclic containing organic aerogels & xerogels

DOEpatents

Fox, Glenn A.; Tillotson, Thomas M.

2005-08-02

An organic aerogel or xerogel formed by a sol-gel reaction using starting materials that exhibit similar reactivity to the most commonly used resorcinol starting material. The new starting materials, including thio-, amine- and nitro-containing molecules and functionalized macrocyclic molecules will produce organic xerogels and aerogels that have improved performance in the areas of detection and sensor technology, as well as water stream remediation. Also, further functionalization of these new organic aerogels or xerogels will yield material that can be extracted with greater facility than current organic aerogels.

Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors

PubMed Central

Sandgren, Veronica; Belda, Oscar; Kvarnström, Ingemar; Lindberg, Jimmy; Samuelsson, Bertil; Dahlgren, Anders

2015-01-01

A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties. PMID:25937848

Effect of degree of sulfonation and casting solvent on sulfonated poly(ether ether ketone) membrane for vanadium redox flow battery

NASA Astrophysics Data System (ADS)

Xi, Jingyu; Li, Zhaohua; Yu, Lihong; Yin, Bibo; Wang, Lei; Liu, Le; Qiu, Xinping; Chen, Liquan

2015-07-01

The properties of sulfonated poly(ether ether ketone) (SPEEK) membranes with various degree of sulfonation (DS) and casting solvent are investigated for vanadium redox flow battery (VRFB). The optimum DS of SPEEK membrane is firstly confirmed by various characterizations such as physicochemical properties, ion selectivity, and VRFB single-cell performance. Subsequently the optimum casting solvent is selected for the optimum DS SPEEK membrane within N,N‧-dimethylformamide (DMF), N,N‧-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), and dimethylsulfoxide (DMSO). The different performance of SPEEK membranes prepared with various casting solvents can be attributed to the different interaction between solvent and -SO3H group of SPEEK. In the VRFB single-cell test, the optimum SPEEK membrane with DS of 67% and casting solvent of DMF (S67-DMF membrane) exhibits higher VRFB efficiencies and better cycle-life performance at 80 mA cm-2. The investigation of various DS and casting solvent will be effective guidance on the selection and modification of SPEEK membrane towards VRFB application.

Effect of additives on eremomycin sorbent selectivity in separation of salbutamol enantiomers using supercritical fluid chromatography

NASA Astrophysics Data System (ADS)

Pokrovskiy, O. I.; Kayda, A. S.; Usovich, O. I.; Parenago, O. O.; Lunin, V. V.

2017-11-01

A regime is found in which chiral stationary phase based on macrocyclic glycopeptide eremomycin allows separation of salbutamol sulfate enantiomers in supercritical fluid chromatography. Enantioseparation occurs only when two dynamic modifiers are used simultaneously: isopropylamin + trifluoroacetic acid or isopropylamin + ammonium acetate. Amine molar concentration in mobile phase has to be higher than acid molar concentration, otherwise enantiomers coelute. We suppose that with amine excess a mechanism of enantiorecognition is realized which involves ionic sorbent-sorbate interactions. Such mechanism is well-known for glycopeptide chiral selectors in liquid chromatography, but for supercritical fluid chromatography it is reported for the first time.

Enantioselective Rhodium-Catalyzed Dimerization of ω-Allenyl Carboxylic Acids: Straightforward Synthesis of C2 -Symmetric Macrodiolides.

PubMed

Steib, Philip; Breit, Bernhard

2018-04-19

Herein, we report on the first enantioselective and atom-efficient catalytic one-step dimerization method to selectively transform ω-allenyl carboxylic acids into C 2 -symmetric 14- to 28-membered bismacrolactones (macrodiolides). This convenient asymmetric access serves as an attractive route towards multiple naturally occuring homodimeric macrocyclic scaffolds and demonstrates excellent efficiency to construct the complex, symmetric core structures. By utilizing a rhodium catalyst with a modified chiral cyclopentylidene-diop ligand, the desired diolides were obtained in good to high yields, high diastereoselectivity, and excellent enantioselectivity. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.

PubMed

Parsy, Christophe; Alexandre, François-René; Brandt, Guillaume; Caillet, Catherine; Cappelle, Sylvie; Chaves, Dominique; Convard, Thierry; Derock, Michel; Gloux, Damien; Griffon, Yann; Lallos, Lisa; Leroy, Frédéric; Liuzzi, Michel; Loi, Anna-Giulia; Moulat, Laure; Musiu, Chiara; Rahali, Houcine; Roques, Virginie; Seifer, Maria; Standring, David; Surleraux, Dominique

2014-09-15

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD). Copyright © 2014 Elsevier Ltd. All rights reserved.

Extreme electronic modulation of the cofacial porphyrin structural motif.

PubMed

Fletcher, James T; Therien, Michael J

2002-04-24

The synthesis, electrochemistry, and optical spectroscopy of an extensive series of cofacial bis[(porphinato)zinc(II)] compounds are reported. These species were synthesized using sequential palladium-catalyzed cross-coupling and cobalt-mediated [2+2+2] cycloaddition reactions. This modular methodology enables facile control of the nature of macrocycle-to-macrocycle connectivity and allows unprecedented modulation of the redox properties of face-to-face porphyrin species. We report the synthesis of 5,6-bis[(5',5''-10',20'-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (1), 5,6-bis[(2'-5',10',15',20'-tetraphenylporphinato)zinc(II)]indane (2), 5-([2'-5',10',15',20'-tetraphenylporphinato]zinc(II))-6-[(5"-10'',20''-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (3), 5-([2'-5',10',15',20'-tetrakis(trifluoromethyl)porphinato]zinc(II))-6-[(5' '-10' ',20' '-bis[4-(3-methoxy-3-methylbutoxy)phenyl]porphinato)zinc(II)]indane (4), 5-(2'-5',10',15',20'-[tetrakis(trifluoromethyl)porphinato]zinc(II))-6-[(2''-5'',10'',15'',20''-tetraphenylporphinato)zinc(II)]indane (5), 5,6-bis([2'-5',15'-diphenyl-10',20'-(trifluoromethyl)porphinato]zinc(II))indane (6), and 5,6-bis([2'-5',10',15',20'-tetrakis(trifluoromethyl)porphinato]zinc(II))indane (7); 4-7 define the first examples of cofacial bis[(porphinato)metal] compounds in which sigma-electron-withdrawing perfluoroalkyl groups serve as macrocycle substituents, while 2, 6, and 7 constitute the first such structures that possess a beta-to-beta linkage topology. Cyclic voltammetric studies show that the electrochemically determined HOMO and LUMO energy levels of these cofacial bis(porphinato) complexes can be lowered by 780 and 945 mV, respectively, relative to the archetypal members of this class of compounds; importantly, these orbital energy levels can be modulated over well-defined increments throughout these wide potentiometric domains. Analyses of these cofacial bis[(porphinato)metal] potentiometric data, in terms of the absolute and relative frontier orbital energies of their constituent [porphinato]zinc(II) building blocks, as well as the nature of macrocycle-to-macrocycle connectivity, provide predictive electronic structural models that rationalize the redox behavior of these species.

Design and synthesis of binucleating macrocyclic clefts derived from Schiff-base calixpyrroles.

PubMed

Givaja, Gonzalo; Volpe, Manuel; Leeland, James W; Edwards, Michael A; Young, Thomas K; Darby, S Barnie; Reid, Stuart D; Blake, Alexander J; Wilson, Claire; Wolowska, Joanna; McInnes, Eric J L; Schröder, Martin; Love, Jason B

2007-01-01

The syntheses, characterisation and complexation reactions of a series of binucleating Schiff-base calixpyrrole macrocycles are described. The acid-templated [2+2] condensations between meso-disubstituted diformyldipyrromethanes and o-phenylenediamines generate the Schiff-base pyrrolic macrocycles H(4)L(1) to H(4)L(6) upon basic workup. The single-crystal X-ray structures of both H(4)L(3).2 EtOH and H(4)L(6).H2O confirm that [2+2] cyclisation has occurred, with either EtOH or H2O hydrogen-bonded within the macrocyclic cleft. A series of complexation reactions generate the dipalladium [Pd2(L)] (L=L(1) to L(5)), dinickel [Ni2(L(1))] and dicopper [Cu2(L)] (L=L(1) to L(3)) complexes. All of these complexes have been structurally characterised in the solid state and are found to adopt wedged structures that are enforced by the rigidity of the aryl backbone to give a cleft reminiscent of the structures of Pacman porphyrins. The binuclear nickel complexes [Ni2(mu-OMe)2Cl2(HOMe)2(H(4)L(1))] and [Ni2(mu-OH)2Cl2(HOMe)(H(4)L(5))] have also been prepared, although in these cases the solid-state structures show that the macrocyclic ligand remains protonated at the pyrrolic nitrogen atoms, and the Ni(II) cations are therefore co-ordinated by the imine nitrogen atoms only to give an open conformation for the complex. The dicopper complex [Cu2(L(3))] was crystallised in the presence of pyridine to form the adduct [Cu2(py)(L(3))], in which, in the solid state, the pyridine ligand is bound within the binuclear molecular cleft. Reaction between H(4)L(1) and [Mn(thf){N(SiMe(3))2}2] results in clean formation of the dimanganese complex [Mn2(L(1))], which, upon crystallisation, formed the mixed-valent complex [Mn2(mu-OH)(L(1))] in which the hydroxo ligand bridges the metal centres within the molecular cleft.

Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 15. Effects of the pyridyl substituents and fused exocyclic rings on the UV-visible spectroscopic properties of Mg(II)-porphyrazines: a combined experimental and DFT/TDDFT study.

PubMed

Donzello, Maria Pia; De Mori, Giorgia; Viola, Elisa; Ercolani, Claudio; Ricciardi, Giampaolo; Rosa, Angela

2014-08-04

Two new Mg(II) porphyrazine macrocycles, the octakis(2-pyridyl)porphyrazinato-magnesium(II), [Py8PzMg(H2O)], and the tetrakis-[6,7-di(2-pyridyl)quinoxalino]porphyrazinato-magnesium(II), [Py8QxPzMg(H2O)], were prepared by Mg-template macrocyclization processes, and their general physicochemical properties were examined. The previously reported porphyrazine analog, the tetrakis-2,3-[5,6-di(2-pyridyl)-pyrazino]porphyrazinato-magnesium(II), [Py8PyzPzMg(H2O)], has been also considered in the present work. The UV-visible solution spectra in nonaqueous solvents of this triad of externally octapyridinated Mg(II) complexes exhibit the usual profile observed for phthalocyanine and porphyrazine macrocycles, with intense absorptions in the Soret (300-450 nm) and Q band (600-800 nm) regions. It is observed that the Q band maximum sensibly shifts toward the red with peak values at 635 → 658 → 759 nm along the series [Py8PzMg(H2O)], [Py8PyzPzMg(H2O)], and [Py8QxPzMg(H2O)], as the extension of the macrocycle π-system increases. TDDFT calculations of the electronic absorption spectra were performed for the related water-free model compounds [Py8PzMg], [Py8PyzPzMg], and [Py8QxPzMg] to provide an interpretation of the UV-visible spectral changes occurring upon introduction of the pyrazine and quinoxaline rings at the periphery of the Pz macrocycle. To discriminate the electronic effects of the fused exocyclic rings from those of the appended 2-pyridyl rings, the UV-visible spectra of [PzMg] and [PyzPzMg] were also theoretically investigated. The theoretical results prove to agree very well with the experimental data, providing an accurate description of the UV-visible spectra. The observed spectral changes are interpreted on the basis of the electronic structure changes occurring along the series.

Synthesis and evaluation of nanoglobular macrocyclic Mn(II) chelate conjugates as non-gadolinium(III) MRI contrast agents.

PubMed

Tan, Mingqian; Ye, Zhen; Jeong, Eun-Kee; Wu, Xueming; Parker, Dennis L; Lu, Zheng-Rong

2011-05-18

Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-1) per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less nonspecific liver enhancement than MnCl(2) and were effective for contrast-enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising nongadolinium based MRI contrast agents.

Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in the indoor environment.

PubMed

Brasel, T L; Martin, J M; Carriker, C G; Wilson, S C; Straus, D C

2005-11-01

The existence of airborne mycotoxins in mold-contaminated buildings has long been hypothesized to be a potential occupant health risk. However, little work has been done to demonstrate the presence of these compounds in such environments. The presence of airborne macrocyclic trichothecene mycotoxins in indoor environments with known Stachybotrys chartarum contamination was therefore investigated. In seven buildings, air was collected using a high-volume liquid impaction bioaerosol sampler (SpinCon PAS 450-10) under static or disturbed conditions. An additional building was sampled using an Andersen GPS-1 PUF sampler modified to separate and collect particulates smaller than conidia. Four control buildings (i.e., no detectable S. chartarum growth or history of water damage) and outdoor air were also tested. Samples were analyzed using a macrocyclic trichothecene-specific enzyme-linked immunosorbent assay (ELISA). ELISA specificity was tested using phosphate-buffered saline extracts of the fungal genera Aspergillus, Chaetomium, Cladosporium, Fusarium, Memnoniella, Penicillium, Rhizopus, and Trichoderma, five Stachybotrys strains, and the indoor air allergens Can f 1, Der p 1, and Fel d 1. For test buildings, the results showed that detectable toxin concentrations increased with the sampling time and short periods of air disturbance. Trichothecene values ranged from <10 to >1,300 pg/m3 of sampled air. The control environments demonstrated statistically significantly (P < 0.001) lower levels of airborne trichothecenes. ELISA specificity experiments demonstrated a high specificity for the trichothecene-producing strain of S. chartarum. Our data indicate that airborne macrocyclic trichothecenes can exist in Stachybotrys-contaminated buildings, and this should be taken into consideration in future indoor air quality investigations.

Optimum threshold selection method of centroid computation for Gaussian spot

NASA Astrophysics Data System (ADS)

Li, Xuxu; Li, Xinyang; Wang, Caixia

2015-10-01

Centroid computation of Gaussian spot is often conducted to get the exact position of a target or to measure wave-front slopes in the fields of target tracking and wave-front sensing. Center of Gravity (CoG) is the most traditional method of centroid computation, known as its low algorithmic complexity. However both electronic noise from the detector and photonic noise from the environment reduces its accuracy. In order to improve the accuracy, thresholding is unavoidable before centroid computation, and optimum threshold need to be selected. In this paper, the model of Gaussian spot is established to analyze the performance of optimum threshold under different Signal-to-Noise Ratio (SNR) conditions. Besides, two optimum threshold selection methods are introduced: TmCoG (using m % of the maximum intensity of spot as threshold), and TkCoG ( usingμn +κσ n as the threshold), μn and σn are the mean value and deviation of back noise. Firstly, their impact on the detection error under various SNR conditions is simulated respectively to find the way to decide the value of k or m. Then, a comparison between them is made. According to the simulation result, TmCoG is superior over TkCoG for the accuracy of selected threshold, and detection error is also lower.

FerriCast: a macrocyclic photocage for Fe3+.

PubMed

Kennedy, Daniel P; Incarvito, Christopher D; Burdette, Shawn C

2010-02-01

The non-siderophoric Fe(3+) photocage FerriCast (4,5-dimethoxy-2-nitrophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl] methanol (2) has been prepared in high yield using an optimized two-step reaction sequence that utilizes a trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted electrophilic aromatic substitution as the key synthetic step. Spectrophotometric assessment of Fe(3+) binding to FerriCast revealed a binding stoichiometry and metal ion affinity dependent on the nature of the counterion. Exposure of FerriCast to 350 nm light initiates a photoreaction that converts FerriCast into FerriUnc (4,5-dimethoxy-2-nitrosophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl]-methanone), which binds Fe(3+) less strongly owing to resonance delocalization of the anilino lone pair into the benzophenone pi-system. The release of Fe(3+) upon photolysis of FerriCast also was evaluated using a previously reported turn-on fluorescent sensor that utilizes the same macrocyclic ligand (4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl, AT(2)12C4). In contrast to the original reports on AT(2)12C4-based Fe(3+) sensors, FerriCast does not interact with ferric iron in aqueous solution. Introduction of oxygen containing solvents (MeOH, H(2)O, DMSO, MES, and phosphate buffers) to CH(3)CN solutions of metalated FerriCast lead to rapid decomplexation as measured by UV-visible spectroscopy. Further investigations contradicted the published conclusions on the aqueous coordination chemistry of AT(2)12C4, but also confirmed the unique and unexpected selectivity of the macrocycle for Fe(3+) in nonaqueous solvents. The crystallographic analysis of [Cu(AT(2)12C4)Cl](+) provides a rare example of a bifurcated hydrogen bond, and evidence for redox chemistry with the ligand. Spectrophotometric analysis of the model ligand with redox active metal ions provide evidence for AT(2)12C4(*+), a quasi-stable species the presence of which suggests caution should be taken when evaluating the interaction of aniline-containing systems with redox active metal ions.

Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms

PubMed Central

Abongwa, Melanie; Buxton, Samuel K.; Robertson, Alan P.; Martin, Richard J.

2016-01-01

Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro-intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 μM abamectin in a non-competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 μM. However, when we increased the concentration of abamectin further to 0.3 μM, 1 μM or 10 μM, we found that the antagonism decreased and was less than with 0.1 μM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 μM derquantel alone and in combination with 0.3 μM abamectin. We found that derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics. PMID:26751958

Cytotoxic Activity and Structure-Activity Relationship of Triazole-Containing Bis(Aryl Ether) Macrocycles.

PubMed

Hernández-Vázquez, Eduardo; Chávez-Riveros, Alejandra; Romo-Pérez, Adriana; Ramírez-Apán, María Teresa; Chávez-Blanco, Alma D; Morales-Bárcenas, Rocío; Dueñas-González, Alfonso; Miranda, Luis D

2018-05-17

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20-, 21-, and 22-membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC-3) and breast (MCF-7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N-phenyl moiety (IC 50 <13 μm). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)-N-cyclohexyl-7-oxo-6-[4-(trifluoromethyl)phenyl]-1 1 H-3,10-dioxa-6-aza-1(4,1)-triazola-4(1,3),9(1,4)-dibenzenacyclotridecaphane-5-carboxamide (12 f) was the most potent in this regard (22.7 % of apoptosis). © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anion-free bambus[6]uril and its supramolecular properties.

PubMed

Svec, Jan; Dusek, Michal; Fejfarova, Karla; Stacko, Peter; Klán, Petr; Kaifer, Angel E; Li, Wei; Hudeckova, Edita; Sindelar, Vladimir

2011-05-09

Methods for the preparation of anion-free bambus[6]uril (BU6) are presented. They are based on the oxidation of iodide anion, which is bound inside the macrocycle, utilizing dark oxidation by hydrogen peroxide or photooxidation in the presence of titanium dioxide. Anion-free BU6 was found to be insoluble in any of the investigated solvents; however, it dissolves in methanol/chloroform (1:1) or acetonitrile/water (1:1) mixtures in the presence of the tetrabutylammonium salt of a suitable anion. The association constants with halide ions, BF(4)(-), NO(3)(-), and CN(-), were measured by (1)H NMR spectroscopy. The highest association constant (8.9×10(5) M(-1)) was found for the 1:1 complex of BU6 with I(-) in acetonitrile/water mixture. A number of crystal structures of BU6 complexes with various anions were obtained. The influence of the anion size on the macrocycle diameter is discussed together with an unusual arrangement of the macrocycles into separate layers. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Parts per billion detection of uranium with a porphyrinoid-containing nanoparticle and in vivo photoacoustic imaging

DOE PAGES

Ho, I-Ting; Sessler, Jonathan L.; Gambhir, Sanjiv Sam; ...

2015-04-01

Chemical tools that can report radioactive isotopes would be of interest to the defense community. Here in this paper we report –250 nm polymeric nanoparticles containing porphyrinoid macrocycles with and without pre-complexed depleted uranium and demonstrate that the latter species may be detected easily and with high sensitivity via photoacoustic imaging. The porphyrinoid macrocycles used in the present study are non-aromatic in the absence of the uranyl cation, but aromatic after cation complexation. We solubilized both the freebase and metalated forms of the macrocycles in poly(lactic-co-glycolic acid) and found a peak in the photoacoustic spectrum at 910 nm excitation inmore » the case of the uranyl complex. The signal was stable for at least 15 minutes and allowed detection of uranium concentrations down to 6.2 ppb (5.7 nM) in vitro and 0.57 ppm (19 fCi; 0.52 μM) in vivo. Furthermore, to the best of our knowledge, this is the first report of a nanoparticle that detects an actinide cation via photoacoustic imaging.« less

Topical cream-based dosage forms of the macrocyclic drug delivery vehicle cucurbit[6]uril.

PubMed

Seif, Marian; Impelido, Michael L; Apps, Michael G; Wheate, Nial J

2014-01-01

The macrocycle family of molecules called cucurbit[n]urils are potential drug delivery vehicles as they are able to form host-guest complexes with many different classes of drugs. This study aimed to examine the utility of Cucurbit[6]uril (CB[6]) in topical cream-based formulations for either localised treatment or for transdermal delivery. Cucurbit[6]uril was formulated into both buffered cream aqueous- and oily cream-based dosage forms. The solid state interaction of CB[6] with other excipients was studied by differential scanning calorimetry and the macrocycle's transdermal permeability was determined using rat skin. Significant solid state interactions were observed between CB[6] and the other dosage form excipients. At concentrations up to 32% w/w the buffered aqueous cream maintained its normal consistency and could be effectively applied to skin, but the oily cream was too stiff and is not suitable as a dosage form. Cucurbit[6]uril does not permeate through skin; as such, the results imply that cucurbituril-based topical creams may potentially only have applications for localised skin treatment and not for transdermal drug delivery.

Topical Cream-Based Dosage Forms of the Macrocyclic Drug Delivery Vehicle Cucurbit[6]uril

PubMed Central

Seif, Marian; Impelido, Michael L.; Apps, Michael G.; Wheate, Nial J.

2014-01-01

The macrocycle family of molecules called cucurbit[n]urils are potential drug delivery vehicles as they are able to form host-guest complexes with many different classes of drugs. This study aimed to examine the utility of Cucurbit[6]uril (CB[6]) in topical cream-based formulations for either localised treatment or for transdermal delivery. Cucurbit[6]uril was formulated into both buffered cream aqueous- and oily cream-based dosage forms. The solid state interaction of CB[6] with other excipients was studied by differential scanning calorimetry and the macrocycle's transdermal permeability was determined using rat skin. Significant solid state interactions were observed between CB[6] and the other dosage form excipients. At concentrations up to 32% w/w the buffered aqueous cream maintained its normal consistency and could be effectively applied to skin, but the oily cream was too stiff and is not suitable as a dosage form. Cucurbit[6]uril does not permeate through skin; as such, the results imply that cucurbituril-based topical creams may potentially only have applications for localised skin treatment and not for transdermal drug delivery. PMID:24454850

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

PubMed

Qian Cutrone, Jingfang Jenny; Huang, Xiaohua Stella; Kozlowski, Edward S; Bao, Ye; Wang, Yingzi; Poronsky, Christopher S; Drexler, Dieter M; Tymiak, Adrienne A

2017-05-10

Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources. Copyright © 2017. Published by Elsevier B.V.

Stimuli-responsive supramolecular micellar assemblies of cetylpyridinium chloride with cucurbit[5/7]urils.

PubMed

Choudhury, Sharmistha Dutta; Barooah, Nilotpal; Aswal, Vinod Kumar; Pal, Haridas; Bhasikuttan, Achikanath C; Mohanty, Jyotirmayee

2014-05-21

This article demonstrates, for the first time, construction of novel cucurbituril (CB)-adorned supramolecular micellar assemblies of a cationic surfactant, cetylpyridinium chloride (CPC), through noncovalent host-guest interactions. The distinct cation receptor features and cavity dimensions of the CB5 and CB7 homologues assert that the macrocyclic hosts remain complexed with the CPC monomers and take part in the micelle formation, a unique observation in contrast to that of the classical host, β-cyclodextrin. The cooperative contributions of the CB macrocycles in the micelle formation have been documented by the photochemical, surface tension, conductivity, DOSY NMR, and SANS measurements. The contrasting downward and upward shifts in the cmc of the CPC surfactant, respectively, with CB5 and CB7 hosts provide a unique opportunity for the controlled tuning of the micellization region for CPC from 0.57 to 1.6 mM, by using a combination of the macrocyclic hosts. The article also establishes the reversible response of these soft supramolecular micellar structures to thermal-stimuli, which projects their utility for on-demand smart drug-delivery vehicles.

Macrocyclic peptide inhibitors for the protein-protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5.

PubMed

Song, Xiao; Lu, Lu-Yi; Passioura, Toby; Suga, Hiroaki

2017-06-21

Ebola virus infection leads to severe hemorrhagic fever in human and non-human primates with an average case fatality rate of 50%. To date, numerous potential therapies are in development, but FDA-approved drugs or vaccines are yet unavailable. Ebola viral protein 24 (VP24) is a multifunctional protein that plays critical roles in the pathogenesis of Ebola virus infection, e.g. innate immune suppression by blocking the interaction between KPNA and PY-STAT1. Here we report macrocyclic peptide inhibitors of the VP24-KPNA5 protein-protein interaction (PPI) by means of the RaPID (Random non-standard Peptides Integrated Discovery) system. These macrocyclic peptides showed remarkably high affinity to recombinant Zaire Ebola virus VP24 (eVP24), with a dissociation constant in the single digit nanomolar range, and could also successfully disrupt the eVP24-KPNA interaction. This work provides for the first time a chemical probe capable of modulating this PPI interaction and is the starting point for the development of unique anti-viral drugs against the Ebola virus.

Effect of the chemical modification of a macrocycle and the acidity of a medium on the spectral properties and basicity of tetraphenylporphyrin in HCl- N, N-dimethylformamide system at 298 K

NASA Astrophysics Data System (ADS)

Ivanova, Yu. B.; Razgonyaev, O. V.; Semeikin, A. S.; Mamardashvili, N. Zh.

2016-05-01

Spectrophotometric titration is used to study the basicity of tetraphenylporphine and its derivatives with electron-donor and electron-acceptor substituents in the 4-positions of meso-aryl fragments (5,10,15,20-tetra(4-R-phenyl)porphine, R:-OH,-NH2,-COOH,-Cl) in a system HCl- N, N-dimethylformamide at 298 K. An equation for calculating the dependence of the Hammett constant ( H 0) on the HCl concentration in a HCl- N, N-dimethylformamide system at 298 K is proposed. It is found that protonation of the intracycle nitrogen atoms of tetrapyrrole macrocycles of the indicated compounds occurs in two stages in this system. The corresponding ionization constants and concentration ranges of the existence of mono- and doubly-protonated dication forms of the indicated compounds are determined. It is found that both the introduction of strong substituents into the macrocycle of porphyrin and the properties of the medium facilitate the formation of mono- and doubly-protonated forms of porphyrins in solutions.

Combined molecular and periodic DFT analysis of the adsorption of co macrocycles on graphene.

PubMed

Calborean, Adrian; Morari, Cristian; Maldivi, Pascale

2018-01-15

The molecular doping of graphene with π-stacked conjugated molecules has been widely studied during the last 10 years, both experimentally or using first-principle calculations, mainly with strongly acceptor or donor molecules. Macrocyclic metal complexes have been far less studied and their behavior on graphene is less clear-cut. The present density functional theory study of cobalt porphyrin and phthalocyanine adsorbed on monolayer or bilayer graphene allows to compare the outcomes of two models, either a finite-sized flake of graphene or an infinite 2D material using periodic calculations. The electronic structures yielded by both models are compared, with a focus on the density of states around the Fermi level. Apart from the crucial choice of calculation conditions, this investigation also shows that unlike strongly donating or accepting organic dopants, these macrocycles do not induce a significant doping of the graphene sheet and that a finite size model of graphene flake may be confidently used for most modeling purposes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Epitope targeting of tertiary protein structure enables target-guided synthesis of a potent in-cell inhibitor of botulinum neurotoxin.

PubMed

Farrow, Blake; Wong, Michelle; Malette, Jacquie; Lai, Bert; Deyle, Kaycie M; Das, Samir; Nag, Arundhati; Agnew, Heather D; Heath, James R

2015-06-08

Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Functionalized apertures for the detection of chemical and biological materials

DOEpatents

Letant, Sonia E.; van Buuren, Anthony W.; Terminello, Louis J.; Thelen, Michael P.; Hope-Weeks, Louisa J.; Hart, Bradley R.

2010-12-14

Disclosed are nanometer to micron scale functionalized apertures constructed on a substrate made of glass, carbon, semiconductors or polymeric materials that allow for the real time detection of biological materials or chemical moieties. Many apertures can exist on one substrate allowing for the simultaneous detection of numerous chemical and biological molecules. One embodiment features a macrocyclic ring attached to cross-linkers, wherein the macrocyclic ring has a biological or chemical probe extending through the aperture. Another embodiment achieves functionalization by attaching chemical or biological anchors directly to the walls of the apertures via cross-linkers.

Disulphide bond exchange inhibited by air - kinetic and thermodynamic products in a library of macrocyclic cysteine derivatives.

PubMed

Cholewiak, Agnieszka; Dobrzycki, Łukasz; Jurczak, Janusz; Ulatowski, Filip

2018-04-04

In this paper we present the synthesis and reactivity of dithiols comprising of two cysteine moieties attached to a dipicolinic acid core. Oxidation of these thiols provides oligomeric macrocycles. Monomers with 13-membered rings are kinetic products which are, however, strained and readily transform into higher oligomers under basic conditions or elevated temperature via a disulphide exchange reaction. Dimers, which are the most stable thermodynamic products, equilibrate only under inert conditions with thiolate as a catalyst. Under aerobic conditions, the thiols are oxidised before the equilibrium is reached.

Synthesis of macrocyclic polyaminocarboxylates and their use for preparing stable radiometal antibody immunoconjugates for therapy, spect and pet imaging

DOEpatents

Mease, Ronnie C.; Mausner, Leonard F.; Srivastava, Suresh C.

1995-06-27

A simple method for the synthesis of 1,4,7,10-tetraazacyclododecane N,N'N",N'"-tetraacetic acid and 1,4,8,11-tetraazacyclotetradecane N,N',N",N'"-tetraacetic acid involves cyanomethylating 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane to form a tetranitrile and hydrolyzing the tetranitrile. These macrocyclic compounds are functionalized through one of the carboxylates and then conjugated to various biological molecules including monoclonal antibodies. The resulting conjugated molecules are labeled with radiometals for SPECT and PET imaging and for radiotherapy.

Hydrolysis of Letrozole catalyzed by macrocyclic Rhodium (I) Schiff-base complexes.

PubMed

Reddy, P Muralidhar; Shanker, K; Srinivas, V; Krishna, E Ravi; Rohini, R; Srikanth, G; Hu, Anren; Ravinder, V

2015-03-15

Ten mononuclear Rhodium (I) complexes were synthesized by macrocyclic ligands having N4 and N2O2 donor sites. Square planar geometry is assigned based on the analytical and spectral properties for all complexes. Rh(I) complexes were investigated as catalysts in hydrolysis of Nitrile group containing pharmaceutical drug Letrozole. A comparative study showed that all the complexes are efficient in the catalysis. The percent yields of all the catalytic reaction products viz. drug impurities were determined by spectrophotometric procedures and characterized by spectral studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Potent Inhibitors of the Hepatitis C Virus NS3 Protease: Design and Synthesis of Macrocyclic Substrate-Based [beta]-Strand Mimics

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

Goudreau, Nathalie; Brochu, Christian; Cameron, Dale R.

2008-06-30

The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring {beta}-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.

Copper(II)-catalyzed amidations of alkynyl bromides as a general synthesis of ynamides and Z-enamides. An intramolecular amidation for the synthesis of macrocyclic ynamides.

PubMed

Zhang, Xuejun; Zhang, Yanshi; Huang, Jian; Hsung, Richard P; Kurtz, Kimberly C M; Oppenheimer, Jossian; Petersen, Matthew E; Sagamanova, Irina K; Shen, Lichun; Tracey, Michael R

2006-05-26

A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further attention from the synthetic organic community.

Optimization in Ecology

ERIC Educational Resources Information Center

Cody, Martin L.

1974-01-01

Discusses the optimality of natural selection, ways of testing for optimum solutions to problems of time - or energy-allocation in nature, optimum patterns in spatial distribution and diet breadth, and how best to travel over a feeding area so that food intake is maximized. (JR)

Subject Specific Optimisation of the Stiffness of Footwear Material for Maximum Plantar Pressure Reduction.

PubMed

Chatzistergos, Panagiotis E; Naemi, Roozbeh; Healy, Aoife; Gerth, Peter; Chockalingam, Nachiappan

2017-08-01

Current selection of cushioning materials for therapeutic footwear and orthoses is based on empirical and anecdotal evidence. The aim of this investigation is to assess the biomechanical properties of carefully selected cushioning materials and to establish the basis for patient-specific material optimisation. For this purpose, bespoke cushioning materials with qualitatively similar mechanical behaviour but different stiffness were produced. Healthy volunteers were asked to stand and walk on materials with varying stiffness and their capacity for pressure reduction was assessed. Mechanical testing using a surrogate heel model was employed to investigate the effect of loading on optimum stiffness. Results indicated that optimising the stiffness of cushioning materials improved pressure reduction during standing and walking by at least 16 and 19% respectively. Moreover, the optimum stiffness was strongly correlated to body mass (BM) and body mass index (BMI), with stiffer materials needed in the case of people with higher BM or BMI. Mechanical testing confirmed that optimum stiffness increases with the magnitude of compressive loading. For the first time, this study provides quantitative data to support the importance of stiffness optimisation in cushioning materials and sets the basis for methods to inform optimum material selection in the clinic.

Structural and kinetic study of reversible CO2 fixation by dicopper macrocyclic complexes. From intramolecular binding to self-assembly of molecular boxes.

PubMed

Company, Anna; Jee, Joo-Eun; Ribas, Xavi; Lopez-Valbuena, Josep Maria; Gómez, Laura; Corbella, Montserrat; Llobet, Antoni; Mahía, José; Benet-Buchholz, Jordi; Costas, Miquel; van Eldik, Rudi

2007-10-29

A study of the reversible CO2 fixation by a series of macrocyclic dicopper complexes is described. The dicopper macrocyclic complexes [Cu2(OH)2(Me2p)](CF3SO3)2, 1(CF3SO3)2, and [Cu2(mu-OH)2(Me2m)](CF3SO3)2, 2(CF3SO3)2, (Scheme 1) containing terminally bound and bridging hydroxide ligands, respectively, promote reversible inter- and intramolecular CO2 fixation that results in the formation of the carbonate complexes [{Cu2(Me2p)}2(mu-CO3)2](CF3SO3)4, 4(CF3SO3)4, and [Cu2(mu-CO3)(Me2m)](CF3SO3)2, 5(CF3SO3)2. Under a N2 atmosphere the complexes evolve CO2 and revert to the starting hydroxo complexes 1(CF3SO3)2 and 2(CF3SO3)2, a reaction the rate of which linearly depends on [H2O]. In the presence of water, attempts to crystallize 5(CF3SO3)2 afford [{Cu2(Me2m)(H2O)}2(mu-CO3)2](CF3SO3)4, 6(CF3SO3)4, which appears to rapidly convert to 5(CF3SO3)2 in acetonitrile solution. [Cu2(OH)2(H3m)]2+, 7, which contains a larger macrocyclic ligand, irreversibly reacts with atmospheric CO2 to generate cagelike [{Cu2(H3m)}2(mu-CO3)2](ClO4)4, 8(ClO4)4. However, addition of 1 equiv of HClO4 per Cu generates [Cu2(H3m)(CH3CN)4]4+ (3), and subsequent addition of Et3N under air reassembles 8. The carbonate complexes 4(CF3SO3)4, 5(CF3SO3)2, 6(CF3SO3)4, and 8(ClO4)4 have been characterized in the solid state by X-ray crystallography. This analysis reveals that 4(CF3SO3)4, 6(CF3SO3)4, and 8(ClO4)4 consist of self-assembled molecular boxes containing two macrocyclic dicopper complexes, bridged by CO32- ligands. The bridging mode of the carbonate ligand is anti-anti-mu-eta1:eta1 in 4(CF3SO3)4, anti-anti-mu-eta2:eta1 in 6(CF3SO3)4 and anti-anti-mu-eta2:eta2 in 5(CF3SO3)2 and 8(ClO4)4. Magnetic susceptibility measurements on 4(CF3SO3)4, 6(CF3SO3)4, and 8(ClO4)4 indicate that the carbonate ligands mediate antiferromagnetic coupling between each pair of bridged CuII ions (J = -23.1, -108.3, and -163.4 cm-1, respectively, H = -JS1S2). Detailed kinetic analyses of the reaction between carbon dioxide and the macrocyclic complexes 1(CF3SO3)2 and 2(CF3SO3)2 suggest that it is actually hydrogen carbonate formed in aqueous solution on dissolving CO2 that is responsible for the observed formation of the different carbonate complexes controlled by the binding mode of the hydroxy ligands. This study shows that CO2 fixation can be used as an on/off switch for the reversible self-assembly of supramolecular structures based on macrocyclic dicopper complexes.

Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years.

PubMed

Kromrey, Marie-Luise; Liedtke, Kim Rouven; Ittermann, Till; Langner, Sönke; Kirsch, Michael; Weitschies, Werner; Kühn, Jens-Peter

2017-02-01

To investigate if application of macrocyclic gadolinium-based contrast agents in volunteers is associated with neuronal deposition detected by magnetic resonance imaging in a 5-year longitudinal survey. Three hundred eighty-seven volunteers who participated in a population-based study were enrolled. Subjects underwent plain T1-weighted brain MRI at baseline and 5 years later with identical sequence parameters. At baseline, 271 participants additionally received intravenous injection of the macrocyclic contrast agent gadobutrol (0.15 mmol/kg). A control group including 116 subjects received no contrast agent. Relative signal intensities of thalamus, pallidum, pons and dentate nucleus were compared at baseline and follow-up. No difference in relative signal intensities was observed between contrast group (thalamus, p = 0.865; pallidum, p = 0.263; pons, p = 0.533; dentate nucleus, p = 0.396) and control group (thalamus, p = 0.683; pallidum; p = 0.970; pons, p = 0.773; dentate nucleus, p = 0.232) at both times. Comparison between both groups revealed no significant differences in relative signal intensities (thalamus, p = 0.413; pallidum, p = 0.653; pons, p = 0.460; dentate nucleus, p = 0.751). The study showed no significant change in globus pallidus-to-thalamus or dentate nucleus-to-pons ratios. Five years after administration of a 1.5-fold dose gadobutrol to normal subjects, signal intensity of thalamus, pallidum, pons and dentate nucleus did not differ from participants who had not received gadobutrol. • Gadobutrol does not lead to neuronal signal alterations after 5 years. • Neuronal deposition of macrocyclic contrast agent could not be confirmed. • Macrocyclic contrast agents in a proven dosage are safe.

NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor.

PubMed

Morais, Maurício; Zamora-Carreras, Héctor; Raposinho, Paula D; Oliveira, Maria Cristina; Pantoja-Uceda, David; Correia, João D G; Jiménez, M Angeles

2017-07-15

Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-MSH analogues, c[NH-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH₂ ( CycN-K6 ) and c[NH-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH₂ ( CycN-K7 ). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by ¹H and 13 C NMR. These results were compared to those of the previously reported analogue c[S-NO₂-C₆H₃-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH₂ ( CycS-C6 ). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC 50 = 155 ± 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC 50 = 495 ± 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC 50 = 1770 ± 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction.

Element specific determination of the magnetic properties of two macrocyclic tetranuclear 3d-4f complexes with a Cu3Tb core by means of X-ray magnetic circular dichroism (XMCD).

PubMed

Balinski, K; Schneider, L; Wöllermann, J; Buling, A; Joly, L; Piamonteze, C; Feltham, H L C; Brooker, S; Powell, A K; Delley, B; Kuepper, K

2018-06-20

We apply X-ray magnetic circular dichroism to study the internal magnetic structure of two very promising star shaped macrocyclic complexes with a CuII3TbIII core. These complexes are rare examples prepared with a macrocyclic ligand that show indications of SMM (Single Molecule Magnet) behavior, and they differ only in ring size: one has a propylene linked macrocycle, [CuII3TbIII(LPr)(NO3)2(MeOH)(H2O)2](NO3)·3H2O (nickname: Cu3Tb(LPr)), and the other has the butylene linked analogue, [CuII3TbIII(LBu)(NO3)2(MeOH)(H2O)](NO3)·3H2O (nickname: Cu3Tb(LBu)). We analyze the orbital and spin contributions to the Cu and Tb ions quantitatively by applying the spin and orbital sum rules concerning the L2 (M4)/L3 (M5) edges. In combination with appropriate ligand field simulations, we demonstrate that the Tb(iii) ions contribute with high orbital magnetic moments to the magnetic anisotropy, whereas the ligand field determines the easy axis of magnetization. Furthermore, we confirm that the Cu(ii) ions in both molecules are in a divalent valence state, the magnetic moments of the three Cu ions appear to be canted due to 3d-3d intramolecular magnetic interactions. For Cu3Tb(LPr), the corresponding element specific magnetization loops reflect that the Cu(ii) contribution to the overall magnetic picture becomes more important as the temperature is lowered. This implies a low value for the 3d-4f coupling.

Clinical, biological, and skin histopathologic effects of ionic macrocyclic and nonionic linear gadolinium chelates in a rat model of nephrogenic systemic fibrosis.

PubMed

Fretellier, Nathalie; Idée, Jean-Marc; Guerret, Sylviane; Hollenbeck, Claire; Hartmann, Daniel; González, Walter; Robic, Caroline; Port, Marc; Corot, Claire

2011-02-01

the purpose of this study was to compare the clinical, pathologic, and biochemical effects of repeated administrations of ionic macrocyclic or nonionic linear gadolinium chelates (GC) in rats with impaired renal function. rats submitted to subtotal nephrectomy were allocated to single injections of 2.5 mmol/kg of gadodiamide (nonionic linear chelate), nonformulated gadodiamide (ie, without the free ligand caldiamide), gadoterate (ionic macrocyclic chelate), or saline for 5 consecutive days. Blinded semi-quantitative histopathologic and immunohistochemical examinations of the skin were performed, as well as clinical, hematological, and biochemical follow-up. Rats were killed at day 11. Long-term (up to day 32) follow-up of rats was also performed in an auxiliary study. epidermal lesions (ulcerations and scabs) were found in 4 of the 10 rats treated with nonformulated gadodiamide. Two rats survived the study period. Inflammatory signs were observed in this group. No clinical, hematological, or biochemical signs were observed in the saline and gadoterate- or gadodiamide-treated groups. Plasma fibroblast growth factor-23 levels were significantly higher in the gadodiamide group than in the gadoterate group (day 11). Decreased plasma transferrin-bound iron levels were measured in the nonformulated gadodiamide group. Histologic lesions were in the range: nonformulated gadodiamide (superficial epidermal lesions, inflammation, necrosis, and increased cellularity in papillary dermis) > gadodiamide (small superficial epidermal lesions and signs of degradation of collagen fibers in the dermis) > gadoterate (very few pathologic lesions, similar to control rats). repeated administration of the nonionic linear GC gadodiamide to renally impaired rats is associated with more severe histologic lesions and higher FGF-23 plasma levels than the macrocyclic GC gadoterate.

Comparative evaluation of distributed-collector solar thermal electric power plants

NASA Technical Reports Server (NTRS)

Fujita, T.; El Gabalawi, N.; Herrera, G. G.; Caputo, R. S.

1978-01-01

Distributed-collector solar thermal-electric power plants are compared by projecting power plant economics of selected systems to the 1990-2000 timeframe. The approach taken is to evaluate the performance of the selected systems under the same weather conditions. Capital and operational costs are estimated for each system. Energy costs are calculated for different plant sizes based on the plant performance and the corresponding capital and maintenance costs. Optimum systems are then determined as the systems with the minimum energy costs for a given load factor. The optimum system is comprised of the best combination of subsystems which give the minimum energy cost for every plant size. Sensitivity analysis is done around the optimum point for various plant parameters.

A study of the selection of microcomputer architectures to automate planetary spacecraft power systems

NASA Technical Reports Server (NTRS)

Nauda, A.

1982-01-01

Performance and reliability models of alternate microcomputer architectures as a methodology for optimizing system design were examined. A methodology for selecting an optimum microcomputer architecture for autonomous operation of planetary spacecraft power systems was developed. Various microcomputer system architectures are analyzed to determine their application to spacecraft power systems. It is suggested that no standardization formula or common set of guidelines exists which provides an optimum configuration for a given set of specifications.

[Study on extraction process of available components of tea].

PubMed

Bai, Qing-Qing; Liu, Yong-Feng; Guo, Mei; Zhao, Jian-Xi; Zhang, Tian-Cai; Di, Duo-Long

2011-09-01

To investigate the optimum ethanol extraction process conditions for the available components in the tea - Catechines (CT) including Epigallo catechin gallate (EGCG) and Caffeine (CF). The content of EGCG, CT and CF, extraction rate, DPPH * Free radical scavenging capacity were chosen as the assessment indexes. With the alcohol ratio (A), solid-liquid ratio (B) and reflux time (C) as investigation factors, the optimum ethanol extraction process of the available components from tea was determined by L9 (3(4)) orthogonal experimental design. It would obtain different extraction conditions to analyze the assessment indexes depending on the different extraction purposes. For the purpose of CT, the contents of EGCG and CT, extraction rate and DPPH * Free radical scavenging capacity were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 75% alcohol was 1: 12, the reflux time was 30 minutes and extraction times were three; For the purpose of CF, the content of CF and extraction rate were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 60% alcohol was 1: 12, the reflux time was 30 minutes and extraction times were three; For the purpose of integrated extraction, the contents of CT and CF, extraction rate and DPPH * Free radical scavenging capacity were chosen as the assessment indexes, the optimum extraction conditions were selected as follows: the ratio of raw material to 60% alcohol was 1: 8, the reflux time was 30 minutes and extraction times were three. The optimum extraction process in order to attain different purposes can give a reference to the research of a new medicine and industry production.

Photocaged Competitor Guests: A General Approach Toward Light-Activated Cargo Release From Cucurbiturils.

PubMed

Romero, Miguel A; Basílio, Nuno; Moro, Artur J; Domingues, Mara; González-Delgado, José A; Arteaga, Jesús F; Pischel, Uwe

2017-09-21

A general approach toward the light-induced guest release from cucurbit[7]uril by means of a photoactivatable competitor was devised. An o-nitrobenzyl-caged competitor is photolyzed to generate a competitive guest that can displace cargo from the host macrocycle solely based on considerations of chemical equilibrium. With this method the release of terpene guests from inclusion complexes with cucurbit[7]uril was demonstrated. The binding of the herein investigated terpenes, all being lead fragrant components in essential oils, has been characterized for the first time. They feature binding constants of up to 10 8  L mol -1 and a high differential binding selectivity (spanning four orders of magnitude for the binding constants for the particular set of terpenes). By fine-tuning the photoactivatable competitor guest, selective and also sequential release of the terpenes was achieved. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Photochemical electron transfer in chlorophyll-porphyrin-quinone triads. The role of the porphyrin-bridging molecule

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

Johnson, D.G.; Niemczyk, M.P.; Minsek, D.W.

1993-06-30

The photochemistry of four chlorophyll-porphyrin-naphthoquinone molecules possessing both fixed distances and orientations between the three components is described. These molecules consist of a methyl pyropheophorbide a or pyrochlorophyllide a that is directly bonded at its 3-position to the 5-position of a 2,8,12,18-tetraethyl-3,7,13,-17-tetramethylporphyrin, which is in turn bonded at its 15-position to a 2-triptycenenaphthoquinone. In addition, porphyrin-quinone compounds in which the chlorins are replaced by a p-tolyl group were also prepared as reference compounds. Selective metalation of the macrocycles with zinc gives the series ZCHPNQ, ZCZPNQ, HCZPNQ, HCHPNQ, HPNQ, and ZPNQ, where H, Z, C, P, and NQ denote free base,more » Zn derivative, chlorophyll, porphyrin, and naphthoquinone, respectively. Selective excitation of ZC in ZCZPNQ and ZCHPNQ, and HC in HCHPNQ dissolved in butyronitrile yields ZC[sup +]ZPNQ[sup [minus

Selective Nitrate Recognition by a Halogen‐Bonding Four‐Station [3]Rotaxane Molecular Shuttle

PubMed Central

Barendt, Timothy A.; Docker, Andrew; Marques, Igor; Félix, Vítor

2016-01-01

Abstract The synthesis of the first halogen bonding [3]rotaxane host system containing a bis‐iodo triazolium‐bis‐naphthalene diimide four station axle component is reported. Proton NMR anion binding titration experiments revealed the halogen bonding rotaxane is selective for nitrate over the more basic acetate, hydrogen carbonate and dihydrogen phosphate oxoanions and chloride, and exhibits enhanced recognition of anions relative to a hydrogen bonding analogue. This elaborate interlocked anion receptor functions via a novel dynamic pincer mechanism where upon nitrate anion binding, both macrocycles shuttle from the naphthalene diimide stations at the periphery of the axle to the central halogen bonding iodo‐triazolium station anion recognition sites to form a unique 1:1 stoichiometric nitrate anion–rotaxane sandwich complex. Molecular dynamics simulations carried out on the nitrate and chloride halogen bonding [3]rotaxane complexes corroborate the 1H NMR anion binding results. PMID:27436297

Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements.

PubMed

Waelès, Philip; Riss-Yaw, Benjamin; Coutrot, Frédéric

2016-05-10

The synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A meta-heuristic method for solving scheduling problem: crow search algorithm

NASA Astrophysics Data System (ADS)

Adhi, Antono; Santosa, Budi; Siswanto, Nurhadi

2018-04-01

Scheduling is one of the most important processes in an industry both in manufacturingand services. The scheduling process is the process of selecting resources to perform an operation on tasks. Resources can be machines, peoples, tasks, jobs or operations.. The selection of optimum sequence of jobs from a permutation is an essential issue in every research in scheduling problem. Optimum sequence becomes optimum solution to resolve scheduling problem. Scheduling problem becomes NP-hard problem since the number of job in the sequence is more than normal number can be processed by exact algorithm. In order to obtain optimum results, it needs a method with capability to solve complex scheduling problems in an acceptable time. Meta-heuristic is a method usually used to solve scheduling problem. The recently published method called Crow Search Algorithm (CSA) is adopted in this research to solve scheduling problem. CSA is an evolutionary meta-heuristic method which is based on the behavior in flocks of crow. The calculation result of CSA for solving scheduling problem is compared with other algorithms. From the comparison, it is found that CSA has better performance in term of optimum solution and time calculation than other algorithms.

A firefly algorithm for optimum design of new-generation beams

NASA Astrophysics Data System (ADS)

Erdal, F.

2017-06-01

This research addresses the minimum weight design of new-generation steel beams with sinusoidal openings using a metaheuristic search technique, namely the firefly method. The proposed algorithm is also used to compare the optimum design results of sinusoidal web-expanded beams with steel castellated and cellular beams. Optimum design problems of all beams are formulated according to the design limitations stipulated by the Steel Construction Institute. The design methods adopted in these publications are consistent with BS 5950 specifications. The formulation of the design problem considering the above-mentioned limitations turns out to be a discrete programming problem. The design algorithms based on the technique select the optimum universal beam sections, dimensional properties of sinusoidal, hexagonal and circular holes, and the total number of openings along the beam as design variables. Furthermore, this selection is also carried out such that the behavioural limitations are satisfied. Numerical examples are presented, where the suggested algorithm is implemented to achieve the minimum weight design of these beams subjected to loading combinations.

Dimacrolide Sesquiterpene Pyridine Alkaloids from the Stems of Tripterygium regelii.

PubMed

Fan, Dongsheng; Zhu, Guo-Yuan; Li, Ting; Jiang, Zhi-Hong; Bai, Li-Ping

2016-08-29

Two new dimacrolide sesquiterpene pyridine alkaloids (DMSPAs), dimacroregelines A (1) and B (2), were isolated from the stems of Tripterygium regelii. The structures of both compounds were characterized by extensive 1D and 2D NMR spectroscopic analyses, as well as HRESIMS data. Compounds 1 and 2 are two rare DMSPAs possessing unique 2-(3'-carboxybutyl)-3-furanoic acid units forming the second macrocyclic ring, representing the first example of DMSPAs bearing an extra furan ring in their second macrocyclic ring system. Compound 2 showed inhibitory effects on the proliferation of human rheumatoid arthritis synovial fibroblast cell (MH7A) at a concentration of 20 μM.

Chemical controls on uranyl citrate speciation and the self-assembly of nanoscale macrocycles and sandwich complexes in aqueous solutions.

PubMed

Basile, M; Unruh, D K; Gojdas, K; Flores, E; Streicher, L; Forbes, T Z

2015-03-28

Uranyl citrate forms trimeric species at pH > 5.5, but exact structural characteristics of these important oligomers have not previously been reported. Crystallization and structural characterization of the trimers suggests the self-assembly of the 3 : 3 and 3 : 2 U : Cit complexes into larger sandwich and macrocyclic molecules. Raman spectroscopy and ESI-MS have been utilized to investigate the relative abundance of these species in solution under varying pH and citrate concentrations. Additional dynamic light scattering experiments indicate that self-assembly of the larger molecules does occur in aqueous solution.

High-performance liquid chromatographic enantioseparation of 2-aminomono- and dihydroxycyclopentanecarboxylic and 2-aminodihydroxycyclohexanecarboxylic acids on macrocyclic glycopeptide-based phases.

PubMed

Berkecz, Róbert; Ilisz, István; Benedek, Gabriella; Fülöp, Ferenc; Armstrong, Daniel W; Péter, Antal

2009-02-06

The direct separation of the enantiomers of four 2-aminomono- or dihydroxycyclopentanecarboxylic acids and four 2-aminodihydroxycyclohexanecarboxylic acids was performed on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Astec Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG) or ristocetin A (Chirobiotic R) as chiral selectors. The effects of the nature of organic modifiers, the pH, the mobile phase composition and the structures of the analytes on the separation were investigated. Chirobiotic TAG, and in some cases Chirobiotic T, proved to be the most useful of these columns. The elution sequence was determined in most cases.

Macrocyclic polyaminocarboxylates for stable radiometal antibody conjugates for therapy, SPECT and PET imaging

DOEpatents

Mease, R.C.; Mausner, L.F.; Srivastava, S.C.

1997-06-17

A simple method for the synthesis of 1,4,7, 10-tetraazacyclododecane N,N{prime}N{double_prime},N{prime}{double_prime}-tetraacetic acid and 1,4,8,11-tetraazacyclotetradecane N,N{prime},N{double_prime},N{prime}{double_prime}-tetraacetic acid involves cyanomethylating 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane to form a tetranitrile and hydrolyzing the tetranitrile. These macrocyclic compounds are functionalized through one of the carboxylates and then conjugated to various biological molecules including monoclonal antibodies. The resulting conjugated molecules are labeled with radiometals for SPECT and PET imaging and for radiotherapy. 4 figs.

8th International Symposium on Supramolecular and Macrocyclic Chemistry

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

Davis, Jeffery T.

2015-09-18

This report summarizes the 8th International Conference on Supramolecular and Macrocyclic Chemistry (ISMSC-8). DOE funds were used to make it more affordable for students, post-docs and junior faculty to attend the conference by covering their registration costs. The conference was held in Crystal City, VA from July 7-11, 2013. See http://www.indiana.edu/~ismsc8/ for the conference website. ISMSC-8 encompassed the broad scope and interdisciplinary nature of the field. We met our goal to bring together leading scientists in molecular recognition and supramolecular chemistry. New research directions and collaborations resulted this conference. The DOE funding was crucial for us achieving our primary goal.

Self-Assembly of a [1+1] Ionic Hexagonal Macrocycle and its Antiproliferative Activity

NASA Astrophysics Data System (ADS)

Singh, Khushwant; Gangrade, Ankit; Bhowmick, Sourav; Jana, Achintya; Mandal, Biman B.; Das, Neeladri

2018-04-01

A unique irregular hexagon was self-assembled using an organic donor clip (bearing terminal pyridyl units) and a complementary organometallic acceptor clip. The resulting metallamacrocycle was characterized by multinuclear NMR, mass spectrometry, and elemental analyses. Molecular modeling confirmed hexagonal shaped cavity for this metallamacrocycle which is a unique example of a discrete hexagonal framework self-assembled from only two building blocks. Cytotoxicity of the Pt-based acceptor tecton and the self-assembled PtII-based macrocycle was evaluated using three cancer cell lines and results were compared with cisplatin. Results confirmed a positive effect of the metallamacrocycle formation on cell growth inhibition.

Determination of molindone enantiomers in human plasma by high-performance liquid chromatography-tandem mass spectrometry using macrocyclic antibiotic chiral stationary phases.

PubMed

Jiang, Hongliang; Li, Yinghe; Pelzer, Mary; Cannon, Michelle J; Randlett, Christopher; Junga, Heiko; Jiang, Xiangyu; Ji, Qin C

2008-05-30

A sensitive and selective bioanalytical assay was developed and validated for the determination of enantiomeric molindone in human plasma using high-performance liquid chromatography-tandem mass spectrometry along with supported liquid extraction procedures. The chiral separation was evaluated and optimized on macrocyclic antibiotic type chiral stationary phases (CSPs) based on teicoplanin aglycone (Chirobiotic TAG) in polar organic, polar ionic, and reversed-phase mode chromatography, respectively. Complete baseline separation was achieved on a Chirobiotic TAG column under isocratic condition in reversed-phase chromatography. The method validation was conducted using a Chirobiotic TAG column (100 mm x 2.1 mm) over the curve range 0.100-100 ng/ml for each molindone enantiomer using 0.0500 ml of plasma sample. The flow rate was 0.8 ml/min and the total run time was 9 min. Supported liquid extraction in a 96-well plate format was used for sample preparation. Parameters including recovery, matrix effect, linearity, sensitivity, specificity, carryover, precision, accuracy, dilution integrity, and stability were evaluated. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels were RSD

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

PubMed Central

Maianti, Juan Pablo; McFedries, Amanda; Foda, Zachariah H.; Kleiner, Ralph E.; Du, Xiu Quan; Leissring, Malcolm A.; Tang, Wei-Jen; Charron, Maureen J.; Seeliger, Markus A.; Saghatelian, Alan; Liu, David R.

2014-01-01

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes1, 2, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene3, 4, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide−/− mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction5, 6. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation. PMID:24847884

Structural Basis of the Antiproliferative Activity of Largazole a Depsipeptide Inhibitor of the Histone Deacetylases

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

K Cole; D Dowling; M Boone

2011-12-31

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 {angstrom}-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with amore » macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.« less

Two Macrocycles in One Shot: Synthesis, Spectroscopy, Photophysics, and Tautomerism of 23-Oxahemiporphycene and 21-Oxacorrole-5-carbaldehyde.

PubMed

Ostapko, Jakub; Kelm, Anna; Kijak, Michał; Leśniewska, Barbara; Waluk, Jacek

2018-04-19

The synthesis of 23-oxahemiporphycene, the first monooxa analogue of hemiporphycene, a structural isomer of porphyrin, is reported. Its generation under McMurry reaction conditions is surprisingly accompanied by the appearance of a formyl derivative of oxacorrole, 21-oxacorrole-5-carbaldehyde. A mechanism for the formation of the latter is proposed, relying on pinacol rearrangement of titanium pinacolate. The structures of the most stable tautomeric forms are established for both compounds based on IR and NMR spectra combined with DFT calculations. Spectral and photophysical characteristics are compared with those of structurally similar macrocycles. Replacement of one nitrogen by oxygen in hemiporphycene has only a minor impact. In contrast, for corrole it leads to the enhancement of stability and to strongly reduced rates of nonradiative deactivation of the lowest excited singlet state. This is explained by the planarity of oxacorroles, achieved by removing one of the inner hydrogen atoms from the inner cavity. Unusual crystal packing is observed for the protonated form of 23-oxahemiporphycene, which exhibits a π-π stacked columnar alignment of positively charged macrocycle units. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Concerted ligand exchange and the roles of counter anions in the reversible structural switching of crystalline peptide metallo-macrocycles.

PubMed

Miyake, Ryosuke; Shionoya, Mitsuhiko

2014-06-02

To understand reversible structural switching in crystalline materials, we studied the mechanism of reversible crystal-to-crystal transformation of a tetranuclear Ni(II) macrocycle consisting of artificial β-dipeptides. On the basis of detailed structural analyses and thermodynamic measurements made in a comparison of pseudo-isostructural crystals (NO3 and BF4 salts), we herein discuss how ligand-exchange reactions take place in the crystal due to changes in water content and temperature. Observations of the structural transformation of NO3 salt indicated that a pseudo crystalline phase transformation takes place through concerted ligand-exchange reactions at the four Ni(II) centers of the macrocycle with hydrogen bond switching. A mechanism for this ligand exchange was supported by IR spectroscopy. Thermodynamic measurements suggested that the favorable compensation relationship of the enthalpy changes due to water uptake and structural changes are keys to the reversible structural transformation. On the basis of a comparison with the pseudo-isostructural crystals, it is apparent that the crystal packing structure and the types of counter anions are important factors for facilitating reversible ligand exchange with single crystallinity.

Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates.

PubMed

Nwe, K; Bernardo, M; Regino, C A S; Williams, M; Brechbiel, M W

2010-08-15

In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N',N',N'',N''-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex(R) G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1, respectively. Molar relaxivity measured at pH 7.4, 22 degrees C, and 3T are comparable (29.5 vs 26.9 mM(-1)s(-1)), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t(1/2)=16 vs 29 min). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties. Published by Elsevier Ltd.

Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates

PubMed Central

Nwe, K.; Bernardo, M; Regino, C. A. S.; Williams, M; Brechbiel, M. W.

2010-01-01

In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N’,N’,N’’, N’’-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex® G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1 respectively. Molar relaxivity measured at pH 7.4, 22°C, and 3T are comparable (29.5 vs. 26.9 mM−1s−1), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t1/2 = 16 vs. 29 min.). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties. PMID:20663676

Macrocyclic trichothecenes are undetectable in kudzu (Pueraria montana) plants treated with a high-producing isolate of Myrothecium verrucaria.

PubMed

Abbas, H K; Tak, H; Boyette, C D; Shier, W T; Jarvis, B B

2001-09-01

Myrothecium verrucaria was found to be an effective pathogen against kudzu grown in the greenhouse and the field. M. verrucaria produced large amounts of macrocyclic trichothecenes when cultured on solid rice medium, including epiroridin E (16.8 mg/g crude extract), epiisororidin E (1 mg/g), roridin E (8.7 mg/g), roridin H (31.3 mg/g), trichoverrin A (0.6 mg/g), trichoverrin B (0.1 mg/g), verrucarin A (37.4 mg/g), and verrucarin J (2.2 mg/g). Most of these toxins were also isolated from M. verrucaria spores and mycelia grown on potato dextrose agar medium, including epiroridin E (32.3 mg/g), epiisororidin E (28.6 mg/g), roridin E (0 mg/g), roridin H (60 mg/g), trichoverrin A (1.3 mg/g), trichoverrin B (1.8 mg/g), verrucarin A (13.8 mg/g), and verrucarin J (131 mg/g). When M. verrucaria was cultured on liquid media, the numbers but not the amounts of toxins decreased. Only epiroridin E (28.3 mg/g), epiisororidin E (29.6 mg/g), verrucarin B (195 mg/g) and verrucarin J (52.6 mg/g) were measured when the fungus was cultured on cornsteep medium. On soyflour-cornmeal broth M. verrucaria produced several toxins, including epiroridin E (58.1 mg/g), epiisororidin E (5.8 mg/g), verrucarin B (29.9 mg/g) and verrucarin J (32 mg/g). In contrast, no macrocyclic trichothecenes were detected by HPLC analysis of plant tissues of kudzu, sicklepod, and soybean treated with aqueous suspensions of M. verrucaria spores formulated with a surfactant. Chloroform-methanol extracts of kudzu leaves and stems treated with M. verrucaria spores were less cytotoxic to four cultured mammalian cell lines than the corresponding extracts from control plants. Purified macrocyclic trichothecenes (verrucarin A and T-2 toxin) were very cytotoxic to the same cell lines (< or = 2 ng/ml). These results show that neither intact macrocyclic trichothecenes nor toxic metabolites could be detected in plant tissues after treatment with M. verrucaria spores. These results argue for both safety and efficacy for the use of M. verrucaria in biological control of kudzu and other noxious weeds, and support proceeding to animal feeding trials for further evaluation of safety.

Chiral analysis of UV nonabsorbing compounds by capillary electrophoresis using macrocyclic antibiotics: 1. Separation of aspartic and glutamic acid enantiomers.

PubMed

Bednar, P; Aturki, Z; Stransky, Z; Fanali, S

2001-07-01

Glycopeptide antibiotics, namely vancomycin or teicoplanin, were evaluated in capillary electrophoresis for the analysis of UV nonabsorbing compounds such as aspartic and glutamic acid enantiomers. Electrophoretic runs were performed in laboratory-made polyacrylamide-coated capillaries using the partial filling-counter current method in order to avoid the presence on the detector path of the absorbing chiral selector. The background electrolyte consisted of an aqueous or aqueous-organic buffer in the pH range of 4.5-6.5 of sorbic acid/histidine and the appropriate concentration of chiral selector. Several experimental parameters such as antibiotic concentration and type, buffer pH, organic modifier, type and concentration of absorbing co-ion (for the indirect UV detection) were studied in order to find the optimum conditions for the chiral resolution of the two underivatized amino acids in their enantiomers. Among the two investigated chiral selectors, vancomycin resulted to be the most useful chiral selector allowing relatively high chiral resolution of the studied compounds even at low concentration. The optimized method (10 mM sorbic acid/histidine, pH 5, and 10 mM of vancomycin) was used for the analysis of real samples such as teeth dentine and beer.

Selection of an Optimum Air Defense Weapon Package Using MAUM (Multi-Attribute Utility Measurement).

DTIC Science & Technology

1983-06-01

SELECTION OF AN OPTIMUM AIR DEFENSE WEAPON PACKAGE USING MAUM by Wilton L. Ham June 1983 Thesis Advisor: R. G. Nickerson Approved for public release...OSSTRIUTON STATEMEN4T (of if AlRpeat) Approved for public release; distribution unlimited. I?. 01STVAGUTgOg STATE[MENT (of me ubeh’ei antered Ian...hold": do not fire except in self defense. 4. Firing Commands. These are commands issued regard- less of the weapons control in effect. There are three

Stability and Response of Polygenic Traits to Stabilizing Selection and Mutation

PubMed Central

de Vladar, Harold P.; Barton, Nick

2014-01-01

When polygenic traits are under stabilizing selection, many different combinations of alleles allow close adaptation to the optimum. If alleles have equal effects, all combinations that result in the same deviation from the optimum are equivalent. Furthermore, the genetic variance that is maintained by mutation–selection balance is 2μ/S per locus, where μ is the mutation rate and S the strength of stabilizing selection. In reality, alleles vary in their effects, making the fitness landscape asymmetric and complicating analysis of the equilibria. We show that that the resulting genetic variance depends on the fraction of alleles near fixation, which contribute by 2μ/S, and on the total mutational effects of alleles that are at intermediate frequency. The interplay between stabilizing selection and mutation leads to a sharp transition: alleles with effects smaller than a threshold value of 2μ/S remain polymorphic, whereas those with larger effects are fixed. The genetic load in equilibrium is less than for traits of equal effects, and the fitness equilibria are more similar. We find that if the optimum is displaced, alleles with effects close to the threshold value sweep first, and their rate of increase is bounded by μS. Long-term response leads in general to well-adapted traits, unlike the case of equal effects that often end up at a suboptimal fitness peak. However, the particular peaks to which the populations converge are extremely sensitive to the initial states and to the speed of the shift of the optimum trait value. PMID:24709633

Statistical Optimization of 1,3-Propanediol (1,3-PD) Production from Crude Glycerol by Considering Four Objectives: 1,3-PD Concentration, Yield, Selectivity, and Productivity.

PubMed

Supaporn, Pansuwan; Yeom, Sung Ho

2018-04-30

This study investigated the biological conversion of crude glycerol generated from a commercial biodiesel production plant as a by-product to 1,3-propanediol (1,3-PD). Statistical analysis was employed to derive a statistical model for the individual and interactive effects of glycerol, (NH 4 ) 2 SO 4 , trace elements, pH, and cultivation time on the four objectives: 1,3-PD concentration, yield, selectivity, and productivity. Optimum conditions for each objective with its maximum value were predicted by statistical optimization, and experiments under the optimum conditions verified the predictions. In addition, by systematic analysis of the values of four objectives, optimum conditions for 1,3-PD concentration (49.8 g/L initial glycerol, 4.0 g/L of (NH 4 ) 2 SO 4 , 2.0 mL/L of trace element, pH 7.5, and 11.2 h of cultivation time) were determined to be the global optimum culture conditions for 1,3-PD production. Under these conditions, we could achieve high 1,3-PD yield (47.4%), 1,3-PD selectivity (88.8%), and 1,3-PD productivity (2.1/g/L/h) as well as high 1,3-PD concentration (23.6 g/L).

[Study on extraction technology of soyasaponins from residual of bean ware].

PubMed

Lu, Rumei; Zhang, Yizhen; Bi, Yi

2003-04-01

To find out the optimum extraction technology of soyasaponins from residual of bean ware. The optimum extraction conditions were investigated by the orthogonal design, and the content of soyasaponins was determined by UV-spectro-pho-tometry. The optimum extraction technology was A3B1C1, that is adding 7 times and 6 times amount of 70% alcohol and refluxing for two times and each time for 1.0 h. The selected technology showed higher yield of soyasaponins, good stability and high efficient.

Optimization of the Use of Selected Non-Phosphate Water Retention Additives in Minced Beef Using Response Surface Methodology

NASA Astrophysics Data System (ADS)

Shang, Xiaolan; Qiao, Jie; Liu, Yujie

2017-12-01

This study looked to determine what the optimum cooking loss for minced beef was when three different non-phosphate water retention additives (L-Arginine, sodium carbonate, and sodium citrate) were combined; the optimum value was determined using a Box-Behnken response surface design method. The optimum value was found to be 8.26%, and it was obtained when 0.29% L-Arginine, 0.45% sodium carbonate, and 0.24% sodium citrate were added to the beef.

Contorted Organic Semiconductors for Molecular Electronics

NASA Astrophysics Data System (ADS)

Zhong, Yu

This thesis focuses on the synthesis, properties and applications of two types of contorted organic molecules: contorted molecular ribbons and conjugated corrals. We utilized the power of reaction chemistry to writing information into conjugated molecules with contorted structures and studied "structure-property" relationships. The unique properties of the molecules were expressed in electronic and optoelectronic devices such as field-effect transistors, solar cells, photodetectors, etc. In Chapter 2, I describe the design and synthesis of a new graphene ribbon architecture that consists of perylenediimide (PDI) subunits fused together by ethylene bridges. We created a prototype series of oligomers consisting of the dimer, trimer, and tetramer. The steric congestion at the fusion point between the PDI units creates helical junctions, and longer oligomers form helical ribbons. Thin films of these oligomers form the active layer in n-type field effect transistors. UV-vis spectroscopy reveals the emergence of an intense long-wavelength transition in the tetramer. From DFT calculations, we find that the HOMO-2 to LUMO transition is isoenergetic with the HOMO to LUMO transition in the tetramer. We probe these transitions directly using femtosecond transient absorption spectroscopy. The HOMO-2 to LUMO transition electronically connects the PDI subunits with the ethylene bridges, and its energy depends on the length of the oligomer. In Chapter 3, I describe an efficiency of 6.1% for a solution processed non-fullerene solar cell using a helical PDI dimer as the electron acceptor. Femtosecond transient absorption spectroscopy revealed both electron and hole transfer processes at the donor-acceptor interfaces, indicating that charge carriers are created from photogenerated excitons in both the electron donor and acceptor phases. Light-intensity-dependent current?voltage measurements suggested different recombination rates under short-circuit and open-circuit conditions. In Chapter 4, I discuss helical molecular semiconductors as electron acceptors that are on par with fullerene derivatives in efficient solar cells. We achieved an 8.3% power conversion efficiency in a solar cell, which is a record high for non-fullerene bulk heterojunctions. Femtosecond transient absorption spectroscopy revealed both electron and hole transfer processes at the donor-acceptor interfaces. Atomic force microscopy reveals a mesh-like network of acceptors with pores that are tens of nanometers in diameter for efficient exciton separation and charge transport. This study describes a new motif for designing highly efficient acceptors for organic solar cells. In Chapter 5, I compare analogous cyclic and acyclic pi-conjugated molecules as n-type electronic materials and find that the cyclic molecules have numerous benefits in organic photovoltaics. We designed two conjugated cycles for this study. Each comprises four subunits; one combines four electron-accepting, redox-active, diphenyl-perylenediimide subunits, and the other alternates two electron-donating bithiophene units with two diphenyl-perylenediimide units. We compare the macrocycles to acyclic versions of these molecules and find that, relative to the acyclic analogs, the conjugated macrocycles have bathochromically shifted UV-vis absorbances and are more easily reduced. In blended films, macrocycle-based devices show higher electron mobility and good morphology. All of these factors contribute to the more than doubling of the power conversion efficiency observed in organic photovoltaic devices with these macrocycles as the n-type, electron transporting material. This study highlights the importance of geometric design in creating new molecular semiconductors. In Chapter 6, I describe a new molecular design that enables high performance organic photodetectors. We use a rigid, conjugated macrocycle as the electron acceptor in devices to obtain high photocurrent and low dark current. We directly compare the macrocyclic acceptor devices to an acyclic control device; we find that the superior performance of the macrocycle originates from its rigid, conjugated, and cyclic structure. The macrocycle's rigid structure reduces the number of charged defects originating from deformed sp 2 carbons and covalent defects from photo/thermo-activation. With this molecular design we are able to suppress dark current density while retaining high responsivity in an ultra-sensitive non-fullerene organic photodetector. Importantly, we achieve a detectivity of 1014 Jones at near zero bias voltage. This is without the need for extra carrier blocking layers commonly employed in fullerene-based devices. Our devices are comparable to the best fullerene-based photodetectors, and the sensitivity at low working voltages (< 0.1 V) is a record for non-fullerene OPDs.

meso-Octamethylcalix[4]pyrrole as an effective macrocyclic receptor for the univalent thallium cation in the gas phase: Experimental and theoretical study

NASA Astrophysics Data System (ADS)

Polášek, Miroslav; Makrlík, Emanuel; Kvíčala, Jaroslav; Křížová, Věra; Vaňura, Petr

2018-02-01

By using electrospray ionization mass spectrometry (ESI-MS), it was proven experimentally that the univalent thallium cation (Tl+) forms with meso-octamethylcalix[4]pyrrole (1) the cationic complex species 1 Tl+. When this kinetically stable cation-π complex 1 Tl+ is collisionally activated, it decomposes by elimination of the whole ligand 1 or small meso-octamethylcalix[4]pyrrole fragments. Further, applying quantum chemical DFT calculations, four different conformations of the resulting complex 1 Tl+ were derived. It means that under the present experimental conditions, this ligand 1 can be considered as a very effective macrocyclic receptor for the thallium cation.

Magneto-electroluminescence effects in the single-layer organic light-emitting devices with macrocyclic aromatic hydrocarbons

NASA Astrophysics Data System (ADS)

Pham, S.-T.; Ikemoto, K.; Suzuki, K. Z.; Izumi, T.; Taka, H.; Kita, H.; Sato, S.; Isobe, H.; Mizukami, S.

2018-02-01

Magneto-electroluminescence (MEL) effects are observed in single-layer organic light-emitting devices (OLEDs) comprising only macrocyclic aromatic hydrocarbons (MAHs). The fluorescence devices were prepared using synthesized MAHs, namely, [n]cyclo-meta-phenylene ([n]CMP, n = 5, 6). The MEL ratio of the resulting OLED is 1%-2% in the spectral wavelength range of 400-500 nm, whereas it becomes negative (-1.5% to -2%) in the range from 650 to 700 nm. The possible physical origins of the sign change in the MEL are discussed. This wavelength-dependent sign change in the MEL ratio could be a unique function for future single-layer OLEDs capable of magnetic-field-induced color changes.

Synthesis of macrocyclic polyaminocarboxylates and their use for preparing stable radiometal antibody immunoconjugates for therapy, SPECT and PET imaging

DOEpatents

Mease, R.C.; Mausner, L.F.; Srivastava, S.C.

1995-06-27

A simple method for the synthesis of 1,4,7,10-tetraazacyclododecane N,N{prime}N{double_prime},N{prime}{double_prime}-tetraacetic acid and 1,4,8,11-tetraazacyclotetradecane N,N{prime},N{double_prime},N{prime}{double_prime}-tetraacetic acid involves cyanomethylating 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane to form a tetranitrile and hydrolyzing the tetranitrile. These macrocyclic compounds are functionalized through one of the carboxylates and then conjugated to various biological molecules including monoclonal antibodies. The resulting conjugated molecules are labeled with radiometals for SPECT and PET imaging and for radiotherapy. 4 figs.

Macrocyclic 2,7-Anthrylene Oligomers.

PubMed

Yamamoto, Yuta; Wakamatsu, Kan; Iwanaga, Tetsuo; Sato, Hiroyasu; Toyota, Shinji

2016-05-06

A macrocyclic compound consisting of six 2,7-anthrylene units was successfully synthesized by Ni-mediated coupling of the corresponding dibromo precursor as a novel π-conjugated compound. This compound was sufficiently stable and soluble in organic solvents due to the presence of mesityl groups. X-ray analysis showed that the molecule had a nonplanar and hexagonal wheel-shaped framework of approximately S6 symmetry. The dynamic process between two S6 structures was observed by using the dynamic NMR technique, the barrier being 58 kJ mol(-1) . The spectroscopic properties of the hexamer were compared with those of analogous linear oligomers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Solar cells incorporating light harvesting arrays

DOEpatents

Lindsey, Jonathan S.; Meyer, Gerald J.

2003-07-22

A solar cell incorporates a light harvesting array that comprises: (a) a first substrate comprising a first electrode; and (b) a layer of light harvesting rods electrically coupled to the first electrode, each of the light harvesting rods comprising a polymer of Formula I: ##EQU1## wherein m is at least 1, and may be from two, three or four to 20 or more; X.sup.1 is a charge separation group (and preferably a porphyrinic macrocycle, which may be one ligand of a double-decker sandwich compound) having an excited-state of energy equal to or lower than that of X.sup.2 ; and X.sup.2 through X.sup.m+1 are chromophores (and again are preferably porphyrinic macrocycles).

A novel alkaloid isolated from Crotalaria paulina and identified by NMR and DFT calculations

NASA Astrophysics Data System (ADS)

Oliveira, Ramon Prata; Demuner, Antonio Jacinto; Alvarenga, Elson Santiago; Barbosa, Luiz Claudio Almeida; de Melo Silva, Thiago

2018-01-01

Pyrrolizidine alkaloids (PAs) are secondary metabolites found in Crotalaria genus and are known to have several biological activities. A novel macrocycle bislactone alkaloid, coined ethylcrotaline, was isolated and purified from the aerial parts of Crotalaria paulina. The novel macrocycle was identified with the aid of high resolution mass spectrometry and advanced nuclear magnetic resonance techniques. The relative stereochemistry of the alkaloid was defined by comparing the calculated quantum mechanical hydrogen and carbon chemical shifts of eight candidate structures with the experimental NMR data. The best fit between the eight candidate structures and the experimental NMR chemical shifts was defined by the DP4 statistical analyses and the Mean Absolute Error (MAE) calculations.

Synthesis and Mossbauer spectroscopy of macrocyclic complexes of iron(III)

NASA Astrophysics Data System (ADS)

Mishra, A.; Sura, Kamaljeet S.; Sharma, P.

2016-10-01

The article deals with a fresh series of the complexes of the type: [Fe(III)(TML)Cl]Cl2; where TML is a tetra-dentate macrocyclic ligand; has been synthesized by condensation of o-phenylenediamine, diethyl malonate and diazonium ion in the ethanolic medium, through refluxing with FeCl3.The synthesized metal complexes were characterized by Mossbauer spectroscopy. Mossbauer measurements were carried out using standard PC-based spectrometer equipped with Weissel velocity drive operating in the constant acceleration mode. Mossbauer study interprets paramagnetic nature of complexes. Mossbauer measurement of complex 1 and 2 has been taken to find out the value of isomer shift and quadrapole splitting and oxidation state after complaxsation.

Systematic Sensor Selection Strategy (S4) User Guide

NASA Technical Reports Server (NTRS)

Sowers, T. Shane

2012-01-01

This paper describes a User Guide for the Systematic Sensor Selection Strategy (S4). S4 was developed to optimally select a sensor suite from a larger pool of candidate sensors based on their performance in a diagnostic system. For aerospace systems, selecting the proper sensors is important for ensuring adequate measurement coverage to satisfy operational, maintenance, performance, and system diagnostic criteria. S4 optimizes the selection of sensors based on the system fault diagnostic approach while taking conflicting objectives such as cost, weight and reliability into consideration. S4 can be described as a general architecture structured to accommodate application-specific components and requirements. It performs combinational optimization with a user defined merit or cost function to identify optimum or near-optimum sensor suite solutions. The S4 User Guide describes the sensor selection procedure and presents an example problem using an open source turbofan engine simulation to demonstrate its application.

Ion transport through lipid bilayers by synthetic ionophores: modulation of activity and selectivity.

PubMed

De Riccardis, Francesco; Izzo, Irene; Montesarchio, Daniela; Tecilla, Paolo

2013-12-17

The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternate-calix[4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.

Evaluation of the efficacy of ProHeart® 6 (moxidectin) against a resistant isolate of Dirofilaria immitis (JYD-34) in dogs.

PubMed

Bowman, Dwight D; McTier, Tom L; Adams, Eric L; Mahabir, Sean P; Login, Joyce A; Bidgood, Tara; Woods, Debra J

2017-11-09

In a previous study, it was demonstrated that ProHeart ® 6 (PH6) (moxidectin, Zoetis) provided only about 20% efficacy in a small six-dog study against a macrocyclic lactone -resistant Dirofilaria immitis isolate (Jd2009-2) when dogs were inoculated with infective third-stage larvae (L3) at the end of the dosing period (ie, 180 days post treatment). The objective of the current study was to determine the prophylactic efficacy of a moxidectin sustained-release formulation (PH6) against a confirmed macrocyclic lactone-resistant isolate of D. immitis (JYD-34) in dogs when administered by subcutaneous injection at the labeled dose of 0.17 mg/kg 2 days before L3 inoculation. This was intended to model the scenario where dogs become infected with resistant heartworms at the end of the PH6 treatment period (ie, 6 months post treatment) when dogs would routinely be given another injection under normal field use. Twelve purpose-bred Beagle dogs (six males and six females) were selected and randomly allocated to two groups, untreated controls and PH6-treated dogs in groups of six each. The dogs were ≥8 months old at the start of the study, and using blood samples collected on Day -7 were shown to be negative for adult heartworm antigen and microfilariae. On Day 0, the dogs in the untreated control group were administered saline subcutaneously by injection, and the dogs in the treated group were administered PH6 according to label instructions. On Day 2, each dog was inoculated in the inguinal area with 50 L3 of D. immitis. The dogs were necropsied on Day 150 (148 days post infection), and the worms were collected and counted. All of the six control dogs were infected and harbored a range of 21 to 37 worms (geometric mean, 25.4; 10.9 males and 13.9 females). Only one of the six PH6 dogs was found to be infected, harboring a single male worm. Efficacy was 99.5% (geometric mean). ProHeart ® 6 was highly effective in preventing the development of heartworms in dogs challenged with a confirmed macrocyclic lactone-resistant heartworm isolate (JYD-34) 2 days prior to treatment.

Screening and Characterization of Polygalacturonase as Potential Enzyme for Keprok Garut Orange (Citrus nobilis var. chrysocarpa) Juice Clarification

NASA Astrophysics Data System (ADS)

Widowati, E.; Utami, R.; Kalistyatika, K.

2017-11-01

Use of thermostable enzyme from bacilli for industrial application is significant. This research aimed to isolate thermophilic pectinolytic bacteria from orange peel and vegetable waste which produced thermostable polygalacturonase, to investigate the polygalacturonase ability in clarifying keprok Garut orange juice, and to characterize polygalacturonase based on pH optimum, temperature optimum, enzyme stability, enzyme kinetics KM, and Vmax. Obtained, 14 isolates that further selected to 4 best isolates based on highest polygalacturonase activity and keprok Garut orange juice clarification ability. Four selected enzyme isolates were AR 2, AR 4, KK 4, and KK 5 had ability to increase juice transmittance, decrease juice viscosity and also reduce total soluble solid. Furthermore 4 selected isolates were partially purified by ammonium sulphate precipitation and dialysis method. Four partially purified enzymes were known that enzyme character of AR 2 optimum at pH 6; AR 4 optimum at pH 5.5; KK 4 optimum at pH 6; and KK 5 optimum at pH 4.5. Four enzymes were optimum at temperature 60°C thus stable at temperature 50-60°C, this characteristic indicate that enzymes were thermostable. AR 2 showed active activity stable at pH 4-7; AR 4 showed active activity stable at pH 6-7; KK 4 showed active activity stable at pH 4-6; however KK 5 stable at pH 4-5. Enzyme AR 2 and KK 4 was getting inactive at pH 11, thus AR 4 and KK 5 inactive at pH 12. KM value of AR 2, AR 4, KK 4, and KK 5 was 0.0959; 0.0974; 0.0966; and 0.178 mg/ml respectively. Vmax of AR 2, AR 4, KK 4, and KK 5 was 0.0203; 0.0202; 0.0185; and 0.0229 U/ml respectively. Enzyme AR 2 was the most compatible enzyme to be applied in keprok Garut orange juice clarification for it had the lowest KM value.

Antiandrogen and Antimicrobial Aspects of Coordination Compounds of Palladium(II), Platinum(II) and Lead(II)

PubMed Central

Joshi, S. C.; Kulshrestha, Shalini; Nagpal, Pooja; Bansal, Anil

2001-01-01

Synthesis, characterization and antimicrobial activities of an interesting class of biologically potent macrocyclic complexes have been carried out. All the complexes have been evaluated for their antimicrobial effects on different species of pathogenic fungi and bacteria. The testicular sperm density, testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in mating trails and biochemical parameters of reproductive organs have been examined and discussed. The resulting biologically active [M(MaLn)(R2)]Cl2 and [Pb(MaLn)(R2)X2] (where, M = PdII or PtII and X = Cl or NO3) type of complexes have been synthesized by the reactions of macrocyclic ligands (MaLn) with metal salts and different diamines in 1:1:1 molar ratio in methanol. Initially the complexes were characterized by elemental analyses, molecular weight determinations and conductivity measurements. The mode of bonding was established on the basis of IR, 1H NMR, 13C NMR, 195Pt NMR, 207Pb NMR, XRD and electronic spectral studies. The macrocyclic ligand coordinates through the four azomethine nitrogen atoms which are bridged by benzil moieties. IR spectra suggest that the pyridine nitrogen is not coordinating. The palladium and platinum complexes exhibit tetracoordinated square-planar geometry, whereas a hexacoordinated octahedral geometry is suggested for lead complexes. PMID:18475989

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

DOE PAGES

Luo, Dan; Callari, Roberta; Hamberger, Britta; ...

2016-08-09

The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon–carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved inmore » the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids.« less

Crystal and molecular structure of the first dibino non-geminal macrocyclic dicyclophosphazene, & {;N 3P 3Cl 4[HN(CH 2) 3O(CH 2) 2O(CH 2) 3NH]&}; 2

NASA Astrophysics Data System (ADS)

Enjalbert, Renée; Galy, Jean; Sournies, François; Labarre, Jean-François

1990-04-01

Reaction of N 3P 3Cl 6 with the 4,7-dioxadecane-1,10-diamine (coded as 3O2O3) using an Et 2O/Na 2CO 3 water interface process leads to the DIBINO non-geminal 30-membered macrocyclic dicyclophosphazene &{;N 3P 3Cl 4[HN(CH 2) 3O(CH 2) 2O(CH 2) 3NH]&}; 2. This 30-crown-ether-like architecture crystallizes in the triclinic system, P1, a=9.019(6), b=9.224(5), c=11.542(8) Å, α=94.87(4), β=95.97(4), γ=99.68(3)°, V=936(1) Å 3, Dx=1.599 Mg m -3, R=0.049 for 2862 unique reflections and 199 variable parameters. The structure exhibits a spatial arrangement of two N 3P 3Cl 4 with two [HN(CH 2) 3O(CH 2) 3O(CH 2) 3NH] as bridges on different P atoms of N 3P 3 rings. Moreover, the two N 3P 3 rings are trans to the average plane of the 30-membered macrocycle ("chair" conformation).

Aggregation of p-Sulfonatocalixarene-Based Amphiphiles and Supra-Amphiphiles

PubMed Central

Basilio, Nuno; Francisco, Vitor; Garcia-Rio, Luis

2013-01-01

p-Sulfonatocalixarenes are a special class of water soluble macrocyclic molecules made of 4-hydroxybenzenesulfonate units linked by methylene bridges. One of the main features of these compounds relies on their ability to form inclusion complexes with cationic and neutral species. This feature, together with their water solubility and apparent biological compatibility, had enabled them to emerge as one the most important host receptors in supramolecular chemistry. Attachment of hydrophobic alkyl chains to these compounds leads to the formation of macrocyclic host molecules with amphiphilic properties. Like other oligomeric surfactants, these compounds present improved performance with respect to their monomeric counterparts. In addition, they hold their recognition abilities and present several structural features that depend on the size of the macrocycle and on the length of the alkyl chain, such as preorganization, flexibility and adopted conformations, which make these molecules very interesting to study structure-aggregation relationships. Moreover, the recognition abilities of p-sulfonatocalixarenes enable them to be applied in the design of amphiphiles constructed from non-covalent, rather than covalent, bonds (supramolecular amphiphiles). In this review, we summarize the developments made on the design and synthesis of p-sulfonatocalixarenes-based surfactants, the characterization of their self-assembly properties and on how their structure affects these properties. PMID:23380960

Artificial photosynthetic systems: assemblies of slipped cofacial porphyrins and phthalocyanines showing strong electronic coupling.

PubMed

Satake, Akiharu; Kobuke, Yoshiaki

2007-06-07

This paper reviews selected types of structurally well defined assemblies of porphyrins and phthalocyanines with strong electronic coupling. Face-to-face, head-to-tail, slipped cofacial, and non-parallel dimeric motifs constructed by covalent and non-covalent bonds are compared in the earlier sections. Their molecular orientation, electronic overlap, and absorption and fluorescence properties are discussed with a view towards the development of artificial photosynthetic systems and molecular electronics. Complementary coordination dimers are fully satisfactory in terms of structural stability, orientation factor, pi-electronic overlap, and zero fluorescence quenching. In later sections, several polymeric and macrocyclic porphyrin assemblies constructed by a combination of covalent bonds and complementary coordination bonds are discussed from the viewpoint of light-harvesting antenna functions.

Enhanced anion exchange for selective sulfate extraction: overcoming the Hofmeister bias.

PubMed

Fowler, Christopher J; Haverlock, Tamara J; Moyer, Bruce A; Shriver, James A; Gross, Dustin E; Marquez, Manuel; Sessler, Jonathan L; Hossain, Md Alamgir; Bowman-James, Kristin

2008-11-05

In this communication, a new approach to enhancing the efficacy of liquid-liquid anion exchange is demonstrated. It involves the concurrent use of appropriately chosen hydrogen-bond-donating (HBD) anion receptors in combination with a traditional quaternary ammonium extractant. The fluorinated calixpyrroles 1 and 2 and the tetraamide macrocycle 4 were found to be particularly effective receptors. Specifically, their use allowed the extraction of sulfate by tricaprylmethylammonium nitrate to be effected in the presence of excess nitrate. As such, the present work provides a rare demonstration of overcoming the Hofmeister bias in a competitive environment and the first to the authors' knowledge wherein this difficult-to-achieve objective is attained using a neutral HBD-based anion binding agent under conditions of solvent extraction.

Cationic aza-macrocyclic complexes of germanium(II) and silicon(IV).

PubMed

Everett, Matthew; Jolleys, Andrew; Levason, William; Light, Mark E; Pugh, David; Reid, Gillian

2015-12-28

[GeCl2(dioxane)] reacts with the neutral aza-macrocyclic ligands L, L = Me3tacn (1,4,7-trimethyl-1,4,7-triazacyclononane), Me4cyclen (1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane) or Me4cyclam (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) and two mol. equiv. of Me3SiO3SCF3 in thf solution to yield the unusual and hydrolytically very sensitive [Ge(L)][O3SCF3]2 as white solids in moderate yield. Using shorter reaction times [Ge(Me3tacn)]Cl2 and [Ge(Me3tacn)]Cl[O3SCF3] were also isolated; the preparation of [Ge(Me4cyclen)][GeCl3]2 is also described. The structures of the Me3tacn complexes show κ(3)-coordination of the macrocycle, with the anions interacting only weakly to produce very distorted five- or six-coordination at germanium. In contrast, the structure of [Ge(Me4cyclen)][O3SCF3]2 shows no anion interactions, and a distorted square planar geometry at germanium from coordination to the tetra-aza macrocycle. Crystal structures of the Si(iv) complexes, [SiCl3(Me3tacn)]Y (Y = O3SCF3, BAr(F); [B{3,5-(CF3)2C6H3}4]) and [SiHCl2(Me3tacn)][BAr(F)], obtained from reaction of SiCl4 or SiHCl3 with Me3tacn, followed by addition of either Me3SiO3SCF3 or Na[BAr(F)], contain distorted octahedral cations, with facialκ(3)-coordinated Me3tacn. The open-chain triamine, Me2NCH2CH2N(Me)CH2CH2NMe2 (pmdta), forms [SiCl3(pmdta)][BAr(F)] and [SiBr3(pmdta)][BAr(F)] under similar conditions, containing mer-octahedral cations.

Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition

PubMed Central

Clerc, Jérôme; Groll, Michael; Illich, Damir J.; Bachmann, André S.; Huber, Robert; Schellenberg, Barbara; Dudler, Robert; Kaiser, Markus

2009-01-01

Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a Ki′ of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics. PMID:19359491

The Screening Compound Collection: A Key Asset for Drug Discovery.

PubMed

Boss, Christoph; Hazemann, Julien; Kimmerlin, Thierry; von Korff, Modest; Lüthi, Urs; Peter, Oliver; Sander, Thomas; Siegrist, Romain

2017-10-25

In this case study on an essential instrument of modern drug discovery, we summarize our successful efforts in the last four years toward enhancing the Actelion screening compound collection. A key organizational step was the establishment of the Compound Library Committee (CLC) in September 2013. This cross-functional team consisting of computational scientists, medicinal chemists and a biologist was endowed with a significant annual budget for regular new compound purchases. Based on an initial library analysis performed in 2013, the CLC developed a New Library Strategy. The established continuous library turn-over mode, and the screening library size of 300'000 compounds were maintained, while the structural library quality was increased. This was achieved by shifting the selection criteria from 'druglike' to 'leadlike' structures, enriching for non-flat structures, aiming for compound novelty, and increasing the ratio of higher cost 'Premium Compounds'. Novel chemical space was gained by adding natural compounds, macrocycles, designed and focused libraries to the collection, and through mutual exchanges of proprietary compounds with agrochemical companies. A comparative analysis in 2016 provided evidence for the positive impact of these measures. Screening the improved library has provided several highly promising hits, including a macrocyclic compound, that are currently followed up in different Hit-to-Lead and Lead Optimization programs. It is important to state that the goal of the CLC was not to achieve higher HTS hit rates, but to increase the chances of identified hits to serve as the basis of successful early drug discovery programs. The experience gathered so far legitimates the New Library Strategy.

Using Classical Reliability Models and Single Event Upset (SEU) Data to Determine Optimum Implementation Schemes for Triple Modular Redundancy (TMR) in SRAM-Based Field Programmable Gate Array (FPGA) Devices

NASA Technical Reports Server (NTRS)

Berg, M.; Kim, H.; Phan, A.; Seidleck, C.; LaBel, K.; Pellish, J.; Campola, M.

2015-01-01

Space applications are complex systems that require intricate trade analyses for optimum implementations. We focus on a subset of the trade process, using classical reliability theory and SEU data, to illustrate appropriate TMR scheme selection.

Carbon nanohoops and methods of making

DOEpatents

Jasti, Ramesh; Bertozzi, Carolyn

2013-06-11

The present invention provides cycloparaphenylene compounds, their macrocyclic precursors, and methods for making the compounds. The cycloparaphenylene compounds can be used to prepare armchair carbon nanotubes.

Carbon nanohoops and methods of making

DOEpatents

Jasti, Ramesh; Bertozzi, Carolyn

2015-03-24

The present invention provides cycloparaphenylene compounds, their macrocyclic precursors, and methods for making the compounds. The cycloparaphenylene compounds can be used to prepare armchair carbon nanotubes.

Carbon nanohoops and methods of making

DOEpatents

Jasti, Ramesh; Bertozzi, Carolyn

2015-10-20

The present invention provides cycloparaphenylene compounds, their macrocyclic precursors, and methods for making the compounds. The cycloparaphenylene compounds can be used to prepare armchair carbon nanotubes.

How do the macrocyclic lactones kill filarial nematode larvae?

PubMed

Wolstenholme, Adrian J; Maclean, Mary J; Coates, Ruby; McCoy, Ciaran J; Reaves, Barbara J

2016-09-01

The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions.

PubMed

Park, Yongho; Harper, Kaid C; Kuhl, Nadine; Kwan, Eugene E; Liu, Richard Y; Jacobsen, Eric N

2017-01-13

Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction. Copyright © 2017, American Association for the Advancement of Science.

Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways

PubMed Central

Doi, Kunio; Uetsuka, Koji

2011-01-01

Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B1 (FB1) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB1 induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways. PMID:21954354

Optimum allocation for a dual-frame telephone survey.

PubMed

Wolter, Kirk M; Tao, Xian; Montgomery, Robert; Smith, Philip J

2015-12-01

Careful design of a dual-frame random digit dial (RDD) telephone survey requires selecting from among many options that have varying impacts on cost, precision, and coverage in order to obtain the best possible implementation of the study goals. One such consideration is whether to screen cell-phone households in order to interview cell-phone only (CPO) households and exclude dual-user household, or to take all interviews obtained via the cell-phone sample. We present a framework in which to consider the tradeoffs between these two options and a method to select the optimal design. We derive and discuss the optimum allocation of sample size between the two sampling frames and explore the choice of optimum p , the mixing parameter for the dual-user domain. We illustrate our methods using the National Immunization Survey , sponsored by the Centers for Disease Control and Prevention.

A methodology for selecting optimum organizations for space communities

NASA Technical Reports Server (NTRS)

Ragusa, J. M.

1978-01-01

This paper suggests that a methodology exists for selecting optimum organizations for future space communities of various sizes and purposes. Results of an exploratory study to identify an optimum hypothetical organizational structure for a large earth-orbiting multidisciplinary research and applications (R&A) Space Base manned by a mixed crew of technologists are presented. Since such a facility does not presently exist, in situ empirical testing was not possible. Study activity was, therefore, concerned with the identification of a desired organizational structural model rather than the empirical testing of it. The principal finding of this research was that a four-level project type 'total matrix' model will optimize the effectiveness of Space Base technologists. An overall conclusion which can be reached from the research is that application of this methodology, or portions of it, may provide planning insights for the formal organizations which will be needed during the Space Industrialization Age.

Dynamic hybrid materials for constitutional self-instructed membranes.

PubMed

Cazacu, Adinela; Legrand, Yves-Marie; Pasc, Andreea; Nasr, Gihane; Van der Lee, Arie; Mahon, Eugene; Barboiu, Mihail

2009-05-19

Constitutional self-instructed membranes were developed and used for mimicking the adaptive structural functionality of natural ion-channel systems. These membranes are based on dynamic hybrid materials in which the functional self-organized macrocycles are reversibly connected with the inorganic silica through hydrophobic noncovalent interactions. Supramolecular columnar ion-channel architectures can be generated by reversible confinement within scaffolding hydrophobic silica mesopores. They can be structurally determined by using X-ray diffraction and morphologically tuned by alkali-salts templating. From the conceptual point of view, these membranes express a synergistic adaptive behavior: the simultaneous binding of the fittest cation and its anion would be a case of "homotropic allosteric interactions," because in time it increases the transport efficiency of the pore-contained superstructures by a selective evolving process toward the fittest ion channel. The hybrid membranes presented here represent dynamic constitutional systems evolving over time to form the fittest ion channels from a library of molecular and supramolecular components, or selecting the fittest ion pairs from a mixture of salts demonstrating flexible adaptation.

Dynamic covalent chemistry enables formation of antimicrobial peptide quaternary assemblies in a completely abiotic manner

NASA Astrophysics Data System (ADS)

Reuther, James F.; Dees, Justine L.; Kolesnichenko, Igor V.; Hernandez, Erik T.; Ukraintsev, Dmitri V.; Guduru, Rusheel; Whiteley, Marvin; Anslyn, Eric V.

2018-01-01

Naturally occurring peptides and proteins often use dynamic disulfide bonds to impart defined tertiary/quaternary structures for the formation of binding pockets with uniform size and function. Although peptide synthesis and modification are well established, controlling quaternary structure formation remains a significant challenge. Here, we report the facile incorporation of aryl aldehyde and acyl hydrazide functionalities into peptide oligomers via solid-phase copper-catalysed azide-alkyne cycloaddition (SP-CuAAC) click reactions. When mixed, these complementary functional groups rapidly react in aqueous media at neutral pH to form peptide-peptide intermolecular macrocycles with highly tunable ring sizes. Moreover, sequence-specific figure-of-eight, dumbbell-shaped, zipper-like and multi-loop quaternary structures were formed selectively. Controlling the proportions of reacting peptides with mismatched numbers of complementary reactive groups results in the formation of higher-molecular-weight sequence-defined ladder polymers. This also amplified antimicrobial effectiveness in select cases. This strategy represents a general approach to the creation of complex abiotic peptide quaternary structures.

Synthesis and structural studies of two pyridine-armed reinforced cyclen chelators and their transition metal complexes.

PubMed

Wilson, Kevin R; Cannon-Smith, Desiray J; Burke, Benjamin P; Birdsong, Orry C; Archibald, Stephen J; Hubin, Timothy J

2016-08-16

Two novel pyridine pendant-armed macrocycles structurally reinforced by an ethyl bridge, either between adjacent nitrogens (for side-bridged) or non-adjacent nitrogens (for cross-bridged), have been synthesized and complexed with a range of transition metal ions (Co 2+ , Ni 2+ , Cu 2+ and Zn 2+ ). X-ray crystal structures of selected cross-bridged complexes were obtained which showed the characteristic cis-V configuration with potential labile cis binding sites. The complexes have been characterized by their electronic spectra and magnetic moments, which show the expected high spin divalent metal complex in most cases. Exceptions are the nickel side-bridged complex, which shows a mixture of high-spin and low spin, and the cobalt cross-bridged complex which has oxidized to cobalt(III). Cyclic voltammetry in acetonitrile was carried out to assess the potential future use of these complexes in oxidation catalysis. Selected complexes offer significant catalytic potential enhanced by the addition of the pyridyl arm to a reinforced cyclen backbone.

Selective Nitrate Recognition by a Halogen-Bonding Four-Station [3]Rotaxane Molecular Shuttle.

PubMed

Barendt, Timothy A; Docker, Andrew; Marques, Igor; Félix, Vítor; Beer, Paul D

2016-09-05

The synthesis of the first halogen bonding [3]rotaxane host system containing a bis-iodo triazolium-bis-naphthalene diimide four station axle component is reported. Proton NMR anion binding titration experiments revealed the halogen bonding rotaxane is selective for nitrate over the more basic acetate, hydrogen carbonate and dihydrogen phosphate oxoanions and chloride, and exhibits enhanced recognition of anions relative to a hydrogen bonding analogue. This elaborate interlocked anion receptor functions via a novel dynamic pincer mechanism where upon nitrate anion binding, both macrocycles shuttle from the naphthalene diimide stations at the periphery of the axle to the central halogen bonding iodo-triazolium station anion recognition sites to form a unique 1:1 stoichiometric nitrate anion-rotaxane sandwich complex. Molecular dynamics simulations carried out on the nitrate and chloride halogen bonding [3]rotaxane complexes corroborate the (1) H NMR anion binding results. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Uncovering the genetic signature of quantitative trait evolution with replicated time series data.

PubMed

Franssen, S U; Kofler, R; Schlötterer, C

2017-01-01

The genetic architecture of adaptation in natural populations has not yet been resolved: it is not clear to what extent the spread of beneficial mutations (selective sweeps) or the response of many quantitative trait loci drive adaptation to environmental changes. Although much attention has been given to the genomic footprint of selective sweeps, the importance of selection on quantitative traits is still not well studied, as the associated genomic signature is extremely difficult to detect. We propose 'Evolve and Resequence' as a promising tool, to study polygenic adaptation of quantitative traits in evolving populations. Simulating replicated time series data we show that adaptation to a new intermediate trait optimum has three characteristic phases that are reflected on the genomic level: (1) directional frequency changes towards the new trait optimum, (2) plateauing of allele frequencies when the new trait optimum has been reached and (3) subsequent divergence between replicated trajectories ultimately leading to the loss or fixation of alleles while the trait value does not change. We explore these 3 phase characteristics for relevant population genetic parameters to provide expectations for various experimental evolution designs. Remarkably, over a broad range of parameters the trajectories of selected alleles display a pattern across replicates, which differs both from neutrality and directional selection. We conclude that replicated time series data from experimental evolution studies provide a promising framework to study polygenic adaptation from whole-genome population genetics data.

Evolutionary biology: variation isn't always sexy.

PubMed

Safran, Rebecca J; Hauber, Mark E

2007-05-15

A recent study has found that differences in a male trait, considered a textbook example of sexual selection, are in fact due to naturally selected variation in the aerodynamic optimum for each individual.

A parameter for the assessment of the segmentation of TEM tomography reconstructed volumes based on mutual information.

PubMed

Okariz, Ana; Guraya, Teresa; Iturrondobeitia, Maider; Ibarretxe, Julen

2017-12-01

A method is proposed and verified for selecting the optimum segmentation of a TEM reconstruction among the results of several segmentation algorithms. The selection criterion is the accuracy of the segmentation. To do this selection, a parameter for the comparison of the accuracies of the different segmentations has been defined. It consists of the mutual information value between the acquired TEM images of the sample and the Radon projections of the segmented volumes. In this work, it has been proved that this new mutual information parameter and the Jaccard coefficient between the segmented volume and the ideal one are correlated. In addition, the results of the new parameter are compared to the results obtained from another validated method to select the optimum segmentation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Optimum viewing distance for target acquisition

NASA Astrophysics Data System (ADS)

Holst, Gerald C.

2015-05-01

Human visual system (HVS) "resolution" (a.k.a. visual acuity) varies with illumination level, target characteristics, and target contrast. For signage, computer displays, cell phones, and TVs a viewing distance and display size are selected. Then the number of display pixels is chosen such that each pixel subtends 1 min-1. Resolution of low contrast targets is quite different. It is best described by Barten's contrast sensitivity function. Target acquisition models predict maximum range when the display pixel subtends 3.3 min-1. The optimum viewing distance is nearly independent of magnification. Noise increases the optimum viewing distance.

Theoretical studies on the possible sensitizers of DSSC: Nanocomposites of graphene quantum dot hybrid phthalocyanine/tetrabenzoporphyrin/tetrabenzotriazaporphyrins/cis-tetrabenzodiazaporphyrins/tetrabenzomonoazaporphyrins and their Cu-metallated macrocycles

NASA Astrophysics Data System (ADS)

Gao, Feng; Yang, Chuan-Lu; Wang, Mei-Shan; Ma, Xiao-Guang; Liu, Wen-Wang

2018-04-01

The feasibility of nanocomposites of cir-coronene graphene quantum dot (GQD) with phthalocyanine, tetrabenzoporphyrin, tetrabenzotriazaporphyrins, cis-tetrabenzodiazaporphyrins, tetrabenzomonoazaporphyrins and their Cu-metallated macrocycles as a sensitizer of dye-sensitized solar cells (DSSC) are investigated. Based on the first principles density functional theory (DFT), the geometrical structures of the separate GQD and 10 macrocycles, and their hybridized nanocomposites are fully optimized. The energy stabilities of the obtained structures are confirmed by harmonic frequency analysis. The optical absorptions of the optimized structures are calculated with time-dependent DFT. The feasibility of the nanocomposites as the sensitizer of DSSC is examined by the charge spatial separation, the electron transfer, the molecular orbital energy levels of the nanocomposites and the electrolyte, and the conduction band minimum of TiO2 electrode. The results demonstrate that all the nanocomposites have enhanced absorptions in the visible light range, and their molecular orbital energies satisfy the requirement of sensitizers. However, only two of the ten considered nanocomposites demonstrate significantly charge spatial separation. The GQD-Cu-TBP is identified as the most favorable candidate sensitizer of DSSC by the most enhanced in optical absorption, obvious charge spatial separation, suitable LUMO energy levels and driving force for electron transfer, and low recombination rate of electron and hole.

Crystal structures of two cross-bridged chromium(III) tetra­aza­macrocycles

PubMed Central

Prior, Timothy J.; Maples, Danny L.; Maples, Randall D.; Hoffert, Wesley A.; Parsell, Trenton H.; Silversides, Jon D.; Archibald, Stephen J.; Hubin, Timothy J.

2014-01-01

The crystal structure of di­chlorido­(4,10-dimethyl-1,4,7,10-tetra­aza­bicyclo­[5.5.2]tetra­deca­ne)chromium(III) hexa­fluorido­phosphate, [CrCl2(C12H26N4)]PF6, (I), has monoclinic symmetry (space group P21/n) at 150 K. The structure of the related di­chlorido­(4,11-dimethyl-1,4,8,11-tetra­aza­bicyclo­[6.6.2]hexa­deca­ne)chromium(III) hexa­fluorido­phosphate, [CrCl2(C14H30N4)]PF6, (II), also displays monoclinic symmetry (space group P21/c) at 150 K. In each case, the CrIII ion is hexa­coordinate with two cis chloride ions and two non-adjacent N atoms bound cis equatorially and the other two non-adjacent N atoms bound trans axially in a cis-V conformation of the macrocycle. The extent of the distortion from the preferred octa­hedral coordination geometry of the CrIII ion is determined by the parent macrocycle ring size, with the larger cross-bridged cyclam ring in (II) better able to accommodate this preference and the smaller cross-bridged cyclen ring in (I) requiring more distortion away from octa­hedral geometry. PMID:25309165

DOTA analogues with a phosphinate-iminodiacetate pendant arm: modification of the complex formation rate with a strongly chelating pendant.

PubMed

Procházková, Soňa; Kubíček, Vojtěch; Böhmová, Zuzana; Holá, Kateřina; Kotek, Jan; Hermann, Petr

2017-08-08

The new ligand H 6 do3aP ida combines the macrocyclic DOTA-like cavity and the open-chain iminodiacetate group connected through a coordinating phosphinate spacer. Its acid-base and coordination properties in solution were studied by potentiometry. Thermodynamic coordination characteristics of both chelating units are similar to those reported for H 4 dota and iminodiacetic acid themselves, respectively, so, macrocyclic and iminodiacetate units behave independently. The formation kinetics of the Ce(iii)-H 6 do3aP ida complex was studied by UV-Vis spectrophotometry. Various out-of-cage intermediates were identified with 1 : 1, 1 : 2 and 2 : 1 ligand-to-metal ratios. The presence of the strongly coordinating iminodiacetate group significantly slows down the metal ion transfer into the macrocyclic cavity and, so, the formation of the in-cage complex is two orders of magnitude slower than that reported for the Ce(iii)-H 4 dota system. The kinetic inertness of the [Ce(do3aP ida )] 3- complex towards acid-assisted dissociation is comparable to that of the [Ce(dota)] - complex. The coordination modes of the ligand are demonstrated in the solid-state structure of [Cu 4 (do3aP ida )(OH)(H 2 O) 4 ]Cl·7.5H 2 O.

Fragrance material review on 16-hydroxy-7-hexadecenoic acid lactone.

PubMed

McGinty, D; Letizia, C S; Api, A M

2011-12-01

A toxicologic and dermatologic review of 16-hydroxy-7-hexadecenoic acid lactone when used as a fragrance ingredient is presented. 16-Hydroxy-7-hexadecenoic acid lactone is a member of the fragrance structural group macrocyclic lactone and lactide derivatives. The fragrance ingredient described herein is one of 12 structurally diverse C14, C15 and C16 compounds that include (1) saturated mono-and (2) saturated di-ester lactones and (3) unsaturated lactones. For the latter, the double bond is not adjacent to (in conjugation with) the ester group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to 16-hydroxy-7-hexadecenoic acid lactone and is not intended as a stand-alone document. Available data were evaluated, then summarized, and include physical properties data. A safety assessment of the entire macrocyclic lactone and lactide derivatives will be published simultaneously with this document. Please refer to Belsito et al., 2011 for an overall assessment of the safe use of this material and all macrocyclic lactone and lactide derivatives in fragrances. Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Hanifin, J.H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2011. A toxicologic and dermatologic assessment of macrocylic lactones and lactide derivatives when used as fragrance ingredients. Copyright © 2011. Published by Elsevier Ltd.

American Chemical Society--238th National Meeting & Exposition. Developments in medicinal chemistry: part 1. 16-20 August 2009, Washington DC, USA.

PubMed

Gater, Deborah; Macauley, Donald

2009-10-01

The 238th National Meeting and Exposition of the American Chemical Society, held in Washington DC, included topics covering new compounds and developments in the field of medicinal chemistry. This conference report highlights selected presentations on a novel KV1.5 blocker, a state-dependent CaV2.2 antagonist, therapeutic uses of macrocycles, a novel P2X7 antagonist, developments using the StaR technology platform, the optimization of a neuropeptide S receptor antagonist, and type 1 glycine transport modulators. Investigational drugs discussed include WYE-160020 (Wyeth), Trox-1 (Neuromed Pharmaceuticals Inc), ulimorelin (Tranzyme Pharma Inc), E-32224 (Ensemble Discovery Corp) and PF-03463275 (Pfizer Inc); the discontinued compound AZD-9056 is also highlighted.

Analysis and Experimental Investigation of Optimum Design of Thermoelectric Cooling/Heating System for Car Seat Climate Control (CSCC)

NASA Astrophysics Data System (ADS)

Elarusi, Abdulmunaem; Attar, Alaa; Lee, HoSung

2018-02-01

The optimum design of a thermoelectric system for application in car seat climate control has been modeled and its performance evaluated experimentally. The optimum design of the thermoelectric device combining two heat exchangers was obtained by using a newly developed optimization method based on the dimensional technique. Based on the analytical optimum design results, commercial thermoelectric cooler and heat sinks were selected to design and construct the climate control heat pump. This work focuses on testing the system performance in both cooling and heating modes to ensure accurate analytical modeling. Although the analytical performance was calculated using the simple ideal thermoelectric equations with effective thermoelectric material properties, it showed very good agreement with experiment for most operating conditions.

Anthelmintic resistance in cattle nematodes in the US.

PubMed

Gasbarre, Louis C

2014-07-30

The first documented case of macrocyclic lactone resistance in gastrointestinal (GI) nematodes of cattle was seen in the US approximately 10 years ago. Since that time the increase incidence of anthelmintic resistance has continued at an alarming rate. Currently parasites of the genera Cooperia and/or Haemonchus resistant to generic or brand-name macrocyclic lactones have be demonstrated in more than half of all operations examined. Both of these parasite genera are capable of causing economic losses by decreasing food intake and subsequently animal productivity. Currently, there are no easy and quick means to detect anthelmintic resistant GI nematodes. Definitive identification requires killing of cattle. The most commonly used field detection method is the fecal egg count reduction test (FECRT). This method can be adapted for use as a screening agent for Veterinarians and producers to identify less than desired clearance of the parasites after anthelmintic treatment. Further studies can then define the reasons for persistence of the egg counts. The appearance of anthelmintic resistance is largely due to the development of very effective nematode control programs that have significantly improved the productivity of the US cattle industry, but at the same time has placed a high level of selective pressure on the parasite genome. The challenges ahead include the development of programs that control the anthelmintic resistant nematodes but at the same time result in more sustainable parasite control. The goal is to maintain high levels of productivity but to exert less selective pressures on the parasites. One of the most effective means to slow the development of drug resistance is through the simultaneous use of multiple classes of anthelmintics, each of which has a different mode of action. Reduction of the selective pressure on the parasites can be attained through a more targeted approach to drug treatments where the producer's needs are met by selective treatment of different classes of animals and not by blanket treatment at a location. The implementation of such programs will vary by the sector of the industry and the individual site. In general, the feedlot will be the easiest sector for developing of programs, while stocker/backgrounder operations will provide the most challenging problems. A major question that must be addressed is whether it is important that parasite control programs to be sustainable over time, or if the pharmaceutical industry develop new control agents at a rate sufficient to render sustainability unimportant. Copyright © 2014. Published by Elsevier B.V.

Porphyrin network materials: Chemical exploration in the supramolecular solid-state

NASA Astrophysics Data System (ADS)

Kosal, Margaret Elizabeth

Rational design of solid-state materials from molecular building blocks possessing desired physical and chemical characteristics remains among the most challenging tasks for the synthetic chemist. Using p-carboxylic acid tetraphenyl porphyrin molecules, H2T(p-CO 2H)PP, as the organic building block, the synthesis of novel microporous coordination framework materials has been pursued for this work. The self-assembly of the anionic carboxylate with divalent alkaline earth or transition metal cations yielded clathrate, lamellar and three-dimensional network materials. The solvothermal synthesis, characterization, and selective sorption properties of a 3-dimensional metalloporphyrin network solid, [CoT( p-CO2)PPCo1.5], named PIZA-1 for Porphyrinic Illinois Zeolite Analogue 1, have been investigated. The extended structure reveals a single, independent, neutral network with large, bi-directional oval-shaped channels (9 x 7 A) along the crystallographic b - and c-axes and another set of channels (14 x 7 A) along the a-axis. At the intersection of channels, an internal chamber (31 x 31 x 10 A) is realized. Channel-shape is attributable to ruffling of the metalloporphyrin macrocycles when coordinated to the bridging trinuclear Co(II)-carboxylate clusters. The void volume of the stable, thermally robust, solvate-free material is calculated to be 74% of the total unit cell volume. Size-, shape- and functional-group-selective sorption indicates a preference for water and amines. This organic zeolite analogue also demonstrates remarkable ability as a molecular sieve for removal of water from common organic solvents. By powder X-ray diffraction, BET gas adsorption studies and FTIR, this material has been shown to maintain its porous structure as a guest-free solid when heated under vacuum to 250°C. PIZA-1 demonstrates extremely high capacity for repeated selective sorption of water. In comparison to 4A molecular sieves, PIZA-1 exhibits higher capacity and faster response for the selective adsorption of water from common organic solvents. Molecular modeling of corroborates experimental results. The large internal cavities of PIZA-1 are a consequence of the trinuclear Co(II)carboxylate cluster forcing the ruffling of the porphyrin building blocks. The linear trinuclear metal-carboxylate cluster of PIZA-1 is contrasted with the bent trinuclear M(II) carboxylate clusters (M = Co, Mn) of isostructural 3-dimensional frameworks: PIZA-2 and PIZA-3. Containing near-planar metalloporphyrin macrocycles, PIZA-2 and PIZA-3 manifest lower void volumes (56%).

Optimum location of external markers using feature selection algorithms for real‐time tumor tracking in external‐beam radiotherapy: a virtual phantom study

PubMed Central

Nankali, Saber; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-01

In external‐beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation‐based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two “Genetic” and “Ranker” searching procedures. The performance of these algorithms has been evaluated using four‐dimensional extended cardiac‐torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro‐fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F‐test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation‐based feature selection algorithm, in combination with a genetic search algorithm, proved to yield best performance accuracy for selecting optimum markers. PACS numbers: 87.55.km, 87.56.Fc PMID:26894358

Optimum location of external markers using feature selection algorithms for real-time tumor tracking in external-beam radiotherapy: a virtual phantom study.

PubMed

Nankali, Saber; Torshabi, Ahmad Esmaili; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-08

In external-beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation-based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two "Genetic" and "Ranker" searching procedures. The performance of these algorithms has been evaluated using four-dimensional extended cardiac-torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro-fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F-test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation-based feature selection algorithm, in combination with a genetic search algorithm, proved to yield best performance accuracy for selecting optimum markers.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

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

Wang, Le; Pratt, John K.; Soltwedel, Todd

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumormore » growth inhibition efficacy in mouse flank xenograft models.« less

Effect of intramolecular charge transfer on fluorescence and singlet oxygen production of phthalocyanine analogues.

PubMed

Vachova, Lenka; Novakova, Veronika; Kopecky, Kamil; Miletin, Miroslav; Zimcik, Petr

2012-10-14

Intramolecular charge transfer (ICT) was studied on a series of magnesium, metal-free and zinc complexes of unsymmetrical tetrapyrazinoporphyrazines and tribenzopyrazinoporphyrazines bearing two dialkylamino substituents (donors) and six alkylsulfanyl or aryloxy substituents (non-donors). The dialkylamino substituents were responsible for ICT that deactivated excited states and led to considerable decrease of fluorescence and singlet oxygen quantum yields. Photophysical and photochemical properties were compared to corresponding macrocycles that do not bear any donor centers. The data showed high feasibility of ICT in the tetrapyrazinoporphyrazine macrocycle and significantly lower efficiency of this deactivation process in the tribenzopyrazinoporphyrazine type molecules. Considerable effect of non-donor peripheral substituents on ICT was also described. The results imply that tetrapyrazinoporphyrazines may be more suitable for development of new molecules investigated in applications based on ICT.

Photochemical Dual-Catalytic Synthesis of Alkynyl Sulfides.

PubMed

Santandrea, Jeffrey; Minozzi, Clémentine; Cruché, Corentin; Collins, Shawn K

2017-09-25

A photochemical dual-catalytic cross-coupling to form alkynyl sulfides via C(sp)-S bond formation is described. The cross-coupling of thiols and bromoalkynes is promoted by a soluble organic carbazole-based photocatalyst using continuous flow techniques. Synthesis of alkynyl sulfides bearing a wide range of electronically and sterically diverse aromatic alkynes and thiols can be achieved in good to excellent yields (50-96 %). The simple continuous flow setup also allows for short reaction times (30 min) and high reproducibility on gram scale. In addition, we report the first application of photoredox/nickel dual catalysis towards macrocyclization, as well as the first example of the incorporation of an alkynyl sulfide functional group into a macrocyclic scaffold. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Three-dimensional aromatic networks.

PubMed

Toyota, Shinji; Iwanaga, Tetsuo

2014-01-01

Three-dimensional (3D) networks consisting of aromatic units and linkers are reviewed from various aspects. To understand principles for the construction of such compounds, we generalize the roles of building units, the synthetic approaches, and the classification of networks. As fundamental compounds, cyclophanes with large aromatic units and aromatic macrocycles with linear acetylene linkers are highlighted in terms of transannular interactions between aromatic units, conformational preference, and resolution of chiral derivatives. Polycyclic cage compounds are constructed from building units by linkages via covalent bonds, metal-coordination bonds, or hydrogen bonds. Large cage networks often include a wide range of guest species in their cavity to afford novel inclusion compounds. Topological isomers consisting of two or more macrocycles are formed by cyclization of preorganized species. Some complicated topological networks are constructed by self-assembly of simple building units.

Solar cells incorporating light harvesting arrays

DOEpatents

Lindsey, Jonathan S.; Meyer, Gerald J.

2002-01-01

A solar cell incorporates a light harvesting array that comprises: (a) a first substrate comprising a first electrode; and (b) a layer of light harvesting rods electrically coupled to the first electrode, each of the light harvesting rods comprising a polymer of Formula I: X.sup.1.paren open-st.X.sup.m+1).sub.m (I) wherein m is at least 1, and may be from two, three or four to 20 or more; X.sup.1 is a charge separation group (and preferably a porphyrinic macrocycle, which may be one ligand of a double-decker sandwich compound) having an excited-state of energy equal to or lower than that of X.sup.2 ; and X.sup.2 through X.sup.m+1 are chromophores (and again are preferably porphyrinic macrocycles).

Light harvesting arrays

DOEpatents

Lindsey, Jonathan S.

2002-01-01

A light harvesting array useful for the manufacture of devices such as solar cells comprises: (a) a first substrate comprising a first electrode; and (b) a layer of light harvesting rods electrically coupled to the first electrode, each of the light harvesting rods comprising a polymer of Formula I: X.sup.1.paren open-st.X.sup.m+1).sub.m (I) wherein m is at least 1, and may be from two, three or four to 20 or more; X.sup.1 is a charge separation group (and preferably a porphyrinic macrocycle, which may be one ligand of a double-decker sandwich compound) having an excited-state of energy equal to or lower than that of X.sup.2, and X.sup.2 through X.sup.m+1 are chromophores (and again are preferably porphyrinic macrocycles).

Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats.

PubMed

Frenzel, Thomas; Apte, Chirag; Jost, Gregor; Schöckel, Laura; Lohrke, Jessica; Pietsch, Hubertus

2017-07-01

Multiple clinical and preclinical studies have reported a signal intensity increase and the presence of gadolinium (Gd) in the brain after repeated administration of Gd-based contrast agents (GBCAs). This bioanalytical study in rat brain tissue was initiated to investigate whether the residual Gd is present as intact GBCA or in other chemical forms by using tissue fractionation and chromatography. Rats were divided randomly in 6 groups of 10 animals each. They received 10 daily injections of 2.5 mmol/kg bodyweight of 1 of 5 different GBCAs: linear GBCAs such as gadodiamide (Omniscan; GE Healthcare), gadopentetate dimeglumine (Gd-DTPA, Magnevist; Bayer), or gadobenate dimeglumine (Multihance; Bracco) and macrocyclic GBCAs such as gadobutrol (Gadovist; Bayer) and gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet) or saline. On days 3 and 24 after the last injection (p.i.), 5 randomly chosen animals of each group were killed by exsanguination, and their brains were excised and divided into cerebrum, pons, and cerebellum. The brain sections were homogenized by sonication in ice-cold buffer at pH 7.4. Soluble and insoluble fractions were separated by centrifugation, and the soluble fractions were further separated by gel permeation chromatography (GPC). The Gd concentration in all tissue fractions and in the GPC eluate was measured by inductively coupled plasma-mass spectrometry. In a recovery control experiment, all GBCAs were spiked to blank brain tissue and more than 94% recovery of Gd in the tissue fractions was demonstrated. Only traces of the administered Gd were found in the rat brain tissue on day 3 and day 24 p.i. In the animals treated with macrocyclic GBCAs, Gd was found only in the soluble brain fraction and was present solely as low molecular weight molecules, most likely the intact GBCA. In the animals treated with linear GBCAs Gd was found to a large extent in the insoluble tissue fraction. The Gd concentration in the soluble fraction was comparable to the macrocyclic agents. According to GPC, a smaller portion of the Gd in the soluble fraction of the linear GBCAs groups was bound to macromolecules larger than 250 to 300 kDa. The nature of the Gd-containing macromolecules and the insoluble species were not determined, but they appeared to be saturable with Gd. The excretion of the soluble Gd species in the linear and macrocyclic GBCA groups was still ongoing between days 3 and 24 p.i. This was also observed for the macromolecular Gd species in the linear GBCA groups, but at a slower rate. The residual Gd found in the rat brain after repeated administration of all 3 linear GBCAs was present in at least 3 distinctive forms-soluble small molecules, including the intact GBCA, soluble macromolecules, and to a large extent in insoluble form. The latter 2 are most likely responsible for the prolonged signal intensity enhancement in brain structures observed in magnetic resonance imaging. No relevant differences between the 3 linear GBCAs were observed. The Gd concentrations in the brain after administration of macrocyclic GBCAs are lower, and the Gd is only present in soluble small molecules, which were slowly excreted. This underlines the crucial importance of the kinetic inertness of macrocyclic agents in the prevention of potential retention of Gd in the brain compared with the 3 linear, kinetically less restricted GBCAs.

Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents

PubMed Central

Frenzel, Thomas; Apte, Chirag; Jost, Gregor; Schöckel, Laura; Lohrke, Jessica; Pietsch, Hubertus

2017-01-01

Objective Multiple clinical and preclinical studies have reported a signal intensity increase and the presence of gadolinium (Gd) in the brain after repeated administration of Gd-based contrast agents (GBCAs). This bioanalytical study in rat brain tissue was initiated to investigate whether the residual Gd is present as intact GBCA or in other chemical forms by using tissue fractionation and chromatography. Materials and Methods Rats were divided randomly in 6 groups of 10 animals each. They received 10 daily injections of 2.5 mmol/kg bodyweight of 1 of 5 different GBCAs: linear GBCAs such as gadodiamide (Omniscan; GE Healthcare), gadopentetate dimeglumine (Gd-DTPA, Magnevist; Bayer), or gadobenate dimeglumine (Multihance; Bracco) and macrocyclic GBCAs such as gadobutrol (Gadovist; Bayer) and gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet) or saline. On days 3 and 24 after the last injection (p.i.), 5 randomly chosen animals of each group were killed by exsanguination, and their brains were excised and divided into cerebrum, pons, and cerebellum. The brain sections were homogenized by sonication in ice-cold buffer at pH 7.4. Soluble and insoluble fractions were separated by centrifugation, and the soluble fractions were further separated by gel permeation chromatography (GPC). The Gd concentration in all tissue fractions and in the GPC eluate was measured by inductively coupled plasma–mass spectrometry. In a recovery control experiment, all GBCAs were spiked to blank brain tissue and more than 94% recovery of Gd in the tissue fractions was demonstrated. Results Only traces of the administered Gd were found in the rat brain tissue on day 3 and day 24 p.i. In the animals treated with macrocyclic GBCAs, Gd was found only in the soluble brain fraction and was present solely as low molecular weight molecules, most likely the intact GBCA. In the animals treated with linear GBCAs Gd was found to a large extent in the insoluble tissue fraction. The Gd concentration in the soluble fraction was comparable to the macrocyclic agents. According to GPC, a smaller portion of the Gd in the soluble fraction of the linear GBCAs groups was bound to macromolecules larger than 250 to 300 kDa. The nature of the Gd-containing macromolecules and the insoluble species were not determined, but they appeared to be saturable with Gd. The excretion of the soluble Gd species in the linear and macrocyclic GBCA groups was still ongoing between days 3 and 24 p.i. This was also observed for the macromolecular Gd species in the linear GBCA groups, but at a slower rate. Conclusions The residual Gd found in the rat brain after repeated administration of all 3 linear GBCAs was present in at least 3 distinctive forms—soluble small molecules, including the intact GBCA, soluble macromolecules, and to a large extent in insoluble form. The latter 2 are most likely responsible for the prolonged signal intensity enhancement in brain structures observed in magnetic resonance imaging. No relevant differences between the 3 linear GBCAs were observed. The Gd concentrations in the brain after administration of macrocyclic GBCAs are lower, and the Gd is only present in soluble small molecules, which were slowly excreted. This underlines the crucial importance of the kinetic inertness of macrocyclic agents in the prevention of potential retention of Gd in the brain compared with the 3 linear, kinetically less restricted GBCAs. PMID:28125438

Double level selection in a constitutional dynamic library of coordination driven supramolecular polygons.

PubMed

Rancan, Marzio; Tessarolo, Jacopo; Casarin, Maurizio; Zanonato, Pier Luigi; Quici, Silvio; Armelao, Lidia

2014-07-21

A constitutional dynamic library (CDL) of Cu(II) metallo-supramolecular polygons has been studied as a bench test to examine an interesting selection case based on molecular recognition. Sorting of the CDL polygons is achieved through a proper guest that is hosted into the triangular metallo-macrocycle constituent. Two selection mechanisms are observed, a guest induced path and a guest templated self-assembly (virtual library approach). Remarkably, the triangular host can accommodate several guests with a degree of selectivity ranging from ∼1 to ∼10(4) for all possible guest pairs. A double level selection operates: guests drive the CDL toward the triangular polygon, and, at the same time, this is able to pick a specific guest from a set of competitive molecules, according to a selectivity-affinity correlation. Association constants of the host-guest systems have been determined. Guest competition and exchange studies have been analyzed through variable temperature UV-Vis absorption spectroscopy and single crystal X-ray diffraction studies. Molecular structures and electronic properties of the triangular polygon and of the host-guest systems also have been studied by means of all electrons density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations including dispersive contributions. DFT outcomes ultimately indicate the dispersive nature of the host-guest interactions, while TDDFT results allow a thorough assignment of the host and host-guests spectral features.

Hybrid maize breeding with doubled haploids: II. Optimum type and number of testers in two-stage selection for general combining ability.

PubMed

Longin, C Friedrich H; Utz, H Friedrich; Melchinger, Albrecht E; Reif, Jochen C

2007-02-01

Optimum allocation of test resources is of crucial importance for the efficiency of breeding programs. Our objectives were to (1) determine the optimum allocation of the number of lines, test locations, as well as number and type of testers in hybrid maize breeding using doubled haploids with two breeding strategies for improvement of general combining ability (GCA), (2) compare the maximum selection gain (DeltaG) achievable under both strategies, and (3) give recommendations for the optimum implementation of doubled haploids in commercial hybrid maize breeding. We calculated DeltaG by numerical integration for two two-stage selection strategies with evaluation of (1) testcross performance in both stages (BS1) or (2) line per se performance in the first stage followed by testcross performance in the second stage (BS2). Different assumptions were made regarding the budget, variance components (VCs), and the correlation between line per se performance and GCA. Selection gain for GCA increased with a broader genetic base of the tester. Hence, testers combining a large number of divergent lines are advantageous. However, in applied breeding programs, the use of single- or double-cross testers in the first and inbred testers in the second selection stage may be a good compromise between theoretical and practical requirements. With a correlation between line per se performance and GCA of 0.50, DeltaG for BS1 is about 5% higher than for BS2, if an economic weight of line per se performance is neglected. With increasing economic weight of line per se performance, relative efficiency of BS2 increased rapidly resulting in a superiority of BS2 over BS1 already for an economic weight for line per se performance larger than 0.1. Considering the importance of an economic seed production, an economic weight larger than 0.1 seems realistic indicating the necessity of separate breeding strategies for seed and pollen parent heterotic groups.

Trivalent scandium, yttrium and lanthanide complexes with thia-oxa and selena-oxa macrocycles and crown ether coordination.

PubMed

Champion, Martin J D; Farina, Paolo; Levason, William; Reid, Gillian

2013-09-28

Complexes of the oxa-thia macrocycles [18]aneO4S2, [15]aneO3S2 and the oxa-selena macrocycle [18]aneO4Se2 (L) of types [MCl2(L)]FeCl4 (M = Sc or Y) were prepared from [ScCl3(thf)3] or [YCl2(THF)5][YCl4(THF)2] and the ligand in anhydrous MeCN, using FeCl3 as a chloride abstractor. The [MI2(L)]I, [LaI3(L)] and [LuI2(L)]I have been prepared from the ligands and the appropriate anhydrous metal triiodide in MeCN. Complexes of type [LaI3(crown)] and [LuI2(crown)]I (crown = 18-crown-6, 15-crown-5) were made for comparison. Use of the metal iodide results in complexes with high solubility compared to the corresponding chlorides, although also with increased sensitivity to moisture. All complexes were characterised by microanalysis, IR, (1)H, (45)Sc and (77)Se NMR spectroscopy as appropriate. X-ray crystal structures are reported for [ScCl2([18]aneO4S2)][FeCl4], [ScI2([18]aneO4S2)]I, [YCl2(18-crown-6)]3[Y2Cl9], [YCl2([18]aneO4S2)][FeCl4], [LaI3(15-crown-5)], [LaI2(18-crown-6)(MeCN)]I, [LuI(18-crown-6)(MeCN)2]I2, [Lu(15-crown-5)(MeCN)2(OH2)]I3, [LaI3([18]aneO4S2)], [LaI([18]aneO4S2)(OH2)]I2, [LaI3([18]aneO4Se2)] and [LuI2([18]aneO4Se2)]I. In each complex all the neutral donor atoms of the macrocycles are coordinated to the metal centre, showing very rare examples of these oxophilic metal centres coordinated to thioether groups, and the first examples of coordinated selenoether donors. In some cases MeCN or adventitious water displaces halide ligands, but not the S/Se donors from La or Lu complexes. A complex of the oxa-tellura macrocycle [18]aneO4Te2, [ScCl2([18]aneO4Te2)][FeCl4] was isolated, but is unstable in MeCN solution, depositing elemental Te. YCl3 and 18-crown-6 produced [YCl2(18-crown-6)]3[Y2Cl9], the asymmetric unit of which contains two cations with a trans-YCl2 arrangement and a third with a cis-YCl2 group.

The handicap process favors exaggerated, rather than reduced, sexual ornaments.

PubMed

Tazzyman, Samuel J; Iwasa, Yoh; Pomiankowski, Andrew

2014-09-01

Why are traits that function as secondary sexual ornaments generally exaggerated in size compared to the naturally selected optimum, and not reduced? Because they deviate from the naturally selected optimum, traits that are reduced in size will handicap their bearer, and could thus provide an honest signal of quality to a potential mate. Thus if secondary sexual ornaments evolve via the handicap process, current theory suggests that reduced ornamentation should be as frequent as exaggerated ornamentation, but this is not the case. To try to explain this discrepancy, we analyze a simple model of the handicap process. Our analysis shows that asymmetries in costs of preference or ornament with regard to exaggeration and reduction cannot fully explain the imbalance. Rather, the bias toward exaggeration can be best explained if either the signaling efficacy or the condition dependence of a trait increases with size. Under these circumstances, evolution always leads to more extreme exaggeration than reduction: although the two should occur just as frequently, exaggerated secondary sexual ornaments are likely to be further removed from the naturally selected optimum than reduced ornaments. © 2014 The Authors. Evolution published by Wiley Periodicals, Inc. on behalf of The Society for the Study of Evolution.

Kinetic approach to the study of froth flotation applied to a lepidolite ore

NASA Astrophysics Data System (ADS)

Vieceli, Nathália; Durão, Fernando O.; Guimarães, Carlos; Nogueira, Carlos A.; Pereira, Manuel F. C.; Margarido, Fernanda

2016-07-01

The number of published studies related to the optimization of lithium extraction from low-grade ores has increased as the demand for lithium has grown. However, no study related to the kinetics of the concentration stage of lithium-containing minerals by froth flotation has yet been reported. To establish a factorial design of batch flotation experiments, we conducted a set of kinetic tests to determine the most selective alternative collector, define a range of pulp pH values, and estimate a near-optimum flotation time. Both collectors (Aeromine 3000C and Armeen 12D) provided the required flotation selectivity, although this selectivity was lost in the case of pulp pH values outside the range between 2 and 4. Cumulative mineral recovery curves were used to adjust a classical kinetic model that was modified with a non-negative parameter representing a delay time. The computation of the near-optimum flotation time as the maximizer of a separation efficiency (SE) function must be performed with caution. We instead propose to define the near-optimum flotation time as the time interval required to achieve 95%-99% of the maximum value of the SE function.

In Silico Syndrome Prediction for Coronary Artery Disease in Traditional Chinese Medicine

PubMed Central

Lu, Peng; Chen, Jianxin; Zhao, Huihui; Gao, Yibo; Luo, Liangtao; Zuo, Xiaohan; Shi, Qi; Yang, Yiping; Yi, Jianqiang; Wang, Wei

2012-01-01

Coronary artery disease (CAD) is the leading causes of deaths in the world. The differentiation of syndrome (ZHENG) is the criterion of diagnosis and therapeutic in TCM. Therefore, syndrome prediction in silico can be improving the performance of treatment. In this paper, we present a Bayesian network framework to construct a high-confidence syndrome predictor based on the optimum subset, that is, collected by Support Vector Machine (SVM) feature selection. Syndrome of CAD can be divided into asthenia and sthenia syndromes. According to the hierarchical characteristics of syndrome, we firstly label every case three types of syndrome (asthenia, sthenia, or both) to solve several syndromes with some patients. On basis of the three syndromes' classes, we design SVM feature selection to achieve the optimum symptom subset and compare this subset with Markov blanket feature select using ROC. Using this subset, the six predictors of CAD's syndrome are constructed by the Bayesian network technique. We also design Naïve Bayes, C4.5 Logistic, Radial basis function (RBF) network compared with Bayesian network. In a conclusion, the Bayesian network method based on the optimum symptoms shows a practical method to predict six syndromes of CAD in TCM. PMID:22567030

Optimum allocation of test resources and comparison of breeding strategies for hybrid wheat.

PubMed

Longin, C Friedrich H; Mi, Xuefei; Melchinger, Albrecht E; Reif, Jochen C; Würschum, Tobias

2014-10-01

The use of a breeding strategy combining the evaluation of line per se with testcross performance maximizes annual selection gain for hybrid wheat breeding. Recent experimental studies confirmed a high commercial potential for hybrid wheat requiring the design of optimum breeding strategies. Our objectives were to (1) determine the optimum allocation of the type and number of testers, the number of test locations and the number of doubled haploid lines for different breeding strategies, (2) identify the best breeding strategy and (3) elaborate key parameters for an efficient hybrid wheat breeding program. We performed model calculations using the selection gain for grain yield as target variable to optimize the number of lines, testers and test locations in four different breeding strategies. A breeding strategy (BS2) combining the evaluation of line per se performance and general combining ability (GCA) had a far larger annual selection gain across all considered scenarios than a breeding strategy (BS1) focusing only on GCA. In the combined strategy, the production of testcross seed conducted in parallel with the first yield trial for line per se performance (BS2rapid) resulted in a further increase of the annual selection gain. For the current situation in hybrid wheat, this relative superiority of the strategy BS2rapid amounted to 67 % in annual selection gain compared to BS1. Varying a large number of parameters, we identified the high costs for hybrid seed production and the low variance of GCA in hybrid wheat breeding as key parameters limiting selection gain in BS2rapid.

Macrocyclic receptor showing extremely high Sr(II)/Ca(II) and Pb(II)/Ca(II) selectivities with potential application in chelation treatment of metal intoxication.

PubMed

Ferreirós-Martínez, Raquel; Esteban-Gómez, David; Tóth, Éva; de Blas, Andrés; Platas-Iglesias, Carlos; Rodríguez-Blas, Teresa

2011-04-18

Herein we report a detailed investigation of the complexation properties of the macrocyclic decadentate receptor N,N'-Bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H(2)bp18c6) toward different divalent metal ions [Zn(II), Cd(II), Pb(II), Sr(II), and Ca(II)] in aqueous solution. We have found that this ligand is especially suited for the complexation of large metal ions such as Sr(II) and Pb(II), which results in very high Pb(II)/Ca(II) and Pb(II)/Zn(II) selectivities (in fact, higher than those found for ligands widely used for the treatment of lead poisoning such as ethylenediaminetetraacetic acid (edta)), as well as in the highest Sr(II)/Ca(II) selectivity reported so far. These results have been rationalized on the basis of the structure of the complexes. X-ray crystal diffraction, (1)H and (13)C NMR spectroscopy, as well as theoretical calculations at the density functional theory (B3LYP) level have been performed. Our results indicate that for large metal ions such as Pb(II) and Sr(II) the most stable conformation is Δ(δλδ)(δλδ), while for Ca(II) our calculations predict the Δ(λδλ)(λδλ) form being the most stable one. The selectivity that bp18c6(2-) shows for Sr(II) over Ca(II) can be attributed to a better fit between the large Sr(II) ions and the relatively large crown fragment of the ligand. The X-ray crystal structure of the Pb(II) complex shows that the Δ(δλδ)(δλδ) conformation observed in solution is also maintained in the solid state. The Pb(II) ion is endocyclically coordinated, being directly bound to the 10 donor atoms of the ligand. The bond distances to the donor atoms of the pendant arms (2.55-2.60 Å) are substantially shorter than those between the metal ion and the donor atoms of the crown moiety (2.92-3.04 Å). This is a typical situation observed for the so-called hemidirected compounds, in which the Pb(II) lone pair is stereochemically active. The X-ray structures of the Zn(II) and Cd(II) complexes show that these metal ions are exocyclically coordinated by the ligand, which explains the high Pb(II)/Cd(II) and Pb(II)/Zn(II) selectivities. Our receptor bp18c6(2-) shows promise for application in chelation treatment of metal intoxication by Pb(II) and (90)Sr(II).

Contrasting guest binding interaction of cucurbit[7-8]urils with neutral red dye: controlled exchange of multiple guests.

PubMed

Shaikh, Mhejabeen; Choudhury, Sharmistha Dutta; Mohanty, Jyotirmayee; Bhasikuttan, Achikanath C; Pal, Haridas

2010-07-14

Interactions among macrocyclic hosts and dyes/drugs have been explored extensively for their direct usage in controlled uptake and release of large number of potential drug molecules. In this paper we report the non-covalent interaction of cucurbit[8]uril macrocycle (CB8) with a biologically important dye, neutral red, by absorption and fluorescence spectroscopy. A comparative analysis with the complexation behaviour of the dye with CB7, the lower homologue of CB8, indicates contrasting guest binding behaviour with significant changes in the photophysical characteristics of the dye. While CB7 interaction leads to a 1 ratio 1 stoichiometry resulting in approximately 6 fold enhancement in the fluorescence emission of the dye, CB8 displays signatures for a 1 ratio 2 host-guest stoichiometry with drastic reduction in the fluorescence emission. Apart from the evaluation of approximately 2 unit shift in the protolytic equilibrium on complexation (pK(a) shift), the measurements with tryptophan established a selective guest exchange to favour a co-localized dimer inside the CB8 cavity. In a protein medium (BSA), the 1 ratio 2 complex was converted to a 1 ratio 1 ratio 1 CB8-NRH(+)-BSA complex. The finding that NRH(+) can be transferred from CB8 to BSA, even though the binding constant for NRH(+)-CB8 is much higher than NRH(+)-BSA, is projected for a controlled slow release of NRH(+) towards BSA. Since the release and activity of drugs can be controlled by regulating the protolytic equilibrium, the macromolecular encapsulation and release of NRH(+) demonstrated here provide information relevant to host-guest based drug delivery systems and its applications.

Molecular mechanics approach for design and conformational studies of macrocyclic ligands

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

Rohini,; Akbar, Rifat; Kanungo, B. K., E-mail: b.kanungo@gmail.com

2015-08-28

Computational Chemistry has revolutionized way of viewing molecules at the quantum mechanical scale by allowing simulating various chemical scenarios that are not possible to study in a laboratory. The remarkable applications of computational chemistry have promoted to design and test of the effectiveness of various methods for searching the conformational space of highly flexible molecules. In this context, we conducted a series of optimization and conformational searches on macrocyclic based ligands, 9N3Me5Ox, (1,4,7-tris(5-methyl-8-hydroxyquinoline)-1,4,7-triazacyclononane) and 12N3Me5Ox, (1,5,9-tris(5-methyl-8-hydroxyquinoline)-1,5,9-triazacyclododecane) and studied their selectivity and coordination behavior with some lanthanide metal ions in molecular mechanics and semiempirical methods. The methods include both systematic andmore » random conformational searches for dihedral angles, torsion angles and Cartesian coordinates. Structural studies were carried out by using geometry optimization, coordination scans and electronic properties were evaluated. The results clearly show that chair-boat conformational isomer of 9N3Me5Ox ligand is more stable due to lower eclipsing ethane interaction and form stronger adduct complexes with lanthanide metal ion. This is because of the fact that, in a central unit of 9N3 of the ligand form six endo type bonds out of nine. The rest of bonds have trans conformation. In contrast, for the adduct of 12N3Me5Ox, two C-C bonds have on eclipsed conformation, and others have synclinal and antiperiplanar confirmations. The distortion of the two eclipsed conformations may affect the yields and the stability of the complexes.« less

Anthelmintic resistance in equine nematodes

PubMed Central

Matthews, Jacqueline B.

2014-01-01

Anthelmintics have been applied indiscriminately to control horse nematodes for over 40 years. Three broad-spectrum anthelmintic classes are currently registered for nematode control in horses: benzimidazoles (fenbendazole, oxibendazole), tetrahydropyrimidines (pyrantel) and macrocyclic lactones (ivermectin, moxidectin). Generally, control strategies have focused on nematode egg suppression regimens that involve the frequent application of anthelmintics to all horses at intervals based on strongyle egg reappearance periods after treatment. The widespread use of such programmes has substantially reduced clinical disease, especially that associated with large strongyle species; however, high treatment frequency has led to considerable selection pressure for anthelmintic resistance, particularly in cyathostomin species. Field studies published over the last decade indicate that benzimidazole resistance is widespread globally in cyathostomins and there are also many reports of resistance to pyrantel in these worms. Cyathostomin resistance to macrocyclic lactone compounds is emerging, principally measured as a reduction in strongyle egg reappearance time observed after treatment. Ivermectin resistance is a further concern in the small intestinal nematode, Parascaris equorum, an important pathogen of foals. These issues indicate that horse nematodes must now be controlled using methods less dependent on anthelmintic use and more reliant on management practices designed to reduce the force of infection in the environment. Such strategies include improved grazing management integrated with targeted anthelmintic administration involving faecal egg count (FEC)-directed treatments. The latter require that the supporting diagnostic tests available are robust and practically applicable. Recent research has focused on maximising the value of FEC analysis in horses and on optimizing protocols for anthelmintic efficacy testing. Other studies have sought to develop diagnostics that will help define levels of pre-patent infection. This review describes recent advances in each of these areas of research. PMID:25516842

Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour.

PubMed

Aldrich, J V; Senadheera, S N; Ross, N C; Reilley, K A; Ganno, M L; Eans, S E; Murray, T F; McLaughlin, J P

2014-07-01

The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. © 2014 The British Pharmacological Society.

Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour

PubMed Central

Aldrich, J V; Senadheera, S N; Ross, N C; Reilley, K A; Ganno, M L; Eans, S E; Murray, T F; McLaughlin, J P

2014-01-01

BACKGROUND AND PURPOSE The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACH The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTS The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28–4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. PMID:24588614

Synthesis, spectroscopic and biological activities studies of acyclic and macrocyclic mono and binuclear metal complexes containing a hard-soft Schiff base

NASA Astrophysics Data System (ADS)

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

Mono- and bi-nuclear acyclic and macrocyclic complexes with hard-soft Schiff base, H2L, ligand derived from the reaction of 4,6-diacetylresorcinol and thiocabohydrazide, in the molar ratio 1:2 have been prepared. The H2L ligand reacts with Co(II), Ni(II), Cu(II), Zn(II), Mn(II) and UO2(VI) nitrates, VO(IV) sulfate and Ru(III) chloride to get acyclic binuclear complexes except for VO(IV) and Ru(III) which gave acyclic mono-nuclear complexes. Reaction of the acyclic mono-nuclear VO(IV) and Ru(III) complexes with 4,6-diacetylresorcinol afforded the corresponding macrocyclic mono-nuclear VO(IV) and Ru(IIII) complexes. Template reactions of the 4,6-diacetylresorcinol and thiocarbohydrazide with either VO(IV) or Ru(III) salts afforded the macrocyclic binuclear VO(IV) and Ru(III) complexes. The Schiff base, H2L, ligand acts as dibasic with two NSO-tridentate sites and can coordinate with two metal ions to form binuclear complexes after the deprotonation of the hydrogen atoms of the phenolic groups in all the complexes, except in the case of the acyclic mononuclear Ru(III) and VO(IV) complexes, where the Schiff base behaves as neutral tetradentate chelate with N2S2 donor atoms. The ligands and the metal complexes were characterized by elemental analysis, IR, UV-vis 1H-NMR, thermal gravimetric analysis (TGA) and ESR, as well as the measurements of conductivity and magnetic moments at room temperature. Electronic spectra and magnetic moments of the complexes indicate the geometries of the metal centers are either tetrahedral, square planar or octahedral. Kinetic and thermodynamic parameters were calculated using Coats-Redfern equation, for the different thermal decomposition steps of the complexes. The ligands and the metal complexes were screened for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria, and Pseudomonas fluorescens as Gram-negative bacteria in addition to Fusarium oxysporum fungus. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

Safety and clinical efficacy of tenvermectin, a novel antiparasitic 16-membered macrocyclic lactone antibiotics.

PubMed

Fei, Chenzhong; She, Rufeng; Li, Guiyu; Zhang, Lifang; Fan, Wushun; Xia, Suhan; Xue, Feiqun

2018-05-30

Tenvermectin (TVM) is a novel 16-membered macrocyclic lactone antibiotics, which contains component TVM A and TVM B. However there is not any report on safety and clinical efficacy of TVM for developing as a potential drug. In order to understand the part of safety and clinical efficacy of TVM, we conducted the acute toxicity test, the standard bacterial reverse mutation (Ames) test and the clinical deworming test. In the acute toxicity studies, TVM, TVM A and ivermectin (IVM) were administrated once by oral gavage to mice and rats. Results showed that the oral LD 50 values of TVM, TVM A and IVM in mice were 74.41, 106.95 and 53.06 mg/kg respectively. The oral LD 50 values of TVM and TVM A in rats were determined to be 164.22 and 749.34 mg/kg respectively. TVM and IVM are moderately toxic substances, meanwhile the TVM A belongs to low toxic compounds, implying that the acute toxicity is highly related to the length of side chain of TVM at position C25. In the Ames test, results showed that TVM did not induce mutagenicity in Salmonella typhimurium TA97a, TA98, TA100, TA102 and TA1535 with and without metabolic activation system, speculating that the mutagenicity is probably not related to the side chain at position C25 of 16-membered macrocyclic lactone antibiotics. In the efficacy trail of TVM against swine nematodes, growing pigs natural infection of Ascaris suum and Trichuris suis were treated with a single subcutaneous injection 0.3 mg/kg b.w.. Results showed that TVM and IVM had excellent effect in expelling Ascaris suum, and TVM had potential efficacy against Trichuris suis, however IVM had no effect on Trichuris suis. This study suggests that the side chain of TVM at position C25 may have important biological functions, which is one of the key sites of the studies on structure-activity relationship of 16-membered macrocyclic lactone compounds. TVM is a new compound exhibited some advantages worthy of developing. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterisation of P-glycoprotein-9.1 in Haemonchus contortus.

PubMed

Godoy, Pablo; Che, Hua; Beech, Robin N; Prichard, Roger K

2016-01-28

The existence nematodes of veterinary importance such as Haemonchus contortus resistant to anthelmintic drugs, including the macrocyclic lactones, has become a major concern in animal health. Macrocyclic lactone resistance in H. contortus seems to be multigenic including the active efflux of these drugs by P-glycoproteins, members of the ABC transporter family, present in this parasite. The goals of the present work were to determine the activity of H. contortus P-glycoprotein 9.1 (Hco-PGP-9.1) and its interaction with the avermectins, ivermectin, abamectin, and also the milbemycin, moxidectin. Additionally, the localisation of Hco-PGP-9.1 was sought in adult worms. Hco-Pgp-9.1 was cloned and expressed in mammalian cells and its expression profile was determined at the transcriptional and protein level by qRT-PCR and Western-blot, respectively. The nematode transport activity was assessed using the tracer dye Rhodamine 123. A ligand competition assay between different macrocyclic lactones and Rhodamine 123 was used to establish whether or not there was interaction between Hco-PGP-9.1 and the avermectins (abamectin and ivermectin) or moxidectin. In addition, immunostaining was carried out to localise Hco-PGP-9.1 expression in the transgenic cells and in adult female parasites. Hco-PGP-9.1 was expressed in the cell membrane of the transfected host cells and was able to extrude Rhodamine 123. Ivermectin and abamectin, but not moxidectin, had a pronounced inhibitory effect on the ability of Hco-PGP-9.1 to transport Rhodamine 123. Antibodies raised against Hco-PGP-9.1 epitopes localised to the uterus of adult female H. contortus. These results suggest a strong interaction of the avermectins with Hco-PGP-9.1. However, possibly due to its physico-chemical properties, moxidectin had markedly less effect on Hco-PGP-9.1. Because of the greater interaction of the avermectins than moxidectin with this transporter, it is more likely to contribute to avermectin resistance than to moxidectin resistance in H. contortus. Possible over expression of Hco-PGP-9.1 in the female reproductive system in resistant worms could reduce paralysis of the uterus by macrocyclic lactones, allowing continued egg release in drug challenged resistant worms.

Synthesis, spectroscopic and biological activities studies of acyclic and macrocyclic mono and binuclear metal complexes containing a hard-soft Schiff base.

PubMed

Abou-Hussein, Azza A A; Linert, Wolfgang

2012-09-01

Mono- and bi-nuclear acyclic and macrocyclic complexes with hard-soft Schiff base, H(2)L, ligand derived from the reaction of 4,6-diacetylresorcinol and thiocabohydrazide, in the molar ratio 1:2 have been prepared. The H(2)L ligand reacts with Co(II), Ni(II), Cu(II), Zn(II), Mn(II) and UO(2)(VI) nitrates, VO(IV) sulfate and Ru(III) chloride to get acyclic binuclear complexes except for VO(IV) and Ru(III) which gave acyclic mono-nuclear complexes. Reaction of the acyclic mono-nuclear VO(IV) and Ru(III) complexes with 4,6-diacetylresorcinol afforded the corresponding macrocyclic mono-nuclear VO(IV) and Ru(IIII) complexes. Template reactions of the 4,6-diacetylresorcinol and thiocarbohydrazide with either VO(IV) or Ru(III) salts afforded the macrocyclic binuclear VO(IV) and Ru(III) complexes. The Schiff base, H(2)L, ligand acts as dibasic with two NSO-tridentate sites and can coordinate with two metal ions to form binuclear complexes after the deprotonation of the hydrogen atoms of the phenolic groups in all the complexes, except in the case of the acyclic mononuclear Ru(III) and VO(IV) complexes, where the Schiff base behaves as neutral tetradentate chelate with N(2)S(2) donor atoms. The ligands and the metal complexes were characterized by elemental analysis, IR, UV-vis (1)H-NMR, thermal gravimetric analysis (TGA) and ESR, as well as the measurements of conductivity and magnetic moments at room temperature. Electronic spectra and magnetic moments of the complexes indicate the geometries of the metal centers are either tetrahedral, square planar or octahedral. Kinetic and thermodynamic parameters were calculated using Coats-Redfern equation, for the different thermal decomposition steps of the complexes. The ligands and the metal complexes were screened for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria, and Pseudomonas fluorescens as Gram-negative bacteria in addition to Fusarium oxysporum fungus. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms. Copyright © 2012 Elsevier B.V. All rights reserved.

Selection on skewed characters and the paradox of stasis

PubMed Central

Bonamour, Suzanne; Teplitsky, Céline; Charmantier, Anne; Crochet, Pierre-André; Chevin, Luis-Miguel

2018-01-01

Observed phenotypic responses to selection in the wild often differ from predictions based on measurements of selection and genetic variance. An overlooked hypothesis to explain this paradox of stasis is that a skewed phenotypic distribution affects natural selection and evolution. We show through mathematical modelling that, when a trait selected for an optimum phenotype has a skewed distribution, directional selection is detected even at evolutionary equilibrium, where it causes no change in the mean phenotype. When environmental effects are skewed, Lande and Arnold’s (1983) directional gradient is in the direction opposite to the skew. In contrast, skewed breeding values can displace the mean phenotype from the optimum, causing directional selection in the direction of the skew. These effects can be partitioned out using alternative selection estimates based on average derivatives of individual relative fitness, or additive genetic covariances between relative fitness and trait (Robertson-Price identity). We assess the validity of these predictions using simulations of selection estimation under moderate samples size. Ecologically relevant traits may commonly have skewed distributions, as we here exemplify with avian laying date – repeatedly described as more evolutionarily stable than expected –, so this skewness should be accounted for when investigating evolutionary dynamics in the wild. PMID:28921508

[Studies on technology optimization for extracting triterpenoid saponins from Picria felterrae by multi-target grading method].

PubMed

Fang, Hong; Ning, De-sheng; Liang, Xiao-yan

2009-12-01

To study the optimum extraction conditions of triterpenoid saponins from Picria felterrae. The optimum extraction conditions were investigated by the contents of the total glycosides and picfeltarraenine I A and I B, using orthogonal test. The optimum extraction conditions were as follows: using 70% alcohol of 19 times than the amount of original material soaking 3 hours, extracting twice with hot reflux method at 80 degrees C, 3h the first time, 1 h the second time. The selected extraction conditions are convenient and practical with high accuracy, and could be used as a reference for industrial production.

Structural adhesives for missile external protection material

NASA Astrophysics Data System (ADS)

Banta, F. L.; Garzolini, J. A.

1981-07-01

Two basic rubber materials are examined as possible external substrate protection materials (EPM) for missiles. The analysis provided a data base for selection of the optimum adhesives which are compatible with the substrate, loads applied and predicted bondline temperatures. Under the test conditions, EA934/NA was found to be the optimum adhesive to bond VAMAC 2273 and/or NBR/EPDM 9969A to aluminum substrate. The optimum adhesive for composite structures was EA956. Both of these adhesives are two-part epoxy systems with a pot life of approximately two hours. Further research is suggested on field repair criteria, nuclear hardness and survivability effects on bondline, and ageing effects.

A macrocyclic ligand as receptor and Zn(II)-complex receptor for anions in water: binding properties and crystal structures.

PubMed

Ambrosi, Gianluca; Formica, Mauro; Fusi, Vieri; Giorgi, Luca; Macedi, Eleonora; Micheloni, Mauro; Paoli, Paola; Pontellini, Roberto; Rossi, Patrizia

2011-02-01

Binding properties of 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Δ(5,8),Δ(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecularly imprinted cavities template the macrocyclization of tetrapeptides.

PubMed

Tai, Dar-Fu; Lin, Yee-Fung

2008-11-21

Cavities formed using cyclic tetrapeptides (CTPs) or heat-induced conformers act as templates for cyclization; the cavities bind to linear tetrapeptides and enforce turn conformations to enhance cyclization to constrained CTPs.

Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products.

PubMed

Villadsen, Nikolaj L; Jacobsen, Kristian M; Keiding, Ulrik B; Weibel, Esben T; Christiansen, Bjørn; Vosegaard, Thomas; Bjerring, Morten; Jensen, Frank; Johannsen, Mogens; Tørring, Thomas; Poulsen, Thomas B

2017-03-01

Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.

Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

NASA Astrophysics Data System (ADS)

Villadsen, Nikolaj L.; Jacobsen, Kristian M.; Keiding, Ulrik B.; Weibel, Esben T.; Christiansen, Bjørn; Vosegaard, Thomas; Bjerring, Morten; Jensen, Frank; Johannsen, Mogens; Tørring, Thomas; Poulsen, Thomas B.

2017-03-01

Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli*

PubMed Central

Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H.; Pessi, Gabriella; Eberl, Leo; Robinson, John A.

2016-01-01

Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM. PMID:26627837

Evaluation of inbreeding in laying hens by applying optimum genetic contribution and gene flow theory.

PubMed

König, S; Tsehay, F; Sitzenstock, F; von Borstel, U U; Schmutz, M; Preisinger, R; Simianer, H

2010-04-01

Due to consistent increases of inbreeding of on average 0.95% per generation in layer populations, selection tools should consider both genetic gain and genetic relationships in the long term. The optimum genetic contribution theory using official estimated breeding values for egg production was applied for 3 different lines of a layer breeding program to find the optimal allocations of hens and sires. Constraints in different scenarios encompassed restrictions related to additive genetic relationships, the increase of inbreeding, the number of selected sires and hens, and the number of selected offspring per mating. All these constraints enabled higher genetic gain up to 10.9% at the same level of additive genetic relationships or in lower relationships at the same gain when compared with conventional selection schemes ignoring relationships. Increases of inbreeding and genetic gain were associated with the number of selected sires. For the lowest level of the allowed average relationship at 10%, the optimal number of sires was 70 and the estimated breeding value for egg production of the selected group was 127.9. At the highest relationship constraint (16%), the optimal number of sires decreased to 15, and the average genetic value increased to 139.7. Contributions from selected sires and hens were used to develop specific mating plans to minimize inbreeding in the following generation by applying a simulated annealing algorithm. The additional reduction of average additive genetic relationships for matings was up to 44.9%. An innovative deterministic approach to estimate kinship coefficients between and within defined selection groups based on gene flow theory was applied to compare increases of inbreeding from random matings with layer populations undergoing selection. Large differences in rates of inbreeding were found, and they underline the necessity to establish selection tools controlling long-term relationships. Furthermore, it was suggested to use optimum genetic contribution theory for conservation schemes or, for example, the experimental line in our study.

Study on the optimum PCM melting temperature for energy savings in residential buildings worldwide

NASA Astrophysics Data System (ADS)

Saffari, M.; de Gracia, A.; Fernández, C.; Zsembinszki, G.; Cabeza, L. F.

2017-10-01

To maintain comfort conditions in residential buildings along a full year period, the use of active systems is generally required to either supply heating or cooling. The heating and cooling demands strongly depend on the climatic conditions, type of building and occupants’ behaviour. The overall annual energy consumption of the building can be reduced by the use of renewable energy sources and/or passive systems. The use of phase change materials (PCM) as passive systems in buildings enhances the thermal mass of the envelope, and reduces the indoor temperature fluctuations. As a consequence, the overall energy consumption of the building is generally lower as compared to the case when no PCM systems are used. The selection of the PCM melting temperature is a key issue to reduce the energy consumption of the buildings. The main focus of this study is to determine the optimum PCM melting temperature for passive heating and cooling according to different weather conditions. To achieve that, numerical simulations were carried out using EnergyPlus v8.4 coupled with GenOpt® v3.1.1 (a generic optimization software). A multi-family residential apartment was selected from ASHRAE Standard 90.1- 2013 prototype building model, and different climate conditions were considered to determine the optimum melting temperature (in the range from 20ºC to 26ºC) of the PCM contained in gypsum panels. The results confirm that the optimum melting temperature of the PCM strongly depends on the climatic conditions. In general, in cooling dominant climates the optimum PCM temperature is around 26ºC, while in heating dominant climates it is around 20ºC. Furthermore, the results show that an adequate selection of the PCM as passive system in building envelope can provide important energy savings for both heating dominant and cooling dominant regions.

Second symposium on macrocyclic compounds

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

Izatt, R.M.; Christensen, J.J.

1978-01-01

Forty papers were presented at the sumposium under five session headings: inorganic reactions, industrial applications, biological and biochemistry, organic synthesis and reactions, and thermodynamics and kinetics. Abstracts of these papers are included in this document. (DLC)

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor.

PubMed

Rhaman, Md Mhahabubur; Powell, Douglas R; Hossain, Md Alamgir

2017-11-30

Understanding the intermolecular interactions between nucleotides and artificial receptors is crucial to understanding the role of nucleic acids in living systems. However, direct structural evidence showing precise interactions and bonding features of a nucleoside monophosphate (NMP) with a macrocycle-based synthetic molecule has not been provided so far. Herein, we present two novel crystal structures of uridine monophosphate (UMP) and thymidine monophosphate (TMP) complexes with a macrocycle-based dinuclear receptor. Structural characterization of these complexes reveals that the receptor recognizes UMP through coordinate-covalent interactions with phosphates and π-π stackings with nucleobases and TMP through coordinate-covalent interactions with phosphate groups. Furthermore, the receptor has been shown to effectively bind nucleoside monophosphates in the order of GMP > AMP > UMP > TMP > CMP in water at physiological pH, as investigated by an indicator displacement assay.

Photochemistry of copper(II) complexes with macrocyclic amine ligands

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

Muralidharan, S.; Ferraudi, G.

1981-07-01

The photochemical properties of Cu(dl-Me/sub 6/(14)aneN/sub 4/)/sup 2 +/ and Cu(rac-Me/sub 6/(14)aneN/sub 4/)/sup 2 +/ in the presence and absence of axially coordinated ligands have been investigated by continuous and flash irradiations. Flash photolysis of the complexes in deaerated aqueous solutions revealed the presence of copper-ligand radical complexes with closed- and open-cycle ligands. Flash photolysis of methanolic solutions of the complexes, in the presence of halides and pseudohalides, shows Cu(III) macrocyclic intermediates. The experimental observations can be explained in terms of two primary photoprocesses with origins in distinctive charge transfer to metal states. These states have been assigned as aminomore » to copper(II) charge-transfer state and acido to copper(II) charge-transfer state.« less

Kinetically and thermodynamically stable isomers of thorium chelates of polyaza polycarboxylic macrocycles

NASA Astrophysics Data System (ADS)

Jacques, Vincent; Desreux, Jean F.

1994-10-01

The solution conformation of the thorium(IV) complexes of two polyaza polycarboxylic macrocycles, DOTA and HEHA (1,4,7,10-tetraazacyclododecane-N, N', N(double prime), N(triple prime)-tetraacetic acid and 1,4,7,10,13,16-hexaazacyclooctadecane-N, N', N(double prime), N(triple prime), N(double prime)(double prime), N(double prime)(triple prime)-hexaacetic acid), was investigated by one- and two-dimensional nuclear magnetic resonance spectroscopy. ThHEHA(2+) forms a kinetically stable topomer of C2 symmetry and a thermodynamically stable topomer of S6 symmetry. Both complexes are assigned an icosahedral geometry. The activation energy for the intermolecular exchange is very high (214 kJ/mol). The behavior of ThHEHA(2+) contrasts with the properties of the other Th(IV) chelates that are known to be fluxional.

Design, synthesis and characterization of macrocyclic ligand based transition metal complexes of Ni(II), Cu(II) and Co(II) with their antimicrobial and antioxidant evaluation

NASA Astrophysics Data System (ADS)

Gull, Parveez; Malik, Manzoor Ahmad; Dar, Ovas Ahmad; Hashmi, Athar Adil

2017-04-01

Three new complexes Ni(II), Cu(II) and Co(II) were synthesized of macrocyclic ligand derived from 1, 4-dicarbonyl-phenyl-dihydrazide and O-phthalaldehyde in the ratio of 2:2. The synthesized compounds were characterized by elemental analyses, molar conductance, magnetic susceptibility measurements, FTIR, UV-Vis., Mass and 1H NMR spectral studies. The electronic spectra of the metal complexes indicate a six coordinate octahedral geometry of the central metal ion. These metal complexes and the ligand were evaluated for antimicrobial activity against bacteria (E. coli, B. subtilis, S. aureus) and fungi (A. niger, A. flavus, C. albicans) and compared against standard drugs chloramphenicol and nystatin respectively. In addition, the antioxidant activity of the compounds was also investigated through scavenging effect on DPPH radicals.

Pyrrole-Based Macrocyclic Small-Molecule Inhibitors That Target Oocyte Maturation.

PubMed

Gunasekaran, Pethaiah; Lee, So-Rim; Jeong, Seung-Min; Kwon, Jeong-Woo; Takei, Toshiki; Asahina, Yuya; Bang, Geul; Kim, Seongnyeon; Ahn, Mija; Ryu, Eun Kyung; Kim, Hak Nam; Nam, Ki-Yub; Shin, Song Yub; Hojo, Hironobu; Namgoong, Suk; Kim, Nam-Hyung; Bang, Jeong Kyu

2017-04-20

Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic compound AB103-8, which targets the polo box domain (PBD) of PLK1, affects oocyte meiotic maturation and the resumption of meiosis. However, to overcome the drawbacks of peptidic compounds, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and tested them for their effects on the rates of porcine oocyte maturation. Among them, the macrocyclic compound (E/Z)-3-(2,16-dioxo-19-(4-phenylbutyl)-3,19-diazabicyclo[15.2.1]icosa-1(20),6,17-trien-3-yl)propyl dihydrogen phosphate (4) showed the highest inhibitory activity with enhanced inhibition against embryonic blastocyst formation. Furthermore, the addition of this compound to culture media efficiently blocked the maturation of porcine and mouse oocytes, indicating its ability to penetrate the zona pellucida and cell membrane. We investigated mouse oocytes treated with compound 4, and the resulting impairment of spindle formation confirmed PLK1 inhibition. Finally, molecular modeling studies with PLK1 PBD also confirmed the presence of significant interactions between compound 4 and PLK1 PBD binding pocket residues, including those in the phosphate, tyrosine-rich, and pyrrolidine binding pockets. Collectively, these results suggest that the macrocyclic compound 4 may serve as a promising template for the development of novel contraceptive agents. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Guanidinium/ammonium competition and proton transfer in the interaction of the amino acid arginine with the tetracarboxylic 18-crown-6 ionophore.

PubMed

Avilés-Moreno, Juan Ramón; Berden, Giel; Oomens, Jos; Martínez-Haya, Bruno

2018-02-07

The recognition of arginine plays a central role in modern proteomics and genomics. Arginine is unique among natural amino acids due to the high basicity of its guanidinium side chain, which sustains specific interactions and proton exchange biochemical processes. The search for suitable macrocyclic ionophores constitutes a promising route towards the development of arginine receptors. This study evaluates the conformational features involved in the binding of free arginine by the polyether macrocycle (18-crown-6)-tetracarboxylic acid. Infrared action vibrational spectroscopy and quantum-chemical computations are combined to characterize the complexes with net charges +1 and +2. The spectrum of the +1 complex can be explained in terms of a configuration predominantly stabilized by a robust bidentate coordination of guanidinium with a carboxylate group formed from the deprotonation of one side group of the crown ether. The released proton is transferred to the amino terminus of arginine, which then coordinates with the crown ether ring. In an alternative type of conformation, partly consistent with experiment, the amino terminus is neutral and the guanidinium group inserts into the crown ether cavity. In the +2 complexes, arginine is always doubly protonated and the most stable conformations are characterized by a tripodal coordination of the ammonium -NH 3 + group of arginine with the oxygen atoms of the macrocycle ring, while the interactions of the amino acid with the side carboxylic acid groups of the crown ether acquire a remarkable lesser role.

Covalent lanthanide(III) macrocyclic complexes: the bonding nature and optical properties of a promising single antenna molecule.

PubMed

Rabanal-León, Walter A; Páez-Hernández, Dayán; Arratia-Pérez, Ramiro

2014-12-21

The present work is focused on the elucidation of the electronic structure, bonding nature and optical properties of a series of low symmetry (C2) coordination compounds of type [Ln(III)HAM](3+), where "Ln(III)" are the trivalent lanthanide ions: La(3+), Ce(3+), Eu(3+) and Lu(3+), while "HAM" is the neutral six-nitrogen donor macrocyclic ligand [C22N6H26]. This systematic study has been performed in the framework of the Relativistic Density Functional Theory (R-DFT) and also using a multi-reference approach via the Complete Active Space (CAS) wavefunction treatment with the aim of analyzing their ground state and excited state electronic structures as well as electronic correlation. Furthermore, the use of the energy decomposition scheme proposed by Morokuma-Ziegler and the electron localization function (ELF) allows us to characterize the bonding between the lanthanide ions and the macrocyclic ligand, obtaining as a result a dative-covalent interaction. Due to a great deal of lanthanide optical properties and their technological applications, the absorption spectra of this set of coordination compounds were calculated using the time-dependent density functional theory (TD-DFT), where the presence of the intense Ligand to Metal Charge Transfer (LMCT) bands in the ultraviolet and visible region and the inherent f-f electronic transitions in the Near-Infra Red (NIR) region for some lanthanide ions allow us to propose these systems as "single antenna molecules" with potential applications in NIR technologies.

Compositional Bias in Naïve and Chemically-modified Phage-Displayed Libraries uncovered by Paired-end Deep Sequencing.

PubMed

He, Bifang; Tjhung, Katrina F; Bennett, Nicholas J; Chou, Ying; Rau, Andrea; Huang, Jian; Derda, Ratmir

2018-01-19

Understanding the composition of a genetically-encoded (GE) library is instrumental to the success of ligand discovery. In this manuscript, we investigate the bias in GE-libraries of linear, macrocyclic and chemically post-translationally modified (cPTM) tetrapeptides displayed on the M13KE platform, which are produced via trinucleotide cassette synthesis (19 codons) and NNK-randomized codon. Differential enrichment of synthetic DNA {S}, ligated vector {L} (extension and ligation of synthetic DNA into the vector), naïve libraries {N} (transformation of the ligated vector into the bacteria followed by expression of the library for 4.5 hours to yield a "naïve" library), and libraries chemically modified by aldehyde ligation and cysteine macrocyclization {M} characterized by paired-end deep sequencing, detected a significant drop in diversity in {L} → {N}, but only a minor compositional difference in {S} → {L} and {N} → {M}. Libraries expressed at the N-terminus of phage protein pIII censored positively charged amino acids Arg and Lys; libraries expressed between pIII domains N1 and N2 overcame Arg/Lys-censorship but introduced new bias towards Gly and Ser. Interrogation of biases arising from cPTM by aldehyde ligation and cysteine macrocyclization unveiled censorship of sequences with Ser/Phe. Analogous analysis can be used to explore library diversity in new display platforms and optimize cPTM of these libraries.

Separation and characterization of metallosupramolecular libraries by ion mobility mass spectrometry.

PubMed

Li, Xiaopeng; Chan, Yi-Tsu; Casiano-Maldonado, Madalis; Yu, Jing; Carri, Gustavo A; Newkome, George R; Wesdemiotis, Chrys

2011-09-01

The self-assembly of Zn(II) ions and bis(terpyridine) (tpy) ligands carrying 120° or 180° angles between their metal binding sites was utilized to prepare metallosupramolecular libraries with the connectivity. These combinatorial libraries were separated and characterized by ion mobility mass spectrometry (IM MS) and tandem mass spectrometry (MS(2)). The 180°-angle building blocks generate exclusively linear complexes, which were used as standards to determine the architectures of the assemblies resulting from the 120°-angle ligands. The latter ligand geometry promotes the formation of macrocyclic hexamers, but other n-mers with smaller (n = 5) or larger ring sizes (n = 7-9) were identified as minor products, indicating that the angles in the bis(terpyridine) ligand and within the coordinative tpy-Zn(II)-tpy bonds are not as rigid, as previously believed. Macrocyclic and linear isomers were detected in penta- and heptameric assemblies; in the larger octa- and nonameric assemblies, ring-opened conformers with compact and folded geometries were observed in addition to linear extended and cyclic architectures. IM MS(2) experiments provided strong evidence that the macrocycles present in the libraries were already formed in solution, during the self-assembly process, not by dissociation of larger complexes in the gas phase. The IM MS/MS(2) methods provide a means to analyze, based on size and shape (architecture), supramolecular libraries that are not amenable to liquid chromatography, LC-MS, NMR, and/or X-ray techniques.

Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth.

PubMed

Mukhopadhyay, Archana; Hanold, Laura E; Thayele Purayil, Hamsa; Gisemba, Solomon A; Senadheera, Sanjeewa N; Aldrich, Jane V

2017-08-03

The oncoprotein c-Myc is often overexpressed in cancer cells, and the stability of this protein has major significance in deciding the fate of a cell. Thus, targeting c-Myc levels is an attractive approach for developing therapeutic agents for cancer treatment. In this study, we report the anti-cancer activity of the macrocyclic peptides [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) and the natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]). [D-Trp]CJ-15,208 reduced c-Myc protein levels in prostate cancer cells and decreased cell proliferation with IC 50 values ranging from 2.0 to 16 µM in multiple PC cell lines. [D-Trp]CJ-15,208 induced early and late apoptosis in PC-3 cells following 48 hours treatment, and growth arrest in the G2 cell cycle phase following both 24 and 48 hours treatment. Down regulation of c-Myc in PC-3 cells resulted in loss of sensitivity to [D-Trp]CJ-15,208 treatment, while overexpression of c-Myc in HEK-293 cells imparted sensitivity of these cells to [D-Trp]CJ-15,208 treatment. This macrocyclic tetrapeptide also regulated PP2A by reducing the levels of its phosphorylated form which regulates the stability of cellular c-Myc protein. Thus [D-Trp]CJ-15,208 represents a new lead compound for the potential development of an effective treatment of prostate cancer.

A crystalline sponge based on dispersive forces suitable for X-ray structure determination of included molecular guests† †Electronic supplementary information (ESI) available: Synthesis of macrocycle 3 together with characterization data. TGA and DSC traces. CIF files of all structures. Computational details and additional calculations. CCDC 1012389–1012397 and 1063714. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc01838b Click here for additional data file. Click here for additional data file.

PubMed Central

Sanna, Elena; Escudero-Adán, Eduardo C.; Bauzá, Antonio; Ballester, Pablo; Frontera, Antonio; Rotger, Carmen

2015-01-01

A crystalline porous material showing one-dimensional (1-D) rectangular micropores (12 × 9 Å2) has been assembled from a semirigid macrocyclic tetraimine and EtOAc as the templating agent. The 1-D nature of the material is intrinsic to the conformationally rigid structure of a macrocyclic sub-unit bearing four cyclohexylidene residues. The multiple dispersive forces established among the aliphatic residues glutted the 1-D channels and provided thermal stability to the material at temperatures below 160 °C. Upon removal of the template, the structure of the empty solid exhibited permanent microporosity (S BET = 342 m2 g–1). Being a true molecular sponge, the channel framework of this material allowed the inclusion of a variety of molecular sample guests without compromising its crystalline nature. Remarkably, this crystalline material enabled the structure determination by X-ray diffraction of the included molecules. Theoretical studies demonstrated the vital role played by the dispersive forces in the overall stabilization of the crystal packing. PMID:28757946

Initial basalt target site selection evaluation for the Mars penetrator drop test

NASA Technical Reports Server (NTRS)

Bunch, T. E.; Quaide, W. L.; Polkowski, G.

1976-01-01

Potential basalt target sites for an air drop penetrator test were described and the criteria involved in site selection were discussed. A summary of the background field geology and recommendations for optimum sites are also presented.

Guidelines for preliminary selection of the optimum interchange type for a specific location

DOT National Transportation Integrated Search

1999-01-01

In Virginia, when new construction or major reconstruction is planned, the current practice is for a location and design engineer to select the interchange type (diamond interchange, single-point urban interchange, trumpet interchange, full cloverlea...

Analytical network process based optimum cluster head selection in wireless sensor network.

PubMed

Farman, Haleem; Javed, Huma; Jan, Bilal; Ahmad, Jamil; Ali, Shaukat; Khalil, Falak Naz; Khan, Murad

2017-01-01

Wireless Sensor Networks (WSNs) are becoming ubiquitous in everyday life due to their applications in weather forecasting, surveillance, implantable sensors for health monitoring and other plethora of applications. WSN is equipped with hundreds and thousands of small sensor nodes. As the size of a sensor node decreases, critical issues such as limited energy, computation time and limited memory become even more highlighted. In such a case, network lifetime mainly depends on efficient use of available resources. Organizing nearby nodes into clusters make it convenient to efficiently manage each cluster as well as the overall network. In this paper, we extend our previous work of grid-based hybrid network deployment approach, in which merge and split technique has been proposed to construct network topology. Constructing topology through our proposed technique, in this paper we have used analytical network process (ANP) model for cluster head selection in WSN. Five distinct parameters: distance from nodes (DistNode), residual energy level (REL), distance from centroid (DistCent), number of times the node has been selected as cluster head (TCH) and merged node (MN) are considered for CH selection. The problem of CH selection based on these parameters is tackled as a multi criteria decision system, for which ANP method is used for optimum cluster head selection. Main contribution of this work is to check the applicability of ANP model for cluster head selection in WSN. In addition, sensitivity analysis is carried out to check the stability of alternatives (available candidate nodes) and their ranking for different scenarios. The simulation results show that the proposed method outperforms existing energy efficient clustering protocols in terms of optimum CH selection and minimizing CH reselection process that results in extending overall network lifetime. This paper analyzes that ANP method used for CH selection with better understanding of the dependencies of different components involved in the evaluation process.

Analytical network process based optimum cluster head selection in wireless sensor network

PubMed Central

Javed, Huma; Jan, Bilal; Ahmad, Jamil; Ali, Shaukat; Khalil, Falak Naz; Khan, Murad

2017-01-01

Wireless Sensor Networks (WSNs) are becoming ubiquitous in everyday life due to their applications in weather forecasting, surveillance, implantable sensors for health monitoring and other plethora of applications. WSN is equipped with hundreds and thousands of small sensor nodes. As the size of a sensor node decreases, critical issues such as limited energy, computation time and limited memory become even more highlighted. In such a case, network lifetime mainly depends on efficient use of available resources. Organizing nearby nodes into clusters make it convenient to efficiently manage each cluster as well as the overall network. In this paper, we extend our previous work of grid-based hybrid network deployment approach, in which merge and split technique has been proposed to construct network topology. Constructing topology through our proposed technique, in this paper we have used analytical network process (ANP) model for cluster head selection in WSN. Five distinct parameters: distance from nodes (DistNode), residual energy level (REL), distance from centroid (DistCent), number of times the node has been selected as cluster head (TCH) and merged node (MN) are considered for CH selection. The problem of CH selection based on these parameters is tackled as a multi criteria decision system, for which ANP method is used for optimum cluster head selection. Main contribution of this work is to check the applicability of ANP model for cluster head selection in WSN. In addition, sensitivity analysis is carried out to check the stability of alternatives (available candidate nodes) and their ranking for different scenarios. The simulation results show that the proposed method outperforms existing energy efficient clustering protocols in terms of optimum CH selection and minimizing CH reselection process that results in extending overall network lifetime. This paper analyzes that ANP method used for CH selection with better understanding of the dependencies of different components involved in the evaluation process. PMID:28719616

Emittance Theory for Cylindrical Fiber Selective Emitter

NASA Technical Reports Server (NTRS)

Chubb, Donald L.

1998-01-01

A fibrous rare earth selective emitter is approximated as an infinitely long cylinder. The spectral emittance, epsilon(lambda), is obtained by solving the radiative transfer equations with appropriate boundary conditions and uniform temperature. For optical depths, Kappa(R) = alpha(lambda)R, where alpha(lambda) is the extinction coefficient and R is the cylinder radius, greater than 1 the spectral emittance is nearly at its maximum value. There is an optimum cylinder radius, R(opt), for maximum emitter efficiency, eta(E). Values for R(opt) are strongly dependent on the number of emission bands of the material. The optimum radius decreases slowly with increasing emitter temperature, while the maximum efficiency and useful radiated power increase rapidly with increasing temperature.

Ecological constraint and the evolution of sexual dichromatism in darters.

PubMed

Bossu, Christen M; Near, Thomas J

2015-05-01

It is not known how environmental pressures and sexual selection interact to influence the evolution of extravagant male traits. Sexual and natural selection are often viewed as antagonistic forces shaping the evolution of visual signals, where conspicuousness is favored by sexual selection and crypsis is favored by natural selection. Although typically investigated independently, the interaction between natural and sexual selection remains poorly understood. Here, we investigate whether sexual dichromatism evolves stochastically, independent from, or in concert with habitat use in darters, a species-rich lineage of North American freshwater fish. We find the evolution of sexual dichromatism is coupled to habitat use in darter species. Comparative analyses reveal that mid-water darter lineages exhibit a narrow distribution of dichromatism trait space surrounding a low optimum, suggesting a constraint imposed on the evolution of dichromatism, potentially through predator-mediated selection. Alternatively, the transition to benthic habitats coincides with greater variability in the levels of dichromatism that surround a higher optimum, likely due to relaxation of the predator-mediated selection and heterogeneous microhabitat dependent selection regimes. These results suggest a complex interaction of sexual selection with potentially two mechanisms of natural selection, predation and sensory drive, that influence the evolution of diverse male nuptial coloration in darters. © 2015 The Author(s).

Improved heliostat field design for solar tower plants

NASA Astrophysics Data System (ADS)

Collado, Francisco J.; Guallar, Jesús

2017-06-01

In solar power tower (SPT) systems, selecting the optimum location of thousands of heliostats and the most profitable tower height and receiver size remains a challenge. Campo code is prepared for the detailed design of such plants in particular, the optimum layout, provided that the plant size is known. Therefore, less exhaustive codes, as DELSOL3, are also needed to perform preliminary parametric analysis that narrows the most economic size of the plant.

Digital Parallel Processor Array for Optimum Path Planning

NASA Technical Reports Server (NTRS)

Kremeny, Sabrina E. (Inventor); Fossum, Eric R. (Inventor); Nixon, Robert H. (Inventor)

1996-01-01

The invention computes the optimum path across a terrain or topology represented by an array of parallel processor cells interconnected between neighboring cells by links extending along different directions to the neighboring cells. Such an array is preferably implemented as a high-speed integrated circuit. The computation of the optimum path is accomplished by, in each cell, receiving stimulus signals from neighboring cells along corresponding directions, determining and storing the identity of a direction along which the first stimulus signal is received, broadcasting a subsequent stimulus signal to the neighboring cells after a predetermined delay time, whereby stimulus signals propagate throughout the array from a starting one of the cells. After propagation of the stimulus signal throughout the array, a master processor traces back from a selected destination cell to the starting cell along an optimum path of the cells in accordance with the identity of the directions stored in each of the cells.

The effect of crumb rubber particle size to the optimum binder content for open graded friction course.

PubMed

Ibrahim, Mohd Rasdan; Katman, Herda Yati; Karim, Mohamed Rehan; Koting, Suhana; Mashaan, Nuha S

2014-01-01

The main objective of this paper is to investigate the relations of rubber size, rubber content, and binder content in determination of optimum binder content for open graded friction course (OGFC). Mix gradation type B as specified in Specification for Porous Asphalt produced by the Road Engineering Association of Malaysia (REAM) was used in this study. Marshall specimens were prepared with four different sizes of rubber, namely, 20 mesh size [0.841 mm], 40 mesh [0.42 mm], 80 mesh [0.177 mm], and 100 mesh [0.149 mm] with different concentrations of rubberised bitumen (4%, 8%, and 12%) and different percentages of binder content (4%-7%). The appropriate optimum binder content is then selected according to the results of the air voids, binder draindown, and abrasion loss test. Test results found that crumb rubber particle size can affect the optimum binder content for OGFC.

Statistically Based Approach to Broadband Liner Design and Assessment

NASA Technical Reports Server (NTRS)

Jones, Michael G. (Inventor); Nark, Douglas M. (Inventor)

2016-01-01

A broadband liner design optimization includes utilizing in-duct attenuation predictions with a statistical fan source model to obtain optimum impedance spectra over a number of flow conditions for one or more liner locations in a bypass duct. The predicted optimum impedance information is then used with acoustic liner modeling tools to design liners having impedance spectra that most closely match the predicted optimum values. Design selection is based on an acceptance criterion that provides the ability to apply increasing weighting to specific frequencies and/or operating conditions. One or more broadband design approaches are utilized to produce a broadband liner that targets a full range of frequencies and operating conditions.

Parallel operation of NH3 screw compressors - the optimum way

NASA Astrophysics Data System (ADS)

Pijnenburg, B.; Ritmann, J.

2015-08-01

The use of more smaller industrial NH3 screw compressors operating in parallel seems to offer the optimum way when it comes to fulfilling maximum part load efficiency, increased redundancy and other highly requested features in the industrial refrigeration industry today. Parallel operation in an optimum way can be selected to secure continuous operation and can in most applications be configured to ensure lower overall operating economy. New compressors are developed to meet requirements for flexibility in operation and are controlled in an intelligent way. The intelligent control system keeps focus on all external demands, but yet striving to offer always the lowest possible absorbed power, including in future scenarios with connection to smart grid.

Approximate maximum likelihood decoding of block codes

NASA Technical Reports Server (NTRS)

Greenberger, H. J.

1979-01-01

Approximate maximum likelihood decoding algorithms, based upon selecting a small set of candidate code words with the aid of the estimated probability of error of each received symbol, can give performance close to optimum with a reasonable amount of computation. By combining the best features of various algorithms and taking care to perform each step as efficiently as possible, a decoding scheme was developed which can decode codes which have better performance than those presently in use and yet not require an unreasonable amount of computation. The discussion of the details and tradeoffs of presently known efficient optimum and near optimum decoding algorithms leads, naturally, to the one which embodies the best features of all of them.

Dynamic hybrid materials for constitutional self-instructed membranes

PubMed Central

Cazacu, Adinela; Legrand, Yves-Marie; Pasc, Andreea; Nasr, Gihane; Van der Lee, Arie; Mahon, Eugene; Barboiu, Mihail

2009-01-01

Constitutional self-instructed membranes were developed and used for mimicking the adaptive structural functionality of natural ion-channel systems. These membranes are based on dynamic hybrid materials in which the functional self-organized macrocycles are reversibly connected with the inorganic silica through hydrophobic noncovalent interactions. Supramolecular columnar ion-channel architectures can be generated by reversible confinement within scaffolding hydrophobic silica mesopores. They can be structurally determined by using X-ray diffraction and morphologically tuned by alkali-salts templating. From the conceptual point of view, these membranes express a synergistic adaptive behavior: the simultaneous binding of the fittest cation and its anion would be a case of “homotropic allosteric interactions,” because in time it increases the transport efficiency of the pore-contained superstructures by a selective evolving process toward the fittest ion channel. The hybrid membranes presented here represent dynamic constitutional systems evolving over time to form the fittest ion channels from a library of molecular and supramolecular components, or selecting the fittest ion pairs from a mixture of salts demonstrating flexible adaptation. PMID:19416909

Optimum Design of Aerospace Structural Components Using Neural Networks

NASA Technical Reports Server (NTRS)

Berke, L.; Patnaik, S. N.; Murthy, P. L. N.

1993-01-01

The application of artificial neural networks to capture structural design expertise is demonstrated. The principal advantage of a trained neural network is that it requires a trivial computational effort to produce an acceptable new design. For the class of problems addressed, the development of a conventional expert system would be extremely difficult. In the present effort, a structural optimization code with multiple nonlinear programming algorithms and an artificial neural network code NETS were used. A set of optimum designs for a ring and two aircraft wings for static and dynamic constraints were generated using the optimization codes. The optimum design data were processed to obtain input and output pairs, which were used to develop a trained artificial neural network using the code NETS. Optimum designs for new design conditions were predicted using the trained network. Neural net prediction of optimum designs was found to be satisfactory for the majority of the output design parameters. However, results from the present study indicate that caution must be exercised to ensure that all design variables are within selected error bounds.

Multi-Response Optimization of WEDM Process Parameters Using Taguchi Based Desirability Function Analysis

NASA Astrophysics Data System (ADS)

Majumder, Himadri; Maity, Kalipada

2018-03-01

Shape memory alloy has a unique capability to return to its original shape after physical deformation by applying heat or thermo-mechanical or magnetic load. In this experimental investigation, desirability function analysis (DFA), a multi-attribute decision making was utilized to find out the optimum input parameter setting during wire electrical discharge machining (WEDM) of Ni-Ti shape memory alloy. Four critical machining parameters, namely pulse on time (TON), pulse off time (TOFF), wire feed (WF) and wire tension (WT) were taken as machining inputs for the experiments to optimize three interconnected responses like cutting speed, kerf width, and surface roughness. Input parameter combination TON = 120 μs., TOFF = 55 μs., WF = 3 m/min. and WT = 8 kg-F were found to produce the optimum results. The optimum process parameters for each desired response were also attained using Taguchi’s signal-to-noise ratio. Confirmation test has been done to validate the optimum machining parameter combination which affirmed DFA was a competent approach to select optimum input parameters for the ideal response quality for WEDM of Ni-Ti shape memory alloy.

Selection on skewed characters and the paradox of stasis.

PubMed

Bonamour, Suzanne; Teplitsky, Céline; Charmantier, Anne; Crochet, Pierre-André; Chevin, Luis-Miguel

2017-11-01

Observed phenotypic responses to selection in the wild often differ from predictions based on measurements of selection and genetic variance. An overlooked hypothesis to explain this paradox of stasis is that a skewed phenotypic distribution affects natural selection and evolution. We show through mathematical modeling that, when a trait selected for an optimum phenotype has a skewed distribution, directional selection is detected even at evolutionary equilibrium, where it causes no change in the mean phenotype. When environmental effects are skewed, Lande and Arnold's (1983) directional gradient is in the direction opposite to the skew. In contrast, skewed breeding values can displace the mean phenotype from the optimum, causing directional selection in the direction of the skew. These effects can be partitioned out using alternative selection estimates based on average derivatives of individual relative fitness, or additive genetic covariances between relative fitness and trait (Robertson-Price identity). We assess the validity of these predictions using simulations of selection estimation under moderate sample sizes. Ecologically relevant traits may commonly have skewed distributions, as we here exemplify with avian laying date - repeatedly described as more evolutionarily stable than expected - so this skewness should be accounted for when investigating evolutionary dynamics in the wild. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Formal Synthesis of (±)-Roseophilin

PubMed Central

Bitar, Abdallah Y.; Frontier, Alison J.

2009-01-01

A formal synthesis of (±)-roseophilin is described. Scandium(III)-catalyzed Nazarov cyclization of 2,5-disubstituted N-tosylpyrrole 19 gives a 5,5’-fused ketopyrrole, and ansa-bridge formation via π-allyl palladium macrocyclization gives 21. PMID:19053717

Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.

PubMed

Sawada, Hiromi; Onoda, Kenji; Morita, Daichi; Ishitsubo, Erika; Matsuno, Kenji; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

2013-12-15

We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands.

PubMed

Das, Samir; Nag, Arundhati; Liang, JingXin; Bunck, David N; Umeda, Aiko; Farrow, Blake; Coppock, Matthew B; Sarkes, Deborah A; Finch, Amethist S; Agnew, Heather D; Pitram, Suresh; Lai, Bert; Yu, Mary Beth; Museth, A Katrine; Deyle, Kaycie M; Lepe, Bianca; Rodriguez-Rivera, Frances P; McCarthy, Amy; Alvarez-Villalonga, Belen; Chen, Ann; Heath, John; Stratis-Cullum, Dimitra N; Heath, James R

2015-11-02

We describe a general synthetic strategy for developing high-affinity peptide binders against specific epitopes of challenging protein biomarkers. The epitope of interest is synthesized as a polypeptide, with a detection biotin tag and a strategically placed azide (or alkyne) presenting amino acid. This synthetic epitope (SynEp) is incubated with a library of complementary alkyne or azide presenting peptides. Library elements that bind the SynEp in the correct orientation undergo the Huisgen cycloaddition, and are covalently linked to the SynEp. Hit peptides are tested against the full-length protein to identify the best binder. We describe development of epitope-targeted linear or macrocycle peptide ligands against 12 different diagnostic or therapeutic analytes. The general epitope targeting capability for these low molecular weight synthetic ligands enables a range of therapeutic and diagnostic applications, similar to those of monoclonal antibodies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular modelling, spectroscopic characterization and biological studies of tetraazamacrocyclic metal complexes

NASA Astrophysics Data System (ADS)

Rathi, Parveen; Sharma, Kavita; Singh, Dharam Pal

2014-09-01

Macrocyclic complexes of the type [MLX]X2; where L is (C30H28N4), a macrocyclic ligand, M = Cr(III) and Fe(III) and X = Cl-, CH3COO- or NO3-, have been synthesized by template condensation reaction of 1,8-diaminonaphthalene and acetylacetone in the presence of trivalent metal salts in a methanolic medium. The complexes have been formulated as [MLX]X2 due to 1:2 electrolytic nature of these complexes. The complexes have been characterized with the help of elemental analyses, molar conductance measurements, magnetic susceptibility measurements, electronic, infrared, far infrared, Mass spectral studies and molecular modelling. Molecular weight of these complexes indicates their monomeric nature. On the basis of all these studies, a five coordinated square pyramidal geometry has been proposed for all these complexes. These metal complexes have also been screened for their in vitro antimicrobial activities.

Supramolecular Assembly of Uridine Monophosphate (UMP) and Thymidine Monophosphate (TMP) with a Dinuclear Copper(II) Receptor

PubMed Central

2017-01-01

Understanding the intermolecular interactions between nucleotides and artificial receptors is crucial to understanding the role of nucleic acids in living systems. However, direct structural evidence showing precise interactions and bonding features of a nucleoside monophosphate (NMP) with a macrocycle-based synthetic molecule has not been provided so far. Herein, we present two novel crystal structures of uridine monophosphate (UMP) and thymidine monophosphate (TMP) complexes with a macrocycle-based dinuclear receptor. Structural characterization of these complexes reveals that the receptor recognizes UMP through coordinate–covalent interactions with phosphates and π–π stackings with nucleobases and TMP through coordinate–covalent interactions with phosphate groups. Furthermore, the receptor has been shown to effectively bind nucleoside monophosphates in the order of GMP > AMP > UMP > TMP > CMP in water at physiological pH, as investigated by an indicator displacement assay. PMID:29214233

Comparison between the electrocatalytic properties of different metal ion phthalocyanines and porphyrins towards the oxidation of hydroxide.

PubMed

De Wael, Karolien; Adriaens, Annemie

2008-02-15

This work reports on the electrocatalytic oxidation of hydroxide using different central metal ion phthalocyanines and porphyrins immobilized on gold electrodes. The apparent electrocatalytic activity of cobalt phthalocyanine or porphyrin modified electrodes was found to be the greatest among the present series of metal ion macrocycles investigated. Copper and unmetallated phthalocyanine or porphyrin modified electrodes show no electrocatalytic behaviour towards hydroxide, such as bare gold. A possible mechanism for the enhanced reactivity of cobalt ion macrocycles towards the oxygen evolution is given. It is also stated that the electrocatalytic activity towards an adsorbate involves several aspects, such as the coordination state of the central metal ion, the nature of the ligand, the stability of the complexes, the number of d electrons, the energy of orbitals and the strength of the bonding between the central metal ion and the axial ligand.

White Light Emission from Cucurbituril-Based Host-Guest Interaction in the Solid State: New Function of the Macrocyclic Host.

PubMed

Xia, Yu; Chen, Shiyan; Ni, Xin-Long

2018-04-18

Energy transfer and interchange are central for fabricating white light-emitting organic materials. However, increasing the efficiency of light energy transfer remains a considerable challenge because of the occurrence of "cross talk". In this work, by exploiting the unique photophysical properties of cucurbituril-triggered host-guest interactions, the two complementary luminescent colors blue and yellow for white light emission were independently obtained from a single fluorophore dye rather than energy transfer. Further study suggested that the rigid cavity of cucurbiturils efficiently prevented the aggregation of the dye and improved its thermal stability in the solid state by providing a regular nanosized fence for each encapsulated dye molecule. As a result, a novel macrocycle-assisted supramolecular approach for obtaining solid, white light-emitting organic materials with low cost, high efficiency, and easy scale-up was successfully demonstrated.

Elucidation of the biosynthesis of the methane catalyst coenzyme F430

PubMed Central

Moore, Simon J.; Sowa, Sven T.; Schuchardt, Christopher; Deery, Evelyne; Lawrence, Andrew D.; Ramos, José Vazquez; Billig, Susan; Birkemeyer, Claudia; Chivers, Peter T.; Howard, Mark J.; Rigby, Stephen E. J.; Layer, Gunhild; Warren, Martin J.

2017-01-01

Summary Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilisation of methane through anaerobic methane oxidation. The enzyme employs an ancillary factor called coenzyme F430, a nickel-containing modified tetrapyrrole that promotes catalysis through a novel methyl radical/Ni(II)-thiolate intermediate. However, the biosynthesis of coenzyme F430 from the common primogenitor uroporphyrinoge III, incorporating 11 steric centres into the macrocycle, has remained poorly understood although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamisation and carbocyclic ring formation. We have now identified the proteins that catalyse coenzyme F430 biosynthesis from sirohydrochlorin, termed CfbA-E, and shown their activity. The research completes our understanding of how nature is able to construct its repertoire of tetrapyrrole-based life pigments, permitting the development of recombinant systems to utilise these metalloprosthetic groups more widely. PMID:28225763

In Situ Cyclization of Native Proteins: Structure-Based Design of a Bicyclic Enzyme.

PubMed

Pelay-Gimeno, Marta; Bange, Tanja; Hennig, Sven; Grossmann, Tom N

2018-05-30

Increased tolerance of enzymes towards thermal and chemical stress is required for many applications and can be achieved by macrocyclization of the enzyme resulting in the stabilizing of its tertiary structure. So far, macrocyclization approaches utilize a very limited structural diversity which complicates the design process. Here, we report an approach that enables cyclization via the installation of modular crosslinks into native proteins composed entirely of proteinogenic amino acids. Our stabilization procedure involves the introduction of three surface exposed cysteines which are reacted with a triselectrophile resulting in the in situ cylization of the protein (INCYPRO). A bicyclic version of Sortase A was designed exhibiting increased tolerance towards thermal as well as chemical denaturation, and proved efficient in protein labeling under denaturing conditions. In addition, we applied INCYPRO to the KIX domain resulting in up to 24 °C increased thermal stability. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Control of the orientation and photoinduced phase transitions of macrocyclic azobenzene.

PubMed

Uchida, Emi; Sakaki, Kouji; Nakamura, Yumiko; Azumi, Reiko; Hirai, Yuki; Akiyama, Haruhisa; Yoshida, Masaru; Norikane, Yasuo

2013-12-16

Photoinduced phase transitions caused by photochromic reactions bring about a change in the state of matter at constant temperature. Herein, we report the photoinduced phase transitions of crystals of a photoresponsive macrocyclic compound bearing two azobenzene groups (1) at room temperature on irradiation with UV (365 nm) and visible (436 nm) light. The trans/trans isomer undergoes photoinduced phase transitions (crystal-isotropic phase-crystal) on UV light irradiation. The photochemically generated crystal exhibited reversible phase transitions between the crystal and the mesophase on UV and visible light irradiation. The molecular order of the randomly oriented crystals could be increased by irradiating with linearly polarized visible light, and the value of the order parameter was determined to be -0.84. Heating enhances the thermal cis-to-trans isomerization and subsequent cooling returned crystals of the trans/trans isomer. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Supramolecular macrocycles reversibly assembled by Te…O chalcogen bonding

PubMed Central

Ho, Peter C.; Szydlowski, Patrick; Sinclair, Jocelyn; Elder, Philip J. W.; Kübel, Joachim; Gendy, Chris; Lee, Lucia Myongwon; Jenkins, Hilary; Britten, James F.; Morim, Derek R.; Vargas-Baca, Ignacio

2016-01-01

Organic molecules with heavy main-group elements frequently form supramolecular links to electron-rich centres. One particular case of such interactions is halogen bonding. Most studies of this phenomenon have been concerned with either dimers or infinitely extended structures (polymers and lattices) but well-defined cyclic structures remain elusive. Here we present oligomeric aggregates of heterocycles that are linked by chalcogen-centered interactions and behave as genuine macrocyclic species. The molecules of 3-methyl-5-phenyl-1,2-tellurazole 2-oxide assemble a variety of supramolecular aggregates that includes cyclic tetramers and hexamers, as well as a helical polymer. In all these aggregates, the building blocks are connected by Te…O–N bridges. Nuclear magnetic resonance spectroscopic experiments demonstrate that the two types of annular aggregates are persistent in solution. These self-assembled structures form coordination complexes with transition-metal ions, act as fullerene receptors and host small molecules in a crystal. PMID:27090355

An Iterative, Bimodular Nonribosomal Peptide Synthetase that Converts Anthranilate and Tryptophan into Tetracyclic Asperlicins

PubMed Central

Gao, Xue; Jiang, Wei; Jiménez-Osés, Gonzalo; Choi, Moon Seok; Houk, Kendall N.; Tang, Yi; Walsh, Christopher T.

2013-01-01

The bimodular 276 kDa nonribosomal peptide synthetase AspA from Aspergillus alliaceus, heterologously expressed in Saccharomyces cerevisiae, converts tryptophan and two molecules of the aromatic β-amino acid anthranilate (Ant) into a pair of tetracyclic peptidyl alkaloids asperlicin C and D in a ratio of 10:1. The first module of AspA activates and processes two molecules of Ant iteratively to generate a tethered Ant-Ant-Trp-S-enzyme intermediate on module two. Release is postulated to involve tandem cyclizations, in which the first step is the macrocyclization of the linear tripeptidyl-S-enzyme, by the terminal condensation (CT) domain to generate the regioisomeric tetracyclic asperlicin scaffolds. Computational analysis of the transannular cyclization of the 11-membered macrocyclic intermediate shows that asperlicin C is the kinetically favored product due to the high stability of a conformation resembling the transition state for cyclization, while asperlicin D is thermodynamically more stable. PMID:23890005

A hybrid feature selection method using multiclass SVM for diagnosis of erythemato-squamous disease

NASA Astrophysics Data System (ADS)

Maryam, Setiawan, Noor Akhmad; Wahyunggoro, Oyas

2017-08-01

The diagnosis of erythemato-squamous disease is a complex problem and difficult to detect in dermatology. Besides that, it is a major cause of skin cancer. Data mining implementation in the medical field helps expert to diagnose precisely, accurately, and inexpensively. In this research, we use data mining technique to developed a diagnosis model based on multiclass SVM with a novel hybrid feature selection method to diagnose erythemato-squamous disease. Our hybrid feature selection method, named ChiGA (Chi Square and Genetic Algorithm), uses the advantages from filter and wrapper methods to select the optimal feature subset from original feature. Chi square used as filter method to remove redundant features and GA as wrapper method to select the ideal feature subset with SVM used as classifier. Experiment performed with 10 fold cross validation on erythemato-squamous diseases dataset taken from University of California Irvine (UCI) machine learning database. The experimental result shows that the proposed model based multiclass SVM with Chi Square and GA can give an optimum feature subset. There are 18 optimum features with 99.18% accuracy.

Evaluation of Amorphous Transformer by Optimum Capacity Selection based on the Load Curve Pattern of Customers

NASA Astrophysics Data System (ADS)

Takagi, Masaaki; Yamamoto, Hiromi; Yamaji, Kenji

Energy loss in transformer is composed of no-load loss and load loss. No-load loss of amorphous transformer (i.e. amorphous metal-based transformer) is less by about 70% compared with traditional transformers (e.g. silicon steel-based transformer). However, amorphous transformers have disadvantages of high cost and high load loss parameter compared with traditional transformers. Furthermore, there are varieties of transformer capacities, and the customers who would buy new transformer have many choices. In this paper, the authors propose an algorithm for optimum transformer selection based on the load curve patterns of customers. It is possible to select the capacity that minimizes the total cost by measuring equivalent load Qe that is the root mean square of load. It becomes clear that amorphous transformer is effective in achieving substantial energy saving compared with traditional transformer.

Comparative analysis of operational forecasts versus actual weather conditions in airline flight planning, volume 1

NASA Technical Reports Server (NTRS)

Keitz, J. F.

1982-01-01

The impact of more timely and accurate weather data on airline flight planning with the emphasis on fuel savings is studied. This volume of the report discusses the results of Task 1 of the four major tasks included in the study. Task 1 compares flight plans based on forecasts with plans based on the verifying analysis from 33 days during the summer and fall of 1979. The comparisons show that: (1) potential fuel savings conservatively estimated to be between 1.2 and 2.5 percent could result from using more timely and accurate weather data in flight planning and route selection; (2) the Suitland forecast generally underestimates wind speeds; and (3) the track selection methodology of many airlines operating on the North Atlantic may not be optimum resulting in their selecting other than the optimum North Atlantic Organized Track about 50 percent of the time.

Advanced composite elevator for Boeing 727 aircraft, volume 2

NASA Technical Reports Server (NTRS)

Chovil, D. V.; Grant, W. D.; Jamison, E. S.; Syder, H.; Desper, O. E.; Harvey, S. T.; Mccarty, J. E.

1980-01-01

Preliminary design activity consisted of developing and analyzing alternate design concepts and selecting the optimum elevator configuration. This included trade studies in which durability, inspectability, producibility, repairability, and customer acceptance were evaluated. Preliminary development efforts consisted of evaluating and selecting material, identifying ancillary structural development test requirements, and defining full scale ground and flight test requirements necessary to obtain Federal Aviation Administration (FAA) certification. After selection of the optimum elevator configuration, detail design was begun and included basic configuration design improvements resulting from manufacturing verification hardware, the ancillary test program, weight analysis, and structural analysis. Detail and assembly tools were designed and fabricated to support a full-scope production program, rather than a limited run. The producibility development programs were used to verify tooling approaches, fabrication processes, and inspection methods for the production mode. Quality parts were readily fabricated and assembled with a minimum rejection rate, using prior inspection methods.

Algorithms for optimization of branching gravity-driven water networks

NASA Astrophysics Data System (ADS)

Dardani, Ian; Jones, Gerard F.

2018-05-01

The design of a water network involves the selection of pipe diameters that satisfy pressure and flow requirements while considering cost. A variety of design approaches can be used to optimize for hydraulic performance or reduce costs. To help designers select an appropriate approach in the context of gravity-driven water networks (GDWNs), this work assesses three cost-minimization algorithms on six moderate-scale GDWN test cases. Two algorithms, a backtracking algorithm and a genetic algorithm, use a set of discrete pipe diameters, while a new calculus-based algorithm produces a continuous-diameter solution which is mapped onto a discrete-diameter set. The backtracking algorithm finds the global optimum for all but the largest of cases tested, for which its long runtime makes it an infeasible option. The calculus-based algorithm's discrete-diameter solution produced slightly higher-cost results but was more scalable to larger network cases. Furthermore, the new calculus-based algorithm's continuous-diameter and mapped solutions provided lower and upper bounds, respectively, on the discrete-diameter global optimum cost, where the mapped solutions were typically within one diameter size of the global optimum. The genetic algorithm produced solutions even closer to the global optimum with consistently short run times, although slightly higher solution costs were seen for the larger network cases tested. The results of this study highlight the advantages and weaknesses of each GDWN design method including closeness to the global optimum, the ability to prune the solution space of infeasible and suboptimal candidates without missing the global optimum, and algorithm run time. We also extend an existing closed-form model of Jones (2011) to include minor losses and a more comprehensive two-part cost model, which realistically applies to pipe sizes that span a broad range typical of GDWNs of interest in this work, and for smooth and commercial steel roughness values.

On Optimum Power Allocation for Multi-Antenna Wideband Helicopter-to-Ground Communications

DTIC Science & Technology

2014-03-01

optimum [1]. In frequency selective fading, the general approach is to use OFDM and apply these techniques on a per subcarrier basis. This work was...Contracting Office under contract W900KK-09-C-0016. Given the constraints described above, OFDM is often of limited interest in helicopter-to-ground...Naguib, and R. Calderbank, “Finite-length MIMO decision feedback equalization for space-time block-coded signals over multipath-fading channels,” IEEE

Synthesis, characterization, nano-sized binuclear nickel complexes, DFT calculations and antibacterial evaluation of new macrocyclic Schiff base compounds

NASA Astrophysics Data System (ADS)

Parsaee, Zohreh; Mohammadi, Khosro

2017-06-01

Some new macrocyclic bridged dianilines tetradentate with N4coordination sphere Schiff base ligands and their nickel(II)complexes with general formula [{Ni2LCl4} where L = (C20H14N2X)2, X = SO2, O, CH2] have been synthesized. The compounds have been characterized by FT-IR, 1H and 13C NMR, mass spectroscopy, TGA, elemental analysis, molar conductivity and magnetic moment techniques. Scanning electron microscopy (SEM) shows nano-sized structures under 100 nm for nickel (II) complexes. NiO nanoparticle was achieved via the thermal decomposition method and analyzed by FT-IR, SEM and X-ray powder diffraction which indicates closeaccordance to standard pattern of NiO nanoparticle. All the Schiff bases and their complexes have been detected in vitro both for antibacterial activity against two gram-negative and two gram-positive bacteria. The nickel(II) complexes were found to be more active than the free macrocycle Schiff bases. In addition, computational studies of three ligands have been carried out at the DFT-B3LYP/6-31G+(d,p) level of theory on the spectroscopic properties, including IR, 1HNMR and 13CNMR spectroscopy. The correlation between the theoretical and the experimental vibrational frequencies, 1H NMR and 13C NMR of the ligands were 0.999, 0.930-0.973 and 0.917-0.995, respectively. Also, the energy gap was determined and by using HOMO and LUMO energy values, chemical hardness-softness, electronegativity and electrophilic index were calculated.

pH-Assisted control over the binding and relocation of an acridine guest between a macrocyclic nanocarrier and natural DNA.

PubMed

Sayed, Mhejabeen; Pal, Haridas

2015-04-14

The differential binding affinity of the hydroxypropyl-β-cyclodextrin (HPβCD) macrocycle, a drug delivery vehicle, towards the protonated and deprotonated forms of the well-known DNA binder and model anticancer drug acridine has been exploited as a strategy for dye-drug transportation and pH-responsive delivery to a natural DNA target. From pH-sensitive changes in the ground state absorption and steady-state fluorescence characteristics of the studied acridine dye-HPβCD-DNA ternary system and strongly supported by fluorescence lifetime, fluorescence anisotropy, Job's plots, (1)H NMR and circular dichroism results, it is revealed that in a moderately alkaline solution (pH ∼ 8.5), the dye can be predominantly bound to the HPβCD macrocycle and when the pH is lowered to a moderately acidic region (pH ∼ 4), the dye efficiently detaches from the HPβCD cavity and almost exclusively binds to DNA. In the present study we are thus able to construct a pH-sensitive supramolecular assembly where pH acts as a simple stimulus for controlled uptake and targeted release of the dye-drug. As pH is an essential and sensitive factor in various biological processes, a simple yet reliable pH-sensitive model such as is demonstrated here can have promising applications in the host-assisted delivery of prodrug to the target sites, such as cancer or tumour microenvironments, with an enhanced stability, bioavailability and activity, and also in the design of new fluorescent probes, sensors and smart materials for applications in nano-science.

77 FR 11560 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... chrysophaetin exhibits antimicrobial activity against drug resistant bacteria, methicillin-resistant... antibiotics due to distinct mechanism of action. Other drugs with similar structure and antibacterial.... Chrysophaentins A-H, antibacterial bisdiarylbutene macrocycles that inhibit the bacterial cell division protein...

Transport of calcium ions through a bulk membrane by use of a dynamic combinatorial library.

PubMed

Saggiomo, Vittorio; Lüning, Ulrich

2009-07-07

In a bulk membrane transport experiment, a dynamic combinatorial library (DCL) has been used to transport calcium ions; the calcium ions amplify the formation of a macrocyclic carrier which results in transport.

Selective Ring Opening of 1-Methylnaphthalene Over NiW-Supported Catalyst Using Dealuminated Beta Zeolite.

PubMed

Kim, Eun-Sang; Lee, You-Jin; Kim, Jeong-Rang; Kim, Joo-Wan; Kim, Tae-Wan; Chae, Ho-Jeong; Kim, Chul-Ung; Lee, Chang-Ha; Jeong, Soon-Yong

2016-02-01

Nanoporous Beta zeolite was dealuminated by weak acid treatment for reducing the acidity. Bi-functional catalysts were prepared using commercial Beta zeolites and the dealuminated zeolites for acidic function, NiW for metallic function. 1-Methylnaphthalene was selected as a model compound for multi-ring aromatics in heavy oil, and its selective ring opening reaction has been investigated using the prepared bi-functional catalysts with different acidity in fixed bed reaction system. The dealuminated Beta zeolites, which crystal structure and nanoporosity were maintained, showed the higher SiO2/Al2O3 ratio and smaller acidity than their original zeolite. NiW-supported catalyst using the dealuminated Beta zeolite with SiO2/Al203 mole ratio of 55 showed the highest performance for the selective ring opening. The acidity of catalyst seemed to play an important role as active sites for the selective ring opening of 1-methylnaphthalene but there should be some optimum catalyst acidity for the reaction. The acidity of Beta zeolite could be controlled by the acid treatment and the catalyst with the optimum acidity for the selective ring opening could be prepared.

Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists.

PubMed

Schieda, Nicola; Blaichman, Jason I; Costa, Andreu F; Glikstein, Rafael; Hurrell, Casey; James, Matthew; Jabehdar Maralani, Pejman; Shabana, Wael; Tang, An; Tsampalieros, Anne; van der Pol, Christian; Hiremath, Swapnil

2018-05-01

Use of gadolinium-based contrast agents (GBCAs) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCAs are absolutely contraindicated in AKI, CKD stage 4 or 5 (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m 2 ) and dialysis-dependent patients is outdated, and may limit access to clinically necessary contrast-enhanced MRI examinations. Following a comprehensive review of the literature and reported NSF cases to date, a committee of radiologists and nephrologists developed clinical practice guidelines to assist physicians in making decisions regarding GBCA administrations. In patients with mild-to-moderate CKD (eGFR ≥30 and <60 mL/min/1.73 m 2 ), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with severe CKD (eGFR <30 mL/min/1.73 m 2 ), or on dialysis, administration of GBCAs should be considered individually and alternative imaging modalities utilized whenever possible. If GBCAs are necessary, newer GBCAs may be administered with patient consent obtained by a physician (or their delegate), citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, with stage 4 or 5 CKD, or on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCAs. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCAs is recommended. Copyright © 2017 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

Shifting the paradigm in Dirofilaria immitis prevention: blocking transmission from mosquitoes to dogs using repellents/insecticides and macrocyclic lactone prevention as part of a multimodal approach.

PubMed

McCall, John W; Varloud, Marie; Hodgkins, Elizabeth; Mansour, Abdelmoneim; DiCosty, Utami; McCall, Scott; Carmichael, James; Carson, Ben; Carter, Justin

2017-11-09

This study assessed the influence of a topical ectoparasiticide (dinotefuran-permethrin-pyriproxyfen, DPP, Vectra® 3D, Ceva Animal Health) combined with a macrocyclic lactone (milbemycin oxime, MBO, Interceptor®, Virbac) on transmission of heartworm L3 from mosquitoes to dogs and subsequent development of worms in treated dogs exposed to infected mosquitoes. Thirty-two beagle dogs were allocated to four groups of eight: Group 1, untreated controls; Group 2, treated topically with DPP on Day 0; Group 3, treated orally with MBO on Day 51; and Group 4, treated with DPP on Day 0 and MBO on Day 51. Dogs were exposed under sedation for 1 h to Dirofilaria immitis (JYD-34)-infected Aedes aegypti on Days 21 and 28. At the end of each exposure, mosquitoes were classified as live, moribund, or dead and engorged or non-engorged. Live or moribund mosquitoes were incubated for daily survival assessment for 3 days. Mosquitoes were dissected before and after exposure to estimate the number of L3 transmitted to each dog. Dogs were necropsied 148 to 149 days postinfection. A total of 418 mosquitoes fed on the 16 dogs in Groups 1 and 3, while only 6 fed on the 16 DPP-treated dogs in Groups 2 and 4. Mosquito anti-feeding (repellency) effect in Groups 2 and 4 was 98.1 and 99.1%, respectively. The estimated numbers of L3 transmitted to controls, DPP-treated, MBO-treated and DPP + MBO-treated dogs were 76, 2, 78, and 1, respectively. No heartworms were detected in any of the DPP + MBO-treated dogs (100% efficacy), while 8 out of 8 were infected in the control group (range, 21-66 worms per dog), 8 out of 8 were infected in the MBO-treated group (58% efficacy), and 3 out of 8 were infected in the DPP-treated group (96% efficacy). DPP repelled and killed most mosquitoes that were capable of transmitting heartworm L3 to dogs. The "Double Defense" protocol of DPP + MBO had better efficacy for protecting dogs against heartworm transmission and infection than MBO alone. This added DPP benefit is more pronounced when macrocyclic lactone-resistant strains of heartworms are involved or lack of compliance in macrocyclic lactone administration is known or suspected.

Optimum data analysis procedures for Titan 4 and Space Shuttle payload acoustic measurements during lift-off

NASA Technical Reports Server (NTRS)

Piersol, Allan G.

1991-01-01

Analytical expressions have been derived to describe the mean square error in the estimation of the maximum rms value computed from a step-wise (or running) time average of a nonstationary random signal. These analytical expressions have been applied to the problem of selecting the optimum averaging times that will minimize the total mean square errors in estimates of the maximum sound pressure levels measured inside the Titan IV payload fairing (PLF) and the Space Shuttle payload bay (PLB) during lift-off. Based on evaluations of typical Titan IV and Space Shuttle launch data, it has been determined that the optimum averaging times for computing the maximum levels are (1) T (sub o) = 1.14 sec for the maximum overall level, and T(sub oi) = 4.88 f (sub i) (exp -0.2) sec for the maximum 1/3 octave band levels inside the Titan IV PLF, and (2) T (sub o) = 1.65 sec for the maximum overall level, and T (sub oi) = 7.10 f (sub i) (exp -0.2) sec for the maximum 1/3 octave band levels inside the Space Shuttle PLB, where f (sub i) is the 1/3 octave band center frequency. However, the results for both vehicles indicate that the total rms error in the maximum level estimates will be within 25 percent the minimum error for all averaging times within plus or minus 50 percent of the optimum averaging time, so a precise selection of the exact optimum averaging time is not critical. Based on these results, linear averaging times (T) are recommended for computing the maximum sound pressure level during lift-off.

Periodontal health status among permanent residents of low, optimum and high fluoride areas in Kolar District, India.

PubMed

Megalamanegowdru, Jayachandra; Ankola, Anil V; Vathar, Jagadishchandra; Vishwakarma, Prashanthkumar; Dhanappa, Kirankumar B; Balappanavar, Aswini Y

2012-01-01

To assess and compare the periodontal health status among permanent residents of low, optimum and high fluoride areas in Kolar District, India. A house-to-house survey was conducted in a population consisting of 925 permanent residents aged 35 to 44 years in three villages having different levels of fluoride concentrations in the drinking water. The fluoride concentrations in selected villages were 0.48 ppm (low), 1.03 ppm (optimum) and 3.21 ppm (high). The ion selective electrode method was used to estimate the fluoride concentration in the drinking water. Periodontal status was assessed using the Community Periodontal Index (CPI) and loss of attachment (LOA). Results were analysed using the chi-square test and logistic regression. The chi-square test was used to find the group differences and logistic regression to find association between the variables. The overall prevalence of periodontitis was 72.9%; specifically, prevalences were 95.4%, 76.3% and 45.7% in low, optimum and high fluoride areas, respectively. The number of sextants with shallow or deep pockets decreased (shallow pockets: 525, 438, 217; deep pockets: 183, 81, 34) from low to high fluoride areas (odds ratio: 71.3). The low fluoride area had a 7.9-fold higher risk of periodontitis than the optimum fluoride area and a 30-fold higher risk than the high fluoride area, which was highly significant (χ2 = 53.5, P < 0.0001 and χ2 = 192.8, P < 0.001, respectively). The severity of periodontal disease is inversely associated with the fluoride concentrations in drinking water. This relation can provide an approach to fluoride treatments to reduce the prevalence or incidence of this disease.

Survey of coatings for solar collectors

NASA Technical Reports Server (NTRS)

Mcdonald, G. E.

1975-01-01

Optimum solar selective properties of black chrome require some tailoring of current and time for plating solution being used. Black zinc is produced from high zinc electroplate by subsequent conversion with chromate dip. Measurements have also been made of reflectance of previously known solar selective coatings of black copper and electroplated black nickel.

Truck Noise VIII : The Determination of the Practical Noise Control Retrofitting of Pre-1970 Truck and Coach Models

DOT National Transportation Integrated Search

1976-06-01

A retrofit noise package was selected for four representative GMC vehicles; i.e., two Heavy Duty Conventionals, one cab-over engine Heavy Duty Astro, and one 53 passenger transit coach, to achieve optimum noise reduction. The selection of this materi...

Palladium-Catalyzed Oxidative Couplings and Applications to the Synthesis of Macrocycles and Strained Cyclic Dienes

NASA Astrophysics Data System (ADS)

Boon, Byron Adrian

The palladium(II)-catalyzed oxidative macrocyclization of bis(vinylboronate esters) is demonstrated as an efficient method for the synthesis of macrocyclic dienes. The macrocyclization reactions feature mild conditions due to a palladium(II) catalytic cycle which obviates the need for a high energy oxidative addition step of standard palladium(0) catalytic cycles. Instead, this oxidative coupling is promoted by chloroacetone as a terminal re-oxidant in the catalytic cycle. An extension of the oxidative coupling/macrocyclization strategy is highlighted where molecular oxygen may be used in place of chloroacetone as the terminal re-oxidant. Homocoupling reactions of vinylboronate esters served as a template to screen reaction conditions for this method. From these experiments, multiple reaction conditions gave the oxidative homocoupling product in high yield. These reaction conditions were successfully applied to the oxidative macrocyclization of a bis(vinylboronate ester) using molecular oxygen as a re-oxidant. Syntheses of strained cyclic dienes were accomplished via the palladium(II)-catalyzed oxidative cyclizations of terminal bis(vinylboronate esters). The reactions generated strained (E,E)-1,3-dienes that underwent spontaneous 4?-electrocyclizations to form bicyclic cyclobutenes. Formation of the cyclobutenes is driven by strain in the medium-ring (E,E)-1,3-diene intermediates. Thermal ring openings of the cyclobutenes give (Z,Z)-1,3-diene products, again for thermodynamic reasons. These results are in contrast with typical acyclic trans-3,4-dialkyl cyclobutenes, which favor outward torquoselective ring-openings to give (E,E)-1,3-dienes. DFT calculations verified the thermodynamic versus kinetic control of the reactions and kinetic studies are in excellent agreement with the calculated energy changes. Investigations on the transannular Pauson-Khand reaction are also highlighted. The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2+2+1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Our successful transannular Pauson-Khand reaction required a cyclic enyne incorporating one short three-membered linker chain and a rigid aryl linker in the backbone of the long linker chain. This rigidity of the aryl linker is proposed to facilitate the transannular [2+2+1] cyclization. Computational studies revealed that transannular Pauson-Khand reactions are thermodynamically favored for cyclic enynes featuring a long linker of at least 5 carbons, but with smaller chains the reactions are thermodynamically disfavored. Experimental studies show that long linking chains with more than 5 members are required to prevent to steric interactions between the dicobalt hexacarbonyl moiety and the linking chain to allow the reaction to be kinetically favored. The final part of this work highlights progress towards the total synthesis of (+)-kingianin A. This natural product was isolated as a racemic mixture from the bark of Endiandra kingiana and is an inhibitor of antiapoptotic protein Bcl-Xl, highlighting its potential use in cancer treatments. Its structure is proposed to arise from an intermolecular Diels-Alder dimerization reaction of bicyclo[4.2.0]octadiene fragments derived from an 8pi/6pi-electrocyclization cascade. Although two total syntheses of (+/-)-kingianin A have been reported, an enantioselective synthesis has not been achieved and is the purpose of this study. This synthetic route begins from L-(+)-dimethyl tartrate, a cheap and commercially available starting material, and aims to follow a biomimetic synthetic pathway featuring a substrate controlled diastereoselective palladium(II)-catalyzed oxidative cyclization and 8pi/6pi-electrocyclization cascade. Although the feasibility of this cascade pathway has not yet been realized, key synthetic transformations to install the requisite carbocyclic framework of (+)-kingianin A have been discovered, paving the way for future investigations on the palladium(II)-catalyzed coupling/electrocyclization cascade and completion of the synthesis.

Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents

PubMed Central

Lohrke, Jessica; Frisk, Anna-Lena; Frenzel, Thomas; Schöckel, Laura; Rosenbruch, Martin; Jost, Gregor; Lenhard, Diana Constanze; Sieber, Martin A.; Nischwitz, Volker; Küppers, Astrid; Pietsch, Hubertus

2017-01-01

Objectives Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution. Materials and Methods Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively. Results No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis–like skin lesions. The Gd concentrations observed in the skin/brain samples (in nanomole Gd per gram of tissue) for each agent were as follows: gadodiamide: 1472 ± 115/11.1 ± 5.1, gadopentetate dimeglumine: 80.8 ± 6.2/13.1 ± 7.3, gadobutrol: 1.1 ± 0.5/0.7 ± 0.4, and gadoteridol: 1.7 ± 0.8/0.5 ± 0.2. The average detected residual Gd concentration in the brain was approximately 15-fold higher for linear than for macrocyclic GBCAs. The highest amounts of Gd found in brain corresponded to less than 0.0002% of the injected dose per gram of tissue. Using LA-ICP-MS, high Gd concentrations in the deep cerebellar nuclei and in the granular layer of the cerebellar cortex were detected only for linear gadodiamide and gadopentetate dimeglumine but not for gadoteridol or gadobutrol. The energy dispersive x-ray spectroscopy analysis revealed Gd-containing spots in the skin of animals administered gadodiamide and gadopentetate dimeglumine. Transmission electron microscopy revealed several Gd-containing spots in the region of the dentate nuclei in the brain of 1 animal injected with gadodiamide. Conclusions After repeated high dosing, nephrogenic systemic fibrosis–like macroscopic and histopathological lesions of the skin were observed only in some of the gadodiamide-treated animals. No histopathological findings were detected in the rodent brain. The administration of linear GBCAs was associated with significantly higher Gd concentrations in the brain and skin compared with macrocyclic GBCA administration. The results of LA-ICP-MS demonstrated local accumulation of Gd within the deep cerebellar nuclei and the granular layer only after the administration of linear agents. In summary, the detected low Gd concentrations in the skin and brain were well correlated with the higher kinetic stability of macrocyclic GBCA. PMID:28323657

Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents.

PubMed

Lohrke, Jessica; Frisk, Anna-Lena; Frenzel, Thomas; Schöckel, Laura; Rosenbruch, Martin; Jost, Gregor; Lenhard, Diana Constanze; Sieber, Martin A; Nischwitz, Volker; Küppers, Astrid; Pietsch, Hubertus

2017-06-01

Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution. Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet [Nissl]) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively. No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis-like skin lesions. The Gd concentrations observed in the skin/brain samples (in nanomole Gd per gram of tissue) for each agent were as follows: gadodiamide: 1472 ± 115/11.1 ± 5.1, gadopentetate dimeglumine: 80.8 ± 6.2/13.1 ± 7.3, gadobutrol: 1.1 ± 0.5/0.7 ± 0.4, and gadoteridol: 1.7 ± 0.8/0.5 ± 0.2. The average detected residual Gd concentration in the brain was approximately 15-fold higher for linear than for macrocyclic GBCAs. The highest amounts of Gd found in brain corresponded to less than 0.0002% of the injected dose per gram of tissue. Using LA-ICP-MS, high Gd concentrations in the deep cerebellar nuclei and in the granular layer of the cerebellar cortex were detected only for linear gadodiamide and gadopentetate dimeglumine but not for gadoteridol or gadobutrol. The energy dispersive x-ray spectroscopy analysis revealed Gd-containing spots in the skin of animals administered gadodiamide and gadopentetate dimeglumine. Transmission electron microscopy revealed several Gd-containing spots in the region of the dentate nuclei in the brain of 1 animal injected with gadodiamide. After repeated high dosing, nephrogenic systemic fibrosis-like macroscopic and histopathological lesions of the skin were observed only in some of the gadodiamide-treated animals. No histopathological findings were detected in the rodent brain. The administration of linear GBCAs was associated with significantly higher Gd concentrations in the brain and skin compared with macrocyclic GBCA administration. The results of LA-ICP-MS demonstrated local accumulation of Gd within the deep cerebellar nuclei and the granular layer only after the administration of linear agents. In summary, the detected low Gd concentrations in the skin and brain were well correlated with the higher kinetic stability of macrocyclic GBCA.

The Fisher-Markov selector: fast selecting maximally separable feature subset for multiclass classification with applications to high-dimensional data.

PubMed

Cheng, Qiang; Zhou, Hongbo; Cheng, Jie

2011-06-01

Selecting features for multiclass classification is a critically important task for pattern recognition and machine learning applications. Especially challenging is selecting an optimal subset of features from high-dimensional data, which typically have many more variables than observations and contain significant noise, missing components, or outliers. Existing methods either cannot handle high-dimensional data efficiently or scalably, or can only obtain local optimum instead of global optimum. Toward the selection of the globally optimal subset of features efficiently, we introduce a new selector--which we call the Fisher-Markov selector--to identify those features that are the most useful in describing essential differences among the possible groups. In particular, in this paper we present a way to represent essential discriminating characteristics together with the sparsity as an optimization objective. With properly identified measures for the sparseness and discriminativeness in possibly high-dimensional settings, we take a systematic approach for optimizing the measures to choose the best feature subset. We use Markov random field optimization techniques to solve the formulated objective functions for simultaneous feature selection. Our results are noncombinatorial, and they can achieve the exact global optimum of the objective function for some special kernels. The method is fast; in particular, it can be linear in the number of features and quadratic in the number of observations. We apply our procedure to a variety of real-world data, including mid--dimensional optical handwritten digit data set and high-dimensional microarray gene expression data sets. The effectiveness of our method is confirmed by experimental results. In pattern recognition and from a model selection viewpoint, our procedure says that it is possible to select the most discriminating subset of variables by solving a very simple unconstrained objective function which in fact can be obtained with an explicit expression.

Development of Non-Optimum Factors for Launch Vehicle Propellant Tank Bulkhead Weight Estimation

NASA Technical Reports Server (NTRS)

Wu, K. Chauncey; Wallace, Matthew L.; Cerro, Jeffrey A.

2012-01-01

Non-optimum factors are used during aerospace conceptual and preliminary design to account for the increased weights of as-built structures due to future manufacturing and design details. Use of higher-fidelity non-optimum factors in these early stages of vehicle design can result in more accurate predictions of a concept s actual weights and performance. To help achieve this objective, non-optimum factors are calculated for the aluminum-alloy gores that compose the ogive and ellipsoidal bulkheads of the Space Shuttle Super-Lightweight Tank propellant tanks. Minimum values for actual gore skin thicknesses and weld land dimensions are extracted from selected production drawings, and are used to predict reference gore weights. These actual skin thicknesses are also compared to skin thicknesses predicted using classical structural mechanics and tank proof-test pressures. Both coarse and refined weights models are developed for the gores. The coarse model is based on the proof pressure-sized skin thicknesses, and the refined model uses the actual gore skin thicknesses and design detail dimensions. To determine the gore non-optimum factors, these reference weights are then compared to flight hardware weights reported in a mass properties database. When manufacturing tolerance weight estimates are taken into account, the gore non-optimum factors computed using the coarse weights model range from 1.28 to 2.76, with an average non-optimum factor of 1.90. Application of the refined weights model yields non-optimum factors between 1.00 and 1.50, with an average non-optimum factor of 1.14. To demonstrate their use, these calculated non-optimum factors are used to predict heavier, more realistic gore weights for a proposed heavy-lift launch vehicle s propellant tank bulkheads. These results indicate that relatively simple models can be developed to better estimate the actual weights of large structures for future launch vehicles.

Preliminary design and implementation of the baseline digital baseband architecture for advanced deep space transponders

NASA Technical Reports Server (NTRS)

Nguyen, T. M.; Yeh, H.-G.

1993-01-01

The baseline design and implementation of the digital baseband architecture for advanced deep space transponders is investigated and identified. Trade studies on the selection of the number of bits for the analog-to-digital converter (ADC) and optimum sampling schemes are presented. In addition, the proposed optimum sampling scheme is analyzed in detail. Descriptions of possible implementations for the digital baseband (or digital front end) and digital phase-locked loop (DPLL) for carrier tracking are also described.

Mastering fundamentals of supramolecular design with carboxylic acids. Common lessons from X-ray crystallography and scanning tunneling microscopy.

PubMed

Ivasenko, Oleksandr; Perepichka, Dmitrii F

2011-01-01

Hydrogen bonding is one of the most important non-covalent interactions in both biological (DNA, peptides, saccharides etc.) and artificial systems (various soft materials, host-guest architectures, molecular networks, etc.). Carboxylic acids are some of the most simple yet powerful hydrogen-bonding building blocks, that possess a particularly rich supramolecular chemistry. This tutorial review focuses on the structural diversity of supramolecular architectures accessible via hydrogen bonding of carboxylic acids, as observed both in single crystals using X-ray analysis and in monolayers on surfaces using scanning probe techniques. It provides a concise overview of the key concepts and principles of modern supramolecular design and is given in the form of case studies of finely selected literature examples, covering formation of macrocycles, chains, ladders, rotaxanes, catenanes, various 2D and 3D nets, host-guest systems and some applications thereof.

Interactions of Native Cyclodextrins with Metal Ions and Inorganic Nanoparticles: Fertile Landscape for Chemistry and Materials Science.

PubMed

Prochowicz, Daniel; Kornowicz, Arkadiusz; Lewiński, Janusz

2017-11-22

Readily available cyclodextrins (CDs) with an inherent hydrophobic internal cavity and hydrophilic external surface are macrocyclic entities that display a combination of molecular recognition and complexation properties with vital implications for host-guest supramolecular chemistry. While the host-guest chemistry of CDs has been widely recognized and led to their exploitation in a variety of important functions over the last five decades, these naturally occurring macrocyclic systems have emerged only recently as promising macrocyclic molecules to fabricate environmentally benign functional nanomaterials. This review surveys the development in the field paying special attention to the synthesis and emerging uses of various unmodified CD-metal complexes and CD-inorganic nanoparticle systems and identifies possible future directions. The association of a hydrophobic cavity of CDs with metal ions or various inorganic nanoparticles is a very appealing strategy for controlling the inorganic subunits properties in the very competitive water environment. In this review we provide the most prominent examples of unmodified CDs' inclusion complexes with organometallic guests and update the research in this field from the past decade. We discuss also the coordination flexibility of native CDs to metal ions in CD-based metal complexes and summarize the progress in the synthesis and characterization of CD-metal complexes and their use in catalysis and sensing as well as construction of molecular magnets. Then we provide a comprehensive overview of emerging applications of native CDs in materials science and nanotechnology. Remarkably, in the past few years CDs have appeared as attractive building units for the synthesis of carbohydrate metal-organic frameworks (CD-MOFs) in a combination of alkali-metal cations. The preparation of this new class of highly porous materials and their applications in the separation of small molecules, the loading of drug molecules, as well as efficient host templates in the construction of nanomaterials with the desired functionality, including the first-in-class devices including sensors and memristors, are highlighted. Finally, CDs as well-known "green" molecular hosts have also been used as ideal functional molecules to improve the solubility, stability, and bioavailability of inorganic nanoparticles. In this regard, we demonstrate various strategies for the preparation of native CDs-modified inorganic nanomaterials such as metal, metal oxide, and semiconductor and magnetic nanoparticles, aiming to take advantage of both the controlled properties of the inorganic core and the controlled properties of the coating molecules. The functionalization of a CD hydrophobic cavity with an inorganic nanoparticle is very prospective for the development of novel catalytic systems and new tools for highly selective and sensitive sensing platforms for various targets.

Switchable host-guest systems on surfaces.

PubMed

Yang, Ying-Wei; Sun, Yu-Long; Song, Nan

2014-07-15

CONSPECTUS: For device miniaturization, nanotechnology follows either the "top-down" approach scaling down existing larger-scale devices or the "bottom-up' approach assembling the smallest possible building blocks to functional nanoscale entities. For synthetic nanodevices, self-assembly on surfaces is a superb method to achieve useful functions and enable their interactions with the surrounding world. Consequently, adaptability and responsiveness to external stimuli are other prerequisites for their successful operation. Mechanically interlocked molecules such as rotaxanes and catenanes, and their precursors, that is, molecular switches and supramolecular switches including pseudorotaxanes, are molecular machines or prototypes of machines capable of mechanical motion induced by chemical signals, biological inputs, light or redox processes as the external stimuli. Switching of these functional host-guest systems on surfaces becomes a fundamental requirement for artificial molecular machines to work, mimicking the molecular machines in nature, such as proteins and their assemblies operating at dynamic interfaces such as the surfaces of cell membranes. Current research endeavors in material science and technology are focused on developing either a new class of materials or materials with novel/multiple functionalities by shifting host-guest chemistry from solution phase to surfaces. In this Account, we present our most recent attempts of building monolayers of rotaxanes/pseudorotaxanes on surfaces, providing stimuli-induced macroscopic effects and further understanding on the switchable host-guest systems at interfaces. Biocompatible versions of molecular machines based on synthetic macrocycles, such as cucurbiturils, pillararenes, calixarenes, and cyclodextrins, have been employed to form self-assembled monolayers of gates on the surfaces of mesoporous silica nanoparticles to regulate the controlled release of cargo/drug molecules under a range of external stimuli, such as light, pH variations, competitive binding, and enzyme. Rotaxanes have also been assembled onto the surfaces of gold nanodisks and microcantilevers to realize active molecular plasmonics and synthetic molecular actuators for device fabrication and function. Pillararenes have been successfully used to control and aid the synthesis of gold nanoparticles, semiconducting quantum dots, and magnetic nanoparticles. The resulting organic-inorganic hydrid nanomaterials have been successfully used for controlled self-assembly, herbicide sensing and detection, pesticide removal, and so forth, taking advantage of the selective binding of pillarenes toward target molecules. Cyclodextrins have also been successfully functionalized onto the surface of gold nanoparticles to serve as recycling extractors for C60. Many interesting prototypes of nanodevices based on synthetic macrocycles and their host-guest chemistry have been constructed and served for different potential applications. This Account will be a summary of the efforts made mainly by us, and others, on the host-guest chemistry of synthetic macrocyclic compounds on the surfaces of different solid supports.

The Effect of Crumb Rubber Particle Size to the Optimum Binder Content for Open Graded Friction Course

PubMed Central

Ibrahim, Mohd Rasdan; Katman, Herda Yati; Karim, Mohamed Rehan; Koting, Suhana; Mashaan, Nuha S.

2014-01-01

The main objective of this paper is to investigate the relations of rubber size, rubber content, and binder content in determination of optimum binder content for open graded friction course (OGFC). Mix gradation type B as specified in Specification for Porous Asphalt produced by the Road Engineering Association of Malaysia (REAM) was used in this study. Marshall specimens were prepared with four different sizes of rubber, namely, 20 mesh size [0.841 mm], 40 mesh [0.42 mm], 80 mesh [0.177 mm], and 100 mesh [0.149 mm] with different concentrations of rubberised bitumen (4%, 8%, and 12%) and different percentages of binder content (4%–7%). The appropriate optimum binder content is then selected according to the results of the air voids, binder draindown, and abrasion loss test. Test results found that crumb rubber particle size can affect the optimum binder content for OGFC. PMID:24574875

Studies with sample conductivity, insertion rates, and particle deflection in a continuous flow electrophoresis system

NASA Technical Reports Server (NTRS)

Williams, G., Jr.

1982-01-01

The continuous flow electrophoresis system makes electrophoresis possible in a free-flowing film of aqueous electrolyte medium. The sample continuously enters the electrolyte at the top of the chamber and is subjected to the action of a lateral dc field. This divides the sample into fractions since each component has a distinctive electrophoretic mobility. Tests were made using monodisperse polystyrene latex microspheres to determine optimum sample conductivity, insertion rates and optimum electric field applications as baseline data for future STS flight experiments. Optimum sample flow rates for the selected samples were determined to be approximately 26 micro-liters/min. Experiments with samples in deionized water yielded best results and voltages in the 20 V/cm to 30 V/cm range were optimum. Deflections of formaldehyde fixed turkey and bovine erythrocytes were determined using the continuous flow electrophoresis system. The effects of particle interactions on sample resolution and migration in the chamber was also evaluated.

Design of slurry bubble column reactors: novel technique for optimum catalyst size selection contractual origin of the invention

DOEpatents

Gamwo, Isaac K [Murrysville, PA; Gidaspow, Dimitri [Northbrook, IL; Jung, Jonghwun [Naperville, IL

2009-11-17

A method for determining optimum catalyst particle size for a gas-solid, liquid-solid, or gas-liquid-solid fluidized bed reactor such as a slurry bubble column reactor (SBCR) for converting synthesis gas into liquid fuels considers the complete granular temperature balance based on the kinetic theory of granular flow, the effect of a volumetric mass transfer coefficient between the liquid and the gas, and the water gas shift reaction. The granular temperature of the catalyst particles representing the kinetic energy of the catalyst particles is measured and the volumetric mass transfer coefficient between the gas and liquid phases is calculated using the granular temperature. Catalyst particle size is varied from 20 .mu.m to 120 .mu.m and a maximum mass transfer coefficient corresponding to optimum liquid hydrocarbon fuel production is determined. Optimum catalyst particle size for maximum methanol production in a SBCR was determined to be in the range of 60-70 .mu.m.

High Valent Manganese and Cobalt Complexes of Oxidatively Robust Nitrogen and Oxygen Donor Ligands.

NASA Astrophysics Data System (ADS)

Gordon-Wylie, Scott Wallace

1995-01-01

The focus of this thesis is to extend the range of ligands that satisfy the Collins criteria through a program of organic synthesis, and to apply the resulting high valent metal ligand complexes to the solution of current problems in structural inorganic chemistry, solid state chemistry (with a particular emphasis on magnetic interactions in solids) and to homogeneous and heterogeneous catalysis. Notable achievements along these directions to date are: (i) A streamlined synthesis of diamide dialkoxide and diamide diphenoxide acyclic ligands which allows for a wide range of both electron withdrawing and electron donating substituents to be incorporated into the ligand framework. (ii) The first example of a LMn(V)O species stable enough to be crystallographically characterized was obtained, utilizing the acyclic ligands of (i). (iii) Catalytic O-atom transfer oxidations utilizing acyclic ligands from (i) have been performed. Planar Co(III) complexes of these ligands can catalyze O-atom transfers, ^1 with 30-50 turnovers, including enantioselective ones,^2 implicating that the ligands remain at least partially intact during the catalytic process. (iv) Unusual magnetic ordering has been observed in an infinite linear chain of S = 2 LMn(III) centers, in collaboration with Edmund P. Day. (v) Ferromagnetic exchange has been obtained in a ((LCo(III)) _3Co(II)) ^{-} complex^4 Magnetic model building in collaboration with Gordon Yee and Emile Bominaar has led to an understanding of the magnetic data suitable for publication.^5 (vi) Adaptation of a range of electronic substituents (see (i)) into a macrocyclic framework^7 allows for the preparation of hydrolytically and oxidatively stable high valent metal complexes. The presence of a range of electronic substituents further allows redox potentials for a single (LM) ^{rm n+}/(LM) ^{(rm n+1)+ } oxidation process to be tuned over a range that spans ca. 1 V. (vii) Initial linear syntheses for these macrocycles involved the use of organic azide intermediates. (viii) A new macrocyclic switching ligand has been synthesized utilizing (vii), that allows H^{+} or other lewis acids to act at the secondary site as electron withdrawing groups from the metal. In the structurally characterized switching (Co(III)( kappa^4-L)) ^{ -} complex, there is a bidentate switching site consisting of a pyridine-N and an adjacent amide-O donor. It has been found that the cobalt(II) derivative (CO(II)(kappa^4-L)) ^{-} readily reduces O _2 by an outer sphere (presumably by 1 e ^{-}) process. (ix) Robust homogeneous metalloredox-active oxidants are an important strategic goal for primary pollution prevention, or what is often called "green chemistry". Use of (vii) provides access to quantities of a macrocyclic ligand, that is derivatized in such a way that it can be attached to a solid polymer support. (x) C-H bond activation has been observed in iron systems^{15} in collaboration with Mike Bartos (the principal investigator) where use of (vii) has allowed quantities of ligand to be synthesized and burned in reaction chemistry with nitriles and oxidants. (xi) Macrocyclic ligands with organic solubilizing groups have been prepared utilizing (vii) and metal complexes with substantial alkane solubility result. (Abstract shortened by UMI.).

An automatic optimum kernel-size selection technique for edge enhancement

USGS Publications Warehouse

Chavez, Pat S.; Bauer, Brian P.

1982-01-01

Edge enhancement is a technique that can be considered, to a first order, a correction for the modulation transfer function of an imaging system. Digital imaging systems sample a continuous function at discrete intervals so that high-frequency information cannot be recorded at the same precision as lower frequency data. Because of this, fine detail or edge information in digital images is lost. Spatial filtering techniques can be used to enhance the fine detail information that does exist in the digital image, but the filter size is dependent on the type of area being processed. A technique has been developed by the authors that uses the horizontal first difference to automatically select the optimum kernel-size that should be used to enhance the edges that are contained in the image. 

Emittance Theory for Cylindrical Fiber Selective Emitter

NASA Technical Reports Server (NTRS)

Chubb, Donald L.

1998-01-01

A fibrous rare earth selective emitter is approximated as an infinitely long, cylinder. The spectral emittance, e(sub x), is obtained L- by solving the radiative transfer equations with appropriate boundary conditions and uniform temperature. For optical depth, K(sub R), where alpha(sub lambda), is the extinction coefficient and R is the cylinder radius, greater than 1 the spectral emittance depths, K(sub R) alpha(sub lambda)R, is nearly at its maximum value. There is an optimum cylinder radius, R(sub opt) for maximum emitter efficiency, n(sub E). Values for R(sub opt) are strongly dependent on the number of emission bands of the material. The optimum radius decreases slowly with increasing emitter temperature, while the maximum efficiency and useful radiated power increase rapidly with increasing, temperature.

Selection for precocious flowering in Pinus sylvestris

Treesearch

Henry D. Gerhold

1966-01-01

The reproductive systems of forest trees that have evolved in wild habitats are usually characterized by delayed flowering age, cyclic seed years, and possibly an optimum, rather than a maximum, number of seeds per tree. Presumably these characteristics are favored by natural selection, though not necessarily in all species or in all situations.

A Study for the Feature Selection to Identify GIEMSA-Stained Human Chromosomes Based on Artificial Neural Network

DTIC Science & Technology

2001-10-25

neural network (ANN) has been adopted for the human chromosome classification. It is important to select optimum features for training neural network...Many studies for computer-based chromosome analysis have shown that it is possible to classify chromosomes into 24 subgroups. In addition, artificial

[Studies on technology optimization for extraction and purification of total flavones from root bark of Artocarpus styracifolius].

PubMed

Ren, Gang; Liu, Rong-hua; Shao, Feng; Huang, Hui-lian; Wen, Li-rong

2010-08-01

To study the technology optimization for extraction and purification of total flavones from root bark of Artocarpus styracifolius. The optimum extraction conditions were investigated by the contents of the total flavones, using orthogonal test; Static adsorption capacity and desorption rate were employed as examine items for the screening of optimum macroporous resin and optimum technology for the purification of total flavones with selected macroporous were also investigated. The optimum extraction conditions were as follows: using 60% alcohol of seven times than amounts of original material soaking 12 hours,extracting once with hot reflux method at 50 degrees C. HPD-500 type macroporous resin showed better adsorption and desorption property. The optimum purification conditions were as follows: the sample solution was prepared at the concentration of 50.0 mg/mL, subjected to HPD-500 type macroporous resin column chromatography with a load ratio of 22.0 mg total flavones per gram of resin. After standing for 1 hour, the column was eluted with 4 BV water before being eluted with 4 BV 80% alcohol. The purity of the product was 86.4%, which enhanced the content of total flavones by 533%. The optimum conditions for extraction and purification of total flavones from root bark of Artocarpus styractifolius are convenient and practical, and could be used as a reference for industrial production.

Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent allelic effects and G x E interactions.

PubMed Central

Turelli, Michael; Barton, N H

2004-01-01

We investigate three alternative selection-based scenarios proposed to maintain polygenic variation: pleiotropic balancing selection, G x E interactions (with spatial or temporal variation in allelic effects), and sex-dependent allelic effects. Each analysis assumes an additive polygenic trait with n diallelic loci under stabilizing selection. We allow loci to have different effects and consider equilibria at which the population mean departs from the stabilizing-selection optimum. Under weak selection, each model produces essentially identical, approximate allele-frequency dynamics. Variation is maintained under pleiotropic balancing selection only at loci for which the strength of balancing selection exceeds the effective strength of stabilizing selection. In addition, for all models, polymorphism requires that the population mean be close enough to the optimum that directional selection does not overwhelm balancing selection. This balance allows many simultaneously stable equilibria, and we explore their properties numerically. Both spatial and temporal G x E can maintain variation at loci for which the coefficient of variation (across environments) of the effect of a substitution exceeds a critical value greater than one. The critical value depends on the correlation between substitution effects at different loci. For large positive correlations (e.g., rho(ij)2>3/4), even extreme fluctuations in allelic effects cannot maintain variation. Surprisingly, this constraint on correlations implies that sex-dependent allelic effects cannot maintain polygenic variation. We present numerical results that support our analytical approximations and discuss our results in connection to relevant data and alternative variance-maintaining mechanisms. PMID:15020487

Optimization of radar imaging system parameters for geological analysis

NASA Technical Reports Server (NTRS)

Waite, W. P.; Macdonald, H. C.; Kaupp, V. H.

1981-01-01

The use of radar image simulation to model terrain variation and determine optimum sensor parameters for geological analysis is described. Optimum incidence angle is determined by the simulation, which evaluates separately the discrimination of surface features possible due to terrain geometry and that due to terrain scattering. Depending on the relative relief, slope, and scattering cross section, optimum incidence angle may vary from 20 to 80 degrees. Large incident angle imagery (more than 60 deg) is best for the widest range of geological applications, but in many cases these large angles cannot be achieved by satellite systems. Low relief regions require low incidence angles (less than 30 deg), so a satellite system serving a broad range of applications should have at least two selectable angles of incidence.