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Sample records for 6-deoxy analogs synthesis

  1. Stereocontrolled Synthesis of the d- and l-glycero-β-d-manno-heptopyranosides and their 6-Deoxy Analogs. Synthesis of Methyl α-l-Rhamnopyranosyl-(1→3)-d-glycero-β-d-manno-heptopyranosyl-(1→3)-6-deoxy-glycero-β-d-manno-heptopyranosyl-(1→4)-α-l-rhamnopyranoside, a Tetrasaccharide Subunit of the Lipopolysaccharide from Plesimonas shigelloides

    PubMed Central

    Crich, David; Banerjee, Abhisek

    2008-01-01

    The synthesis of d- and l-glycero-α-manno-thioheptopyranosides, protected with 4,6-O-alkylidene-type acetals is described. In glycosylations carried out with preactivation with the 1-benzenesulfinylpiperidine/trifluoromethanesulfonic anhydride couple, both the d- and l-glycero series exhibit excellent β-selectivity with a range of glycosyl acceptors. In contrast a 4,7-O-alkylidene acetal was found not to afford β-selectivity. With a 4,6-O-[1-cyano-2-(2-iodophenyl)ethylidene] acetal protected thioglycoside, excellent β-selectivity was obtained in glycosylation reactions, and subsequent treatment with tributyltin hydride and azoisobutyronitrile brought about clean fragmentation to the 6-deoxy-glycero-β-d-manno-heptopyranosides. This chemistry was applied to the stereocontrolled synthesis of Methyl α-l-Rhamnopyranosyl-(1→3)-d-glycero-β-D-manno-heptopyranosyl-(1→3)-6-deoxy-glycero-β-d-manno-heptopyranosyl-(1→4)-α-l-rhamnopyranoside, a component of the lipopolysaccharide from Plesimonas shigelloides. PMID:16771524

  2. Facile synthesis of mono-6-amino-6-deoxy-alpha-, beta-, gamma-cyclodextrin hydrochlorides for molecular recognition, chiral separation and drug delivery.

    PubMed

    Tang, Weihua; Ng, Siu-Choon

    2008-01-01

    We describe a protocol for the synthesis of mono-6-amino-6-deoxy-cyclodextrin hydrochloride (CD-NH3Cl), applicable to alpha-, beta- and gamma-cyclodextrin. These structurally simplest, highly water-soluble cationic cyclodextrins can be widely used in molecular recognition, chiral separation and drug delivery studies. Starting from commercially available chemicals, CD-NH3Cl is synthesized in four steps: (i) selective tosylation of cyclodextrin by the use of p-toluenesulfonyl chloride to afford mono-6-(p-toluenesulfonyl)-6-deoxy-cyclodextrin (Ts-CD); (ii) azide substitution of Ts-CD with sodium azide to afford mono-6-azido-6-deoxy-cyclodextrin (CD-N3); (iii) reduction of CD-N3 with triphenylphospine followed by hydrolysis to prepare mono-6-amino-6-deoxy-cyclodextrin (CD-NH2); and (iv) treatment of CD-NH2 with hydrochloric acid to afford the titled CD-NH3Cl with good yield. The overall protocol requires approximately 2 weeks. PMID:18388952

  3. Regioselective synthesis of cationic 6-deoxy-6-(N,N,N-trialkylammonio)curdlan derivatives.

    PubMed

    Zhang, Ruoran; Liu, Shu; Edgar, Kevin J

    2016-01-20

    Curdlan, a bioactive β-1,3-glucan, is of intense interest for pharmaceutical and biomedical applications. Cationic derivatives of curdlan and other polysaccharides are especially attractive for their potential to interact in controlled fashion with proteins, among many other possible applications, but relatively few methods exist for their synthesis. Herein we report a regioselective method for preparation of cationic, water-soluble 6-(N,N,N-trialkylammonio)-6-deoxycurdlan salts by reaction of 6-bromo-6-deoxycurdlan and its 2,4-O-diesters with trialkylamines. Dimethyl sulfoxide was identified as the optimal solvent for this nucleophilic displacement to produce cationic curdlan derivatives (80 °C, 24h), providing maximum degree of triethylammonium substitution (DS) of 0.89, exclusively at the C-6 position. 6-Bromo-6-deoxycurdlan was also reacted with heterocyclic amines such as pyridine and imidazole, providing ammonium-substituted curdlan derivatives with substantial DS (0.66 and 0.86, respectively). The new combination of regioselective Furuhata bromination and bromine displacement under optimized conditions with tertiary amines provides access to quaternized curdlan derivatives that possess high, permanent positive charge and are readily water-soluble, properties that indicate potential application promise including for mucoadhesion, permeation enhancement, and delivery of genes and anionic drugs. Regioselectivity and DS of those curdlan ammonium derivatives were quantified by means of (1)H NMR, (13)C NMR and FTIR spectroscopic methods and by elemental analysis. PMID:26572378

  4. Water soluble heptakis(6-deoxy-6-thio)cyclomaltoheptaose capped gold nanoparticles via metal vapour synthesis: NMR structural characterization and complexation properties.

    PubMed

    Uccello-Barretta, Gloria; Evangelisti, Claudio; Balzano, Federica; Vanni, Letizia; Aiello, Federica; Jicsinszky, Laszlo

    2011-05-01

    The complexation of heptakis(6-deoxy-6-thio)cyclomaltoheptaose to gold nanoparticles prepared by using the Metal Vapour Synthesis (MVS) led to water soluble gold nanoaggregates, thermally stable at 25°C. The role of gold concentration in the MVS-derived starting solution as well as of the cyclodextrin to gold molar ratio on the size of cyclodextrin-capped gold nanoparticles were investigated. The ability of cyclodextrin bonded to gold nanoparticles to include deoxycytidine was also probed in comparison with that of 1-thio-β-D-glucose sodium salt. PMID:21367401

  5. Synthesis and Anti-Influenza A Virus Activity of 6'-amino-6'-deoxy-glucoglycerolipids Analogs.

    PubMed

    Ren, Li; Zhang, Jun; Ma, Haizhen; Sun, Linlin; Zhang, Xiaoshuang; Yu, Guangli; Guan, Huashi; Wang, Wei; Li, Chunxia

    2016-01-01

    A series of aminoglucoglycerolipids derivatives had been synthesized, including 6'-acylamido-glucoglycerolipids 1a-1f and corresponding 2'-acylamido-glucoglycerolipids 2a-2c bearing different fatty acids, glucosyl diglycerides 3a-3e bearing different functional groups at C-6' and ether-linked glucoglycerolipids 4a-4c with double-tailed alkyl alcohol. The anti-influenza A virus (IAV) activity was evaluated by the cytopathic effects (CPE) inhibition assay. The results indicated that the integral structure of the aminoglycoglycerolipid was essential for the inhibition of IAV in MDCK cells. Furthermore, oral administration of compound 1d was able to significantly improve survival and decrease pulmonary viral titers in IAV-infected mice, which suggested that compound 1d merited further investigation as a novel anti-IAV candidate in the future. PMID:27322292

  6. A two-step strategy for the preparation of 6-deoxy-l-sorbose.

    PubMed

    Wen, Liuqing; Huang, Kenneth; Zheng, Yuan; Liu, Yunpeng; Zhu, He; Wang, Peng George

    2016-09-01

    A two-step enzymatic strategy for the efficient and convenient synthesis of 6-deoxy-l-sorbose was reported herein. In the first reaction step, the isomerization of l-fucose (6-deoxy-l-galactose) to l-fuculose (6-deoxy-l-tagatose) catalyzed by l-fucose isomerase (FucI), and the epimerization of l-fuculose to 6-deoxy-l-sorbose catalyzed by d-tagatose 3-epimerase (DTE) were coupled with the targeted phosphorylation of 6-deoxy-l-sorbose by fructose kinase from human (HK) in a one-pot reaction. The resultant 6-deoxy-l-sorbose 1-phosphate was purified by silver nitrate precipitation method. In the second reaction step, the phosphate group of the 6-deoxy-l-sorbose 1-phosphate was hydrolyzed with acid phosphatase (AphA) to produce 6-deoxy-l-sorbose in 81% yield with regard to l-fucose. PMID:27485385

  7. One-Pot Domino Aldol Reaction of Indium Enolates Affording 6-Deoxy-α-D,L-altropyranose Derivatives: Synthesis, Mechanism, and Computational Results.

    PubMed

    Cinar, M Emin; Schmittel, Michael

    2015-08-21

    The domino-aldol-aldol-hemiacetal-reaction cascade of indium and other group 13 metal enolates furnished 6-deoxy-α-D,L-altropyranose derivatives in up to 99% yield under thermodynamic control. At lower temperature and thus under kinetic control, the reaction proceeded in a much less diastereoselective manner. The changeover from kinetic to thermodynamic control operating in this multistep domino-aldol-aldol-hemiacetal protocol was used for probing the efficiency of DFT computations. Calculations at the B3LYP/6-31G(d)/LANL2DZ level provided a mechanistic picture in full agreement with the experimental outcome. PMID:26258596

  8. 6-Azido-6-deoxy-l-idose as a Hetero-Bifunctional Spacer for the Synthesis of Azido-Containing Chemical Probes.

    PubMed

    Hamagami, Hiroki; Kumazoe, Motofumi; Yamaguchi, Yoshiki; Fuse, Shinichiro; Tachibana, Hirofumi; Tanaka, Hiroshi

    2016-08-26

    The design of 6-azido-6-deoxy-l-idose for use as a hetero-bifunctional spacer is reported. The hemiacetal at one terminus is an equivalent of an aldehyde and can react with nucleophiles, such as amino groups and electron-rich aromatics. The azido group at the other terminus bio-orthogonally undergoes a Hüisgen [3+2] cycloaddition with an acetylene. The idose derivative exhibited a higher level of reactivity towards oxime formation than a corresponding glucose derivative. The (13) C NMR spectrum of the uniformly (13) C-labeled 6-azido-idose indicated that the acyclic forms of the sugar totaled 0.3 % of all the isomers, whereas those of glucose totaled 0.01 %. The larger population of the acyclic forms of the idose derivative would result in higher reactivity towards electrophilic addition in comparison with glucose derivatives. Finally, we prepared a C-idosyl epigallocatechin gallate (EGCG) that bears an azido group through C-glycosylation of EGCG with 6-azido-idose. This glycosyl form of the C-idosyl EGCG exhibited a cytotoxicity against U266 cells that was comparable to that of EGCG. These results suggested that the EGCG derivative could be used as an effective chemical probe for the elucidation of EGCG biological functions. PMID:27482948

  9. Pen and Pal Are Nucleotide-Sugar Dehydratases That Convert UDP-GlcNAc to UDP-6-Deoxy-d-GlcNAc-5,6-ene and Then to UDP-4-Keto-6-deoxy-l-AltNAc for CMP-Pseudaminic Acid Synthesis in Bacillus thuringiensis*♦

    PubMed Central

    Li, Zi; Hwang, Soyoun; Ericson, Jaime; Bowler, Kyle; Bar-Peled, Maor

    2015-01-01

    CMP-pseudaminic acid is a precursor required for the O-glycosylation of flagellin in some pathogenic Gram-negative bacteria, a process known to be critical in bacterial motility and infection. However, little is known about flagellin glycosylation in Gram-positive bacteria. Here, we identified and functionally characterized an operon, named Bti_pse, in Bacillus thuringiensis israelensis ATCC 35646, which encodes seven different enzymes that together convert UDP-GlcNAc to CMP-pseudaminic acid. In contrast, Gram-negative bacteria complete this reaction with six enzymes. The first enzyme, which we named Pen, converts UDP-d-GlcNAc to an uncommon UDP-sugar, UDP-6-deoxy-d-GlcNAc-5,6-ene. Pen contains strongly bound NADP+ and has distinct UDP-GlcNAc 4-oxidase, 5,6-dehydratase, and 4-reductase activities. The second enzyme, which we named Pal, converts UDP-6-deoxy-d-GlcNAc-5,6-ene to UDP-4-keto-6-deoxy-l-AltNAc. Pal is NAD+-dependent and has distinct UDP-6-deoxy-d-GlcNAc-5,6-ene 4-oxidase, 5,6-reductase, and 5-epimerase activities. We also show here using NMR spectroscopy and mass spectrometry that in B. thuringiensis, the enzymatic product of Pen and Pal, UDP-4-keto-6-deoxy-l-AltNAc, is converted to CMP-pseudaminic acid by the sequential activities of a C4″-transaminase (Pam), a 4-N-acetyltransferase (Pdi), a UDP-hydrolase (Phy), an enzyme (Ppa) that adds phosphoenolpyruvate to form pseudaminic acid, and finally a cytidylyltransferase that condenses CTP to generate CMP-pseudaminic acid. Knowledge of the distinct dehydratase-like enzymes Pen and Pal and their role in CMP-pseudaminic acid biosynthesis in Gram-positive bacteria provides a foundation to investigate the role of pseudaminic acid and flagellin glycosylation in Bacillus and their involvement in bacterial motility and pathogenicity. PMID:25414257

  10. The click-compatible sugar 6-deoxy-alkynyl glucose metabolically incorporates into Arabidopsis root hair tips and arrests their growth.

    PubMed

    McClosky, Daniel D; Wang, Bo; Chen, Gong; Anderson, Charles T

    2016-03-01

    Plant cell walls are dynamic structures whose polysaccharide components are rearranged and recycled during growth and morphogenesis. Covalent fluorescent tagging of these polysaccharides following a metabolic labeling approach can help elucidate these changes. Herein reported are the synthesis and seedling-incorporation of a plant polysaccharide chemical reporter, 6-deoxy-alkynyl glucose (6dAG), that is modeled on D-glucose. Whereas fucose-alkyne, a previously reported chemical reporter for pectin, incorporates diffusely throughout growing cell walls, 6dAG incorporated specifically into root hair tips. This incorporation occurs in a time- and concentration-dependent manner. 6dAG exposure both induces and colocalizes with callose deposition in this tissue, and arrests both root hair and root growth. These results show that plants can incorporate an additional alkynyl-modified sugar analog into their metabolism, and into a discrete subcellular location. PMID:26833385

  11. PEGylation of 6-amino-6-deoxy-curdlan for efficient in vivo siRNA delivery.

    PubMed

    Altangerel, Altanzul; Cai, Jia; Liu, Lixia; Wu, Yinga; Baigude, Huricha; Han, Jingfen

    2016-05-01

    RNA interference (RNAi) is an evolutionarily conserved gene-silencing phenomenon that shows great promise for developing new therapies. However, the development of small interfering RNA (siRNA)-based therapies need to establish efficient delivery system that silences target genes with siRNA doses that is clinically feasible in humans. Here we report synthesis and in vivo study of a novel PEGylated curdlan-based nanoparticle, designated as 6AC-100PEG, obtained by conjugation of mPEG 2000 to 6-amino-6-deoxy-curdlan. The complex of siRNA/6AC-100PEG showed homogenous nanoparticles with an average diameter of 200nm. MTT assay indicated that 6AC-100PEG does not have apparent cytotoxicity. Systemic administration of a complex of siapoB/6AC-100PEG significantly reduced the level of apoB mRNA in mouse liver, indicating that 6AC-100PEG can efficiently deliver siRNA to mouse liver and induce RNAi. Administration of siRNA/6AC-100PEG to mouse did not elevate liver enzyme level in the serum, indicating that 6AC-100PEG nanoparticle is a promising in vivo siRNA delivery agent. PMID:26877000

  12. Synthesis and biological evaluation of new jasplakinolide (jaspamide) analogs

    PubMed Central

    Ghosh, Arun K.; Dawson, Zachary L.; Moon, Deuk Kyu; Bai, Ruoli; Hamel, Ernest

    2010-01-01

    Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide. PMID:20678932

  13. Synthesis and biodistribution of radioiodinated nicotine analogs

    SciTech Connect

    Chan, S.M.; Basmadjian, G.P.; Marten, D.F.; Sadek, S.; Magarian, R.A.; Grunder, J.R.; Ice, R.D.

    1984-01-01

    The authors reported previously on the synthesis and biodistribution of radioiodinated 5-iodonicotine. In their continuous effort to search for a potential brain as well as adrenal medulla imaging agent, the authors synthesized four radioiodinated nicotine analogs. The labeled compounds were prepared by brominating nicotinic acid, and reacting the acylated product with the appropriate amines to give the respective amides which were then reduced with diborane to the amines. I-125 labeling was done by halogen exchange. Biodistribution studies performed in female Sprague-Dawley rats showed that all these compounds were taken up rapidly by the brain and the adrenal. The highest uptake of all these compounds in both organs occurred at 2 minutes after tail vein injections. The organ:blood ratios at 2 minutes and the T/sub 1/3/ (min.) of radioactivity in these organs were compared.

  14. Synthesis and biological evaluation of destruxin A and related analogs.

    PubMed

    Ast, T; Barron, E; Kinne, L; Schmidt, M; Germeroth, L; Simmons, K; Wenschuh, H

    2001-07-01

    This report describes the development of an efficient solid-phase synthesis protocol and adaptation of reported solution phase procedures for the synthesis of the cyclic depsihexapeptide destruxin A and related analogs. The solid-phase method described is based on standard Fmoc peptide chemistry, including a new synthetic method for the assembly of the depsi bond-containing unit. In order to select analogs of destruxin A for synthesis and evaluation of insecticidal activity, the work of Hellberg et al., describing a set of Z-descriptors for amino acid side-chains comparing their physicochemical properties, was utilized. Destruxin A and 27 different analogs with structural variations in four residues were synthesized and insecticidal activity was evaluated via injections into tobacco budworm (Heliothis virescens) larvae. Several destruxin A analogs were found to be at least as potent as the native compound. PMID:11454164

  15. Synthesis of mono- and dideoxygenated α,α-trehalose analogs

    PubMed Central

    Lin, Fiona L.; van Halbeek, Herman; Bertozzi, Carolyn R.

    2007-01-01

    In this work we describe the synthesis and NMR characterization of four mono- and four dideoxygenated analogs of α,α-d-trehalose. The symmetrical (2,2′-, 3,3′-, 4,4′- and 6,6′-) dideoxy analogs were obtained via selective protection and subsequent radical deoxygenation of the desired hydroxyl group set. The unsymmetrical (2′-, 3′-, 4′- and 6′-) monodeoxy analogs were synthesized by desymmetrization of α,α-trehalose and subsequent deoxygenation under radical conditions. Complete assignment of all 1H and 13C resonances in the spectra of these deoxytrehaloses was achieved through the extensive use of 2D {1H,1H} and {1H,13C} correlation NMR experiments. The synthesis of these trehalose analogs sets the stage for future biochemical and NMR-based studies to probe the substrate interactions of trehalose with the recently identified mycobacterial sulfotransferase Stf0. PMID:17559818

  16. Synthesis and Evaluation of 2'-Deoxy-2'-Spirodiflurocyclopropyl Nucleoside Analogs.

    PubMed

    Liu, Xiao; Xia, Xueliang; Sun, Chenghai; Lin, Cai; Zhou, Yiqian; Hussain, Muzammal; Tang, Fei; Liu, Lu; Li, Xue; Zhang, Jiancun

    2016-09-01

    The preparation of 2'-deoxy-2'-siprodifluorocyclopropany-lnucleoside analogs has been achieved from α-d-glucose in several steps. The key step in the synthesis was the introduction of the difluorocyclopropane through a difluorocarbene type reaction at the 2'-position. Then, a series of novel 2'-deoxy-2'-spirodifluorocyclopropanyl nucleoside analogs were synthesized using the Vorbrüggen method. All the synthesized nucleosides were characterized and subsequently evaluated against hepatitis C and influenza A virus strains in vitro. PMID:27556785

  17. Synthesis and biological evaluation of platensimycin analogs

    SciTech Connect

    Shen, Hong C.; Ding, Fa-Xiang; Singh, Sheo B.; Parthasarathy, Gopalakrishnan; Soisson, Stephen M.; Ha, Sookhee N.; Chen, Xun; Kodali, Srinivas; Wang, Jun; Dorso, Karen; Tata, James R.; Hammond, Milton L.; MacCoss, Malcolm; Colletti, Steven L.

    2009-07-23

    Platensimycin (1) displays antibacterial activity due to its inhibition of the elongation condensing enzyme (FabF), a novel mode of action that could potentially lead to a breakthrough in developing a new generation of antibiotics. The medicinal chemistry efforts were focused on the modification of the enone moiety of platensimycin and several analogs showed significant activity against FabF and possess antibacterial activity.

  18. Geometrically constrained parasitic-aware synthesis of analog ICs

    NASA Astrophysics Data System (ADS)

    Castro-Lopez, Rafael; Fernandez, Francisco V.; Rodriguez Vazquez, Angel

    2005-06-01

    In order to speed up the design process of analog ICs, iterations between different design stages should be avoided as much as possible. More specifically, spins between electrical and physical synthesis should be reduced for this is a very time-consuming task: if circuit performance including layout-induced degradations proves unacceptable, a re-design cycle must be entered, and electrical, physical, or both synthesis processes, would have to be repeated. It is also worth noting that if geometric optimization (e.g., area minimization) is undertaken after electrical synthesis, it may add up as another source of unexpected degradation of the circuit performance due to the impact of the geometric variables (e.g., transistor folds) on the device and the routing parasitic values. This awkward scenario is caused by the complete separation of said electrical and physical synthesis, a design practice commonly followed so far. Parasitic-aware synthesis, consisting in including parasitic estimates to the circuit netlist directly during electrical synthesis, has been proposed as solution. While most of the reported contributions either tackle parasitic-aware synthesis without paying special attention to geometric optimization or approach both issues only partially, this paper addresses the problem in a unified way. In what has been called layout-aware electrical synthesis, a simulation-based optimization algorithm explores the design space with geometric variables constrained to meet certain user-defined goals, which provides reliable estimates of layout-induced parasitics at each iteration, and, thereby, accurate evaluation of the circuit ultimate performance. This technique, demonstrated here through several design examples, requires knowing layout details beforehand; to facilitate this, procedural layout generation is used as physical synthesis approach due to its rapidness and ability to capture analog layout know-how.

  19. 40 CFR 721.2076 - D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium salt. 721.2076 Section 721...-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium... identified as D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium...

  20. 40 CFR 721.2076 - D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium salt. 721.2076 Section 721...-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium... identified as D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium...

  1. Synthesis and biological activity of Wuweizisu C and analogs.

    PubMed

    Chang, J B; Wang, Q; Li, Y F

    2009-01-01

    Lignans are widely distributed in nature. The earliest recorded medicinal use of lignans dated back to over 1000 years ago. Lignan-rich plant products were also active ingredients in Chinese and Japanese folk medicines for the treatment of various diseases. The dried root and stem of this plant are listed in the Chinese pharmacopoeia for the treatment of rheumatoid arthritis, gastric, duodenal ulcers and many other diseases. This review highlights synthetic strategies for the Wuweizisu C analogs and the important pharmacological activities as well as therapeutic findings related to the treatment of HBV and other diseases. Notably a significant and ongoing project on Wuweizisu C and its analogs has led to the discovery and development of two potent derivatives alpha-DDB and BICYCLOL which are currently in clinical trials against HBV, especially in lowering elevated SGPT levels. Further design, synthesis, and evaluation of Wuweizisu C analogs are discussed. PMID:19903156

  2. Facilitated diffusion of 6-deoxy-D-glucose in bakers' yeast: evidence against phosphorylation-associated transport of glucose.

    PubMed Central

    Romano, A H

    1982-01-01

    6-Deoxy-D-glucose, a structural homomorph of D-glucose which lacks a hydroxyl group at carbon 6 and thus cannot be phosphorylated, is transported by Saccharomyces cerevisiae via a facilitated diffusion system with affinity equivalent to that shown with D-glucose. This finding supports the facilitated diffusion mechanism for glucose transport and contradicts theories of transport-associated phosphorylation which hold that sugar phosphorylation is necessary for high-affinity operation of the glucose carrier. PMID:6754704

  3. Automatic Synthesis of CMOS Algorithmic Analog To-Digital Converter.

    NASA Astrophysics Data System (ADS)

    Jusuf, Gani

    The steady decrease in technological feature size is allowing increasing levels of integration in analog/digital interface functions. These functions consist of analog as well as digital circuits. While the turn around time for an all digital IC chip is very short due to the maturity of digital IC computer-aided design (CAD) tools over the last ten years, most analog circuits have to be designed manually due to the lack of analog IC CAD tools. As a result, analog circuit design becomes the bottleneck in the design of mixed signal processing chips. One common analog function in a mixed signal processing chip is an analog-to-digital conversion (ADC) function. This function recurs frequently but with varying performance requirements. The objective of this research is to study the design methodology of a compilation program capable of synthesizing ADC's with a broad range of sampling rates and resolution, and silicon area and performance comparable with the manual approach. The automatic compilation of the ADC function is a difficult problem mainly because ADC techniques span such a wide spectrum of performance, with radically different implementations being optimum for different ranges of conversion range, resolution, and power dissipation. We will show that a proper choice of the ADC architectures and the incorporation of many analog circuit design techniques will simplify the synthesis procedure tremendously. Moreover, in order to speed up the device sizing, hierarchical optimization procedure and behavioral simulation are implemented into the ADC module generation steps. As a result of this study, a new improved algorithmic ADC without the need of high precision comparators has been developed. This type of ADC lends itself to automatic generation due to its modularity, simplicity, small area consumption, moderate speed, low power dissipation, and single parameter trim capability that can be added at high resolution. Furthermore, a performance-driven CMOS ADC module

  4. Proposal for analog synthesis of a land mine detection system

    NASA Astrophysics Data System (ADS)

    Pardo, Fernando; Domenech, Gines; Ruiz, Ramon; Cabello, Diego; Lopez, Paula

    2003-08-01

    The detection of buried landmines is an important problem in regions where an army conflict has occurred. In particular, antipersonnel plastic mines cannot be detected with classical techniques, such as metal detectors. So a very promising detection technique based on a thermal model of the soil is applied to detect this kind of mines, in which infrared (IR) images of the soil are used. The core of this technique is the solution of the heat transfer process in the soil and at the soil-air interface, which is a very time consuming process. To overcome this problem we propose an analog circuit which can solve the equations that model the system reducing time cost by taking advantage of the inherent massive parallelism of the circuit. The description of the equations is made with VHDL--AMS and then an automatic synthesis tool generates a circuit which solves the equations.

  5. C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

    PubMed Central

    Rabe, Sebastian; Moschner, Johann; Bantzi, Marina

    2014-01-01

    Summary The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine analogs. PMID:25161712

  6. Synthesis and spectral characterization of environmentally responsive fluorescent deoxycytidine analogs

    PubMed Central

    Elmehriki, Adam AH; Suchý, Mojmír; Chicas, Kirby J; Wojciechowski, Filip; Hudson, Robert HE

    2014-01-01

    Herein, we describe the synthesis and spectroscopic properties of five novel pyrrolodeoxycytidine analogs, and the related 5-(1-pyrenylethynyl)-2’-deoxycytidine analog; as well as fluorescence characterization of 5-(p-methoxyphenylethynyl)-2’-deoxyuridine. Within this series of compounds, rigidification of the structure from 6-phenylpyrrolodeoxycytidine to 5,6-benzopyrroldeoxycytidine made remarkable improvement of the fluorescence quantum yield (Φ ~1, EtOH) and substantially increased the Stokes shift. Exchange of the phenyl group of 6-phenylpyrrolodeoxycytidine for other heterocycles (benzofuryl or indolyl) produced an increase in the extinction coefficient at the excitation wavelength while preserving high quantum yields. The steady-state fluorescence response to the environment was determined by sensitivity of Stokes shift to solvent polarity. The effect of solvent polarity on fluorescence emission intensity was concurrently examined and showed that 5,6-benzopyrrolodeoxycytidine is highly sensitive to the presence of water. On the other hand, the previously synthesized 5-(p-methoxyphenylethynyl)-2’-deoxyuridine was found to be sensitive to solvent viscosity indicating molecular rotor behavior. PMID:25483932

  7. The Synthesis of Guanosine 5′-Diphosphate l-Fucose from Guanosine 5′-Diphosphate 3,5-d-[3H]Mannose Catalyzed by an Enzyme Extract from Fruits of the Flax

    PubMed Central

    Barber, George A.

    1980-01-01

    An enzyme system from fruits of the flax plant is described that catalyzes the synthesis of the sugar nucleotide guanosine 5′-diphosphate l-fucose from guanosine 5′-diphosphate d-mannose with the intermediate formation of guanosine 5′-diphosphate 4-keto-6-deoxy-d-mannose. Tritium from-[3H]H2O was incorporated into the l-fucose portion of the sugar nucleotide in the course of the reaction, and tritium at the 3,5-carbons of the d-mannose moiety of GDP-d-mannose was exchanged with protons in the medium. These results support a mechanism of synthesis analogous to that proposed for the formation of l-rhamnose and other 6-deoxy sugars. PMID:16661431

  8. Chemoenzymatic synthesis and in situ application of S-adenosyl-L-methionine analogs

    PubMed Central

    Thomsen, Marie; Vogensen, Stine B.; Buchardt, Jens; Burkart, Michael D.

    2013-01-01

    Analogs of S-adenosyl-L-methionine (SAM) are increasingly applied to the methyltransferase (MT) catalysed modification of biomolecules including proteins, nucleic acids, and small molecules. However, SAM and analogs suffer from an inherent instability, and their chemical synthesis is challenged by low yields and difficulties in stereoisomer isolation and inhibition. Here we report the chemoenzymatic synthesis of a series of SAM analogs using wild-type (wt) and point mutants of two recently identified halogenases, SalL and FDAS. Molecular modelling studies are used to guide the rational design of mutants, and the enzymatic conversion of L-Met and other analogs into SAM analogs is demonstrated. We also apply this in situ enzymatic synthesis to the modification of a small peptide substrate by protein arginine methyltransferase 1 (PRMT1). This technique offers an attractive alternative to chemical synthesis and can be applied in situ to overcome stability and activity issues. PMID:24100405

  9. Stepwise synthesis of oligonucleotides. XXII. The synthesis of Tpsi-loop fragments of yeast tRNAIVal and their analogs.

    PubMed Central

    Zhenodarova, S M; Klyagina, V P; Smolyaninova, O A; Khabarova, M I; Antonovich, E G; Prokof'yev, M A

    1977-01-01

    The method of the combined use of nucleolytic enzymes was used for the synthesis of Tpsi-loop fragments of yeast valine tRNA and their analogs. Dinucleoside monophosphates, trinucleoside diphosphates and tetranucleoside triphosphates having the sequences of fragments 54-57 and 59-62 or their analogs were synthesized. PMID:896487

  10. 40 CFR 721.2076 - D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium salt. 721.2076 Section 721...-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium... potassium sodium salt (PMN P-00-7; CAS No.125005-87-0) is subject to reporting under this section for...

  11. 40 CFR 721.2076 - D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium salt. 721.2076 Section 721...-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium... potassium sodium salt (PMN P-00-7; CAS No.125005-87-0) is subject to reporting under this section for...

  12. 40 CFR 721.2076 - D-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium salt. 721.2076 Section 721...-Glucuronic acid, polymer with 6-deoxy-L-mannose and D-glucose, acetate, calcium magnesium potassium sodium... potassium sodium salt (PMN P-00-7; CAS No.125005-87-0) is subject to reporting under this section for...

  13. Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to anti-malarial agents we synthesized three cyclen analogs of chloroquine (4,6,7). Compound 4 displays the most potent in vitro and in vivo antimalarial activities. It displays an IC50 of 7.5 ...

  14. Chemoenzymatic synthesis and utilization of a SAM analog with an isomorphic nucleobase.

    PubMed

    Vranken, C; Fin, A; Tufar, P; Hofkens, J; Burkart, M D; Tor, Y

    2016-07-14

    SalL, an enzyme that catalyzes the synthesis of SAM from l-methionine and 5'-chloro-5'-deoxyoadenosine, is shown to accept 5'-chloro-5'-deoxythienoadenosine as a substrate and facilitate the synthesis of a synthetic SAM analog with an unnatural nucleobase. This synthetic cofactor is demonstrated to replace SAM in the DNA methylation reaction with M.TaqI. PMID:27270873

  15. Design, synthesis and biological evaluation of dinucleotide mRNA cap analog containing propargyl moiety.

    PubMed

    Shanmugasundaram, Muthian; Charles, Irudaya; Kore, Anilkumar R

    2016-03-15

    The first example of the synthesis of new dinucleotide cap analog containing propargyl group such as m(7,3'-)(O)(-propargyl)G[5']ppp[5']G is reported. The effect of propargyl cap analog with standard cap was evaluated with respect to their capping efficiency, in vitro T7 RNA polymerase transcription efficiency, and translation activity using cultured HeLa cells. It is noteworthy that propargyl cap analog outperforms standard cap by 3.1 fold in terms of translational properties. The propargyl cap analog forms a more stable complex with translation initiation factor eIF4E based on the molecular modeling studies. PMID:26899596

  16. Synthesis and biological activity of nifuroxazide and analogs. II.

    PubMed

    Tavares, L C; Chisté, J J; Santos, M G; Penna, T C

    1999-09-01

    Nifuroxazyde and six analogs were synthesized by varying the substitute from the para-position of the benzenic ring and the heteroatom of the heterocyclic ring. The MIC of seven resultant compounds was determined by serial dilutions, testing the ATCC 25923 strain of Staphylococcus aureus. A significant increase in the anti-microbial activity of thyophenic analogs, as compared with furanic and pyrrholic analogs, was observed. In addition, unlike the cyano and hydroxyl groups, the acetyl group promoted anti-microbial activity. PMID:10622109

  17. Synthesis and bioactivity of a Goralatide analog with antileukemic activity.

    PubMed

    Li, Zhiliang; Lebedyeva, Iryna O; Golubovskaya, Vita M; Cance, William G; Alamry, Khalid A; Faidallah, Hassan M; Dennis Hall, C; Katritzky, Alan R

    2015-08-01

    Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively. PMID:26048023

  18. Synthesis and bioactivity of 2',3'-benzoabscisic acid analogs.

    PubMed

    Han, Xiaoqiang; Wan, Chuan; Li, Xiuyun; Li, Hong; Yang, Dongyan; Du, Shijie; Xiao, Yumei; Qin, Zhaohai

    2015-06-01

    2',3'-Benzoabscisic acid 4a is significantly more active than (±)-ABA and can be potentially used as a plant growth regulator for agriculture. In this study, six 4a analogs were designed and synthesized. Bioassay showed that 4a displayed greater activity than (±)-ABA and the six analogs produced less inhibition than 4a itself. Specially, some analogs displayed markedly different activities to different physiological and biochemical process, which were largely different from ABA and 4a. Compared to (±)-ABA, 4b and 4c were more effective germination inhibitors for lettuce, but less effective inhibitors for rice elongation. Five-membered analog 5 was higher or slightly weaker in inhibiting Arabidopsis seed germination and rice elongation, respectively, but at least 10 times less effective than (±)-ABA in lettuce seed germination. Dual acid 6 and alkyne acid 20 nearly produced no inhibitory activity for Arabidopsis seed germination, but displayed excellent activity in inhibiting rice seedling growth. The preference of the analogs to different physiology process indicated that they might provide a strategy to develop novel ABA agonists or antagonist and be used as probe to investigate the function of different ABA receptors. PMID:25913114

  19. The synthesis of spermine analogs of the shark aminosterol squalamine.

    PubMed

    Shu, Youheng; Jones, Stephen R; Kinney, William A; Selinsky, Barry S

    2002-03-01

    Aminosterols isolated from the dogfish shark Squalus acanthias are promising therapeutic agents in the treatment of infection and cancer. One of these, MSI-1436, has been shown to possess antimicrobial activity slightly better than squalamine. In this study, a series of analogs of MSI-1436 have been synthesized from stigmasterol. The 7 alpha-hydroxy substituent of MSI-1436 was either omitted or the stereochemistry modified to the 7 beta position. Also, analogs of MSI-1436 with 24-sulfate, 24-amino, and 24-hydroxy substituents were synthesized in order to assess the importance of the side chain functional group on antimicrobial activity. All of the analogs possess significant antimicrobial activity, suggesting that substitution at C7 and C24 of the aminosterols plays a minor role in their antimicrobial potency. PMID:11856553

  20. On automatic synthesis of analog/digital circuits

    SciTech Connect

    Beiu, V.

    1998-12-31

    The paper builds on a recent explicit numerical algorithm for Kolmogorov`s superpositions, and will show that in order to synthesize minimum size (i.e., size-optimal) circuits for implementing any Boolean function, the nonlinear activation function of the gates has to be the identity function. Because classical and--or implementations, as well as threshold gate implementations require exponential size, it follows that size-optimal solutions for implementing arbitrary Boolean functions can be obtained using analog (or mixed analog/digital) circuits. Conclusions and several comments are ending the paper.

  1. Pharmacokinetic and toxicological evaluation of multi-functional thiol-6-fluoro-6-deoxy-d-glucose gold nanoparticles in vivo

    NASA Astrophysics Data System (ADS)

    Roa, Wilson; Xiong, Yeping; Chen, Jie; Yang, Xiaoyan; Song, Kun; Yang, Xiaohong; Kong, Beihua; Wilson, John; Xing, James Z.

    2012-09-01

    We synthesized a novel, multi-functional, radiosensitizing agent by covalently linking 6-fluoro-6-deoxy-d-glucose (6-FDG) to gold nanoparticles (6-FDG-GNPs) via a thiol functional group. We then assessed the bio-distribution and pharmacokinetic properties of 6-FDG-GNPs in vivo using a murine model. At 2 h, following intravenous injection of 6-FDG-GNPs into the murine model, approximately 30% of the 6-FDG-GNPs were distributed to three major organs: the liver, the spleen and the kidney. PEGylation of the 6-FDG-GNPs was found to significantly improve the bio-distribution of 6-FDG-GNPs by avoiding unintentional uptake into these organs, while simultaneously doubling the cellular uptake of GNPs in implanted breast MCF-7 adenocarcinoma. When combined with radiation, PEG-6-FDG-GNPs were found to increase the apoptosis of the MCF-7 breast adenocarinoma cells by radiation both in vitro and in vivo. Pharmacokinetic data indicate that GNPs reach their maximal concentrations at a time window of two to four hours post-injection, during which optimal radiation efficiency can be achieved. PEG-6-FDG-GNPs are thus novel nanoparticles that preferentially accumulate in targeted cancer cells where they act as potent radiosensitizing agents. Future research will aim to substitute the 18F atom into the 6-FDG molecule so that the PEG-6-FDG-GNPs can also function as radiotracers for use in positron emission tomography scanning to aid cancer diagnosis and image guided radiation therapy planning.

  2. Synthesis and biological activity of nifuroxazide and analogs.

    PubMed

    Tavares, L C; Penna, T C; Amaral, A T

    1997-03-01

    Nifuroxazide and thirteen analogs were synthesized from substituted benzoic acids and minimal inhibitory concentrations were determined using the serial dilution tests, in three sequential steps. Nifuroxazide and chloramphenicol were used as reference standards. The tests were performed in TSB against the standard bacterial strain of Staphylococcus aureus ATCC 25923. PMID:9164164

  3. Antibacterial activity and inhibition of protein synthesis in Escherichia coli by antisense DNA analogs.

    PubMed

    Rahman, M A; Summerton, J; Foster, E; Cunningham, K; Stirchak, E; Weller, D; Schaup, H W

    1991-01-01

    Protein synthesis, which takes place within ribosomes, is essential for the survival of any living organism. Ribosomes are composed of both proteins and RNA. Specific interaction between the 3' end CCUCC sequence of prokaryotic 16S rRNA and a partially complementary sequence preceding the initiating codon of mRNA is believed to be a prerequisite for initiation of protein synthesis. Here we report the use of short (three to six nucleotides) synthetic DNA analogs complementary to this sequence to block protein synthesis in vitro and in vivo in Escherichia coli. In the DNA analogs the normal phosphodiester bond in the antisense DNA was replaced by methylcarbamate internucleoside linkages to enhance transport across plasma membranes. Of the analogs tested, those with the sequence AGG and GGA inhibit protein synthesis and colony formation by E. coli strains lacking an outer cell wall. Polyethylene glycol 1000 (PEG 1000) was attached to the 5' end of some of the test methylcarbamate DNAs to enhance solubility. Analogs of AGG and GGAG with PEG 1000 attached inhibited colony formation in normal E. coli. These analogs may be useful food additives to control bacterial spoilage and biomedically as antibiotics. PMID:1821653

  4. Design and Synthesis of an Inositol Phosphate Analog Based on Computational Docking Studies

    PubMed Central

    Peng, Zhenghong; Maxwell, David; Sun, Duoli; Ying, Yunming; Schuber, Paul T.; Bhanu Prasad, Basvoju A.; Gelovani, Juri; Yung, Wai-Kwan Alfred; Bornmann, William G.

    2014-01-01

    A virtual library of 54 inositol analog mimics of In(1,4,5)P3 has been docked, scored, and ranked within the binding site of human inositol 1,4,5-trisphosphate 3-kinase A (IP3-3KA). Chemical synthesis of the best scoring structure that also met distance criteria for 3′-OH to -P in Phosphate has been attempted along with the synthesis of (1S,2R,3S,4S)-3-fluoro-2,4-dihydroxycyclohexanecarboxylic acid as an inositol analog, useful for non-invasive visualization and quantitation of IP3-3KA enzymatic activity PMID:25110363

  5. Synthesis and Antibacterial Activity of Pentacyclines: A Novel Class of Tetracycline Analogs

    PubMed Central

    2011-01-01

    Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey. PMID:21500832

  6. Synthesis of tritium-labeled vitamin A and its analogs

    SciTech Connect

    Rhee, S.W.; Bubb, J.E.

    1985-11-01

    Metabolic and pharmacologic studies of Vitamin A and its analogs related to the prevention of lung cancer and other epithelial cancers required tritium-labeled Vitamin A analogs and ..beta..-carotene at high specific activity. Syntheses of some of the isomers were therefore developed in the laboratory, as described in the paper. The advantages of the scheme shown are that : 1. Tritiums are introduced into the molecule by catalytic hydrogenation, thus affording high specific activity. 2. It uses an allylic rearrangement of tritiated vinyl-..beta..-ionol to C/sub 15/-phosphonium salt, which is condensed with C/sub 5/-nitrile to give C/sub 20/-skeleton of retinonitrile. 3. It permits the development of milder methods to convert tritium-labeled retinaldehyde, as a common intermediate, to the other retinoids (i.e., retinoic acid, retinol, and retinyl acetate). Furthermore, tritium-labeled all-trans-..beta..-carotene, an important carotenoid, has been obtained from the retinaldehyde.

  7. Synthesis and radiolabeling of a somatostatin analog for multimodal imaging

    NASA Astrophysics Data System (ADS)

    Edwards, W. Barry; Liang, Kexian; Xu, Baogang; Anderson, Carolyn J.; Achilefu, Samuel

    2006-02-01

    A new multimodal imaging agent for imaging the somatostatin receptor has been synthesized and evaluated in vitro and in vivo. A somatostatin analog, conjugated to both 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid (DOTA) and cypate (BS-296), was synthesized entirely on the solid phase (Fmoc) and purified by RP-HPLC. DOTA was added as a ligand for radiometals such as 64Cu or 177Lu for either radio-imaging or radiotherapy respectively. Cytate, a cypatesomatostatin analog conjugate, has previously demonstrated the ability to visualize somatostatin receptor rich tumor xenografts and natural organs by optical imaging techniques. BS-296 exhibited low nanomolar inhibitory capacity toward the binding of radiolabeled somatostatin analogs in cell membranes enriched in the somatostatin receptor, demonstrating the high affinity of this multimodal imaging peptide and indicating its potential as a molecular imaging agent. 64Cu, an isotope for diagnostic imaging and radiotherapy, was selected as the isotope for radiolabeling BS-296. BS-296 was radiolabeled with 64Cu in high specific activity (200 μCi/μg) in 90% radiochemical yield. Addition of 2,5-dihydroxybenzoic acid (gentisic acid) prevented radiolysis of the sample, allowing for study of the 64Cu -BS-296 the day following radiolabeling. Furthermore, inclusion of DMSO at a level of 20% was found not to interfere with radiolabeling yields and prevented the adherence of 64Cu -BS-296 to the walls of the reaction vessel.

  8. An Efficient, Optimized Synthesis of Fentanyl and Related Analogs

    PubMed Central

    Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.

    2014-01-01

    The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73–78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids. PMID:25233364

  9. Large-scale asymmetric synthesis of the bioprotective agent JP4-039 and analogs

    PubMed Central

    Frantz, Marie-Céline; Pierce, Joshua G.; Pierce, Joan M.; Kangying, Li; Qingwei, Wan; Johnson, Matthew; Wipf, Peter

    2011-01-01

    JP4-039 is a novel nitroxide conjugate capable of crossing lipid bilayer membranes and scavenging reactive oxygen species (ROS). An efficient and scalable one-pot hydrozirconation-transmetalation-imine addition methodology has been developed for its asymmetric preparation. Furthermore, this versatile methodology allows for the synthesis of cyclopropyl and fluorinated analogs of the parent lead structure. PMID:21452836

  10. Synthesis of γ-Phosphate-Labeled and Doubly Labeled Adenosine Triphosphate Analogs.

    PubMed

    Hacker, Stephan M; Welter, Moritz; Marx, Andreas

    2015-01-01

    This unit describes the synthesis of γ-phosphate-labeled and doubly labeled adenosine triphosphate (ATP) analogs and their characterization using the phosphodiesterase I from Crotalus adamanteus (snake venom phosphodiesterase; SVPD). In the key step of the synthesis, ATP or an ATP analog, bearing a linker containing a trifluoroacetamide group attached to the nucleoside, are modified with an azide-containing linker at the terminal phosphate using an alkylation reaction. Subsequently, different labels are introduced to the linkers by transformation of one functional group to an amine and coupling to an N-hydroxysuccinimide ester. Specifically, the Staudinger reaction of the azide is employed as a straightforward means to obtain an amine in the presence of various labels. Furthermore, the fluorescence characteristics of a fluorogenic, doubly labeled ATP analog are investigated following enzymatic cleavage by SVPD. PMID:25754889

  11. Synthesis of guanidino sugar conjugates as GlcβArg analogs.

    PubMed

    Srivastava, Amrita; Loganathan, Duraikkannu

    2013-11-01

    The β-glucosyl linkage to the guanidine group of arginine (Arg) is found in amylogenin, a glycoprotein from sweet corn. Such a linkage is formed by a rare N-glycosylation of proteins. Synthesis of analogs of the unusual N-glycosidic linkage (GlcβArg) with an acetamido or triazole spacer between the glycosyl residue and the guanidine moiety was accomplished by the reaction of fully acetylated sugar unit containing a free amino group with bis-Boc-thiourea. Synthesis of N-glucosylarginine with an amido linker was also achieved during the present study. This methodology was also extended to the synthesis of cationic glucolipid. PMID:23760535

  12. Synthesis and P-glycoprotein induction activity of colupulone analogs.

    PubMed

    Bharate, Jaideep B; Batarseh, Yazan S; Wani, Abubakar; Sharma, Sadhana; Vishwakarma, Ram A; Kaddoumi, Amal; Kumar, Ajay; Bharate, Sandip B

    2015-05-21

    Brain amyloid-beta (Aβ) plaques are one of the primary hallmarks associated with Alzheimer's disease (AD) pathology. Efflux pump proteins located at the blood-brain barrier (BBB) have been reported to play an important role in the clearance of brain Aβ, among which the P-glycoprotein (P-gp) efflux transporter pump has been shown to play a crucial role. Thus, P-gp has been considered as a potential therapeutic target for treatment of AD. Colupulone, a prenylated phloroglucinol isolated from Humulus lupulus, is known to activate pregnane-X-receptor (PXR), which is a nuclear receptor controlling P-gp expression. In the present work, we aimed to synthesize and identify analogs of colupulone that are potent P-gp inducer(s) with an ability to enhance Aβ transport across the BBB. A series of colupulone analogs were synthesized by modifications at both prenyl as well as acyl domains. All compounds were screened for P-gp induction activity using a rhodamine 123 based efflux assay in the P-gp overexpressing human adenocarcinoma LS-180 cells, wherein all compounds showed significant P-gp induction activity at 5 μM. In the western blot studies in LS-180 cells, compounds 3k and 5f were able to induce P-gp as well as LRP1 at 1 μM. The effect of compounds on the Aβ uptake and transport was then evaluated. Among all tested compounds, diprenylated acyl phloroglucinol displayed a significant increase (29%) in Aβ transport across bEnd3 cells grown on inserts as a BBB model. The results presented here suggest the potential of this scaffold to enhance clearance of brain Aβ across the BBB and thus its promise for development as a potential anti-Alzheimer agent. PMID:25875530

  13. Deoxyadenosine family: improved synthesis, DNA damage and repair, analogs as drugs.

    PubMed

    Biswas, Himadri; Kar, Indrani; Chattopadhyaya, Rajagopal

    2013-08-01

    Improved synthesis of 2'-deoxyadenosine using Escherichia coli overexpressing some enzymes and gram-scale chemical synthesis of 2'-deoxynucleoside 5'-triphosphates reported recently are described in this review. Other topics include DNA damage induced by chromium(VI), Fenton chemistry, photoinduction with lumazine, or by ultrasound in neutral solution; 8,5'-cyclo-2'-deoxyadenosine isomers as potential biomarkers; and a recapitulation of purine 5',8-cyclonucleoside studies. The mutagenicities of some products generated by oxidizing 2'-deoxyadenosine 5'-triphosphate, nucleotide pool sanitization, and translesion synthesis are also reviewed. Characterizing cross-linking between nucleosides in opposite strands of DNA and endonuclease V-mediated deoxyinosine excision repair are discussed. The use of purine nucleoside analogs in the treatment of rarer chronic lymphoid leukemias is reviewed. Some analogs at the C8 position induced delayed polymerization arrest during HIV-1 reverse transcription. The susceptibility of clinically metronidazole-resistant Trichomonas vaginalis to two analogs, toyocamycin and 2-fluoro-2'-deoxyadenosine, were tested in vitro. GS-9148, a dAMP analog, was translocated to the priming site in a complex with reverse transcriptase and double-stranded DNA to gain insight into the mechanism of reverse transcriptase inhibition. PMID:25436589

  14. Synthesis and anticancer evaluation of furfurylidene 4-piperidone analogs.

    PubMed

    Jadhav, Rahul L; Magdum, Chandrakant S; Patil, Manisha V

    2014-06-01

    Recently different series of compounds have been designed that utilize the 1,5-diaryl-3-oxo-1,4-pentadinenyl pharmacophore for the development of novel cytotoxic and anticancer agents. These compounds interact with cellular thiols and thiols are not part of nucleic acids. Hence, these compounds are free from the problem of mutagenicity and carcinogenicity. The Claisen-Schmidt reaction is used for synthesizing furfurylidene analogs in a basic medium. The title compounds were prepared by reacting furfurylidenes with aryl sulfonyl, benzoyl, acroylyl, or acetyl chloride. The resulting synthesized compounds were screened for their in vitro cytotoxic properties by MTT and SRB assays against leukemic and colon cancer cell lines. Acute toxicity was determined by OECD-423 guidelines. The in vivo anticancer activities were evaluated against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The MTT assay showed that compounds 2d and 3d have significant cytotoxicity against the Molt-4 human cell line as compared to the standard, 5-fluorouracil. In addition, the SRB assay indicated that the compounds 2, 2a, 2d, and 3d showed equipotent cytotoxicity against human leukemia cell lines as compared to the standard, doxorubicin. Compounds 2a and 2d showed significant anticancer activity against EAC in Swiss albino mice. This study revealed the potential of these molecules for further development as anticancer agents. PMID:24623392

  15. Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway.

    PubMed

    Hvid, Henning; Fendt, Sarah-Maria; Blouin, Marie-José; Birman, Elena; Voisin, Gregory; Svendsen, Angela Manegold; Frank, Russell; Vander Heiden, Matthew G; Stephanopoulos, Gregory; Hansen, Bo Falck; Pollak, Michael

    2012-08-01

    Recent evidence suggests that type II diabetes is associated with increased risk and/or aggressive behavior of several cancers, including those arising from the colon. Concerns have been raised that endogenous hyperinsulinemia and/or exogenous insulin and insulin analogs might stimulate proliferation of neoplastic cells. However, the mechanisms underlying possible growth-promoting effects of insulin and insulin analogs in cancer cells in vivo, such as changes in gene expression, are incompletely described. We observed that administration of the insulin analog X10 significantly increased tumor growth and proliferation in a murine colon cancer model (MC38 cell allografts). Insulin and X10 altered gene expression in MC38 tumors in a similar fashion, but X10 was more potent in terms of the number of genes influenced and the magnitude of changes in gene expression. Many of the affected genes were annotated to metabolism, nutrient uptake, and protein synthesis. Strikingly, expression of genes encoding enzymes in the serine synthesis pathway, recently shown to be critical for neoplastic proliferation, was increased following treatment with insulin and X10. Using stable isotopic tracers and mass spectrometry, we confirmed that insulin and X10 increased glucose contribution to serine synthesis in MC38 cells. The data demonstrate that the tumor growth-promoting effects of insulin and X10 are associated with changes in expression of genes involved in cellular energy metabolism and reveal previously unrecognized effects of insulin and X10 on serine synthesis. PMID:22685267

  16. Synthesis and psychobiological evaluation of modafinil analogs in mice

    PubMed Central

    2013-01-01

    Background and the purpose of the study Modafinil, a novel wake-promoting agent with low potential for abuse and dependence, has a reliable structure to find some novel derivatives with better activity and lower potential for abuse and risk of dependency. This study was designed to evaluate psychobiological activity of some novel N-aryl modafinil derivatives. Methods Seven novel N-aryl modafinil derivatives were synthesized through three reactions: a) preparation of benzhydrylsulfanyl acetic acid through reaction of benzhydrol with thioglycolic acid, b) formation of desired amide by adding the substituted aniline to activated acid with EDC (1-ethyl-3-(3-dimethyl amino propyl) carbodiimide). This reaction was catalyzed by HOBt (N- hydroxylbenzotriazole), and c) oxidation of sulfur to sulfoxide group with H2O2. Then, their psychobiological effect on the performance of male albino mice were compared to that of modafinil as following: wakefulness by determining the effects of derivatives on phenobarbital-induced loss of the righting reflex (LOPR); exploratory activity by measuring activity in the open field test (OFT); depression by measuring immobility time (IT) during forced swimming test (FST) and the anxiogenic and anxiolytic like effects by using elevated plus-maze test (EPM). All tests were videotaped and analyzed for the frequency and duration of the behaviors during the procedures. Conclusions 2-(Benzhydrylsulfonyl)-N-(4-chlorophenyl)acetamide (4c) showed comparable result in LOPR test. However, all analogs were found to be stimulant except 2-(benzhydrylsulfinyl)-N-phenylacetamide (4a). Also 4c led the most exploratory activity in mice among derivatives. FST results showed that 4a had the longest IT while modafinil, 2-(benzhydrylsulfinyl)-N-(3-chlorophenyl) acetamide (4b) and 2-(benzhydrylsulfinyl)-N-(4-ethylphenyl) acetamide (4d) had the shortest IT. In EPM, all derivatives showed anxiogenic-like behavior since they decreased open arms time and open arms

  17. Solid-Phase Synthesis of Oligodeoxynucleotide Analogs Containing Phosphorodithioate Linkages.

    PubMed

    Yang, Xianbin

    2016-01-01

    The oligodeoxynucleotide phosphorodithioate modification (PS2-ODN) uses two sulfur atoms to replace two non-bridging oxygen atoms at an internucleotide phosphordiester backbone linkage. Like a natural phosphodiester ODN backbone linkage, a PS2-modified backbone linkage is achiral at phosphorus. PS2-ODNs are highly stable to nucleases and numerous in vitro assays have demonstrated their biological activity. For example, PS2-ODNs activated RNase H in vitro, strongly inhibited human immunodeficiency virus (HIV) reverse transcriptase, induced B-cell proliferation and differentiation, and bound to protein targets in the form of PS2-aptamers (thioaptamers). Thus, the interest in and promise of PS2-ODNs has spawned a variety of strategies for synthesizing, isolating, and characterizing this compounds. ODN-thiophosphoramidite monomers are commercially available from either AM Biotechnologies or Glen Research and this unit describes an effective methodology for solid-phase synthesis, deprotection, and purification of ODNs having PS2 internucleotide linkages. © 2016 by John Wiley & Sons, Inc. PMID:27584703

  18. Synthesis of Pelorol and Its Analogs and Their Inhibitory Effects on Phosphatidylinositol 3-Kinase

    PubMed Central

    Luo, Yongjie; Chen, Huixuan; Weng, Jiang; Lu, Gui

    2016-01-01

    There are numerous biologically active substances with novel structures and unique physiological functions in marine organisms. These substances are important sources of new lead compounds. Pelorol is a natural product isolated from marine organisms that possesses a novel structure with high bioactivity. In this paper, the synthesis of pelorol has been completed, and the synthesis of some intermediates has been optimized and scaled up. Five pelorol analogs have also been prepared. Preliminary biological activity testing demonstrated that compounds 5 and 6 might be potential lead compounds for cancer therapy. PMID:27338420

  19. A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis.

    PubMed

    Lühmann, Tessa; Mong, Surin K; Simon, Mark D; Meinel, Lorenz; Pentelute, Bradley L

    2016-04-01

    H2 relaxin is a pleiotropic peptide hormone with clinical potential. Here we report on the reaction and use of hexafluorobenzene as an intramolecular disulfide replacement between Cys10 and Cys15 in the A-chain of H2 relaxin. Using flow-based Fmoc solid-phase peptide synthesis methodology we were able to obtain high-quality H2 relaxin fragments that were previously reported as challenging to synthesize. Subsequent native chemical ligation and oxidative folding enabled total synthesis of both wild type H2 relaxin and a C6F4 linked analog. Cell-based activity assays revealed modest activity for the C6F4 linked H2 relaxin analog, albeit 100-fold reduced relative to wild type. This work demonstrates how perfluoroarylation-cysteine SNAr chemistry may be a useful tool for the selective replacement of native disulfide bonds in proteins. PMID:26954512

  20. Analogs of sex pheromone of processionary moth,Thaumetopoea pityocampa: Synthesis and biological activity.

    PubMed

    Camps, F; Fabriàs, G; Gasol, V; Guerrero, A; Hernández, R; Montoya, R

    1988-05-01

    The synthesis and biological activity of some analogs of (Z)-13-hexadecen-11-ynyl acetate1, the major component of the sex pheromone of the processionary mothThaumetopoea pityocampa is described. The analogs have been formally derived by structural modification of the enyne and acetate functions of the parent compound1. In field tests, trifluoroacetate ester16 and the analog,11, with fluorine substitution at the olefin site, decreased the pheromone action, whereas epoxy derivative,10, from epoxidation of the olefin moiety in1, and propionate ester15 gave synergistic activity. The formate14 had a variable effect according to the composition of the lure. Formal reduction of the enyne to give the acetylene2 was found to retain activity. Alcohols12 and13, resulting from hydrolysis of the enyne1 and acetylene2, respectively, inhibited the action of their parent compounds. PMID:24276283

  1. Synthesis, biological evaluation and structural analysis of novel peripherally active morphiceptin analogs.

    PubMed

    Adamska, Anna; Kluczyk, Alicja; Cerlesi, Maria Camilla; Calo, Girolamo; Janecka, Anna; Borics, Attila

    2016-04-01

    Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a tetrapeptide amide, is a selective ligand of the μ-opioid receptor (MOR). This study reports the synthesis and biological evaluation of a series of novel morphiceptin analogs modified in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F2Pro) in l or d configuration. Depending on the fluorinated amino acid configuration and its position in the sequence, new analogs behaved as selective full MOR agonists showing high, moderate, or relatively low potency. The most potent analog, Tyr-F2Pro-Phe-d-F2Pro-NH2, was also able to activate the κ-opioid receptor (KOR), although with low potency. Docking studies and the comparison of results with the high resolution crystallographic structure of a MOR-agonist complex revealed possible structure-activity relationships of this compound family. PMID:26944625

  2. Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice

    PubMed Central

    Yadav, Shiv Kumar; Maurya, Chandra Kant; Gupta, Pradeep Kumar; Jain, Ajai Kumar; Ganesan, Kumaran

    2014-01-01

    Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management. PMID:26109885

  3. A Proposed Model of Self-Generated Analogical Reasoning for the Concept of Translation in Protein Synthesis

    ERIC Educational Resources Information Center

    Salih, Maria

    2008-01-01

    This paper explored and described the analogical reasoning occurring in the minds of different science achievement groups for the concept of translation in protein synthesis. "What is the process of self-generated analogical reasoning?", "What types of matching was involved?" and "What are the consequences of the matching processes?" were some of…

  4. Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin.

    PubMed

    Lone, Shabir H; Bhat, Khursheed A; Majeed, Rabiya; Hamid, Abid; Khuroo, Mohd A

    2014-02-15

    A convenient and modular synthesis involving diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-triazoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the synthesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and 8.5 μM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 μM against human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines, respectively. The present synthesis was designed based on the previous literature reports of Ludartin as an aromatase inhibitor. Our work provides an initial study on structure-activity relationship of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular. PMID:24484897

  5. Potent oxazoline analog of apratoxin C: Synthesis, biological evaluation, and conformational analysis.

    PubMed

    Yoshida, Masahito; Onda, Yuichi; Masuda, Yuichi; Doi, Takayuki

    2016-11-01

    In this research, the synthesis, biological evaluation, and conformational analysis of an apratoxin C oxazoline analog (3) have been demonstrated. The preparation of synthetic key intermediate 9 was achieved using an improved strategy that involves commercially available 3-methylglutaric anhydride (12), an enzymatic enantioselective alcoholysis, and a diastereoselective reduction. The Pro-Dtrina (3,7-dihydroxy-2,5,8-trimethylnonanoic acid) moiety 8 was successfully synthesized in a similar manner as our previously reported synthesis of apratoxin C (1). The cyclization precursor 5 was formed after the coupling of Pro-Dtrina 8 with a known tetrapeptide 7 to afford a linear peptide 6, the formation of an oxazoline, and the removal of the protecting groups. Finally, the macrolactamization of 5 with O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIEA) furnished an apratoxin C oxazoline analog (3), which exhibited a potent cytotoxicity against HeLa cells (IC50 value of 22 nM) that was comparable with the cytotoxicity of apratoxin C (1) (IC50 value of 4.2 nM). Conformational analyses of 1 and 3 through NMR experiments showed that oxazoline analog 3 formed a tertiary structure that was similar to the apratoxin C (1) structure in CD3 CN, which provided a probable explanation for their comparable cytotoxicities. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 404-414, 2016. PMID:26584466

  6. Structural and functional studies on a 3'-epimerase involved in the biosynthesis of dTDP-6-deoxy-D-allose.

    PubMed

    Kubiak, Rachel L; Phillips, Rebecca K; Zmudka, Matthew W; Ahn, Melissa R; Maka, E Malaika; Pyeatt, Gwen L; Roggensack, Sarah J; Holden, Hazel M

    2012-11-20

    Unusual deoxy sugars are often attached to natural products such as antibiotics, antifungals, and chemotherapeutic agents. One such sugar is mycinose, which has been found on the antibiotics chalcomycin and tylosin. An intermediate in the biosynthesis of mycinose is dTDP-6-deoxy-D-allose. Four enzymes are required for the production of dTDP-6-deoxy-D-allose in Streptomyces bikiniensis, a soil-dwelling microbe first isolated from the Bikini and Rongelap atolls. Here we describe a combined structural and functional study of the enzyme ChmJ, which reportedly catalyzes the third step in the pathway leading to dTDP-6-deoxy-D-allose formation. Specifically, it has been proposed that ChmJ is a 3'-epimerase that converts dTDP-4-keto-6-deoxyglucose to dTDP-4-keto-6-deoxyallose. This activity, however, has never been verified in vitro. As reported here, we demonstrate using (1)H nuclear magnetic resonance that ChmJ, indeed, functions as a 3'-epimerase. In addition, we determined the structure of ChmJ complexed with dTDP-quinovose to 2.0 Å resolution. The structure of ChmJ shows that it belongs to the well-characterized "cupin" superfamily. Two active site residues, His 60 and Tyr 130, were subsequently targeted for study via site-directed mutagenesis and kinetic analyses, and the three-dimensional architecture of the H60N/Y130F mutant protein was determined to 1.6 Å resolution. Finally, the structure of the apoenzyme was determined to 2.2 Å resolution. It has been previously suggested that the position of a conserved tyrosine, Tyr 130 in the case of ChmJ, determines whether an enzyme in this superfamily functions as a mono- or diepimerase. Our results indicate that the orientation of the tyrosine residue in ChmJ is a function of the ligand occupying the active site cleft. PMID:23116432

  7. Total synthesis, structural, and biological evaluation of stylissatin A and related analogs.

    PubMed

    Shaheen, Farzana; Jabeen, Almas; Ashraf, Samreen; Nadeem-Ul-Haque, Muhammad; Shah, Zafar Ali; Ziaee, Muhammad Asad; Dastagir, Nida; Ganesan, A

    2016-09-01

    The natural product cyclic peptide stylissatin A (1a) was reported to inhibit nitric oxide production in LPS-stimulated murine macrophage RAW 264.7 cells. In the current study, solid-phase total synthesis of stylissatin A was performed by using a safety-catch linker and yielded the peptide with a trans-Phe(7) -Pro(6) linkage, whereas the natural product is the cis rotamer at this position as evidenced by a marked difference in NMR chemical shifts. In order to preclude the possibility of 1b being an epimer of the natural product, we repeated the synthesis using d-allo-Ile in place of l-Ile and a different site for macrocyclization. The resulting product (d-allo-Ile(2) )-stylissatin A (1c) was also found to have the trans-Phe(7) -Pro(6) peptide conformations like rotamer 1b. Applying the second route to the synthesis of stylissatin A itself, we obtained stylissatin A natural rotamer 1a accompanied by rotamer 1b as the major product. Rotamers 1a, 1b, and the epimer 1c were separable by HPLC, and 1a was found to match the natural product in structure and biological activity. Six related analogs 2-7 of stylissatin A were synthesized on Wang resin and characterized by spectral analysis. The natural product (1a), the rotamer (1b), and (d-allo-Ile(2) )-stylissatin A (1c) exhibited significant inhibition of NO(.) . Further investigations were focused on 1b, which also inhibited proliferation of T-cells and inflammatory cytokine IL-2 production. The analogs 2-7 weakly inhibited NO(.) production, but strongly inhibited IL-2 cytokine production compared with synthetic peptide 1b. All analogs inhibited the proliferation of T-cells, with analog 7 having the strongest effect. In the analogs, the Pro(6) residue was replaced by Glu/Ala, and the SAR indicates that the nature of this residue plays a role in the biological function of these peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27526945

  8. Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP

    PubMed Central

    Baguley, Tyler D.; Nairn, Angus C.; Lombroso, Paul J.; Ellman, Jonathan A.

    2015-01-01

    Striatal-enriched protein tyrosine phosphatase (STEP) is a brain specific protein tyrosine phosphatase that has been implicated in many neurodegenerative diseases, such as Alzheimer’s disease. We recently reported the benzopentathiepin TC-2153 as a potent inhibitor of STEP in vitro, cells and animals. Herein, we report the synthesis and evaluation of TC-2153 analogs in order to define what structural features are important for inhibition and to identify positions tolerant of substitution for further study. The trifluoromethyl substitution is beneficial for inhibitor potency, and the amine is tolerant of acylation, and thus provides a convenient handle for introducing additional functionality such as reporter groups. PMID:25666825

  9. Synthesis, DNA-binding and biological activity of a double intercalating analog of ethidium bromide.

    PubMed Central

    Kuhlmann, K F; Charbeneau, N J; Mosher, C W

    1978-01-01

    A bis-phenanthridinium salt has been synthesized and its DNA-binding studied. Evidence provided by UV and CD spectra, by thermal denaturation profiles and by equilibrium dialysis of the drug-DNA complex lead to the conclusion that both phenanthridine moieties intercalate in the helix. The double intercalator appears to be less potent than ethidium chloride as an inhibitor of nucleic acid synthesis in cultured L1210 cells, though it is more potent than a monomeric analog. The low potency may be due to a low cell influx rate. PMID:673863

  10. An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin

    PubMed Central

    Yoganathan, Sabesan; Yin, Ning; He, Yong; Mesleh, Michael; Gu, Yu Gui; Miller, Scott J.

    2014-01-01

    Herein we report a direct and efficient method for the synthesis of four new carboxylate-isostere analogs of daptomycin. The side chain carboxylic acid moieties of the aspartic acids (Asp-3, Asp-7 and Asp-9) and β-methyl glutamic acid (MeGlu-12) were all converted into the corresponding carboxylate isosteres using direct synthetic procedures. The present study also describes an esterification protocol to overcome the possible backbone cyclization of the activated side chain carboxylic acid group of either Asp or Glu, onto the backbone amide. PMID:23752953

  11. Synthesis and anti-oomycete activity of novel quinazolin- and benzothiazol-6-yloxyacetamides: Potent aza-analogs and five-ring analogs of quinoline fungicides.

    PubMed

    Beaudegnies, Renaud; Quaranta, Laura; Murphy Kessabi, Fiona; Lamberth, Clemens; Knauf-Beiter, Gertrud; Fraser, Torquil

    2016-02-01

    Novel quinazolin- and benzothiazol-6-yloxyacetamides show excellent in vivo activity against the three economically most important Oomycete pathogens Phytophthora infestans, Plasmopara viticola and Pythium ultimum. They are polar analogs of known quinolin-6-yloxyacetamides, which are not active against the soil-borne damping-off disease caused by Pythium ultimum. The Bogert quinazoline synthesis, an almost forgotten heterocyclization technique, proved to be highly useful for the concise construction of required quinazolin-6-ol building blocks. PMID:26346670

  12. Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation.

    PubMed

    Mishra, Ram Chandra; Karna, Prasanthi; Gundala, Sushma Reddy; Pannu, Vaishali; Stanton, Richard A; Gupta, Kamlesh Kumar; Robinson, M Hope; Lopus, Manu; Wilson, Leslie; Henary, Maged; Aneja, Ritu

    2011-07-15

    Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling. PMID:21501599

  13. Synthesis and evaluation of antiproliferative activity of a novel series of hydroxychavicol analogs.

    PubMed

    Yadav, Yogesh; Owens, Eric A; Sharma, Vibhuti; Aneja, Ritu; Henary, Maged

    2014-03-21

    We have recently demonstrated that hydroxychavicol is a major constituent and the most active biophenolic of Piper betel leaves with significant antiproliferative activity in the micro molar range. Herein we present the design, synthesis and evaluation of fifteen novel hydroxychavicol analogs with varying antiproliferative activities in cancer cell lines from two representative tissue types, namely, the prostate and cervix that show very encouraging results compared to the parent compounds. Our long range goal is to develop a structure-activity guided relationship to gain mechanistic insights into novel molecular targets of this class of bioactive molecules for rational drug development. Cytotoxicity-guided experimentation on these novel analogs yielded the following structural factors as the key activity regulators: 1) unlike the hydroxyl substituent at position-4, the position-3 hydroxyl is vital for enhanced activity 2) acetoxyl groups are dispensable for activity as corroborated earlier by others 3) allylic double bonds at 2'C-3'C serve to positively influence antiproliferative activity 4) long saturated side chains at 1'-position negatively regulate antiproliferative activity and 5) maneuvering position-4 with a benzyl group positively impacted the biological activity profile. Most amphiphilic compounds showed moderate to good therapeutic potential as expected on the basis of medicinal chemistry principles. Intriguingly, the most active compound with ten-fold higher activity than the parent molecule was realized by sheer serendipity to employ a silica gel based rearrangement that was further explored using nuclear magnetic resonance spectroscopy and density functional theory calculations. This is the first report to describe strategies for optimal synthesis of a novel series of 15 analogs based upon hydroxychavicol, a simple phytochemical of immense anticancer potential. PMID:24508612

  14. Solid Phase-Assisted Synthesis and Screening of a Small Library of N-(4-Hydroxyphenyl)retinamide (4-HPR) Analogs

    PubMed Central

    Mershon, Serena M.; Anding, Allyson L.; Chapman, Jason S.; Clagett-Dame, Margaret; Stonerock, Laura A.; Curley, Robert W.

    2007-01-01

    Using solid phase-assisted synthesis and purification, a 49 member library of analogs of the mammary tumor chemopreventive retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been prepared. After prescreening for growth inhibitory activity in human mammary tumor cells (MCF-7) in culture, most of those analogs which showed activity (12 of them) were assayed for apoptosis-inducing activity in the MCF-7 cells. At least 3 of the analogs (13, 24, and 28) showed activity approaching that of 4-HPR. PMID:17112722

  15. [Synthesis of GnRH analogs and their application in targeted gene delivery systems].

    PubMed

    Iablokova, T V; Chelushkin, P S; Dorosh, M Iu; Efremov, A M; Orlov, S V; Burov, S V

    2012-01-01

    A set of GnRH analogues containing nuclear localization signal (NLS) of SV-40 virus large T-antigen have been synthesized using solid phase peptide synthesis and chemical ligation technique. Selective chemical ligation was achieved as a result of hydrazone formation in the course of interaction between NLS hydrazide and GnRH analog modified by pyruvic acid. The efficiency of synthesized peptide carriers was demonstrated in experiments with human cancer cells transfected by reporter luciferase and beta-galactosidase genes or suicide HSV-1 thymidine kinase gene. It was shown that selectivity of action on cancer cells can be achieved as a result of peptide/DNA complex penetration through the cell membrane by GnRH receptor-mediated endocytosis pathway. PMID:22792703

  16. Dexamethasone-Induced Insulin Resistance: Kinetic Modeling Using Novel PET Radiopharmaceutical 6-Deoxy-6-[18F]fluoro-D-glucose

    PubMed Central

    Su, Kuan-Hao; Chandramouli, Visvanathan; Ismail-Beigi, Faramarz; Muzic, Raymond F.

    2015-01-01

    Purpose An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis–Menten-based kinetic model using 6-deoxy-6-[18F]fluoro-D-glucose (6-[18F]FDG) to quantify glucose transport with PET. Procedures Seventeen, male, Sprague–Dawley rats were studied in three groups: control (Ctrl), control+insulin (Ctrl+I), and dexamethasone+insulin (Dex+I). PET scans were acquired for 2 h under euglycemic conditions in the Ctrl group and under hyperinsulinemic-euglycemic conditions in the Ctrl+I and Dex+I groups. Results Glucose transport, assessed according to the 6-[18F]FDG concentration, was highest in skeletal muscle in the Ctrl+I, intermediate in the Dex+I, and lowest in the Ctrl group, while that in the brain was similar among the groups. Modeling analysis applied to the skeletal muscle uptake curves yielded values of parameters related to glucose transport that were greatest in the Ctrl+I group and increased to a lesser degree in the Dex+I group, compared to the Ctrl group. Conclusion 6-[18F]FDG and the Michaelis–Menten-based model can be used to measure insulin-stimulated glucose transport under basal and an insulin resistant state in vivo. PMID:24819311

  17. A First Microwave-Assisted Synthesis of a New Class of Purine and Guanine Thioglycoside Analogs.

    PubMed

    Elgemeie, Galal; Abu-Zaied, Mamdouh; Hebishy, Ali; Abbas, Nermen; Hamed, Mai

    2016-09-01

    A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogs from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a]pyrimidine-7-thiolate and 7-mercaptopyrazolo[1,5-a]pyrimidine derivatives via condensation of 5-amino-1H-pyrazoles with sodium 2,2-dicyanoethene-1,1-bis(thiolate) salts or 2-(dimercaptomethylene)malononitrile, respectively, under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogs. The obtained purines and purines thioglycosides derivatives were evaluated in vitro against lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3) cancer cell lines. Some of these compounds (5b, 5d, 5f, and 9a-d) exhibited little potency toward the four cell lines. On the other hand, compound 5a elicited higher cytotoxicity on both prostate (PC3) and colon (HCT116), respectively, while it was found moderate on lung (A549), and inactive on liver (HEPG2). Moreover, compound 5c was found moderate with LC50 values 52.0-88.9 μM for almost all the cell lines. PMID:27556784

  18. Synthesis and evaluation of 3-aryl piperidine analogs as potent and efficacious dopamine D4 receptor agonists.

    PubMed

    Wang, Xueqing; Bhatia, Pramila A; Daanen, Jerome F; Latsaw, Steve P; Rohde, Jeffrey; Kolasa, Teodozyi; Hakeem, Ahmed A; Matulenko, Mark A; Nakane, Masaki; Uchic, Marie E; Miller, Loan N; Chang, Renjie; Moreland, Robert B; Brioni, Jorge D; Stewart, Andrew O

    2005-08-01

    A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed. PMID:15896964

  19. Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents.

    PubMed

    Li, Wen-Shan; More, Shivaji V; Wang, Chie-Hong; Jen, Ya Ching; Yao, Ching-Fa; Wang, Tein-Fu; Hung, Chin-Chun; Jao, Shu-Chuan

    2010-02-01

    This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. PMID:20022505

  20. Chemoenzymatic synthesis of the bacterial polysaccharide repeating unit undecaprenyl pyrophosphate and its analogs.

    PubMed

    Li, Lei; Woodward, Robert L; Han, Weiqing; Qu, Jingyao; Song, Jing; Ma, Cheng; Wang, Peng G

    2016-07-01

    Polysaccharides are essential and immunologically relevant components of bacterial cell walls. These biomolecules can be found covalently attached to lipids (e.g., O-polysaccharide (PS) contains undecaprenyl and lipopolysaccharide (LPS) contains lipid A) or noncovalently associated with cell wells (e.g., capsular PS (CPS)). Although extensive genetic studies have indicated that the Wzy-dependent biosynthetic pathway is primarily responsible for producing such polysaccharides, in vitro biochemical studies are needed to determine, for example, which gene product is responsible for catalyzing each step in the pathway, and to reveal molecular details about the Wzx translocase, Wzy polymerase and O-PS chain-length determinant. Many of these biochemical studies require access to a structurally well-defined PS repeating unit undecaprenyl pyrophosphate (RU-PP-Und), the key building block in this pathway. We describe herein the chemoenzymatic synthesis of Escherichia coli (serotype O157) RU-PP-Und. This involves (i) chemical synthesis of precursor N-acetyl-D-galactosamine (GalNAc)-PP-Und (2 weeks) and (ii) enzymatic extension of the precursor to produce RU-PP-Und (2 weeks). Undecaprenyl phosphate and peracetylated GalNAc-1-phosphate are prepared from commercially available undecaprenol and peracetylated GalNAc. The chemical coupling of these two products, followed by structural confirmation (mass spectrometry and NMR) and deprotection, generates GalNAc-PP-Und. This compound is then sequentially modified by enzymes in the E. coli serotype O157 (E. coli O157) O-PS biosynthetic pathway. Three glycosyltransferases (GTs) are involved (WbdN, WbdO and WbdP) and they transfer glucose (Glc), L-fucose (L-Fuc) and N-acetylperosamine (PerNAc) onto GalNAc-PP-Und to form the intact RU-PP-Und in a stepwise manner. Final compounds and intermediates are confirmed by mass spectrometry. The procedure can be adapted to the synthesis of analogs with different PS or lipid moieties. PMID:27336706

  1. Synthesis and biological evaluation of cyclic analogs of L-carnitine as potential agents in the treatment of myocardial ischemia

    SciTech Connect

    Woster, P.M.

    1987-01-01

    The purpose of this research was to synthesize a number of cyclic, rigid analogs of L-carnitine, having a variety of predetermined positional and stereochemical orientations, to be used as probes into the spatial and conformational requirements of the enzyme known as carnitine/acylcarnitine translocase. The ability of these analogs to serve as substrates for this enzyme was to be determined by assessing the degree to which they initiate efflux of {sup 14}C-L-carnitine from isolated heart mitochondria. Toward this end, synthesis of several such analogs was attempted, resulting in the isolation and characterization of 9 cyclic analogs of carnitine, 5 of which are previously unreported. Bioevaluation of these synthetic carnitine analogs was conducted in a previously described assay system. Rat heart mitochondria were isolated by differential centrifugation and prepared for the study by incubation with {sup 14}C-L-carnitine. Efflux of radiolabeled carnitine was then monitored in the presence of the compound being evaluated. This represents the first instance in which non-naturally occurring analogs of L-carnitine have been shown to undergo transport via this mitochondrial translocase, suggesting the possibility that cyclic carnitine analogs may find utility as agents in the treatment of myocardial ischemia.

  2. Imaging opiate receptors by positron tomography (PET): Evaluation by displacement of 3-Acetyl-6-Deoxy-6-Beta-/sup 18/F-flouronaltrexone with active and inactive naloxone

    SciTech Connect

    Larson, S.M.; Channing, M.A.; Rice, K.R.; Pert, C.B.; Eckelman, W.C.; Burke, T.R.; Bennett, J.M.; Carson, R.E.; Di Chiro, G.

    1985-05-01

    We recently reported the development of a new radiopharmaceutical for in vivo PET imaging of opiate receptors, 3-acetyl-6-deoxy-6-Beta-/sup 18/F-fluoronaltrexone: 3-acetylcyclofoxy, or /sup 18/F-ACF. These studies involved displacement of /sup 18/F-ACF from sites of uptake in the baboon sub-cortical gray matter, and provided strong proof of the opiate receptor specificity of the tracer. We now report on the anatomic localization of /sup 18/F-ACF in the sub-cortical grapy matter of baboon, and the kinetics of uptake and displacement of the tracer. /sup 18/F-ACF was prepared from the known 3-acetyl-6-alpha-naltrexol via the triflate, using /sup 18/F produced by neutron bombardment of /sup 6/Li/sub 2/CO/sub 3/. Anesthetized baboons were imaged after injection of /sup 18/F-ACF (sp.ac.=20Ci/mmol), using the NIH NEUROPET, a high resolution PET scanner. After bolus injection, the initial distribution to brain was rapid with peak uptake at 6 minutes post-injection. Clearance from opiate receptor rich regions of thalamus and basal ganglia was gradual, but after injection of active (but not after inactive), naloxone, clearance from these regions more than doubled. In non-opiate rich regions, (e.g. cerebellum), the predominant component of clearance was equally rapid with or without the active naloxone. Displacement studies of positron labelled ligands provide a powerful tool for non-invasive study of opiate receptor in living primates.

  3. CDP-6-deoxy-delta 3,4-glucoseen reductase from Yersinia pseudotuberculosis: enzyme purification and characterization of the cloned gene.

    PubMed Central

    Lo, S F; Miller, V P; Lei, Y; Thorson, J S; Liu, H W; Schottel, J L

    1994-01-01

    The 3,6-dideoxyhexoses, usually confined to the cell wall lipopolysaccharide of gram-negative bacteria, are essential to serological specificity and are formed via a complex biosynthetic pathway beginning with CDP-D-hexoses. In particular, the biosynthesis of CDP-ascarylose, one of the naturally occurring 3,6-dideoxyhexoses, consists of five enzymatic steps, with CDP-6-deoxy-delta 3,4-glucoseen reductase (E3) participating as the key enzyme in this catalysis. This enzyme has been previously purified from Yersinia pseudotuberculosis by an unusual procedure (protocol I) including a trypsin digestion step (O. Han, V.P. Miller, and H.-W. Liu, J. Biol. Chem. 265:8033-8041, 1990). However, the cloned gene showed disparity with the expected gene characteristics, and upon expression, the resulting gene product exhibited no E3 activity. These findings strongly suggested that the protein isolated by protocol I may have been misidentified as E3. A reinvestigation of the purification protocol produced a new and improved procedure (protocol II) consisting of DEAE-Sephacel, phenyl-Sepharose, Cibacron blue A, and Sephadex G-100 chromatography, which efficiently yielded a new homogeneous enzyme composed of a single polypeptide with a molecular weight of 39,000. This highly purified protein had a specific activity nearly 8,000-fold higher than that of cell lysates, and more importantly, the corresponding gene (ascD) was found to be part of the ascarylose biosynthetic cluster. Presented are the identification and confirmation of the E3 gene through cloning and overexpression and the culminating purification and unambiguous assignment of homogeneous E3. The nucleotide and translated amino acid sequences of the genuine E3 are also presented. Images PMID:8288541

  4. First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs.

    PubMed

    Song, Ying-Ying; Kinami, Kyoko; Kato, Atsushi; Jia, Yue-Mei; Li, Yi-Xian; Fleet, George W J; Yu, Chu-Yi

    2016-06-14

    The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC50 = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition. PMID:27184090

  5. The chemical synthesis of α-conotoxins and structurally modified analogs with enhanced biological stability.

    PubMed

    Banerjee, Jayati; Gyanda, Reena; Chang, Yi-Pin; Armishaw, Christopher J

    2013-01-01

    α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone snails that exhibit exquisite pharmacological potency and selectivity for various nicotinic acetylcholine receptor subtypes. As such, they are important research tools and drug leads for treating various diseases of the central nervous system, including pain and tobacco addiction. Despite their therapeutic potential, the chemical synthesis of α-conotoxins for use in structure-activity relationship studies is complicated by the possibility of three disulfide bond isomers, where inefficient folding methods can lead to a poor recovery of the pharmacologically active isomer. In order to achieve higher yields of the native isomer, especially in high-throughput syntheses it is necessary to select appropriate oxidative folding conditions. Moreover, the poor biochemical stability exhibited by α-conotoxins limits their general therapeutic applicability in vivo. Numerous strategies to enhance their stability including the substitution of disulfide bond with diselenide bond and N-to-C cyclization via an oligopeptide spacer have successfully overcome these limitations. This chapter describes methods for performing both selective and nonselective disulfide bond oxidation strategies for controlling the yields and formation of α-conotoxin disulfide bond isomers, as well as methods for the production of highly stable diselenide-containing and N-to-C cyclized conotoxin analogs. PMID:24014431

  6. Computer-Guided Design, Synthesis, and Protein Kinase C Affinity of a New Salicylate-Based Class of Bryostatin Analogs

    PubMed Central

    2015-01-01

    Bryostatin 1 is in clinical trials for the treatment of cancer and Alzheimer’s disease and is a candidate for a first-in-class approach to HIV/AIDS eradication. It is neither readily available nor optimally suited for clinical use. Using a function oriented synthesis strategy, a new class of bryostatin-inspired analogs was designed with a simplified salicylate-derived subunit, enabling step-economical synthesis (23 total steps) of agents exhibiting bryostatin-like affinity to protein kinase C (PKC). PMID:25238583

  7. δ-Carbolines and their ring-opened analogs: Synthesis and evaluation against fungal and bacterial opportunistic pathogens

    PubMed Central

    Mazu, Tryphon K.; Etukala, Jagan R.; Jacob, Melissa R.; Khan, Shabana I.; Walker, Larry A.; Ablordeppey, Seth Y

    2011-01-01

    Previous studies have indicated that the δ-carboline (2) ring system derived from the natural product cryptolepine (1) may represent a pharmacophore for anti-infective activity. This paper describes the design and synthesis of a small library of substituted δ-carbolines and the evaluation of the antifungal and antibacterial activities. An evaluation of the anti-bacterial activity of a previously reported library of ring-opened analogs was also conducted to provide an opportunity to test the hypothesis that both group of compounds may have the same biological target. Results indicate that against a selected group of fungal pathogens, substituted δ-carbolinium analogs displayed higher potency and several fold lower cytotoxicity than cryptolepine the parent natural product. Both the δ-carbolinium compounds and their ring-opened analogs, exhibited equally high anti-bacterial activity against the selected pathogens and especially against the gram positive bacteria evaluated. PMID:21459492

  8. Analogies in the Teaching of Chemical Equilibrium: A Synthesis/Analysis of the Literature

    ERIC Educational Resources Information Center

    Raviolo, Andres; Garritz, Andoni

    2009-01-01

    This paper presents a thorough literature review of the analogies used to teach chemical equilibrium. The main objective is to compile all the analogies that have been found to be of service to the teacher and the student. Additionally, we categorize and analyze analogies in relation to the following aspects: representation of the dynamic nature…

  9. Biosynthesis of 2-acetamido-2,6-dideoxy-L-hexoses in bacteria follows a pattern distinct from those of the pathways of 6-deoxy-L-hexoses.

    PubMed Central

    Kneidinger, Bernd; Larocque, Suzon; Brisson, Jean-Robert; Cadotte, Nicolas; Lam, Joseph S

    2003-01-01

    6-Deoxy-L-hexoses have been shown to be synthesized from dTDP-D-glucose or GDP-D-mannose so that the gluco/galacto-configuration is converted into the manno/talo-configuration, and manno/talo is switched to gluco/galacto. Our laboratory has been investigating the biosynthesis of 2-acetamido-2,6-dideoxy-L-hexoses in both Gram-positive and Gram-negative bacteria, and in a recent paper we described the biosynthesis of the talo (pneumosamine) and galacto (fucosamine) derivatives from UDP-D-N-acetylglucosamine a 2-acetamido sugar [Kneidinger, O'Riordan, Li, Brisson, Lee and Lam (2003) J. Biol. Chem. 278, 3615-3627]. In the present study, we undertake the task to test the hypothesis that UDP-D-N-acetylglucosamine is the common precursor for the production of 2-acetamido-2,6-dideoxy-L-hexoses in the gluco-, galacto-, manno- and talo-configurations. We present data to reveal the steps for the biosynthesis of the gluco (quinovosamine)- and manno (rhamnosamine)-configured compounds. The corresponding enzymes WbvB, WbvR and WbvD from Vibrio cholerae serotype O37 have been overexpressed and purified to near homogeneity. The enzymic reactions have been analysed by capillary electrophoresis and NMR spectroscopy. Our data have revealed a general feature of reaction cascades due to the three enzymes. First, UDP-D-N-acetylglucosamine is catalysed by the multi-functional enzyme WbvB, whereby dehydration occurs at C-4, C-6 and epimerization at C-5, C-3 to produce UDP-2-acetamido-2,6-dideoxy-L-lyxo-4-hexulose. Secondly, this intermediate is converted by the C-4 reductase, WbvR, in a stereospecific reaction to yield UDP-2-acetamido-L-rhamnose. Thirdly, UDP-2-acetamido-L-rhamnose is epimerized at C-2 to UDP-2-acetamido-L-quinovose by WbvD. Interestingly, WbvD is also an orthologue of WbjD, but not vice versa. Incubation of purified WbvD with UDP-2-acetamido-2,6-dideoxy-L-talose and analysing the reaction products by capillary electrophoresis revealed the same product peak as when Wbj

  10. Methyl 6-Amino-6-deoxy-d-pyranoside-Conjugated Platinum(II) Complexes for Glucose Transporter (GLUT)-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism.

    PubMed

    Li, Taoli; Gao, Xiangqian; Yang, Liu; Shi, Yunli; Gao, Qingzhi

    2016-05-19

    Methyl 6-aminodeoxy-d-pyranoside-derived platinum(II) glycoconjugates were designed and synthesized based on the clinical drug oxaliplatin for glucose transporter (GLUT)-mediated tumor targeting. In addition to a substantial improvement in water solubility, the conjugates exhibited cytotoxicity similar to or higher than that of oxaliplatin in six different human cancer cell lines. GLUT-mediated transport of the complexes was investigated with a cell-based fluorescence competition assay and GLUT-inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing human colorectal adenocarcinoma (HT29) cell line. The antitumor effect of the aminodeoxypyranoside-conjugated platinum(II) complexes was found to depend significantly on the GLUT inhibitor, and the cellular uptake of the molecules was regulated by GLUT-mediated transport. The results from this study demonstrate the potential advantages of aminodeoxypyranosides as sugar motifs for glycoconjugation for Warburg-effect-targeted drug design. These fundamental results also support the potential of aminodeoxypyranoside-conjugated platinum(II) complexes as lead compounds for further preclinical evaluation. PMID:27135196

  11. α-Azido Acids in Solid-Phase Peptide Synthesis: Compatibility with Fmoc Chemistry and an Alternative Approach to the Solid Phase Synthesis of Daptomycin Analogs.

    PubMed

    Lohani, Chuda Raj; Rasera, Benjamin; Scott, Bradley; Palmer, Michael; Taylor, Scott D

    2016-03-18

    α-Azido acids have been used in solid phase peptide synthesis (SPPS) for almost 20 years. Here we report that peptides bearing an N-terminal α-azidoaspartate residue undergo elimination of an azide ion when treated with reagents that are commonly used for removing the Fmoc group during SPPS. We also report an alternative solid-phase route to the synthesis of an analog of daptomycin that uses a reduced number of α-azido amino acids and without elimination of an azide ion. PMID:26938305

  12. Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation

    PubMed Central

    Zhao, Jielu; Bane, Susan; Snyder, James P.; Hu, Haipeng; Mukherjee, Kamalika; Slebodnick, Carla; Kingston, David G. I.

    2011-01-01

    A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37-39, 41 and the open-chain analogs 27-29 and 43 were prepared. The bridged analogs 37-39 and 41 were synthesized by Grubbs' metatheses of compounds 30-32 and 33, which, in turn, were prepared by coupling β-lactams 24-26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity. PMID:22071526

  13. Synthesis and characterization of multiply-tyrosinated, multiply-iodinated somatostatin analogs

    SciTech Connect

    Woltering, E A.; O'Dorisio, M S.; Murphy, W A.; Chen, F; Drouant, G J.; Espenan, G D.; Fisher, Darrell R.; Sharma, C; Diaco, D S.; Maloney, T M.; Fuselier, J A.; Nelson, J A.; O'Dorisio, T M.; Coy, D H.

    1999-02-01

    Radio-labeled somatostatin analogs have recently gained popularity as agents useful in intraoperative tumor localization, external scintigraphy and in situ radiotherapy. We have synthesized and characterized a series of novel N-terminally extended multiply-tyrosinated somatostatin analogs that possess high binding affinity for somatostatin receptors, exhibit biological activity comparable to the native peptide and retain these characteristics after iodination. These analogs can be radio-iodinated to high specific activities. Following radio-iodination, these analogs exhibit minimal radiolysis and may be clinically useful for tumor localization, scanning and therapy.

  14. Synthesis of carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases

    PubMed Central

    Cho, Jong hyun; Coats, Steven J.; Schinazi, Raymond F.

    2015-01-01

    New carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases were synthesized and evaluated as potential anti-HIV and anti-HCV agents. Among the synthesized carbocyclic nucleoside analogs, the pyrazole amide 15f exhibited modest selective anti-HIV-1 activity (EC50 = 24 µM). PMID:26028788

  15. Design, Synthesis, Biological Evaluation and Docking Studies of Pterostilbene Analogs Inside PPARa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pterostilbene, a naturally occurring analog of resveratrol, has previously shown PPARa activation in H4IIEC3 cells and was found to decrease cholesterol levels in animals. In this study, analogs of pterostilbene were synthesized and their ability to activate PPARa was investigated. Among the analo...

  16. Design, synthesis and aphicidal activity of N-terminal modified insect kinin analogs.

    PubMed

    Zhang, Chuanliang; Qu, Yanyan; Wu, Xiaoqing; Song, Dunlun; Ling, Yun; Yang, Xinling

    2015-06-01

    The insect kinins are a class of multifunctional insect neuropeptides present in a diverse variety of insects. Insect kinin analogs showed multiple bioactivities, especially, the aphicidal activity. To find a biostable and bioactive insecticide candidate with simplified structure, a series of N-terminal modified insect kinin analogs was designed and synthesized based on the lead compound [Aib]-Phe-Phe-[Aib]-Trp-Gly-NH2. Their aphicidal activity against the soybean aphid Aphis glycines was evaluated. The results showed that all the analogs maintained the aphicidal activity. In particular, the aphicidal activity of the pentapeptide analog X Phe-Phe-[Aib]-Trp-Gly-NH2 (LC50=0.045mmol/L) was similar to the lead compound (LC50=0.048mmol/L). This indicated that the N-terminal protective group may not play an important role in the activity and the analogs structure could be simplified to pentapeptide analogs while retaining good aphicidal activity. The core pentapeptide analog X can be used as the lead compound for further chemical modifications to discover potential insecticides. PMID:25116632

  17. Synthesis and Biological Evaluation of a Valinomycin Analog Bearing a Pentafluorophenyl Active Ester Moiety.

    PubMed

    D'Accolti, Lucia; Denora, Nunzio; La Piana, Gianluigi; Marzulli, Domenico; Siwy, Zuzanna S; Fusco, Caterina; Annese, Cosimo

    2015-12-18

    A valuable analog of the K(+)-ionophore valinomycin (1), bearing a pentafluorophenyl ester moiety, has been obtained by selective reaction between the tertiary hydroxyl moiety of analog 2 (available from valinomycin hydroxylation) and the isocyanate group of pentafluorophenyl N-carbonyl glycinate (3) catalyzed by bis(N,N-dimethylformamide)dichlorodioxomolybdenum(VI). LC-HRMS studies show that analog 4 undergoes easy derivatization under mild conditions by reaction with OH- and NH2-containing compounds. Mitochondrial depolarization assays suggest that 4 acts as a K(+)-ionophore, provided that the glycine carboxyl group is appropriately masked. PMID:26566090

  18. Synthesis of the Tetrasaccharide Motif and Its Structural Analog Corresponding to the Lipopolysaccharide of Escherichia coli O75

    PubMed Central

    Sau, Abhijit; Misra, Anup Kumar

    2012-01-01

    Background Extraintestinal pathogenic E. coli are mostly responsible for a diverse spectrum of invasive human and animal infections leading to the urinary tract infections. Bacterial lipopolysaccharides are responsible for their pathogenicity and their interactions with host immune responses. In spite of several breakthroughs in the development of therapeutics to combat urinary tract infections and related diseases, the emergence of multidrug-resistant bacterial strains is a serious concern. Lipopolysaccharides are attractive targets for the development of long-term therapeutic agents to eradicate the infections. Since the natural sources cannot provide the required amount of oligosaccharides, development of chemical synthetic strategies for their synthesis is relevant to gain access to a reservoir of oligosaccharides and their close analogs. Methodology Two tetrasaccharide derivatives were synthesized from a single disaccharide intermediate. β-d-mannoside moiety was prepared from β-d-glucoside moiety following oxidation–reduction methodology. A [2+2] stereoselective block glycosylation strategy has been adopted for the preparation of tetrasaccharide derivative. α-d-Glucosamine moiety was prepared from α-d-mannosidic moiety following triflate formation at C-2 and SN2 substitution. A one-pot iterative glycosylation exploiting the orthogonal property of thioglycoside was carried out during the synthesis of tetrasaccharide analog. Results Synthesis of the tetrasaccharide motif (1) and its structural analog (2) corresponding to the lipopolysaccharide of Escherichia coli O75 was successfully achieved in excellent yield. Most of the reactions are clean and high yielding. Both compounds 1 and 2 were synthesized as their 4-methoxyphenyl glycoside, which can act as a temporary anomeric protecting group for further use of these tetrasaccharides in the preparation of glycoconjugates. PMID:22662142

  19. On the suitability and development of layout templates for analog layout reuse and layout-aware synthesis

    NASA Astrophysics Data System (ADS)

    Castro-Lopez, Rafael; Fernandez, Francisco V.; Rodriguez Vazquez, Angel

    2005-06-01

    Accelerating the synthesis of increasingly complex analog integrated circuits is key to bridge the widening gap between what we can integrate and what we can design while meeting ever-tightening time-to-market constraints. It is a well-known fact in the semiconductor industry that such goal can only be attained by means of adequate CAD methodologies, techniques, and accompanying tools. This is particularly important in analog physical synthesis (a.k.a. layout generation), where large sensitivities of the circuit performances to the many subtle details of layout implementation (device matching, loading and coupling effects, reliability, and area features are of utmost importance to analog designers), render complete automation a truly challenging task. To approach the problem, two directions have been traditionally considered, knowledge-based and optimization-based, both with their own pros and cons. Besides, recently reported solutions oriented to speed up the overall design flow by means of reuse-based practices or by cutting off time-consuming, error-prone spins between electrical and layout synthesis (a technique known as layout-aware synthesis), rely on a outstandingly rapid yet efficient layout generation method. This paper analyses the suitability of procedural layout generation based on templates (a knowledge-based approach) by examining the requirements that both layout reuse and layout-aware solutions impose, and how layout templates face them. The ability to capture the know-how of experienced layout designers and the turnaround times for layout instancing are considered main comparative aspects in relation to other layout generation approaches. A discussion on the benefit-cost trade-off of using layout templates is also included. In addition to this analysis, the paper delves deeper into systematic techniques to develop fully reusable layout templates for analog circuits, either for a change of the circuit sizing (i.e., layout retargeting) or a change of

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

    PubMed

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

    2016-06-01

    Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and (1)H NMR, and evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory potential varying from 1.4±0.10 to 34.43±2.10μM when compared with standard thiourea (IC50 19.46±1.20μM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20 with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity than compound 20 having 3-methoxy substituent. The binding interactions of these active analogs were confirmed through molecular docking. PMID:27038849

  1. Synthesis of analogs of amathamide A and their preliminary antimicrobial activity.

    PubMed

    Ramírez-Osuna, Moisés; Chávez, Daniel; Hernández, Lourdes; Molins, Elias; Somanathan, Ratnasamy; Aguirre, Gerardo

    2005-01-01

    Syntheses of three non-brominated analogs of amathamide A (1), a natural alkaloid isolated from the Tasmanian marine bryozoan Amathia wilsoni, are described. Antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomona aeruginosa, and Candida albicans was tested. Test results for amathamide A (1) showed a weak activity against C. albicans and E. coli. The three non-natural analogs 2-4 proved to be inactive compounds. PMID:18007299

  2. Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin.

    PubMed

    Bandyopadhyay, Saibal; Dutta, Supratik; Spilling, Christopher D; Dupureur, Cynthia M; Rath, Nigam P

    2008-11-01

    Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than the cis isomer against AChE from two sources. PMID:18821801

  3. Synthesis and evaluation of novel lipidated neuromedin U analogs with increased stability and effects on food intake.

    PubMed

    Dalbøge, Louise S; Pedersen, Søren L; van Witteloostuijn, Søren B; Rasmussen, Jakob E; Rigbolt, Kristoffer T G; Jensen, Knud J; Holst, Birgitte; Vrang, Niels; Jelsing, Jacob

    2015-02-01

    Neuromedin U (NMU) is a 25 amino acid peptide expressed and secreted in the brain and gastrointestinal tract. Data have shown that peripheral administration of human NMU decreases food intake and body weight and improves glucose tolerance in mice, suggesting that NMU receptors constitute a possible anti-diabetic and anti-obesity drug target. However, the clinical use of native NMU is hampered by a poor pharmacokinetic profile. In the current study, we report in vitro and in vivo data from a series of novel lipidated NMU analogs. In vitro plasma stability studies of native NMU were performed to investigate the proteolytic stability and cleavage sites using LC-MS. Native NMU was found to be rapidly cleaved at the C-terminus between Arg(24) and Asn(25) , followed by cleavage between Arg(16) and Gly(17) . Lipidated NMU analogs were generated using solid-phase peptide synthesis, and in vitro potency was investigated using a human embryonic kidney 293-based inositol phosphate accumulation assay. All lipidated analogs had preserved in vitro activity on both NMU receptors with potency improving as the lipidation site was moved away from the receptor-interacting C-terminal octapeptide segment. In vivo efficacy was assessed in lean mice as reduction in food intake after acute subcutaneous administration of 1, 0.3, 0.1, and 0.03 µmol/kg. These lipidated NMU analogs prolonged the anorectic effect of NMU in a dose-dependent manner. This was likely an effect of improved pharmacokinetic properties because of improved vitro plasma stability. Accordingly, the data demonstrate that lipidated NMU analogs may represent drug candidates for the treatment of obesity. PMID:25521062

  4. Synthesis of poly(ester-carbonate) with a pendant acetylcholine analog for promoting neurite growth.

    PubMed

    Xing, Dongming; Ma, Lie; Gao, Changyou

    2014-10-01

    The modification of biodegradable polyesters with bioactive molecules has become an important strategy for controlling neuron adhesion and neurite outgrowth in nerve regeneration. In this study we report a biodegradable poly(ester-carbonate) with a pendant acetylcholine analog, which a neurotransmitter for the enhancement of neuron adhesion and outgrowth. The acetylcholine-functionalized poly(ester-carbonate) (Ach-P(LA-ClTMC)) was prepared by copolymerizing l-lactide (LA) and 5-methyl-5-chloroethoxycarbonyl trimethylene carbonate (ClTMC), followed by quaternization with trimethylamine. The acetylcholine analog content could be modulated by changing the molar feeding fraction of ClTMC. The incorporation of the acetylcholine analog improved the hydrophilicity of the films, but the acetylcholine analog content did not significantly influence the surface morphology of the acetylcholine-functionalized films. The results of PC12 cell culture showed that the acetylcholine analog promoted cell viability and neurite outgrowth in a concentration-dependent manner. The longest length of neurite and the percentage of cells bearing neurites were obtained on the Ach-P(LA-ClTMC)-10 film. All the results indicate that the integration of the acetylcholine analog at an appropriate fraction could be an effective strategy for optimizing the existing biodegradable polyesters for nerve regeneration applications. PMID:24998182

  5. Synthesis of Structurally Simplified Analogs of Pancratistatin: Truncation of the Cyclitol Ring

    PubMed Central

    Manpadi, Madhuri; Kireev, Artem S.; Magedov, Igor V.; Altig, Jeff; Tongwa, Paul; Antipin, Mikhail Yu.; Evidente, Antonio; van Otterlo, Willem A. L.; Kornienko, Alexander

    2009-01-01

    Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral and antiparasitic properties have attracted the attention of synthetic, biological and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogs with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogs with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to γ-alkoxy-α,β-enoates and syn-selective azidation at the α-position of ester enolates. Analogs with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogs exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analog. From these results implications for the design of future pancratistatin analogs are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs. PMID:19743883

  6. Synthesis and biological activity of FGLamide allatostatin analogs with Phe(3) residue modifications.

    PubMed

    Xie, Yong; Wang, Meizi; Zhang, Li; Wu, Xiaoqing; Yang, Xinling; Tobe, Stephen S

    2016-09-01

    A FGLamide allatostatin neuropeptide mimic (H17) is a potential insect growth regulator which inhibits the production of juvenile hormone by the corpora allata. To find more evidence to reveal the structure-activity relationships of the Phe(3) residue in the C-terminal conserved pentapeptide and search for novel analogs with high activity, a series of Phe(3) residue-modified analogs were designed and synthesized using H17 as the lead compound. Bioassay using juvenile hormone (JH) production by corpora allata of the cockroach Diploptera punctata indicated that analogs 4, 11, and 13 showed strong ability to inhibit JH production in vitro, with IC50 of 38.5, 22.5, and 26 nM, respectively. As well, the activity of analog 2 (IC50 : 89.5 nM) proved roughly equivalent to that of H17. Based on the primary structure-activity relationships of Phe(3) residue, we suggest that for analogs containing six-membered aromatic rings, removing the methylene group of Phe(3) or an o-halogen or p-halogen-substituted benzene ring could increase the ability to inhibit biosynthesis of JH. This study will be useful for the design of new allatostatin analogs for insect management. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27477941

  7. Synthesis of Reblastatin, Autolytimycin, Non-Benzoquinone Analogs: Potent Inhibitors of Heat Shock Protein 90 (Hsp90)

    PubMed Central

    Wrona, Iwona E.; Gozman, Alexander; Taldone, Tony; Chiosis, Gabriela; Panek, James S.

    2010-01-01

    A full account of an asymmetric synthesis of reblastatin (1), the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio-and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6–9) of phenolic ansamycins. Ansamycin natural products and selected structural analogs were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the Hsp90 protein with enhanced binding activity (~25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (~100 nM). PMID:20392070

  8. Characterization of TDP-4-keto-6-deoxy-D-glucose-3,4-ketoisomerase from the D-mycaminose biosynthetic pathway of Streptomyces fradiae: in vitro activity and substrate specificity studies.

    PubMed

    Melançon, Charles E; Hong, Lin; White, Jess A; Liu, Yung-nan; Liu, Hung-wen

    2007-01-16

    Deoxysugars are critical structural elements for the bioactivity of many natural products. Ongoing work on elucidating a variety of deoxysugar biosynthetic pathways has paved the way for manipulation of these pathways for the generation of structurally diverse glycosylated natural products. In the course of this work, the biosynthesis of d-mycaminose in the tylosin pathway of Streptomyces fradiae was investigated. Attempts to reconstitute the entire mycaminose biosynthetic machinery in a heterologous host led to the discovery of a previously overlooked gene, tyl1a, encoding an enzyme thought to convert TDP-4-keto-6-deoxy-d-glucose to TDP-3-keto-6-deoxy-d-glucose, a 3,4-ketoisomerization reaction in the pathway. Tyl1a has now been overexpressed, purified, and assayed, and its activity has been verified by product analysis. Incubation of Tyl1a and the C-3 aminotransferase TylB, the next enzyme in the pathway, produced TDP-3-amino-3,6-dideoxy-d-glucose, confirming that these two enzymes act sequentially. Steady state kinetic parameters of the Tyl1a-catalyzed reaction were determined, and the ability of Tyl1a and TylB to process a C-2 deoxygenated substrate and a CDP-linked substrate was also demonstrated. Enzymes catalyzing 3,4-ketoisomerization of hexoses represent a new class of enzymes involved in unusual sugar biosynthesis. The fact that Tyl1a exhibits a relaxed substrate specificity holds potential for future deoxysugar biosynthetic engineering endeavors. PMID:17209568

  9. A Laboratory Preparation of Aspartame Analogs Using Simultaneous Multiple Parallel Synthesis Methodology

    ERIC Educational Resources Information Center

    Qvit, Nir; Barda, Yaniv; Gilon, Chaim; Shalev, Deborah E.

    2007-01-01

    This laboratory experiment provides a unique opportunity for students to synthesize three analogues of aspartame, a commonly used artificial sweetener. The students are introduced to the powerful and useful method of parallel synthesis while synthesizing three dipeptides in parallel using solid-phase peptide synthesis (SPPS) and simultaneous…

  10. Synthesis and Cytotoxic Evaluation of Monocarbonyl Analogs of Curcumin as Potential Anti‐Tumor Agents

    PubMed Central

    Pan, Zheer; Chen, Chengwei; Zhou, Yeli; Xu, Feng

    2016-01-01

    Abstract Preclinical Research A series of mono‐carbonyl curcumin analogs with different substituents at the 4/4’‐position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines using a methyl thiazolyl tetrazolium assay. Several of the curcumin analogs, especially B114, exhibited a wide‐spectrum of anti‐tumor properties in all tested cell lines, indicating their potential in as anti‐cancer lead compounds. Further toxicity testing in the NRK‐52E kidney cell line revealed that the analogs A111, A113, and B114 had comparable or higher safety than curcumin. These data suggested that the introduction of appropriate substituents in the 4/4’‐positions could be a promising approach for curcumin‐based drug design. Drug Dev Res 77 : 43–49, 2016. © 2016 Wiley Periodicals, Inc. PMID:26846154

  11. Synthesis, Antifungal Activity, and Structure Activity Relationships of Coruscanone A Analogs

    PubMed Central

    Babu, K. Suresh; Li, Xing-Cong; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; Ferreira, Daneel; Clark, Alice M.

    2008-01-01

    Coruscanone A, a plant derived cyclopentenedione derivative, showed potent in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, comparable to amphotericin B and fluconazole. A series of analogs have been synthesized by modification of the cyclopentenedione ring, the enolic methoxy functionality, and the side chain styryl moiety of this natural product lead. A structurally close 1,4-benzoquinone analog was also prepared. All the compounds were examined for their in vitro activity against major opportunistic fungal pathogens including C. albicans, C. neoformans and Aspergillus fumigatus, and fluconazole-resistant C. albicans strains, with several analogs demonstrating potent antifungal activity. Structure activity relationship studies indicate that the 2-methoxymethylene-cyclopent-4-ene-1,3-dione structural moiety is the pharmacophore responsible for the antifungal activity of this class of compounds, while the side chain styryl-like moiety plays an important complementary role, presumably contributing to target binding. PMID:17181171

  12. Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors

    PubMed Central

    Kálai, Tamás; Altman, Robin; Maezawa, Izumi; Balog, Mária; Morisseau, Christophe; Petrlova, Jitka; Hammock, Bruce D.; Jin, Lee-Way; Trudell, James; Voss, John C.; Hideg, Kálmán

    2014-01-01

    A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetyl cholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer’s and antioxidant). PMID:24657571

  13. Synthesis and evaluation of backbone/amide-modified analogs of leualacin.

    PubMed

    Hu, M K; Yang, F C; Chou, C C; Yen, M H

    1999-02-22

    Leualacin (1), a cyclic depsi-pentapeptide, and its backbone/amide-modified analogs 2-4 were synthesized. Amide analogue 3 exhibited stronger vasodilatory effects. It also strongly inhibited collagen- and arachidonic acid (AA)-induced platelet aggregations with IC50s of 0.6 microM and 2.0 microM, respectively. PMID:10098664

  14. The Petasis Reaction: Microscale Synthesis of a Tertiary Amine Antifungal Analog

    ERIC Educational Resources Information Center

    Koroluk, Katherine J.; Jackson, Derek A.; Dicks, Andrew P.

    2012-01-01

    Students prepare a tertiary amine antifungal analog in an upper-level undergraduate organic laboratory. A microscale Petasis reaction is performed to generate a liquid compound readily characterized via IR and proton NMR spectroscopy. The biological relevance of the product is highlighted, with the tertiary amine scaffold being an important…

  15. Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine†

    PubMed Central

    Mo, Tingting; Geib, Steven J.; Caridha, Diana; Dow, Geoffrey S.; Gerena, Lucia; Roncal, Norma; Milner, Erin E.

    2010-01-01

    Two novel SF5 analogs of the antimalarial agent mefloquine were synthesized in 5 steps and 10–23% overall yields and found to have improved activity and selectivity against malaria parasites. This work also represents the first report of SF5-substituted quinolines. PMID:19795052

  16. [Use of the peptide hormone melanostatin and its analogs for the synthesis of new antitumor compounds].

    PubMed

    Lagova, N D; Smirnova, Z S; Sof'ina, Z P; Smirnova, L I; Kashnikova, N M

    1988-01-01

    A hypothalamic hormone--melanostatin H-L-Pro-L-Leu-NH2- and its 9 analogs were synthesized and their antitumor properties studied. Melanostatin caused a 52-72% inhibition of tumor growth (p less than 0.05) in mice bearing adenocarcinoma of the mammary gland Ca-755, cervical carcinoma CC-5 and melanoma B-16. Non-cytotoxic analogs containing D-leucine or L-lysine showed low activity. Among analogs containing sarcolysine stereomers, chlorphenacyl or chlorambucil, derivatives with L-sarcolysin exerted a high antitumor effect on Ca-755, CC-5, Lewis lung carcinoma, lymphoid leukemia L-1210, sarcoma-37, melanoma B-16 and S-91 (80-99% inhibition of tumor growth, p less than 0.05). L-sarcolysin alone had a higher effect on S-91 only (p less than 0.05). Antitumor effect of melanostatin is due to its amino acid sequences. Melanostatin analogs modified by L-phenylalanine retain their antitumor properties. PMID:2893489

  17. Synthesis, biological evaluation, and live cell imaging of novel fluorescent duocarmycin analogs.

    PubMed

    Tietze, Lutz F; Behrendt, Frank; Pestel, Galina F; Schuberth, Ingrid; Mitkovski, Mišo

    2012-11-01

    For a better understanding of the mode of action of duocarmycin and its analogs, the novel fluorescent duocarmycin derivatives 13-15 and 17b-19b were synthesized, and their bioactivity as well as their cellular uptake investigated using confocal laser scanning microscopy (CLSM) in live-cell imaging experiments. PMID:23161634

  18. Optimization of cocoa butter analog synthesis variables using neural networks and genetic algorithm.

    PubMed

    Shekarchizadeh, Hajar; Tikani, Reza; Kadivar, Mahdi

    2014-09-01

    Cocoa butter analog was prepared from camel hump fat and tristearin by enzymatic interesterification in supercritical carbon dioxide (SC-CO2) using immobilized Thermomyces lanuginosus lipase (Lipozyme TL IM) as a biocatalyst. Optimal process conditions were determined using neural networks and genetic algorithm optimization. Response surfaces methodology was used to design the experiments to collect data for the neural network modelling. A general regression neural network model was developed to predict the response of triacylglycerol (TAG) distribution of cocoa butter analog from the process pressure, temperature, tristearin/camel hump fat ratio, water content, and incubation time. A genetic algorithm was used to search for a combination of the process variables for production of most similar cocoa butter analog to the corresponding cocoa butter. The combinations of the process variables during genetic algorithm optimization were evaluated using the neural network model. The pressure of 10 MPa; temperature of 40 °C; SSS/CHF ratio of 0.6:1; water content of 13 % (w/w); and incubation time of 4.5 h were found to be the optimum conditions to achieve the most similar cocoa butter analog to the corresponding cocoa butter. PMID:25190869

  19. Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors.

    PubMed

    Raeppel, Stéphane L; Therrien, Eric; Raeppel, Franck

    2015-09-01

    New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained. PMID:26112445

  20. Quasi-Biomimetic Ring Contraction Catalyzed by a Cysteine-Based Nucleophile: Total Synthesis of Sch-642305, Some Analogs and their Putative anti-HIV Activities

    PubMed Central

    Dermenci, Alpay; Selig, Philipp S.; Domaoal, Robert A.; Spasov, Krasimir A.; Anderson, Karen S.

    2013-01-01

    Cysteine plays a number of important functional and structural roles in Nature, often in the realm of catalysis. Herein, we present an example of a cysteine-catalyzed Rauhut-Currier reaction for a potentially biomimetic synthesis of Sch-642305 and related analogs. In this key step of the synthesis we discuss interesting new discoveries and the importance of substrate-catalyst recognition, as well as cysteine’s structural features. Also, we investigate the activity of Sch-642305 and four analogs in HIV-infected T-cells. PMID:24179673

  1. Diverted Total Synthesis of Promysalin Analogs Demonstrates That an Iron-Binding Motif Is Responsible for Its Narrow-Spectrum Antibacterial Activity.

    PubMed

    Steele, Andrew D; Keohane, Colleen E; Knouse, Kyle W; Rossiter, Sean E; Williams, Sierra J; Wuest, William M

    2016-05-11

    Promysalin is a species-specific Pseudomonad metabolite with unique bioactivity. To better understand the mode of action of this natural product, we synthesized 16 analogs utilizing diverted total synthesis (DTS). Our analog studies revealed that the bioactivity of promysalin is sensitive to changes within its hydrogen bond network whereby alteration has drastic biological consequences. The DTS library not only yielded three analogs that retained potency but also provided insights that resulted in the identification of a previously unknown ability of promysalin to bind iron. These findings coupled with previous observations hint at a complex multifaceted role of the natural product within the rhizosphere. PMID:27096543

  2. Synthesis and anthelmintic activity of osthol analogs against Dactylogyrus intermedius in goldfish.

    PubMed

    Liu, Guang-Lu; Hao, Bing; Liu, Shao-Peng; Wang, Gao-Xue

    2012-08-01

    In an attempt to develop novel anthelmintic agents, our previously isolated osthol was used as lead structures for further optimization. In our research, a series of coumarin analogs, prepared from 7-hydroxy coumarin or 7-hydroxy-4-methyl coumarin, have been evaluated for their anthelmintic activities. In all of the compounds, 6 and 7 were first synthesized, and their structures were identified based on NMR and MS values. Among the candidates, 8-allyl-7-allyloxycoumarin showed better anthelmintic activity than other compounds against Dactylogyrus infestation with EC(50) value of 1.81 mg/L. The quantitative structure-activity relationship (QSAR) of 16 osthol analogs with anthelmintic activity expressed as pEC(50) and toxicity to goldfish expressed pLC(50), such results can offer useful theoretical references for future experimental works. PMID:22749191

  3. Design, synthesis, and fungicidal activities of imino diacid analogs of valine amide fungicides.

    PubMed

    Sun, Man; Yang, Hui-Hui; Tian, Lei; Li, Jian-Qiang; Zhao, Wei-Guang

    2015-12-15

    The novel imino diacid analogs of valine amides were synthesized via several steps, including the protection, amidation, deprotection, and amino alkylation of valine, with the resulting structures confirmed by (1)H and (13)C NMR and HRMS. Bioassays showed that some of these compounds exhibited good fungicidal activity. Notably, isopropyl 2-((1-((1-(3-fluorophenyl)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)propanoate 5i displayed significant levels of control, at 50%, against Erysiphe graminis at 3.9μM as well as a level of potency very similar to the reference azoxystrobin, which gave 60% activity at this concentration. The present work demonstrates that imino diacid analogs of valine amides could be potentially useful key compounds for the development of novel fungicides against wheat powdery mildew. PMID:26546215

  4. Novel sulfonanilide analogs decrease aromatase activity in breast cancer cells: synthesis, biological evaluation, and ligand-based pharmacophore identification.

    PubMed

    Su, Bin; Tian, Ran; Darby, Michael V; Brueggemeier, Robert W

    2008-03-13

    Aromatase converts androgens to estrogens and is a particularly attractive target in the treatment of estrogen receptor positive breast cancer. Previously, the COX-2 selective inhibitor nimesulide and analogs decreased aromatase expression and enzyme activity independent of COX-2 inhibition. In this manuscript, a combinatorial approach was used to generate diversely substituted novel sulfonanilides by parallel synthesis. Their pharmacological evaluation as agents for suppression of aromatase activity in SK-BR-3 breast cancer cells was extensively explored. A ligand-based pharmacophore model was elaborated for selective aromatase modulation (SAM) using the Catalyst HipHop algorithms. The best qualitative model consisted of four features: one aromatic ring, two hydrogen bond acceptors, and one hydrophobic function. Several lead compounds have also been tested in aromatase transfected MCF-7 cells, and they significantly suppressed cellular aromatase activity. The results suggest that both genomic and nongenomic mechanisms of these compounds are involved within the aromatase suppression effect. PMID:18271519

  5. Biosynthesis of a 3,6-dideoxyhexose: crystallization and X-ray diffraction of CDP-6-deoxy-l-threo-d-glycero-4-hexulose-3-dehydrase (E{sub 1}) for ascarylose biosynthesis

    SciTech Connect

    Smith, Peter; Lin, Ava; Szu, Ping-hui; Liu, Hung-wen; Tsai, Shiou-Chuan

    2006-03-01

    E{sub 1} dehydrase, which is important in the biosynthesis of the 3,6-dideoxy sugar ascarylose and is the only known PMP-containing enzyme to carry out one-electron chemistry, has been crystallized and diffracted to 1.9 Å. CDP-6-deoxy-l-threo-d-glycero-4-hexulose-3-dehydrase (E{sub 1}), along with its reductase (E{sub 3}), catalyzes the unusual C-3 deoxygenation of CDP-6-deoxy-l-threo-d-glycero-4-hexulose to form CDP-3,6-dideoxy-l-threo-d-glycero-4-hexulose in CDP-ascarylose biosynthesis [Chen et al. (1996 ▶), Biochemistry, 35, 16412–16420]. This dimeric [2Fe–2S] protein, cloned from the bacteria Yersinia pseudotuberculosis, is currently the only known example of an enzyme that uses a vitamin B{sub 6}-derived pyridoxamine 5′-phosphate (PMP) cofactor to carry out one-electron chemistry [Agnihotri & Liu (2001 ▶), Bioorg. Chem.29, 234–257]. It also exhibits a [2Fe–2S] cluster-binding motif (C-X{sub 57}-C-X{sub 1}-C-X{sub 7}-C) which has not been observed previously [Agnihotri et al. (2004 ▶), Biochemistry, 43, 14265–14274] The recombinant 97.7 kDa dimer was crystallized in the trigonal space group P3{sub 2}, with unit-cell parameters a = b = 97.37, c = 142.2 Å, α = β = 90, γ = 120°. A data set has been collected to 1.9 Å resolution. A full MAD data set was also collected at the iron absorption edge that diffracted to 2.0 Å.

  6. Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents.

    PubMed

    Mishra, Ram C; Gundala, Sushma R; Karna, Prasanthi; Lopus, Manu; Gupta, Kamlesh K; Nagaraju, Mulpuri; Hamelberg, Donald; Tandon, Vibha; Panda, Dulal; Reid, Michelle D; Aneja, Ritu

    2015-01-01

    Noscapine is an opium-derived kinder-gentler microtubule-modulating drug, currently in Phase I/II clinical trials for cancer chemotherapy. Here, we report the synthesis of four more potent di-substituted brominated derivatives of noscapine, 9-Br-7-OH-NOS (2), 9-Br-7-OCONHEt-NOS (3), 9-Br-7-OCONHBn-NOS (4), and 9-Br-7-OAc-NOS (5) and their chemotherapeutic efficacy on PC-3 and MDA-MB-231 cells. The four derivatives were observed to have higher tubulin binding activity than noscapine and significantly affect tubulin polymerization. The equilibrium dissociation constant (KD) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55±6μM, 44±6μM, 26±3μM, and 21±1μM respectively, which is comparable to parent analog. The effects of these di-substituted noscapine analogs on cell cycle parameters indicate that the cells enter a quiescent phase without undergoing further cell division. The varying biological activity of these analogs and bulk of substituent at position-7 of the benzofuranone ring system of the parent molecule was rationalized utilizing predictive in silico molecular modeling. Furthermore, the immunoblot analysis of protein lysates from cells treated with 4 and 5, revealed the induction of apoptosis and down-regulation of survivin levels. This result was further supported by the enhanced activity of caspase-3/7 enzymes in treated samples compared to the controls. Hence, these compounds showed a great potential for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers. PMID:25891106

  7. Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.

    PubMed

    Ng, Chean Hui; Rullah, Kamal; Aluwi, Mohd Fadhlizil Fasihi Mohd; Abas, Faridah; Lam, Kok Wai; Ismail, Intan Safinar; Narayanaswamy, Radhakrishnan; Jamaludin, Fadzureena; Shaari, Khozirah

    2014-01-01

    The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 μM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity. PMID:25100256

  8. Chemical synthesis of echistatin, a potent inhibitor of platelet aggregation from Echis carinatus: synthesis and biological activity of selected analogs.

    PubMed

    Garsky, V M; Lumma, P K; Freidinger, R M; Pitzenberger, S M; Randall, W C; Veber, D F; Gould, R J; Friedman, P A

    1989-06-01

    Echistatin, a polypeptide from the venom of the saw-scaled viper, Echis carinatus, containing 49 amino acids and 4 cystine bridges was synthesized by solid-phase methodology in 4% yield. In the final step, air oxidation of the octahydroderivative was found to be optimal at pH 8. The synthetic product was shown to be physically and biologically indistinguishable from native material. It inhibits fibrinogen-dependent platelet aggregation stimulated by ADP with IC50 = 3.3 x 10(-8) M and also prevents aggregation initiated by thrombin, epinephrine, collagen, or platelet-activating factor. Reduction of purified synthetic echistatin to octahydroechistatin with dithiothreitol followed by air oxidation regenerated homogeneous echistatin in quantitative yield. This highly specific refolding strongly suggests that the linear sequence of octahydroechistatin contains all of the information that is required for the proper folding of the peptide. The sequence Arg24-Gly-Asp of echistatin occurs also in adhesive glycoproteins that bind to the platelet fibrinogen receptor--a heterodimeric complex composed of glycoproteins IIb and IIIa. In an effort to evaluate the role of this putative binding site we have synthesized analogs of echistatin with substitution of Arg-24. Replacement with ornithine-24 (Orn-24) resulted in an analog having a platelet aggregation inhibitory activity with IC50 = 1.05 x 10(-7) M. Substitution with Ala-24 gave IC50 = 6.1 x 10(-7) M. The inhibitory activity of the corresponding short sequence analogs Arg-Gly-Asp-Phe (IC50 = 6 x 10(-6) M), Orn-Gly-Asp-Phe (IC50 = 1.3 x 10(-4) M), and Ala-Gly-Asp-Phe (IC50 = 5.0 x 10(-4) M) was also determined. These results suggest that arginine plays a more important role in the binding of the tetrapeptide than in that of echistatin. PMID:2726764

  9. Aircraft interior noise prediction using a structural-acoustic analogy in NASTRAN modal synthesis

    NASA Technical Reports Server (NTRS)

    Grosveld, Ferdinand W.; Sullivan, Brenda M.; Marulo, Francesco

    1988-01-01

    The noise induced inside a cylindrical fuselage model by shaker excitation is investigated theoretically and experimentally. The NASTRAN modal-synthesis program is used in the theoretical analysis, and the predictions are compared with experimental measurements in extensive graphs. Good general agreement is obtained, but the need for further refinements to account for acoustic-cavity damping and structural-acoustic interaction is indicated.

  10. Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

    PubMed Central

    Bai, Yu; Dai, Mingji

    2016-01-01

    Neopeltolide, isolated in 2007, with its novel structural features and potent anti cancer cell proliferation activity, has attracted a tremendous amount of synthetic efforts. This review briefly and chronologically summarizes each of the synthesis with the main focus on the strategies and methodologies for the construction of its cis-tetrahydropyran-containing macrolactone core.

  11. Synthesis, characterization and evaluation of bone targeting salmon calcitonin analogs in normal and osteoporotic rats.

    PubMed

    Bhandari, Krishna Hari; Newa, Madhuri; Chapman, Jillian; Doschak, Michael R

    2012-02-28

    In order to assess the therapeutic efficacy of an antiresorptive drug with imparted bone targeting potential using bisphosphonate (BP) conjugation and an improved pharmacokinetic profile using PEGylation, we synthesized, characterized and evaluated in vivo efficacy of bone-targeting PEGylated salmon calcitonin (sCT) analog (sCT-PEG-BP). sCT-PEG-BP was compared with non-PEGylated bone targeting sCT analog (sCT-BP) and unmodified, commercially available sCT. sCT-PEG-BP conjugates were characterized by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) analysis. The effect of PEG-BP or BP upon sCT secondary structure was examined by Circular Dichroism and sCT-PEG-BP was evaluated for in vitro bone mineral Hydroxyapatite (HA) binding ability and calcium salts specificity using a binding assay for bone HA and several calcium salts. Anti-calcitonin antibody binding ability of these analogs was determined using enzyme-linked immunosorbent assay (ELISA), by reacting bone targeting sCT analogs with calcium phosphate coated Osteologic® plates and detecting the bound sCT using anti-sCT antibody. Potential cytotoxicity of these compounds was evaluated in monocytic RAW 264.7 cells, and sCT bioactivity was evaluated using an in vitro intracellular cAMP stimulation assay in human T47D breast cancer cells. Finally, in vivo efficacy of each compound was evaluated by determining the plasma levels of calcium after s.c. administration in normal rats, and in a rat model of Osteoporosis, secondary to ovariectomy (OVX). In vivo micro-computed tomography (micro-CT) was used to temporally map and quantify alterations in bone volume and bone mineral density (BMD) in the same animals at 1, 4, 8 and 12 weeks after OVX surgery. Sixteen 6 week old virgin female rats underwent OVX surgery followed by the daily s.c. injection of 2.5IU/kg/day sCT or equivalent analogs, and compared to four sham-operated, placebo treated control rats. Our results showed the chemical coupling of

  12. Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

    PubMed Central

    Surya Prakash, G. K.; Zibinsky, Mikhail; Upton, Thomas G.; Kashemirov, Boris A.; McKenna, Charles E.; Oertell, Keriann; Goodman, Myron F.; Batra, Vinod K.; Pedersen, Lars C.; Beard, William A.; Shock, David D.; Wilson, Samuel H.; Olah, George A.

    2010-01-01

    It is difficult to overestimate the importance of nucleoside triphosphates in cellular chemistry: They are the building blocks for DNA and RNA and important sources of energy. Modifications of biologically important organic molecules with fluorine are of great interest to chemists and biologists because the size and electronegativity of the fluorine atom can be used to make defined structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been around for some time, the progress in the area of modified triphosphates was limited by the lack of synthetic methods allowing to access bisCF2-substituted nucleotide analogs—one of the most interesting classes of nonhydrolyzable nucleotides. These compounds have “correct” polarity and the smallest possible steric perturbation compared to natural nucleotides. No other known nucleotides have these advantages, making bisCF2-substituted analogs unique. Herein, we report a concise route for the preparation of hitherto unknown highly acidic and polybasic bis(difluoromethylene)triphosphoric acid 1 using a phosphorous(III)/phosphorous(V) interconversion approach. The analog 1 compared to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of two bridging oxygen atoms with CF2 groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the triphosphate polyanion. The fluorinated triphosphoric acid 1 was used for the preparation of the corresponding fluorinated deoxynucleotides (dNTPs). One of these dNTP analogs (dT) was demonstrated to fit into DNA polymerase beta (DNA pol β) binding pocket by obtaining a 2.5 Å resolution crystal structure of a ternary complex with the enzyme. Unexpected dominating effect of triphosphate/Mg2+ interaction over Watson–Crick hydrogen bonding was found and discussed. PMID:20724659

  13. Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.

    PubMed

    Macchia, B; Balsamo, A; Breschi, M C; Chiellini, G; Lapucci, A; Macchia, M; Manera, C; Martinelli, A; Martini, C; Scatizzi, R

    1993-10-15

    In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors. PMID:8230093

  14. Simplification of antitumoral phenanthroindolizidine alkaloids: short synthesis of cytotoxic indolizidinone and pyrrolidine analogs.

    PubMed

    Miguélez, Javier; Boto, Alicia; Marín, Raquel; Díaz, Mario

    2013-08-01

    Hydroxylated seco-analogs of cytotoxic phenanthroindolizidine alkaloids were prepared in good yields from inexpensive 4-hydroxyproline derivatives, in just two steps. Thus, a sequential oxidative radical scission-oxidation was used for the direct conversion of the proline derivative into a 2-(2-aryl-oxoethyl)pyrrolidine with a variety of aryl and heteroaryl groups. The 4R-stereogenic center allowed ready isomer separation, and stereocontrol in the introduction of new chains (interestingly, the 2,4-cis isomers predominated). In the second step, a cyclization reaction afforded alkaloid analogs with an indolizidinone core; a partial isomerization took place but the isomers were readily purified. Then the cytotoxic activity of the bicyclic indolizidinones and the simpler pyrrolidine derivatives was compared against tumorogenic human neuronal SHSY-5Y and breast cancer MCF7 cells. All the biphenyl derivatives displayed a potent activity (one derivative caused >80% cell death in both tumor lines at micromolar dosis), being comparable in the pyrrolidine and indolizidinone series. PMID:23845713

  15. Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit.

    PubMed

    Wu, Chunjiang; Wang, Min; Tang, Qidong; Luo, Rong; Chen, Le; Zheng, Pengwu; Zhu, Wufu

    2015-01-01

    Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by ¹H-NMR, ¹³C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 cancer cell lines. Some of the compounds showed moderate cytotoxic activity, especially compounds 1-(2,4-difluorophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6c) and 1-(4-bromophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6f) with the IC50 values against four cancer cell lines ranging from 16.54±1.22 to 63.92±1.81 μM, respectively. Inhibitory rates against vascular endothelial growth factor receptor-2 (VEGFR2/KDR) kinase at 10 μM of target compounds were further carried out in this paper in order to investigate the target of these compounds. Structure-activity relationships (SARs) and docking studies indicated that the sulfonylurea unit was important to these kinds of compounds. None of the substitutions in the phenoxy group and small halogen atoms such as 2,4-difluoro substitution of the aryl group contributed to the activity. The results suggested that sulfonylurea sorafenib analogs are worthy of further study. PMID:26512636

  16. Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs.

    PubMed

    Tyagi, Vikas; Alwaseem, Hanan; O'Dwyer, Kristen M; Ponder, Jessica; Li, Qi Ying; Jordan, Craig T; Fasan, Rudi

    2016-09-01

    Parthenolide is a naturally occurring terpene with promising anticancer properties, particularly in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50 values in the low micromolar range. These studies demonstrate that different O-H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 22a and 25b were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells. PMID:27396927

  17. Studies toward the Total Synthesis of Itralamide B and Biological Evaluation of Its Structural Analogs

    PubMed Central

    Wang, Xiaoji; Lv, Chanshan; Feng, Junmin; Tang, Linjun; Wang, Zhuo; Liu, Yuqing; Meng, Yi; Ye, Tao; Xu, Zhengshuang

    2015-01-01

    Itralamides A and B were isolated from the lipophilic extract of Lyngbya majuscula collected from the eastern Caribbean. Itralamide B (1) showed cytotoxic activity towards human embryonic kidney cells (HEK293, IC50 = 6 μM). Preliminary studies disapproved the proposed stereochemistry of itralamide. In this paper, we will provide a full account of the total synthesis of four stereoisomers of itralamide B and the results derived from biological tests of these structural congeners. PMID:25871289

  18. Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors.

    PubMed

    An, Ying; Lee, Eun; Yu, Yeongji; Yun, Jieun; Lee, Myeong Youl; Kang, Jong Soon; Kim, Woo-Young; Jeon, Raok

    2016-07-01

    A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure-activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model. PMID:27209235

  19. Synthesis of imperatorin analogs and their evaluation as acetylcholinesterase and butyrylcholinesterase inhibitors.

    PubMed

    Granica, Sebastian; Kiss, Anna K; Jarończyk, Małgorzata; Maurin, Jan K; Mazurek, Aleksander P; Czarnocki, Zbigniew

    2013-11-01

    In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins. PMID:24123207

  20. 6,6-Spiroimine analogs of (-)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptors.

    PubMed

    Duroure, Leslie; Jousseaume, Thierry; Aráoz, Rómulo; Barré, Elvina; Retailleau, Pascal; Chabaud, Laurent; Molgó, Jordi; Guillou, Catherine

    2011-12-01

    Simple models of the spiroimine core of (-)-gymnodimine A have been synthesized in racemic and optically active forms. The quaternary carbon of the racemic spiroimines was created by Michael addition of a β-ketoester to acrolein, whereas the asymmetric allylic alkylation of the same β-ketoester was used to access the spiroimines in an enantioselective fashion. Both racemic and enantio-enriched mixtures were tested for their biological activities on Xenopus oocytes either expressing (human α4β2) or having incorporated (Torpedoα1(2)βγδ) nicotinic acetylcholine receptors (nAChRs). These spiroimine analogs of (-)-gymnodimine A inhibited acetylcholine-evoked nicotinic currents, but were less active than the phycotoxin. Our results reveal that the 6,6-spiroimine moiety is important for the blockade of nAChRs and support the hypothesis that it is one of the pharmacophores of this group of toxins. PMID:22024965

  1. Enhancing Physicochemical Properties through Synthesis and Formulation of Piclamilast- and Lapatinib-Derived Analogs

    NASA Astrophysics Data System (ADS)

    Woodring, Jennifer L.

    Human African trypanosomiasis (HAT) is a neglected tropical disease of significant morbidity and mortality in sub-Saharan Africa. Current chemotherapeutics targeting the causative agent Trypanosoma brucei lack oral bioavailability, efficacy, and safety. New small molecule drugs are desperately needed for HAT. Target repurposing represents one method for rapidly discovering new anti-trypanosomal compounds. This concept has been applied to repurposing small molecule inhibitors of human phosphodiesterases (PDEs) and protein tyrosine kinases (PTKs) for HAT, while improving physicochemical properties. The first project in this dissertation begins with the human PDE4 inhibitor piclamilast, which has an IC50 value of 4.7 microM against T. brucei PDEB1. Based upon this scaffold, new analogs were designed, synthesized, and screened for their biological activity against TbrPDEB1. Secondly, previous optimization of the human tyrosine kinase inhibitor lapatinib led to the discovery of the 4-anilino-quinazoline NEU-617, a potent (EC 50 = 42 nM) antitrypanosomal agent. Since alkynyl thienopyrimidines are well-known scaffolds for tyrosine kinase inhibitors, we assessed this scaffold as an alternative to the quinazoline of NEU-617. In addition, analogs of the NEU-617 were designed and synthesized to improve their physicochemical properties, such as lipophilicity and predicted central nervous system penetration. Lastly, nanoformulations have been shown to improve the oral bioavailability and circulation half-life of their encapsulated drug components. Because of this, nanoemulsions, liposomes, and polymeric nanoparticles were explored for their potential parasitic inhibitory effects and their ability to improve the physicochemical properties of NEU-617.

  2. Expediting analog design retargeting by design knowledge re-use and circuit synthesis: a practical example on a Delta-Sigma modulator

    NASA Astrophysics Data System (ADS)

    Webb, Matthew; Tang, Hua

    2016-08-01

    In the past decade or two, due to constant and rapid technology changes, analog design re-use or design retargeting to newer technologies has been brought to the table in order to expedite the design process and improve time-to-market. If properly conducted, analog design retargeting could significantly cut down design cycle compared to designs starting from the scratch. In this article, we present an empirical and general method for efficient analog design retargeting by design knowledge re-use and circuit synthesis (CS). The method first identifies circuit blocks that compose the source system and extracts the performance parameter specifications of each circuit block. Then, for each circuit block, it scales the values of design variables (DV) from the source design to derive an initial design in the target technology. Depending on the performance of this initial target design, a design space is defined for synthesis. Subsequently, each circuit block is automatically synthesised using state-of-art analog synthesis tools based on a combination of global and local optimisation techniques to achieve comparable performance specifications to those extracted from the source system. Finally, the overall system is composed of those synthesised circuit blocks in the target technology. We illustrate the method using a practical example of a complex Delta-Sigma modulator (DSM) circuit.

  3. Synthesis of fluorescent analogs of relaxin family peptides and their preliminary in vitro and in vivo characterization.

    PubMed

    Chan, Linda J; Smith, Craig M; Chua, Berenice E; Lin, Feng; Bathgate, Ross A D; Separovic, Frances; Gundlach, Andrew L; Hossain, Mohammed Akhter; Wade, John D

    2013-01-01

    Relaxin, a heterodimeric polypeptide hormone, is a key regulator of collagen metabolism and multiple vascular control pathways in humans and rodents. Its actions are mediated via its cognate G-protein-coupled receptor, RXFP1 although it also "pharmacologically" activates RXFP2, the receptor for the related, insulin-like peptide 3 (INSL3), which has specific actions on reproduction and bone metabolism. Therefore, experimental tools to facilitate insights into the distinct biological actions of relaxin and INSL3 are required, particularly for studies of tissues containing both RXFP1 and RXFP2. Here, we chemically functionalized human (H2) relaxin, the RXFP1-selective relaxin analog H2:A(4-24)(F23A), and INSL3 to accommodate a fluorophore without marked reduction in binding or activation propensity. Chemical synthesis of the two chains for each peptide was followed by sequential regioselective formation of their three disulfide bonds. Click chemistry conjugation of Cy5.5 at the B-chain N-terminus, with conservation of the disulfide bonds, yielded analogs displaying appropriate selective binding affinity and ability to activate RXFP1 and/or RXFP2 in vitro. The in vivo biological activity of Cy5.5-H2 relaxin and Cy5.5-H2:A(4-24)(F23A) was confirmed in mice, as acute intracerebroventricular (icv) infusion of these peptides (but not Cy5.5-INSL3) stimulated water drinking, an established behavioral response elicited by central RXFP1 activation. The central distribution of Cy5.5-conjugated peptides was examined in mice killed 30 min after infusion, revealing higher fluorescence within brain tissue near-adjacent to the cerebral ventricle walls relative to deeper brain areas. Production of fluorophore-conjugated relaxin family peptides will facilitate future pharmacological studies to probe the function of H2 relaxin/RXFP1 and INSL3/RXFP2 signaling in vivo while tracking their distribution following central or peripheral administration. PMID:24790958

  4. Synthesis of novel diterpenoid analogs with in-vivo antitumor activity.

    PubMed

    Wang, Ying-Ying; He, Yuan; Yang, Lian-Fang; Peng, Shi-Hong; He, Xiao-Long; Wang, Jin-Hua; Lv, Fang; Hao, Yun; Liu, Ming-Yao; Yi, Zhengfang; Qiu, Wen-Wei

    2016-09-14

    A lead compound 7 has antitumor effect, which was discovered by screening our small synthetic natural product-like compound (NPL) library. Based on the lead compound, a series of novel tricyclic diterpene analogs were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. To our delight, most aromatic amide compounds exhibited more potent antitumor activity than the lead compound. The most active compound 19 (QW30) showed an average IC50 0.33 μM, which was 15-fold more potent than the lead compound. Most of the compounds with potent antitumor activity displayed less toxic on normal human fibroblasts (HAF) in comparison with the tumor cell lines. Especially 19, its selectivity indexes (SI) between HAF and cancer cell lines was 17.3 times better than the positive control compound podophyllotoxin. The apoptosis, colony formation and transwell migration assays of 7 and 19 were performed on T47D cell line. The in-vivo antitumor effect of 19 was also observed in T47D tumor-bearing mice without obvious toxicity. PMID:27187855

  5. Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation

    PubMed Central

    Ghirmai, Senait; Azar, Marc R.; Cashman, John R.

    2010-01-01

    A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (μ), delta (δ) and kappa (κ) opioid and nociceptin (NOP) receptors. Binding assays showed that 4–10 had subnanomolar Ki values for μ and κ opioid receptors. Functional assays for stimulation of [35S] GTPγS binding showed that several compounds acted as partial or inverse agonists and antagonists of the μ and δ, κ opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4–9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5–8 to have very potent efficacy (ED50 values 19–50 μg/kg). PMID:19683449

  6. Centrally truncated and stabilized porcine neuropeptide Y analogs: design, synthesis, and mouse brain receptor binding.

    PubMed Central

    Krstenansky, J L; Owen, T J; Buck, S H; Hagaman, K A; McLean, L R

    1989-01-01

    Porcine neuropeptide Y (pNPY) has been proposed to form an intramolecularly stabilized structure characterized by N- and C-terminal helical regions arranged antiparallel due to a central turn region. Analogs based on this structural model that have the central turn region and various amounts of the helical regions removed, yet retain the N and C termini in a similar spatial orientation were designed. The gap formed by removal of the central residues (residues 8-17 or 7-20) was spanned with a single 8-aminooctanoic acid residue (Aoc) and the structure was further stabilized by the introduction of a disulfide bridge. [D-Cys7,Aoc8-17,Cys20]pNPY and [Cys5,Aoc7-20,D-Cys24]pNPY were synthesized and found to have receptor binding affinities of 2.3 nM and 150 nM, respectively, in mouse brain membranes (pNPY affinity is 3.6 nM in this assay). It is proposed that the central region (residues 7-17) of pNPY serves a structural role in the peptide and is not involved in direct receptor interaction. PMID:2543973

  7. Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation.

    PubMed

    Ghirmai, Senait; Azar, Marc R; Cashman, John R

    2009-09-15

    A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K(i) values for mu and kappa opioid receptors. Functional assays for stimulation of [(35)S]GTPgammaS binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED(50) values 19-50 microg/kg). PMID:19683449

  8. Synthesis and in vitro antitumor activity of new octapeptide analogs of somatostatin containing unnatural amino acids.

    PubMed

    Staykova, Svetlana Ts; Wesselinova, Diana W; Vezenkov, Lyubomir T; Naydenova, Emilia D

    2015-05-01

    Some modified octapeptide analogs of somatostatin with the following structure D-Phe-c(Cys-Phe-D-Trp-Xxx-Yyy-Cys)-Thr-NH2, where Xxx is Lys or Orn and Yyy is Aib (α-aminoisobutyric acid), Ac5c (1-aminocyclopentanecarboxylic acid) or Ac6c (1-aminocyclohexane carboxylic acid) have been synthesized. The peptides were prepared by standard Fmoc-solid phase peptide chemistry method. The direct disulphide bond formation has been employed on the solid phase by Tl(CF3CO2)3. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29 (human colorectal cancer cell line), MDA-MB-23 (human breast cancer cell line), Hep-G2 (human hepatocellular carcinoma cell line), HeLa (cervical cancer cell line) and normal human diploid cell line Lep-3. The new peptides exhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 24 h treatment. The compounds were most effective to the HT-29 tumor cells. The compound 4C (Orn(5), Aib(6)) demonstrated the most pronounced antiproliferative effects on HT-29 cells with the IC50 = 0.0199 μM. PMID:25655387

  9. Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.

    PubMed

    Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping

    2013-06-28

    A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity. PMID:23657615

  10. Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis.

    PubMed

    Krishnasamy, Sivakumar Kullampalayam; Namasivayam, Vigneshwaran; Mathew, Sincy; Eakambaram, Ragavendran S; Ibrahim, Ibrahim A; Natarajan, Adhirajan; Palaniappan, Senthilkumar

    2016-05-01

    Twenty-seven hybridized pyrazolone analogs were designed, docked, synthesized in two series and evaluated for their in vitro antimycobacterial properties. In the first series, four Schiff base derivatives, 6b, 7b, 7h, and 7i, show good antitubercular activity with minimum inhibition concentration (MIC) values in the range of 32.56-42.55 µM. In the second series, two compounds, 8b and 8c, possessed significant antitubercular activity with MIC <0.37 and <0.44 μM, respectively; they were even more potent than the standards pyrazinamide (12.99 μM), ciprofloxacin (4.82 μM), and streptomycin (5.36 μM), with a selectivity index of >630. Compounds 8b and 8c showed shikimate kinase inhibition activity at 5.84 and 6.93 µM, respectively. The activity and docking results lead to the conclusion that the compounds without double bond in the imine side chain and hydrophobic clashes at the pyrazolone end are necessary for good accommodation in the binding pocket and for imparting flexibility. All the compounds were also tested for antimicrobial activity (antibacterial and antifungal) and show highly significant activities against all the microorganisms tested. PMID:27135906

  11. Novel analogs of alloferon: Synthesis, conformational studies, pro-apoptotic and antiviral activity.

    PubMed

    Kuczer, Mariola; Czarniewska, Elżbieta; Majewska, Anna; Różanowska, Maria; Rosiński, Grzegorz; Lisowski, Marek

    2016-06-01

    In this study, we report the structure-activity relationships of novel derivatives of the insect peptide alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH). The peptide structure was modified by exchanging His at position 9 or 12 for natural or non-natural amino acids. Biological properties of these peptides were determined in antiviral in vitro test against Human Herpes Virus 1 McIntrie strain (HHV-1MC) using a Vero cell line. The peptides were also evaluated for the pro-apoptotic action in vivo on hemocytes of the Tenebrio molitor beetle. Additionally, the structural properties of alloferon analogs were examined by the circular dichroism in water and methanol. It was found that most of the evaluated peptides can reduce the HHV-1 titer in Vero cells. [Ala(9)]-alloferon exhibits the strongest antiviral activity among the analyzed compounds. However, no cytotoxic activity against Vero cell line was observed for all the studied peptides. In vivo assays with hemocytes of T. molitor showed that [Lys(9)]-, [Phg(9)]-, [Lys(12)]-, and [Phe(12)]-alloferon exhibit a twofold increase in caspases activity in comparison with the native peptide. The CD conformational studies indicate that the investigated peptides seem to prefer the unordered conformation. PMID:26986636

  12. Novel pyrazine analogs of chalcones: synthesis and evaluation of their antifungal and antimycobacterial activity.

    PubMed

    Kucerova-Chlupacova, Marta; Kunes, Jiri; Buchta, Vladimir; Vejsova, Marcela; Opletalova, Veronika

    2015-01-01

    Infectious diseases, such as tuberculosis and invasive mycoses, represent serious health problems. As a part of our long-term efforts to find new agents for the treatment of these diseases, a new series of pyrazine analogs of chalcones bearing an isopropyl group in position 5 of the pyrazine ring was prepared. The structures of the compounds were corroborated by IR and NMR spectroscopy and their purity confirmed by elemental analysis. The susceptibility of eight fungal strains to the studied compounds was tested. The results have been compared with the activity of some previously reported propyl derivatives. The only strain that was susceptible to the studied compounds was Trichophyton mentagrophytes. It was found that replacing a non-branched propyl with a branched isopropyl did not have a decisive and unequivocal influence on the in vitro antifungal activity against T. mentagrophytes. In vitro activity against Trichophyton mentagrophytes comparable with that of fluconazole was exhibited by nitro-substituted derivatives. Unfortunately, no compound exhibited efficacy comparable with that of terbinafine, which is the most widely used agent for treating mycoses caused by dermatophytes. Some of the prepared compounds were assayed for antimycobacterial activity against M. tuberculosis H37Rv. The highest potency was also displayed by nitro-substituted compounds. The results of the present study are in a good agreement with our previous findings and confirm the positive influence of electron-withdrawing groups on the B-ring of chalcones on the antifungal and antimycobacterial activity of these compounds. PMID:25587786

  13. Synthesis and anti-HBV activity of α-stereoisomer of aristeromycin based analogs.

    PubMed

    Kasula, Mohan; Toyama, Masaaki; Samunuri, Ramakrishnamraju; Rozy, Farhana; Yadav, Monika; Bal, Chandralata; Jha, Ashok Kumar; Baba, Masanori; Sharon, Ashoke

    2016-08-15

    The potential antiviral activity of aristeromycin type of derivatives (I) is limited by associated toxicity due to its possible 5'-O-phosphorylation and S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitory activity. Aristeromycin structure has major pharmacophoric motif as 5'-OH and adenosine base, which may have significant role in enzyme binding followed by activity and or toxicity. Thus, the structural optimization to alter this major motif by replacing with its bioisostere and changing the 5'-O conformation through stereochemistry reversal was of interest. Thus, the inverted stereochemistry at 4'-position coupled with bioisostere of adenosine base in the target compounds (6-7) to access antiviral potential. The stereoselective formation of a key stereoisomer (2a) was achieved exclusively from neplanocin sugar (1a) by reduction in a single step. The novel target molecules (6-7) were synthesized in 4 steps with 55-62% yield. Compound 6 was analyzed by single crystal X-ray diffraction, which confirms the stereoselective formation of α-analogs with highly puckered cyclopentane ring and 2'-endo conformation. The compound 6 shown significant anti-hepatitis B virus activity of 6.5μM with CC50>100μM and yielded a promising lead with novel structural feature. PMID:27426303

  14. Synthesis and structural characterization of some trisulfide analoges of thiouracil-based antithyroid drugs

    NASA Astrophysics Data System (ADS)

    Bhabak, Krishna P.; Bhowmick, Debasish

    2012-08-01

    Thiourea-based antithyroid drugs are effectively used for the treatment of hyperthyroidism. In this paper, we describe the synthesis of new trisulfides (11-12) from the commonly used thiourea-based antithyroid drugs such as 6-n-propyl-2-thiouracil (PTU) and 6-methyl-2-thiouracil (MTU) in the reaction with I2/KI system. Structural analysis by single crystal X-ray diffraction studies revealed the stabilization of trisulfides by a lactam-lactim tautomerism facilitating effective intramolecular as well as intermolecular non-covalent interactions. Although the structures of both trisulfides were found to be quite similar, a notable difference in the intermolecular interactions was observed between compounds 11 and 12 leading to different structural patterns. Structural stabilization of these trisulfides by tautomerism followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule.

  15. SYNTHESIS AND BIOLOGICAL ACTIVITY OF SULFUR COMPOUNDS SHOWING STRUCTURAL ANALOGY WITH COMBRETASTATIN A-4

    PubMed Central

    dos Santos, Edson dos A.; Prado, Paulo C.; de Carvalho, Wanderley R.; de Lima, Ricardo V.; Beatriz e, Adilson; de Lima, Dênis P.; Hamel, Ernest; Dyba, Marzena A.; Albuquerque, Sergio

    2013-01-01

    We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15). PMID:23766547

  16. Design, synthesis and crystallization of a novel glucagon analog as a therapeutic agent

    SciTech Connect

    Li, Pengyun; Rogers, Tanya; Smiley, David; DiMarchi, Richard D.; Zhang, Faming

    2007-07-01

    The synthesis and crystallization of glucagon-Cex are reported. Glucagon and glucagon-like peptide 1 (GLP-1) are drugs or drug candidates for the treatment of metabolic diseases such as diabetes and obesity. The native hormones have pharmacological deficiencies such as short half-life and poor solubility. A novel glucagon receptor agonist named glucagon-Cex has been designed, synthesized and crystallized. This peptide was highly soluble under physiological conditions and crystallized readily. The crystal diffracted X-rays to 2.2 Å resolution and the diffraction was consistent with space group P23, with unit-cell parameters a = b = c = 48.20 Å, α = β = γ = 90.0°. The crystals were suitable for a full structural determination to reveal the conformational differences between glucagon-Cex and the native hormone.

  17. Synthesis, characterization and biological activity of hydroxyl-bisphosphonic analogs of bile acids.

    PubMed

    Bortolini, Olga; Fantin, Giancarlo; Fogagnolo, Marco; Rossetti, Stefano; Maiuolo, Loredana; Di Pompo, Gemma; Avnet, Sofia; Granchi, Donatella

    2012-06-01

    Bisphosphonates (BPs) are now the most widely used drugs for diseases associated with increased bone resorption, such as osteoporosis, and tumor bone diseases. A significant drawback of the BPs is their poor oral absorption that is enhanced by the presence of bile acid substituents in the bisphosphonate framework, with no toxic effects. A straightforward synthesis of bile acid-containing hydroxy-bisphosphonates and a full characterization of these pharmaceutically important molecules, including an evaluation of affinity and the mechanism of binding to hydroxyapatite, is presented. The biological activity of bile acid-containing bisphosphonate salts was determined using the neutral-red assay on the L929 cell line and primary cultures of osteoclasts. The bioactivity of the new compounds was found superior than bisphosphonates of established activity. PMID:22483634

  18. Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand

    PubMed Central

    Bhojani, Mahaveer S.; Ranga, Rajesh; Luker, Gary D.; Rehemtulla, Alnawaz; Ross, Brian D.; Van Dort, Marcian E.

    2011-01-01

    A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3-[125I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [125I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C5 maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells. Additionally, F3Cys conjugated with NIR fluorochrome AlexaFluor 647 C2 maleimide demonstrated high tumor specific uptake in melanoma cancer MDA-MB-435 and lung cancer A549 xenografts in nude mice whereas a similarly labeled control peptide did not show any tumor uptake. These results were also confirmed by ex vivo tissue analysis. No-carrier-added [125I]IBMF3 was synthesized by a radioiododestannylation approach in 73% overall radiochemical yield. In vitro cell uptake studies conducted with [125I]IBMF3 displayed a 5-fold increase in its cell uptake at 4 h when compared to controls. SPECT imaging studies with [125I]IBMF3 in tumor bearing nude mice showed clear visualization of MDA-MB-435 xenografts on systemic administration. These studies demonstrate a potential utility of F3 peptide-based radioligands for tumor imaging with PET or SPECT techniques. PMID:21811604

  19. Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands.

    PubMed

    Geyer, Roland; Kaske, Melanie; Baumeister, Paul; Buschauer, Armin

    2014-02-01

    Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50  = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R. PMID:24493592

  20. Design, synthesis and pharmacological characterization of coumarin-based fluorescent analogs of excitatory amino acid transporter subtype 1 selective inhibitors, UCPH-101 and UCPH-102.

    PubMed

    Huynh, Tri H V; Abrahamsen, Bjarke; Madsen, Karsten K; Gonzalez-Franquesa, Alba; Jensen, Anders A; Bunch, Lennart

    2012-12-01

    The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure-activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC(50)=0.66μM) and UCPH-102 (IC(50)=0.43μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC(50) values >300μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC(50) values in the medium micromolar range (17μM and 14μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F. PMID:23072958

  1. Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents.

    PubMed

    Gadekar, Pradip K; Roychowdhury, Abhijit; Kharkar, Prashant S; Khedkar, Vijay M; Arkile, Manisha; Manek, Hardik; Sarkar, Dhiman; Sharma, Rajiv; Vijayakumar, V; Sarveswari, S

    2016-10-21

    The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 μg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents. PMID:27423637

  2. Facile synthesis and biological assays of novel 2,4-disubstituted hydrazinyl-thiazoles analogs.

    PubMed

    Ghanbari Pirbasti, Fateme; Mahmoodi, Nosrat O

    2016-05-01

    A convenient, one-pot multi-component synthesis of new 2,4-disubstituted hydrazinyl-thiazoles was accomplished using different aldehydes/ketones, thiosemicarbazide, and 4-methoxy phenacyl bromide in the presence of a catalytic amount of AcOH in EtOH. Products were obtained in reasonable yields and high purity. The in vitro antioxidant activity of hydrazinyl-thiazoles was evaluated by DPPH radical scavenging activity in comparison to ascorbic acid. Synthesized thiazoles 14c and 14g possessed the lowest IC50 values. Also, hydrazinyl-thiazoles were screened for their in vitro antibacterial activity against six strains of bacteria including S. aureus, M. luteus, E. coli, Ps. aeruginosa, B. subtilis, and A. hydrophila where some products showed good antibacterial activity. Moreover, compound 14a showed anticancer activity against melanoma cancerous cell lines A375 with LC50=0.55 mg/ml, slightly selective versus normal cell lines (Hu-2) with LC50=1.19 mg/ml.. PMID:26754629

  3. Physical vapor deposition synthesis of amorphous silicate layers and nanostructures as cosmic dust analogs

    NASA Astrophysics Data System (ADS)

    De Sio, A.; Tozzetti, L.; Wu, Ziyu; Marcelli, A.; Cestelli Guidi, M.; Della Ventura, G.; Zhao, Haifeng; Pan, Zhiyun; Li, Wenjie; Guan, Yong; Pace, E.

    2016-05-01

    Cosmic dust grains (CD) are part of the evolution of stars and planetary systems and pervade the interstellar medium. Thus, their spectral signature may be used to deduce the physical features of the observed astronomical objects or to study many physical and chemical processes in the interstellar medium. However, CD samples are available only from sample-and-return space missions. Thus, they are rare and not sufficient to be used to perform laboratory experiments of astrophysical interest, such as to produce reference spectra. In this contribution, we describe a new physical vapor deposition (PVD) technique that allows the production of amorphous samples with controlled chemical and morphological characteristics. In particular, this technique was developed to grow uniform or microstructured layers of Mg-Fe amorphous silicates (olivine or pyroxene) that are materials of wide interest for laboratory experiments. We discuss the first results that were achieved by applying this new synthesis method. The layers were studied by combining infrared spectroscopy, scanning electron microscopy, and X-ray spectroscopy. The X-ray microscopy was used for the first time to characterize the internal structure of the grains in these synthetic samples. Finally, future improvements of the technique and foreseen applications are discussed.

  4. Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs.

    PubMed

    Wang, Hao-Meng; Zhang, Li; Liu, Jiang; Yang, Zhao-Liang; Zhao, Hong-Ye; Yang, Yao; Shen, Di; Lu, Kui; Fan, Zhen-Chuan; Yao, Qing-Wei; Zhang, Yong-Min; Teng, Yu-Ou; Peng, Yu

    2015-03-01

    Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by (1)H NMR, (13)C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5'-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis. PMID:25590864

  5. Design, Synthesis and Biological Evaluation of N-Acetyl-S-(pchlorophenylcarbamoyl)cysteine and Its Analogs as a Novel Class of Anticancer Agents

    PubMed Central

    Chen, Wei; Seefeldt, Teresa; Young, Alan; Zhang, Xiaoying; Guan, Xiangming

    2010-01-01

    N-Acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) was identified as a metabolite of sulofenur. Sulofenur was demonstrated to have broad activity against solid tumors in preclinical studies but exhibited disappointing clinical responses due to its high protein binding related adverse effects. NACC exhibited low protein binding and excellent activity against a sulofenur sensitive human colon cancer cell line. In this study, analogs of NACC were synthesized and evaluated with four human cancer cell lines. Two of the NACC analogs showed excellent activity against two human melanoma cell lines, while NACC remains the most potent of the series. All three compounds were more potent than dacarbazine, which is used extensively in treating melanoma. NACC was shown to induce apoptosis without affecting the cell cycle. Further, NACC exhibited low toxicity against monkey kidney cells. The selective anticancer activity, low toxicity, an unknown yet but unique anticancer mechanism and ready obtainability through synthesis make NACC and its analogs promising anticancer agents. PMID:21131205

  6. A retro-evolution study of CDP-6-deoxy-D-glycero-L-threo-4-hexulose-3-dehydrase (E1) from Yersinia pseudotuberculosis: implications for C-3 deoxygenation in the biosynthesis of 3,6-dideoxyhexoses.

    PubMed

    Wu, Qingquan; Liu, Yung-Nan; Chen, Huawei; Molitor, Erich J; Liu, Hung-wen

    2007-03-27

    CDP-6-deoxy-l-threo-d-glycero-4-hexulose-3-dehydrase (E1), which catalyzes C-3 deoxygenation of CDP-4-keto-6-deoxyglucose in the biosynthesis of 3,6-dideoxyhexoses, shares a modest sequence identity with other B6-dependent enzymes, albeit with two important distinctions. It is a rare example of a B6-dependent enzyme that harbors a [2Fe-2S] cluster, and a highly conserved lysine that serves as an anchor for PLP in most B6-dependent enzymes is replaced by histidine at position 220 in E1. Since alteration of His220 to a lysine residue may produce a putative progenitor of E1, the H220K mutant was constructed and tested for the ability to process the predicted substrate, CDP-4-amino-4,6-dideoxyglucose, using PLP as the coenzyme. Our data showed that H220K-E1 has no dehydrase activity, but can act as a PLP-dependent transaminase. However, the reaction is not catalytic since PLP cannot be regenerated during turnover. Reported herein are the results of this investigation and the implications for the role of His220 in the catalytic mechanism of E1. PMID:17323931

  7. Synthesis of fluorescent analogs of relaxin family peptides and their preliminary in vitro and in vivo characterization

    PubMed Central

    Chan, Linda J.; Smith, Craig M.; Chua, Berenice E.; Lin, Feng; Bathgate, Ross A. D.; Separovic, Frances; Gundlach, Andrew L.; Hossain, Mohammed Akhter; Wade, John D.

    2013-01-01

    Relaxin, a heterodimeric polypeptide hormone, is a key regulator of collagen metabolism and multiple vascular control pathways in humans and rodents. Its actions are mediated via its cognate G-protein-coupled receptor, RXFP1 although it also “pharmacologically” activates RXFP2, the receptor for the related, insulin-like peptide 3 (INSL3), which has specific actions on reproduction and bone metabolism. Therefore, experimental tools to facilitate insights into the distinct biological actions of relaxin and INSL3 are required, particularly for studies of tissues containing both RXFP1 and RXFP2. Here, we chemically functionalized human (H2) relaxin, the RXFP1-selective relaxin analog H2:A(4-24)(F23A), and INSL3 to accommodate a fluorophore without marked reduction in binding or activation propensity. Chemical synthesis of the two chains for each peptide was followed by sequential regioselective formation of their three disulfide bonds. Click chemistry conjugation of Cy5.5 at the B-chain N-terminus, with conservation of the disulfide bonds, yielded analogs displaying appropriate selective binding affinity and ability to activate RXFP1 and/or RXFP2 in vitro. The in vivo biological activity of Cy5.5-H2 relaxin and Cy5.5-H2:A(4-24)(F23A) was confirmed in mice, as acute intracerebroventricular (icv) infusion of these peptides (but not Cy5.5-INSL3) stimulated water drinking, an established behavioral response elicited by central RXFP1 activation. The central distribution of Cy5.5-conjugated peptides was examined in mice killed 30 min after infusion, revealing higher fluorescence within brain tissue near-adjacent to the cerebral ventricle walls relative to deeper brain areas. Production of fluorophore-conjugated relaxin family peptides will facilitate future pharmacological studies to probe the function of H2 relaxin/RXFP1 and INSL3/RXFP2 signaling in vivo while tracking their distribution following central or peripheral administration. PMID:24790958

  8. Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

    PubMed Central

    Kowalska, Joanna; Wypijewska del Nogal, Anna; Darzynkiewicz, Zbigniew M.; Buck, Janina; Nicola, Corina; Kuhn, Andreas N.; Lukaszewicz, Maciej; Zuberek, Joanna; Strenkowska, Malwina; Ziemniak, Marcin; Maciejczyk, Maciej; Bojarska, Elzbieta; Rhoads, Robert E.; Darzynkiewicz, Edward; Sahin, Ugur; Jemielity, Jacek

    2014-01-01

    Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide cap analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5′,5′-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m27,3′-OGpppG. Higher expression of cancer antigens would make mRNAs containing m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2 favorable for anticancer immunization. PMID:25150148

  9. Synthesis of analogs of the radiation mitigator JP4-039 and visualization of BODIPY derivatives in mitochondria

    PubMed Central

    Frantz, Marie-Céline; Skoda, Erin M.; Sacher, Joshua R.; Epperly, Michael W.; Goff, Julie P.; Greenberger, Joel S.

    2013-01-01

    JP4-039 is a lead structure in a series of nitroxide conjugates that are capable of accumulating in mitochondria and scavenging reactive oxygen species (ROS). To explore structure-activity relationships (SAR), new analogs with variable nitroxide moieties were prepared. Furthermore, fluorophore-tagged analogs were synthesized and provided the opportunity for visualization in mitochondria. All analogs were tested for radioprotective and radiomitigative effects in 32Dcl3 cells. PMID:23715589

  10. Synthesis of analogs of the radiation mitigator JP4-039 and visualization of BODIPY derivatives in mitochondria.

    PubMed

    Frantz, Marie-Céline; Skoda, Erin M; Sacher, Joshua R; Epperly, Michael W; Goff, Julie P; Greenberger, Joel S; Wipf, Peter

    2013-07-01

    JP4-039 is a lead structure in a series of nitroxide conjugates that are capable of accumulating in mitochondria and scavenging reactive oxygen species (ROS). To explore structure-activity relationships (SAR), new analogs with variable nitroxide moieties were prepared. Furthermore, fluorophore-tagged analogs were synthesized and provided the opportunity for visualization in mitochondria. All analogs were tested for radioprotective and radiomitigative effects in 32Dcl3 cells. PMID:23715589

  11. Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

    PubMed Central

    Horník, Štěpán; Červenková Šťastná, Lucie; Cuřínová, Petra; Sýkora, Jan; Káňová, Kateřina; Hrstka, Roman; Císařová, Ivana; Dračínský, Martin

    2016-01-01

    Summary Background: Derivatives of D-glucosamine and D-galactosamine represent an important family of the cell surface glycan components and their fluorinated analogs found use as metabolic inhibitors of complex glycan biosynthesis, or as probes for the study of protein–carbohydrate interactions. This work is focused on the synthesis of acetylated 3-deoxy-3-fluoro, 4-deoxy-4-fluoro and 3,4-dideoxy-3,4-difluoro analogs of D-glucosamine and D-galactosamine via 1,6-anhydrohexopyranose chemistry. Moreover, the cytotoxicity of the target compounds towards selected cancer cells is determined. Results: Introduction of fluorine at C-3 was achieved by the reaction of 1,6-anhydro-2-azido-2-deoxy-4-O-benzyl-β-D-glucopyranose or its 4-fluoro analog with DAST. The retention of configuration in this reaction is discussed. Fluorine at C-4 was installed by the reaction of 1,6:2,3-dianhydro-β-D-talopyranose with DAST, or by fluoridolysis of 1,6:3,4-dianhydro-2-azido-β-D-galactopyranose with KHF2. The amino group was introduced and masked as an azide in the synthesis. The 1-O-deacetylated 3-fluoro and 4-fluoro analogs of acetylated D-galactosamine inhibited proliferation of the human prostate cancer cell line PC-3 more than cisplatin and 5-fluorouracil (IC50 28 ± 3 μM and 54 ± 5 μM, respectively). Conclusion: A complete series of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine is now accessible by 1,6-anhydrohexopyranose chemistry. Intermediate fluorinated 1,6-anhydro-2-azido-hexopyranoses have potential as synthons in oligosaccharide assembly. PMID:27340467

  12. 1 alpha,25-dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: design, synthesis, and preliminary biological testing.

    PubMed

    Posner, G H; Li, Z; White, M C; Vinader, V; Takeuchi, K; Guggino, S E; Dolan, P; Kensler, T W

    1995-10-27

    Aromatic compounds 2a-c, analogs of 1 alpha, 25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1 alpha, 25-dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent compounds while avoiding previtamin D equilibrium. Convergent and facile total syntheses of the analogs (+)-2b, (+)-2c, (-)-4b, and (-)-5b were achieved via carbonyl addition of regiospecifically formed organolithium nucleophiles to the enantiomerically pure C,D-ring ketone (+)-17, characteristic of natural calcitriol (1). Likewise, hybrid analogs 20a-c were prepared to determine whether incorporation of a known potentiating side chain would lead to increased biological activity. Preliminary in vitro biological testing showed that aromatic analogs (+)-2b, (+)-2c, and 20a-c as well as heteroaromatic analogs (-)-4b and (-)-5b have very low affinities for the calf thymus vitamin D receptor but considerable antiproliferative activities in murine keratinocytes at micromolar concentration. No biological advantage was observed in this keratinocyte assay for the doubly modified hybrid analogs 20a-c over the singly modified parent (+)-2b. Analog (+)-2b, but surprisingly not the corresponding analog 20b differing from (+)-2b only in the side chain, showed considerable activity in nongenomic opening of calcium channels in rat osteosarcoma cells. PMID:7473581

  13. Design, synthesis, and anti-breast cancer evaluation of new triarylethylene analogs bearing short alkyl- and polar amino-/amido-ethyl chains.

    PubMed

    Kaur, Gurleen; Mahajan, Mohinder P; Pandey, Manoj K; Singh, Parvesh; Ramisetti, Srinivasa R; Sharma, Arun K

    2016-04-15

    The synthesis of novel triarylethylene analogs, designed based on well-known Selective Estrogen Receptor Modulators (SERMs), i.e., ospemifene and tamoxifen, as potential anti-breast cancer agents is described. The cytotoxic potential of these analogs against ER-positive (MCF-7) and ER-negative (MDA-MB-231) human breast cancer cell lines was determined and compared with the standards, ospemifene and tamoxifen. In initial screening, analogs 5, 14 and 15 were found to be much more effective than the standards against both the cell lines. The results showed that these novel analogs inhibit the expression of proteins involved in the migration and metastasis, compound 5 being most effective. Compound 5 inhibited the expression of MMP-9, c-Myc and Caveolin in both MCF-7 and MDA-MB-231 cells, and suppressed the invasion of ER-negative cells in a dose dependent manner. Finally, in silico docking simulations of the representative compounds in the binding sites of the estrogen receptors (ERs) indicated a good binding affinity of the compounds with the ERs, and supported their experimental toxicity against MCF-7 cancer cell lines. PMID:26972118

  14. Antitumor Agents 250.† Design and Synthesis of New Curcumin Analogs as Potential Anti-Prostate Cancer Agents

    PubMed Central

    Lin, Li; Shi, Qian; Nyarko, Alexander K.; Bastow, Kenneth F.; Wu, Chin-Chung; Su, Ching-Yuan; Shih, Charles C.-Y; Lee, Kuo-Hsiung

    2008-01-01

    In a continuing study of curcumin analogs as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogs classified into four series: monophenyl analogs (series A), heterocycle-containing analogs (series B), analogs bearing various substituents on the phenyl rings (series C) and analogs with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells; seven only against LNCaP; and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogs with better anti-prostate cancer activity. PMID:16789753

  15. Lunar Analog

    NASA Technical Reports Server (NTRS)

    Cromwell, Ronita L.

    2009-01-01

    In this viewgraph presentation, a ground-based lunar analog is developed for the return of manned space flight to the Moon. The contents include: 1) Digital Astronaut; 2) Bed Design; 3) Lunar Analog Feasibility Study; 4) Preliminary Data; 5) Pre-pilot Study; 6) Selection of Stockings; 7) Lunar Analog Pilot Study; 8) Bed Design for Lunar Analog Pilot.

  16. Differential half-maximal effects of human insulin and its analogs for in situ glucose transport and protein synthesis in rat soleus muscle

    NASA Technical Reports Server (NTRS)

    Weinstein, Randi B.; Eleid, Noura; LeCesne, Catherine; Durando, Bianca; Crawford, Julie T.; Heffner, Michelle; Layton, Christle; O'Keefe, Matthew; Robinson, Jennifer; Rudinsky, Suzy; Henriksen, Erik J.; Tischler, Marc E.

    2002-01-01

    Analogs of human insulin have been used to discriminate between responses of metabolic and mitogenic (growth-related) pathways. This study compared the stimulatory effects of human insulin (HI) and 2 analogs (X2, B-Asp(9), B-Glu(27) and H2, A-His(8),B-His(4),B-Glu(10), B-His(27)) on glucose uptake and protein synthesis in rat soleus muscle in situ. Glucose uptake, estimated by intramuscular (IM) injection of 2-deoxy[1,2-3H]glucose with or without insulin, was maximally increased at 10(-6) mol/L for HI and X2 and 10(-7) mol/L for H2. HI had a larger effect (318%) than either X2 (156%) or H2 (124%). The half-maximal effect (ED(50)) values for HI, X2, and H2 were 3.3 x10(-8) mol/L, 1.7 x 10(-7) mol/L, and 1.6 x 10(-9) mol/L, respectively. Protein synthesis, estimated by protein incorporation of [(3)H]phenylalanine injected into muscles with or without insulin, was maximally increased at 10(-5) mol/L for HI and 10(-6) for X2 and H2. HI had a larger effect in stimulating protein synthesis (34%) than either X2 (25%) or H2 (19.8%). The ED(50) values for HI, X2, and H2 were 3.0 x 10(-7) mol/L, 3.2 x 10(-7) mol/L, and 1.0 x 10(-9) mol/L, respectively. The biological potency of each analog (ED(50)insulin/ED(50)analog) showed X2 to be less potent than HI for both glucose uptake (0.2) and protein synthesis (0.9), whereas H2 is more potent than HI with ratios of 20 and 300, respectively. These data suggest that this approach for studying insulin responsiveness in a single muscle in situ may be a useful tool for investigating insulin signaling in muscle in vivo. Copyright 2002, Elsevier Science (USA). All rights reserved.

  17. Synthesis, structural characterization and effect on human granulocyte intracellular cAMP levels of abscisic acid analogs.

    PubMed

    Bellotti, Marta; Salis, Annalisa; Grozio, Alessia; Damonte, Gianluca; Vigliarolo, Tiziana; Galatini, Andrea; Zocchi, Elena; Benatti, Umberto; Millo, Enrico

    2015-01-01

    The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure-activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2' and C-3' abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti-inflammatory compounds. PMID:25496807

  18. Pyrrolidine analogs of GZ-793A: Synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2)

    PubMed Central

    Penthala, Narsimha Reddy; Ponugoti, Purushothama Rao; Nickell, Justin R.; Deaciuc, Agripina G.; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a–i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [3H]-DTBZ binding (Ki=560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki=8.29 μM). Analog 11f also showed similar potency of inhibition of [3H]-DA uptake into vesicles (Ki=45 nM) compared to that for GZ-793A (Ki=29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function. 2009 Elsevier Ltd. All rights reserved. PMID:23597792

  19. Synthesis of [18F]-labelled Maltose Derivatives as PET Tracers for Imaging Bacterial Infection

    PubMed Central

    Namavari, Mohammad; Gowrishankar, Gayatri; Hoehne, Aileen; Jouannot, Erwan; Gambhir, Sanjiv S

    2015-01-01

    Purpose To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections. Procedures It is known that maltose and maltodextrins are energy sources for bacteria. Hence, 18F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(α-D-glucopyranosyl)-6-deoxy-6-[18F]fluoro-D-glucopyranoside (6-[18F]fluoromaltose) and 4-O-(α-D-glucopyranosyl)-1-deoxy-1-[18F]fluoro-D-glucopyranoside (1-[18F]fluoromaltose) as bacterial infection PET imaging agents. 6-[18F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2′,3′,-di-O-acetyl-4′,6′-benzylidene-α-D-glucopyranosyl)-6-deoxy-6-nosyl-D-glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[18F]fluoromaltose. In an analogous procedure, 1-[18F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O-(2′,3′,4′,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D-glucopranoside (9). Stability of 6-[18F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 °C was determined. Escherichia coli uptake of 6-[18F]fluoromaltose was examined. Results A reliable synthesis of 1- and 6-[18F]fluoromaltose has been accomplished with 4–6 and 5–8 % radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[18F]fluoromaltose was sufficiently stable over the time span needed for PET studies (~96 % intact compound after 1-h and ~65 % after 2-h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[18F]fluoromaltose. Competition assays showed that the uptake of 6-[18F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose. Conclusion We have successfully synthesized 1- and 6-[18F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake

  20. Synthesis and characterization of 1-deoxy-. beta. -D-glucopyranosyl-methanephosphonyl-5'-uridine monophosphate: a phosphono analog of UDP-glucose

    SciTech Connect

    Andre, J.C.; Mervic, M.; Armstrong, R.N.

    1987-05-01

    The phosphono analog of UDP-glucose (UDPG) has been synthesized as a first entry into potential dead-end inhibitors of glycosyltransferases using UDP-sugars such as UDP-glucuronyltransferase and possible alternative substrates for UDPG dehydrogenase and epimerase. 1-Deoxy-..beta..-D-glucopyranosylmethanephosphonate (G-1-CH/sub 2/P) was synthesized by modifications of literature procedures and characterized by /sup 1/H, /sup 31/P and /sup 13/C NMR. Condensation of G-1-CH/sub 2/P with UMP morpholidate gave the expected phosphono analog of UDPG (UDPCH/sub 2/G) in low yield. G-1-CH/sub 2/P was found to be a substrate for UTP: glucose-1-phosphate pyrophosphoyrlase. Thus, UDPCH/sub 2/G can be prepared enzymatically from G-1-CH/sub 2/P and UTP by the coupled action of the pyrophosphoyrlase and inorganic pyrophosphatase. Preliminary evidence suggests UDPCH/sub 2/G is a very poor substrate for UDPG dehydrogenase. Thus, efficient enzymatic synthesis of the phosphono analog (UDPCH/sub 2/GA) of UDP-glucuronate appears unlikely.

  1. Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents.

    PubMed

    Carroll, F Ivy; Gichinga, Moses G; Kormos, Chad M; Maitra, Rangan; Runyon, Scott P; Thomas, James B; Mascarella, S Wayne; Decker, Ann M; Navarro, Hernán A

    2015-10-01

    The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists. PMID:26342544

  2. Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar cycloaddition of 3-vinylindoles.

    PubMed

    Marcin, Lawrence R; Mattson, Ronald J; Gao, Qi; Wu, Dedong; Molski, Thaddeus F; Mattson, Gail K; Lodge, Nicholas J

    2010-02-01

    Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET. PMID:20034793

  3. Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer.

    PubMed

    Agarwal, Hitesh K; Khalil, Ahmed; Ishita, Keisuke; Yang, Weilian; Nakkula, Robin J; Wu, Lai-Chu; Ali, Tehane; Tiwari, Rohit; Byun, Youngjoo; Barth, Rolf F; Tjarks, Werner

    2015-07-15

    A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogs (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3-4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analog. Both 2 and 3 appeared to be 5'-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogs and will profoundly impact future design strategies for these agents. PMID:26087030

  4. Synthesis and biological activity of a lysine-containing cyclic analog of (Leu/sup 5/)enkephalin

    SciTech Connect

    Bobrova, I.V.; Abissova, N.A.; Rozental', G.F.; Nikiforovich, G.V.; Chipens, G.I.

    1986-09-01

    A cyclic analog of enkephalin - cyclo(Lys-Tyr-Gly-Gly-Phe-Leu) -- and two corresponding linear hexapeptides containing a residue of the amino acid lysine at the beginning and the end of the molecule - Lys-Tyr-Gly-Gly-Phe-Leu and Tyr-Gly-Gly-Phe-Leu-Lys - have been synthesized by the classical methods of peptide chemistry. The addition of a lysine residue to the N-end of the enkephalin molecule or the cyclization of this hexapeptide decreased the action of the analogs on the central and peripheral opiate receptors. The addition of lysine through the epsilon-amino group to the C-end of the enkephalin molecule scarcely changed the interaction of the analog with the ..mu..-type of opiate receptor but lowered its affinity for the delta-type of receptor approximately 10-fold. All three analogs that were synthesized possessed an analgesic activity comparable in magnitude with the activity of (Leu/sup 5/)enkephalin determined by the tail pinch method on intracisternal administration to mice.

  5. Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.

    PubMed

    Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna

    2016-02-15

    Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs. PMID:26785295

  6. Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway

    PubMed Central

    Krishnegowda, Gowdahalli; Gowda, A. S. Prakasha; Tagaram, Hephzibah Rani S.; Staveley-O’ Carroll, Kevin F; Irby, Rosalyn B.; Sharma, Arun K.; Amin, Shantu

    2011-01-01

    A novel series of 5,7-dibromoisatin analogs were synthesized and evaluated for their cytotoxicities against four human cancer cell lines including colon HT29, breast MCF-7, lung A549 and melanoma UACC903. Analogs 6, 11 and 13 displayed good in vitro anticancer activity on the HT29 human colon cancer cell line in the 1 µM range. Analogs 5, 9 and 12, containing a selenocyanate group in the alkyl chain were the most promising compounds on the breast cancer MCF-7 cell line. Biological assays relating to apoptosis were performed to understand the mechanism of action of these analogs. Compounds 5 and 6 were found to inhibit tubulin polymerization to the same extent as the anticancer drug vinblastine sulfate, but compounds 11 and 13 inhibited significantly better than vinblastine. Further western blot analysis suggested that compound 6 at 2 µM reduced both levels and phosphorylation state of Akt. Compounds 11 and 13 at 1 µM caused reduced Akt protein levels and strongly suppressed the phosphorylation of Akt. Therefore, 11 and 13 were demonstrated as efficient dual inhibitors of both tubulin polymerization and the Akt pathway and good candidates for further study. More importantly, the strategy of microtubule and Akt dual inhibitors might be a promising direction for developing novel drugs for cancer. PMID:21920762

  7. Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells.

    PubMed

    Yamamoto, Yumi; Arai, Jun; Hisa, Takuya; Saito, Yohei; Mukai, Takahiro; Ohshima, Takashi; Maeda, Minoru; Yamamoto, Fumihiko

    2016-08-15

    Isomeric iodinated derivatives of nimesulide, with an iodine substituent on the phenoxy ring, were prepared with the aim of identifying potential candidate compounds for the development of imaging agents targeting cyclooxygenase-2 (COX-2) in the brain. Both the experimental logP7.4 and pKa values for these iodinated analogs were in the acceptable range for passive brain penetration. The para-iodo-substituted analog was a more potent and selective COX-2 inhibitor than nimesulide, with a potency that was comparable to the reference drug, celecoxib. Iodination at the ortho- or meta-position of the phenoxy ring was associated with a substantial loss of COX-2 inhibitory activity. Transport studies across Caco-2 cell monolayers in the presence and absence of a P-glycoprotein (P-gp) inhibitor, verapamil, indicated that the para-iodo-substituted analog was not a P-gp transport substrate; this feature is a prerequisite for potential in vivo brain imaging compounds. The para-iodo-substituted analog of nimesulide appears to be an attractive candidate for the development of radioiodine-labeled tracers for in vivo brain imaging of COX-2 levels. PMID:27325447

  8. Synthesis and antioxidant property of novel 1,2,3-triazole-linked starch derivatives via 'click chemistry'.

    PubMed

    Tan, Wenqiang; Li, Qing; Li, Wancong; Dong, Fang; Guo, Zhanyong

    2016-01-01

    Based on the copper (I) catalyzed Huisgen azide-alkyne cycloaddition (click chemistry), the novel synthesis of a variety of 1,2,3-triazole-linked starch derivatives was developed, including 6-hydroxymethyltriazole-6-deoxy starch (HMTST), 6-hydroxyethyltriazole-6-deoxy starch (HETST), 6-hydroxypropyltriazole-6-deoxy starch (HPTST), and 6-hydroxybutyltriazole-6-deoxy starch (HBTST). Their antioxidant properties against hydroxyl-radical, DPPH-radical, and superoxide-radical were evaluated in vitro, respectively. The antioxidant activity of the obtained novel amphiprotic starch derivatives via 'click reaction' exhibited remarkable improvement over starch. And the scavenging effect indices of most of the products were higher than 60% at 1.6 mg/mL against hydroxyl-radical and DPPH-radical. Moreover, the scavenging effect of the products against superoxide-radical attained 90% above at 0.1mg/mL. Generally, the antioxidant activity decreased in the order: HBTST>HPTST>HETST>HMTST>starch. Furthermore, the order of their antioxidant activity was consistent with the electron-donating ability of different substituted groups of the 1,2,3-triazoles. The substituted groups with stronger electron supplying capacity provided more electrons to the various radicals, which relatively enhanced the capacity for scavenging free radicals. PMID:26449530

  9. Synthesis and anticancer activity of new flavonoid analogs and inconsistencies in assays related to proliferation and viability measurements

    PubMed Central

    FORBES, ALAINA M.; LIN, HUIMIN; MEADOWS, GARY G.; MEIER, G. PATRICK

    2014-01-01

    Flavonoids have been studied intensely for their ability to act as anti-carcinogenic, anti-inflammatory, anti-viral and anti-aging agents and are often marketed as supplements related to their anti-inflammatory activity. Previous studies have primarily focused on the effects of polar natural flavonoids. We examined the activity of novel hydrophobic and lipophilic flavonols against human DU-145 and PC-3 prostate cancer cell lines. All flavonol analogs were more active than the naturally occurring flavonols quercetin, kaempferol, kaempferide and galangin. The most potent analogs were 6.5-fold more active against DU-145 and PC-3 cells than quercetin and fell within the biologically relevant concentration range (low micromolar). We also evaluated the potential toxic effects of flavonol analogs on normal cells, an assessment that has frequently been ignored when studying the anticancer effects of flavonoids. During these analyses, we discovered that various metabolic and DNA staining assays were unreliable methods for assessing cell viability of flavonoids. Flavonoids reduce colorimetric dyes such as MTT and Alamar Blue in the absence of cells. We showed that flavonol-treated prostate cancer cells were stained less intensely with crystal violet than untreated cells at non-toxic concentrations. The trypan blue exclusion assay was selected as a reliable alternative for measuring cell viability. PMID:24859601

  10. The carbocyclic analog of 2'-deoxyguanosine induces a prolonged inhibition of duck hepatitis B virus DNA synthesis in primary hepatocyte cultures and in the liver.

    PubMed Central

    Fourel, I; Saputelli, J; Schaffer, P; Mason, W S

    1994-01-01

    The carbocyclic analog of 2'-deoxyguanosine (2'-CDG) is a strong inhibitor of hepatitis B virus (HBV) DNA synthesis in HepG2 cells (P.M. Price, R. Banerjee, and G. Acs, Proc. Natl. Acad. USA 86:8543-8544, 1989). We now report that 2'-CDG inhibited duck hepatitis B virus (DHBV) DNA synthesis in primary cultures of duck hepatocytes and in experimentally infected ducks. Like foscarnet (phosphonoformic acid [PFA]) and 2'-,3'-dideoxycytidine (ddC), 2'-CDG blocked viral DNA replication in primary hepatocyte cultures when present during an infection but failed to inhibit the DNA repair reaction that occurs during the initiation of infection to convert virion relaxed circular DNA to covalently closed circular DNA, the template for viral mRNA transcription. Moreover, as for PFA and ddC, viral RNA synthesis was detected when infection was initiated in the presence 2'-CDG. In another respect, however, 2'-CDG exhibited antiviral activity unlike that of ddC or PFA: a single 1-day treatment of hepatocytes with 2'-CDG blocked initiation of viral DNA synthesis for at least 8 days, irrespective of whether DHBV infection was carried out at the time of drug treatment or several days later. Furthermore, orally administered 2'-CDG was long-acting against DHBV in experimentally infected ducklings. Virus replication was delayed by up to 4 days in ducklings infected after administration of 2'-CDG. These observations of long-lasting efficacy in vitro and in vivo even after oral administration suggest that this inhibitor or a nucleoside with similar pharmacological properties may be ideal for reducing virus replication in patients with chronic HBV infection. Images PMID:8289335

  11. Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents.

    PubMed

    Wen, Jiachen; Bao, Yu; Niu, Qun; Liu, Jiang; Yang, Jinyu; Wang, Wanqiao; Jiang, Tao; Fan, Yinbo; Li, Kun; Wang, Jian; Zhao, Linxiang; Liu, Dan

    2016-09-01

    In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds, 5d and 5e showed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on the para-position of benzene, interacting with Glu203 at the entrance to the active site tunnel. PMID:27460171

  12. Synthesis and characterization of N-parinaroyl analogs of ganglioside GM3 and de-N-acetyl GM3. Interactions with the EGF receptor kinase

    NASA Technical Reports Server (NTRS)

    Song, W.; Welti, R.; Hafner-Strauss, S.; Rintoul, D. A.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    A specific plasma membrane glycosphingolipid, known as ganglioside GM3, can regulate the intrinsic tyrosyl kinase activity of the epidermal growth factor (EGF) receptor; this modulation is not associated with alterations in hormone binding to the receptor. GM3 inhibits EGF receptor tyrosyl kinase activity in detergent micelles, in plasma membrane vesicles, and in whole cells. In addition, immunoaffinity-purified EGF receptor preparations contain ganglioside GM3 (Hanai et al. (1988) J. Biol. Chem. 263, 10915-10921), implying that the glycosphingolipid is intimately associated with the receptor kinase in cell membranes. Both the nature of this association and the molecular mechanism of kinase inhibition remain to be elucidated. In this report, we describe the synthesis of a fluorescent analog of ganglioside GM3, in which the native fatty acid was replaced with trans-parinaric acid. This glycosphingolipid inhibited the receptor kinase activity in a manner similar to that of the native ganglioside. A modified fluorescent glycosphingolipid, N-trans-parinaroyl de-N-acetyl ganglioside GM3, was also prepared. This analog, like the nonfluorescent de-N-acetyl ganglioside GM3, had no effect on receptor kinase activity. Results from tryptophan fluorescence quenching and steady-state anisotropy measurements in membranes containing these fluorescent probes and the human EGF receptor were consistent with the notion that GM3, but not de-N-acetyl GM3, interacts specifically with the receptor in intact membranes.

  13. Celastrol Analogs as Inducers of the Heat Shock Response. Design and Synthesis of Affinity Probes for the Identification of Protein Targets

    PubMed Central

    Klaić, Lada; Morimoto, Richard I.; Silverman, Richard B.

    2012-01-01

    The natural product celastrol (1) possesses numerous beneficial therapeutic properties and affects numerous cellular pathways. The mechanism of action and cellular target(s) of celastrol, however, remain unresolved. While a number of studies have proposed that the activity of celastrol is mediated through reaction with cysteine residues, these observations have been based on studies with specific proteins or by in vitro analysis of a small fraction of the proteome. In this study, we have investigated the spatial and structural requirements of celastrol for the design of suitable affinity probes to identify cellular binding partners of celastrol. Although celastrol has several potential sites for modification, some of these were not synthetically amenable or yielded unstable analogs. Conversion of the carboxylic acid functionality to amides and long-chain analogs, however, yielded bioactive compounds that induced the heat shock response (HSR) and antioxidant response and inhibited Hsp90 activity. This led to the synthesis of biotinylated celastrols (23 and 24) that were used as affinity reagents in extracts of human Panc-1 cells to identify Annexin II, eEF1A, and β-tubulin as potential targets of celastrol. PMID:22380712

  14. Human neutrophil elastase peptide sensors conjugated to cellulosic and nanocellulosic materials: part I, synthesis and characterization of fluorescent analogs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Here we describe the synthesis and characterization of peptide conjugated cellulose and nanocellulose materials as sensors for fluorescent detection of human neutrophil elastase (HNE). The cellulose sensor surfaces selected are filter paper (FP) and print cloth (PC) fabric, which are composed of pro...

  15. FeCl3-promoted and ultrasound-assisted synthesis of resveratrol O-derived glycoside analogs.

    PubMed

    Marzag, Hamid; Robert, Guillaume; Dufies, Maeva; Bougrin, Khalid; Auberger, Patrick; Benhida, Rachid

    2015-01-01

    Phenol derived O-glycosides were synthesized using a direct and convenient O-glycosidation, starting from acetylated sugars in the presence of FeCl3, an inexpensive, mild and benign Lewis acid catalyst. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvement in rates and yields were observed when reactions were carried out under sonication compared with conventional conditions leading to the corresponding β-O-glycosides as the major anomer. Post-synthetic transformations of iodophenol intermediates led to new resveratrol O-glycoside analogs in good overall yields. PMID:24961448

  16. Synthesis of C-4 and C-7 Triazole Analogs of Zanamivir as Multivalent Sialic Acid Containing Scaffolds

    PubMed Central

    Lu, Yan; Gervay-Hague, Jacquelyn

    2007-01-01

    The relative reactivities of C-4 and C-7 azides derived from zanamivir were compared in cycloadition reactions with a panel of alkynes. All of the reactions proceeded efficiently with no observable differences between primary and secondary azides. Significant rate differences were observed between several members of the alkyne panel. Most notably, a trialkyne derived from a 1,3,5-triazine core underwent complete reaction within four hours whereas an analogous trialkyne with an all carbon aromatic core required 18 hours. These results suggest that the triazine core serves as an internal catalyst. PMID:17597592

  17. Efficient synthesis of glycosylated phenazine natural products and analogs with DISAL (methyl 3,5-dinitrosalicylate) glycosyl donors.

    PubMed

    Laursen, Jane B; Petersen, Lars; Jensen, Knud J; Nielsen, John

    2003-09-21

    Inspired by the occurrence and function of phenazines in natural products, new glycosylated analogs were designed and synthesized. DISAL (methyl 3,5-dinitrosalicylate) glycosyl donors were used in an efficient and easily-handled glycosylation protocol compatible with combinatorial chemistry. Benzoylated D-glucose, D-galactose and L-quinovose DISAL glycosyl donors were synthesized in high yields and used under mild conditions to glycosylate methyl saphenate and 2-hydroxyphenazine. The glycosides were screened for biological activity and one compound showed inhibitory activity towards topoisomerase II. PMID:14527145

  18. Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent

    PubMed Central

    Walls, Thomas H.; Grindrod, Scott C.; Beraud, Dawn; Zhang, Li; Baheti, Aparna R.; Dakshanamurthy, Sivanesan; Patel, Manoj K.; Brown, Milton L.; MacArthur, Linda H.

    2013-01-01

    Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities. PMID:22863530

  19. Synthesis and biological evaluation of open-chain analogs of cyclic peptides as inhibitors of cellular Shp2 activity.

    PubMed

    Zhen, Xiao-Li; Yin, Wen-Hui; Tian, Xia; Ma, Zhen-Jie; Fan, Shi-Ming; Han, Jian-Rong; Liu, Shouxin

    2015-05-15

    A series of open-chain analogs of cyclic peptides was designed and synthesized using sansalvamide A as a model compound. All compounds exhibited low antitumor activity. Furthermore, the evaluation of their inhibitory potency toward IMPDH, SHP2, ACHE, proteasome, MAGL, and cathepsin B showed that all of the compounds were potent against protein tyrosine phosphatase Shp2. Specifically, compounds 1a, 1d, 2b, and 2f were found to inhibit SHP2 with IC50 values in the low micromolar range and good selectivity. Based on the molecular docking results, the binding modes of the chain cyclic peptides in the active center of SHP2 were discussed. PMID:25865131

  20. Synthesis and antiproliferative activity of benzofuran-based analogs of cercosporamide against non-small cell lung cancer cell lines.

    PubMed

    Bazin, Marc-Antoine; Bodero, Lizeth; Tomasoni, Christophe; Rousseau, Bénédicte; Roussakis, Christos; Marchand, Pascal

    2013-11-01

    A novel series of 3-methyl-1-benzofuran derivatives were synthesized and screened in vitro for their antiproliferative activity against two human NSCLC cell lines (NSCLC-N6 mutant p53 and A549 wild type p53). Most promising compounds presented a structural analogy with the west part of cercosporamide, a natural product of biological interest. In particular, compounds 10, 12 and 31 showed cytotoxic activities at micromolar concentrations (IC₅₀ < 9.3 μM) and compounds 13, 18 and 32 displayed moderate IC₅₀ values (25-40 μM). PMID:24121233

  1. Antitumor Agents 295. E-ring Hydroxylated Antofine and Cryptopleurine Analogs as Antiproliferative Agents: Design, Synthesis, and Mechanistic Studies

    PubMed Central

    Yang, Xiaoming; Shi, Qian; Lai, Chin Yu; Chen, Chi-Yuan; Ohkoshi, Emika; Yang, Shuenn-Chen; Wang, Chih-Ya; Bastow, Kenneth F.; Wu, Tian-Shung; Pan, Shiow-Lin; Teng, Che-Ming; Yang, Pan-Chyr; Lee, Kuo-Hsiung

    2012-01-01

    Various E-ring hydroxylated antofine and cryptopleurine analogs were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of non-small cell lung cancer (NSCLC) cell lines, in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating Hedgehog pathway-driven tumorigenesis. PMID:22823514

  2. Design, Synthesis, and Biological Evaluation of Tetrazole Analogs of Cl-Amidine as Protein Arginine Deiminase Inhibitors

    PubMed Central

    2016-01-01

    Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiology of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isozyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isozyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isozymes. Importantly, one of the compounds, biphenyl tetrazole tert-butyl Cl-amidine (compound 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs. PMID:25559347

  3. Stable isotope-labeled vitamin D, metabolites and chemical analogs: Synthesis and use in mass spectrometric studies

    SciTech Connect

    Coldwell, R.D.; Trafford, D.J.; Varley, M.J.; Kirk, D.N.; Makin, H.L. )

    1990-10-01

    Methods for the measurement of vitamin D and its metabolites using stable isotope-labeled internal standards and mass spectrometry are reviewed. The synthesis of both labeled and unlabeled standards is illustrated, and details of the synthesis of (26,26,27,27,27(-2)H5)-25,26-dihydroxyvitamin D3 and (28,28,28(-2)H3)-24,25-dihydroxyvitamin D2 are given. The use of in vitro biologic systems for the production of further metabolites of deuterated 25-hydroxyvitamin D3 is discussed. Use of deuterated 25-hydroxydihydrotachysterol3 as a substrate in the isolated perfused rat kidney has provided valuable data for the assignment of structure to a number of metabolites of 25-hydroxydihydrotachysterol3 formed in this system. 51 refs.

  4. O-Methyl sugars in lipopolysaccharides of Rhodospirillacea. Identification of 3-O-methyl-d-mannose in Rhodopseudomonas viridis and of 4-O-methyl-d-xylose and 3-O-methyl-6-deoxy-d-talose in Rhodopseudomonas palustris respectively

    PubMed Central

    Weckesser, Jürgen; Mayer, Hubert; Fromme, Inge

    1973-01-01

    1. This paper deals with the identification of three O-methyl sugars in lipopolysaccharides isolated from strains of the Gram-negative photosynthetic family Rhodospirillaceae. In addition to the previously described 3-O-methyl-l-xylose, a second O-methyl sugar was encountered in the lipopolysaccharide of Rhodopseudomonas viridis F, namely 3-O-methyl-d-mannose. The lipopolysaccharides of two strains of Rhodopseudomonas palustris (strain 1e5 and 8/1) contain two O-methylsugars, 4-O-methyl-d-xylose and 3-O-methyl-6-deoxy-d-talose (d-acovenose). 4-O-Methyl-d-xylose, but not 3-O-methyl-6-deoxy-d-talose, could be identified in the lipopolysaccharides of the strains K/1 and 2/2 of the same species. 2. The O-methyl sugars described in this communication were isolated by paper chromatography and identified by g.l.c., paper chromatography, high-voltage electrophoresis and mass spectrometry. Besides the genuine sugars, their alditol acetates and their demethylated (parental) forms were investigated. Optical rotation measurements and, in one case, enzymic reactions were used to establish the optical configuration of the sugars under investigation. PMID:4764262

  5. Synthesis and Anti-HIV-1 Evaluation of Some Novel MC-1220 Analogs as Non-Nucleoside Reverse Transcriptase Inhibitors.

    PubMed

    Loksha, Yasser M; Pedersen, Erik B; Loddo, Roberta; La Colla, Paolo

    2016-05-01

    Some novel MC-1220 analogs were synthesized by condensation of 4,6-dichloro-N-methylpyrimidin-2-amine derivatives (1a,b and 15) and/or 4-chloro-6-methoxy-N,N,5-trimethylpyrimidin-2-amine (2a) with the sodium salt of 2,6-difluorophenylacetonitrile followed by treatment with aqueous sodium hydroxide in methanol, alkylation, reduction, halogenation, and/or acidic hydrolysis. All synthesized compounds were evaluated for their activity against HIV-1. The most active compound in this study was compound 7, which showed activity against HIV-1 comparable to that of MC-1220. The only difference in structure between compound 7 and MC-1220 is a fluoro atom instead of a CH3 group. PMID:26996241

  6. Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors.

    PubMed

    Kwon, Hongmok; Kim, YunHye; Park, Kieung; Choi, Soo An; Son, Sang-Hyun; Byun, Youngjoo

    2016-01-15

    Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors. PMID:26711145

  7. Synthesis of new 8(S)-HETE analogs and their biological evaluation as activators of the PPAR nuclear receptors.

    PubMed

    Liutkus, Mélanie; Caijo, Frédéric; Girard, Anne-Lise; Ayral, Erwan; Audinot, Valérie; Boutin, Jean A; Renard, Pierre; Caignard, Daniel Henri; Dacquet, Catherine; Ktorza, Alain; Mosset, Paul; Grée, René

    2010-10-01

    Structural modifications around 8-HETE (8-hydroxyeicosatetraenoic acid), a natural agonist of the PPAR (peroxisome proliferator-activated receptor) nuclear receptors have led previously to the identification of a promising analog, the quinoline S 70655. Series of novel quinoline or benzoquinoline derivatives were designed through the modification of this lead. Variations of the nature of the aromatic core and of the side chains were carried out. The SAR studies indicated the high sensitivity of the upper acid chain to modifications as well as the strong effect of the length and size of the lipophilic side chain. They afforded several new promising PPARalpha/gamma dual agonists with a high PPARalpha activity in vitro. PMID:20518620

  8. Synthesis and spectral luminescent properties of certain pyridine and quinoline analogs of isomeric distyrylnaphthalenes and styryl- and distrylanthracenes

    SciTech Connect

    Vernigor, E.M.; Koz'menko, M.V; Lebedev, S.A.; Luk'yanets, E.A.; Savvina, L.P.; Shalaev, V.K.

    1987-12-01

    A series of pyridine and quinoline analogs of isomeric distyrylnaphthalenes and styryl- and distyrylanthracenes has been synthesized. Their spectral-luminescent properties were studied. Compounds whose structures are sterically hindered in the ground state have the highest Stokes' shift. The compounds synthesized have a trans-configuration; in their IR spectra there are absorption bands in the 970-990 cm/sup -1/ region, characteristic for trans-disubstituted alkenes. In the PMR spectrum of 9,10-di(..beta..-(4-pyridyl)vinyl)anthracene, two doublets of the AB spin system are observed with chemical shifts of 6.91 and 7.37 ppm, belonging to the vinyl protons. The SSCC (J = 16.5 Hz) indicates a trans-configuration of this compound.

  9. Synthesis of a fluorescence resonance energy transfer-based probe containing a tricyclic nucleoside analog for single nucleotide polymorphism typing.

    PubMed

    Hayai, Aya; Maeda, Yusuke; Ueno, Yoshihito

    2016-08-01

    Here, we report the synthesis of a fluorescence resonance energy transfer (FRET)-based probe for single nucleotide polymorphism (SNP) typing. The probe contains a fluorescent tricyclic base, 8-amino-3-(2,3-dihydroxypropyl)imidazo[4',5':5,6]pyrido[2,3-d]pyrimidine, as a donor molecule and 7-diethylaminocoumarin-3-carboxylic acid as an acceptor molecule. FRET was observed between the donor and acceptor molecules on the probe. The identity of the target bases on DNA and RNA strands could be determined using the probe. PMID:27329795

  10. Imidase catalyzing desymmetric imide hydrolysis forming optically active 3-substituted glutaric acid monoamides for the synthesis of gamma-aminobutyric acid (GABA) analogs.

    PubMed

    Nojiri, Masutoshi; Hibi, Makoto; Shizawa, Hiroaki; Horinouchi, Nobuyuki; Yasohara, Yoshihiko; Takahashi, Satomi; Ogawa, Jun

    2015-12-01

    The recent use of optically active 3-substituted gamma-aminobutyric acid (GABA) analogs in human therapeutics has identified a need for an efficient, stereoselective method of their synthesis. Here, bacterial strains were screened for enzymes capable of stereospecific hydrolysis of 3-substituted glutarimides to generate (R)-3-substituted glutaric acid monoamides. The bacteria Alcaligenes faecalis NBRC13111 and Burkholderia phytofirmans DSM17436 were discovered to hydrolyze 3-(4-chlorophenyl) glutarimide (CGI) to (R)-3-(4-chlorophenyl) glutaric acid monoamide (CGM) with 98.1% enantiomeric excess (e.e.) and 97.5% e.e., respectively. B. phytofirmans DSM17436 could also hydrolyze 3-isobutyl glutarimide (IBI) to produce (R)-3-isobutyl glutaric acid monoamide (IBM) with 94.9% e.e. BpIH, an imidase, was purified from B. phytofirmans DSM17436 and found to generate (R)-CGM from CGI with specific activity of 0.95 U/mg. The amino acid sequence of BpIH had a 75% sequence identity to that of allantoinase from A. faecalis NBRC13111 (AfIH). The purified recombinant BpIH and AfIH catalyzed (R)-selective hydrolysis of CGI and IBI. In addition, a preliminary investigation of the enzymatic properties of BpIH and AfIH revealed that both enzymes were stable in the range of pH 6-10, with an optimal pH of 9.0, stable at temperatures below 40 °C, and were not metalloproteins. These results indicate that the use of this class of hydrolase to generate optically active 3-substituted glutaric acid monoamide could simplify the production of specific chiral GABA analogs for drug therapeutics. PMID:26205522

  11. Design, synthesis, and in vitro biological evaluation of novel 6-methyl-7-substituted-7-deaza purine nucleoside analogs as anti-influenza A agents.

    PubMed

    Lin, Cai; Sun, Chenghai; Liu, Xiao; Zhou, Yiqian; Hussain, Muzammal; Wan, Junting; Li, Minke; Li, Xue; Jin, Ruiliang; Tu, Zhengchao; Zhang, Jiancun

    2016-05-01

    Among many subtypes of influenza A viruses, influenza A(H1N1) and A(H3N2) subtypes are currently circulating among humans (WHO report 2014-15). Therapeutically, the emergence of viral resistance to currently available drugs (adamantanes and neuraminidase inhibitors) has heightened alarms for developing novel drugs that could address diverse targets in the viral replication cycle in order to improve treatment outcomes. To this regard, the design and synthesis of nucleoside analog inhibitors as potential anti-influenza A agents is a very active field of research nowadays. In this study, we designed and synthesized a series of hitherto unknown 6-methyl-7-substituted-7-deaza purine nucleoside analogs, and evaluated for their biological activities against influenza A virus strains, H1N1 and H3N2. From the viral inhibition assay, we identified some effective compounds, among which, compounds 5x (IC50 = 5.88 μM and 6.95 μM for H1N1 and H3N2, respectively) and 5z (IC50 = 3.95 μM and 3.61 μM for H1N1 and H3N2, respectively) demonstrated potent anti-influenza A activity. On the basis of selectivity index, we conceive that compound 5x may serve as a chemical probe of interest for further lead optimization studies with a general aim of developing novel and effective anti-influenza A virus agents. PMID:26802557

  12. Synthesis and kinetic evaluation of Cyclophostin and Cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases

    PubMed Central

    Point, Vanessa; Malla, Raj K.; Diomande, Sadia; Martin, Benjamin P.; Delorme, Vincent; Carriere, Frederic; Canaan, Stephane; Rath, Nigam P.; Spilling, Christopher D.; Cavalier, Jean-François

    2012-01-01

    New series of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. Best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat towards same enzymes. Our results have revealed that chemical group at the γ-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these 7-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents. PMID:23095026

  13. Design, synthesis and biological evaluation of 3'-benzylated analogs of 3'-epi-neoponkoranol as potent α-glucosidase inhibitors.

    PubMed

    Liu, Dan; He, Weigang; Wang, Zihao; Liu, Long; Wang, Chengqian; Zhang, Chenxi; Wang, Chengcheng; Wang, Yuxuan; Tanabe, Genzoh; Muraoka, Osamu; Wu, Xiaoming; Wu, Liang; Xie, Weijia

    2016-03-01

    A group of 3'-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3'-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3'-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase. PMID:26840363

  14. Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever.

    PubMed

    Carreño Otero, Aurora L; Vargas Méndez, Leonor Y; Duque L, Jonny E; Kouznetsov, Vladimir V

    2014-05-01

    Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-aminonitrile series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained α-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 μM (10.3-124.0 μg/mL). Among this series, the best AChE inhibitor was the pyrrolidine α-aminonitrile 3 (IC50 = 42 μM), followed by the piperidine α-aminonitriles 2 and 6 (IC50 = 45 μM and IC50 = 51 μM, respectively), and the compound 7 (IC50 = 51 μM). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides. PMID:24704612

  15. Thermal contraction crack polygons on Mars: A synthesis from HiRISE, Phoenix, and terrestrial analog studies

    NASA Astrophysics Data System (ADS)

    Levy, Joseph S.; Marchant, David R.; Head, James W.

    2010-03-01

    Thermal contraction crack polygons are complex landforms that have begun to be deciphered on Earth and Mars by the combined investigative efforts of geomorphology, environmental monitoring, physical models, paleoclimate reconstruction, and geochemistry. Thermal contraction crack polygons are excellent indicators of the current or past presence of ground ice, ranging in ice content from weakly cemented soils to debris-covered massive ice. Relative to larger topographic features, polygons may form rapidly, and reflect climate conditions at the time of formation—preserving climate information as relict landforms in the geological record. Polygon morphology and internal textural characteristics can be used to distinguish surfaces modified by the seasonal presence of a wet active layer or dry active layer, and to delimit subsurface ice conditions. Analysis of martian polygon morphology and distribution indicates that geologically-recent thermal contraction crack polygons on Mars form predominantly in an ice-rich latitude-dependent mantle, more likely composed of massive ice deposited by precipitation than by cyclical vapor diffusion into regolith. Regional and local heterogeneities in polygon morphology can be used to distinguish variations in ice content, deposition and modification history, and to assess microclimate variation on timescales of ka to Ma. Analyses of martian polygon morphology, guided by investigations of terrestrial analog thermal contraction crack polygons, strongly suggest the importance of excess ice in the formation and development of many martian thermal contraction crack polygons—implying the presence of an ice-rich substrate that was fractured during and subsequent to obliquity-driven depositional periods and continually modified by ongoing vapor equilibration processes.

  16. Radiolabeled new somatostatin analogs conjugated to DOMA chelator used as targeted tumor imaging agent: synthesis and radiobiological evaluation.

    PubMed

    De, Kakali; Banerjee, Indranil; Misra, Mridula

    2015-06-01

    Several receptor-specific radiopeptides have been developed and effective in the diagnosis of malignant diseases. Among them, somatostatin receptor (SSTR) scintigraphy with (111)In-DTPA-octreotide has become a tumor diagnostic radiopharmaceutical in nuclear medicine. However, it suffers some drawbacks concerning the imaging properties and elevated radiation burden of (111)In. Here, we report the synthesis of radiolabeled two new octapeptides with improved uptake in SSTR2-positive tumors in comparison with (99m)Tc-HYNIC-Tyr(3)-octreotide (HYNIC-TOC). Octapeptides were synthesized in high yield by Fmoc solid-phase synthesis and coupling the macrocyclic chelator DOMA(1,4,7-Tri-Boc-10-(carboxymethyl)-1,4,7,10-tetraazocyclododecane-1-yl-monoacetic acid) to these peptides for (99m)Tc labeling. New peptides DOMA-Asn(3)-octreotate(DOMA-AATE) and DOMA-Pro(3)-octreotate(DOMA-PATE) were purified, characterized by RP-HPLC, MALDI-mass, (1)H-NMR, (13)C-NMR. Labeling was performed by SnCl2 method to get products with excellent radiochemical purity (97 %). Radiopeptides were found to be substantially stable under physiological condition for 24 h. Internalization and receptor-binding studies were determined in somatostatin receptor-expressing C6-glioma cell line and rat brain cortex membrane and the results compared with HYNIC-TOC as standard. The IC50 values of (99m)Tc-DOMA-AATE(1.10 ± 0.48 nM) and (99m)Tc-DOMA-PATE(1.76 ± 0.06 nM) showed high affinity binding for SSTR2 receptor and they internalized rapidly in C6 cells. Biodistribution and imaging studies were performed in C6 tumor-bearing rat under gamma camera showing significant uptake in kidney, urine and C6 tumor. Radiopeptides exhibited fast blood clearance and rapid elimination through the urinary systems. However, (99m)Tc-DOMA-AATE exhibited the highest tumor to muscle and tumor to blood uptake ratios among three. These favorable characteristics validate (99m)Tc-DOMA-AATE as a more promising (99m)Tc-radiotracer than (99

  17. Part 1: synthesis of irreversible inhibitors of aldose reductase with subsequent development of a carbon-13 NMR protein probe. Part 2: synthesis of selenium analogs of dopamine as potential dopamine receptor agonists

    SciTech Connect

    Ares, J.J.

    1986-01-01

    Aldose reductase converts glucose into sorbitol using NADPH as a cofactor. Sorbitol accumulation in various tissues is believed to play a major role in the development of debilitating complications of diabetes; thus, much effort has been directed toward the preparation of aldose reductase inhibitors. Of the compounds prepared, the most active are the isothiocyanate and azide analogs of the reversible aldose reductase inhibitor alrestatin. The potency of the alrestatin isothiocyanate prompted the authors to examine the possibility that isothiocyanates enriched with carbon-13 could be used as carbon-13 NMR protein probes. Toward this end, a synthesis of carbon-13 enriched phenylisothiocyanate has been developed. This reagent has been successfully utilized to study peptides via carbon-13 NMR spectroscopy. Research in their laboratory over the years has focused on answering two fundamental questions regarding the interaction of dopamine with its receptor. First, can the concept of bioisosterism be applied to dopamine agonists. Secondly, what is the actual molecular species of dopamine which interacts with the dopamine receptor. In an effort to answer these questions, methyl selenide and dimethyl selenonium analogs of dopamine have been synthesized.

  18. Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents.

    PubMed

    Pan, Guojun; Zhao, Lianbo; Xiao, Na; Yang, Ke; Ma, Yantao; Zhao, Xia; Fan, Zhenchuan; Zhang, Yongmin; Yao, Qingwei; Lu, Kui; Yu, Peng

    2016-10-21

    The naturally occurring flavone 8-(6″-umbelliferyl)apigenin, a hybrid structure of apigenin and coumarin, as well as seven of its analogues were synthesized for the first time by using iodination and Suzuki coupling reactions as key steps. The synthesis of 8-(6″-umbelliferyl)-apigenin was achieved in seven linear steps from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one and 7-hydroxyl coumarine with 31% overall yield. Effects of these compounds on glucose disposal were investigated in adipocytes. All of the flavonoid and coumarin hydrids were found to have better bioactivities than their corresponding flavonoid cores. The most potent compound 15 (10 μΜ) could promote glucose consumption by 57% which exhibited similar effect as the positive control metformin at 1 mM. Moreover, fluorescence microscopy showed that four 8-(6″-umbelliferyl)apigenin analogues 2, 15, 30 and 31 could promote the 2-NBDG uptake into 3T3-L1 cells, which consist with those observed in the regulation of glucose. PMID:27448923

  19. Synthesis of analogs of juvenile hormone on the basis of the telomerization reaction of piperylene with sulfones

    SciTech Connect

    Tolstikov, G.A.; Rozentsvet, O.A.; Pantukh, B.I.; Khalilov, L.M.

    1986-10-20

    In continuing the work on the study of the telomerization of 1,3-dienes with sulfones containing an active H atom, and also with the aim of synthesizing analogs of juvenile hormone (JH) based on the telomers obtained, they studied the catalytic telomerization of 1,3-pentadiene (piperylene) with ..beta..-substituted sulfonates. It was established that trans-piperlyene participates in the telomerization reaction with sulfones in the presence of the catalytic system PdCl/sub 2/(Ph/sub 3/P)/sub 2/-PhONa. Methyl 2-phenylsulfonyl-3,7-dimethyl-4(E), 9-decadienecarboxylate (II) is formed in a yield of 65% by the reaction of methyl phenylsulfonylacetate (I) with piperylene in the course of 20 h at 85/sup 0/C. The presence of absorption bands at 920 (CH/sub 2/=C) and 980 cm/sup -1/ (E-CH=CH) in the IR spectrum of compound (II) and the presence of a group of multiplet signals at delta 4.8-5.3 ppm in the PMR spectrum, corresponding to five protons of double bonds, indicate the addition of two molecules of piperylene to the molecule of the sulfone (I). The oxidation with oxygen on a Pd/Cu-catalyst proceeds smoothly to the methyl ketone (III); this clearly confirms the presence of the terminal C=C bond in the telomer (II). In the PMR spectrum of (II), notice is taken of the group of signals in the region of 3.30-3.53 ppm corresponding to three methoxy protons. There are three pairs of doublets (J = 7 Hz) in the region of 0.1-1.3 ppm which correspond to the methyl group. The complexity of the PMR spectrum is probably explained by the fact that the reaction leads to the formation of a complex mixture of diastereoisomers. As was to be expected, methyl 3,7-dimethyl-4,9-decadienoate (IV) is formed as the sole product with a yield of 70% in the desulfonation of the telomer (II) using Na/Hg in methanol according to the method of (5); the structure of (IV) was established with the aid of /sup 13/C NMR spectroscopy.

  20. Synthesis, structure-activity relationship and molecular docking of cyclohexenone based analogous as potent non-nucleoside reverse-transcriptase inhibitors

    NASA Astrophysics Data System (ADS)

    Nazar, Muhammad Faizan; Abdullah, Muhammad Imran; Badshah, Amir; Mahmood, Asif; Rana, Usman Ali; Khan, Salah Ud-Din

    2015-04-01

    The chalcones core in compounds is advantageously chosen effective synthons, which offer exciting perspectives in biological and pharmacological research. The present study reports the successful development of eight new cyclohexenone based anti-reverse transcriptase analogous using rational drug design synthesis principles. These new cyclohexenone derivatives (CDs) were synthesized by following a convenient route of Robinson annulation, and the molecular structure of these CDs were later confirmed by various analytical techniques such as 1H NMR, 13C NMR, FT-IR, UV-Vis spectroscopy and mass spectrometry. All the synthesized compounds were screened theoretically and experimentally against reverse transcriptase (RT) and found potentially active reverse transcriptase (RT) inhibitors. Of the compounds studied, the compound 2FC4 showed high interaction with RT at non-nucleoside binding site, contributing high free binding energy (ΔG -8.01 Kcal) and IC50 (0.207 μg/ml), respectively. Further results revealed that the compounds bearing more halogen groups, with additional hydrophobic character, offered superior anti-reverse transcriptase activity as compared to rest of compounds. It is anticipate that the present study would be very useful for the selection of potential reverse transcriptase inhibitors featuring inclusive pharmacological profiles.

  1. Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction.

    PubMed

    Khan, Firoz A Kalam; Patil, Rajendra H; Shinde, Devanand B; Sangshetti, Jaiprakash N

    2016-08-15

    Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a-m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16μM), 5d (IC50 value=15.66μM) and 5j (IC50 value=19.16μM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00-15.83μg/mL), 5b (MIC range=23.75-28.50μg/mL) and 5j (MIC range=7.66-16.91μg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25-50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a-m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates. PMID:27269198

  2. Analog earthquakes

    SciTech Connect

    Hofmann, R.B.

    1995-09-01

    Analogs are used to understand complex or poorly understood phenomena for which little data may be available at the actual repository site. Earthquakes are complex phenomena, and they can have a large number of effects on the natural system, as well as on engineered structures. Instrumental data close to the source of large earthquakes are rarely obtained. The rare events for which measurements are available may be used, with modfications, as analogs for potential large earthquakes at sites where no earthquake data are available. In the following, several examples of nuclear reactor and liquified natural gas facility siting are discussed. A potential use of analog earthquakes is proposed for a high-level nuclear waste (HLW) repository.

  3. Synthesis and insecticidal activity of spinosyn analogs functionally altered at the 2'-,3'- and 4'-positions of the rhamnose moiety.

    PubMed

    Creemer, L C; Kirst, H A; Paschal, J W; Worden, T V

    2000-02-01

    In an effort to increase the insecticidal activity of the spinosyn family of naturally occurring macrolides, the 2'-, 3'- and 4'-O-desmethyl-O-acetyl analogs and the 2'-, 3'-, and 4'-O-desmethoxy analogs have been synthesized. These analogs were prepared synthetically from the minor spinosyn factors H, J, K, L and Q either via direct acylation of the corresponding factor or deoxygenation of an intermediate xanthate. The acylated analogs were all more potent insecticides against Heliothis virescens larvae than their respective parent factors, but not as potent as spinosyns A or D. The deoxy analogs were also more potent insecticides than their respective parent factors. The 2'-desmethoxy analogs showed, for the first time, analogs with insecticidal potency against H. virescens greater than that of spinosyns A and D, indicating that polarity is not well tolerated in the rhamnose moiety of spinosyn A. PMID:10805578

  4. Triptycene analogs

    NASA Technical Reports Server (NTRS)

    Hua, Duy (Inventor); Perchellet, Jean-Pierre (Inventor)

    2004-01-01

    This invention provides analogs of triptycene which are useful as anticancer drugs, as well as for other uses. The potency of these compounds is in a similar magnitude as daunomycin, a currently used anticancer drug. Each compound of the invention produces one or more desired effects (blocking nucleoside transport, inhibiting nucleic acid or protein syntheses, decreasing the proliferation and viability of cancer cells, inducing DNA fragmentation or retaining their effectiveness against multidrug-resistant tumor cells).

  5. Probing for improved potency and in vivo bioavailability of excitatory amino acid transporter subtype 1 inhibitors UCPH-101 and UCPH-102: design, synthesis and pharmacological evaluation of substituted 7-biphenyl analogs.

    PubMed

    Erichsen, Mette N; Hansen, Jeanette; Ruiz, Josep A; Demmer, Charles S; Abrahamsen, Bjarke; Bastlund, Jesper F; Bundgaard, Christoffer; Jensen, Anders A; Bunch, Lennart

    2014-10-01

    Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent inhibitors UCPH-101 and UCPH-102. In the present study, we set out to improve the solubility properties of these EAAT1 inhibitors with the objective to develop analogs more suited as pharmacological tools for in vivo studies of EAAT1 in terms of their bioavailability. A total of 23 novel UCPH-101/102 analogs were designed, synthesized and characterized pharmacologically at EAAT1-3 in a [(3)H]-D-aspartate uptake assay. Most notably, the potent EAAT1 inhibition displayed of UCPH-101 and UCPH-102 was retained in analog 1d in which the napht-1-yl group in the 7-position of UCPH-102 has been replaced by an o-biphenyl moiety. In contrast, EAAT1 activity was dramatically compromised in analogs 1e and 1f comprising m- and p-biphenyl groups as 7-substituents, respectively. Analog 1d displayed low bioavailability after oral administration in rats, and this problem was addressed by the synthesis of a series of analogs with different chloro, fluoro, methoxy, triflouromethyl and carboxy substitution patterns at the o-biphenyl group of 1d (1h-1s) and m- and p-pyridine analogs of 1d (1t and 1v). Unfortunately, all of the modifications resulted in substantial decreased EAAT1 inhibitory activity, which supports the notion of a very lipophilic binding pocket in EAAT1 for the aromatic 7-substituent in these ligands. In conclusion, while we have not succeeded in developing UCPH-101/102 analogs possessing improved bioavailability properties, this study does offer interesting SAR information about this inhibitor class, and analog 1d seems to be an interesting lead for future SAR studies with focus on the development of more potent EAAT1 inhibitors. PMID:24682739

  6. Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin.

    PubMed

    Martin, Benjamin P; Vasilieva, Elena; Dupureur, Cynthia M; Spilling, Christopher D

    2015-12-15

    New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. PMID:26585276

  7. A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties.

    PubMed

    Kupchinsky, Stanley; Centioni, Sara; Howard, Tiffany; Trzupek, John; Roller, Shane; Carnahan, Virginia; Townes, Heather; Purnell, Bethany; Price, Carly; Handl, Heather; Summerville, Kaitlin; Johnson, Kimberly; Toth, James; Hudson, Stephen; Kiakos, Konstantinos; Hartley, John A; Lee, Moses

    2004-12-01

    The synthesis, DNA binding properties, and in vitro and in vivo anticancer activity of fifteen achiral seco-cyclopropylindoline (or achiral seco-CI) analogs (5a-o) of CC-1065 and the duocarmycins are described. The achiral seco-CI analogs contain a 4-hydroxyphenethyl halide moiety that is attached to a wide range of indole, benzimidazole, pyrrole, and pyridyl-containing noncovalent binding components. The 4-hydroxyphenethyl halide moiety represents the simplest mimic of the seco-cyclopropylpyrroloindoline (seco-CPI) pharmacophore found in the natural products, and it lacks a chiral center. The sequence and minor groove specificity of the achiral compounds was ascertained using a Taq DNA polymerase stop assay and a thermal induced DNA cleavage experiment using either a fragment of pBR322 or pUC18 plasmid DNA. For example, seco-CI-InBf (5a) and seco-CI-TMI (5c) demonstrated specificity for AT-rich sequences, particularly by reacting with the underlined adenine-N3 position of 5'-AAAAA(865)-3'. This is also the sequence that CC-1065 and adozelesin prefer to alkylate. The achiral seco-CI compounds were subjected to cytotoxicity studies against several human (K562, LS174T, PC3, and MCF-7) and murine cancer cell lines (L1210 and P815). Following continuous drug exposure, the achiral compounds were found to be cytotoxic, with IC(50) values in the muM range. Interestingly, the carbamate protected compound 5p was significantly less cytotoxic than agent 5c, supporting the hypothesis that loss of HCl and formation of a spiro[2,5]cyclopropylcyclohexadienone intermediate is necessary for biological activity. The achiral seco-CI compounds 5a and 5c were submitted to the National Cancer Institute for further cytotoxicity screening against a panel of 60 different human cancer cell lines. Both compounds showed significant activity, particularly against several solid tumor cell lines. Flow cytometry studies of P815 cells that were incubated with compound 5c at its IC(50

  8. Synthesis, Metal Ion Binding, and Biological Evaluation of New Anticancer 2-(2’-Hydroxyphenyl)benzoxazole Analogs of UK-1

    PubMed Central

    McKee, Mireya L.; Kerwin, Sean M.

    2008-01-01

    UK-1 is a bis(benzoxazole) natural product displaying activity against a wide range of human cancer cell lines. A simplified analog of UK-1, 4-carbomethoxy-2-(2’-hydroxyphenyl)benzoxazole, was previously found to be almost as active as UK-1 against cancer cell lines, and similar to the natural product, formed complexes with variety of metal ions such as Mg2+ and Zn2+. A series 4-substituted-2-(2’-hydroxyphenyl)benzoxazole analogs of this “minimal pharmacophore” of UK-1 were prepared. The anti-cancer activity of these analogs was examined in breast and lung cancer cell lines. Spectrophotometric titrations in methanol were carried out in order to assess the ability of UK-1 and these analogs to coordinate with Mg2+ and Cu2+ ions. Although none of the new analogs were more cytotoxic than 4-carbomethoxy-2-(2’-hydroxyphenyl)benzoxazole, some analogs were identified that display similar cytotoxicity to this simplified UK-1 analog with improved water solubility. UK-1 and all of these new analogs bind Cu2+ ions better than Mg2+ ions, and the nature of the 4-substituent is important for the Mg2+ ion binding ability of these 2-(2’-hydroxyphenyl)benzoxazoles. Previous studies of a limited number of UK-1 analogs demonstrated a correlation between Mg2+ ion binding ability and cytotoxicity; however, within this series of 4-substituted-2-(2’-hydroxyphenyl)benzoxazoles the variations in cytotoxicity do not correlate with either Mg2+ or Cu2+ ion binding ability. These results, together with recent ESI-MS studies of Cu2+-mediated DNA binding by UK-1 and analogs, indicate that UK-1 and analogs may exert their cytotoxic effects by interaction with Cu2+ or other transition metal ions, rather than Mg2+, and that metal ion-mediated DNA binding, rather than metal ion binding affinity, is important for the cytotoxic effect of these compounds. The potential role of Cu2+ ions in the cytotoxic action of UK-1 is further supported by observation that UK-1 in the presence of Cu2

  9. Synthesis of a novel 4H-pyran analog as minor groove binder to DNA using ethidium bromide as fluorescence probe.

    PubMed

    Ramana, M M V; Betkar, Rahul; Nimkar, Amey; Ranade, Prasanna; Mundhe, Balaji; Pardeshi, Sachin

    2016-01-01

    In the present work, isopropyl-6-amino-4-(3,5-bis(trifluoromethyl)phenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (4H-pyran analog) has been synthesized by a three component reaction catalyzed by CsOH/γ-Al2O3 and characterized. The interaction of 4H-pyran analog with herring sperm DNA (hs DNA) under physiological conditions (phosphate buffer of pH 7.2) was investigated by UV absorption, FT-IR, fluorescence, (31)P NMR and circular dichroism (CD) spectroscopy. Fluorescence quenching results reveal that static quenching mechanism is involved in binding between 4H-pyran analog and hs DNA. The calculated thermodynamic parameters (ΔH° and ΔS°) indicate that hydrogen bonding plays a major role in binding between them. UV absorption and fluorescence shows the binding mode of 4H-pyran analog with hs DNA as non-intercalative. According to the IR spectroscopy, 4H-pyran analog binds to guanine, thymine, adenine bases of hs DNA but not to phosphate backbone of hs DNA which is also in good agreement with (31)P NMR results. CD and competitive binding experiment results confirms the minor groove binding of 4H-pyran analog to hs DNA. PMID:26208271

  10. Synthesis of a novel 4H-pyran analog as minor groove binder to DNA using ethidium bromide as fluorescence probe

    NASA Astrophysics Data System (ADS)

    Ramana, M. M. V.; Betkar, Rahul; Nimkar, Amey; Ranade, Prasanna; Mundhe, Balaji; Pardeshi, Sachin

    2016-01-01

    In the present work, isopropyl-6-amino-4-(3,5-bis(trifluoromethyl)phenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (4H-pyran analog) has been synthesized by a three component reaction catalyzed by CsOH/γ-Al2O3 and characterized. The interaction of 4H-pyran analog with herring sperm DNA (hs DNA) under physiological conditions (phosphate buffer of pH 7.2) was investigated by UV absorption, FT-IR, fluorescence, 31P NMR and circular dichroism (CD) spectroscopy. Fluorescence quenching results reveal that static quenching mechanism is involved in binding between 4H-pyran analog and hs DNA. The calculated thermodynamic parameters (ΔH° and ΔS°) indicate that hydrogen bonding plays a major role in binding between them. UV absorption and fluorescence shows the binding mode of 4H-pyran analog with hs DNA as non-intercalative. According to the IR spectroscopy, 4H-pyran analog binds to guanine, thymine, adenine bases of hs DNA but not to phosphate backbone of hs DNA which is also in good agreement with 31P NMR results. CD and competitive binding experiment results confirms the minor groove binding of 4H-pyran analog to hs DNA.

  11. Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells.

    PubMed

    Friedrichsen, Gerda Marie; Chen, Weiqing; Begtrup, Mikael; Lee, Chao-Pin; Smith, Philip L; Borchardt, Ronald T

    2002-07-01

    L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1. PMID:12113886

  12. EFFECT OF THE LEUCINE ANALOGS, ALPHA-KETOISOCAPROIC ACID (KIC) AND NORLEUCINE, ON MUSCLE PROTEIN SYNTHESIS AND TRANSLATION INITIATION FACTOR ACTIVATION IN NEONATAL PIGS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leucine acts as a nutrient signal to stimulate protein synthesis in skeletal muscle of neonatal pigs; however, the chemical structure responsible for this effect has not been identified. We have shown that isoleucine and valine are not able to stimulate protein synthesis when raised in plasma withi...

  13. Synthesis and mutagenicity of selectively methylated analogs of tris(2,3-dibromopropyl)phosphate and 1,2-dibromo-3-chloropropane.

    PubMed

    Omichinski, J G; Søderlund, E J; Bausano, J A; Dybing, E; Nelson, S D

    1987-07-01

    Five selectively methylated analogs of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and of the nematocide 1,2-dibromo-3-chloropropane (DBCP) were synthesized and their relative mutagenicities determined in Salmonella typhimurium TA100 in the presence of rat liver microsomes. In all cases, methylation decreased mutagenicity relative to the parent compound, but the relative degree of reduced mutagenicity varied considerably depending on the position of the methyl substitution. The mutagenicity studies with the selectively methylated analogs and with suspected mutagenic metabolites (2-bromocrotonaldehyde and methyl 1-dibromovinyl ketone) supported earlier work with selectively deuterated analogs of Tris-BP and DBCP. They demonstrated that initial oxidation at C-3, followed by spontaneous dehydrohalogenation and dehydrophosphorylation, was the major route of formation of mutagenic metabolites from Tris-BP. In the case of DBCP, formation of mutagenic metabolites can result following initial oxidation at either C-1 or C-3. PMID:3325760

  14. Synthesis of S-Adenosyl-L-Methionine Analogs with Extended Transferable Groups for Methyltransferase-Directed Labeling of DNA and RNA.

    PubMed

    Masevičius, Viktoras; Nainytė, Milda; Klimašauskas, Saulius

    2016-01-01

    S-Adenosyl-L-methionine (AdoMet) is a ubiquitous methyl donor for a variety of biological methylation reactions catalyzed by methyltransferases (MTases). AdoMet analogs with extended propargylic chains replacing the sulfonium-bound methyl group can serve as surrogate cofactors for many DNA and RNA MTases enabling covalent deposition of these linear chains to their cognate targets sites in DNA or RNA. Here we describe synthetic procedures for the preparation of two representative examples of AdoMet analogs with a transferable hex-2-ynyl group carrying a terminal azide or amine functionality. Our approach is based on direct chemoselective alkylation of S-adenosyl-L-homocysteine at sulfur with corresponding nosylates under acidic conditions. We also describe synthetic routes to 6-substituted hex-2-yn-1-ols and their conversion to the corresponding nosylates. Using these protocols, synthetic AdoMet analogs can be prepared within 1 to 2 weeks. PMID:26967468

  15. Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2.

    PubMed

    Nickell, Justin R; Culver, John P; Janganati, Venumadhav; Zheng, Guangrong; Dwoskin, Linda P; Crooks, Peter A

    2016-09-15

    A small library of 1,4-diphenethylpiperazine analogs was synthesized and evaluated for inhibition of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). Results from these studies identified three novel molecules, 6b, 6e and 9a (Ki=35nM, 48nM and 37nM, respectively) that exhibit similar potency for inhibition of VMAT2 function compared with lobelane (Ki=45nM), and importantly, have enhanced water-solubility when compared to the previously reported 1,4-diphenethylpiperidine analogs. These 1,4-diphenethylpiperazine analogs constitute promising new leads in the discovery of potential pharmacotherapeutics for treatment of methamphetamine use disorders. PMID:27524311

  16. Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3′,5′difluorophenyl)-alanine

    PubMed Central

    Martín-Gago, Pablo; Rol, Álvaro; Todorovski, Toni; Aragón, Eric; Martin-Malpartida, Pau; Verdaguer, Xavier; Vallès Miret, Mariona; Fernández-Carneado, Jimena; Ponsati, Berta; Macias, Maria J.; Riera, Antoni

    2016-01-01

    Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1–5). We have designed six new Somatostatin analogs with L-3-(3′,5′-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor aromatic ring in the network of aromatic interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aqueous solution by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, respectively. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin. PMID:27271737

  17. Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3',5'difluorophenyl)-alanine.

    PubMed

    Martín-Gago, Pablo; Rol, Álvaro; Todorovski, Toni; Aragón, Eric; Martin-Malpartida, Pau; Verdaguer, Xavier; Vallès Miret, Mariona; Fernández-Carneado, Jimena; Ponsati, Berta; Macias, Maria J; Riera, Antoni

    2016-01-01

    Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1-5). We have designed six new Somatostatin analogs with L-3-(3',5'-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor aromatic ring in the network of aromatic interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aqueous solution by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, respectively. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin. PMID:27271737

  18. Design and synthesis of 3,5-disubstituted boron-containing 1,2,4-oxadiazoles as potential combretastatin A-4 (CA-4) analogs

    PubMed Central

    Das, Bhaskar C.; Tang, Xiang-Ying; Rogler, Patrick; Evans, Todd

    2013-01-01

    We have designed and synthesized a small library of 3,5-disubstituted-1,2,4-oxadiazole containing combretastatin A-4 (CA-4) analogs. Our objective is to increase the efficacy of the CA-4 as an anti-tubulin and antimitotic agent by substituting the cis-alkene bond with one of its bioisosteres, the 1,2,4-oxadiazole ring. We also modified the substituents attached to both of the phenyl rings (ring A and B in Fig. 1) of CA-4 for the purpose of diversifying our analogs based on SAR. These compounds were synthesized via a coupling reaction between an amidoxime and a carboxylic acid in DMF solvent, with HOBt as a base, and utilizing EDCI as a coupling reagent. Using this protocol, we synthesized a small library of 10 compounds with moderate to good yields. A detailed biological study is currently undergoing in our laboratory to evaluate the activity of these compounds. PMID:24039307

  19. The synthesis and characterization of analogs of the antimicrobial compound squalamine: 6 beta-hydroxy-3-aminosterols synthesized from hyodeoxycholic acid.

    PubMed

    Jones, S R; Kinney, W A; Zhang, X; Jones, L M; Selinsky, B S

    1996-10-01

    Analogs of the aminosterol antimicrobial agent squalamine have been synthesized beginning from hyodeoxycholic acid. After carboxylic acid esterification and oxidation of both alcohol functions to ketones, the A/B ring junction was converted from cis to trans by acid-catalyzed isomerization. Different polyamines were added to the 3-keto group by reductive amination, yielding both the 3 alpha and 3 beta addition products. The synthetic products exhibited potent, broad-spectrum antimicrobial activity similar to that of the parent compound. Changing the identity of the polyamine or the stereochemistry of addition has little effect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexpensive starting materials and are promising alternatives to squalamine as potential antibiotics. PMID:8910969

  20. Design and Synthesis of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one Analogs as Potent Antitumor Agents that Inhibit Tubulin Assembly

    PubMed Central

    Chang, Yu-Hsun; Hsu, Mei-Hua; Wang, Sheng-Hung; Huang, Li-Jiau; Qian, Keduo; Morris-Natschke, Susan L.; Hamel, Ernest; Kuo, Sheng-Chu; Lee, Kuo-Hsiung

    2009-01-01

    As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogs was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones identified by CoMFA models. The newly synthesized analogs were evaluated for cytotoxicity against seven human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogs 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07–0.19 µM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents. PMID:19719238

  1. Synthesis, Biological Activity, and NMR-Based Structural Studies of Deltorphin I Analogs Modified in Message Domain with a New α,α-Disubstituted Glycines.

    PubMed

    Lasota, Anika; Frączak, Oliwia; Muchowska, Adriana; Nowakowski, Michał; Maciejczyk, Maciej; Ejchart, Andrzej; Olma, Aleksandra

    2016-06-01

    This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)-α-benzyl-β-azidoalanine, α-benzyl-β-(1-pyrrolidinyl)alanine, α-benzyl-β-(1-piperidinyl)alanine, and α-benzyl-β-(4-morpholinyl)-alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand). The affinity of analogs containing (R) or (S)-α-benzyl-β-azidoalanine in position 3 to δ-receptors strongly depended on the chirality of the α,α-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-α-benzyl-β-(1-piperidinyl)Ala, which displays the opposite selectivity, was analyzed by (1) H and (13) C NMR. The μ-selective Tyr-d-Ala-(R)-α-benzyl-β-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the δ-selective Tyr-d-Ala-(S)-α-benzyl-β-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 . Our results support the proposal that differences between δ- and μ-selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N-terminal message domain and the C-terminal address domain. PMID:26808639

  2. Synthesis and Bio-Evaluation of New (18) F-Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice.

    PubMed

    Mou, Tiantian; Zhao, Zuoquan; Zhang, Pu; Fang, Wei; Peng, Cheng; Lu, Jie; Wang, Qian; Ma, Yunchuan; Zhang, Xianzhong

    2015-09-01

    To improve the stability of (18) F-labeled pyridaben analogs for myocardial perfusion imaging, three new analogs of pyridaben ([(18) F]FPTP2, [(18) F]FPTP-P2, and [(18) F]FPTP-P3) were synthesized with 'side chain' modifications. The radiolabeled tracers and corresponding non-radioactive compounds were obtained by substituting tosyl group with (18/19) F. The effect of structure modification on myocardial targeting and physicochemical properties of new tracers were evaluated in vitro and in vivo. The total radiosynthesis time of these tracers was approximately 70-90 min with high decay-corrected radiochemical yields (36-65%) and good radiochemical purity (> 98%). These lipophilic tracers exhibited obvious improved stability in water. Studies of their biodistribution in normal Kunming mice demonstrated that [(18) F]FPTP2 exhibited very high initial heart uptake (39.70 ± 2.81 %ID/g at 2 min after injection) and low background in the liver, blood, and soft tissues. The heart-to-liver, heart-to-lung, and heart-to-blood ratios were 3.59, 19.34, and 67.34 at 15 min postinjection, respectively. Favorable myocardial targeting property and remarkable improvement of stability of [(18) F]FPTP2 suggest that the substitution of the phenyl 'sidechain' with other non-phenyl rings has no effect on the myocardial targeting property of (18) F-labeled pyridaben analogs. PMID:25529021

  3. Synthesis and in vitro evaluation of (R), (S) and (R/S)-2-hexyne-1,4-diol, a natural product produced by fungus Clitocybe catinus, and related analogs as potential anticancer agents.

    PubMed

    Princival, Iza Mirela R G; Ferreira, Jeiely G; Silva, Teresinha G; Aguiar, Jaciana S; Princival, Jefferson L

    2016-06-15

    The search for natural products and related analogs as potential anticancer agents has seen a significant growth worldwide. Since small sized propargylic diols can be found in nature and chemically synthesized, their evaluation against cancer cells has been of great interest, being a topic of relevance to be investigated. For this purpose, a scalable approach aiming at the synthesis of several propargylic diols and their bioactivity against seven tumor cell lines were evaluated. Interestingly, when the compound 1a, a natural product produced by fungus Clitocybe catinus, was tested in its racemic mixture a more effective activity was observed if compared when enantiopure R-1a or S-1a were tested separately. PMID:27142752

  4. Science Teachers' Analogical Reasoning

    NASA Astrophysics Data System (ADS)

    Mozzer, Nilmara Braga; Justi, Rosária

    2013-08-01

    Analogies can play a relevant role in students' learning. However, for the effective use of analogies, teachers should not only have a well-prepared repertoire of validated analogies, which could serve as bridges between the students' prior knowledge and the scientific knowledge they desire them to understand, but also know how to introduce analogies in their lessons. Both aspects have been discussed in the literature in the last few decades. However, almost nothing is known about how teachers draw their own analogies for instructional purposes or, in other words, about how they reason analogically when planning and conducting teaching. This is the focus of this paper. Six secondary teachers were individually interviewed; the aim was to characterize how they perform each of the analogical reasoning subprocesses, as well as to identify their views on analogies and their use in science teaching. The results were analyzed by considering elements of both theories about analogical reasoning: the structural mapping proposed by Gentner and the analogical mechanism described by Vosniadou. A comprehensive discussion of our results makes it evident that teachers' content knowledge on scientific topics and on analogies as well as their pedagogical content knowledge on the use of analogies influence all their analogical reasoning subprocesses. Our results also point to the need for improving teachers' knowledge about analogies and their ability to perform analogical reasoning.

  5. endo/exo stereoselectivity in Diels-Alder reactions of α,β-dialkylated conjugated enals to cyclic 1,3-dienes: intermediates in the synthesis of (-)-β-santalol and its analogs.

    PubMed

    Chapuis, Christian; Skuy, David; de Saint Laumer, Jean-Yves; Brauchli, Robert

    2014-10-01

    Highly exo-selective [4+2] cycloadditions of cyclopenta-1,3-diene 2a to α,β-dialkyl conjugated enals 5 are compared with the analogous endo-favored Diels-Alder reaction of cyclohexa-1,3-diene 7. The exo-stereoselectivity is lower in the homologous case of methylcyclopenta-1,3-diene 9. This diastereoselectivity is discussed either in terms of a retro-homo-Diels-Alder reaction, associated with thermodynamic control, or with respect to either a competing hetero-Diels-Alder/Claisen or Cope domino pathway, or retro-Claisen/retro-hetero-Diels-Alder of the endo-homo-cycloadducts. These hypothetical mechanisms have been examined by DFT calculations at the MPW1K(CH2 Cl2 )/6-31+G** level of theory for the AlCl3 -mediated cycloadditions of 5d to 2a and 7. Application of Corey's methodology to the γ-halogeno-α-methyl-substituted dienophiles 5a and 5b allowed an enantioselective preparation of known and useful intermediates for the synthesis of either the naturally occurring (-)-β-santalol or its potentially olfactive structural analogs. PMID:25329781

  6. Design, synthesis and in vitro biological evaluation of short-chain C12-sphinganine and its 1,2,3-triazole analogs as potential antimicrobial and anti-biofilm agents.

    PubMed

    Vijai Kumar Reddy, T; Jyotsna, A; Prabhavathi Devi, B L A; Prasad, R B N; Poornachandra, Y; Ganesh Kumar, C

    2016-08-01

    A conceptual synthetic approach of short-chain C12-sphinganine 1 and a small library of its 1,2,3-triazole analogs 2(a-f) has been accomplished using the commercially available and inexpensive 10-undecenoic acid as a starting material. Miyashita's C-2 selective endo mode azidolysis and Huisgen click reaction was employed for the synthesis of the designed analogs. Based on biological evaluation studies of all the synthesized compounds, it was observed that, (2S,3R)-2-(4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)dodecan-1,3-diol (2b) exhibited promising antimicrobial and antifungal activities. Furthermore, compound 2b was able to inhibit the biofilm formation of Candida albicans MTCC 227, Micrococcus luteus MTCC 2470 and Staphylococcus aureus MTCC 96 with IC50 values of 1.9, 2.1 and 2.9 μg/mL, respectively. Compound 2b increased the levels of reactive oxygen species (ROS) in C. albicans MTCC 227. PMID:27128176

  7. Analogical Reasoning in the Engineering Design Process and Technology Education Applications

    ERIC Educational Resources Information Center

    Daugherty, Jenny; Mentzer, Nathan

    2008-01-01

    This synthesis paper discusses the research exploring analogical reasoning, the role of analogies in the engineering design process, and educational applications for analogical reasoning. Researchers have discovered that analogical reasoning is often a fundamental cognitive tool in design problem solving. Regarding the possible role of analogical…

  8. Synthesis of new fluorinated analogs of GABA, Pregabalin bioisosteres, and their effects on [(3)H]GABA uptake by rat brain nerve terminals.

    PubMed

    Borisova, T; Pozdnyakova, N; Shaitanova, E; Gerus, I; Dudarenko, M; Mironets, R; Haufe, G; Kukhar, V

    2015-08-01

    Fluorinated analogs of natural substances take an essential place in the design of new biologically active compounds. New fluorinated analogs of γ-aminobutyric acid, that is, β-polyfluoroalkyl-GABAs (FGABAs), were synthesized with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3). FGABAs are bioisosteres of Pregabalin (Lyrica®, Pfizer's blockbuster drug, β-i-Bu-GABA), and have lipophilicity close to this medicine. The effects of synthesized FGABAs on [(3)H]GABA uptake by isolated rat brain nerve terminals (synaptosomes) were assessed and compared with those of Pregabalin. FGABAs 1-3 (100μM) did not influence the initial velocity of [(3)H]GABA uptake when applied acutely, whereas an increase in this parameter was found after preliminary incubation of FGABAs with synaptosomes. Pregabalin after preliminary incubation with synaptosomes caused unidirectional changes in the initial velocity of [(3)H]GABA uptake. Using specific inhibitors of GAT1 and GAT3, NO-711 and SNAP5114, respectively, the ability of FGABAs 1-3 to influence non-GAT1 and non-GAT3 uptake activity of nerve terminals was analyzed, but no specificity was found. Therefore, new synthesized FGABAs are structural but not functional analogs of GABA (because they did not inhibit synaptosomal [(3)H]GABA uptake). Moreover, FGABAs are able to increase the initial velocity of [(3)H]GABA uptake by synaptosomes, and this effect is higher than that of Pregabalin. PMID:26138193

  9. Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors.

    PubMed

    Bruel, Amélie; Bénéteau, Romain; Chabanne, Mylène; Lozach, Olivier; Le Guevel, Rémy; Ravache, Myriam; Bénédetti, Hélène; Meijer, Laurent; Logé, Cédric; Robert, Jean-Michel

    2014-11-01

    New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines. PMID:25248682

  10. Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

    PubMed Central

    Maftei, Catalin V; Fodor, Elena; Jones, Peter G; Franz, M Heiko; Kelter, Gerhard; Fiebig, Heiner

    2013-01-01

    Summary Taking into consideration the biological activity of the only natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were synthesized starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)aniline (1) in two steps by isolating the intermediates 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) and (Z)-4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobut-2-enoic acid (6). The two natural product analogs 4 and 7 were then tested for antitumor activity toward a panel of 11 cell lines in vitro by using a monolayer cell-survival and proliferation assay. Compound 7 was the most potent and exhibited a mean IC50 value of approximately 9.4 µM. Aniline 1 was synthesized by two routes in one-pot reactions starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography. PMID:24222789

  11. Synthesis and biological evaluation of a novel class of curcumin analogs as anti-inflammatory agents for prevention and treatment of sepsis in mouse model.

    PubMed

    Zhao, Chengguang; Zhang, Yali; Zou, Peng; Wang, Jian; He, Wenfei; Shi, Dengjian; Li, Huameng; Liang, Guang; Yang, Shulin

    2015-01-01

    A novel class of asymmetric mono-carbonyl analogs of curcumin (AMACs) were synthesized and screened for anti-inflammatory activity. These analogs are chemically stable as characterized by UV absorption spectra. In vitro, compounds 3f, 3m, 4b, and 4d markedly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 in a dose-dependent manner, with IC50 values in low micromolar range. In vivo, compound 3f demonstrated potent preventive and therapeutic effects on LPS-induced sepsis in mouse model. Compound 3f downregulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 MAPK and suppressed IκBα degradation, which suggests that the possible anti-inflammatory mechanism of compound 3f may be through downregulating nuclear factor kappa binding (NF-κB) and ERK pathways. Also, we solved the crystal structure of compound 3e to confirm the asymmetrical structure. The quantitative structure-activity relationship analysis reveals that the electron-withdrawing substituents on aromatic ring of lead structures could improve activity. These active AMACs represent a new class of anti-inflammatory agents with improved stability, bioavailability, and potency compared to curcumin. Our results suggest that 3f may be further developed as a potential agent for prevention and treatment of sepsis or other inflammation-related diseases. PMID:25834403

  12. Synthesis of nisin AB dicarba analogs using ring-closing metathesis: influence of sp(3) versus sp(2) hybridization of the α-carbon atom of residues dehydrobutyrine-2 and dehydroalanine-5 on the lipid II binding affinity.

    PubMed

    Slootweg, Jack C; van Herwerden, Eric F; van Doremalen, Mark F M; Breukink, Eefjan; Liskamp, Rob M J; Rijkers, Dirk T S

    2015-06-01

    Herein the synthesis of two nisin AB dicarba analogs is described, focusing on amino acid modifications at positions 2 and 5. The nisin mimics were synthesized by a combination of solid phase synthesis of the linear peptides, followed by macrocyclization via ring-closing metathesis and fragment assembly by means of solution phase chemistry. The two N-terminal nisin AB-fragment mimics contain either the native dehydrobutyrine (Dhb)/dehydroalanine (Dha) amino acid residues or alanine at position 2 and 5, respectively. The native dehydrobutyrine at position 2 and dehydroalanine at position 5 were introduced as their precursors, namely threonine and serine, respectively, and subsequent dehydration was carried out by EDCI/CuCl as the condensing agent. Both AB-fragment mimics were analyzed in a lipid II binding assay and it was found that the Ala2/Ala5 AB-mimic (2) showed a reduced activity, while the Dhb2/Dha5 AB-mimic (3) was as active as the native AB-fragment (1). PMID:25940216

  13. Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution.

    PubMed

    Gauthier, Sylvain; Cloutier, Julie; Dory, Yves L; Favre, Alexandre; Mailhot, Josée; Ouellet, Carl; Schwerdtfeger, Annette; Mérand, Yves; Martel, Céline; Simard, Jacques; Labrie, Fernand

    2005-04-01

    EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively. PMID:15968821

  14. Synthesis and biological evaluation of fluorine-18 labeled RS-15385-197 analogs: Potent and selective alpha-2 adrenergic receptor radioligands for PET

    SciTech Connect

    Enas, J.D.; VanBrocklin, H.F.; Budinger, T.F.; Clark, R.D.

    1997-12-31

    Aberrations in the {alpha}{sub 2}-adrenergic receptor system have been implicated in a number of disease states including hypertension, drug abuse, depression, and neurodegenerative disorders such as Alzheimer`s Disease. RS-15385-FP (1) and RS-15385-FPh (2) are analogs of the {alpha}{sub 2}-adrenergic receptor antagonist RS- 15385-197 which display a high receptor binding affinity (K{sub i} = 0.2 and 0.5 nM, respectively) as well as a high degree of {alpha}{sub 2}/{alpha}{sub 1} selectivity (7000:1 and 2000:1, respectively). We synthesized [F-18]-2 was synthesized by fluoro-for-nitro exchange on the corresponding nitrophenyl derivative which was produced in two steps from the hydroxypropyl sulfonamide. In vivo distribution studies in rats and PET studies in monkeys demonstrate uptake in {alpha}{sub 2}-adrenergic receptor rich regions of the brain, particularly the locus coeruleus.

  15. Radioactive Decay - An Analog.

    ERIC Educational Resources Information Center

    McGeachy, Frank

    1988-01-01

    Presents an analog of radioactive decay that allows the student to grasp the concept of half life and the exponential nature of the decay process. The analog is devised to use small, colored, plastic poker chips or counters. Provides the typical data and a graph which supports the analog. (YP)

  16. Student-Generated Analogies: Another Way of Knowing?

    ERIC Educational Resources Information Center

    Pittman, Kim M.

    1999-01-01

    Explores relationships among school students' (n=189) acquisition of meaningful understandings of protein synthesis. Analysis of student-generated analogies revealed unique patterns in students' understandings of this topic. Contains 41 references. (Author/WRM)

  17. RIO Tinto Faulted Volcanosedimentary Deposits as Analog Habitats for Extant Subsurface Biospheres on Mars: A Synthesis of the MARTE Drilling Project Geobiology Results

    NASA Technical Reports Server (NTRS)

    Fernandez-Remolar, D. C.; Prieto-Ballesteros, O.; Rodriquez, N.; Davila, F.; Stevens, T.; Amils, R.; Gomez-Elvira, J.; Stoker, C.

    2005-01-01

    Geochemistry and mineralogy on Mars surface characterized by the MER Opportunity Rover suggest that early Mars hosted acidic environments in the Meridiani Planum region [1, 2]. Such extreme paleoenvironments have been suggested to be a regional expression of the global Mars geological cycle that induced acidic conditions by sulfur complexation and iron buffering of aqueous solutions [3]. Under these assumptions, underground reservoirs of acidic brines and, thereby, putative acidic cryptobiospheres, may be expected. The MARTE project [4, 5] has performed a drilling campaign to search for acidic and anaerobic biospheres in R o Tinto basement [6] that may be analogs of these hypothetical communities occurring in cryptic habitats of Mars. This Rio Tinto geological region is characterized by the occurrence of huge metallic deposits of iron sulfides [7]. Late intensive diagenesis of rocks driven by a compressive regimen [8] largely reduced the porosity of rocks and induced a cortical thickening through thrusting and inverse faulting and folding. Such structures play an essential role in transporting and storing water underground as any other aquifers do in the Earth. Once the underground water reservoirs of the Ro Tinto basement contact the hydrothermal pyrite deposits, acidic brines are produced by the release of sulfates and iron through the oxidation of sulfides [9].

  18. Design, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles

    PubMed Central

    Gangjee, Aleem; Namjoshi, Ojas A.; Raghavan, Sudhir; Queener, Sherry F.; Kisliuk, Roy L.; Cody, Vivian

    2013-01-01

    Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg) and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogs. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. PMID:23627352

  19. Synthesis and Antimicrobial Screening of Novel Thioglycosides and Acyclonucleoside Analogs Carrying 1,2,3-Triazole and 1,3,4-Oxadiazole Moieties.

    PubMed

    Aouad, M R

    2016-01-01

    The solvent-free 1,3-dipolar cycloaddition reaction of dimethylacetylene dicarboxylate (1) with 2-chlorophenyl azide (2) afforded 1,2,3-triazole diester 3 that upon hydrazinolysis, furnished the corresponding bis-acid hydrazide 4. The treatment of compound 4 with carbon disulfide in a refluxing potassium hydroxide solution furnished the desired bis-1,3,4-oxadiazole-2-thione 5 tethered to a 1,2,3-triazole moiety. The respective SOx-glycosides 9-11 were obtained by glycosylation of bis-oxadiazole 5 with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (6), 2,3,4,6-tetra-O-acetyl-α-d-galactopyranosyl bromide (7), and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl chloride (8) in dry acetone in the presence of Et3N, which acted as a base. However, alkylation of 5 with halogeno-alkanol 12 or 13, chloroglycerol 14, bromoethers 20 or 21, and epichlohydrin 22 in the presence of K2CO3 in DMF yielded the corresponding acyclonucleoside analogs 16-18 and 23-25. The isopropylidenes 19 and acetyl derivatives 26-28 of the products were also prepared. The newly synthesized compounds were characterized by (1)H NMR, (13)C NMR, 2D NMR, and mass spectra. The compounds were screened for their antibacterial and antifungal activities. A number of the tested compounds exhibited significant antimicrobial activity compared to the reference drugs. PMID:26810028

  20. Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals.

    PubMed

    Veerman, Johan; van den Bergh, Toine; Orrling, Kristina M; Jansen, Chimed; Cos, Paul; Maes, Louis; Chatelain, Eric; Ioset, Jean-Robert; Edink, Ewald E; Tenor, Hermann; Seebeck, Thomas; de Esch, Iwan; Leurs, Rob; Sterk, Geert Jan

    2016-04-01

    Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease. PMID:26935942

  1. Synthesis and characterization of ( sup 3 H)-5 prime azido-N-1-naphthylphthlamic acid, a photolabile N-1-naphthylphthalamic acid analog

    SciTech Connect

    Voet, J.G.; Dodge, B.; Harris, K.; Jacobs, M.; Larkin, L.; Bader, S.; Schnitzler, G.; Sutherland, J. )

    1990-05-01

    The NPA (N-1-naphthylphthalamic acid) receptor is an important protein involved in the regulation of transport of indole-3-acetic acid (IAA). In our attempt to isolate and characterize this protein we have previously synthesized and characterized a photolabile analog of NPA, 5{prime}-azido-NPA (Az-NPA) and shown it to be a competitor of NPA for binding sites on the NPA receptor as well as an inhibitor of auxin transport. We have now synthesized and characterized ({sup 3}H)-Az-NPA. The precursor, 2,3,4,5-Br-5{prime}-amino-NPA was dehydrohalogenated with tritium gas by Research Products International. The amino group was converted to an azido group and the product purified by HPLC. ({sup 3}H)-Az-NPA was found to be photolabile and to co-chromatograph with our synthetic unlabeled Az-NPA. Furthermore, the tritiated material was found to bind to zucchini hypocotyl cell membranes in a manner competitive with NPA as well as unlabeled Az-NPA. Photolysis of zucchini phase-partitioned plasma membranes in the presence of ({sup 3}H)-Az-NPA resulted in covalent association of tritium with the membranes. Much of this covalent association could be prevented by prior treatment of the membranes with excess NPA.

  2. Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres.

    PubMed

    Kormos, Chad M; Gichinga, Moses G; Runyon, Scott P; Thomas, James B; Mascarella, S Wayne; Decker, Ann M; Navarro, Hernán A; Carroll, F Ivy

    2016-08-15

    The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a-b, 4a-b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b) had the best overall binding potency and selectivity in a [(35)S]GTPγS functional assay, with a Ke=0.18nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood-brain barrier. PMID:27364611

  3. 5'-azido-N-1-naphthylphthalamic acid, a photolabile analog of the auxin transport inhibitor, N-1-naphthylphthalamic acid: synthesis and binding properties

    SciTech Connect

    Voet, J.G.; Howley, K.; Shumsky, J.S.

    1987-05-01

    The polar transport of the plant growth regulator, auxin (indole-3-acetic acid, IAAH), is thought to involve the participation of several proteins in the plasma membrane, including a specific, saturable, voltage independent H/sup +//IAA/sup -/ efflux carrier located preferentially at the basal end of each cell. Auxin transport is specifically inhibited by the herbicide, N-1-naphthylphthalamic acid (NPA), which binds specifically to a protein in the plasma membrane, thought to be either the IAA/sup -/ efflux carrier or an allosteric effector protein. They have synthesized and characterized a photolabile analog of NPA, 5'-azido-N-1-naphthylphthalamic acid (Az-NPA). This potential photoaffinity label for the NPA binding protein competes with /sup 3/H-NPA for binding sites on Curcurbita pepo L. (zucchini) stem cell membranes with K/sub j/ = 1.5 x 10/sup -7/ M. The K/sub i/ for NPA under these conditions is 2 x 10/sup -8/M, indicating that the affinity of Az-NPA for the membranes is only 7.5 fold lower than NPA. While the binding of 4.6 x 10/sup -6/ M Az-NPA to NPA binding sites is reversible in the dark, exposure to light results in a 30% loss in /sup 3/H-NPA binding ability. Pretreatment with 10/sup -4/ M NPA protects the membranes against photodestruction of /sup 3/H-NPA binding sites by Az-NPA, supporting the conclusion that Az-NPA destroys these sites by specific covalent attachment.

  4. Anti-parallel triplexes: Synthesis of 8-aza-7-deazaadenine nucleosides with a 3-aminopropynyl side-chain and its corresponding LNA analog.

    PubMed

    Kosbar, Tamer R; Sofan, Mamdouh A; Waly, Mohamed A; Pedersen, Erik B

    2015-05-15

    The phosphoramidites of DNA monomers of 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine (Y) and 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine LNA (Z) are synthesized, and the thermal stability at pH 7.2 and 8.2 of anti-parallel triplexes modified with these two monomers is determined. When, the anti-parallel TFO strand was modified with Y with one or two insertions at the end of the TFO strand, the thermal stability was increased 1.2°C and 3°C at pH 7.2, respectively, whereas one insertion in the middle of the TFO strand decreased the thermal stability 1.4°C compared to the wild type oligonucleotide. In order to be sure that the 3-aminopropyn-1-yl chain was contributing to the stability of the triplex, the nucleobase X without the aminopropynyl group was inserted in the same positions. In all cases the thermal stability was lower than the corresponding oligonucleotides carrying the 3-aminopropyn-1-yl chain, especially at the end of the TFO strand. On the other hand, the thermal stability of the anti-parallel triplex was dramatically decreased when the TFO strand was modified with the LNA monomer analog Z in the middle of the TFO strand (ΔTm=-9.1°C). Also the thermal stability decreased about 6.1°C when the TFO strand was modified with Z and the Watson-Crick strand with adenine-LNA (A(L)). The molecular modeling results showed that, in case of nucleobases Y and Z a hydrogen bond (1.69 and 1.72Ǻ, respectively) was formed between the protonated 3-aminopropyn-1-yl chain and one of the phosphate groups in Watson-Crick strand. Also, it was shown that the nucleobase Y made a good stacking and binding with the other nucleobases in the TFO and Watson-Crick duplex, respectively. In contrast, the nucleobase Z with LNA moiety was forced to twist out of plane of Watson-Crick base pair which is weakening the stacking interactions with the TFO nucleobases and the binding with the duplex part. PMID:25868748

  5. Nonvolatile Analog Memory

    NASA Technical Reports Server (NTRS)

    MacLeod, Todd C. (Inventor)

    2007-01-01

    A nonvolatile analog memory uses pairs of ferroelectric field effect transistors (FFETs). Each pair is defined by a first FFET and a second FFET. When an analog value is to be stored in one of the pairs, the first FFET has a saturation voltage applied thereto, and the second FFET has a storage voltage applied thereto that is indicative of the analog value. The saturation and storage voltages decay over time in accordance with a known decay function that is used to recover the original analog value when the pair of FFETs is read.

  6. Analog synthetic biology.

    PubMed

    Sarpeshkar, R

    2014-03-28

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  7. Novel stilbene-based Fischer base analog of leuco-TAM - (2E,2'Z)-{2-(4-(E)-styrylphenyl)propane-1,3-diylidene}bis(1,3,3-trimethylindoline) - derivatives: synthesis and structural consideration by 1D NMR and 2D NMR spectroscopy.

    PubMed

    Keum, Sam-Rok; Lim, Hyun-Woo

    2016-02-01

    We report the synthesis of a series of novel stilbene-based (St) Fischer base analogs of leuco-triarylmethane (LTAM) dyes by treating Fischer base with (E)-4-styrylbenzaldehyde derivatives. All St-LTAM molecules examined herein are characterized by 1D and 2D NMR. They were found to exhibit ZE configuration and isomerize to their diastereomers EE and ZZ in 2-3 h. They exhibit type I behavior of diastereomeric isomerization. PMID:26448377

  8. Analog synthetic biology

    PubMed Central

    Sarpeshkar, R.

    2014-01-01

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog–digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA–protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  9. Analog pulse processor

    DOEpatents

    Wessendorf, Kurt O.; Kemper, Dale A.

    2003-06-03

    A very low power analog pulse processing system implemented as an ASIC useful for processing signals from radiation detectors, among other things. The system incorporates the functions of a charge sensitive amplifier, a shaping amplifier, a peak sample and hold circuit, and, optionally, an analog to digital converter and associated drivers.

  10. Challenges in Using Analogies

    ERIC Educational Resources Information Center

    Lin, Shih-Yin; Singh, Chandralekha

    2011-01-01

    Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same…

  11. Hydraulic Capacitor Analogy

    ERIC Educational Resources Information Center

    Baser, Mustafa

    2007-01-01

    Students have difficulties in physics because of the abstract nature of concepts and principles. One of the effective methods for overcoming students' difficulties is the use of analogies to visualize abstract concepts to promote conceptual understanding. According to Iding, analogies are consistent with the tenets of constructivist learning…

  12. Meat analog: a review.

    PubMed

    Malav, O P; Talukder, S; Gokulakrishnan, P; Chand, S

    2015-01-01

    The health-conscious consumers are in search of nutritious and convenient food item which can be best suited in their busy life. The vegetarianism is the key for the search of such food which resembles the meat in respect of nutrition and sensory characters, but not of animal origin and contains vegetable or its modified form, this is the point when meat analog evolved out and gets shape. The consumers gets full satisfaction by consumption of meat analog due to its typical meaty texture, appearance and the flavor which are being imparted during the skilled production of meat analog. The supplement of protein in vegetarian diet through meat alike food can be fulfilled by incorporating protein-rich vegetative food grade materials in meat analog and by adopting proper technological process which can promote the proper fabrication of meat analog with acceptable meat like texture, appearance, flavor, etc. The easily available vegetables, cereals, and pulses in India have great advantages and prospects to be used in food products and it can improve the nutritional and functional characters of the food items. The various form and functional characters of food items are available world over and attracts the meat technologists and the food processors to bring some innovativeness in meat analog and its presentation and marketability so that the acceptability of meat analog can be overgrown by the consumers. PMID:24915320

  13. Biosynthesis of amphetamine analogs in plants.

    PubMed

    Hagel, Jillian M; Krizevski, Raz; Marsolais, Frédéric; Lewinsohn, Efraim; Facchini, Peter J

    2012-07-01

    Amphetamine analogs are produced by plants in the genus Ephedra and by Catha edulis, and include the widely used decongestants and appetite suppressants pseudoephedrine and ephedrine. A combination of yeast (Candida utilis or Saccharomyces cerevisiae) fermentation and subsequent chemical modification is used for the commercial production of these compounds. The availability of certain plant biosynthetic genes would facilitate the engineering of yeast strains capable of de novo pseudoephedrine and ephedrine biosynthesis. Chemical synthesis has yielded amphetamine analogs with myriad functional group substitutions and diverse pharmacological properties. The isolation of enzymes with the serendipitous capacity to accept novel substrates could allow the production of substituted amphetamines in synthetic biosystems. Here, we review the biology, biochemistry and biotechnological potential of amphetamine analogs in plants. PMID:22502775

  14. Fatty acid analogs

    DOEpatents

    Elmaleh, David R.; Livni, Eli

    1985-01-01

    In one aspect, a radioactively labeled analog of a fatty acid which is capable of being taken up by mammalian tissue and which exhibits an in vivo beta-oxidation rate below that with a corresponding radioactively labeled fatty acid.

  15. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua; Takahashi, Kazuyuki

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  16. Electrical Circuits and Water Analogies

    ERIC Educational Resources Information Center

    Smith, Frederick A.; Wilson, Jerry D.

    1974-01-01

    Briefly describes water analogies for electrical circuits and presents plans for the construction of apparatus to demonstrate these analogies. Demonstrations include series circuits, parallel circuits, and capacitors. (GS)

  17. Organic Synthesis in Simulated Interstellar Ice Analogs

    NASA Technical Reports Server (NTRS)

    Dworkin, Jason P.; Bernstein, Max P.; Sandford, Scott A.; Allamandola, Louis J.; Deamer, David W.; Elsila, Jamie; Zare, Richard N.; DeVincenzi, Donald (Technical Monitor)

    2001-01-01

    Comets and carbonaceous micrometeorites may have been significant sources of organic compounds on the early Earth. Ices on grains in interstellar dense molecular clouds contain a variety of simple molecules as well as aromatic molecules of various sizes. While in these clouds the icy grains are processed by ultraviolet light and cosmic radiation which produces more complex organic molecules. ID We have run laboratory simulations to identify the types of molecules which could have been generated photolytically in pre-cometary ices. Experiments were conducted by forming various realistic interstellar mixed-molecular ices with and without polycyclic aromatic hydrocarbons (PAHs) at approx. 10 K under high vacuum irradiated with LTV light from a hydrogen plasma lamp: The residue that remained after warming to room temperature was analyzed by HPLC, and by laser desorption mass spectrometry. The residue contains several classes of compounds which may be of prebiotic significance.

  18. Organic Synthesis in Simulated Interstellar Ice Analogs

    NASA Technical Reports Server (NTRS)

    Dworkin, Jason P.; Bernstein, Max P.; Sandford, Scott A.; Allamandola, Louis J.; Deamer, David W.; Elsila, Jamie; Zare, Richard N.

    2001-01-01

    Comets and carbonaceous micrometeorites may have been significant sources of organic compounds on the early Earth. Ices on grains in interstellar dense molecular clouds contain a variety of simple molecules as well as aromatic molecules of various sizes. While in these clouds the icy grains are processed by ultraviolet light and cosmic radiation which produces more complex organic molecules. We have run laboratory simulations to identify the types of molecules which could have been generated photolytically in pre-cometary ices. Experiments were conducted by forming various realistic interstellar mixed-molecular ices with and without polycyclic aromatic hydrocarbons (PAHs) at approx. 10 K under high vacuum irradiated with UV light from a hydrogen plasma lamp. The residue that remained after warming to room temperature was analyzed by HPLC, and by laser desorption mass spectrometry. The residue contains several classes of compounds which may be of prebiotic significance.

  19. Digital and analog communication systems

    NASA Technical Reports Server (NTRS)

    Shanmugam, K. S.

    1979-01-01

    The book presents an introductory treatment of digital and analog communication systems with emphasis on digital systems. Attention is given to the following topics: systems and signal analysis, random signal theory, information and channel capacity, baseband data transmission, analog signal transmission, noise in analog communication systems, digital carrier modulation schemes, error control coding, and the digital transmission of analog signals.

  20. Analogical Reasoning in Geometry Education

    ERIC Educational Resources Information Center

    Magdas, Ioana

    2015-01-01

    The analogical reasoning isn't used only in mathematics but also in everyday life. In this article we approach the analogical reasoning in Geometry Education. The novelty of this article is a classification of geometrical analogies by reasoning type and their exemplification. Our classification includes: analogies for understanding and setting a…

  1. Electrical analogous in viscoelasticity

    NASA Astrophysics Data System (ADS)

    Ala, Guido; Di Paola, Mario; Francomano, Elisa; Li, Yan; Pinnola, Francesco P.

    2014-07-01

    In this paper, electrical analogous models of fractional hereditary materials are introduced. Based on recent works by the authors, mechanical models of materials viscoelasticity behavior are firstly approached by using fractional mathematical operators. Viscoelastic models have elastic and viscous components which are obtained by combining springs and dashpots. Various arrangements of these elements can be used, and all of these viscoelastic models can be equivalently modeled as electrical circuits, where the spring and dashpot are analogous to the capacitance and resistance, respectively. The proposed models are validated by using modal analysis. Moreover, a comparison with numerical experiments based on finite difference time domain method shows that, for long time simulations, the correct time behavior can be obtained only with modal analysis. The use of electrical analogous in viscoelasticity can better reveal the real behavior of fractional hereditary materials.

  2. Continuous Fourier transform method and apparatus. [for the analysis of simultaneous analog signal components

    NASA Technical Reports Server (NTRS)

    Munoz, R. M. (Inventor)

    1974-01-01

    An input analog signal to be frequency analyzed is separated into N number of simultaneous analog signal components each identical to the original but delayed relative to the original by a successively larger time delay. The separated and delayed analog components are combined together in a suitable number of adders and attenuators in accordance with at least one component product of the continuous Fourier transform and analog signal matrices to separate the analog input signal into at least one of its continuous analog frequency components of bandwidth 1/N times the bandwidth of the original input signal. The original analog input signal can be reconstituted by combining the separate analog frequency components in accordance with the component products of the continuous Fourier transform and analog frequency component matrices. The continuous Fourier transformation is useful for spectrum analysis, filtering, transfer function synthesis, and communications.

  3. Reasoning through Instructional Analogies

    ERIC Educational Resources Information Center

    Kapon, Shulamit; diSessa, Andrea A.

    2012-01-01

    This article aims to account for students' assessments of the plausibility and applicability of analogical explanations, and individual differences in these assessments, by analyzing properties of students' underlying knowledge systems. We developed a model of explanation and change in explanation focusing on knowledge elements that provide a…

  4. Quantum Analog Computing

    NASA Technical Reports Server (NTRS)

    Zak, M.

    1998-01-01

    Quantum analog computing is based upon similarity between mathematical formalism of quantum mechanics and phenomena to be computed. It exploits a dynamical convergence of several competing phenomena to an attractor which can represent an externum of a function, an image, a solution to a system of ODE, or a stochastic process.

  5. Learning by Analogical Bootstrapping.

    ERIC Educational Resources Information Center

    Miao, Chun-Hui; Kurtz, Kenneth J.; Gentner, Dedre

    2001-01-01

    Reports on research into whether mutual alignment of partially known situations can be an effective strategy when compared to the common procedure of drawing analogies from a well understood situation to one that is poorly understood. Results suggest that such mutual alignment is an effective means of promoting insight. (MM)

  6. Analogy, explanation, and proof

    PubMed Central

    Hummel, John E.; Licato, John; Bringsjord, Selmer

    2014-01-01

    People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic) whose truth was not even known prior to the existence of the explanation (proof). What do the cognitive operations underlying the inference that the milk is sour have in common with the proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This seemingly small difference poses a challenge to the task of marshaling our understanding of analogical reasoning to understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence. PMID:25414655

  7. An Interesting Analogy

    ERIC Educational Resources Information Center

    Pacheco, Jose M.; Fernandez, Isabel

    2002-01-01

    The aim of this note is to give some insight into the formal unity of a very applicable area of mathematics by showing an interesting analogy between the weak part of the Rouche-Frobenius theorem and the existence result for the initial value problem for the general first-order linear two-dimensional PDE.

  8. How Analogy Drives Physics

    SciTech Connect

    Hofstadter, Doug

    2004-05-05

    Many new ideas in theoretical physics come from analogies to older ideas in physics. For instance, the abstract notion of 'isospin' (or isotopic spin) originated in the prior concept of 'spin' (quantized angular momentum); likewise, the concept of 'phonon' (quantum of sound, or quantized collective excitation of a crystal) was based on the prior concept of 'photon' (quantum of light, or quantized element of the electromagnetic field). But these two examples, far from being exceptions, in fact represent the bread and butter of inventive thinking in physics. In a nutshell, intraphysics analogy-making -- borrowing by analogy with something already known in another area of physics -- is central to the progress of physics. The aim of this talk is to reveal the pervasiveness -- indeed, the indispensability -- of this kind of semi-irrational, wholly intuitive type of thinking (as opposed to more deductive mathematical inference) in the mental activity known as 'doing physics'. Speculations as to why wild analogical leaps are so crucial to the act of discovery in physics (as opposed to other disciplines) will be offered.

  9. Arterial Pressure Analog.

    ERIC Educational Resources Information Center

    Heusner, A. A.; Tracy, M. L.

    1980-01-01

    Describes a simple hydraulic analog which allows students to explore some physical aspects of the cardiovascular system and provides them with a means to visualize and conceptualize these basic principles. Simulates the behavior of arterial pressure in response to changes in heart rate, stroke volume, arterial compliance, and peripheral…

  10. C-Glycosyl Analogs of Oligosaccharides

    NASA Astrophysics Data System (ADS)

    Vauzeilles, Boris; Urban, Dominique; Doisneau, Gilles; Beau, Jean-Marie

    This chapter covers the synthesis of a large collection of "C-oligosaccharides ", synthetic analogs of naturally occurring oligosaccharides in which a carbon atom replaces the anomeric, interglycosidic oxygen atom. These non-natural constructs are stable to chemical and enzymatic degradation, and are primarily devised to probe carbohydrate-based biological processes. These mainly target carbohydrate-protein interactions such as the modulation of glycoenzyme (glycosylhydrolases and transferases) activities or the design of ligands for lectin Carbohydrate Recognition Domains. The discussion is based on the key carbon-carbon bond assembling steps on carbohydrate templates: ionic (anionic and cationic chemistries, sigmatropic rearrangements) or radical assemblage, and olefin metathesis. Synthetic schemes in which at least one of the monosaccharide units is constructed by total synthesis or by cyclization of acyclic chiral chains are presented separately in a "partial de novo synthesis" section. The review also provides comments, when they are known, on the conformational and binding properties of these synthetic analogs, as well as their biological behavior when tested.

  11. Some non-anomerically C-C-linked carbohydrate amino acids related to leucine-synthesis and structure determination.

    PubMed

    Steiner, Bohumil; Micová, Júlia; Koós, Miroslav; Langer, Vratislav; Gyepesová, Dalma

    2003-06-23

    (5'R)-5'-Isobutyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-L-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was synthesised starting from methyl 2,3-O-isopropylidene-alpha-D-lyxo-pentodialdo-1,4-furanoside via methyl 6-deoxy-6-isopropyl-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosid-5-ulose applying the Bucherer-Bergs reaction. Its 5'-R configuration was confirmed by X-ray crystallography. Corresponding alpha-amino acid-methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-6-isopropyl-alpha-D-lyxo-hexofuranoside (alternative name: 2-[methyl (4R)-beta-L-erythrofuranosid-4-C-yl]-D-leucine) was obtained from the above hydantoin by acid hydrolysis of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Analogous derivatives with 5S configuration, formed in a minority, were also isolated and characterised. PMID:12801708

  12. Terrestrial Spaceflight Analogs: Antarctica

    NASA Technical Reports Server (NTRS)

    Crucian, Brian

    2013-01-01

    Alterations in immune cell distribution and function, circadian misalignment, stress and latent viral reactivation appear to persist during Antarctic winterover at Concordia Station. Some of these changes are similar to those observed in Astronauts, either during or immediately following spaceflight. Others are unique to the Concordia analog. Based on some initial immune data and environmental conditions, Concordia winterover may be an appropriate analog for some flight-associated immune system changes and mission stress effects. An ongoing smaller control study at Neumayer III will address the influence of the hypoxic variable. Changes were observed in the peripheral blood leukocyte distribution consistent with immune mobilization, and similar to those observed during spaceflight. Alterations in cytokine production profiles were observed during winterover that are distinct from those observed during spaceflight, but potentially consistent with those observed during persistent hypobaric hypoxia. The reactivation of latent herpesviruses was observed during overwinter/isolation, that is consistently associated with dysregulation in immune function.

  13. Analogy Construction versus Analogy Solution, and Their Influence on Transfer

    ERIC Educational Resources Information Center

    Harpaz-Itay, Yifat; Kaniel, Shlomo; Ben-Amram, Einat

    2006-01-01

    This study compares transfer performed by subjects trained to solve verbal analogies, with transfer by subjects trained to construct them. The first group (n = 57) received instruction in a strategy to solve verbal analogies and the second group (n = 66) was trained in strategies for constructing such analogies. Before and after intervention, all…

  14. Analog storage integrated circuit

    DOEpatents

    Walker, J.T.; Larsen, R.S.; Shapiro, S.L.

    1989-03-07

    A high speed data storage array is defined utilizing a unique cell design for high speed sampling of a rapidly changing signal. Each cell of the array includes two input gates between the signal input and a storage capacitor. The gates are controlled by a high speed row clock and low speed column clock so that the instantaneous analog value of the signal is only sampled and stored by each cell on coincidence of the two clocks. 6 figs.

  15. Antarctic analogs for Enceladus

    NASA Astrophysics Data System (ADS)

    Murray, A. E.; Andersen, D. T.; McKay, C. P.

    2014-12-01

    Enceladus is a new world for Astrobiology. The Cassini discovery of the icy plume emanating from the South Polar region indicates an active world, where detection of water, organics, sodium, and nano-particle silica in the plume strongly suggests that the source is a subsurface salty ocean reservoir. Recent gravity data from Cassini confirms the presence of a regional sea extending north to 50°S. An ocean habitat under a thick ice cover is perhaps a recurring theme in the Outer Solar System, but what makes Enceladus unique is that the plume jetting out into space is carrying samples of this ocean. Therefore, through the study of Enceladus' plumes we can gain new insights not only of a possible habitable world in the Solar Systems, but also about the formation and evolution of other icy-satellites. Cassini has been able to fly through this plume - effectively sampling the ocean. It is time to plan for future missions that do more detailed analyses, possibly return samples back to Earth and search for evidence of life. To help prepare for such missions, the need for earth-based analog environments is essential for logistical, methodological (life detection) and theoretical development. We have undertaken studies of two terrestrial environments that are close analogs to Enceladus' ocean: Lake Vida and Lake Untersee - two ice-sealed Antarctic lakes that represent physical, chemical and possibly biological analogs for Enceladus. By studying the diverse biology and physical and chemical constraints to life in these two unique lakes we will begin to understand the potential habitability of Enceladus and other icy moons, including possible sources of nutrients and energy, which together with liquid water are the key ingredients for life. Analog research such as this will also enable us to develop and test new strategies to search for evidence of life on Enceladus.

  16. Analog storage integrated circuit

    DOEpatents

    Walker, J. T.; Larsen, R. S.; Shapiro, S. L.

    1989-01-01

    A high speed data storage array is defined utilizing a unique cell design for high speed sampling of a rapidly changing signal. Each cell of the array includes two input gates between the signal input and a storage capacitor. The gates are controlled by a high speed row clock and low speed column clock so that the instantaneous analog value of the signal is only sampled and stored by each cell on coincidence of the two clocks.

  17. A Transiting Jupiter Analog

    NASA Astrophysics Data System (ADS)

    Kipping, D. M.; Torres, G.; Henze, C.; Teachey, A.; Isaacson, H.; Petigura, E.; Marcy, G. W.; Buchhave, L. A.; Chen, J.; Bryson, S. T.; Sandford, E.

    2016-04-01

    Decadal-long radial velocity surveys have recently started to discover analogs to the most influential planet of our solar system, Jupiter. Detecting and characterizing these worlds is expected to shape our understanding of our uniqueness in the cosmos. Despite the great successes of recent transit surveys, Jupiter analogs represent a terra incognita, owing to the strong intrinsic bias of this method against long orbital periods. We here report on the first validated transiting Jupiter analog, Kepler-167e (KOI-490.02), discovered using Kepler archival photometry orbiting the K4-dwarf KIC-3239945. With a radius of (0.91+/- 0.02) {R}{{J}}, a low orbital eccentricity ({0.06}-0.04+0.10), and an equilibrium temperature of (131+/- 3) K, Kepler-167e bears many of the basic hallmarks of Jupiter. Kepler-167e is accompanied by three Super-Earths on compact orbits, which we also validate, leaving a large cavity of transiting worlds around the habitable-zone. With two transits and continuous photometric coverage, we are able to uniquely and precisely measure the orbital period of this post snow-line planet (1071.2323 ± 0.0006d), paving the way for follow-up of this K = 11.8 mag target.

  18. Experiments on the evolution of digital to analog converters

    NASA Technical Reports Server (NTRS)

    Zebulum, R. S.; Stoica, A.; Keymeulen, D.

    2001-01-01

    Currently, there is a research effort in Evolvable Hardware being driven towards two purposes: the synthesis of circuits of medium to high complexity; and the design of reconfigurable architectures that facilitate the system evolvability and on-chip implementation of the evolved circuits. This work addresses these issues by describing the evolution of Digital to Analog Converters (DACs).

  19. Neural Analog Information Processing

    NASA Astrophysics Data System (ADS)

    Hecht-Nielsen, Robert

    1982-07-01

    Neural Analog Information Processing (NAIP) is an effort to develop general purpose pattern classification architectures based upon biological information processing principles. This paper gives an overview of NAIP and its relationship to the previous work in neural modeling from which its fundamental principles are derived. It also presents a theorem concerning the stability of response of a slab (a two dimensional array of identical simple processing units) to time-invariant (spatial) patterns. An experiment (via computer emulation) demonstrating classification of a spatial pattern by a simple, but complete NAIP architecture is described. A concept for hardware implementation of NAIP architectures is briefly discussed.

  20. Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of d-Gulose, 6-Deoxy-d-gulose, l-Glucose, 6-Deoxy-l-glucose, and Related Sugars.

    PubMed

    Liu, Zilei; Yoshihara, Akihide; Jenkinson, Sarah F; Wormald, Mark R; Estévez, Ramón J; Fleet, George W J; Izumori, Ken

    2016-08-19

    Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l-gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d-guloheptitol available in two steps is an ideal entry point for the study of the biotechnological production of heptoses. PMID:27487167

  1. Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells.

    PubMed

    Qin, Hua-Li; Leng, Jing; Zhang, Cheng-Pan; Jantan, Ibrahim; Amjad, Muhammad Wahab; Sher, Muhammad; Naeem-Ul-Hassan, Muhammad; Hussain, Muhammad Ajaz; Bukhari, Syed Nasir Abbas

    2016-04-14

    Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure-activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC50 value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF(V600E), EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF(V600E) inhibitory activity with an IC50 value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC50 of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents. PMID:27010345

  2. 1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities.

    PubMed

    Shaikh, Qurat-Ul-Ain; Yang, Meiting; Memon, Khadim Hussain; Lateef, Mehreen; Na, Du; Wan, Shengbiao; Eric, Deslandes; Zhang, Lijuan; Jiang, Tao

    2016-07-22

    1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) 12 has been reported for its antioxidant activities, where the free OH groups in PGG seem to be critical for activities. To explore PGG-based compounds as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. Compound 12 (PGG) had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61 µM and 3.02 µM, respectively. In contrast, the compound 16 (1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,β-D-glucopyranose, PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76 µM and 3.65 µM, respectively, indicating the mutual contribution of m-methoxy and p-hydroxy groups to the observed cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to saturated 2-C side chain enhance the cytotoxicities in all four cell lines. Compounds also possess good anti-oxidant and reducing activities. Compound 12 and 26 show the highest antioxidant and reducing activities. PMID:27196315

  3. Antarctic Space Analog Program

    NASA Technical Reports Server (NTRS)

    Palinkas, Lawrence A; Gunderson, E. K. Eric; Johnson, Jeffrey C.; Holland, Albert W.

    1998-01-01

    The primary aim of this project was to examine group dynamics and individual performance in extreme, isolated environments and identify human factors requirements for long-duration space missions using data collected in an analog environment. Specifically, we wished to determine: 1) the characteristics of social relations in small groups of individuals living and working together in extreme, isolated environments, and 2) the environmental, social and psychological determinants of performance effectiveness in such groups. These two issues were examined in six interrelated studies using data collected in small, isolated research stations in Antarctica from 1963 to the present. Results from these six studies indicated that behavior and performance on long-duration space flights is likely to be seasonal or cyclical, situational, social, and salutogenic in nature. The project responded to two NASA program emphases for FY 1997 as described in the NRA: 1) the primary emphasis of the Behavior and Performance Program on determining long-term individual and group performance responses to space, identifying critical factors affecting those responses and understanding underlying mechanisms involved in behavior and performance, and developing and using ground-based models and analogs for studying space-related behavior and performance; and 2) the emphasis of the Data Analysis Program on extended data analysis. Results from the study were used to develop recommendations for the design and development of pre-flight crew training and in-flight psychological countermeasures for long-duration manned space missions.

  4. Vorticity in analog gravity

    NASA Astrophysics Data System (ADS)

    Cropp, Bethan; Liberati, Stefano; Turcati, Rodrigo

    2016-06-01

    In the analog gravity framework, the acoustic disturbances in a moving fluid can be described by an equation of motion identical to a relativistic scalar massless field propagating in curved space-time. This description is possible only when the fluid under consideration is barotropic, inviscid, and irrotational. In this case, the propagation of the perturbations is governed by an acoustic metric that depends algebrically on the local speed of sound, density, and the background flow velocity, the latter assumed to be vorticity-free. In this work we provide a straightforward extension in order to go beyond the irrotational constraint. Using a charged—relativistic and nonrelativistic—Bose–Einstein condensate as a physical system, we show that in the low-momentum limit and performing the eikonal approximation we can derive a d’Alembertian equation of motion for the charged phonons where the emergent acoustic metric depends on flow velocity in the presence of vorticity.

  5. Analog and digital signal processing

    NASA Astrophysics Data System (ADS)

    Baher, H.

    The techniques of signal processing in both the analog and digital domains are addressed in a fashion suitable for undergraduate courses in modern electrical engineering. The topics considered include: spectral analysis of continuous and discrete signals, analysis of continuous and discrete systems and networks using transform methods, design of analog and digital filters, digitization of analog signals, power spectrum estimation of stochastic signals, FFT algorithms, finite word-length effects in digital signal processes, linear estimation, and adaptive filtering.

  6. Spaceflight Sensorimotor Analogs: Simulating Acute and Adaptive Effects

    NASA Technical Reports Server (NTRS)

    Taylor, Laura C.; Harm, Deborah L.; Kozlovskaya, Inessa; Reschke, Millard F.; Wood, Scott J.

    2009-01-01

    Adaptive changes in sensorimotor function during spaceflight are reflected by spatial disorientation, motion sickness, gaze destabilization and decrements in balance, locomotion and eye-hand coordination that occur during and following transitions between different gravitational states. The purpose of this study was to conduct a meta-synthesis of data from spaceflight analogs to evaluate their effectiveness in simulating adaptive changes in sensorimotor function. METHODS. The analogs under review were categorized as either acute analogs used to simulate performance decrements accompanied with transient changes, or adaptive analogs used to drive sensorimotor learning to altered sensory feedback. The effectiveness of each analog was evaluated in terms of mechanisms of action, magnitude and time course of observed deficits compared to spaceflight data, and the effects of amplitude and exposure duration. RESULTS. Parabolic flight has been used extensively to examine effects of acute variation in gravitational loads, ranging from hypergravity to microgravity. More recently, galvanic vestibular stimulation has been used to elicit acute postural, locomotor and gaze dysfunction by disrupting vestibular afferents. Patient populations, e.g., with bilateral vestibular loss or cerebellar dysfunction, have been proposed to model acute sensorimotor dysfunction. Early research sponsored by NASA involved living onboard rotating rooms, which appeared to approximate the time course of adaptation and post-exposure recovery observed in astronauts following spaceflight. Exposure to different bed-rest paradigms (6 deg head down, dry immersion) result in similar motor deficits to that observed following spaceflight. Shorter adaptive analogs have incorporated virtual reality environments, visual distortion paradigms, exposure to conflicting tilt-translation cues, and exposure to 3Gx centrifugation. As with spaceflight, there is considerable variability in responses to most of the analogs

  7. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001) analogs: Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

    PubMed Central

    Bruno, Robert D.; Vasaitis, Tadas S.; Gediya, Lalji K.; Purushottamachar, Puranik; Godbole, Abhijit M.; Ates-Alagoz, Zeynep; Brodie, Angela M. H.; Njar, Vincent C. O.

    2011-01-01

    In a continuing study of our clinical candidate 5 (VN/124-1 or TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ~2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer. PMID:21729712

  8. Conformationally restricted analog and biotin-labeled probe based on beauveriolide III.

    PubMed

    Doi, Takayuki; Muraoka, Terushige; Ohshiro, Taichi; Matsuda, Daisuke; Yoshida, Masahito; Takahashi, Takashi; Omura, Satoshi; Tomoda, Hiroshi

    2012-01-01

    A conformationally restricted oxazoline analog 7 was designed on the basis of a SAR study of beauveriolide III (2) and its analogs reported previously. Conformational analysis by molecular mechanics calculation suggested that the three side chains of 7 mostly occupy the same spaces as those of 2. The analog 7 was synthesized by peptide coupling of the d-cyclohexylglycine-containing ester 11 and d-Ser-containing dipeptide 12, macrolactamization, and cyclodehydration of 6 for the construction of an oxazoline ring. The bicyclic 7 exhibited potential inhibitory activity for cholesteryl ester synthesis similar to that by 2. These results revealed biologically important 3D spaces of the three side chains in inhibitory activity for cholesteryl ester synthesis. In addition, we accomplished the synthesis of a biotin-labeled probe 8 by copper-catalyzed (3+2) cycloaddition of a biotin-containing alkyne 16 and azido-containing beauveriolide analog 15 prepared from 6. PMID:22079027

  9. Natural analog studies: Licensing perspective

    SciTech Connect

    Bradbury, J.W.

    1995-09-01

    This report describes the licensing perspective of the term {open_quotes}natural analog studies{close_quotes} as used in CFR Part 60. It describes the misunderstandings related to its definition which has become evident during discussions at the U.S Nuclear Regulatory Commission meetings and tries to clarify the appropriate applications of natural analog studies to aspects of repository site characterization.

  10. Pictorial Analogies XII: Stoichiometric Calculations.

    ERIC Educational Resources Information Center

    Fortman, John J.

    1994-01-01

    Pictorial analogies that demonstrate concepts of amounts allow instructors to teach that in stoichiometric problems, the number--or moles--of molecules of a chemical is what matters, even though it must be measured in masses or volumes. Analogies to stoichiometric relationships include the ratio of four wheels to one body in making wagons and…

  11. Isolated transfer of analog signals

    NASA Technical Reports Server (NTRS)

    Bezdek, T.

    1974-01-01

    Technique transfers analog signal levels across high isolation boundary without circuit performance being affected by magnetizing reactance or leakage inductance. Transfers of analog information across isolated boundary are made by interrupting signal flow, with switch, in such a manner as to produce alternating signal which is applied to transformer.

  12. Conjecturing via Reconceived Classical Analogy

    ERIC Educational Resources Information Center

    Lee, Kyeong-Hwa; Sriraman, Bharath

    2011-01-01

    Analogical reasoning is believed to be an efficient means of problem solving and construction of knowledge during the search for and the analysis of new mathematical objects. However, there is growing concern that despite everyday usage, learners are unable to transfer analogical reasoning to learning situations. This study aims at facilitating…

  13. Drawing Analogies in Environmental Education

    ERIC Educational Resources Information Center

    Affifi, Ramsey

    2014-01-01

    Reconsidering the origin, process, and outcomes of analogy-making suggests practices for environmental educators who strive to disengage humans from the isolating illusions of dichotomizing frameworks. We can view analogies as outcomes of developmental processes within which human subjectivity is but an element, threading our sense of self back…

  14. High-pressure synthesis, crystal structure, and electromagnetic properties of CdRh2O4: an analogous oxide of the postspinel mineral MgAl2O4.

    PubMed

    Wang, Xia; Guo, Yanfeng; Shi, Youguo; Belik, Alexei A; Tsujimoto, Yoshihiro; Yi, Wei; Sun, Ying; Shirako, Yuichi; Arai, Masao; Akaogi, Masaki; Matsushita, Yoshitaka; Yamaura, Kazunari

    2012-06-18

    The postspinel mineral MgAl(2)O(4) exists only under the severe pressure conditions in the subducted oceanic lithosphere in the Earth's deep interior. Here we report that its analogous oxide CdRh(2)O(4) exhibits a structural transition to a quenchable postspinel phase under a high pressure of 6 GPa at 1400 °C, which is within the general pressure range of a conventional single-stage multianvil system. In addition, the complex magnetic contributions to the lattice and metal nonstoichiometry that often complicate investigations of other analogues of MgAl(2)O(4) are absent in CdRh(2)O(4). X-ray crystallography revealed that this postspinel phase has an orthorhombic CaFe(2)O(4) structure, thus making it a practical analogue for investigations into the geophysical role of postspinel MgAl(2)O(4). Replacement of Mg(2+) with Cd(2+) appears to be effective in lowering the pressure required for transition, as was suggested for CdGeO(3). In addition, Rh(3+) could also contribute to this reduction, as many analogous Rh oxides of aluminous and silicic minerals have been quenched from lower-pressure conditions. PMID:22663173

  15. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2′,2′-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

    PubMed Central

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-01-01

    In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were two-fold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  16. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    PubMed

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  17. INTERSTELLAR ANALOGS FROM DEFECTIVE CARBON NANOSTRUCTURES ACCOUNT FOR INTERSTELLAR EXTINCTION

    SciTech Connect

    Tan, Zhenquan; Abe, Hiroya; Sato, Kazuyoshi; Ohara, Satoshi; Chihara, Hiroki; Koike, Chiyoe; Kaneko, Kenji

    2010-11-15

    Because interstellar dust is closely related to the evolution of matter in the galactic environment and many other astrophysical phenomena, the laboratory synthesis of interstellar dust analogs has received significant attention over the past decade. To simulate the ultraviolet (UV) interstellar extinction feature at 217.5 nm originating from carbonaceous interstellar dust, many reports focused on the UV absorption properties of laboratory-synthesized interstellar dust analogs. However, no general relation has been established between UV interstellar extinction and artificial interstellar dust analogs. Here, we show that defective carbon nanostructures prepared by high-energy collisions exhibit a UV absorption feature at 220 nm which we suggest accounts for the UV interstellar extinction at 217.5 nm. The morphology of some carbon nanostructures is similar to that of nanocarbons discovered in the Allende meteorite. The similarity between the absorption feature of the defective carbon nanostructures and UV interstellar extinction indicates a strong correlation between the defective carbon nanostructures and interstellar dust.

  18. Simple analogs of the toxin callicarpone.

    PubMed

    McChesney, J D; Kabra, P M; Fraher, P

    1979-09-01

    Callicarpone, a component 10 times as toxic to fish as rotenone, has been isolated from the leaves of Callicarpa candicans. It is reasonable to assume that callicarpone will act as an insecticidal agent as does rotenone. Therefore, the structure-activity relationship of callicarpone was examined by synthesizing a series of compounds having certain of its structural features. Those compounds were tested for insecticidal and antimicrobial activities. A study of synthetic analogs elucidated the functional group chemistry of callicarpone so that a synthesis might be undertaken. Piperitone oxide showed approximately 1/100th the activity of rotenone against Daphnia magna. 1-(alpha-Hydroxyisopropyl)-3-oxocyclohexene oxide showed activity against myobacterium while 2,3,4,6,7,8-hexahydronaphthalene-1,4-dione showed inhibitory activity against the mycobacterium and two yeasts. PMID:501532

  19. One-pot synthesis of 1,4-dihydroxy-2-((E)-1-hydroxy-4-phenylbut-3-enyl)anthracene-9,10-diones as novel shikonin analogs and evaluation of their antiproliferative activities.

    PubMed

    Zhao, Li-Ming; Cao, Feng-Xia; Jin, Hai-Shan; Zhang, Jie-Huan; Szwaya, Jeffrey; Wang, Guangdi

    2016-06-01

    A series of shikonin analogs have been synthesized in a one-pot reaction of quinizarin with β,γ-unsaturated aldehydes in MeOH under mild conditions and investigated for their cytotoxicity against four cancer cell lines and one normal cell line. The synthesized compounds were found to be cytotoxic against HeLa cells with no apparent toxicity against normal cell line. Further modification led to the discovery of a novel tetracyclic anthraquinone (4b/4b') with potent cytotoxic activities against cervical, breast and pancreatic cancer cell lines with no significant effect on the growth of the control mammary epithelial cell line MCF-10. The good cytotoxicity and selectivity of compound 4b/4b' suggest that it could be a promising lead for further optimization. PMID:27080175

  20. Synthesis of small interfering RNAs containing acetal-type nucleoside analogs at their 3'-ends and analysis of their silencing activity and their ability to bind to the Argonaute2 PAZ domain.

    PubMed

    Inada, Natsumi; Nakamoto, Kosuke; Yokogawa, Takashi; Ueno, Yoshihito

    2015-10-20

    In this study, we aimed to create small interfering RNAs (siRNAs) with increased silencing activities and nuclease resistance properties. Therefore, we designed and synthesized five types of siRNA containing acetal-type nucleoside analogs at their 3'-dangling ends. We found that the siRNA containing 1-O-(2,2,2-trifluoroethyl)-β-D-ribofuranose at the 3'-dangling end was the most potent among the synthesized siRNAs and showed more resistance to nucleolytic degradation by a 3' exonuclease than a natural RNA did. Thus, modification of siRNAs by addition of 1-O-(2,2,2-trifluoroethyl)-β-D-ribofuranose may hold promise as a means of improving the silencing activity and nuclease resistance of siRNAs. PMID:26397394

  1. Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats.

    PubMed

    Zhu, Heping; Xu, Tingting; Qiu, Chenyu; Wu, Beibei; Zhang, Yali; Chen, Lingfeng; Xia, Qinqin; Li, Chenglong; Zhou, Bin; Liu, Zhiguo; Liang, Guang

    2016-10-01

    A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-α and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI). PMID:27240273

  2. Flight Analogs (Bed Rest Research)

    NASA Video Gallery

    Flight Analogs / Bed Rest Research Projects provide NASA with a ground based research platform to complement space research. By mimicking the conditions of weightlessness in the human body here on ...

  3. Solving a problem by analogy

    NASA Astrophysics Data System (ADS)

    Easton, Don

    1999-03-01

    This note is a description of a student solution to a problem. I found the solution exciting because it exemplifies the kind of solution by analogy that Feynman describes in The Feynman Lectures on Physics.

  4. Evaluating countermeasures in spaceflight analogs.

    PubMed

    Ploutz-Snyder, Lori

    2016-04-15

    Countermeasures are defined as solutions to prevent the undesirable physiologic outcomes associated with spaceflight. Spaceflight analogs provide a valuable opportunity for the evaluation of countermeasures because they allow for the evaluation of more subjects, more experimental control, and are considerably less expensive than actual spaceflight. The various human analogs have differing strengths and weaknesses with respect to the development and evaluation of countermeasures. The human analogs are briefly reviewed with a focus on their suitability for countermeasure evaluation. Bed rest is the most commonly used analog for evaluating countermeasures. While countermeasures are typically developed to target one or maybe two particular physiologic issues, it is increasingly important to evaluate all of the organ systems to discern whether they might be unintended consequences on nontargeted tissues. In preparation for Mars exploration it will be necessary to fully integrate countermeasures to protect all organ systems. The synergistic and antagonistic effects of multiple countermeasures needs to be the focus of future work. PMID:26662054

  5. Introduction to Analog Field Testing

    NASA Video Gallery

    NASA tests systems and operational concepts in analog environments, which include locations underwater, in the arctic, on terrestrial impact craters, in the desert, and on the International Space S...

  6. An approach towards azafuranomycin analogs by gold-catalyzed cycloisomerization of allenes: synthesis of (αS,2R)-(2,5-dihydro-1H-pyrrol-2-yl)glycine

    PubMed Central

    Erdsack, Jörg

    2013-01-01

    Summary The synthesis of (αS,2R)-(2,5-dihydro-1H-pyrrol-2-yl)glycine (22, normethylazafuranomycin) by the gold-catalyzed cycloisomerization of α-aminoallene 17 is described. The target molecule was synthesized in 13 linear steps from Cbz-protected Garner aldehyde (R)-2 in an overall yield of 2.4%. The approach was first examined in model studies, which afforded the alkylated azafuranomycin derivative 13a in 2.9% yield over 12 steps. PMID:24204404

  7. The Robustness of Acoustic Analogies

    NASA Technical Reports Server (NTRS)

    Freund, J. B.; Lele, S. K.; Wei, M.

    2004-01-01

    Acoustic analogies for the prediction of flow noise are exact rearrangements of the flow equations N(right arrow q) = 0 into a nominal sound source S(right arrow q) and sound propagation operator L such that L(right arrow q) = S(right arrow q). In practice, the sound source is typically modeled and the propagation operator inverted to make predictions. Since the rearrangement is exact, any sufficiently accurate model of the source will yield the correct sound, so other factors must determine the merits of any particular formulation. Using data from a two-dimensional mixing layer direct numerical simulation (DNS), we evaluate the robustness of two analogy formulations to different errors intentionally introduced into the source. The motivation is that since S can not be perfectly modeled, analogies that are less sensitive to errors in S are preferable. Our assessment is made within the framework of Goldstein's generalized acoustic analogy, in which different choices of a base flow used in constructing L give different sources S and thus different analogies. A uniform base flow yields a Lighthill-like analogy, which we evaluate against a formulation in which the base flow is the actual mean flow of the DNS. The more complex mean flow formulation is found to be significantly more robust to errors in the energetic turbulent fluctuations, but its advantage is less pronounced when errors are made in the smaller scales.

  8. Producing and recognizing analogical relations.

    PubMed

    Lipkens, Regina; Hayes, Steven C

    2009-01-01

    Analogical reasoning is an important component of intelligent behavior, and a key test of any approach to human language and cognition. Only a limited amount of empirical work has been conducted from a behavior analytic point of view, most of that within Relational Frame Theory (RFT), which views analogy as a matter of deriving relations among relations. The present series of four studies expands previous work by exploring the applicability of this model of analogy to topography-based rather than merely selection-based responses and by extending the work into additional relations, including nonsymmetrical ones. In each of the four studies participants pretrained in contextual control over nonarbitrary stimulus relations of sameness and opposition, or of sameness, smaller than, and larger than, learned arbitrary stimulus relations in the presence of these relational cues and derived analogies involving directly trained relations and derived relations of mutual and combinatorial entailment, measured using a variety of productive and selection-based measures. In Experiment 1 participants successfully recognized analogies among stimulus networks containing same and opposite relations; in Experiment 2 analogy was successfully used to extend derived relations to pairs of novel stimuli; in Experiment 3 the procedure used in Experiment 1 was extended to nonsymmetrical comparative relations; in Experiment 4 the procedure used in Experiment 2 was extended to nonsymmetrical comparative relations. Although not every participant showed the effects predicted, overall the procedures occasioned relational responses consistent with an RFT account that have not yet been demonstrated in a behavior-analytic laboratory setting, including productive responding on the basis of analogies. PMID:19230515

  9. Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol : Synthesis, biological characterization, and development of a pharmacophore model

    PubMed Central

    Sharma, Horrick; Santra, Soumava; Debnath, Joy; Antonio, Tamara; Reith, Maarten; Dutta, Aloke

    2014-01-01

    In this study we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The model revealed features important for inhibitors to exhibit a balanced activity against dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In particular, a ‘folded’ conformation was found common to the active pyran compounds in the training set and was crucial to triple uptake inhibitory activity. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. The present work has also resulted in the discovery of a new series of asymmetric tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and 42 exhibited moderate TUI activity. Interestingly, the highest TUI activity by lead tetrahydrofuran compounds e.g. 41 and 42, was exhibited in a stereochemical preference similar to pyran TUI e.g. D-161. PMID:24315194

  10. Synthesis, crystal structures and spectral characterization of imidazo[1,2-a]pyrimidin-2-yl-acetic acid and related analog with imidazo[2,1-b]thiazole ring

    NASA Astrophysics Data System (ADS)

    Dylong, Agnieszka; Goldeman, Waldemar; Sowa, Michał; Ślepokura, Katarzyna; Drożdżewski, Piotr; Matczak-Jon, Ewa

    2016-08-01

    Imidazo[1,2-a]pyrimidin-2-yl-acetic acid (HIPM-2-ac) and its analog with imidazo[2,1-b]thiazole ring (HITZ-6-ac) were synthesized and structurally characterized by single-crystal X-ray diffraction corroborated with calculations of Hirshfeld surfaces, which provided detailed insight into intermolecular interactions constituting both crystals. The IR and Raman spectra of HIPM-2-ac and HITZ-6-ac were recorded and interpreted in details with the aid of Density Functional Theory (DFT) calculations and Potential Energy Distribution (PED) analysis of computed normal vibrations. Special attention was paid on hydroxyl and methylene groups involved in hydrogen bonds, which vibrations were monitored by H/D substitution. Recrystallization of parent compounds from deuterium oxide (D2O) solutions resulted in deuteration of their carboxylic OH groups and almost complete deuteration of HIPM-2-ac methylene group. The latter phenomenon is clearly reflected in the vibrational spectra and confirmed by 1H NMR experiments in solution.

  11. Synthesis, Structure, and Properties of a Mixed-Valent Triiron Complex of Tetramethyl Reductic Acid, an Ascorbic Acid Analog, and its Relationship to a Functional Non-Heme Iron Oxidation Catalyst System

    PubMed Central

    Kim, YooJin; Feng, Xudong; Lippard, Stephen J.

    2011-01-01

    The purple triiron(II,III,III) complex, [Fe3Cl2(TMRASQ)4(HTMRA)2]·C5H12 (1·C5H12), where H2(TMRA) is tetramethyl reductic acid, 4,4,5,5-tetramethyl-2,3-dihydroxy-2-cyclopenten-1-one, and H(TMRASQ) is the semiquinone form of this ligand, was prepared from (Et4N)2[Fe2OCl6] and H2(TMRA) and characterized by X-ray crystallography, Mössbauer spectroscopy, and redox titrations. The physical properties of the complex in solution are consistent with its mixed-valent character, as delineated by a solid-state structure analysis. Assignments of the iron and ligand oxidation states in the crystal were made on the basis of a valence bond sum analysis and the internal ligand geometry. As the first well-characterized iron complex of an ascorbic acid H2(AA) analog, 1 provides insight into the possible coordination geometry of the family of complexes containing H2AA and its analogues. In the presence of air and H2TMRA, 1 is able to catalyze the oxidation of cyclohexane to cyclohexanol with remarkable selectivity, but the nature of the true catalyst remains unknown. PMID:17579400

  12. A facile, regioselective synthesis of novel 3-(N-phenylcarboxamide)pyrazolo[1,5-a]pyrimidine analogs in the presence of KHSO[Formula: see text] in aqueous media assisted by ultrasound and their antibacterial activities.

    PubMed

    Kaping, Shunan; Boiss, Ivee; Singha, Laishram Indira; Helissey, Philippe; Vishwakarma, Jai N

    2016-05-01

    An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method. PMID:26511367

  13. Biomimetic Analogs for Collagen Biomineralization

    PubMed Central

    Gu, L.; Kim, Y.K.; Liu, Y.; Ryou, H.; Wimmer, C.E.; Dai, L.; Arola, D.D.; Looney, S.W.; Pashley, D.H.; Tay, F.R.

    2011-01-01

    Inability of chemical phosphorylation of sodium trimetaphosphate to induce intrafibrillar mineralization of type I collagen may be due to the failure to incorporate a biomimetic analog to stabilize amorphous calcium phosphates (ACP) as nanoprecursors. This study investigated adsorption/desorption characteristics of hydrolyzed and pH-adjusted sodium trimetaphosphate (HPA-Na3P3O9) to collagen. Based on those results, a 5-minute treatment time with 2.8 wt% HPA-Na3P3O9 was used in a single-layer reconstituted collagen model to confirm that both the ACP-stabilization analog and matrix phosphoprotein analog must be present for intrafibrillar mineralization. The results of that model were further validated by complete remineralization of phosphoric-acid-etched dentin treated with the matrix phosphoprotein analog and lined with a remineralizing lining composite, and with the ACP-stabilization analog supplied in simulated body fluid. An understanding of the basic processes involved in intrafibrillar mineralization of reconstituted collagen fibrils facilitates the design of novel tissue engineering materials for hard tissue repair and regeneration. PMID:20940362

  14. Crows spontaneously exhibit analogical reasoning.

    PubMed

    Smirnova, Anna; Zorina, Zoya; Obozova, Tanya; Wasserman, Edward

    2015-01-19

    Analogical reasoning is vital to advanced cognition and behavioral adaptation. Many theorists deem analogical thinking to be uniquely human and to be foundational to categorization, creative problem solving, and scientific discovery. Comparative psychologists have long been interested in the species generality of analogical reasoning, but they initially found it difficult to obtain empirical support for such thinking in nonhuman animals (for pioneering efforts, see [2, 3]). Researchers have since mustered considerable evidence and argument that relational matching-to-sample (RMTS) effectively captures the essence of analogy, in which the relevant logical arguments are presented visually. In RMTS, choice of test pair BB would be correct if the sample pair were AA, whereas choice of test pair EF would be correct if the sample pair were CD. Critically, no items in the correct test pair physically match items in the sample pair, thus demanding that only relational sameness or differentness is available to support accurate choice responding. Initial evidence suggested that only humans and apes can successfully learn RMTS with pairs of sample and test items; however, monkeys have subsequently done so. Here, we report that crows too exhibit relational matching behavior. Even more importantly, crows spontaneously display relational responding without ever having been trained on RMTS; they had only been trained on identity matching-to-sample (IMTS). Such robust and uninstructed relational matching behavior represents the most convincing evidence yet of analogical reasoning in a nonprimate species, as apes alone have spontaneously exhibited RMTS behavior after only IMTS training. PMID:25532894

  15. All-optical analog comparator.

    PubMed

    Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

    2016-01-01

    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical '1' or '0' by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function. PMID:27550874

  16. All-optical analog comparator

    PubMed Central

    Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai

    2016-01-01

    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function. PMID:27550874

  17. Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease.

    PubMed

    Shaik, Jeelan Basha; Palaka, Bhagath Kumar; Penumala, Mohan; Eadlapalli, Siddhartha; Darla Mark, Manidhar; Ampasala, Dinakara Rao; Vadde, Ramakrishna; Amooru Gangaiah, Damu

    2016-07-01

    Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a-q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1-42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy. PMID:26833890

  18. Synthesis of Novel Chiral Sulfonamide-Bearing 1,2,4-Triazole-3-thione Analogs Derived from D- and L-Phenylalanine Esters as Potential Anti-Influenza Agents.

    PubMed

    Başaran, Eyüp; Karaküçük-Iyidoğan, Ayşegül; Schols, Dominique; Oruç-Emre, Emine Elçin

    2016-06-01

    Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 μM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 μM for and IC50 : 19-23 μM for ). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc. PMID:27225330

  19. Synthesis and characterization of novel N3O3-Schiff base complexes of 99gTc, and in vivo imaging studies with analogous 99mTc complexes.

    PubMed

    Marmion, M E; Woulfe, S R; Newmann, W L; Pilcher, G; Nosco, D L

    1996-07-01

    Sixteen novel derivatives of 1,1,1-tris (salicylaldiminomethyl)ethane have been synthesized for the purpose of encapsulating 99mTc(IV) ions and generating new 99mTc radiopharmaceuticals. Two methods for the preparation of the 99gTc(IV) analog complexes are presented; one utilizes SnCl2 reduction on 99gTcO4- and the other a direct substitution route starting with [99gTcCl6]2-. Free ligands (H3L) are characterized by melting points, 1H NMR, 13C NMR, mass spectroscopy, TLC, and/or elemental analyses. [99gTcL]+ complexes are characterized by FAB-ms, UV-VIS, IR and/or CV. An X-ray structural analysis was performed on a crystal of [M(6,6'-[[2-[[((4-Methoxy-2-hydroxyphenyl) methylene)-amino]methyl]-2-methyl- 1,3-propanediyl]bis(nitrilomethylidyne)]-bis-3-methoxyphenol )] tetraphenylborate, where M represents a 1/3 isomorphous mixture of 99gTc/Sn as determined by SEM. The metal coordination site is 6-coordinate, composed of N3O3 donor atoms, and intermediate between octahedral and trigonal prismatic geometry. The [99mTcL]+ complexes were prepared in a stannous environment; equivalence of the 99mTc and 99gTc complexes is demonstrated by HPLC techniques. The [SnL]+ complex was prepared for comparison purposes. An unusual ligand oxidation occurs for one series of ligands in which in situ amine-->imine conversion is observed during the complexation reaction in reducing media. Guinea pig, rat, dog, and human metabolism studies are reported for selected [99mTcL]+ complexes, the myocardial uptake of which approaches 2% of the injected dose. PMID:8905821

  20. Digital plus analog output encoder

    NASA Technical Reports Server (NTRS)

    Hafle, R. S. (Inventor)

    1976-01-01

    The disclosed encoder is adapted to produce both digital and analog output signals corresponding to the angular position of a rotary shaft, or the position of any other movable member. The digital signals comprise a series of binary signals constituting a multidigit code word which defines the angular position of the shaft with a degree of resolution which depends upon the number of digits in the code word. The basic binary signals are produced by photocells actuated by a series of binary tracks on a code disc or member. The analog signals are in the form of a series of ramp signals which are related in length to the least significant bit of the digital code word. The analog signals are derived from sine and cosine tracks on the code disc.

  1. Multilateral Collaborations in Analog Research

    NASA Technical Reports Server (NTRS)

    Cromwell, R. l.

    2016-01-01

    International collaborations in studies utilizing ground-based space flight analogs are an effective means for answering research questions common to participating agencies. These collaborations bring together worldwide experts to solve important space research questions. By collaborating unnecessary duplication of science is reduced, and the efficiency of analog use is improved. These studies also share resources among agencies for cost effective solutions to study implementation. Recently, NASA has engaged in collaborations with international partners at a variety of analog sites. The NASA Human Exploration Research Analog (HERA) is currently hosting investigator studies from NASA and from the German Space Agency (DLR). These isolation studies will answer questions in the areas of team cohesion, sleep and circadian rhythms, and neurobehavioral correlates to function. Planning for the next HERA campaign is underway as proposal selections are being made from the International Life Sciences Research Announcement (ILSRA). Studies selected from the ILSRA will be conducted across 4 HERA missions in 2017. NASA is planning collaborative studies with DLR at the :envihab facility in Cologne, Germany. Investigations were recently selected to study the effects of 0.5% CO2 exposure over 30 days of bed rest. These studies will help to determine the fidelity of this ground-based analog for studying the visual impairment intracranial pressure syndrome. NASA is also planning a multilateral collaboration at :envihab with DLR and the European Space Agency (ESA) to examine artificial gravity as a countermeasure to mitigate the effects of 60 days of bed rest. NASA is also considering collaborations with the Russian Institute for Biomedical Problems (IBMP) in studies that will utilize their Ground-based Experimental Facility (NEK). The NEK is comprised of 4 interconnected modules and a Martian surface simulator. This isolation analog can support 3 -10 crew members for long duration

  2. Microwave assisted synthesis of bis and tris(ω-bromoacetophenones): versatile precursors for novel bis(imidazo[1,2-a]pyridines), bis(imidazo[1,2-a]pyrimidines) and their tris-analogs

    PubMed Central

    2013-01-01

    Background α-Bromination of the side chain of aromatic ketones using NBS in the presence of p-toluenesulfonic acid (p-TsOH) in acetonitrile is very common. However, regioselective bromination of bis and tris(ω-bromoacetophenones) with NBS in the presence of p-TsOH in acetonitrile under microwave irradiation is quite novel. The bis- and tris(ω-bromoacetophenones) are used in synthesis of bis and tris(heterocycles). bis(heterocycles) have received a great deal of attention, because many biologically active natural and synthetic products have molecular symmetry. The use of the pressurized microwave irradiation is very advantageous to many syntheses and provide a large rate enhancement. Results Bis and tris(ω-bromoacetophenones) were obtained as single monobrominated derivatives in a shorter time than the conventional conditions. The results clearly demonstrate the better reactivity and selectivity of NBS/p-TsOH/CH3CN as a brominating mixture under microwave conditions. The reaction of bis and tris(ω-bromoacetophenone) with 2-aminopyridine and 2-aminopyrimidine proceeded smoothly in a mixture of anhydrous ethanol and DMF under reflux or using 300 W/105°C/ 20 min microwave irradiation conditions to afford the corresponding bis(imidazo[1,2-a]pyridine), bis(imidazo[1,2-a]pyrimidine) and tris(imidazo[1,2-a]pyridine) derivatives in moderate to excellent yields. The carbonyl analogue of the targeted bis(imidazopyridines) could be synthesized by the reaction of N,N-dimethyl-N'-(pyridin-2-yl)formimidamide with bis(ω-bromoacetophenone) in refluxing ethanol. The structures of the newly synthesized compounds were confirmed by their spectral data as well as their elemental analyses. Conclusion In conclusion, selective α-bromination of bis- and tris(acetophenones) has been accomplished efficiently utilizing NBS/p-TsOH/CH3CN under microwave irradiation. In addition, a facile synthesis of novel series of bis- and tris(imidazopyridine) and bis(imidazopyrimidine) derivatives

  3. Analog enhancement of radiographic images

    NASA Technical Reports Server (NTRS)

    Baily, N. A.; Nachazel, R. J.

    1976-01-01

    The paper shows how analog methods for edge sharpening, contrast enhancement, and expansion of the range of gray levels of particular interest are effective for easy on-line application to video viewing of X-ray roentgenograms or to fluoroscopy. The technique for analog enhancement of radiographic images is a modified version of the system designed by Fuchs et al. (1972), whereby an all directional second derivative signal called detail signal is used to produce both vertical and horizontal enhancement of the image. Particular attention is given to noise filtration and contrast enhancement. Numerous radiographs supplement the text.

  4. Analog video to ARINC 818

    NASA Astrophysics Data System (ADS)

    Grunwald, Paul

    2015-05-01

    Many commercial and military aircraft still use analog video, such as RS-170, RS-343, or STANEG 3350. Though the individual digital components many be inexpensive, the cost to certify and retrofit an entire aircraft fleet may be prohibitively expensive. A partial or incremental upgrade program where analog cameras remain in use but data is converted and processed digitally can be an attractive option. This paper describes Great River Technology's experience in converting multiple channels of RS-170 and multiplexing them through a concentrator to put them onto a single fiber or cable. The paper will also discuss alternative architectures and how ARINC 818 can be utilized with legacy systems.

  5. Synthesis of variants of Marfey's reagent having d-amino acids as chiral auxiliaries and liquid-chromatographic enantioseparation of (RS)-Mexiletine in spiked plasma: assessment and comparison with L-amino acid analogs.

    PubMed

    Bhushan, Ravi; Vashistha, Vinod Kumar

    2015-01-30

    Five d-amino acids have been used for the first time to synthesize chiral derivatizing reagents (as variants of Marfey's reagent) by nucleophilic displacement of one of the fluorine atoms in 1,5-difluoro-2,4-dinitrobenzene as against the literature reports on application of only l-amino acids or their amides as chiral auxiliaries in dinitrobenzene (DNB) moiety. Five other DNB based reagents were also prepared by nucleophilic substitution of fluorine atom with the set of the same amino acids in l-configuration, as chiral auxiliaries. These reagents were characterized and used for synthesis of diastereomers of (RS)-Mexiletine spiked in human plasma. Diastereomers were synthesized employing microwave irradiation and were separated on reversed-phase C18 column. Performance of the two types of chiral derivatizing reagents was compared. The reagents containing d-amino acids provided enhanced separation of diastereomers than those containing l-amino acids. The best resolution was obtained using mobile phase consisting of acetonitrile and 0.1% trifluoroacetic acid in gradient mode. The detection was carried out at 340nm. The method so developed was validated for linearity, accuracy and precision. The limit of quantitation was found to be approximately 25.2ngmL(-1) in human plasma. PMID:25576038

  6. Optical analogs of model atoms in fields

    SciTech Connect

    Milonni, P.W.

    1991-05-02

    The equivalence of the paraxial wave equation to a time-dependent Schroedinger equation is exploited to construct optical analogs of model atoms in monochromatic fields. The approximation of geometrical optics provides the analog of the corresponding classical mechanics. Optical analogs of Rabi oscillations, photoionization, stabilization, and the Kramers-Henneberger transformation are discussed. One possibility for experimental realization of such optical analogs is proposed. These analogs may be useful for studies of quantum chaos'' when the ray trajectories are chaotic. 9 refs.

  7. Terrestrial analogs for space exploration habitation systems

    NASA Technical Reports Server (NTRS)

    Campbell, Paul D.; Brown, Jeri W.

    1992-01-01

    The Space Exploration Initiative (SEI) can use early earth-based analogs to simulate many aspects of space flight missions and system operation. These analogs can thus provide information supporting future missions to the moon and to Mars. A study was performed to investigate the potential of terrestrial analogs in simulating human space exploration missions. The study resulted in preliminary requirements and concepts for analog habitation systems, and further study in this area is necessary for SEI terrestrial analog development.

  8. Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.

    PubMed

    Gududuru, Veeresa; Zeng, Kui; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Pigg, Kathryn R; Baker, Daniel L; Tigyi, Gabor; Miller, Duane D

    2006-01-15

    Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics. PMID:16290140

  9. Analogies and "Modeling Analogies" in Teaching: Some Examples in Basic Electricity.

    ERIC Educational Resources Information Center

    Dupin, J. J.; Johsua, S.

    1989-01-01

    Investigates the effect of modeling analogy on learning of the concepts of electricity in grade 6, 8, and 10. Describes 2 analogies (train analogy and thermal analogy) with diagrams and examples. Discusses the accessibility, transferability, and difficulty of each analogy. Reports treatment effect and some further implications. (YP)

  10. Mathematical Analogy and Metaphorical Insight

    ERIC Educational Resources Information Center

    Zwicky, Jan

    2010-01-01

    How are we to understand the power of certain literary metaphors? The author argues that the apprehension of good metaphors is importantly similar to the apprehension of fruitful mathematical analogies: both involve a structural realignment of vision. The author then explores consequences of this claim, drawing conceptually significant parallels…

  11. International Alligator Rivers Analog Project

    SciTech Connect

    Bichard, G.F.

    1988-01-01

    The Australian Nuclear Science and Technology Organization (ANSTO), the Japan Atomic Energy Research Institute, the Swedish Nuclear Power Inspectorate, the U.K. Department of the Environment, the US Nuclear Regulatory Commission (NRC), and the Power Reactor and Nuclear Fuel Development Corporation of Japan are participating under the aegis of the Nuclear Energy Agency in the International Alligator Rivers Analog Project. The project has a duration of 3 yr, starting in 1988. The project has grown out of a research program on uranium ore bodies as analogs of high-level waste (HLW) repositories undertaken by ANSTO supported by the NRC. A primary objective of the project is to develop an approach to radionuclide transport model validation that may be used by the participants to support assessments of the safety of radioactive waste repositories. The approach involves integrating mathematical and physical modeling with hydrological and geochemical field and laboratory investigations of the analog site. The Koongarra uranium ore body has been chosen as the analog site because it has a secondary ore body that has formed over the past million years as a result of leaching by groundwater flowing through fractures in the primary ore body.

  12. Analog Simulation of a Laser.

    ERIC Educational Resources Information Center

    Kessler, Gary

    1982-01-01

    Presents an analog simulation of laser properties (finding time evolution of the intensity of a ruby laser pulse) which serves as the basis of a three-four hour laboratory experiment. Includes programs for solution to rate equations of a three-level laser and production of a giant pulse in a ruby laser. (Author/SK)

  13. Understanding & Teaching Genetics Using Analogies

    ERIC Educational Resources Information Center

    Woody, Scott; Himelblau, Ed

    2013-01-01

    We present a collection of analogies that are intended to help students better understand the foreign and often nuanced vocabulary of the genetics curriculum. Why is it called the "wild type"? What is the difference between a locus, a gene, and an allele? What is the functional (versus a rule-based) distinction between dominant and…

  14. Algicidal Activity of Stilbene Analogs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As part of our continuing search for natural product and natural product-based compounds for the control of off-flavor in catfish, a total of twenty nine stilbene analogs were synthesized and evaluated for algicidal activity against the 2-methylisoborneol (MIB)-producing cyanobacterium Oscillatoria ...

  15. Bayesian Analogy with Relational Transformations

    ERIC Educational Resources Information Center

    Lu, Hongjing; Chen, Dawn; Holyoak, Keith J.

    2012-01-01

    How can humans acquire relational representations that enable analogical inference and other forms of high-level reasoning? Using comparative relations as a model domain, we explore the possibility that bottom-up learning mechanisms applied to objects coded as feature vectors can yield representations of relations sufficient to solve analogy…

  16. Analog Input Data Acquisition Software

    NASA Technical Reports Server (NTRS)

    Arens, Ellen

    2009-01-01

    DAQ Master Software allows users to easily set up a system to monitor up to five analog input channels and save the data after acquisition. This program was written in LabVIEW 8.0, and requires the LabVIEW runtime engine 8.0 to run the executable.

  17. Analogy of the Cell Project

    ERIC Educational Resources Information Center

    Science Scope, 2005

    2005-01-01

    In this project, students compare the makeup of a cell to an everyday working unit or system. They create a three-dimensional object that represents their analogy. For example, students could create a car motor or manufacturing plant. (Of course, this is totally hand-created by them, so it can be a homemade re-creation of a system, not an actual…

  18. Multichannel analog temperature sensing system

    NASA Astrophysics Data System (ADS)

    Gribble, R.

    1985-08-01

    A multichannel system that protects the numerous and costly water-cooled magnet coils on the translation section of the FRX-C/T magnetic fusion experiment is described. The system comprises a thermistor for each coil, a constant current circuit for each thermistor, and a multichannel analog-to-digital converter interfaced to the computer.

  19. Geometrical Analogies in Mathematics Lessons

    ERIC Educational Resources Information Center

    Eid, Wolfram

    2007-01-01

    A typical form of thinking to approach problem solutions humanly is thinking in analogous structures. Therefore school, especially mathematical lessons should help to form and to develop corresponding heuristic abilities of the pupils. In the contribution, a summary of possibilities of mathematics lessons regarding this shall particularly be…

  20. Bayesian analogy with relational transformations.

    PubMed

    Lu, Hongjing; Chen, Dawn; Holyoak, Keith J

    2012-07-01

    How can humans acquire relational representations that enable analogical inference and other forms of high-level reasoning? Using comparative relations as a model domain, we explore the possibility that bottom-up learning mechanisms applied to objects coded as feature vectors can yield representations of relations sufficient to solve analogy problems. We introduce Bayesian analogy with relational transformations (BART) and apply the model to the task of learning first-order comparative relations (e.g., larger, smaller, fiercer, meeker) from a set of animal pairs. Inputs are coded by vectors of continuous-valued features, based either on human magnitude ratings, normed feature ratings (De Deyne et al., 2008), or outputs of the topics model (Griffiths, Steyvers, & Tenenbaum, 2007). Bootstrapping from empirical priors, the model is able to induce first-order relations represented as probabilistic weight distributions, even when given positive examples only. These learned representations allow classification of novel instantiations of the relations and yield a symbolic distance effect of the sort obtained with both humans and other primates. BART then transforms its learned weight distributions by importance-guided mapping, thereby placing distinct dimensions into correspondence. These transformed representations allow BART to reliably solve 4-term analogies (e.g., larger:smaller::fiercer:meeker), a type of reasoning that is arguably specific to humans. Our results provide a proof-of-concept that structured analogies can be solved with representations induced from unstructured feature vectors by mechanisms that operate in a largely bottom-up fashion. We discuss potential implications for algorithmic and neural models of relational thinking, as well as for the evolution of abstract thought. PMID:22775500

  1. Synaptic dynamics in analog VLSI.

    PubMed

    Bartolozzi, Chiara; Indiveri, Giacomo

    2007-10-01

    Synapses are crucial elements for computation and information transfer in both real and artificial neural systems. Recent experimental findings and theoretical models of pulse-based neural networks suggest that synaptic dynamics can play a crucial role for learning neural codes and encoding spatiotemporal spike patterns. Within the context of hardware implementations of pulse-based neural networks, several analog VLSI circuits modeling synaptic functionality have been proposed. We present an overview of previously proposed circuits and describe a novel analog VLSI synaptic circuit suitable for integration in large VLSI spike-based neural systems. The circuit proposed is based on a computational model that fits the real postsynaptic currents with exponentials. We present experimental data showing how the circuit exhibits realistic dynamics and show how it can be connected to additional modules for implementing a wide range of synaptic properties. PMID:17716003

  2. Battery hydrometer with analog output

    SciTech Connect

    Patis, B.L.

    1982-09-21

    There is disclosed a battery hydrometer for providing an analog electrical signal having a magnitude related to the specific gravity of a battery electrolyte. The hydrometer includes a source of radiation for providing a detectable beam of radiation and a piston member arranged to be submerged within the electrolyte and to intercept and modulate the beam of radiation in response to the specific gravity of the electrolyte. The piston member is suspended within the electrolyte by a spring which exerts a compressive force upon the piston member against which the electrolyte must act. The hydrometer further includes a radiation detector aligned with the radiation source for providing an analog electrical signal having a magnitude responsive to the modulated beam of radiation.

  3. Classical Analog to Entanglement Reversibility

    NASA Astrophysics Data System (ADS)

    Chitambar, Eric; Fortescue, Ben; Hsieh, Min-Hsiu

    2015-08-01

    In this Letter we study the problem of secrecy reversibility. This asks when two honest parties can distill secret bits from some tripartite distribution pX Y Z and transform secret bits back into pX Y Z at equal rates using local operation and public communication. This is the classical analog to the well-studied problem of reversibly concentrating and diluting entanglement in a quantum state. We identify the structure of distributions possessing reversible secrecy when one of the honest parties holds a binary distribution, and it is possible that all reversible distributions have this form. These distributions are more general than what is obtained by simply constructing a classical analog to the family of quantum states known to have reversible entanglement. An indispensable tool used in our analysis is a conditional form of the Gács-Körner common information.

  4. Analog Nonvolatile Computer Memory Circuits

    NASA Technical Reports Server (NTRS)

    MacLeod, Todd

    2007-01-01

    In nonvolatile random-access memory (RAM) circuits of a proposed type, digital data would be stored in analog form in ferroelectric field-effect transistors (FFETs). This type of memory circuit would offer advantages over prior volatile and nonvolatile types: In a conventional complementary metal oxide/semiconductor static RAM, six transistors must be used to store one bit, and storage is volatile in that data are lost when power is turned off. In a conventional dynamic RAM, three transistors must be used to store one bit, and the stored bit must be refreshed every few milliseconds. In contrast, in a RAM according to the proposal, data would be retained when power was turned off, each memory cell would contain only two FFETs, and the cell could store multiple bits (the exact number of bits depending on the specific design). Conventional flash memory circuits afford nonvolatile storage, but they operate at reading and writing times of the order of thousands of conventional computer memory reading and writing times and, hence, are suitable for use only as off-line storage devices. In addition, flash memories cease to function after limited numbers of writing cycles. The proposed memory circuits would not be subject to either of these limitations. Prior developmental nonvolatile ferroelectric memories are limited to one bit per cell, whereas, as stated above, the proposed memories would not be so limited. The design of a memory circuit according to the proposal must reflect the fact that FFET storage is only partly nonvolatile, in that the signal stored in an FFET decays gradually over time. (Retention times of some advanced FFETs exceed ten years.) Instead of storing a single bit of data as either a positively or negatively saturated state in a ferroelectric device, each memory cell according to the proposal would store two values. The two FFETs in each cell would be denoted the storage FFET and the control FFET. The storage FFET would store an analog signal value

  5. Basic Electricity--a Novel Analogy.

    ERIC Educational Resources Information Center

    Grant, Richard

    1996-01-01

    Uses the analogy of water flow to introduce concepts in basic electricity. Presents a demonstration that uses this analogy to help students grasp the relationship between current, voltage, and resistance. (JRH)

  6. Thermal analog device reduces machining errors

    NASA Technical Reports Server (NTRS)

    Mcclure, E. R.

    1972-01-01

    Thermal analog devices predict thermal expansion and contraction of machine structures subjected to various heat inputs. Analog devices correct positioning of machine tools to compensate for distortion of machine frame.

  7. Simple Electronic Analog of a Josephson Junction.

    ERIC Educational Resources Information Center

    Henry, R. W.; And Others

    1981-01-01

    Demonstrates that an electronic Josephson junction analog constructed from three integrated circuits plus an external reference oscillator can exhibit many of the circuit phenomena of a real Josephson junction. Includes computer and other applications of the analog. (Author/SK)

  8. Preparation of 2-hydroxy-5-oxoproline and analogs thereof

    DOEpatents

    Martinez, Rodolfo A.; Unkefer, Pat J.

    2001-01-01

    The compound 2-hydroxy-5-oxoproline and analogs thereof may be used to produce an increase in carbon dioxide fixation, growth, dry weight, nutritional value (proteins and amino acids), nodulation and nitrogen fixation and photosynthetically derived chemical energy when applied to plants through their roots and/or through their foliar portions. The present invention includes an essentially quantitative chemical synthesis for this compound which is performed in a single step reaction of Fremy's Salt (potassium nitrosodisulphonate) with either glutamine or 2-pyrrolidone-5-carboxylic acid. Fremy's salt (potassium nitrosodisulphonate) is available commercially, or can be readily synthesized.

  9. Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors

    PubMed Central

    Bergman, Joel A.; Hahne, Kalub; Hrycyna, Christine A.; Gibbs, Richard A.

    2012-01-01

    Inhibition of isoprenylcysteine carboxyl methyltransferase (Icmt) offers a promising strategy for K-Ras driven cancers. We describe the synthesis and inhibitory activity of substrate-based analogs derived from several novel scaffolds. Modifications of both the prenyl group and thioether of N-acetyl-S-farnesyl-l-cysteine (AFC), a substrate for human Icmt (hIcmt), have resulted in low micromolar inhibitors of Icmt and have given insights into the nature of the prenyl binding site of hIcmt. PMID:21782433

  10. Hegel, Analogy, and Extraterrestrial Life

    NASA Astrophysics Data System (ADS)

    Ross, Joseph T.

    Georg Wilhelm Friedrich Hegel rejected the possibility of life outside of the Earth, according to several scholars of extraterrestrial life. Their position is that the solar system and specifically the planet Earth is the unique place in the cosmos where life, intelligence, and rationality can be. The present study offers a very different interpretation of Hegel's statements about the place of life on Earth by suggesting that, although Hegel did not believe that there were other solar systems where rationality is present, he did in fact suggest that planets in general, not the Earth exclusively, have life and possibly also intelligent inhabitants. Analogical syllogisms are superficial, according to Hegel, insofar as they try to conclude that there is life on the Moon even though there is no evidence of water or air on that body. Similar analogical arguments for life on the Sun made by Johann Elert Bode and William Herschel were considered by Hegel to be equally superficial. Analogical arguments were also used by astronomers and philosophers to suggest that life could be found on other planets in our solar system. Hegel offers no critique of analogical arguments for life on other planets, and in fact Hegel believed that life would be found on other planets. Planets, after all, have meteorological processes and therefore are "living" according to his philosophical account, unlike the Moon, Sun, and comets. Whereas William Herschel was already finding great similarities between the Sun and the stars and had extended these similarities to the property of having planets or being themselves inhabitable worlds, Hegel rejected this analogy. The Sun and stars have some properties in common, but for Hegel one cannot conclude from these similarities to the necessity that stars have planets. Hegel's arguments against the presence of life in the solar system were not directed against other planets, but rather against the Sun and Moon, both of which he said have a different

  11. Two-Step Semi-Microscale Preparation of a Cinnamate Ester Sunscreen Analog

    ERIC Educational Resources Information Center

    Stabile, Ryan G.; Dicks, Andrew P.

    2004-01-01

    A student procedure focusing on multistep sunscreen synthesis and spectroscopic analysis is reported. A two-step synthetic pathway towards sunscreens, an analog of a commercially available UV light blocker is designed, given the current high profile nature of skin cancer and media attention towards sunscreens.

  12. Metabolic precursors in astrophysical ice analogs: implications for meteorites and comets.

    PubMed

    Smith, Karen E; Gerakines, Perry A; Callahan, Michael P

    2015-07-28

    We report the synthesis of complex organic compounds including nicotinic and quinolinic acid, two members involved in the nicotinamide adenine dinucleotide (NAD) biosynthetic pathway, in irradiated astrophysical ice analogs. If delivered to Earth by meteorites and comets, these compounds may have contributed to the origin and early evolution of life. PMID:26107786

  13. Science Teachers' Analogical Reasoning

    ERIC Educational Resources Information Center

    Mozzer, Nilmara Braga; Justi, Rosária

    2013-01-01

    Analogies can play a relevant role in students' learning. However, for the effective use of analogies, teachers should not only have a well-prepared repertoire of validated analogies, which could serve as bridges between the students' prior knowledge and the scientific knowledge they desire them to understand, but also know how to…

  14. Reasoning by Analogy in Constructing Mathematical Ideas.

    ERIC Educational Resources Information Center

    English, Lyn D.

    A powerful way of understanding something new is by analogy with something already known. An analogy is defined as a mapping from one structure, which is already known (the base or source), to another structure that is to be inferred or discovered (the target). The research community has given considerable attention to analogical reasoning in the…

  15. Classical analog of quantum phase

    SciTech Connect

    Ord, G.N.

    1992-07-01

    A modified version of the Feynman relativistic chessboard model (FCM) is investigated in which the paths involved are spirals in the space-time. Portions of the paths in which the particle`s proper time is reversed are interpreted in terms of antiparticles. With this intepretation the particle-antiparticle field produced by such trajectories provides a classical analog of the phase associated with particle paths in the unmodified FCM. It is shwon that in the nonrelativistic limit the resulting kernel is the correct Dirac propagator and that particle-antiparticle symmetry is in this case responsible for quantum interference. 7 refs., 3 figs.

  16. Approaches to synthetic platelet analogs.

    PubMed

    Modery-Pawlowski, Christa L; Tian, Lewis L; Pan, Victor; McCrae, Keith R; Mitragotri, Samir; Sen Gupta, Anirban

    2013-01-01

    Platelet transfusion is routinely used for treating bleeding complications in patients with hematologic or oncologic clotting disorders, chemo/radiotherapy-induced myelosuppression, trauma and surgery. Currently, these transfusions mostly use allogeneic platelet concentrates, while products like lyophilized platelets, cold-stored platelets and infusible platelet membranes are under investigation. These natural platelet-based products pose considerable risks of contamination, resulting in short shelf-life (3-5 days). Recent advances in pathogen reduction technologies have increased shelf-life to ~7 days. Furthermore, natural platelets are short in supply and also cause several biological side effects. Hence, there is significant clinical interest in platelet-mimetic synthetic analogs that can allow long storage-life and minimum side effects. Accordingly, several designs have been studied which decorate synthetic particles with motifs that promote platelet-mimetic adhesion or aggregation. Recent refinement in this design involves combining the adhesion and aggregation functionalities on a single particle platform. Further refinement is being focused on constructing particles that also mimic natural platelet's shape, size and elasticity, to influence margination and wall-interaction. The optimum design of a synthetic platelet analog would require efficient integration of platelet's physico-mechanical properties and biological functionalities. We present a comprehensive review of these approaches and provide our opinion regarding the future directions of this research. PMID:23092864

  17. Analog computation with dynamical systems

    NASA Astrophysics Data System (ADS)

    Siegelmann, Hava T.; Fishman, Shmuel

    1998-09-01

    Physical systems exhibit various levels of complexity: their long term dynamics may converge to fixed points or exhibit complex chaotic behavior. This paper presents a theory that enables to interpret natural processes as special purpose analog computers. Since physical systems are naturally described in continuous time, a definition of computational complexity for continuous time systems is required. In analogy with the classical discrete theory we develop fundamentals of computational complexity for dynamical systems, discrete or continuous in time, on the basis of an intrinsic time scale of the system. Dissipative dynamical systems are classified into the computational complexity classes P d, Co-RP d, NP d and EXP d, corresponding to their standard counterparts, according to the complexity of their long term behavior. The complexity of chaotic attractors relative to regular ones leads to the conjecture P d ≠ NP d. Continuous time flows have been proven useful in solving various practical problems. Our theory provides the tools for an algorithmic analysis of such flows. As an example we analyze the continuous Hopfield network.

  18. Strigolactone analogs derived from ketones using a working model for germination stimulants as a blueprint.

    PubMed

    Mwakaboko, Alinanuswe S; Zwanenburg, Binne

    2011-04-01

    Strigolactones are important signaling compounds in the plant kingdom. Here we focus on their germination stimulatory effect on seeds of the parasitic weeds Striga and Orobanche spp. and more particularly on the design and synthesis of new active strigolactone analogs derived from simple cyclic ketones. New analogs derived from 1-indanone, 1-tetralone, cyclopentanone, cyclohexanone and a series of substituted cyclohexanones (including carvone and pulegone) are prepared by formylation of the ketones with ethyl formate followed by coupling with a halo butenolide. Both enantiomers of the analog derived from 1-tetralone have been prepared by employing a homochiral synthon for the coupling reaction. For three other strigolactone analogs the antipodes have been obtained by chromatography on a chiral column. All analogs have an appreciable germinating activity towards seeds of Striga hermomonthica and Orobanche crenata and O. cernua. Stereoisomers having the same configuration at the D-ring as in naturally occurring strigol have a higher stimulatory effect than the corresponding antipodes. The analogs obtained from 1-indanone and 1-tetralone have an activity comparable with that of the well known stimulant GR 24. Analogs derived from 2-phenyl-cylohexanone, carvone and pulegone also have a good germinating response. The results show that the working model for designing new bioactive strigolactones is applicable. PMID:21421570

  19. [Acyclic analogs of ribavirin. Synthesis and antiviral activity].

    PubMed

    Tsilevich, T L; Shchaveleva, I L; Nosach, L N; Zhovnovataia, V L; Smirnov, I P

    1988-05-01

    Activity of several ribavirin analogues, viz.1-(2-hydroxyethoxymethyl)-, 1-(3-hydroxypropoxymethyl)-, 1-(4-hydroxybutoxymethyl)- and 1-(2,3-dihydroxypropyl)-1,2,4-triazole 5- and 3-carboxamides, against human adenovirus type 2 in the Hep-2 cell culture has been studied. The ether oxygen atom imitating the ribose O4' was shown to be essential for the antiviral activity. 1-(2-Hydroxyethoxymethyl)-1,2,4-triazole 3-carboxamide, a structural analogue of ribavirin in which the hydroxyl group is apparently equivalent to the ribose 5'-OH, possesses the highest activity among the compounds studied. Lengthening of the alkyl side chain reduces essentially the antiviral activity. PMID:3422011

  20. Convenient Microscale Synthesis of a Coumarin Laser Dye Analog

    ERIC Educational Resources Information Center

    Aktoudianakis, Evangelos; Dicks, Andrew P.

    2006-01-01

    Coumarin (2H-1-benzopyran-2-one) and its derivatives constitute a fascinating class of organic substances that are utilized industrially in areas such as cosmetics, food preservatives, insecticides and fluorescent laser dyes. The product can be synthesized, purified, and characterized within two hours with benefits of microscale reactivity being…

  1. Synthesis and Antimicrobial Evaluation of 5-Iodopyrimidine Analogs

    PubMed Central

    Goudgaon, N. M.; Basha, N. J.; Patil, S. B.

    2009-01-01

    4-Substituted-5-iodo-2-benzylthiopyrimidines were prepared efficiently in three steps. 2-Benzylthiopyrimidine on iodination in presence of base gave 5-iodo-2-benzylthiopyrimidine (1), which on chlorination with excess of POCl3 furnished 4-chloro-5-iodo-2-benzylthiopyrimidine (2). Reaction of 2 with substituted aromatic amines, 2-aminopyridine and hydrazine hydrate yielded 4-amino-5-iodo-2-benzylthiopyrimidines 3(a-e), (3f) and (3g) respectively. Further, 4-hydrazino-5-iodo-2-benzylthiopyrimidine on condensation with substituted aromatic and heterocyclic aldehydes afforded the corresponding schiff bases 4(a-h). The structure of synthesized compounds have been established by spectral studies and elemental analysis. Synthesized compounds have been screened for antimicrobial activity. Compound 3f exhibited good antifungal activity against A. niger. The compounds 4a, 4c, 4d, 4g and 4h exhibited good antibacterial activity. PMID:20376222

  2. Automatic activation of categorical and abstract analogical relations in analogical reasoning.

    PubMed

    Green, Adam E; Fugelsang, Jonathan A; Dunbar, Kevin N

    2006-10-01

    We examined activation of concepts during analogical reasoning. Subjects made either analogical judgments or categorical judgments about four-word sets. After each four-word set, they named the ink color of a single word in a modified Stroop task. Words that referred to category relations were primed (as indicated by longer response times on Stroop color naming) subsequent to analogical judgments and categorical judgments. This finding suggests that activation of category concepts plays a fundamental role in analogical thinking. When colored words referred to analogical relations, priming occurred subsequent to analogical judgments, but not to categorical judgments, even though identical four-word stimuli were used for both types of judgments. This finding lends empirical support to the hypothesis that, when people comprehend the analogy between two items, they activate an abstract analogical relation that is distinct from the specific content items that compose the analogy. PMID:17263066

  3. [Active vitamin D3 analog].

    PubMed

    Takata, Shinjiro

    2015-10-01

    Vitamin D is a fat-soluble vitamin and exerts effects on skeletal and extraskeletal health in children and adults of all ages. Vitamin D insufficiency is related to low muscle strength, increasing body sway, falls in the elderly. Supplementation with vitamin D reduces risk of osteoporotic fracture, and improves muscle strength and postural balance to prevent the elderly from fall. The preferred vitamin D analog for daily supplementation is cholecalciferol (vitamin D3). The active form of vitamin D3 is 1,25-dihydroxy-vitamin D3. Alfacalcidol, calcitriol and eldecalcitol are used to treat osteoporosis in Japan. Randomized placebo-controlled, double-blinded clinical trial for osteoporotic subjects showed that eldecalcitol is more efficacious to increase bone mineral density and prevent vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency than alfacalcidol. PMID:26529933

  4. Analog computing by Brewster effect.

    PubMed

    Youssefi, Amir; Zangeneh-Nejad, Farzad; Abdollahramezani, Sajjad; Khavasi, Amin

    2016-08-01

    Optical computing has emerged as a promising candidate for real-time and parallel continuous data processing. Motivated by recent progresses in metamaterial-based analog computing [Science343, 160 (2014)SCIEAS0036-807510.1126/science.1242818], we theoretically investigate the realization of two-dimensional complex mathematical operations using rotated configurations, recently reported in [Opt. Lett.39, 1278 (2014)OPLEDP0146-959210.1364/OL.39.001278]. Breaking the reflection symmetry, such configurations could realize both even and odd Green's functions associated with spatial operators. Based on such an appealing theory and by using the Brewster effect, we demonstrate realization of a first-order differentiator. Such an efficient wave-based computation method not only circumvents the major potential drawbacks of metamaterials, but also offers the most compact possible device compared to conventional bulky lens-based optical signal and data processors. PMID:27472595

  5. QCD analogy for quantum gravity

    NASA Astrophysics Data System (ADS)

    Holdom, Bob; Ren, Jing

    2016-06-01

    Quadratic gravity presents us with a renormalizable, asymptotically free theory of quantum gravity. When its couplings grow strong at some scale, as in QCD, then this strong scale sets the Planck mass. QCD has a gluon that does not appear in the physical spectrum. Quadratic gravity has a spin-2 ghost that we conjecture does not appear in the physical spectrum. We discuss how the QCD analogy leads to this conjecture and to the possible emergence of general relativity. Certain aspects of the QCD path integral and its measure are also similar for quadratic gravity. With the addition of the Einstein-Hilbert term, quadratic gravity has a dimensionful parameter that seems to control a quantum phase transition and the size of a mass gap in the strong phase.

  6. The Young Solar Analogs Project

    NASA Astrophysics Data System (ADS)

    Gray, Richard O.; Saken, J. M.; Corbally, C. J.; Fuller, V.; Kahvaz, Y.; Lambert, R.; Newsome, I.; Seeds, M.

    2013-01-01

    We are carrying out a long-term project of measuring chromospheric activity and brightness variations in 31 young solar analogs (YSAs) using facilities at the Dark Sky Observatory (DSO - Appalachian State University) and the Vatican Advanced Technology Telescope (VATT). These YSAs are solar-type (spectral types F8 - K2) stars with ages ranging from 0.3 - 1.5 Gyr. The goal of this project is to gain better understanding of the magnetic activity of the early Sun, and especially how that activity may have impacted the development of life on the Earth. This project will also yield insights into the space environments experienced by young Earth analogs. We are currently in the 6th year of spectroscopic measurements of these stars: these data include Ca II H & K chromospheric flux measurements, and narrow-band measurements in the photospheric G-band, both obtained with the G/M spectrograph on the DSO 32-inch telescope. We will present evidence of activity cycles in a number of our stars, as well as periods determined from rotational modulation of the spectroscopic indices. The relationship between the Ca II activity index and the G-band index will be explored. NSF support for our project has provided funds for the construction of a robotic photometric telescope to monitor the program stars in a 5-passband system (Strömgren-v, Johnson-Cousins B, V, and R, and a 3-nm wide Hα filter). The robotic telescope has been functional since April 2012 and observes the program stars on every clear night; combined with the Piggy-back telescope attached to the DSO 32-inch, we now have photometric observations on over 130 nights stretching over nearly 2 years. We will examine the relationships between variations in the Ca II H & K index, the G-band index and the photometric bands. This project is supported by the National Science Foundation, grant AST-1109158.

  7. The Young Solar Analogs Project

    NASA Astrophysics Data System (ADS)

    Gray, Richard O.; Saken, J. M.; Corbally, C. J.; Seeds, M. F.; Morrison, S. S.

    2012-01-01

    We are carrying out a long-term project of measuring chromospheric activity and brightness variations in 31 young solar analogs (YSAs) using the Dark Sky Observatory (DSO -- Appalachian State University) 32-inch telescope and the G/M spectrograph. These YSAs are solar-type (spectral types F8 - K2) stars with ages ranging from 0.3 - 1.5 Gyr. The goal of this project is to gain better understanding of the magnetic activity of the early Sun, and especially how that activity may have impacted the development of life on the Earth. This project will also yield insights into the space environments experienced by young Earth analogs. We are currently in our 5th year of obtaining Ca II K & H chromospheric flux measurements, and are beginning to see signs of long-term activity cycles in a number of our stars. In addition, rotational modulation of the chromospheric fluxes is detectable in our data, and we have determined rotational periods for many of our stars. Short timescale increases in the K & H fluxes have been observed in a number of our stars; these events may be related to stellar flares. VATTSpec, a new moderate-resolution spectrograph on the 1.8-m Vatican Telescope in Arizona, has recently become involved with the project. This spectrograph will increase our ability to detect short-term changes in stellar activity on timescales of hours to minutes. We have been monitoring the program stars for one year in a multi-band photometric system consisting of Stromgren-v, and Johnson B, V, and R filters. We will soon add a narrow-band H-alpha filter to the system. Photometry is being carried out with a small piggy-back telescope on the 32-inch, but a robotic photometric telescope is currently being installed at DSO for this purpose. This project is supported by the National Science Foundation.

  8. Priming analogical reasoning with false memories.

    PubMed

    Howe, Mark L; Garner, Sarah R; Threadgold, Emma; Ball, Linden J

    2015-08-01

    Like true memories, false memories are capable of priming answers to insight-based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment 1, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments 2a and 2b, we extended these findings by demonstrating priming on newly created homonym analogies that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems. PMID:25784574

  9. Analysis of analogies used by science teachers

    NASA Astrophysics Data System (ADS)

    Dagher, Zoubeida R.

    Science teachers use analogies that display a rich variety of form and content. An account of science teacher analogies that relies solely on systems of analysis imported from other fields of inquiry tends to obscure the unique features of these analogies as they operate within classroom discourse. This study examines teachers' analogies in context and highlights some of their special characteristics. The purpose of this analysis is to increase our understanding of how analogies operate in naturalistic instructional settings and to generate new research questions about science teaching and learning in view of the broader dimensions of the curriculum.Science isa very human activity. It involves human actors and judgements, rivalries and antagonisms, mysteries and surprises, the creative use of metaphor and analogy. It is fallible, often uncertain, and sometimes creatively ambiguous [Lemke, 1990, p. 134].Received: 1 June 1993; Revised: 29 November 1993;

  10. Chemical Synthesis of Ubiquitin Chains.

    PubMed

    Hemantha, Hosahalli P; Bondalapati, Somasekhar; Singh, Sumeet K; Brik, Ashraf

    2015-01-01

    Chemical synthesis of complex biomolecules such as proteins is a challenging adventure, yet rewarding in driving various biochemical and biophysical research activities. Over the years, the refinement of peptide synthesis and invention of ligation methodologies have led to the successful synthesis of several complex protein targets. Ubiquitin bioconjugates, which are being studied intensively by many groups due to their involvement in numerous biological processes, represent a fine example where chemistry is greatly aiding these studies. In this article, we describe the synthetic routes and strategies to prepare different ubiquitin analogs with desired modifications, as well as di-ubiquitin chains. PMID:26629614

  11. Terrestrial Analogs for Planetary Wrinkle Ridges

    NASA Technical Reports Server (NTRS)

    Plescia, J. B.; Golombek, M. P.

    1985-01-01

    Wrinkle ridges are common physiographic features on the terrestrial planets. Their origin has remained enigmatic, although two different types of models, volcanic and tectonic, have been proposed. The major impediment to deciphering the origin of wrinkle ridges has been the lack of a terrestrial analog. Seven terrestrial analogs were discussed, two in detail. Their implications for the origin for planetary wrinkle ridges were considered. All of the terrestrial analogs were formed in compressional environments and are the surface breaks of thrust faults.

  12. Properties of compressible elastica from relativistic analogy.

    PubMed

    Oshri, Oz; Diamant, Haim

    2016-01-21

    Kirchhoff's kinetic analogy relates the deformation of an incompressible elastic rod to the classical dynamics of rigid body rotation. We extend the analogy to compressible filaments and find that the extension is similar to the introduction of relativistic effects into the dynamical system. The extended analogy reveals a surprising symmetry in the deformations of compressible elastica. In addition, we use known results for the buckling of compressible elastica to derive the explicit solution for the motion of a relativistic nonlinear pendulum. We discuss cases where the extended Kirchhoff analogy may be useful for the study of other soft matter systems. PMID:26563905

  13. Robust hyperchaotic synchronization via analog transmission line

    NASA Astrophysics Data System (ADS)

    Sadoudi, S.; Tanougast, C.

    2016-02-01

    In this paper, a novel experimental chaotic synchronization technique via analog transmission is discussed. We demonstrate through Field-Programmable Gate Array (FPGA) implementation design the robust synchronization of two embedded hyperchaotic Lorenz generators interconnected with an analog transmission line. The basic idea of this work consists in combining a numerical generation of chaos and transmitting it with an analog signal. The numerical chaos allows to overcome the callback parameter mismatch problem and the analog transmission offers robust data security. As application, this technique can be applied to all families of chaotic systems including time-delayed chaotic systems.

  14. Real World: Analog Testing in Extreme Environments

    NASA Video Gallery

    See how NASA uses analog testing to simulate space exploration. Explore extreme environments like the Aquarius underwater laboratory in Key Largo, Florida. Find out how scientists use mathematical ...

  15. Fermilab accelerator control system: Analog monitoring facilities

    SciTech Connect

    Seino, K.; Anderson, L.; Smedinghoff, J.

    1987-10-01

    Thousands of analog signals are monitored in different areas of the Fermilab accelerator complex. For general purposes, analog signals are sent over coaxial or twinaxial cables with varying lengths, collected at fan-in boxes and digitized with 12 bit multiplexed ADCs. For higher resolution requirements, analog signals are digitized at sources and are serially sent to the control system. This paper surveys ADC subsystems that are used with the accelerator control systems and discusses practical problems and solutions, and it describes how analog data are presented on the console system.

  16. Metabolomic Discovery of Novel Urinary Galabiosylceramide Analogs as Fabry Disease Biomarkers

    NASA Astrophysics Data System (ADS)

    Boutin, Michel; Auray-Blais, Christiane

    2015-03-01

    Fabry disease is an X-linked, complex, multisystemic lysosomal storage disorder presenting marked phenotypic and genotypic variability among affected male and female patients. Glycosphingolipids, mainly globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, as well as galabiosylceramide (Ga2) isoforms/analogs accumulate in the vascular endothelium, nerves, cardiomyocytes, renal glomerular and tubular epithelial cells, and biological fluids. The search for biomarkers reflecting disease severity and progression is still on-going. A metabolomic study using quadrupole time-of-flight mass spectrometry has revealed 22 galabiosylceramide isoforms/analogs in urine of untreated Fabry patients classified in seven groups according to their chemical structure: (1) Saturated fatty acid; (2) one extra double bond; (3) two extra double bonds; (4) hydroxylated saturated fatty acid; (5) hydroxylated fatty acid and one extra double bond; (6) hydrated sphingosine and hydroxylated fatty acid; (7) methylated amide linkage. Relative quantification of both Ga2 and Gb3 isoforms/analogs was performed. All these biomarkers are significantly more abundant in urine samples from untreated Fabry males compared with healthy male controls. A significant amount of Ga2 isoforms/analogs, accounting for 18% of all glycosphingolipids analyzed (Ga2 + Gb3 and respective isoforms/analogs), were present in urine of Fabry patients. Gb3 isoforms containing saturated fatty acids are the most abundant (60.9%) compared with 26.3% for Ga2. A comparison between Ga2 isoforms/analogs and their Gb3 counterparts also showed that the proportion of analogs with hydroxylated fatty acids is significantly greater for Ga2 (35.8%) compared with Gb3 (1.9%). These results suggest different biological pathways involved in the synthesis and/or degradation of Gb3 and Ga2 metabolites.

  17. Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration.

    PubMed

    Fichna, Jakub; Mazur, Marzena; Grzywacz, Daria; Kamysz, Wojciech; Perlikowska, Renata; Piekielna, Justyna; Sobczak, Marta; Sałaga, Maciej; Toth, Geza; Janecka, Anna; Chen, Chunqiu; Olczak, Jacek

    2013-12-15

    We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous μ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a β-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS. PMID:24220171

  18. In vitro and In vivo Evaluation of Select Kahalalide F Analogs with Antitumor and Antifungal Activities

    PubMed Central

    Shilabin, Abbas Gholipour; Hamann, Mark T.

    2012-01-01

    Kahalalide F (KF) and the regioisomer isoKF are novel anticancer drugs of marine origin and currently under clinical investigation. Here we report the synthesis of two new KF analogs with significant in vitro and in vivo antifungal and antitumor activities. The primary amine hydrogen of ornithine in KF has been replaced with 4-fluoro-3-methylbenzyl and morpholin-4-yl-benzyl via reductive N-alkylation. The TGI of these analogs using the NCI-60 cell line screening revealed promising results when compared to paclitaxel. The result of in vivo hollow fiber and animal toxicity assays are presented. PMID:21839640

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

    PubMed Central

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

    2014-01-01

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

  20. Expert analogy use in a naturalistic setting

    PubMed Central

    Kretz, Donald R.; Krawczyk, Daniel C.

    2014-01-01

    The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker's goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption) of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance. PMID:25505437

  1. Unpowered wireless analog resistance sensor

    NASA Astrophysics Data System (ADS)

    Andringa, Matthew M.; Neikirk, Dean P.; Wood, Sharon L.

    2004-07-01

    Our society depends heavily on a network of buildings, bridges and roadways. In order to properly maintain this civil infrastructure and avoid damage and costly repairs due to structural failure, it is necessary to monitor the health of these structures. Sensors must frequently be placed in inaccessible locations under harsh conditions and should ideally last the lifetime of the structure the sensors are monitoring. This paper presents the development of a low cost, passive, un-powered wireless analog resistance sensor. The sensor was originally designed for monitoring corrosion in concrete, but there are many other potential applications including remote temperature monitoring, embedded accelerometers, and embedded strain gauges. The passive wireless nature makes the sensor ideally suited for embedding in inaccessible locations under harsh conditions. The sensor consists of a resonant inductor-capacitor circuit containing a resistive transducer. The sensor is interrogated by measuring the impedance through a remote, magnetically coupled reader loop. The width of the resonance is directly related to the resistance of the transducer. The sensor has been simulated under a variety of conditions using a circuit model and compared to actual test sensors built and evaluated in the laboratory.

  2. Novel Analog For Muscle Deconditioning

    NASA Technical Reports Server (NTRS)

    Ploutz-Snyder, Lori; Ryder, Jeff; Buxton, Roxanne; Redd, Elizabeth; Scott-Pandorf, Melissa; Hackney, Kyle; Fiedler, James; Bloomberg, Jacob

    2010-01-01

    Existing models of muscle deconditioning are cumbersome and expensive (ex: bedrest). We propose a new model utilizing a weighted suit to manipulate strength, power or endurance (function) relative to body weight (BW). Methods: 20 subjects performed 7 occupational astronaut tasks while wearing a suit weighted with 0-120% of BW. Models of the full relationship between muscle function/BW and task completion time were developed using fractional polynomial regression and verified by the addition of pre- and post-flight astronaut performance data using the same tasks. Spline regression was used to identify muscle function thresholds below which task performance was impaired. Results: Thresholds of performance decline were identified for each task. Seated egress & walk (most difficult task) showed thresholds of: leg press (LP) isometric peak force/BW of 18 N/kg, LP power/BW of 18 W/kg, LP work/ BW of 79 J/kg, knee extension (KE) isokinetic/BW of 6 Nm/Kg and KE torque/BW of 1.9 Nm/kg. Conclusions: Laboratory manipulation of strength / BW has promise as an appropriate analog for spaceflight-induced loss of muscle function for predicting occupational task performance and establishing operationally relevant exercise targets.

  3. Novel Analog For Muscle Deconditioning

    NASA Technical Reports Server (NTRS)

    Ploutz-Snyder, Lori; Ryder, Jeff; Buxton, Roxanne; Redd. Elizabeth; Scott-Pandorf, Melissa; Hackney, Kyle; Fiedler, James; Ploutz-Snyder, Robert; Bloomberg, Jacob

    2011-01-01

    Existing models (such as bed rest) of muscle deconditioning are cumbersome and expensive. We propose a new model utilizing a weighted suit to manipulate strength, power, or endurance (function) relative to body weight (BW). Methods: 20 subjects performed 7 occupational astronaut tasks while wearing a suit weighted with 0-120% of BW. Models of the full relationship between muscle function/BW and task completion time were developed using fractional polynomial regression and verified by the addition of pre-and postflightastronaut performance data for the same tasks. Splineregression was used to identify muscle function thresholds below which task performance was impaired. Results: Thresholds of performance decline were identified for each task. Seated egress & walk (most difficult task) showed thresholds of leg press (LP) isometric peak force/BW of 18 N/kg, LP power/BW of 18 W/kg, LP work/BW of 79 J/kg, isokineticknee extension (KE)/BW of 6 Nm/kg, and KE torque/BW of 1.9 Nm/kg.Conclusions: Laboratory manipulation of relative strength has promise as an appropriate analog for spaceflight-induced loss of muscle function, for predicting occupational task performance and establishing operationally relevant strength thresholds.

  4. Fault diagnosis of analog circuits

    SciTech Connect

    Bandler, J.W.; Salama, A.E.

    1985-08-01

    In this paper, various fault location techniques in analog networks are described and compared. The emphasis is on the more recent developments in the subject. Four main approaches for fault location are addressed, examined, and illustrated using simple network examples. In particular, we consider the fault dictionary approach, the parameter identification approach, the fault verification approach, and the approximation approach. Theory and algorithms that are associated with these approaches are reviewed and problems of their practical application are identified. Associated with the fault dictionary approach we consider fault dictionary construction techniques, methods of optimum measurement selection, different fault isolation criteria, and efficient fault simulation techniques. Parameter identification techniques that either utilize linear or nonlinear systems of equations to identify all network elements are examined very thoroughly. Under fault verification techniques we discuss node-fault diagnosis, branch-fault diagnosis, subnetwork testability conditions as well as combinatorial techniques, the failure bound technique, and the network decomposition technique. For the approximation approach we consider probabilistic methods and optimization-based methods. The artificial intelligence technique and the different measures of testability are also considered. The main features of the techniques considered are summarized in a comparative table. An extensive, but not exhaustive, bibliography is provided.

  5. Antibacterial and Antibiofilm Activities of Makaluvamine Analogs

    PubMed Central

    Nijampatnam, Bhavitavya; Nadkarni, Dwayaja H.; Wu, Hui; Velu, Sadanandan E.

    2015-01-01

    Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity. PMID:25767719

  6. Alaskan thermokarst terrain and possible Martian analog

    NASA Technical Reports Server (NTRS)

    Gatto, L. W.; Anderson, D. M.

    1975-01-01

    A first-order analog to Martian fretted terrain has been recognized on enhanced, ERTS-1 (Earth Resources Technology Satellite) imagery of Alaskan Arctic thermokarst terrain. The Alaskan analog displays flat-floored valleys and intervalley uplands characteristic of fretted terrain. The thermokarst terrain has formed in a manner similar to one of the processes postulated for the development of the Martian fretted terrain.

  7. Analog disc recorder system: operator's reference manual

    SciTech Connect

    O'Brien, J.D.; Smith, E.L.

    1984-07-01

    The FM Analog Disc Recorder System is a cost-efficient means of capturing analog transient data from many channels; it has high-frequency response and long record time. It can digitize recorded signals, correct internal distortion, and present the data as plots either on a CRT, hardcopy plot, or both. The system is easy to use, self-contained, and compact.

  8. Rotanone analogs: method of preparation and use

    DOEpatents

    VanBrocklin, Henry F; O& #x27; Neil, James P; Gibbs, Andrew R; Erathodiyil, Nandanan

    2013-10-08

    The present invention provides rotenone analogs and methods of making and using them. Labeled with single photon and positron emitting isotopes, the rotenone analogs of the present invention are useful in, for example, clinical imaging applications as tracers to measure cardiac blood flow and detect regions of ischemia.

  9. Using Analogies to Develop Conceptual Abilities.

    ERIC Educational Resources Information Center

    Jorgensen, Sally

    Because analogies are such powerful tools for communicating they should be exploited more consciously for instructional purposes. Unfortunately, analogies as a topic of investigation in the school curriculum tend to surface only as a subheading within a figurative language lesson in English class or as a test item on the SAT, MAT, or GRE. Analogy…

  10. Mathematical Analogs and the Teaching of Fractions.

    ERIC Educational Resources Information Center

    Charles, Kathy; Nason, Rod; Cooper, Tom

    The literature has noted that some mathematical analogs are more effective than others for the teaching of fractions. This study aimed to evaluate the efficacy of seven mathematical analogs commonly used in the teaching of the partitive quotient fraction construct. A sample of twelve purposively selected Year Three children were presented with…

  11. Predicting Naming Latencies with an Analogical Model

    ERIC Educational Resources Information Center

    Chandler, Steve

    2008-01-01

    Skousen's (1989, Analogical modeling of language, Kluwer Academic Publishers, Dordrecht) Analogical Model (AM) predicts behavior such as spelling pronunciation by comparing the characteristics of a test item (a given input word) to those of individual exemplars in a data set of previously encountered items. While AM and other exemplar-based models…

  12. Piperazine-based nucleic acid analogs

    DOEpatents

    Schmidt, Jurgen; Silks, Louis A.; Michalczyk, Ryszard

    2005-01-11

    A novel nucleoside analog is disclosed which comprises a piperazine ring in the place of the ring ribose or deoxyribose sugar. Monomers utilizing a broad variety of nucleobases are disclosed, as well as oligomers comprising the monomers disclosed herein linked by a variety of linkages, including amide, phosphonamide, and sulfonamide linkages. A method of synthesizing the nucleoside analogs is also disclosed.

  13. The Pennies-as-Electrons Analogy

    ERIC Educational Resources Information Center

    Ashmann, Scott

    2009-01-01

    Everyday experiences familiarize students with the ways in which electricity is used, but often the underlying concepts remain a mystery. Teachers often use analogies to help students relate the flow of electrons to other common systems, but many times these analogies are incomplete and lead to more student misconceptions. However, the "pass the…

  14. The Multidimensionality of Verbal Analogy Items

    ERIC Educational Resources Information Center

    Ullstadius, Eva; Carlstedt, Berit; Gustafsson, Jan-Eric

    2008-01-01

    The influence of general and verbal ability on each of 72 verbal analogy test items were investigated with new factor analytical techniques. The analogy items together with the Computerized Swedish Enlistment Battery (CAT-SEB) were given randomly to two samples of 18-year-old male conscripts (n = 8566 and n = 5289). Thirty-two of the 72 items had…

  15. A Mechanical Analogy for the Photoelectric Effect

    ERIC Educational Resources Information Center

    Kovacevic, Milan S.; Djordjevich, Alexandar

    2006-01-01

    Analogy is a potent tool in the teacher's repertoire. It has been particularly well recognized in the teaching of science. However, careful planning is required for its effective application to prevent documented drawbacks when analogies are stretched too far. Befitting the occasion of the World Year of Physics commemorating Albert Einstein's 1905…

  16. An Analog Computer for Electronic Engineering Education

    ERIC Educational Resources Information Center

    Fitch, A. L.; Iu, H. H. C.; Lu, D. D. C.

    2011-01-01

    This paper describes a compact analog computer and proposes its use in electronic engineering teaching laboratories to develop student understanding of applications in analog electronics, electronic components, engineering mathematics, control engineering, safe laboratory and workshop practices, circuit construction, testing, and maintenance. The…

  17. A Computer Analogy for Illustrating Entropy Concepts.

    ERIC Educational Resources Information Center

    Powers, Michael H.

    1982-01-01

    Describes a computer program for Commodore PET (requiring 8K) which illustrates the statistical nature of entropy by providing a simple analogy. The analogy involves the distribution of objects free to move in a box divided into two compartments. A listing of program statements is also included. (JN)

  18. Analogical Processes and College Developmental Reading

    ERIC Educational Resources Information Center

    Paulson, Eric J.

    2014-01-01

    Although a solid body of research concerning the role of analogies in reading processes has emerged at a variety of age groups and reading proficiencies, few of those studies have focused on analogy use by readers enrolled in college developmental reading courses. The current study explores whether 232 students enrolled in mandatory (by placement…

  19. Young Children's Analogical Reasoning in Science Domains

    ERIC Educational Resources Information Center

    Haglund, Jesper; Jeppsson, Fredrik; Andersson, Johanna

    2012-01-01

    This exploratory study in a classroom setting investigates first graders' (age 7-8 years, N = 25) ability to perform analogical reasoning and create their own analogies for two irreversible natural phenomena: mixing and heat transfer. We found that the children who contributed actively to a full-class discussion were consistently successful at…

  20. Play with Language: Overextensions as Analogies.

    ERIC Educational Resources Information Center

    Hudson, Judith; Nelson, Katherine

    1984-01-01

    Defines criteria to identify children's language overextensions and investigates how young children in the early stages of language acquisition rename objects analogically during a standardized play situation. Results indicate that analogic extensions are well within the capabilities of children from one year, eight months to two years, four…

  1. Developing Analogy Cost Estimates for Space Missions

    NASA Technical Reports Server (NTRS)

    Shishko, Robert

    2004-01-01

    The analogy approach in cost estimation combines actual cost data from similar existing systems, activities, or items with adjustments for a new project's technical, physical or programmatic differences to derive a cost estimate for the new system. This method is normally used early in a project cycle when there is insufficient design/cost data to use as a basis for (or insufficient time to perform) a detailed engineering cost estimate. The major limitation of this method is that it relies on the judgment and experience of the analyst/estimator. The analyst must ensure that the best analogy or analogies have been selected, and that appropriate adjustments have been made. While analogy costing is common, there is a dearth of advice in the literature on the 'adjustment methodology', especially for hardware projects. This paper discusses some potential approaches that can improve rigor and repeatability in the analogy costing process.

  2. An Analog Earth Climate Model

    NASA Astrophysics Data System (ADS)

    Varekamp, J. C.

    2010-12-01

    The earth climate is broadly governed by the radiative power of the sun as well as the heat retention and convective cooling of the atmosphere. I have constructed an analog earth model for an undergraduate climate class that simulates mean climate using these three parameters. The ‘earth’ is a hollow, black, bronze sphere (4 cm diameter) mounted on a thin insulated rod, and illuminated by two opposite optic fibers, with light focused on the sphere by a set of lenses. The sphere is encased in a large double-walled aluminum cylinder (34 cm diameter by 26 cm high) with separate water cooling jackets at the top, bottom, and sides. The cylinder can be filled with a gas of choice at a variety of pressures or can be run in vacuum. The exterior is cladded with insulation, and the temperature of the sphere, atmosphere and walls is monitored with thermocouples. The temperature and waterflow of the three cooling jackets can be monitored to establish the energy output of the whole system; the energy input is the energy yield of the two optic fibers. A small IR transmissive lens at the top provides the opportunity to hook up the fiber of a hyper spectrometer to monitor the emission spectrum of the black ‘earth’ sphere. A pressure gauge and gas inlet-outlet system for flushing of the cell completes it. The heat yield of the cooling water at the top is the sum of the radiative and convective components, whereas the bottom jacket only carries off the radiative heat of the sphere. Undergraduate E&ES students at Wesleyan University have run experiments with dry air, pure CO2, N2 and Ar at 1 atmosphere, and a low vacuum run was accomplished to calibrate the energy input. For each experiment, the lights are flipped on, the temperature acquisition routine is activated, and the sphere starts to warm up until an equilibrium temperature has been reached. The lights are then flipped off and the cooling sequence towards ambient is registered. The energy input is constant for a given

  3. Investigation of Celestial Solid Analogs

    NASA Technical Reports Server (NTRS)

    Sievers, A. J.

    2003-01-01

    Our far infrared studies of both hydrophobic and hydrophilic aerogel grains have demonstrated that the mm and sub-mm wave absorption produced by the fundamental two level systems (TLS) mechanism represents a more significant contribution for these open grain structures than for bulk amorphous silicate grains. We found that the region with the anomalous temperature dependence of the spectral index due to the TLS excitations can extend in a fluffy material up to 80 per cm, which is well beyond its typical upper limit for bulk glasses. Currently there is no theoretical explanation for this surprising result. The effects of reduced dimensionality on the optical properties of carbonaceous grains have been studied with a systematic investigation of carbon aerogels. This spectroscopic approach has permitted a more reliable determination of the single grain mass normalized absorption coefficient based on the experimentally determined characteristics of the fluffy material rather than on first principles calculations involving the bulk properties of the substance. Our finding is that the electrical connectivity of the material is the main factor affecting its far infrared absorption coefficient. Another one of the main constituents of the interstellar dust, amorphous ice, has been investigated in the mm-wave region both in the high (HDA) and low (LDA) density amorphous phases and as a function of impurities. We found that doping either phase with ionic (LiCl) or molecular (methanol) impurities decreases the difference in the mm-wave absorption coefficient between the HDA and LDA ice phases so that the HDA spectrum can be used as an analog for impure ice absorption in the far infrared spectral region.

  4. Rate in template-directed polymer synthesis

    NASA Astrophysics Data System (ADS)

    Saito, Takuya

    2014-06-01

    We discuss the temporal efficiency of template-directed polymer synthesis, such as DNA replication and transcription, under a given template string. To weigh the synthesis speed and accuracy on the same scale, we propose a template-directed synthesis (TDS) rate, which contains an expression analogous to that for the Shannon entropy. Increasing the synthesis speed accelerates the TDS rate, but the TDS rate is lowered if the produced sequences are diversified. We apply the TDS rate to some production system models and investigate how the balance between the speed and the accuracy is affected by changes in the system conditions.

  5. Fostering Multilateral Involvement in Analog Research

    NASA Technical Reports Server (NTRS)

    Cromwell, Ronita L.

    2015-01-01

    International collaboration in space flight research is an effective means for conducting investigations and utilizing limited resources to the fullest extent. Through these multilateral collaborations mutual research questions can be investigated and resources contributed by each international partner to maximize the scientific benefits to all parties. Recently the international partners embraced this approach to initiate collaborations in ground-based space flight analog environments. In 2011, the International Analog Research Working Group was established, and later named the International Human Space Flight Analog Research Coordination Group (HANA). Among the goals of this working group are to 1) establish a framework to coordinate research campaigns, as appropriate, to minimize duplication of effort and enhance synergy; 2) define what analogs are best to use for collaborative interests; and 3) facilitate interaction between discipline experts in order to have the full benefit of international expertise. To accomplish these goals, HANA is currently engaged in developing international research campaigns in ground-based analogs. Plans are being made for an international solicitation for proposals to address research of common interest to all international partners. This solicitation with identify an analog environment that will best accommodate the types of investigations requested. Once selected, studies will be integrated into a campaign and implemented at the analog site. Through these combined efforts, research beneficial to all partners will be conducted efficiently to further address human risks of space exploration.

  6. Analogies: Explanatory Tools in Web-Based Science Instruction

    ERIC Educational Resources Information Center

    Glynn, Shawn M.; Taasoobshirazi, Gita; Fowler, Shawn

    2007-01-01

    This article helps designers of Web-based science instruction construct analogies that are as effective as those used in classrooms by exemplary science teachers. First, the authors explain what analogies are, how analogies foster learning, and what form analogies should take. Second, they discuss science teachers' use of analogies. Third, they…

  7. Current prospects of synthetic curcumin analogs and chalcone derivatives against mycobacterium tuberculosis.

    PubMed

    Bukhari, Syed Nasir Abbas; Franzblau, Scott G; Jantan, Ibrahim; Jasamai, Malina

    2013-11-01

    Tuberculosis, caused by Mycobacterium tuberculosis, is amongst the foremost infectious diseases. Treatment of tuberculosis is a complex process due to various factors including a patient's inability to persevere with a combined treatment regimen, the difficulty in eradicating the infection in immune-suppressed patients, and multidrug resistance (MDR). Extensive research circumscribing molecules to counteract this disease has led to the identification of many inhibitory small molecules. Among these are chalcone derivatives along with curcumin analogs. In this review article, we summarize the reported literature regarding anti tubercular activity of chalcone derivatives and synthetic curcumin analogs. Our goal is to provide an analysis of research to date in order to facilitate the synthesis of superior antitubercular chalcone derivatives and curcumin analogs. PMID:23305394

  8. Programmable Analog-To-Digital Converter

    NASA Technical Reports Server (NTRS)

    Kist, Edward H., Jr.

    1993-01-01

    High-speed analog-to-digital converter with programmable voltage steps that can be changed during operation. Allows concentration of converter resolution over specific portion of waveform. Particularly useful in digitizing wind-shear radar and lidar return signals, in digital oscilloscopes, and other applications in which desirable to increase digital resolution over specific area of waveform while accepting lower resolution over rest of waveform. Effective increase in dynamic range achieved without increase in number of analog-to-digital converter bits. Enabling faster analog-to-digital conversion.

  9. Analog detection for cavity lifetime spectroscopy

    DOEpatents

    Zare, Richard N.; Harb, Charles C.; Paldus, Barbara A.; Spence, Thomas G.

    2003-01-01

    An analog detection system for determining a ring-down rate or decay rate 1/.tau. of an exponentially decaying ring-down beam issuing from a lifetime or ring-down cavity during a ring-down phase. Alternatively, the analog detection system determines a build-up rate of an exponentially growing beam issuing from the cavity during a ring-up phase. The analog system can be employed in continuous wave cavity ring-down spectroscopy (CW CRDS) and pulsed CRDS (P CRDS) arrangements utilizing any type of ring-down cavity including ring-cavities and linear cavities.

  10. Analog detection for cavity lifetime spectroscopy

    DOEpatents

    Zare, Richard N.; Harb, Charles C.; Paldus, Barbara A.; Spence, Thomas G.

    2001-05-15

    An analog detection system for determining a ring-down rate or decay rate 1/.tau. of an exponentially decaying ring-down beam issuing from a lifetime or ring-down cavity during a ring-down phase. Alternatively, the analog detection system determines a build-up rate of an exponentially growing beam issuing from the cavity during a ring-up phase. The analog system can be employed in continuous wave cavity ring-down spectroscopy (CW CRDS) and pulsed CRDS (P CRDS) arrangements utilizing any type of ring-down cavity including ring-cavities and linear cavities.

  11. Comparative conformational analysis of peptide T analogs

    NASA Astrophysics Data System (ADS)

    Akverdieva, Gulnare; Godjayev, Niftali; Akyuz, Sevim

    2009-01-01

    A series of peptide T analogs were investigated within the molecular mechanics framework. In order to determine the role of the aminoacid residues in spatial formation of peptide T the conformational peculiarities of the glycine-substituted analogs were investigated. The conformational profiles of some biologically tested analogs of this peptide were determined independently. The received data permit to assess the active form of this peptide. It is characterized by β-turn at the C-terminal physiologically active pentapeptide fragment of peptide molecule. The received results are important for the investigation of the structure-activity relationship and may be used at design of a rigid-molecule drug against HIV.

  12. Military Importance of Natural Toxins and Their Analogs.

    PubMed

    Pitschmann, Vladimír; Hon, Zdeněk

    2016-01-01

    Toxin weapon research, development, production and the ban on its uses is an integral part of international law, with particular attention paid to the protection against these weapons. In spite of this, hazards associated with toxins cannot be completely excluded. Some of these hazards are also pointed out in the present review. The article deals with the characteristics and properties of natural toxins and synthetic analogs potentially constituting the basis of toxin weapons. It briefly describes the history of military research and the use of toxins from distant history up to the present age. With respect to effective disarmament conventions, it mentions certain contemporary concepts of possible toxin applications for military purposes and the protection of public order (suppression of riots); it also briefly refers to the question of terrorism. In addition, it deals with certain traditional as well as modern technologies of the research, synthesis, and use of toxins, which can affect the continuing development of toxin weapons. These are, for example, cases of new toxins from natural sources, their chemical synthesis, production of synthetic analogs, the possibility of using methods of genetic engineering and modern biotechnologies or the possible applications of nanotechnology and certain pharmaceutical methods for the effective transfer of toxins into the organism. The authors evaluate the military importance of toxins based on their comparison with traditional chemical warfare agents. They appeal to the ethics of the scientific work as a principal condition for the prevention of toxin abuse in wars, military conflicts, as well as in non-military attacks. PMID:27136512

  13. Inhibition of biotin carboxylase by a reaction intermediate analog: implications for the kinetic mechanism.

    PubMed

    Blanchard, C Z; Amspacher, D; Strongin, R; Waldrop, G L

    1999-12-20

    The first committed step in long-chain fatty acid synthesis is catalyzed by the multienzyme complex acetyl CoA carboxylase. One component of the acetyl CoA carboxylase complex is biotin carboxylase which catalyzes the ATP-dependent carboxylation of biotin. The Escherichia coli form of biotin carboxylase can be isolated from the other components of the acetyl CoA carboxylase complex such that enzymatic activity is retained. The synthesis of a reaction intermediate analog inhibitor of biotin carboxylase has been described recently (Organic Lett. 1, 99-102, 1999). The inhibitor is formed by coupling phosphonoacetic acid to the 1'-N of biotin. In this paper the characterization of the inhibition of biotin carboxylase by this reaction-intermediate analog is described. The analog showed competitive inhibition versus ATP with a slope inhibition constant of 8 mM. Noncompetitive inhibition was found for the analog versus biotin. Phosphonoacetate exhibited competitive inhibition with respect to ATP and noncompetitive inhibition versus bicarbonate. Biotin was found to be a noncompetitive substrate inhibitor of biotin carboxylase. These data suggested that biotin carboxylase had an ordered addition of substrates with ATP binding first followed by bicarbonate and then biotin. PMID:10600526

  14. An Electrical Analog Computer for Poets

    ERIC Educational Resources Information Center

    Bruels, Mark C.

    1972-01-01

    Nonphysics majors are presented with a direct current experiment beyond Ohms law and series and parallel laws. This involves construction of an analog computer from common rheostats and student-assembled voltmeters. (Author/TS)

  15. An Electronic Analog of the Diffraction Grating.

    ERIC Educational Resources Information Center

    MacLeod, A. M.

    1978-01-01

    Gives an outline description of electronic circuitry which is analogous to the optical diffraction grating or to crystals used in the Bragg reflection of X-rays or electron waves, and explains how to use it. (Author/GA)

  16. Optical analog-to-digital converter

    DOEpatents

    Vawter, G. Allen; Raring, James; Skogen, Erik J.

    2009-07-21

    An optical analog-to-digital converter (ADC) is disclosed which converts an input optical analog signal to an output optical digital signal at a sampling rate defined by a sampling optical signal. Each bit of the digital representation is separately determined using an optical waveguide interferometer and an optical thresholding element. The interferometer uses the optical analog signal and the sampling optical signal to generate a sinusoidally-varying output signal using cross-phase-modulation (XPM) or a photocurrent generated from the optical analog signal. The sinusoidally-varying output signal is then digitized by the thresholding element, which includes a saturable absorber or at least one semiconductor optical amplifier, to form the optical digital signal which can be output either in parallel or serially.

  17. Analog Computer Laboratory with Biological Examples.

    ERIC Educational Resources Information Center

    Strebel, Donald E.

    1979-01-01

    The use of biological examples in teaching applications of the analog computer is discussed and several examples from mathematical ecology, enzyme kinetics, and tracer dynamics are described. (Author/GA)

  18. Computer Analogies: Teaching Molecular Biology and Ecology.

    ERIC Educational Resources Information Center

    Rice, Stanley; McArthur, John

    2002-01-01

    Suggests that computer science analogies can aid the understanding of gene expression, including the storage of genetic information on chromosomes. Presents a matrix of biology and computer science concepts. (DDR)

  19. Identifying Solar Analogs in the Kepler Field

    NASA Astrophysics Data System (ADS)

    Buzasi, Derek L.; Lezcano, Andrew; Preston, Heather L.

    2014-06-01

    Since human beings live on a planet orbiting a G2 V star, to us perhaps the most intrinsically interesting category of stars about which planets have been discovered is solar analogs. While Kepler has observed more than 26000 targets which have effective temperatures within 100K of the Sun, many of these are not true solar analogs due to activity, surface gravity, metallicity, or other considerations. Here we combine ground-based measurements of effective temperature and metallicity with data on rotational periods and surface gravities derived from 16 quarters of Kepler observations to produce a near-complete sample of solar analogs in the Kepler field. We then compare the statistical distribution of stellar physical parameters, including activity level, for subsets of solar analogs consisting of KOIs and those with no detected exoplanets. Finally, we produce a list of potential solar twins in the Kepler field.

  20. NASA Now: Exploring Asteroids: An Analog Mission

    NASA Video Gallery

    NASA’s Extreme Environment Mission Operations, or NEEMO, project lead Bill Todd describes this analog mission and how aquanauts living and working in an undersea habitat are helping NASA prepare ...

  1. Photoresistance analog multiplier has wide range

    NASA Technical Reports Server (NTRS)

    Hartenstein, R. G.

    1965-01-01

    Photoactivated bridge facilitates equal performance of analog multipliers over a wide frequency range. The multiplier operates from direct current to an upper frequency limited by either the light source or the closed-loop amplifier.

  2. The Analog (Computer) As a Physiology Adjunct.

    ERIC Educational Resources Information Center

    Stewart, Peter A.

    1979-01-01

    Defines and discusses the analog computer and its use in a physiology laboratory. Includes two examples: (1) The Respiratory Control Function and (2) CO-Two Control in the Respiratory System. Presents diagrams and mathematical models. (MA)

  3. Analog hardware for learning neural networks

    NASA Technical Reports Server (NTRS)

    Eberhardt, Silvio P. (Inventor)

    1991-01-01

    This is a recurrent or feedforward analog neural network processor having a multi-level neuron array and a synaptic matrix for storing weighted analog values of synaptic connection strengths which is characterized by temporarily changing one connection strength at a time to determine its effect on system output relative to the desired target. That connection strength is then adjusted based on the effect, whereby the processor is taught the correct response to training examples connection by connection.

  4. Synthetic heparin-binding growth factor analogs

    DOEpatents

    Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

    2007-01-23

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

  5. ANALOG-TO-DIGITAL DATA CONVERTER

    DOEpatents

    Rodgers, G.W.; Althouse, J.E.; Anderson, D.P.; Bussey, G.R.; Minnear, L.H.

    1960-09-01

    Electrical apparatus is described, particularly useful in telemetry work, for converting analog signals into electrical pulses and recording them. An electronic editor commands the taking of signal readings at a frequency which varies according to linearity of the analog signal being converted. Readings of information signals are recorded, along with time base readings and serial numbering, if desired, on magnetic tape and the latter may be used to operate a computer or the like. Magnetic tape data may be transferred to punched cards.

  6. Analog environments in space human factors

    NASA Technical Reports Server (NTRS)

    Connors, Mary M.

    1992-01-01

    An account is given of what has been learned from space analog environments, which mimic such significant features of space as isolation, confinement, risk, and deprivation; emphasis is placed on the especially successful environments constituted by extended submarine research, undersea habitats, and Antarctic station wintering. Attention is also given to the advantages and limitations of the use of analog environments for space human factors research, and possibilities for such research efforts' management.

  7. AMiBA Wideband Analog Correlator

    NASA Astrophysics Data System (ADS)

    Li, Chao-Te; Kubo, Derek Y.; Wilson, Warwick; Lin, Kai-Yang; Chen, Ming-Tang; Ho, P. T. P.; Chen, Chung-Cheng; Han, Chih-Chiang; Oshiro, Peter; Martin-Cocher, Pierre; Chang, Chia-Hao; Chang, Shu-Hao; Altamirano, Pablo; Jiang, Homin; Chiueh, Tzi-Dar; Lien, Chun-Hsien; Wang, Huei; Wei, Ray-Ming; Yang, Chia-Hsiang; Peterson, Jeffrey B.; Chang, Su-Wei; Huang, Yau-De; Hwang, Yuh-Jing; Kesteven, Michael; Koch, Patrick; Liu, Guo-Chin; Nishioka, Hiroaki; Umetsu, Keiichi; Wei, Tashun; Proty Wu, Jiun-Huei

    2010-06-01

    A wideband analog correlator has been constructed for the Yuan-Tseh Lee Array for Microwave Background Anisotropy. Lag correlators using analog multipliers provide large bandwidth and moderate frequency resolution. Broadband intermediate frequency distribution, back-end signal processing, and control are described. Operating conditions for optimum sensitivity and linearity are discussed. From observations, a large effective bandwidth of around 10 GHz has been shown to provide sufficient sensitivity for detecting cosmic microwave background variations.

  8. Analog modelling of obduction processes

    NASA Astrophysics Data System (ADS)

    Agard, P.; Zuo, X.; Funiciello, F.; Bellahsen, N.; Faccenna, C.; Savva, D.

    2012-04-01

    Obduction corresponds to one of plate tectonics oddities, whereby dense, oceanic rocks (ophiolites) are presumably 'thrust' on top of light, continental ones, as for the short-lived, almost synchronous Peri-Arabic obduction (which took place along thousands of km from Turkey to Oman in c. 5-10 Ma). Analog modelling experiments were performed to study the mechanisms of obduction initiation and test various triggering hypotheses (i.e., plate acceleration, slab hitting the 660 km discontinuity, ridge subduction; Agard et al., 2007). The experimental setup comprises (1) an upper mantle, modelled as a low-viscosity transparent Newtonian glucose syrup filling a rigid Plexiglas tank and (2) high-viscosity silicone plates (Rhodrosil Gomme with PDMS iron fillers to reproduce densities of continental or oceanic plates), located at the centre of the tank above the syrup to simulate the subducting and the overriding plates - and avoid friction on the sides of the tank. Convergence is simulated by pushing on a piston at one end of the model with velocities comparable to those of plate tectonics (i.e., in the range 1-10 cm/yr). The reference set-up includes, from one end to the other (~60 cm): (i) the piston, (ii) a continental margin containing a transition zone to the adjacent oceanic plate, (iii) a weakness zone with variable resistance and dip (W), (iv) an oceanic plate - with or without a spreading ridge, (v) a subduction zone (S) dipping away from the piston and (vi) an upper, active continental margin, below which the oceanic plate is being subducted at the start of the experiment (as is known to have been the case in Oman). Several configurations were tested and over thirty different parametric tests were performed. Special emphasis was placed on comparing different types of weakness zone (W) and the extent of mechanical coupling across them, particularly when plates were accelerated. Displacements, together with along-strike and across-strike internal deformation in all

  9. Optical domain analog to digital conversion methods and apparatus

    DOEpatents

    Vawter, Gregory A

    2014-05-13

    Methods and apparatus for optical analog to digital conversion are disclosed. An optical signal is converted by mapping the optical analog signal onto a wavelength modulated optical beam, passing the mapped beam through interferometers to generate analog bit representation signals, and converting the analog bit representation signals into an optical digital signal. A photodiode receives an optical analog signal, a wavelength modulated laser coupled to the photodiode maps the optical analog signal to a wavelength modulated optical beam, interferometers produce an analog bit representation signal from the mapped wavelength modulated optical beam, and sample and threshold circuits corresponding to the interferometers produce a digital bit signal from the analog bit representation signal.

  10. Symbolic representation for analog realization of a family of fractional order controller structures via continued fraction expansion.

    PubMed

    Pakhira, Anindya; Das, Saptarshi; Pan, Indranil; Das, Shantanu

    2015-07-01

    This paper uses the Continued Fraction Expansion (CFE) method for analog realization of fractional order differ-integrator and few special classes of fractional order (FO) controllers viz. Fractional Order Proportional-Integral-Derivative (FOPID) controller, FO[PD] controller and FO lead-lag compensator. Contemporary researchers have given several formulations for rational approximation of fractional order elements. However, approximation of the controllers studied in this paper, due to having fractional power of a rational transfer function, is not available in analog domain; although its digital realization already exists. This motivates us for applying CFE based analog realization technique for complicated FO controller structures to get equivalent rational transfer functions in terms of the controller tuning parameters. The symbolic expressions for rationalized transfer function in terms of the controller tuning parameters are especially important as ready references, without the need of running CFE algorithm every time and also helps in the synthesis of analog circuits for such FO controllers. PMID:25661163

  11. Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-D-alanine.

    PubMed

    Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Perlikowska, Renata; Adamska, Anna; Olczak, Jacek; Mazur, Marzena; Artali, Roberto; Modranka, Jakub; Janecki, Tomasz; Tömböly, Csaba; Janecka, Anna

    2014-12-01

    Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of D-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4-aminocyclohexyl-D-alanine (D-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2',6'-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-D-ACAla showed high affinity for both, μ- and δ-opioid receptors (MOR and DOR, respectively) and moderate affinity for the κ-opioid receptor (KOR), while analog with Dmt and cis-D-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity. PMID:25456075

  12. Choline transport in Leishmania major promastigotes and its inhibition by choline and phosphocholine analogs.

    PubMed

    Zufferey, Rachel; Mamoun, Choukri Ben

    2002-01-01

    Phosphatidylcholine is the most abundant phospholipid in the membranes of the human parasite Leishmania. The metabolic pathways leading to its biosynthesis are likely to play a critical role in parasite development and survival and may offer a good target for antileishmanial chemotherapy. Phosphatidylcholine synthesis via the CDP-choline pathway requires transport of the choline precursor from the host. Here, we report the first characterization of choline transport in this parasite, which is carrier-mediated and exhibits Michaelis-Menten kinetics with an apparent K(m) value of 2.5 microM for choline. This process is Na(+)-independent and requires an intact proton gradient to be fully functional. Choline transport into Leishmania is highly specific for choline and is inhibited by the choline carrier inhibitor hemicholinium-3, the channel blocker quinacrine, the antimalarial aminoquinolines quinine and quinidine, the antileishmanial phosphocholine analogs, miltefosine and edelfosine, and by choline analogs, most of which have antimalarial activities. Most importantly, choline analogs kill the promastigote form of the parasite in vitro in the low micromolar range. These results set the stage for the use of choline analogs in antileishmanial chemotherapy and shed new lights on the mechanism of action of the leishmanicidal phosphocholine analogs. PMID:12467980

  13. Analog Signal Correlating Using an Analog-Based Signal Conditioning Front End

    NASA Technical Reports Server (NTRS)

    Prokop, Norman; Krasowski, Michael

    2013-01-01

    This innovation is capable of correlating two analog signals by using an analog-based signal conditioning front end to hard-limit the analog signals through adaptive thresholding into a binary bit stream, then performing the correlation using a Hamming "similarity" calculator function embedded in a one-bit digital correlator (OBDC). By converting the analog signal into a bit stream, the calculation of the correlation function is simplified, and less hardware resources are needed. This binary representation allows the hardware to move from a DSP where instructions are performed serially, into digital logic where calculations can be performed in parallel, greatly speeding up calculations.

  14. Antinociceptive and antidepressant-like action of endomorphin-2 analogs with proline surrogates in position 2.

    PubMed

    Perlikowska, Renata; Piekielna, Justyna; Mazur, Marzena; Koralewski, Robert; Olczak, Jacek; do Rego, Jean-Claude; Fichna, Jakub; Modranka, Jakub; Janecki, Tomasz; Janecka, Anna

    2014-09-01

    In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-β-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-β-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-β-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-β-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the μ-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail suspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the δ-selective antagonist, naltrindole (NLT) and κ-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the δ- and κ-receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-β-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies. PMID:25047937

  15. Analog forecasting with dynamics-adapted kernels

    NASA Astrophysics Data System (ADS)

    Zhao, Zhizhen; Giannakis, Dimitrios

    2016-09-01

    Analog forecasting is a nonparametric technique introduced by Lorenz in 1969 which predicts the evolution of states of a dynamical system (or observables defined on the states) by following the evolution of the sample in a historical record of observations which most closely resembles the current initial data. Here, we introduce a suite of forecasting methods which improve traditional analog forecasting by combining ideas from kernel methods developed in harmonic analysis and machine learning and state-space reconstruction for dynamical systems. A key ingredient of our approach is to replace single-analog forecasting with weighted ensembles of analogs constructed using local similarity kernels. The kernels used here employ a number of dynamics-dependent features designed to improve forecast skill, including Takens’ delay-coordinate maps (to recover information in the initial data lost through partial observations) and a directional dependence on the dynamical vector field generating the data. Mathematically, our approach is closely related to kernel methods for out-of-sample extension of functions, and we discuss alternative strategies based on the Nyström method and the multiscale Laplacian pyramids technique. We illustrate these techniques in applications to forecasting in a low-order deterministic model for atmospheric dynamics with chaotic metastability, and interannual-scale forecasting in the North Pacific sector of a comprehensive climate model. We find that forecasts based on kernel-weighted ensembles have significantly higher skill than the conventional approach following a single analog.

  16. Neurotoxic Alkaloids: Saxitoxin and Its Analogs

    PubMed Central

    Wiese, Maria; D’Agostino, Paul M.; Mihali, Troco K.; Moffitt, Michelle C.; Neilan, Brett A.

    2010-01-01

    Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs—each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids. PMID:20714432

  17. Analogy, higher order thinking, and education.

    PubMed

    Richland, Lindsey Engle; Simms, Nina

    2015-01-01

    Analogical reasoning, the ability to understand phenomena as systems of structured relationships that can be aligned, compared, and mapped together, plays a fundamental role in the technology rich, increasingly globalized educational climate of the 21st century. Flexible, conceptual thinking is prioritized in this view of education, and schools are emphasizing 'higher order thinking', rather than memorization of a cannon of key topics. The lack of a cognitively grounded definition for higher order thinking, however, has led to a field of research and practice with little coherence across domains or connection to the large body of cognitive science research on thinking. We review literature on analogy and disciplinary higher order thinking to propose that relational reasoning can be productively considered the cognitive underpinning of higher order thinking. We highlight the utility of this framework for developing insights into practice through a review of mathematics, science, and history educational contexts. In these disciplines, analogy is essential to developing expert-like disciplinary knowledge in which concepts are understood to be systems of relationships that can be connected and flexibly manipulated. At the same time, analogies in education require explicit support to ensure that learners notice the relevance of relational thinking, have adequate processing resources available to mentally hold and manipulate relations, and are able to recognize both the similarities and differences when drawing analogies between systems of relationships. PMID:26263071

  18. NaturAnalogs for the Unsaturated Zone

    SciTech Connect

    A. Simmons; A. Unger; M. Murrell

    2000-03-08

    The purpose of this Analysis/Model Report (AMR) is to document natural and anthropogenic (human-induced) analog sites and processes that are applicable to flow and transport processes expected to occur at the potential Yucca Mountain repository in order to build increased confidence in modeling processes of Unsaturated Zone (UZ) flow and transport. This AMR was prepared in accordance with ''AMR Development Plan for U0135, Natural Analogs for the UZ'' (CRWMS 1999a). Knowledge from analog sites and processes is used as corroborating information to test and build confidence in flow and transport models of Yucca Mountain, Nevada. This AMR supports the Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR) and the Yucca Mountain Site Description. The objectives of this AMR are to test and build confidence in the representation of UZ processes in numerical models utilized in the UZ Flow and Transport Model. This is accomplished by: (1) applying data from Boxy Canyon, Idaho in simulations of UZ flow using the same methodologies incorporated in the Yucca Mountain UZ Flow and Transport Model to assess the fracture-matrix interaction conceptual model; (2) Providing a preliminary basis for analysis of radionuclide transport at Pena Blanca, Mexico as an analog of radionuclide transport at Yucca Mountain; and (3) Synthesizing existing information from natural analog studies to provide corroborating evidence for representation of ambient and thermally coupled UZ flow and transport processes in the UZ Model.

  19. Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

    PubMed Central

    Malinowski, Justin T.; Sharpe, Robert J.; Johnson, Jeffrey S.

    2014-01-01

    Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally-intricate aminocyclopentitol antibiotic, displays potent anti-prolific properties across multiple phylogenetic domains, but is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Herein, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction/symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals fifteen steps and is immediately amenable for structural analog synthesis. PMID:23580525

  20. Not All Analogies Are Created Equal: Associative and Categorical Analogy Processing following Brain Damage

    ERIC Educational Resources Information Center

    Schmidt, Gwenda L.; Cardillo, Eileen R.; Kranjec, Alexander; Lehet, Matthew; Widick, Page; Chatterjee, Anjan

    2012-01-01

    Current research on analogy processing assumes that different conceptual relations are treated similarly. However, just as words and concepts are related in distinct ways, different kinds of analogies may employ distinct types of relationships. An important distinction in how words are related is the difference between associative (dog-bone) and…

  1. Students' Pre- and Post-Teaching Analogical Reasoning when They Draw Their Analogies

    ERIC Educational Resources Information Center

    Mozzer, Nilmara Braga; Justi, Rosaria

    2012-01-01

    Analogies are parts of human thought. From them, we can acquire new knowledge or change that which already exists in our cognitive structure. In this sense, understanding the analogical reasoning process becomes an essential condition to understand how we learn. Despite the importance of such an understanding, there is no general agreement in…

  2. The Importance of Explicitly Mapping Instructional Analogies in Science Education

    ERIC Educational Resources Information Center

    Asay, Loretta Johnson

    2013-01-01

    Analogies are ubiquitous during instruction in science classrooms, yet research about the effectiveness of using analogies has produced mixed results. An aspect seldom studied is a model of instruction when using analogies. The few existing models for instruction with analogies have not often been examined quantitatively. The Teaching With…

  3. Analogy-Enhanced Instruction: Effects on Reasoning Skills in Science

    ERIC Educational Resources Information Center

    Remigio, Krisette B.; Yangco, Rosanelia T.; Espinosa, Allen A.

    2014-01-01

    The study examined the reasoning skills of first year high school students after learning general science concepts through analogies. Two intact heterogeneous sections were randomly assigned to Analogy-Enhanced Instruction (AEI) group and Non Analogy-Enhanced (NAEI) group. Various analogies were incorporated in the lessons of the AEI group for…

  4. Value and Limitations of Analogs in Teaching Mathematics.

    ERIC Educational Resources Information Center

    Halford, Graeme S.; Boulton-Lewis, Gillian M.

    Analogical reasoning is frequently used in acquisition of mathematical concepts. Concrete representations used to teach mathematics are essentially analogs of mathematical concepts, and it is argued that analogies enter into mathematical concept acquisition in numerous other ways as well. According to Gentner's theory, analogies entail a…

  5. Gravitoelectromagnetic analogy based on tidal tensors

    SciTech Connect

    Costa, L. Filipe O.; Herdeiro, Carlos A. R.

    2008-07-15

    We propose a new approach to a physical analogy between general relativity and electromagnetism, based on tidal tensors of both theories. Using this approach we write a covariant form for the gravitational analogues of the Maxwell equations, which makes transparent both the similarities and key differences between the two interactions. The following realizations of the analogy are given. The first one matches linearized gravitational tidal tensors to exact electromagnetic tidal tensors in Minkowski spacetime. The second one matches exact magnetic gravitational tidal tensors for ultrastationary metrics to exact magnetic tidal tensors of electromagnetism in curved spaces. In the third we show that our approach leads to a two-step exact derivation of Papapetrou's equation describing the force exerted on a spinning test particle. Analogous scalar invariants built from tidal tensors of both theories are also discussed.

  6. Interaction of Chloramphenicol Tripeptide Analogs with Ribosomes.

    PubMed

    Tereshchenkov, A G; Shishkina, A V; Tashlitsky, V N; Korshunova, G A; Bogdanov, A A; Sumbatyan, N V

    2016-04-01

    Chloramphenicol amine peptide derivatives containing tripeptide fragments of regulatory "stop peptides" - MRL, IRA, IWP - were synthesized. The ability of the compounds to form ribosomal complexes was studied by displacement of the fluorescent erythromycin analog from its complex with E. coli ribosomes. It was found that peptide chloramphenicol analogs are able to bind to bacterial ribosomes. The dissociation constants were 4.3-10 µM, which is 100-fold lower than the corresponding values for chloramphenicol amine-ribosome complex. Interaction of the chloramphenicol peptide analogs with ribosomes was simulated by molecular docking, and the most probable contacts of "stop peptide" motifs with the elements of nascent peptide exit tunnel were identified. PMID:27293096

  7. Polymeric nanogel formulations of nucleoside analogs

    PubMed Central

    Vinogradov, Serguei V

    2008-01-01

    Nanogels are colloidal microgel carriers that have been introduced recently as a prospective drug delivery system for nucleotide therapeutics. The crosslinked protonated polymer network of nanogels binds oppositely charged drug molecules, encapsulating them into submicron particles with a core-shell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and vectorisation. This review reveals recent attempts to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5′-triphosphates; discusses structural approaches to the optimisation of nanogel properties, and; discusses the development of targeted nanogel drug formulations for systemic administration. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing across the blood–brain barrier. The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery. PMID:17184158

  8. Parallel Analog-to-Digital Image Processor

    NASA Technical Reports Server (NTRS)

    Lokerson, D. C.

    1987-01-01

    Proposed integrated-circuit network of many identical units convert analog outputs of imaging arrays of x-ray or infrared detectors to digital outputs. Converter located near imaging detectors, within cryogenic detector package. Because converter output digital, lends itself well to multiplexing and to postprocessing for correction of gain and offset errors peculiar to each picture element and its sampling and conversion circuits. Analog-to-digital image processor is massively parallel system for processing data from array of photodetectors. System built as compact integrated circuit located near local plane. Buffer amplifier for each picture element has different offset.

  9. Associative Pattern Recognition In Analog VLSI Circuits

    NASA Technical Reports Server (NTRS)

    Tawel, Raoul

    1995-01-01

    Winner-take-all circuit selects best-match stored pattern. Prototype cascadable very-large-scale integrated (VLSI) circuit chips built and tested to demonstrate concept of electronic associative pattern recognition. Based on low-power, sub-threshold analog complementary oxide/semiconductor (CMOS) VLSI circuitry, each chip can store 128 sets (vectors) of 16 analog values (vector components), vectors representing known patterns as diverse as spectra, histograms, graphs, or brightnesses of pixels in images. Chips exploit parallel nature of vector quantization architecture to implement highly parallel processing in relatively simple computational cells. Through collective action, cells classify input pattern in fraction of microsecond while consuming power of few microwatts.

  10. Discrete analog computing with rotor-routers.

    PubMed

    Propp, James

    2010-09-01

    Rotor-routing is a procedure for routing tokens through a network that can implement certain kinds of computation. These computations are inherently asynchronous (the order in which tokens are routed makes no difference) and distributed (information is spread throughout the system). It is also possible to efficiently check that a computation has been carried out correctly in less time than the computation itself required, provided one has a certificate that can itself be computed by the rotor-router network. Rotor-router networks can be viewed as both discrete analogs of continuous linear systems and deterministic analogs of stochastic processes. PMID:20887076

  11. A quadratic analog-to-digital converter

    NASA Technical Reports Server (NTRS)

    Harrison, D. C.; Staples, M. H.

    1980-01-01

    An analog-to-digital converter with a square root transfer function has been developed for use with a pair of CCD imaging detectors in the White Light Coronagraph/X-ray XUV Telescope experiment to be flown as part of the Internal Solar Polar Mission. It is shown that in background-noise-limited instrumentation systems a quadratic analog-to-digital converter will allow a maximum dynamic range with a fixed number of data bits. Low power dissipation, moderately fast conversion time, and reliability are achieved in the proposed design using standard components and avoiding nonlinear elements.

  12. Analog graphic display method and apparatus

    DOEpatents

    Kronberg, James W.

    1991-01-01

    An apparatus and method for using an output device such as an LED to show the approximate analog level of a variable electrical signal wherein a modulating AC waveform is superimposed either on the signal or a reference voltage, both of which are then fed to a comparator which drives the output device. Said device flashes at a constant perceptible rate with a duty cycle which varies in response to variations in the level of the input signal. The human eye perceives these variations in duty cycle as analogous to variations in the level of the input signal.

  13. Synthetic heparin-binding factor analogs

    DOEpatents

    Pena, Louis A.; Zamora, Paul O.; Lin, Xinhua; Glass, John D.

    2010-04-20

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain, and preferably two peptide chains branched from a dipeptide branch moiety composed of two trifunctional amino acid residues, which peptide chain or chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a linker, which may be a hydrophobic linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

  14. Landauer bound for analog computing systems.

    PubMed

    Diamantini, M Cristina; Gammaitoni, Luca; Trugenberger, Carlo A

    2016-07-01

    By establishing a relation between information erasure and continuous phase transitions we generalize the Landauer bound to analog computing systems. The entropy production per degree of freedom during erasure of an analog variable (reset to standard value) is given by the logarithm of the configurational volume measured in units of its minimal quantum. As a consequence, every computation has to be carried on with a finite number of bits and infinite precision is forbidden by the fundamental laws of physics, since it would require an infinite amount of energy. PMID:27575108

  15. Space flight nutrition research: platforms and analogs

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Uchakin, Peter N.; Tobin, Brian W.

    2002-01-01

    Conducting research during actual or simulated weightlessness is a challenging endeavor, where even the simplest activities may present significant challenges. This article reviews some of the potential obstacles associated with performing research during space flight and offers brief descriptions of current and previous space research platforms and ground-based analogs, including those for human, animal, and cell-based research. This review is intended to highlight the main issues of space flight research analogs and leave the specifics for each physiologic system for the other papers in this section.

  16. Space flight nutrition research: platforms and analogs.

    PubMed

    Smith, Scott M; Uchakin, Peter N; Tobin, Brian W

    2002-10-01

    Conducting research during actual or simulated weightlessness is a challenging endeavor, where even the simplest activities may present significant challenges. This article reviews some of the potential obstacles associated with performing research during space flight and offers brief descriptions of current and previous space research platforms and ground-based analogs, including those for human, animal, and cell-based research. This review is intended to highlight the main issues of space flight research analogs and leave the specifics for each physiologic system for the other papers in this section. PMID:12361789

  17. Analog graphic display method and apparatus

    DOEpatents

    Kronberg, J.W.

    1991-08-13

    Disclosed are an apparatus and method for using an output device such as an LED to show the approximate analog level of a variable electrical signal wherein a modulating AC waveform is superimposed either on the signal or a reference voltage, both of which are then fed to a comparator which drives the output device. Said device flashes at a constant perceptible rate with a duty cycle which varies in response to variations in the level of the input signal. The human eye perceives these variations in duty cycle as analogous to variations in the level of the input signal. 21 figures.

  18. Phase Shift of the Circadian Rhythm of Lemna Caused by Pulses of a Leucine Analog, Trifluoroleucine

    PubMed Central

    Kondo, Takao

    1988-01-01

    Pulses of a fluorinated analog of leucine, 5′,5′,5′-trifluoroleucine, reset the phase of the circadian rhythm of K+ uptake in Lemna gibba G3 under continuous light conditions. The trifluoroleucine pulse caused the largest delay phase-shifts during the early subjective phase but it caused only small phase advances. The action of trifluoroleucine was investigated and the following results were obtained. (a) The uptake of trifluoroleucine was essentially the same at all circadian phases, even though phase shifting was dramatically different at different phases. At effective phases, the magnitude of phase shifting was well correlated with the amount of trifluoroleucine taken up by the duckweed. (b) The trifluoroleucine pulse lowered the endogenous content of valine and leucine but these decreases did not correlate with phase shifting. (c) Protein synthesis was not affected by trifluoroleucine pulses which caused large phase shifts. (d) Pulses of 4-azaleucine, a different structural analog of leucine, also caused phase shifting. However, neither the direction nor the effective times of phase shifting were similar to those of trifluoroleucine. Taken together, these results negate the proposition that trifluoroleucine and azaleucine caused phase shift by disturbing amino acid metabolism and/or inhibiting protein synthesis, but they suggest instead that these analogs are incorporated into some protein(s) which are necessary for normal clock operation. PMID:16666410

  19. Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: Sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors

    PubMed Central

    Majmudar, Jaimeen D.; Hahne, Kalub

    2012-01-01

    Human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target as it is important for the post-translational modification of oncogenic Ras proteins. We herein report the synthesis and biochemical activity of 41 farnesyl-cysteine based analogs versus hIcmt. We have demonstrated that the amide linkage of a hIcmt substrate can be replaced by a sulfonamide bond to achieve hIcmt inhibition. The most potent sulfonamide-modified farnesylcysteine analog was 6ag with an IC50 of 8.8±0.5 µM for hIcmt. PMID:21334890

  20. New mitomycin analogs produced by directed biosynthesis.

    PubMed

    Claridge, C A; Bush, J A; Doyle, T W; Nettleton, D E; Moseley, J E; Kimball, D; Kammer, M F; Veitch, J

    1986-03-01

    When the normal fermentation medium for the production of mitomycin C with Streptomyces caespitosus is supplemented with a number of primary amines, two new types of mitomycin analogs described as Type I and Type II are produced. Type I analogs are related to mitomycin C with the amine substitution at position C7 on the mitosane ring. Type II analogs also contain the same substitutions at C7 but the conformation of the mitosane ring is related to mitomycin B having an OH at positions C9a and a methyl substituted aziridine. The products obtained from the supplementation of the medium with methylamine, ethylamine, propylamine, propargylamine and 2-methylallylamine were isolated and characterized. In all cases the Type I analogs are more active in a prophage induction test and against L1210 lymphatic leukemia in mice. A number of other amines have been tested and shown to yield new products that have not yet been isolated. No secondary amines are incorporated. PMID:3700245

  1. Presence, Analogy, and "Earth in the Balance."

    ERIC Educational Resources Information Center

    Murphy, John M.

    1994-01-01

    Uses vice president Albert Gore Jr.'s book "Earth in the Balance" as a case study to examine the relationship between analogy and "presence." Argues that presence is a flexible critical construct allowing for examination of the relationship between the style, substance, and structure of arguments. Explores relationships between C. Perelman and the…

  2. A Mechanical Analogy for Ohm's Law.

    ERIC Educational Resources Information Center

    do Couto Tavares, Milton; And Others

    1991-01-01

    A mechanical analogy between the microscopic motion of a charged carrier in an ordinary resistor and the macroscopic motion of a ball falling along a slanted board covered with a lattice of nails is introduced. The Drude model is also introduced to include the case of inelastic collisions. Computer simulation of the motion is described. (KR)

  3. (-)-Botryodiplodin, A Unique Ribose Analog Toxin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many toxins owe their mechanisms of action to being structural analogs of essential metabolites, messengers or structural components. Examples range from tubo-curare to penicillin. Ribose plays a unique role in the metabolism of living organisms, whether prokaryotes or eukaryotes. It and its deri...

  4. RF digital-to-analog converter

    DOEpatents

    Conway, P.H.; Yu, D.U.L.

    1995-02-28

    A digital-to-analog converter is disclosed for producing an RF output signal proportional to a digital input word of N bits from an RF reference input, N being an integer greater or equal to 2. The converter comprises a plurality of power splitters, power combiners and a plurality of mixers or RF switches connected in a predetermined configuration. 18 figs.

  5. Radiation Behavior of Analog Neural Network Chip

    NASA Technical Reports Server (NTRS)

    Langenbacher, H.; Zee, F.; Daud, T.; Thakoor, A.

    1996-01-01

    A neural network experiment conducted for the Space Technology Research Vehicle (STRV-1) 1-b launched in June 1994. Identical sets of analog feed-forward neural network chips was used to study and compare the effects of space and ground radiation on the chips. Three failure mechanisms are noted.

  6. The GMO-Nanotech (Dis)Analogy?

    ERIC Educational Resources Information Center

    Sandler, Ronald; Kay, W. D.

    2006-01-01

    The genetically-modified-organism (GMO) experience has been prominent in motivating science, industry, and regulatory communities to address the social and ethical dimensions of nanotechnology. However, there are some significant problems with the GMO-nanotech analogy. First, it overstates the likelihood of a GMO-like backlash against…

  7. Invention through Form and Function Analogy

    ERIC Educational Resources Information Center

    Rule, Audrey C.

    2015-01-01

    "Invention through Form and Function Analogy" is an invention book for teachers and other leaders working with youth who are involving students in the invention process. The book consists of an introduction and set of nine learning cycle formatted lessons for teaching the principles of invention through the science and engineering design…

  8. Analog optical computing primitives in silicon photonics

    NASA Astrophysics Data System (ADS)

    Jiang, Yunshan; DeVore, Peter T. S.; Jalali, Bahram

    2016-03-01

    Optical computing accelerators may help alleviate bandwidth and power consumption bottlenecks in electronics. We show an approach to implementing logarithmic-type analog co-processors in silicon photonics and use it to perform the exponentiation operation. The function is realized by exploiting nonlinear-absorption-enhanced Raman amplification saturation in a silicon waveguide.

  9. Plasma analog of particle-pair production

    SciTech Connect

    Tsidulko, Yu.A.; Berk, H.L.

    1996-09-01

    It is shown that the plasma axial shear flow instability satisfies the Klein-Gordon equation. The plasma instability is then shown to be analogous to spontaneous particle-pair production when a potential energy is present that is greater than twice the particle rest mass energy. Stability criteria can be inferred based on field theoretical conservation laws.

  10. Biological Analogs for Language Contact Situations

    ERIC Educational Resources Information Center

    Seliger, Herbert W.

    1977-01-01

    This article proposes that language contact can be best understood if the entire range of such situations from second language learning to evolution of dialects and creoles is studied within a framework analogical to the symbiosis of living organisms. Language contact is viewed in terms of dynamic evolutionary stages. (CHK)

  11. Resistance Gene Analogs in Cherries (Prunus spp.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic studies have shown that NBS-LRR Resistance Gene Analogs (RGAs) tend to occur in clusters and often map to major resistances gene or QTL. The identification and use of specific RGAs as molecular markers among plant material displaying differential resistance phenotypes has the potential to di...

  12. The Lenz Vector and Orbital Analog Computers

    ERIC Educational Resources Information Center

    Harter, W. G.

    1976-01-01

    Describes a single geometrical diagram based on the Lenz vector which shows the qualitative and quantitative features of all three types of Coulomb orbits. Explains the use of a simple analog computer with an overhead projector to demonstrate many of these effects. (Author/CP)

  13. Double point modified analogs of vitamin d as potent activators of vitamin D receptor.

    PubMed

    Nadkarni, Sharmin; Chodynski, Michal; Corcoran, Aoife; Marcinkowska, Ewa; Brown, Geoffrey; Kutner, Andrzej

    2015-01-01

    Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional activity and lowered calcemic side effect. Recent in vivo experiments clearly demonstrated the potential use of these analogs in new therapeutic areas such as autoimmune and hyper-proliferative diseases, including cancer and the systemic treatment of psoriasis. Although some of these analogs are already approaching clinical trials, the molecular mechanism of action and their improved efficiency still remain to be fully understood. In this review the key steps of the convergent synthetic strategies that combine the modified A-ring and the CD-ring fragment carrying the altered side-chain are presented. The advantages of using the natural alicyclic and acyclic precursors are demonstrated as well as all the modern synthetic methodologies used for combining structural fragments. The results of molecular mechanics modeling are critically examined as well as the advantages and limitations of the use of the models of vitamin D proteins for the docking experiments and the design of new analogs. The potential use of advanced structural approaches, including high resolution X-ray crystallography, is discussed as to the prospect of providing a better understanding of the observed activity of modified analogs. Biological profiles in vitro and in vivo for groups of analogs are presented in a new tabular form to illustrate structure activity relationships. PMID:25483861

  14. Inhibition of Enterovirus 71 by Adenosine Analog NITD008

    PubMed Central

    Deng, Cheng-Lin; Yeo, Huimin; Ye, Han-Qing; Liu, Si-Qing; Shang, Bao-Di; Gong, Peng; Alonso, Sylvie

    2014-01-01

    ABSTRACT Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 μM and a 50% cytotoxic concentration of 119.97 μM. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment. IMPORTANCE Human enterovirus 71 (EV71) has emerged as a major cause of viral encephalitis in children worldwide, especially in the Asia-Pacific region. Vaccines and antivirals are urgently needed to prevent and treat EV71 infections. In this study, we report the in vitro and in vivo efficacy of NITD008 (an adenosine analog) as an inhibitor of EV71. The efficacy results validated the potential of nucleoside analogs as antiviral drugs for EV71 infections. Mechanistically, we showed that mutations in the viral 3A and 3D polymerases alone or in combination could confer resistance to NITD008. The resistance results suggest an intrinsic interaction between viral proteins 3A and 3D during replication, as well as the importance of

  15. X-ray Emission from Early Universe Analog Galaxies

    NASA Astrophysics Data System (ADS)

    Brorby, Matthew; Kaaret, Philip; Prestwich, Andrea H.; Mirabel, I. Felix; Feng, Hua

    2016-01-01

    Around 300,000 years after the Big Bang, the Universe had cooled enough to combine and form neutral atoms. This signified the beginning of a time known as the Dark Ages. Neutral matter began to fall into the dark matter gravitational wells that were seeded after the initial moments of the Big Bang. As the first stars and galaxies formed within these gravitational wells, the surrounding baryonic matter was heated and started to ionize. The source of energetic photons that heated and reionized the early Universe remains uncertain. Early galaxies had low metallicity and recent population synthesis calculations suggest that the number and luminosity of high-mass X-ray binaries are enhanced in star-forming galaxies with low metallicity, offering a potentially important and previously overlooked source of heating and reionization. Here we examine two types of local galaxies that have been shown to be good analogs to the early galaxies in the Universe: Blue compact dwarf galaxies (BCDs) and Lyman Break Analogs (LBAs).A BCD is defined by its blue optical colors, low metallicities, and physically small size. This makes BCDs the best available local analogs for early star formation. We analyzed data from a sample of 25 metal-poor BCDs and compared our results with those of near-solar metallicity galaxies. Using a Bayesian approach, we showed that the X-ray luminosity function for the low-metallicity BCDs is significantly elevated relative to the XLF for near-solar metallicity galaxies.Larger, gas-rich galaxies may have formed shortly after these first galaxies. These larger galaxies would be similar in their properties to the high-redshift Lyman break galaxies (LBGs). LBAs provide the best local comparison to the LBGs. We studied a sample of 10 LBAs in order to measure the relation between star formation rate and X-ray luminosity for these galaxies. We found that for LBAs with intermediate sub-solar metallicities, there is enhanced X-ray emission relative to the expected

  16. 8[prime]-Methylene Abscisic Acid (An Effective and Persistent Analog of Abscisic Acid).

    PubMed Central

    Abrams, S. R.; Rose, P. A.; Cutler, A. J.; Balsevich, J. J.; Lei, B.; Walker-Simmons, M. K.

    1997-01-01

    We report here the synthesis and biological activity of a new persistent abscisic acid (ABA) analog, 8[prime]-methylene ABA. This ABA analog has one additional carbon atom attached through a double bond to the 8[prime]-carbon of the ABA molecule. (+)-8[prime]-Methylene ABA is more active than the natural hormone (+)-ABA in inhibiting germination of cress seed and excised wheat embryos, in reducing growth of suspension-cultured corn cells, and in reducing transpiration in wheat seedlings. The (+)-8[prime]-methylene analog is slightly weaker than (+)-ABA in increasing expression of ABA-inducible genes in transgenic tobacco, but is equally active in stimulating a transient elevation of the pH of the medium of corn cell cultures. In corn cells, both (+)-ABA and (+)-8[prime]-methylene ABA are oxidized at the 8[prime] position. ABA is oxidized to phaseic acid and (+)-8[prime]-methylene ABA is converted more slowly to two isomeric epoxides. The alteration in the ABA structure causes the analog to be metabolized more slowly than ABA, resulting in longer-lasting and more effective biological activity relative to ABA. PMID:12223691

  17. Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells

    PubMed Central

    Matsumoto, Yoshihiro; Rodriguez, Victoria; Whitford, Tracy A.; Beeharry, Neil; Ide, Hiroshi; Tomkinson, Alan E.

    2015-01-01

    5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2′-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2′-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2′-deoxyuridine and, to a lesser extent, 5-hydroxy-2′-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2′-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies. PMID:25897430

  18. Multilateral Research Opportunities in Ground Analogs

    NASA Technical Reports Server (NTRS)

    Corbin, Barbara J.

    2015-01-01

    The global economy forces many nations to consider their national investments and make difficult decisions regarding their investment in future exploration. International collaboration provides an opportunity to leverage other nations' investments to meet common goals. The Humans In Space Community shares a common goal to enable safe, reliable, and productive human space exploration within and beyond Low Earth Orbit. Meeting this goal requires efficient use of limited resources and International capabilities. The International Space Station (ISS) is our primary platform to conduct microgravity research targeted at reducing human health and performance risks for exploration missions. Access to ISS resources, however, is becoming more and more constrained and will only be available through 2020 or 2024. NASA's Human Research Program (HRP) is actively pursuing methods to effectively utilize the ISS and appropriate ground analogs to understand and mitigate human health and performance risks prior to embarking on human exploration of deep space destinations. HRP developed a plan to use ground analogs of increasing fidelity to address questions related to exploration missions and is inviting International participation in these planned campaigns. Using established working groups and multilateral panels, the HRP is working with multiple Space Agencies to invite International participation in a series of 30- day missions that HRP will conduct in the US owned and operated Human Exploration Research Analog (HERA) during 2016. In addition, the HRP is negotiating access to Antarctic stations (both US and non-US), the German :envihab and Russian NEK facilities. These facilities provide unique capabilities to address critical research questions requiring longer duration simulation or isolation. We are negotiating release of international research opportunities to ensure a multilateral approach to future analog research campaigns, hoping to begin multilateral campaigns in the

  19. Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets.

    PubMed

    Tudurí, Eva; López, Miguel; Diéguez, Carlos; Nadal, Angel; Nogueiras, Rubén

    2016-05-01

    Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis. PMID:27062006

  20. Not all analogies are created equal: Associative and categorical analogy processing following brain damage

    PubMed Central

    Schmidt, Gwenda L.; Cardillo, Eileen R.; Kranjec, Alexander; Lehet, Matthew; Widick, Page; Chatterjee, Anjan

    2012-01-01

    Current research on analogy processing assumes that different conceptual relations are treated similarly. However, just as words and concepts are related in distinct ways, different kinds of analogies may employ distinct types of relationships. An important distinction in how words are related is the difference between associative (dog-bone) and categorical (dog-cat) relations. To test the hypothesis that analogical mapping of different types of relations would have different neural instantiations, we tested patients with left and right hemisphere lesions on their ability to understand two types of analogies, ones expressing an associative relationship and others expressing a categorical relationship. Voxel-based lesion-symptom mapping (VLSM) and behavioral analyses revealed that associative analogies relied on a large left-lateralized language network while categorical analogies relied on both left and right hemispheres. The verbal nature of the task could account for the left hemisphere findings. We argue that categorical relations additionally rely on the right hemisphere because they are more difficult, abstract, and fragile; and contain more distant relationships. PMID:22402184